Balancing: a basic process in end-of-life cancer care

In this grounded theory study, the authors interviewed caregivers and patients in end-of-life cancer care and found Balancing to be a fundamental process explaining the problem-solving strategies of most participants and offering a comprehensive perspective on both health care in general and end-of-life cancer care in particular. Balancing stages were Weighing--sensing needs and wishes signaled by patients, gauging them against caregiver resources in diagnosing and care planning; Shifting--breaking bad news, changing care places, and treatments; and Compensating--controlling symptoms, educating and team-working, prioritizing and "stretching" time, innovating care methods, improvising, and maintaining the homeostasis of hope. The Balancing outcome is characterized by Compromising, or "Walking a fine line," at best an optimized situation, at worst a deceit.     

Dengue fever in travelers to the tropics, 1998 and 1999

Dengue fever (DF) has become common in western travelers to the tropics. To improve the basis for travel advice, risk factors and dengue manifestations were assessed in 107 Swedish patients for whom DF was diagnosed after return from travel in 1998 and 1999. Patient data were compared with data on a sample of all Swedish travelers to dengue-endemic countries in the same years. Only three of the patients had received pretravel advice concerning DF from their physicians. Hemorrhagic manifestations were common (21 of 74 patients) but caused no deaths. Risk factors for a DF diagnosis were travel to the Malay Peninsula (odds ratio [OR] 4.95; confidence interval [CI] 2.92 to 8.46), age 15-29 years (OR 3.03; CI 1.87 to 4.92), and travel duration >25 days (OR 8.75; CI 4.79 to 16.06). Pretravel advice should be given to all travelers to DF-endemic areas, but young persons traveling to southern and Southeast Asia for >3 weeks (who constituted 31% of the patients in our study) may be more likely to benefit by adhering to it.     

Polycationic peptides as inhibitors of mast cell serine proteases

When mast cells are activated, e.g. during allergic responses, they secrete the serine proteases chymase and tryptase, which both are complex-bound to heparin proteoglycan in vivo. Previous reports have demonstrated potent pro-inflammatory effects of both tryptase and chymase in different animal models, suggesting that these serine proteases may be relevant targets for therapeutic intervention. Recent investigations have shown that heparin-binding compounds can cause tryptase inhibition and it has been suggested that the inhibitory activity of such compounds is due to interference with the binding of heparin to tryptase. Here we tested various polycationic peptides for their ability to inhibit heparin-free human recombinant betaI-tryptase. We demonstrate powerful direct inhibition of tryptase (IC(50) values approximately 1-100 nM) by poly-Arg and poly-Lys of different molecular weights. Poly-Arg and poly-Lys showed predominantly competitive inhibition kinetics, although decreases in the k(cat) values for the chromogenic substrate S-2288 were also observed. Peptides built up from heparin-binding motifs were also inhibitors of tryptase, albeit of lower efficiency than poly-Arg/Lys. Tryptase inhibition was strongly dependent on the size of the polycationic peptides. The various polycationic peptides were also inhibitory for heparin-dependent activities of chymase. The tryptase inhibition caused by the polycationic peptides could be reversed by adding heparin. After heparin-induced rescue of tryptase activity, the major part of the tryptase activity was sensitive to inhibition by bovine pancreatic trypsin inhibitor, whereas tryptase before addition of polycationic peptide was completely resistant. Taken together, our findings indicate that polycationic peptides can be used as powerful agents for combined inhibition of mast cell tryptase and chymase.     

Identification of human cytochrome P(450)s that metabolise anti-parasitic drugs and predictions of in vivo drug hepatic clearance from in vitro data

Objective Knowledge about the metabolism of anti-parasitic drugs (APDs) will be helpful in ongoing efforts to optimise dosage recommendations in clinical practise. This study was performed to further identify the cytochrome P₄₅₀ (CYP) enzymes that metabolise major APDs and evaluate the possibility of predicting in vivo drug clearances from in vitro data.Methods In vitro systems, rat and human liver microsomes (RLM, HLM) and recombinant cytochrome P₄₅₀ (rCYP), were used to determine the intrinsic clearance (CL_int) and identify responsible CYPs and their relative contribution in the metabolism of 15 commonly used APDs.Results and discussion CL_int determined in RLM and HLM showed low (r²=0.50) but significant (P<0.01) correlation. The CL_int values were scaled to predict in vivo hepatic clearance (CL_H) using the 'venous equilibrium model'. The number of compounds with in vivo human CL data after intravenous administration was low (n=8), and the range of CL values covered by these compounds was not appropriate for a reasonable quantitative in vitro–in vivo correlation analysis. Using the CL_H predicted from the in vitro data, the compounds could be classified into three different categories: high-clearance drugs (>70% liver blood flow; amodiaquine, praziquantel, albendazole, thiabendazole), low-clearance drugs (<30% liver blood flow; chloroquine, dapsone, diethylcarbamazine, pentamidine, primaquine, pyrantel, pyrimethamine, tinidazole) and intermediate clearance drugs (artemisinin, artesunate, quinine). With the exception of artemisinin, which is a high clearance drug in vivo, all other compounds were classified using in vitro data in agreement with in vivo observations. We identified hepatic CYP enzymes responsible for metabolism of some compounds (praziquantel—1A2, 2C19, 3A4; primaquine—1A2, 3A4; chloroquine—2C8, 2D6, 3A4; artesunate—2A6; pyrantel—2D6). For the other compounds, we confirmed the role of previously reported CYPs for their metabolism and identified other CYPs involved which had not been reported before.Conclusion Our results show that it is possible to make in vitro–in vivo predictions of high, intermediate and low CL_int drug categories. The identified CYPs for some of the drugs provide a basis for how these drugs are expected to behave pharmacokinetically and help in predicting drug–drug interactions in vivo.     

Should tumor depth be included in prognostication of soft tissue sarcoma?

Background  

Most staging systems for soft tissue sarcoma are based on histologic malignancy-grade, tumor size and tumor depth. These factors are generally dichotomized, size at 5 cm. We believe it is unlikely that tumor depth per se should influence a tumor's metastatic capability. Therefore we hypothesized that the unfavourable prognostic importance of depth could be explained by the close association between size and depth, deep-seated tumors on average being larger than the superficial ones. When tumor size is dichotomized, this effect should be most pronounced in the large size (>5 cm) group in which the size span is larger.     

Cross-national comparisons of the Cambridge Cognitive Examination-revised: the CAMCOG-R: results from the European Harmonization Project for Instruments in Dementia

BACKGROUND: Transnational and psychometrically appropriate versions of instruments used in the diagnosis of dementia are essential for comparing information between different countries. The Cambridge Examination for Mental Disorders of the Elderly incorporates a brief neuropsychological test battery, Cambridge Cognitive Examination (recently revised version), which provides objective data on performance across a number of cognitive domains. OBJECTIVE: To harmonise the Cambridge Cognitive Examination between seven European countries. METHOD: 40 patients with probable or possible Alzheimer's disease of each of the seven countries were administered the Cambridge Cognitive Examination. The Nurse Observation Scale for Geriatrics was used to assess concordance between cognitive and behavioural measures. RESULTS: Only small differences between the various Cambridge Cognitive Examination versions were found, and patterns of correlation between Cambridge Cognitive Examination and the Nurse Observation Scale for Geriatrics were consistent. CONCLUSION: These findings indicate that the harmonisation of the Cambridge Cognitive Examination was successful.     

Regional oxygenation and systemic inflammatory response during cardiopulmonary bypass: influence of temperature and blood flow variations

OBJECTIVE: To evaluate the role of target temperature (28 degrees or 34 degrees C) in cardiac surgery on regional oxygenation during hypothermia and rewarming and systemic inflammatory response. DESIGN: Prospective, controlled, and randomized clinical study. SETTING: University hospital. PARTICIPANTS: Elderly patients (mean age 70 +/- 2 years) with acquired heart disease with an anticipated bypass time exceeding 120 minutes (n = 30). INTERVENTIONS: The patients were cooled to either 28 degrees C (n = 15) or 34 degrees C (n = 15). At hypothermia, bypass blood flow was reduced twice from full flow (2.4 L/min/m(2) body surface area [BSA]) to 2.0 L/min/m(2). MEASUREMENTS AND MAIN RESULTS: Hepatic and jugular venous oxygen tension and saturation were higher at 28 degrees C than at 34 degrees C. In comparison with the preoperative values, at 28 degrees C hepatic venous values were higher; whereas at 34 degrees C, they were lower. The reduction of pump blood flow during hypothermia, from 2.4 to 2.0 L/min/m(2)was accompanied by reductions of central, jugular, and hepatic oxygenation at both target temperatures. During rewarming, central and regional venous oxygenation decreased irrespective of the preceding temperature. The decrease was most pronounced in hepatic venous blood, with the lowest individual values <10%. Serum concentrations of C3a and IL-6 increased during hypothermia and increased further during rewarming irrespective of the preceding temperature. CONCLUSION: During cardiopulmonary bypass, hypothermia at 28 degrees C increases regional and central venous oxygenation better than at 34 degrees C. In contrast, venous oxygenation decreases during rewarming irrespective of the preceding temperature. No significant difference in the systemic inflammatory response associated with target temperature was detected.