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Biomedical subjects

J Finkelstein

Publications and source records attributed to J Finkelstein.

At least 55 records · Page 3Linked to original sources
PubMed1995

Assembly of a chromosomal replication machine: two DNA polymerases, a clamp loader, and sliding clamps in one holoenzyme particle. III. Interface between two polymerases and the clamp loader.

The nine-subunit DNA polymerase (Pol) III* coupled to its beta sliding clamp is a rapid and highly processive replicating machine. The multiple subunits are needed for the complicated task of duplicating the Escherichia coli chromosome. In this report, Pol III* was constituted from individual pure proteins, and its structure was studied. Constitution of the Pol III* particle requires an ordered addition of the subunits, and the final structure contains 14 polypeptides in the ratio alpha 2 epsilon 2 theta 2 tau 2 gamma 2 delta 1 delta' 1 chi 1 psi 1. The structure can be summarized as being composed of two core polymerases (alpha epsilon theta) held together by a dimer of tau and one gamma complex clamp loader (gamma 2 delta 1 delta' 1 chi 1 psi 1) for loading beta onto DNA. At the center of the structure, the related tau and gamma subunits form a heterotetramer upon which the two core polymerases and clamp loader proteins assemble. The single copy nature of the delta, delta', chi, and psi subunits confers a structural asymmetry with respect to the two polymerases, presumably for the different functions of replicating the leading and lagging strands.

Chromosomes, Bacterial↗
PubMed1994

Psychosocial Issues Associated with Short Stature.

Adolescents do not innately conclude that being short is undesirable; they learn it through environmental interactions. The authors of this chapter address society's expectations and perceptions regarding short stature as well as the effects of growth hormone treatment on the psychosocial status of both children and adults. They conclude that all short children should have the benefit of the evaluation and management of psychosocial problems.

Journal Article↗
PubMed1992

Thermal degradation events as health hazards: particle vs gas phase effects, mechanistic studies with particles.

Exposure to thermal degradation products arising from fire or smoke could be a major concern for manned space missions. Severe acute lung damage has been reported in people after accidental exposure to fumes from plastic materials, and animal studies revealed the extremely high toxicity of freshly generated fumes whereas a decrease in toxicity of aged fumes has been found. This and the fact that toxicity of the freshly generated fumes can be prevented with filters raises the question whether the toxicity may be due to the particulate rather than the gas phase components of the thermodegradation products. Indeed, results from recent studies implicate ultrafine particles (particle diameter in the nm range) as potential severe pulmonary toxicants. We have conducted a number of in vivo (inhalation and instillation studies in rats) and in vitro studies to test the hypothesis that ultrafine particles possess an increased potential to injure the lung compared to larger-sized particles. We used as surrogate particles ultrafine TiO2 particles (12 and 20 nm diameter). Results in exposed rats showed that the ultrafine TiO2 particles not only induce a greater acute inflammatory reaction in the lung than larger-sized TiO2 particles, but can also lead to persistent chronic effects, as indicated by an adverse effect on alveolar macrophage mediated clearance function of particles. Release of mediators from alveolar macrophages during phagocytosis of the ultrafine particles and an increased access of the ultrafine particles to the pulmonary interstitium are likely factors contributing to their pulmonary toxicity. In vitro studies with lung cells (alveolar macrophages) showed, in addition, that ultrafine TiO2 particles have a greater potential to induce cytokines than larger-sized particles. We conclude from our present studies that ultrafine particles have a significant potential to injure the lung and that their occurrence in thermal degradation events can play a major role in the highly acute toxicity of fumes. Future studies will include adsorption of typical gas phase components (HCl, HF) on surrogate particles to differentiate between gas and particle phase effects and to perform mechanistic studies aimed at introducing therapeutic/preventive measures. These studies will be complemented by a comparison with actual thermal degradation products.

Administration, Inhalation↗
PubMed1992

Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: interrelationship between the alveolar macrophage and the septal fibroblast.

Pulmonary fibrosis is a crippling, essentially lethal chronic disease due to an interplay of events following irradiation between the pneumonitic and fibrotic phases. In this series of experiments it is demonstrated that there is no latent period after irradiation, but an immediate intercellular communication system which springs into action to initiate recovery. Latency was only a function of our inability to uncover the molecular events that precede and underlie the clinical pathologic course of organ/tissue irradiation. Current advances in understanding the production of growth factors by different cells provides new insights to autocrine, paracrine and endocrine messages as a basis for understanding radiation pathophysiology as a progressive process that is amplified by other injurious events such as chemotoxicity. This is the first demonstrated release of trophic factors (cytokines) after in vivo irradiation that persists up to a month after exposure, suggesting that the persistence of a small incremental stimulus during a silent "latent" period can be the basis for the clinical pathologic expression of a late radiation effect, that is, pulmonary interstitial fibrosis.

Animals↗
PubMed1992

Role of pulmonary blood flow in postpneumonectomy lung growth.

To study the influence of blood flow on postpneumonectomy lung growth, we banded the left caudal lobe pulmonary artery of eight ferrets in such a way that blood flow to the caudal lobe did not increase when the right lung was excised 1 wk later. The fraction of the cardiac output received by the right lung before pneumonectomy was therefore directed entirely to the left cranial lobe. Three weeks after pneumonectomy the weight, volume, and protein and DNA contents of the two lobes of the left lung were measured and compared with those of five unoperated animals and eight animals after right pneumonectomy alone. Although its perfusion did not increase after pneumonectomy, the left caudal lobe of banded animals participated in compensatory growth, increasing in weight and protein and DNA contents. Although the cranial lobe of banded animals received 25% more of the cardiac output than the same lobe in pneumonectomized animals, cranial lobe volume and protein and DNA contents in the two groups were similar. Caudal lobes were smaller in banded than in simple pneumonectomized animals and tended to contain less protein, whereas the cranial lobes tended to be heavier. We conclude that increased pulmonary perfusion is not necessary for compensatory lung growth in adult ferrets, but it may modify this response.

Animals↗
PubMed1992

Role of the alveolar macrophage in lung injury: studies with ultrafine particles.

We conducted a series of experiments with ultrafine particles (approximately 20 nm) and larger particles (less than 200 nm) of "nuisance" dusts to evaluate the involvement of alveolar macrophages (AM) in particle-induced lung injury and particle translocation in rats. After intratracheal instillation of both ultrafine particles and larger particles of TiO2, we found a highly increased interstitial access of the ultrafine particles combined with a large acute inflammatory reaction as determined by lung lavage parameters. An additional experiment revealed that intratracheal instillation of phagocytized ultrafine TiO2 particles (inside AM) prevented both the pulmonary inflammatory reaction and the interstitial access of the ultrafine particles. Another experiment showed that the influx of polymorphonuclear cells (PMN) into the alveolar space unexpectedly decreased with higher doses of ultrafine particles, whereas alveolar epithelial permeability (protein leakage) increased. The divergence between PMN influx into the alveolar space and changes in alveolar epithelial permeability implies that they are separate events. Pulmonary inflammatory parameters determined by lung lavage analysis correlated best with the surface area of the retained particles rather than with their mass, volume, or numbers. Because higher doses resulted in an increased interstitialized fraction of particles, we suggest that inflammatory events induced by particles in the interstitial space can modify the inflammation in the alveolar space detectable by lung lavage. Our results demonstrate the dual role of AM for modifying particle-induced lung injury, i.e., both preventing such injury and contributing to it. We conclude that the increased pulmonary toxicity of ultrafine particles is related to their larger surface area and to their increased interstitial access.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Pharmacology of fludarabine phosphate after a phase I/II trial by a loading bolus and continuous infusion in pediatric patients.

Fludarabine phosphate is a nucleotide analogue of adenine arabinoside with antitumor activity in murine and human lymphoid malignancies; it has occasional, unpredictable neurotoxicity after high dose bolus injections in adults. To avoid this toxicity, we studied a loading dose plus 5-day continuous infusion in 47 evaluable pediatric patients. Dose limiting myelosuppression was seen in children with solid tumors after a loading dose of 8 mg/m2 followed by 23.5 mg/m2/day for 5 days. In children with leukemia, no dose limiting toxicity was seen at dose level 6, consisting of a loading dose of 10 mg/m2 and an infusion of 30.5 mg/m2/day for 5 days. One complete and 3 partial remissions were seen in 26 evaluable children with acute lymphoblastic leukemia. 9-beta-D-arabinofuranosyl-2-fluoroadenine plasma concentrations and the area under the moment curve increased linearly with dose. The terminal half-life was similar, while the total body clearance was shorter than that reported for adults receiving bolus or continuous doses. Lymphoblasts isolated from 2 patients during fludarabine phosphate (9-beta-D-arabinofuranosyl-2-fluoroadenine) treatment increased their ability to convert 1-beta-D-arabinofuranosylcytosine to 1-beta-D-arabinofuranosylcytosine 5'-triphosphate by more than 10-fold. The antileukemic activity of 9-beta-D-arabinofuranosyl-2-fluoroadenine 5'-phosphate and its ability to alter the metabolism of 1-beta-D-arabinofuranosylcytosine indicate that timed combinations of these 2 agents should be tested.

Antimetabolites, Antineoplastic↗
PubMed1989

Drug-induced toxic epidermal necrolysis in children.

Nine pediatric patients with drug-induced toxic epidermal necrolysis were treated with a regimen of basic burn care and without the use of steroids or topical or systemic antimicrobial agents. Although septic complications continue to occur frequently, infections are better tolerated when potential iatrogenic sources of decreased host resistance, such as steroids, are eliminated. Neutropenia, gram-negative sepsis, and mortality were all greatly reduced with this regimen, while healing was neither impaired nor prolonged. Thus, steroids and sulfa-containing topical agents should be avoided in the treatment of this disorder.

Adolescent↗
PubMed1989

Tracheostomies in burn patients.

The use of tracheostomies in burned patients with inhalation injuries is now reserved for specific indications rather than as prophylactic airway management. A 5-year burn center experience with tracheostomies used in this fashion is presented. Ninety-nine tracheostomies were performed in 3246 patients who had indications of prolonged respiratory failure or acute loss of airway. Although colonization of the sputum was universal, neither rates of pulmonary sepsis nor mortality were significantly increased in patients who underwent tracheostomies. Twenty-eight patients developed late upper airway sequelae, including tracheal stenosis (TS), tracheoesophageal fistula (TEF), and tracheoarterial fistula (TAF). Duration of intubation correlated only with development of TAF, whereas patients in whom TEF developed were significantly older and more likely to have evidence of tracheal necrosis at the time of tracheostomy. The pathogenesis of upper airway sequelae in these patients as divergent responses to the combined insults of inhalation injury, infection, and intubation is considered.

Burns↗
PubMed1989

Ioversol. Double-blind study of a new low osmolar contrast agent for peripheral and visceral arteriography.

The new low-osmolar contrast agent ioversol was compared with the conventional ionic contrast agent diatrizoate in 60 patients undergoing routine abdominal (21 patients) and peripheral (39 patients) arteriography. The effects on hemodynamics, various laboratory parameters, and patient comfort were evaluated. In peripheral arteriography, there was less discomfort with ioversol as well as decreased magnitude and incidence of hypotension (P less than .001) after injection. In visceral arteriography, there was no significant difference between the two agents. Overall, the incidence of ECG changes was small in both groups (ioversol 2%, diatrizoate 8%). The two media were equivalent in incidence of adverse reactions (eg, nausea, vomiting, urticaria), the effect on laboratory parameters, and in the diagnostic adequacy of the radiographs. We conclude that ioversol is safe and efficacious for peripheral and visceral arteriography. In peripheral arteriography it causes less patient discomfort and, perhaps more importantly, fewer hemodynamic alterations than diatrizoate. These differences in hemodynamic effects may be important in patients with hemodynamic instability or limited cardiovascular reserve.

Angiography↗
PubMed1988

Double-blind study of a new nonionic contrast agent for cardiac angiography.

A randomized, double-blind study of a new nonionic contrast agent (ioversol) was performed in 80 patients undergoing routine coronary angiography and left ventriculography. Its hemodynamic and electrocardiographic (ECG) effects were compared with those of a conventional ionic contrast agent (sodium meglumine diatrizoate). There were 40 patients in each group. The radiographic quality and incidence of adverse reactions were comparable for both agents. Following left ventriculography, there was a smaller decrease in systemic and left ventricular systolic blood pressure and a smaller increase in heart rate and pulmonary artery systolic pressure (P less than .05) with ioversol than with meglumine diatrizoate. There was also a slight decrease in cardiac output with ioversol at 1 and 3 minutes after left ventriculography, while meglumine diatrizoate produced a modest increase. In selective coronary angiography, the fall in diastolic blood pressure was also greater (P less than .05). The Q-T interval was more prolonged with meglumine diatrizoate. Ioversol appears to be both safe and efficacious for cardiac angiography, causing fewer and less severe hemodynamic and ECG alterations than meglumine diatrizoate.

Blood Pressure↗
PubMed1987

Contrast venography of the leg: diagnostic efficacy, tolerance, and complication rates with ionic and nonionic contrast media.

A prospective, three-center study of two contrast agents for leg venography was performed to evaluate both the relative frequency of adverse effects and whether low-osmolality agents provided significant advantages for this procedure. Fifty-four patients were studied with the standard preparation (iothalamate meglumine) and 57 with a nonionic agent (iopamidol). Both were used at an iodine concentration of 200 mg/mL, and there were no differences in volume of contrast material, duration of infusion, percentage of positive studies, or overall diagnostic adequacy. Patient discomfort was less with iopamidol than with iothalamate (18% vs. 44%), although discomfort was generally mild in both groups. By objective follow-up studies, the frequency of postvenographic thrombosis was not significantly different in the two groups (8% vs. 9%). Contrast venography, then, had a low frequency of complications when either a dilute conventional or a low-osmolality agent was employed. Although the frequency of postvenographic thrombosis was low with both agents, patient discomfort was less with the low-osmolality formulation.

Clinical Trials as Topic↗