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Biomedical subjects

G Ross

Publications and source records attributed to G Ross.

At least 55 records · Page 3Linked to original sources
PubMed2000

Phase I pharmacologic study of oral topotecan and intravenous cisplatin: sequence-dependent hematologic side effects.

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m(2) either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m(2)/d x 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m(2)/d x 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m(2)/d PO x 5 preceded by cisplatin 75 mg/m(2) IV day 1 once every 3 weeks, and topotecan 2.0 mg/m(2)/d PO followed by cisplatin 75 mg/m(2) IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.

Adult↗
PubMed2000

Effects of Lipochromin and Levosinum in the modulation of radiation-induced injury to pig skin.

Pig skin was used as a model to study the effectiveness of two topically applied creams, Lipochromin and Levosinum, in modifying the development of both early and late radiation damage to pig skin. Irradiated skin sites that received daily topical application of Levosinum or Lipochromin after exposure were compared with sites on the contralateral flank of the same animal that received irradiation only. Irradiation was with graded doses of 90Sr/90Y beta-rays. Incidence of moist desquamation (acute) and ischaemic dermal necrosis (late) were used as end-points. The latency period for the development of moist desquamation and its healing time was also assessed. The latency period for the development of moist desquamation in this model ranged from 4.00-6.75 weeks. There was no significant difference between the cream treatment and control sites. Application of Levosinum shortened the healing time of moist desquamation at each dose level by 5-10 days. In three out of four dose levels used, this shortening of the healing time was statistically significant (p < 0.03). Treatment with these topical applications also reduced the incidence of late dermal necrosis and increased the ED50 values for the incidence of dermal necrosis. This increase in ED50 values was equivalent to a dose modification factor of 1.11-1.13.

Administration, Cutaneous↗
PubMed2000

Troponin I sensitivity and specificity for the diagnosis of acute myocardial infarction.

This article describes the sensitivity and specificity of troponin I when compared to creatine kinase-MB (CK-MB) and electrocardiography (ECG) for diagnosing acute myocardial infarction (AMI). Two different lower levels for defining positive results with troponin I were evaluated. A retrospective study of 153 patients who presented to the emergency department of a community hospital supplied the pool of patients for this study. Patients included in this study were those for whom a CK-MB was ordered. The majority of these patients were evaluated for chest pain or symptoms suggesting an acute cardiac event. Of the 153 patients studied, CK-MB results were positive in 91 (59%) patients; ECG revealed AMI in 72 (47%) patients. There were 103 (67%) patients who had either positive CK-MB or ECG results. Ninety (59%) patients had a troponin I level greater than 2.0 ng/mL, and 18 (12%) patients had a troponin I level between 0.6 and 2.0 ng/mL. Seven patients whose troponin I level was between 0.6 and 2.0 ng/mL had negative CK-MB and ECG results. Therefore, 11 patients with troponin I between 0.6 and 2.0 ng/mL had AMI. Five patients with positive troponin I results (> 2.0 ng/mL) had negative CK-MB and ECG results. When a troponin I level greater than 0.6 ng/mL was used as a positive value, compared to CK-MB and ECG using either time zero or time 6 hours, the sensitivity was 94% and specificity was 81%. When troponin I greater than 2.0 ng/mL was used to define a positive test, the sensitivity was 85% and specificity was 91% when compared to CK-MB and ECG.

Adult↗
PubMed2000

Phase II study of oral topotecan in advanced non-small cell lung cancer.

This study was designed to assess the activity of oral topotecan (TPT) in patients with advanced non-small cell lung cancer previously untreated with chemotherapy. Eligible patients had inoperable stage III or stage IV non-small cell lung cancer and were chemotherapy-naive. Other inclusion criteria were Eastern Cooperative Oncology Group performance status 0, 1, or 2, adequate bone marrow, and renal and hepatic function. Of 30 patients, 29 were assessable for response. Oral TPT was administered for 5 days every 21 days for up to six cycles unless disease progression or unacceptable toxicity occurred. Patients received a dose of 2.3 mg/m2/day for the first cycle. Dose modification for subsequent cycles was based on tolerability. Patients completed symptom questionnaires every 3 weeks. Pharmacokinetics were evaluated in all patients during cycle 1. Three patients had radiological responses with a reduction in tumor size of 30-40%. No patients achieved complete or partial responses to treatment. Thirteen patients had a stable disease (43.3%), and the median survival was 39.9 weeks with a 1-year survival of 33.3%. At the time of analysis, 27 patients had died. Median time to progression was 12.3 weeks. Treatment was well tolerated. A total of 125 cycles of treatment were completed. Twelve patients (40%) experienced grade III/IV neutropenia. Five patients (16.6%) had grade III/IV anemia. There were two episodes of grade III/IV thrombocytopenia. The main nonhematological toxicities consisted of grade III nausea (13%) and grade III vomiting (13%). The most frequently reported disease-related symptoms at baseline were dyspnea, cough, and fatigue. There was a subsequent improvement in patient scores of dyspnea in 17% of patients, 31% showed improvement in cough, and 32% showed improvement in fatigue. The mean area under the curve of TPT following 2.3 mg/m2 p.o. was 51.6 ng.h/ml (%SD, 25%). The area under the curve of TPT on day 1 of the first cycle was correlated with the percentage fall in leukocytes. Although oral TPT at the applied dose and schedule showed modest activity as a single agent, almost one-half of the patients had a stable disease, and median time to progression was 12.3 weeks. The overall median survival was a promising 39.9 weeks, and useful palliation of symptoms was seen.

Administration, Oral↗
PubMed1999

Absence of Brca2 causes genome instability by chromosome breakage and loss associated with centrosome amplification.

Women heterozygous for mutations in the breast-cancer susceptibility genes BRCA1 and BRCA2 have a highly elevated risk of developing breast cancer [1]. BRCA1 and BRCA2 encode large proteins with no sequence similarity to one another. Although involvement in DNA repair and transcription has been suggested, it is still not understood how loss of function of these genes leads to breast cancer [2]. Embryonic fibroblasts (MEFs) derived from mice homozygous for a hypomorphic mutation (Brca2(Tr2014)) within the 3' region of exon 11 in Brca2 [3], or a similar mutation (Brca2(Tr)) [4], proliferate poorly in culture and overexpress the tumour suppressor p53 and the cyclin-dependent kinase inhibitor p21(Waf1/Cip1). These MEFs have intact p53-dependent DNA damage G(1)-S [3] [4] and G(2)-M checkpoints [4], but are impaired in DNA double-strand break repair [3] and develop chromosome aberrations [4]. Here, we report that Brca2(Tr2014/Tr2014) MEFs frequently develop micronuclei. These abnormal DNA-containing bodies were formed through both loss of acentric chromosome fragments and by chromosome missegregation, which resulted in aneuploidy. Absence of Brca2 also led to centrosome amplification, which we found associated with the formation of micronuclei. These data suggest a potential mechanism whereby loss of BRCA2 may, within subclones, drive the loss of cell-cycle regulation genes, enabling proliferation and tumourigenesis.

Aneuploidy↗
PubMed1999

How valid is the assumption of equal effect per fraction?

BACKGROUND AND PURPOSE: The validity of the assumption of equal biological effect with dose per fraction in fractionated radiotherapy has been examined for the acute skin reaction in a rat foot model using a variable number of 2-Gy daily fractions followed by graded top-up doses. MATERIAL AND METHODS: Mature female rats were used. Both hind feet of each rat were irradiated with a range of fractionated and top-up doses of 60Co gamma-rays. The dose-related incidence of moist desquamation was used as an end-point. Quantal data for the incidence of moist desquamation were analysed using probit analysis and ED50 (+/-SE) values were obtained. The results were also compared with predicted values obtained from the application LQ-model. RESULTS: After a single 2-Gy fraction followed by top-up doses 24 h later, the dose effect curve for the top-up doses used was shifted to lower doses as expected and the ED50 for moist desquamation of 19.78 +/- 0.13 Gy was 1.16 Gy less than the ED50 of 20.94 +/- 0.15 Gy for large single dose exposure alone. This implied that only approximately 58% of the initial 2-Gy fraction was effective, and the rest was repaired within a 24-h interval between the 2 Gy and top-up doses. However, after two or three 2-Gy daily fractions the dose effect curves for the subsequent top-up doses moved to the higher doses again and the ED50 for top-up dose increased to 20.33 +/- 0.21 and 20.75 +/- 0.11 Gy, respectively. A further increase in the number of 2-Gy daily fractions shifted the dose effect curves for the top-up doses to lower doses and ED50 values for the top-up doses decreased progressively. CONCLUSIONS: The findings were not in keeping with values predicted based on the assumption of equal effect per fraction and could not be explained by the use of a single alpha/beta ratio in the LQ-model.

Animals↗
PubMed1999

Inhibition of phagosome-lysosome fusion in ovine polymorphonuclear leucocytes by Ehrlichia (Cytoecetes) phagocytophila.

Ehrlichia (Cytoecetes) phagocytophila, the causative agent of tick-borne fever, is an intracellular bacterium that survives and multiplies within granulocytes and monocytes. In the present study, the possible fusion of lysosomes with phagosomes containing E. phagocytophila was investigated in poly-morphonuclear (PMN) cells of sheep infected with the agent, acid phosphatase cytochemistry and cationized ferritin being used as markers of primary and secondary lysosomal enzymes. Latex beads or Candida albicans were incubated with infected and uninfected PMN cells and labelled with the same lysosomal markers. Lysosomal enzymes labelled with the markers were commonly found in phagosomes containing latex beads or C. albicans, but there was no evidence of phagosome-lysosome (P-L) fusion in phagosomes containing E. phagocytophila. It was significant that in cells that contained E. phagocytophila, latex beads and C. albicans, P-L fusion occurred only in phagosomes containing latex beads or C. albicans. However, evidence of P-L fusion with phagosomes containing E. phagocytophila was obtained when PMN cells were incubated with oxytetracycline, which is known to inhibit synthesis of bacterial proteins. These findings indicate that E. phagocytophila is capable of inhibiting P-L fusion and that oxytetracycline depresses this capability.

Acid Phosphatase↗
PubMed1999

Antibody and cellular immune responses of swine following immunisation with plasmid DNA encoding the PRRS virus ORF's 4, 5, 6 and 7.

The objectives of this study was to investigate the role of DNA vaccines in the generation of an immune response and that elicited against individually encoded proteins of PRRSV. The genomic regions encoding ORF s 4, 5, 6 and 7 of the PRRS virus vaccine strain were cloned into the mammalian expression vector pc DNA 3.1 (+). Inoculations with the recombinant plasmids resulted in detection of PRRS virus-specific antibodies in 71 per cent of the immunized animals by ELISA, virus neutralization and/or Western blotting assays. In addition, cellular immune responses were detected in 86 per cent of the immunized pigs by interferon gamma assay and/or proliferation assay. Pigs in the control group had no detectable immune response to PRRS virus. The results obtained demonstrated that DNA immunization against PRRS virus results in the production of both humoral and cell mediated immune responses in pigs. The results also indicate that neutralization epitopes for PRRS virus are present on the viral envelope glycoproteins encoded by ORF 4 and ORF 5.

Animals↗
PubMed1999

Performance of an enzyme-linked immunosorbent assay for the diagnosis of Brucella ovis infection in rams.

AIM: To describe the performance characteristics (sensitivity and specificity) of an enzyme-linked immunosorbent assay (ELISA) for the diagnosis of Brucella ovis infection in rams. METHODS: Sera from a negative (n = 2535) and a positive (n = 589) reference population were tested in an ELISA for anti-B. ovis antibodies and cut-off values calculated from the raw, log10-transformed and fitted data. Statistical methods were used to fit curves to the frequency distribution of the data and receiver-operated characteristics analysis used to optimise the cut-off values. RESULTS: Analysis of the frequency distribution of the positive ELISA values suggested a normal distribution of the data, whereas, in the case of the negative population, a Pearson type IV curve appeared to best fit the data. The cut-off values calculated as the mean plus 1.96 standard deviations (s.d.) from the raw, log-transformed and fitted ELISA data did not differ markedly. The differences were much greater at the mean plus 3.09 s.d. cut-off, with the cut-off value calculated from the log-transformed data giving a much better estimate of specificity. Optimisation (minimisation of classification error) of the cut-off calculated from the fitted curves suggested varying cut-off values, depending on the prevalence of B. ovis infection. DISCUSSION: Calculation of cut-off values from curves that were fitted from the observed data give more accurate estimations of the performance characteristics of an assay than traditional calculations from observed values. They also allow the calculation of optimal cut-off values taking into account the prevalence of B. ovis infection and give additional information about the performance of the assay at cut-off values varied according to the epidemiological situation.

Journal Article↗
PubMed1999

Harmful effects of UVA on the structure and barrier function of engineered human cutaneous tissues.

PURPOSE: To investigate the effects of a single UVA exposure on engineered human cutaneous tissues. MATERIALS AND METHODS: Skin equivalents (SE) were obtained by culturing keratinocytes on fibroblast-populated collagen gels; epidermal equivalents (EE) were obtained by seeding keratinocytes on non-populated collagen gels. After maturation and differentiation of the epidermis, SE and EE were exposed to 50 or 100 J/cm2 UVA. Structural damage and total epidermal lipids were analysed and diffusion of radioactive oestradiol was monitored 24 and 72h post-irradiation. RESULTS: Twenty-four hours after UVA irradiation, a disorganization of the living epidermis is observed. UVA also significantly reduced the skin barrier function and led to an increase in phospholipid and in a decrease of ceramide levels. However, both the structure and the barrier function of SE were recovered 72 h post-irradiation, thereby suggesting that an intrinsic repair process might exist within the irradiated SE. CONCLUSION: This study provides a strong evidence that UVA radiation alters both the epidermal and dermal structures, the synthesis of epidermal lipids, and the permeability of the human skin.

Cells, Cultured↗
PubMed1999

Two consecutive outbreaks of Stenotrophomonas maltophilia (Xanthomonas maltophilia) in an intensive-care unit defined by restriction fragment-length polymorphism typing.

OBJECTIVE: To investigate and control consecutive outbreaks of Stenotrophomonas maltophilia infections in intensive-care-unit (ICU) patients. DESIGN: Epidemiological investigation; restriction fragment-length polymorphism typing by pulsed-field gel electrophoresis (PFGE) of genomic DNA of outbreak strains; institution of infection control measures to limit spread. SETTING: The medical-surgical ICU in an 800-bed tertiary-care center in Calgary, Alberta, Canada. RESULTS: S. maltophilia was recovered from 14 ICU patients (12 infected, 2 colonized) between February 1993 and February 1994. Ten of the 14 patient isolates and 1 environmental isolate were available for PFGE typing. Patient isolates from 6 of the first 10 patients were identical. Isolates from the next 3 of 4 patients and an isolate recovered from a ventilator being used by a patient not infected with S. maltophilia also were identical, but different from the first 6. The ventilator isolate was temporally associated with the latter 4 patients. CONCLUSION: Molecular typing allowed us to determine that there were two separate consecutive S maltophilia outbreaks rather than a single protracted outbreak. Recovery of S. maltophilia from patient ventilators and an in-line suction catheter suggests that the organism may have been spread by cross-contamination from contaminated equipment or from an environmental source.

Aged↗
PubMed1999

Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer.

PURPOSE: Topotecan and cyclophosphamide, doxorubicin, and vincristine (CAV) were evaluated in a randomized, multicenter study of patients with small-cell lung cancer (SCLC) who had relapsed at least 60 days after completion of first-line therapy. PATIENTS AND METHODS: Patients received either topotecan (1.5 mg/m2) as a 30-minute infusion daily for 5 days every 21 days (n = 107) or CAV (cyclophosphamide 1,000 mg/m2, doxorubicin 45 mg/m2, and vincristine 2 mg) infused on day 1 every 21 days (n = 104). Eligibility included the following: bidimensionally measurable disease, Eastern Cooperative Oncology Group performance status of less than or equal to 2, and adequate marrow, liver, and renal function. Response was confirmed by blinded independent radiologic review. RESULTS: Response rate was 26 of 107 patients (24.3%) treated with topotecan and 19 of 104 patients (18.3%) treated with CAV (P = .285). Median times to progression were 13.3 weeks (topotecan) and 12.3 weeks (CAV) (P = .552). Median survival was 25.0 weeks for topotecan and 24.7 weeks for CAV (P = .795). The proportion of patients who experienced symptom improvement was greater in the topotecan group than in the CAV group for four of eight symptoms evaluated, including dyspnea, anorexia, hoarseness, and fatigue, as well as interference with daily activity (P< or =.043). Grade 4 neutropenia occurred in 37.8% of topotecan courses versus 51.4% of CAV courses (P<.001). Grade 4 thrombocytopenia and grade 3/4 anemia occurred more frequently with topotecan, occurring in 9.8% and 17.7% of topotecan courses versus 1.4% and 7.2% of CAV courses, respectively (P<.001 for both). Nonhematologic toxicities were generally grade 1 to 2 for both regimens. CONCLUSION: Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms.

Antineoplastic Agents↗
PubMed1999

Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients.

To assess the value of disease stabilization (SD) as a predictor of survival following chemotherapy, data were analyzed from multicenter clinical trials in small cell lung cancer (SCLC) and ovarian cancer (OC) patients receiving various second-line chemotherapy regimens. In both patient populations, SD (lasting >8 weeks) and partial responses (PR) were associated with a survival benefit versus progressive disease (PD); interestingly, the survival benefit was similar between the two groups (PR and SD). These results suggest that, at least in these populations, SD may represent a potential benefit of chemotherapy and therefore the distinction between SD and PR may not be useful.

Adult↗
PubMed1999

Caries diagnosis with the DIAGNOdent laser: a user's product evaluation.

In the study, the DIAGNOdent has shown itself to be very accurate in the diagnosis of pit and fissure lesions. In the clinical situation, it showed a 92.1 per cent accuracy in diagnosing lesions, as well as their severity. In addition, when the unit showed a reading of less than 30, it was 100 per cent accurate in the virgin teeth. When the unit indicated that there was no caries in extracted teeth, it was accurate 98.1 per cent of the time. Now, for the first time, dentists can do research as to the speed of progression of caries, as well as what percentage of caries becomes arrested and what percentage deteriorate.

Dental Caries↗
PubMed1999

Rupture of the peroneus longus tendon in a military athlete.

A 38-year-old active-duty Marine Corps officer with a history of ankle instability presented to the orthopedic clinic complaining of left lateral ankle and leg pain. A diagnosis of rupture of the tendon of the peroneus longus was made. This is an unusual diagnosis in an active Marine Corps officer. Surgical treatment markedly improved his symptoms.

Adult↗