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Biomedical subjects

J Finkelstein

Publications and source records attributed to J Finkelstein.

At least 37 records · Page 2Linked to original sources
PubMed1998

Blockade of CD40-CD40 ligand interactions protects against radiation-induced pulmonary inflammation and fibrosis.

This study investigated whether CD40-CD40 ligand (L) interactions are important in mediating ionizing radiation-induced lung toxicity. Radiotherapy is a key component in the management of malignant diseases and is a conditioning regimen for bone marrow transplantation. Unfortunately, radiation therapy is particularly toxic to the lung, potentially inducing a fatal pneumonitis and fibrosis, thus limiting its effectiveness. There are no therapies that protect against the development of radiation-induced lung toxicity. Using a mouse model of radiation-induced lung toxicity, a monoclonal anti-CD40L antibody (MR1) that disrupts CD40-CD40L interactions was tested for the ability to reduce lung injury. C57BL/6 mice were pretreated with either nothing, MR1, or hamster IgG 24 h prior to a single dose of 15 Gray ionizing radiation to the thorax. During the following 26 weeks, mice continued to receive MR1 or hamster IgG twice per week. MR1 protected against death from radiation pneumonitis and fibrosis and dramatically reduced lung pathology as evidenced by a limited influx of inflammatory cells, minimal collagen deposition, and septal thickening. MR1 also prevented radiation-induced pulmonary mastocytosis and blunted expression of cyclooxygenase-2, a proinflammatory enzyme responsible for prostaglandin synthesis. Disruption of CD40-CD40L interactions may offer a new mode of intervention to protect against radiation-induced pulmonary toxicity.

Animals↗
PubMed1998

Telematic system for monitoring of asthma severity in patients' homes.

Despite advances in the treatment of asthma the morbidity and mortality of this disease has increased significantly in the past several years. Recent studies have shown that monitoring of asthma severity in the patient home especially combined with patient education can reduce incidence of asthma exacerbation and subsequent hospitalization. The existing methods for home asthma monitoring are limited by four factors; they completely rely on a patient's ability to document and to evaluate test results; there is no easy way for a physician to review data in a timely manner; they use imprecise tools for evaluation of asthma severity and they don't provide clinical decision support tools. The goal of this study is to develop and to evaluate a telematic system for asthma severity monitoring which will minimize patients' efforts in performing self-testing at their homes and allow prompt reciprocal exchange of all relevant information between patients and health care providers. In our setting, patients use portable spirometer and pocket-sized palmtop computer for data exchange. Our system allows daily serial monitoring of asthma severity at patients' homes using Forced Vital Capacity test and symptom diary. The results of the tests become available for physicians review immediately after completion of self-testing procedures via Web browser. The results can be transmitted from patients' homes (or any other remote location) to the medical records database via landline or wireless networks in several minutes. Each time the remote server receives patient's results, it invokes the application which tests the validity of data, analyzes parameters trends and dispatches corresponding messages for the patient and, if necessary, for physicians. Such an approach provides constant feedback loop between asthma patient and physician. The system has been tested in 10 healthy volunteers and asthma patients. Patients participated in the study from two to 21 days. The test results showed that the system provides reliable reciprocal exchange of all relevant information between a physician and asthma patient in home settings. Average transmission time from the patient's palmtop to the remote central data repository was about 1 minute for 14.4 Kbps landline modem, 6 minutes for cellular network and 8 minutes for RAM Mobile network. After transmission, the test results were immediately available for review at our web site.

Asthma↗
PubMed1998

Disruption of the CD40-CD40 ligand system prevents an oxygen-induced respiratory distress syndrome.

Oxygen therapy is a mainstay treatment for infants and adults with poor lung function. Unfortunately, oxygen itself is toxic and incites respiratory cell damage and inflammation. Therapies for oxygen-induced lung damage are nonexistent. Employing a mouse model of hyperoxic lung injury, a monoclonal anti-CD40 ligand (L) antibody (MR1), which disrupts CD40-CD40L interactions, was tested for the ability to reduce pulmonary injury. Intraperitoneal administration of MR1, either before or after oxygen exposure, was remarkably effective in reducing and in many cases preventing lung injury. The pro-inflammatory enzyme cyclooxygenase-2 (Cox-2), responsible for prostaglandin production, is massively up-regulated in the lungs after hyperoxic exposure. Immunohistochemical staining for Cox-2 revealed that MR1 greatly reduces the oxygen-induced induction of Cox-2. The remarkable effectiveness of MR1 in blunting hyperoxic lung injury in this preclinical model may be relevant to the hundreds of thousands of patients who require treatment with high oxygen and who are at risk for developing severe pulmonary inflammation and consequent fibrosis. Strategies to disrupt CD40-CD40L interactions may offer a new mode of intervention for oxygen-induced acute respiratory distress syndrome and other inflammatory lung disorders.

Animals↗
PubMed1998

Patients' acceptance of Internet-based home asthma telemonitoring.

We studied asthma patients from a low-income inner-city community without previous computer experience. The patients were given portable spirometers to perform spirometry tests and palmtop computers to enter symptoms in a diary, to exchange messages with physician and to review test results. The self-testing was performed at home on a daily basis. The results were transmitted to the hospital information system immediately after completion of each test. Physician could review results using an Internet Web browser from any location. A constantly active decision support server monitored all data traffic and dispatched alerts when certain clinical conditions were met. Seventeen patients, out of 19 invited, agreed to participate in the study and have been monitored for three weeks. They have been surveyed then using standardized questionnaire. Most of the patients (82.4%) characterized self-testing procedures as "not complicated at all." In 70.6% of cases self-testing did not interfere with usual activities, and 82.4% of patients felt the self-testing required a "very little" amount of their time. All patients stated that it is important for them to know that the results can be reviewed by professional staff in a timely manner. However, only 29.5% of patients reviewed their results at least once a week at home independently. The majority of the patients (94.1%) were strongly interested in using home asthma telemonitoring in the future. We concluded that Internet-based home asthma telemonitoring can be successfully implemented in the group of patients without previous computer background.

Adult↗
PubMed1997

The clinical phenotype of succinic semialdehyde dehydrogenase deficiency (4-hydroxybutyric aciduria): case reports of 23 new patients.

OBJECTIVES: To further define the clinical spectrum of the disease for pediatric and metabolic specialists, and to suggest that the general pediatrician and pediatric neurologist consider succinic semialdehyde dehydrogenase (SSADH) deficiency in the differential diagnosis of patients with (idiopathic) mental retardation and emphasize the need for accurate, quantitative organic acid analysis in such patients. PATIENTS: The clinical features of 23 patients (20 families) with SSADH deficiency (4-hydroxybutyric acid-uria) are presented. The age at diagnosis ranged from 3 months to 25 years in the 11 male and 12 female patients; consanguinity was noted in 39% of families. OUTCOME MEASUREMENTS: The following abnormalities were observed (frequency in 23 patients): motor delay, including fine-motor skills, 78%; language delay, 78%; hypotonia, 74%; mental delay, 74%; seizures, 48%; decreased or absent reflexes, 39%; ataxia, 30%; behavioral problems, 30%; hyperkinesis, 30%; neonatal problems, 26%; and electroencephalographic abnormalities, 26%. Associated findings included psychoses, cranial magnetic resonance or computed tomographic abnormalities, and ocular problems in 22% or less of patients. Therapy with vigabatrin proved beneficial to varying degrees in 35% of the patients. Normal early development was noted in 30% of patients. CONCLUSIONS: Our data imply that two groups of patients with SSADH deficiency exist, differentiated by the course of early development. Our recommendation would be that accurate, quantitative organic acid analysis in an appropriate specialist laboratory be requested for any patients presenting with two or more features of mental, motor, or language delay and hypotonia of unknown cause. Such analyses are the only definitive way to diagnose SSADH deficiency; the diagnosis can be confirmed by determination of enzyme activity in white cells from whole blood. We think that increased use of organic acid determination will lead to increased diagnosis of SSADH deficiency and a more accurate representation of disease frequency. As additional patients are identified, we should have a better understanding of both the metabolic and clinical profiles of SSADH deficiency.

Adolescent↗
PubMed1996

Reconstitution of human replication factor C from its five subunits in baculovirus-infected insect cells.

Human replication factor C (RFC, also called activator 1) is a five-subunit protein complex (p140, p40, p38, p37, and p36) required for proliferating cell nuclear antigen (PCNA)-dependent processive DNA synthesis catalyzed by DNA polymerase delta or epsilon. Here we report the reconstitution of the RFC complex from its five subunits simultaneously overexpressed in baculovirus-infected insect cells. The purified baculovirus-produced RFC appears to contain equimolar levels of each subunit and was shown to be functionally identical to its native counterpart in (i) supporting DNA polymerase delta-catalyzed PCNA-dependent DNA chain elongation; (ii) catalyzing DNA-dependent ATP hydrolysis that was stimulated by PCNA and human single-stranded DNA binding protein; (iii) binding preferentially to DNA primer ends; and (iv) catalytically loading PCNA onto singly nicked circular DNA and catalytically removing PCNA from these DNA molecules.

Adenosine Triphosphatases↗
PubMed1996

In vitro reconstitution of human replication factor C from its five subunits.

Replication factor C (RFC, also called Activator I) is part of the processive eukaryotic DNA polymerase holoenzymes. The processive elongation of DNA chains requires that DNA polymerases are tethered to template DNA at primer ends. In eukaryotes the ring-shaped homotrimeric protein, proliferating cell nuclear antigen (PCNA), ensures tight template-polymerase interaction by encircling the DNA strand. Proliferating cell nuclear antigen is loaded onto DNA through the action of RFC in an ATP-dependent reaction. Human RFC is a protein complex consisting of five distinct subunits that migrate through SDS/polyacrylamide gels as protein bands of 140, 40, 38, 37, and 36 kDa. All five genes encoding the RFC subunits have been cloned and sequenced. A functionally identical RFC complex has been isolated from Saccharomyces cerevisiae and the deduced amino acid sequences among the corresponding human and yeast subunits are homologous. Here we report the expression of the five cloned human genes using an in vitro coupled transcription/translation system and show that the gene products form a complex resembling native RFC that is active in supporting an RFC-dependent replication reaction. Studies on the interactions between the five subunits suggest a cooperative mechanism in the assembly of the RFC complex. A three-subunit core complex, consisting of p36, p37, and p40, was identified and evidence is presented that p38 is essential for the interaction between this core complex and the large p140 subunit.

DNA Replication↗
PubMed1996

The effects of burn blister fluid on cultured keratinocytes.

OBJECTIVE: Previous studies have suggested that burn blister fluid (BBF) may be detrimental to the healing of the underlying wound bed. In this study, the effects of burn blister fluid on cultured keratinocyte proliferation and differentiation were examined and quantitated using various techniques. METHODS: At three different concentrations (2%, 10%, 20% in 20% fetal bovine serum/complete culture medium), 19 BBFs were tested in triplicate using 12 populations of cultured keratinocytes. All BBFs were collected from partial thickness burns within 72 hours of injury,. BBF was added on day 4 of the keratinocyte culture. The effect on proliferation and viability was assessed using trypan blue dye exclusion. Multiparameter flow cytometric analysis was used to quantitate population kinetics and cell size distribution. Keratinocyte differentiation was determined using immunohistochemical staining of differentiation markers and quantitation of cornified envelope formation. RESULTS: Relative to control fluid, the BBF caused a variable effect on proliferation, ranging from 67% inhibition to 103% stimulation with an overall 4% inhibition. The range of keratinocyte viability was narrower, with a similar overall 4% reduction. Using flow cytometry to analyze RNA/DNA content and cell size, the BBF caused a subtle shift in keratinocyte population kinetics and cell size distribution toward larger, less rapidly dividing cells. The BBF had no significant effect on expression of the differentiation markers, filaggrin and involucrin. Finally, the BBF did not alter terminal differentiation as it did not influence formation of cornified envelopes (BBF = 9.1 +/- 4.8%, control = 9.9 +/- 6.6%). CONCLUSION: Previous biochemical analysis has shown that BBF consists primarily of human serum filtrate with locally produced acute reactants. Our study suggests that BBF is biologically similar to serum and does not significantly alter keratinocyte proliferation or differentiation in vitro.

Adolescent↗
PubMed1995

Protein structure. Why have six-fold symmetry?

Why do proteins proteins that encircle DNA have six-fold symmetry? One important factor may be the economy in protein mass with which DNA can be encircled by six globular subunits arranged in a ring.

Animals↗
PubMed1995

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

The gamma complex of DNA polymerase III holoenzyme, the replicase of Escherichia coli, couples ATP hydrolysis to the loading of beta sliding clamps onto primed DNA. The beta sliding clamp tethers the holoenzyme replicase to DNA for rapid and processive synthesis. In this report, the gamma complex has been constituted from its five different subunits. Size measurements and subunit stoichiometry studies show a composition of gamma 2 delta 1 delta' 1 1 chi 1 psi 1. Strong intersubunit contacts have been identified by gel filtration, and weaker contacts were identified by surface plasmon resonance measurements. An analogous tau complex has also been constituted and characterized; it is nearly as active as the gamma complex in clamp loading activity, but as shown in the fourth report of this series, it is at a disadvantage in binding the delta, delta', chi, and psi subunits when core is present (Xiao, H., Naktinis, V., and O'Donnell, M. (1995) J. Biol. Chem. 270, 13378-13383). The single copy subunits within the gamma complex provide the basis for the structural asymmetry inherent within DNA polymerase III holoenzyme.

Chromatography, High Pressure Liquid↗
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↗