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Biomedical subjects

P Rubin

Publications and source records attributed to P Rubin.

At least 127 records · Page 7Linked to original sources
PubMed1994

Early alterations in extracellular matrix and transforming growth factor beta gene expression in mouse lung indicative of late radiation fibrosis.

PURPOSE: Fibrosis, characterized by the accumulation of collagen, is a late result of thoracic irradiation. The expression of late radiation injury can be found immediately after irradiation by measuring messenger RNA (mRNA) abundance. METHODS AND MATERIALS: To determine if extracellular matrix mRNA and transforming growth factor beta abundance was affected acutely after irradiation, we measured mRNA levels of collagen I (CI), collagen III (CIII), collagen IV (CIV), fibronectin (FN), and transforming growth factor beta (TGF beta 1,2&3) in mouse lungs on day 1 and day 14 after graded doses of radiation. C57BL/6 female mice were irradiated with a single dose to the thorax of 5 or 12.5 Gy. Total lung RNA was prepared and immobilized by Northern and slot blotting and hybridized with radiolabelled cDNA probes for CI, CIII, CIV, FN, TGF beta 1,2&3 and a control probe encoding for glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Autoradiographic data were quantified by video densitometry and results normalized to GAPDH. RESULTS: Changes in the expression of CI, CIII, CIV, FN and TGF beta 1,2&3 were observed as early as 1 day after exposure. Through 14 days, changes in mRNA up to 5-fold were seen for any one dose. Dose related changes as high as 10-fold were also evident. The CI:CIII ratio increased gradually for the 5 Gy dose at 14 days postirradiation while the CI:CII ratio for the 12.5 Gy dose decreased by approximately 4-fold as compared to the control. CONCLUSION: These studies suggest that alterations in expression of extracellular matrix and TGF beta mRNA occur very early after radiation injury even at low doses and may play a role in the development of chronic fibrosis.

Animals↗
PubMed1994

Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma.

BACKGROUND: A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. METHODS: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. RESULTS: Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. CONCLUSION: The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.

Adult↗
PubMed1994

Regional cerebral blood flow distribution in newly diagnosed schizophrenia and schizophreniform disorder.

Regional cerebral blood flow distribution (rCBF) in 24 first admissions with schizophrenia or schizophreniform disorder and in 17 healthy volunteers was examined. Single photon emission computed tomography with a brain-retained tracer, technetium-99m-d,l-hexamethyl-propylene amine oxime, was used to study subjects under resting conditions and during performance of the Wisconsin Card Sorting Test. The study is a replication of a previous investigation in an independent series of patients and healthy volunteers. The patients had significantly lower relative blood flow in prefrontal regions during activation than did the healthy volunteers. An earlier series of 19 patients and 7 healthy volunteers was studied using exactly the same procedure. Analyses of the combined samples from the two studies (43 patients and 24 healthy volunteers) showed the patients to have significantly lower relative flow in prefrontal regions both at rest and during activation and higher flow in the left striatum during activation. The same finding emerged when analyses were confined to drug-naive patients and patients educationally matched to the healthy volunteers. The study suggests a defective frontostriatal interrelationship in schizophrenia and schizophreniform disorder.

Adolescent↗
PubMed1994

Disruption of the blood-brain barrier as the primary effect of CNS irradiation.

The blood-brain barrier (BBB) is believed to be unique in organ microcirculation due to the 'tight junctions' which exist between endothelial cells and, some argue, the additional functional components represented by the perivascular boundary of neuroglial cells; these selectively exclude proteins and drugs from the brain parenchyma. This study was designed to examine the effects of irradiation on the BBB and determine the impact of the altered pathophysiology on the production of central nervous system (CNS) late effects such as demyelination, gliosis and necrosis. Rats, irradiated at 60 Gy, were serially sacrificed at 2, 6, 12 and 24 weeks. Magnetic resonance image analysis (MRI) was obtained prior to sacrifice with selected animals from each group. The remaining animals underwent horse-radish peroxidase (HRP) perfusion at the time of sacrifice. The serial studies showed a detectable disruption of the BBB at 2 weeks post-irradiation and this was manifested as discrete leakage; late injury seen at 24 weeks indicated diffuse vasculature leakage, severe loss of the capillary network, cortical atrophy and white matter necrosis. Reversal or repair of radiation injury was seen between 6 and 12 weeks, indicating a bimodal peak in events. Blood-brain barrier disruption is an early, readily recognizable pathophysiological event occurring after radiation injury, is detectable in vivo/in vitro by MRI and HRP studies, and appears to precede white matter necrosis. Dose response studies over a wide range of doses, utilizing both external and interstitial irradiation, are in progress along with correlative histopathologic and ultrastructural studies.

Animals↗
PubMed1994

Relationship between brain structure and function in disorders of the schizophrenic spectrum: single positron emission computerized tomography, computerized tomography and psychopathology of first episodes.

Fifty newly diagnosed, briefly treated or drug-naive patients with schizophrenia or schizophreniform disorder were examined by psychopathology scales for positive (SAPS), negative (SANS) and overall psychotic symptoms (PSE and BPRS). CT-scan and regional cerebral blood flow (rCBF) measurement by 99mTc-HMPAO SPECT during rest and mental activation by Wisconsin Card Sorting Test was performed as well. Twenty-five age-matched normal healthy volunteers served as controls. Thought disorders and fundamental symptoms correlated positively with relatively high, though subnormal prefrontal (PFC) rCBF and high rCBF in temporal cortex; positive symptoms correlated positively with high rCBF in the striatum and temporal cortex during activation. Negative symptoms correlated with high prefrontal rCBF. The patients had sulcal enlargement and smaller brain volume compared with the healthy volunteers. There were no signs of ventricular enlargement. Neither total negative symptoms, thought disorder nor fundamental symptoms correlated with any CT measurements. Total positive symptoms correlated negatively with the size of the temporal horns. The relatively high rCBF in PFC and temporal cortex of cases with pronounced positive and negative symptoms and thought disorder may imply that an aberrant cortical network has to be active to express a malattuned clinical output. The striatal hyperfunction mainly in productive cases may be a secondary phenomenon and more pronounced in cases where no signs of subcortical atrophy has (yet?) ensued.

Adolescent↗
PubMed1994

Neurological abnormalities in patients with schizophrenia or schizophreniform disorder at first admission to hospital: correlations with computerized tomography and regional cerebral blood flow findings.

Forty-five patients with schizophrenia or schizophreniform disorder admitted to hospital for the first time had a neurological examination, including integrative sensory and complex motor acts, by a trained neurologist. The patients were studied by CT (computerized tomography) and rCBF (regional cerebral blood flow) as well. A control group of 24 healthy volunteers was included. The patients had significantly more neurological abnormalities (NA) than the healthy volunteers. Medication did not explain the discrepancy. The NA were associated with sulcal enlargement and smaller brains as visualized by CT but not with ventricular enlargement. There was no association between the regional flow values and NA.

Adult↗
PubMed1994

Input/output characteristics of a matrix ion-chamber electronic portal imaging device.

The input/output characteristics of a matrix liquid ion-chamber electronic portal imaging device (EPID) are investigated to elucidate the imaging properties of EPIDs. The radiation input to the detector, represented by dose rate, and the pixel value output from the device are related by a characteristic curve. Various incident radiation intensities are obtained by changing the source-to-detector distance (SDD). For each incident radiation intensity, an electronic portal image is obtained using a field size of 5 x 5 cm2. The output pixel value of the EPID is represented by the average pixel value of a region of interest of 9 x 9 pixels centered at a selected point. The effects of various accelerator settings, such as the repetition-rate setting and photon energy, gantry angle, field size, SDD, and acquisition mode of the EPID on characteristic curves are investigated at the central axis. The off-axis response of the detector is also examined. The derivative of the pixel value with respect to the input dose rate is used to analyze the detector contrast. Results indicate that the output pixel value is not a linear function of the incident radiation intensity. The detector contrast is comparable between photon energies of 10 and 6 MV and increases at low dose rates. The response of the imaging device varies substantially with acquisition mode, but is less sensitive to the SDD used for calibration. Characteristic curves are consistent for different gantry angles at the central axis and with the off-axis locations when the gantry angle is used for imaging and calibration, but vary with off-axis locations when the gantry angle is not at the calibration direction. Characteristic curves are also found to vary with different field sizes, but are similar in shape.

Humans↗
PubMed1994

A technique of automating compensator design for lung inhomogeneity correction using an electron portal imaging device.

A technique of automating compensator design for lung inhomogeneity correction using an electron portal imaging device (EPID) has been investigated. This technique utilizes exit-radiation information as detected by an EPID to determine the thickness of the compensator desired. In this particular study, the compensator thickness is determined to provide a uniform gray-level distribution (related to uniform exit-dose distribution) in the region of the portal image to be compensated. Initially, a compensation characteristic curve, which relates the compensator thickness to the pixel value of the electronic portal image, is measured for both the Lead and Lipowitz compensator materials and a 6-MV photon beam. Then, a chest-treatment field is simulated using an anthropomorphic phantom. Based on the analysis of the profile (gray-level distribution) across the lung and mediastinum regions in the electronic portal image, the average of pixel values within the mediastinum region is selected as the matching level and the regions to be compensated are determined. With the aid of the predetermined compensation characteristic curve and proper distance scaling, the compensator thickness at each pixel location is automatically calculated at the block tray level to correct lung inhomogeneity. In a simple test using a single anterioposterior (AP) chest field, the compensated profile in the electronic portal image presents a uniform gray-level distribution (related to uniform exit dose) compared to the uncompensated profile.(ABSTRACT TRUNCATED AT 250 WORDS)

Biophysical Phenomena↗
PubMed1994

Taking care of the customer.

Taking care of the customer while running an efficient manufacturing operation is a challenge. This article describes the success one contract manufacturer had in developing a customer service department to manage a growing and diverse customer base. Balancing customer and plant requirements during a period of organizational change is discussed.

Consumer Behavior↗
PubMed1994

Quantitation of prostate-specific acid phosphatase in prostate cancer: reproducibility and correlation with subjective grade.

In this study, we quantitatively evaluated the intensity and extent of prostate-specific acid phosphatase in immunocytochemically stained prostate carcinoma tissue sections by using a dual-wave-length-based image processing technique. Tissue sections were doubly stained in a standard way, i.e., prostate-specific acid phosphatase was immunocytochemically labeled by peroxidase-antiperoxidase (PAP) technique using diaminobenezidene (DAB) as the substrate and hematoxylin as a nuclear counterstain. Statistical analysis in this study indicated that the quantitative measures of the prostate-specific acid phosphatase staining (PAP-DAB) are reproducible. We found that the quantitative intensity was generally proportional to the subjective intensity (graded as 1 to 4+) of PAP-DAB. Although the quantitative extent measurements compared with the subjective estimates of the percentage of tumor showing staining with PAP-DAB had a similar tendency, there were significant overlaps between extent of tumor staining falling in the mid-ranges. Because subjective grading of immunocytochemical prostate-specific acid phosphatase has been thought to be a useful marker of tumor differentiation in patients with prostate carcinoma, we also evaluated the relationship of the quantitative measures of PAP-DAB staining to other predictors of patient outcome, including histologic grades (Gleason score and MD Anderson grading scheme) and clinical stage. We confirmed that quantitative intensity and extent of PAP-DAB staining were independent of histologic grades and stage, just as the subjective measures of intensity and extent were found to be. Possible explanations of this lack of correlation are discussed.

3,3'-Diaminobenzidine↗
PubMed1994

The use of intensive clinic support to permit outpatient autologous bone marrow transplantation for breast cancer.

Recent studies have explored feasibility and cost considerations of administering high-dose chemotherapy with hematopoietic support in the outpatient setting. Between October 1991 and April 1993, we studied 110 women with primary metastatic breast cancer undergoing high-dose chemotherapy with hematopoietic support. Ninety-two patients were managed in an outpatient clinic after high-dose chemotherapy and autologous bone marrow transplantation and peripheral blood progenitor cells. The remaining 18 patients received the same high-dose treatment and hematopoietic support in the hospital and were discharged to a nearby hotel each night; these patients were the pilot group for this effort and also served as a control group. High-dose chemotherapy consisted of cyclophosphamide/cisplatin/carmustine. Chemotherapy was well tolerated, allowing 95% of 65 eligible patients enrolled since November 1992 to be discharged soon after chemotherapy for outpatient posttransplant support. Approximately 70% of these patients required either no hospital readmission or brief readmissions of 1 to 4 days. Median days of hospitalization required for historical groups of patients receiving high-dose chemotherapy plus bone marrow support as inpatient therapy, high-dose chemotherapy with colony-stimulating factor-primed peripheral blood progenitor cells and autologous bone marrow transplantation as inpatient therapy in a traditional transplant model, and outpatient management of autologous bone marrow transplantation patients were 37, 24.5, and 7 days, respectively, despite the same high-dose chemotherapy. Charges related to the transplant procedure were reduced by 50% over the last 2 to 5 years using the outpatient management approach. This procedure may be applicable to patients with other forms of cancer receiving intensive chemotherapeutic regimens. The use of outpatient management in a transplant setting is highly cost effective.

Adult↗
PubMed1993

The effect of inhibition of 5-lipoxygenase by zileuton in mild-to-moderate asthma.

OBJECTIVE: To evaluate the effectiveness of inhibiting the formation of the 5-lipoxygenase products of arachidonic acid by the 5-lipoxygenase inhibitor zileuton in the treatment of mild-to-moderate asthma. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: University hospitals and private allergy and pulmonary practices. PATIENTS: A total of 139 persons with asthma who had a forced expiratory volume in 1 second (FEV1) of 40% to 75% of the predicted value and who were not being treated with inhaled or oral steroids. INTERVENTION: Zileuton, 2.4 g/d or 1.6 g/d, or placebo for 4 weeks. MEASUREMENTS: Airway function, beta-agonist use, and symptoms; inhibition of 5-lipoxygenase assessed by measurement of urinary leukotriene E4 (LTE4). RESULTS: Zileuton produced a 0.35-L (95% CI, 0.25 to 0.45 L) increase in the FEV1 within 1 hour of administration (P < 0.001 compared with placebo), equivalent to a 14.6% increase from baseline. After 4 weeks of zileuton therapy, airway function and symptoms improved, with the greatest improvements occurring in the 2.4 g/d group: This group's FEV1 increased by 0.32 L (CI, 0.16 to 0.48 L), a 13.4% increase, compared with a 0.05-L (CI, -0.10 to 0.20 L) increase in patients taking placebo (P = 0.02). Symptoms and frequency of beta-agonist use also decreased with zileuton, 2.4 g/d. The mean urinary LTE4 level decreased by 39.2 pg/mg creatinine (CI, 18.1 to 60.4 pg/mg creatinine) and 26.5 pg/mg creatinine (CI, 6.6 to 46.5 pg/mg creatinine) in the 2.4 g/d and 1.6 g/d groups, respectively, compared with a slight increase in the placebo group (P = 0.007 and P = 0.05). No difference was noted in the number of adverse events among treatment groups. CONCLUSIONS: Inhibition of 5-lipoxygenase can improve airway function and decrease symptoms and medication use in patients with asthma, suggesting that this inhibition can be useful therapy for asthma. Also, 5-lipoxygenase products may mediate part of the baseline airway obstruction in patients with mild-to-moderate asthma.

Adult↗
PubMed1993

Preclinical and clinical activity of zileuton and A-78773.

The importance of leukotrienes as mediators of inflammation and bronchoconstriction was examined with two recently described 5-lipoxygenase inhibitors, zileuton and A-78773. Preclinical evaluation of these two molecules indicates that they are potent, selective, direct, reversible inhibitors of 5-lipoxygenase with activity in a variety of purified cells and in more complex biological systems such as whole blood, lung fragments, and tracheal tissues. In various animals models of inflammation and allergy, the molecules inhibited edema, inflammatory cell influx, and bronchospasm. These observations are consistent with the recent clinical success of zileuton in treating asthma and inflammatory bowel disease. In all preclinical systems tested thus far, A-78773 is more potent and longer acting than zileuton, indicating that the molecule could be even more effective in the clinic than zileuton and that both molecules are useful tools in defining the role of leukotrienes in preclinical and clinical settings.

Animals↗
PubMed1993

Combined Betaseron R (recombinant human interferon beta) and radiation for inoperable non-small cell lung cancer.

PURPOSE: Based on in vitro evidence of radiosensitization by Betaseron (beta-IFN), a Phase I/II study was undertaken to determine toxicity and response using combined radiation (RT) and B-IFN in patients with unresectable Stage III and nonsmall cell lung cancer. METHODS AND MATERIALS: Varying doses of beta-IFN(10 to 90 x 10(6) IU) were administered IV immediately preceding RT on the first three days of weeks 1, 3, and 5. The RT dose was 1.8 Gy/day, 5 days/week for a total of 54 or 59.4 Gy. RESULTS: Thirty-nine patients were entered, 32 of whom were evaluable. The median follow-up time at time of analysis was 60 months. Responses were based on CT scan. The response rate for the total group was 81% with 44% achieving complete response. Seventy-eight percent of patients with complete response survived a minimum of 21 months. Twenty-six patients had Stage III A/B disease with a median tumor size of 6.5 cm. and median survival was 19.7 months. The 5-year actuarial survival for this group was 31%, with a plateau persisting after 3 years. There were no treatment related deaths nor any event of life threatening toxicity. Of eight patients surviving 3-5 years, no long-term toxicity has been observed. Karnofsky indices were 90-100 and respiratory symptoms were minimal. CONCLUSION: beta-IFN is well-tolerated. Response and survival rates are sufficiently encouraging to warrant further investigation in a randomized trial which has been accepted as an RTOG study awaiting drug availability.

Adult↗
PubMed1993

Influence of location and extent of surgical resection on survival of patients with glioblastoma multiforme: results of three consecutive Radiation Therapy Oncology Group (RTOG) clinical trials.

PURPOSE: The influence of tumor site, size, and extent of surgery on the survival of patients with glioblastoma multiforme treated on three consecutive prospectively randomized Radiation Therapy Oncology Group trials employing surgery and irradiation plus or minus chemotherapy was studied. METHODS AND MATERIALS: Six hundred forty-five patients with a diagnosis of glioblastoma multiforme on central pathological review were analyzed for survival with respect to known prognostic factors, that is, age and Karnofsky Performance Status, as well as extent of surgery, site, and size. Surgical treatment consisted of biopsy only in 17%, partial resection in 64%, and total resection in 19%. Tumors were located in frontal lobe in 43%, temporal lobe in 28%, and parietal lobe in 25%. Maximum tumor diameter as determined on computed tomography or magnetic resonance imaging scans was less than 5 cm for 38%, between 5-10 cm for 56% and greater than 10 cm for 6% of patients. The extent of surgical therapy was the same for tumors greater than 5 or greater than 10 cm, whereas total resection was more often performed for tumors less than 5 cm. The extent of surgery did not appear to vary with age or site. RESULTS: Patients undergoing total resection had a median survival of 11.3 months compared to 6.6 months for patients with a biopsy only. A significant difference in median survival was also found for partial resection versus biopsy only treatment (10.4 vs. 6.6 months). There was no difference in survival for the different tumor sizes. Patients with frontal lobe tumors survived longer than those with temporal or parietal lobe lesions (11.4 months, 9.1 months, and 9.6 months, respectively) (p = 0.01). A Cox multivariate model confirmed a significant correlation of age, Karnofsky Performance Status, extent of surgery, and primary site with survival. The best survival rates occurred in patients who had at least three of the following features: < 40 years of age, high Karnofsky Performance Status, frontal tumors, and total resection (17 months median). CONCLUSION: We conclude that biopsy only yields inferior survival to more extensive surgery for patients with glioblastoma multiforme treated with surgery and radiation therapy.

Adult↗