Bone metastasis: review and critical analysis of random allocation trial of local field treatment: regarding Ratanatharathorn et al. IJROB 44(1):1-18; 1999.
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Bone Neoplasms↗
Biomedical subjects
J Finkelstein
Publications and source records attributed to J Finkelstein.
Palliation of bone metastases: a survey of patterns of practice among Canadian radiation oncologists.
BACKGROUND: Palliative radiotherapy constitutes nearly 50% of the workload in radiotherapy. Surveys on the patterns of practice in radiotherapy have been published from North America and Europe. Our objective was to determine the current pattern of practice of radiation oncologists in Canada for the palliation of bone metastases. METHOD: A survey was sent to 300 practicing radiation oncologists in Canada. Five case scenarios were presented. The first three were patients with a single symptomatic site: breast cancer patient with pelvic metastasis, lung cancer male with metastasis to L3 and L1, respectively. The last two were breast and prostate cancer patients with multiple symptomatic bone metastases. RESULTS: A total of 172 questionnaires were returned (57%) for a total of 860 responses. For the three cases with a single painful bone metastasis, over 98% would prescribe radiotherapy. The doses ranged from a single 8 to 30 Gy in ten fractions. Of the 172 respondents, 117 (68%) would use the same dose fractionation for all three cases, suggesting that they had a standard dose fractionation for palliative radiotherapy. The most common dose fractionation was 20 Gy in five fractions used by 84/117 (72%), and 8 Gy in one fraction by 19/117 (16%). In all five case scenarios, 81% would use a short course of radiotherapy (single 8 Gy, 17%; 20 Gy in five fractions, 64%), while 10% would prescribe 30 Gy in ten fractions. For the two cases with diffuse symptomatic bone metastases, half body irradiation (HBI) and radionuclides were recommended more frequently in prostate cancer than in breast cancer (46/172 vs. 4/172, P<0. 0001; and 93/172 vs. 10/172, P<0.0001, respectively). Strontium was the most commonly recommended radionuclide (98/103=95%). Since systemic radionuclides are not readily available in our health care system, 41/98 (42%) of radiation oncologists who would recommend strontium were not familiar with the dose. Bisphosphonates were recommended more frequently in breast cancer than in prostate cancer 13/172 (8%) vs. 1/172 (0.6%), P=0.001. CONCLUSION: Local field external radiotherapy remains the mainstay of therapy, and the most common fractionation for bone metastases in Canada is 20 Gy in five fractions compared with 30 Gy in ten fractions in the US. Despite randomized trials showing similar results for single compared with fractionated radiotherapy, the majority of us still advocate five fractions. The frequency of employing a single fractionation has not changed since the last national survey in 1992. Nearly 70% use a standard dose fractionation to palliate localized painful metastasis by radiotherapy, independent of the site of involvement or tumor type. The pattern of practice of palliative radiotherapy for bone metastases in Canada is different to that reported previously from the US. The reasons why the results of randomized studies on bone metastases have no impact on the patterns of practice are worth exploring.
Bone Neoplasms↗
Induction of adaptation to inhaled lipopolysaccharide in young and old rats and mice.
Lipopolysaccharide (LPS) is a component of the gram-negative bacterial cell wall that is known to activate inflammatory cells and enhance the production of inflammatory mediators in the lung. As it is a ubiquitous compound, inhalation exposure is highly likely in the human environment. Adaptation is a phenomenon by which a previous exposure results in improved survival or reduced injury as compared to a single exposure alone. We hypothesized that the basic proinflammatory effects of LPS in the lung could result in the development of adaptation in animals. Based on evidence of age- and species-related differences in lung injury, we used an acute lung injury model with inhaled LPS to compare the development of adaptation in young and old Fisher 344 rats and C57Bl/6J mice. Animals were exposed to low-dose (predicted lung deposition approximately 20 ng in rats and approximately 5 ng in mice) LPS aerosols for 10 min on 3 consecutive days; on day 4, a high dose (rats approximately 200 ng; mice approximately 25 ng) was delivered. Another group of animals received only the high LPS dose on day 4, whereas controls were unexposed. Twenty-four hours after the last exposure, cellular and inflammatory parameters in bronchoalveolar lavage (BAL) were determined. An adaptive response was found in both rats and mice. Adapted animals showed significantly fewer BAL neutrophils compared to nonadapted ones; there was also a significantly lower release of oxidants from phorbol methyl ester-stimulated BAL cells from adapted compared to nonadapted animals, which, in turn, showed a greater response than controls. Furthermore, studies in old animals (21 mo of age) showed that adaptation also occurs in this age group. The adaptive response is clear in old mice; in rats, there is greater variability in the response, but an adaptive trend is apparent. Therefore, we have demonstrated that inhaled low-dose LPS can induce adaptation to subsequent higher doses, much as has been shown for other toxicants that induce oxidative lung injury.
Administration, Inhalation↗
Internet-based home asthma telemonitoring: can patients handle the technology?
STUDY OBJECTIVE: To evaluate the validity of spirometry self-testing during home telemonitoring and to assess the acceptance of an Internet-based home asthma telemonitoring system by asthma patients. DESIGN: We studied an Internet-based telemonitoring system that collected spirometry data and symptom reports from asthma patients' homes for review by physicians in the medical center's clinical information system. After a 40-min training session, patients completed an electronic diary and performed spirometry testing twice daily on their own from their homes for 3 weeks. A medical professional visited each patient by the end of the third week of monitoring, 10 to 40 min after the patient had performed self-testing, and asked the patient to perform the spirometry test again under his supervision. We evaluated the validity of self-testing and surveyed the patients attitude toward the technology using a standardized questionnaire. SETTING: Telemonitoring was conducted in patients' homes in a low-income inner city area. PATIENTS: Thirty-one consecutive asthma patients without regard to computer experience. MEASUREMENT AND RESULTS: Thirty-one asthma patients completed 3 weeks of monitoring. A paired t test showed no difference between unsupervised and supervised home spirometry self-testing. The variability of FVC (4.1%), FEV(1) (3. 7%), peak expiratory flow (7.9%), and other spirometric indexes in our study was similar to the within-subject variability reported by other researchers. Despite the fact that the majority of the patients (71%) had no computer experience, they indicated that the self-testing was "not complicated at all" or only "slightly complicated." The majority of patients (87.1%) were strongly interested in using home asthma telemonitoring in the future. CONCLUSIONS: Spirometry self-testing by asthma patients during telemonitoring is valid and comparable to those tests collected under the supervision of a trained medical professional. Internet-based home asthma telemonitoring can be successfully implemented in a group of patients with no computer background.
Adult↗
The ultimate one-stop for cancer patients with bone metastases: new combined bone metastases clinic.
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Ambulatory Care Facilities↗
[Zenker diverticulum: therapeutic approach].
BACKGROUND: Pharyngoesophageal or Zenker diverticula are a few frequent pathology that could represent between 1 and 3% of the patients with dysphagia and their physiopathology even at present is scarcity clear. OBJECTIVE: Therapeutic procedures results about this pathology were analyzed. SETTING: Caraffa and Sucre Clinic. DESIGN: Retrospective observational study. METHOD: It analyzed 13 patients operated by Zenker diverticula 9 of which were male and 4 were female sex with an average age of 55.6 years. Dysphagia occurred in 100% of the cases. Besides clinical finding the diagnosis was made evident by esophageal X-ray with contrast medium and endoscopy. Diverticulectomy by one stage through a left cervicotomy was the surgical procedure of choice. RESULTS: There was no surgical mortality. Related with morbility 2 patients presented fistulas managed medically and in other 2 patients abscesses of surgical wound occurred. The follow-up was carried on 6 months, 4 and 7 years respectively without relapses and with a good posterior evolution. CONCLUSIONS: Based on our short experience and the results attained we think the treatment of Zenker or pharyngoesophageal diverticulum by diverticulectomy through a left cervicotomy is safe and effective procedure to control this pathology.
Adult↗
ATP hydrolysis catalyzed by human replication factor C requires participation of multiple subunits.
Human replication factor C (hRFC) is a five-subunit protein complex (p140, p40, p38, p37, and p36) that acts to catalytically load proliferating cell nuclear antigen onto DNA, where it recruits DNA polymerase delta or epsilon to the primer terminus at the expense of ATP, leading to processive DNA synthesis. We have previously shown that a subcomplex of hRFC consisting of three subunits (p40, p37, and p36) contained DNA-dependent ATPase activity. However, it is not clear which subunit(s) hydrolyzes ATP, as all five subunits include potential ATP binding sites. In this report, we introduced point mutations in the putative ATP-binding sequences of each hRFC subunit and examined the properties of the resulting mutant hRFC complex and the ATPase activity of the hRFC or the p40.p37.p36 complex. A mutation in any one of the ATP binding sites of the p36, p37, p40, or p140 subunits markedly reduced replication activity of the hRFC complex and the ATPase activity of the hRFC or the p40.p37.p36 complex. A mutation in the ATP binding site of the p38 subunit did not alter the replication activity of hRFC. These findings indicate that the replication activity of hRFC is dependent on efficient ATP hydrolysis contributed to by the action of four hRFC subunits.
Adenosine Triphosphate↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
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↗
Ultrafine particles as a potential environmental health hazard. Studies with model particles.
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Air Pollutants↗
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↗
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↗