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Biomedical subjects

Per Rosenberg

Publications and source records attributed to Per Rosenberg.

9 recordsLinked to original sources
PubMed2006

mdr-1 single nucleotide polymorphisms in ovarian cancer tissue: G2677T/A correlates with response to paclitaxel chemotherapy.

PURPOSE: P-glycoprotein, encoded by the mdr-1 gene, confers multidrug resistance to a variety of antineoplastic agents, e.g., paclitaxel. Recently, different polymorphisms in the mdr-1 gene have been identified and their consequences for the function of P-glycoprotein, as well as for the treatment response to P-glycoprotein substrates, are being clarified. We analyzed the allelic frequencies at polymorphic sites G2677T/A and C3435T in ovarian cancer patients with good or poor response to treatment with paclitaxel in combination with carboplatin in order to evaluate their predictive values. EXPERIMENTAL DESIGN: Fifty-three patients were included in the study; 28 of them had been relapse-free for at least 1 year and 25 had progressive disease or relapsed within 12 months. A reference material consisting of 200 individuals was also analyzed. The genotypes of each single nucleotide polymorphism (SNP) were determined using Pyrosequencing. RESULTS: The G2677T/A SNP was found to significantly correlate with treatment outcome. The probability of responding to paclitaxel treatment was higher in homozygously mutated patients (T/T or T/A; Fisher's exact test; P < 0.05). The frequency of the T or A alleles was also higher in the group of patients who had a good response (P < 0.05). There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment (chi2 test for linear-by-linear association; P = 0.03). However, the C3435T SNP was not found to correlate to treatment outcome. CONCLUSIONS: The mdr-1 polymorphism G2677T/A in exon 21 correlates with the paclitaxel response in ovarian cancer and may be important for the function of P-glycoprotein and resistance to paclitaxel and provide useful information for individualized therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2006

The in vivo contributions of TASK-1-containing channels to the actions of inhalation anesthetics, the alpha(2) adrenergic sedative dexmedetomidine, and cannabinoid agonists.

Inhalation anesthetics activate and cannabinoid agonists inhibit TWIK-related acid-sensitive K(+) channels (TASK)-1 two-pore domain leak K(+) channels in vitro. Many neuromodulators, such as noradrenaline, might also manifest some of their actions by modifying TASK channel activity. Here, we have characterized the basal behavioral phenotype of TASK-1 knockout mice and tested their sensitivity to the inhalation anesthetics halothane and isoflurane, the alpha(2) adrenoreceptor agonist dexmedetomidine, and the cannabinoid agonist WIN55212-2 mesylate [R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3,-de]-1,4-benzoxazinyl]-(1-naphtalenyl)methanone mesylate)]. TASK-1 knockout mice had a largely normal behavioral phenotype. Male, but not female, knockout mice displayed an enhanced acoustic startle response. The knockout mice showed increased sensitivity to thermal nociception in a hot-plate test but not in a tail-flick test. The analgesic, sedative, and hypothermic effects of WIN55212-2 (2-6 mg/kg s.c.) were reduced in TASK-1 knockout mice. These results implicate TASK-1-containing channels in supraspinal pain pathways, in particular those modulated by endogenous cannabinoids. TASK-1 knockout mice were less sensitive to the anesthetic effects of halothane and isoflurane than wild-type littermates, requiring higher anesthetic concentrations to induce immobility as reflected by loss of the tail-withdrawal reflex. Our results support the idea that the activation of multiple background K(+) channels is crucial for the high potency of inhalation anesthetics. Furthermore, TASK-1 knockout mice were less sensitive to the sedative effects of dexmedetomidine (0.03 mg/kg s.c.), suggesting a role for the TASK-1 channels in the modulation of function of the adrenergic locus coeruleus nuclei and/or other neuronal systems.

Adrenergic alpha-2 Receptor Agonists↗
PubMed2005

beta-Tubulin mutations in ovarian cancer using single strand conformation analysis-risk of false positive results from paraffin embedded tissues.

Mutations in the beta-tubulin gene have been proposed as a resistance mechanism to paclitaxel. We therefore investigated the presence of mutations in the beta-tubulin M40 gene in 40 ovarian tumours (16 paraffin-embedded and 24 freshly frozen) selected for good or poor response to chemotherapy with paclitaxel or non-tubulin-affecting regimens. The presence of mutations was investigated using single strand conformation analysis followed by sequencing of the products with altered mobility. No sequence variants in the exons of the beta-tubulin M40 gene were detected. Non-reproducible shifts were identified, in eight out of 16 paraffin embedded samples. This may explain some of the previously published discrepancies. In conclusion, sequence variants in the beta-tubulin M40 gene are rare and are unlikely to be a clinically relevant explanation of resistance to paclitaxel.

Antineoplastic Agents, Phytogenic↗
PubMed2005

Spatial variability in the mineralisation of the phenylurea herbicide linuron within a Danish agricultural field: multivariate correlation to simple soil parameters.

The spatial variability in the mineralisation rate of linuron [N-(3,4-dichlorophenyl)-N'-methoxy-N'-methylurea] was studied within a previously treated Danish agricultural field by sampling soils from eleven different plots randomly distributed across an area of 20 x 20 m. The soils were characterised with respect to different abiotic and biotic properties including moisture content, organic matter content, pH, nutrient content, bacterial biomass, potential for mineralisation of MCPA [(4-chloro-2-methylphenoxy)acetic acid] and linuron. Five soils had a potential for mineralisation of linuron, with 5-15% of the added [ring-U-14C]linuron metabolised to 14CO2 within 60 days at 10 degrees C, while no extensive mineralisation of linuron was observed in the six remaining soils within this period. A TLC analysis of the methanol-extractable residues showed no development of 14C-labelled metabolites from linuron in any of the samples. Multivariate analysis was conducted to elucidate relationships between the intrinsic properties of single soil samples and initial rate of linuron mineralisation. The analysis indicated that important soil parameters in determining the spatial heterogeneity included the C(total)/N(total) ratio, pH and the water-extractable potassium contents, with the first of these highly negatively correlated and the last two highly positively correlated to the initial linuron mineralisation rate. This study shows that enhanced biodegradation of linuron may develop with successive field treatments, but that considerable in-field spatial heterogeneity in the degradation rate still exists. Combined with a parallel enrichment study focused on the underlying microbial processes, the present results suggest that intrinsic soil properties affect the linuron-metabolising bacterial population and thereby determine the spatial variability in the linuron mineralisation activity.

Biodegradation, Environmental↗
PubMed2004

Adherence to guidelines when positioning the defibrillation electrodes.

BACKGROUND: Placement of the defibrillation electrodes affects the transmyocardial current and thus the success of a defibrillation attempt. In the international guidelines 2000, the placement of the apical electrode was changed more laterally to the mid-axillary line. Finnish national guidelines, based on the international guidelines, were published in 2002. OBJECTIVES: The purpose of this study was to determine to what extent health care professionals adhere to the new guidelines when positioning the electrodes. METHODS: Professionals were recruited from emergency medical services, university hospitals and primary care. Not revealing the purpose of the test, participants were asked to place self-adhesive electrodes on a manikin as they would do in the resuscitation situation and to answer a questionnaire about resuscitation training and familiarity with the guidelines. The distance of electrodes from the recommended position was measured in horizontal and vertical planes. RESULTS: One-hundred and thirty six professionals participated in the study, and only 25.4% (95% CI 18.5-32.9) of them placed both electrodes within 5 cm from the recommended position. The majority of the participants placed the apical electrode too anteriorly. Of the participants, 36.0% were not aware of the new guidelines. Awareness of the guidelines did not increase the accuracy in electrode placement. CONCLUSIONS: The publication of the national evidence based resuscitation guidelines did not seem to have influenced the practice of placement of the defibrillation electrodes to any major extent. The correct placement of the electrodes needs be emphasized more in the resuscitation training.

Attitude of Health Personnel↗
PubMed2002

Role of weekly paclitaxel in the treatment of advanced ovarian cancer.

Dose-dense weekly administration of paclitaxel has the potential advantage of allowing a larger percentage of cancer cells to enter the vulnerable phase of their cell cycle when cytotoxic paclitaxel concentrations are present. The lower doses and shorter infusion times used with weekly dosing should also minimize bone marrow suppression and other toxicities associated with standard paclitaxel 3-weekly administration. Clinical studies have confirmed that paclitaxel can be safely delivered on a weekly schedule as a 1-h infusion to patients with advanced ovarian cancer. Weekly administration of paclitaxel also appears to be better tolerated than 3-weekly administration. Single-agent weekly paclitaxel is associated with response rates of 20-65%. Combination therapy with weekly paclitaxel has mainly involved carboplatin and response rates with such regimens range from 60-88%. Triple-drug combination therapy has produced response rates of 42-67.5%. Such therapy has included weekly paclitaxel in combination with carboplatin/cisplatin plus topotecan, and carboplatin plus doxorubicin. In an attempt to avoid problems with high corticosteroid doses, dexamethasone doses of 10 and 8 mg have been used successfully in premedication regimens for weekly paclitaxel in ovarian cancer.

Adenocarcinoma↗
PubMed2002

Characteristics of discrepancies between clinical and autopsy diagnoses in the intensive care unit: a 5-year review.

OBJECTIVES: To characterise discrepancies between clinical and autopsy diagnoses in patients who die in the intensive care unit. DESIGN: Retrospective chart review. SETTING: Ten-bed closed mixed adult intensive care unit in a tertiary referral teaching hospital. PARTICIPANTS: All the clinical notes and autopsy reports of 346 patients who died in the intensive care unit in 1996-2000. INTERVENTIONS: Discrepancies between clinical and autopsy diagnoses were reviewed by two intensivists, a specialist in infectious diseases, a pathologist and an anaesthesiologist. New findings which would have changed current therapy in the intensive care unit were categorised as a Class I discrepancy, and those related to death but which would not have altered therapy as a Class II discrepancy. RESULTS: Of 2370 patients admitted, 388 (16.4%) died. An autopsy was performed in 346 (89%) of the deceased patients. A Class I discrepancy was found in 8 patients (2.3%) and a Class II discrepancy in 11 patients (3.2%). Five of the eight (62%) Class I discrepancies were infections which occurred in patients already treated for another infections. CONCLUSION: Despite the availability of advanced diagnostic facilities, especially infectious complications seem to remain undiagnosed. Autopsy is a valuable tool with which to monitor diagnostic accuracy in these patients.

Aged↗
PubMed2002

Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum.

The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B). and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m2/week in the weekly arm, and 72.7 mg/m2/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m2/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids.

Administration, Oral↗