Evaluation of Viability of Excised Rat Intestinal Segments in the Ussing Chamber: Investigation of Morphology,Electrical Parameters,and Permeability Characteristics

Purpose. To clarify relations between alterations in electrical and permeability data with time and to elaborate accompanying structural changes of intestinal segments in Ussing chamber experiments. Methods. Excised intestinal segments from the rat were studied in a modified Ussing chamber. Experiments were run up to 180 minutes during which the electrical parameters, PD, SCC, and R, were measured and the permeability coefficients (P_app) of mannitol and propranolol were determined. Each segment was observed under the light microscope for morphological evaluation. Results. PD and SCC values showed a decrease for most segments while the R values remained steady throughout the experiment. The P_app for propranolol increased aborally to the small intestine. For mannitol, the reversed was observed. In some cases, there was a time-dependent change in permeability for these marker molecules. The main morphological changes observed were a decreased nucleo-apical distance, decreased villi amplification factor, initial edema, cell sloughing, and epithelial restitution. Conclusions. The time-dependent changes in permeability coefficients of mannitol and propranolol are suggested to be related to changes in electrical parameters and morphological alterations. Presented data illustrates the importance of information regarding time-dependent structural changes for correct interpretation of permeability data.     

Expression of GADD153 in tumor cells and stromal cells from xenografted tumors in nude mice treated with cisplatin: correlations with cisplatin-DNA adducts

Purpose: Cisplatin is a commonly used antineoplastic agent that acts by forming adducts with DNA, and causing a response to the cellular injury. One of the components of this cellular injury response is the activation of the “growth arrest and DNA damage gene”GADD153. The level of GADD153 induction in tumor cells has been associated with the degree of cytotoxicity. The pupose of this study was to determine whether cisplatin activates GADD153 also in nontumor cells and how GADD153 protein levels correlate with cisplatin-DNA adducts in different cell types. Methods: Nude mice with xenografted squamous cell carcinoma were treated with cisplatin 10 mg/kg. Tumors were removed at 0 h (untreated controls), 24 h, and 48 h and immunohistochemically stained for GADD153 protein and cisplatin-DNA adducts. The staining reaction was quantitated in tumor cells and nonmalignant stromal cells separately, using computerized image analysis. Results: The GADD153 level was 4.5 times higher in tumor cells than in stromal cells in untreated mice. At 24 h after cisplatin treatment the GADD153 level had increased by 50% and 72% in tumor cells and stromal cells, respectively. Analysis of the cisplatin-DNA adducts showed a reversed pattern, with six-fold higher levels in stromal cells than in tumor cells at 24 h after treatment. By combining these data, we estimated that approximately 25-fold more GADD153 per cisplatin-DNA adduct was induced in tumor cells than in stromal cells. Conclusion: Our data suggest that different cell types may respond differently to DNA damage caused by cisplatin. Received: 5 March 1998 / Accepted: 21 July 1998     

Use of oral contraceptives and endometrial cancer risk (Sweden)

Objectives: To estimate the magnitude and persistence of the protective effect of use of combined oral contraceptives (COCs) and endometrial cancer risk.Methods: We performed a nation-wide, population-based case–control study among postmenopausal women aged 50–74 years in Sweden, which included 709 subjects with incident, histopathologically verified endometrial cancer, and 3,368 controls with an intact uterus. We used unconditional logistic regression to calculate odds ratios as estimates of relative risks.Results: Use of any sort of oral contraceptive decreased risk for endometrial cancer by 30%, while progestin-only pills reduced risk more markedly. For COCs the reduction in risk was noticeable following 3 or more years of use (OR 0.5, 95% CI 0.3–0.7), and increased with duration of intake, reaching 80% lower risk after 10 years of use. The protective effect of COC use was similar for all degrees of tumor differentiation and invasiveness, and remained for at least 20 years after cessation of use. Subsequent use of hormone replacement did not modify these protective effects.Conclusions: We conclude that COC use confers a long-lasting protection against endometrial cancer risk which is particularly marked for long-term users.(institution where the work has been performed)     

CYP2D6 is involved in O-demethylation of diltiazem

OBJECTIVE: In a previous study of diltiazem (DTZ) pharmacokinetics in renal transplant patients, we speculated that a polymorphic enzyme could be involved in O-demethylation of diltiazem. The aim of this in vitro study was to investigate whether O-demethylation of DTZ is mediated by cytochrome P450-2D6 (CYP2D6). METHODS: DTZ was incubated with transfected human liver epithelial (THLE) cells expressing CYP2D6 (T5-2D6 clone). Metabolism of DTZ was studied over a concentration range of 12.5-400 microM and in the presence of quinidine (a CYP2D6 inhibitor) or erythromycin (a CYP3A4 inhibitor). THLE cells lacking CYP2D6 activity (T5-neo clone) were used as control. The culture medium of the cells, in which DTZ was dissolved, was analysed for DTZ and metabolites prior to and after 8 h of incubation using high-performance liquid chromatography (HPLC, UV detection). Authentic O-demethyl-DTZ (Mx) was not available, and this metabolite was therefore not identifiable. RESULTS: Desacetyl-O-demethyl-DTZ (M4) was exclusively produced during incubations of DTZ with THLE cells expressing CYP2D6. The rate of M4 formation was described using Michaelis Menten kinetics in the concentration range of DTZ used. Production of M4 was inhibited by quinidine, but not erythromycin. An unidentified chromatographic peak, which was interpreted to be Mx, showed the same pattern of formation as M4 both in absence and presence of inhibitors. N-demethylated metabolites, formed by CYP3A4, were not observed in any of the cell lines. CONCLUSION: Evidence was provided in vitro that O-demethylation of DTZ is mediated by the polymorphic isoenzyme CYP2D6. Involvement of CYP2D6 in the metabolism of DTZ may have clinical implications regarding pharmacokinetic variability and interactions.     

General practitioners' reactions to non-compliant patients

Objective - To examine how general practitioners (GPs) respond to patients who are non-compliant with medical advice and who doctors believe act irresponsibly towards their health. Design - Quantitative analysis of responses to questionnaire with case histories. Setting and subjects - 93 questionnaires completed by a random stratified sample of Norwegian GPs. Main outcome measures - Scores relating to GPs' feelings and choice of main and sub-strategies for further treatment of patients. Results - The respondents typically felt discouraged or unaffected by non-compliant patients, younger doctors more often felt helpless while older ones were more content, and female doctors more often than male doctors felt irritated or angry. The main strategy preferred was to give the patient a new appointment. The young, the inexperienced, and females tended more often to ask a colleague for advice or refer to a specialist. Patient-centred sub-strategies were generally preferred, especially by younger doctors. Conclusion - GPs' feelings towards and strategies for dealing with non-compliant patients vary, and the doctor's age, sex and clinical experience are central variables.     

Performance of a capnodynamic method estimating effective pulmonary blood flow during transient and sustained hypercapnia

The capnodynamic method is a minimally invasive method continuously calculating effective pulmonary blood flow (CO_EPBF), equivalent to cardiac output when intra pulmonary shunt flow is low. The capnodynamic equation joined with a ventilator pattern containing cyclic reoccurring expiratory holds, provides breath to breath hemodynamic monitoring in the anesthetized patient. Its performance however, might be affected by changes in the mixed venous content of carbon dioxide (C_vCO₂). The aim of the current study was to evaluate CO_EPBF during rapid measurable changes in mixed venous carbon dioxide partial pressure (P_vCO₂) following ischemia–reperfusion and during sustained hypercapnia in a porcine model. Sixteen pigs were submitted to either ischemia–reperfusion (n?=?8) after the release of an aortic balloon inflated during 30 min or to prolonged hypercapnia (n?=?8) induced by adding an instrumental dead space. Reference cardiac output (CO) was measured by an ultrasonic flow probe placed around the pulmonary artery trunk (CO_TS). Hemodynamic measurements were obtained at baseline, end of ischemia and during the first 5 min of reperfusion as well as during prolonged hypercapnia at high and low CO states. Ischemia–reperfusion resulted in large changes in P_vCO₂, hemodynamics and lactate. Bias (limits of agreement) was 0.7 (?0.4 to 1.8) L/min with a mean error of 28% at baseline. CO_EPBF was impaired during reperfusion but agreement was restored within 5 min. During prolonged hypercapnia, agreement remained good during changes in CO. The mean polar angle was ?4.19° (?8.8° to 0.42°). Capnodynamic CO_EPBF is affected but recovers rapidly after transient large changes in P_vCO₂ and preserves good agreement and trending ability during states of prolonged hypercapnia at different levels of CO.     

Disease activity level, remission and response in established rheumatoid arthritis: Performance of various criteria sets in an observational cohort, treated with anti-TNF agents

Background  

Most composite indices of disease activity and response criteria in RA have been validated and compared in clinical trials rather than routine care. We therefore wanted to compare the performance of the DAS28, SDAI and CDAI activity indices, their activity states, their response criteria, and also compare with the ACR response criteria in an observational clinical setting.     

Changing clinical presentation of angiosarcomas after breast cancer: from late tumors in edematous arms to earlier tumors on the thoracic wall

Angiosarcoma is a rare complication of breast cancer treatment. In order to define predictors, clinical presentation, and outcome, we characterized a population-based 50-year cohort of angiosarcomas after breast cancer. Clinical data were collected from all females with previous breast cancer who developed angiosarcomas/lymphangiosarcomas on the thoracic wall/upper extremity between 1958 and 2008 in the Southern Swedish health care region. In total, 31 angiosarcomas developed at a median age of 71 years. The patients formed two distinct groups; 14 females treated for breast cancer with radical mastectomy and radiotherapy 1949–1988 developed angiosarcomas in edematous arms (Stewart–Treves syndrome) after median 11 years, and 17 females treated by segmental resection, anti-hormonal treatment and radiotherapy 1980–2005 developed angiosarcomas in the irradiated field on the thoracic wall after median 7.3 years. The clinical presentations were heterogeneous and included hematoma-like lesions, multiple bluish-reddish nodules, and asymptomatic lumps. The overall 5-year survival was 16%. In this population-based cohort, the early angiosarcomas developed in edematous arms after radical mastectomies, whereas more recent cases occurred after a shorter time period in the irradiated fields following breast conserving surgery. We conclude that the clinical presentation of angiosarcomas has changed, parallel with altered treatment principles for breast cancer.     

What is the role of clinical tests and ultrasound in acetabular labral tear diagnostics?

Background and purpose An acetabular labral tear is a diagnostic challenge. Various clinical tests have been described, but little is known about their diagnostic sensitivity and specificity. We investigated the diagnostic validity of clinical tests and ultra-sound as compared with MR arthrography.Patients and methods We examined 18 patients (18 hips, 2 men, median age 43 (32–56) years) with impingement test, FABER test, resisted straight leg raise test, ultrasound, and MR arthrography. They had had previous periacetabular osteotomies due to symptomatic, acetabular dysplasia. All hips showed no or only slight signs of osteoarthritis (Tönnis grade 0–1).Results MR arthrography identified labral tears in 17 of the 18 hips. Ultrasound had a sensitivity of 94%, a positive predictive value of 94%, and was false negative in only 1 case compared to MR arthrography. The impingement test had the best diagnostic ability of the clinical tests, with a sensitivity of 59% and a specificity of 100%. The positive predictive value was 100% while the negative predictive value was 13%.Interpretation The impingement test is helpful in identifying acetabular labral tears. If this test is negative and if a labral tear is still suspected, ultrasound can reliably diagnose most tears of the acetabular labrum. MR arthrography is indicated in cases where ultrasound is negative, but the patient suffers continued, specific symptoms.