A novel pathway determining multidrug sensitivity in Schizosaccharomyces pombe

In this study, we show that a mutation isolated during a screen for determinants of chemosensitivity in S. pombe results in loss of function of a previously uncharacterized protein kinase now named Hal4. Hal4 shares sequence homology to Hal4 and Hal5 in S. cerevisiae, and previous evidence indicates that these kinases positively regulate the major potassium transporter Trk1,2 and thereby maintain the plasma membrane potential. Disruption of this ion homeostasis pathway results in a hyperpolarized membrane and a concomitant increased sensitivity to cations. We demonstrate that a mutation in hal4+ results in hyperpolarization of the plasma membrane. In addition to the original selection agent, the hal4-1 mutant is sensitive to a variety of chemotherapeutic agents and stress-inducing compounds. Furthermore, this wider chemosensitive phenotype is also displayed by corresponding mutants in S. cerevisiae, and in a trk1deltatrk2delta double deletion mutant in S. pombe. We propose that this pathway and its role in regulating the plasma membrane potential may act as a pleiotropic determinant of sensitivity to chemotherapeutic agents.     

Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test-based classification

Hereditary protein S (PS) deficiency type I is an established risk factor for venous thromboembolism. Contradictionary data on type III deficiency suggests a difference in risk between both types. We studied 156 first degree relatives (90% of eligible relatives) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) to determine the absolute risk of venous and arterial thromboembolism. Annual incidences of venous thromboembolism were 1.47 and 0.17 per 100 person-years in deficient and non-deficient relatives in cohort 1 [relative risk (RR) 8.9; 95% confidence interval (CI) 2.6-30.0], and 0.27 vs. 0.24 in cohort 2 (RR 0.9; 95% CI 0.4-2.2). Type III deficiency was demonstrated in 20% of non-deficient relatives in cohort 1 and the annual incidence in this subgroup was 0.70 (RR 4.3;0.95-19.0). The cut-off level of free PS to identify subjects at risk was 30%, the lower limit of its normal range (65%). PS deficiency was not a risk factor for arterial thromboembolism. In conclusion, type I deficiency was found to be a strong risk factor for venous thromboembolism, in contrast with type III deficiency. This was because of lower free PS levels in type I deficient subjects and a free PS cut-off level far below the lower limit of its normal range.     

Kinematic alterations in the ipsilateral shoulder of patients with hemiplegia due to stroke

OBJECTIVE: To evaluate the assumption that shoulder kinematic patterns of the ipsilateral, nonparetic shoulder in hemiplegia are similar to kinematics recorded in a healthy population. DESIGN: Case control study of a convenience sample of ten patients with hemiplegia due to stroke in the subacute phase compared with a control group of similar age. Three-dimensional positions of the scapula and humerus were measured and expressed in Euler angles as a function of active arm elevation in the frontal and sagittal plane and during passive humeral internal/external rotation at an elevation angle of 90 degrees in the frontal and sagittal plane. RESULTS: Compared with controls, in the ipsilateral shoulder of patients, we found both a statistically significant diminished scapular protraction during elevation in the sagittal plane (35 +/- 5 vs. 51 +/- 8 degrees at 110 degrees of humeral elevation) and humeral external rotation during arm elevation in the frontal plane (51 +/- 7 vs. 69 +/- 14 degrees at 110 degrees of humeral elevation). Maximal passive humeral external rotation was found to be impaired in the frontal (64 +/- 13 vs. 98 +/- 14 degrees) and sagittal planes (65 +/- 11 vs. 94 +/- 12 degrees). In addition, there was significantly diminished anterior spinal tilt during humeral internal rotation (-5 +/- 10 vs. -20 +/- 9 degrees) and diminished posterior spinal tilt during external rotation in the frontal plane (-14 +/- 8 vs. -3 +/- 6 degrees). Maximal thoracohumeral elevation in patients was significantly impaired (126 +/- 12 vs. 138 +/- 8 degrees). CONCLUSION: Clear kinematic changes in the ipsilateral shoulder in patients with hemiplegia were found, indicating underlying alterations in muscle contraction patterns. The cause remains speculative. These results suggest that the ipsilateral shoulder should not be considered to function normally beforehand.     

Prescribing for chronic heart failure in Europe: does the country make the difference? A European survey

PURPOSE: International differences in prescribing patterns for chronic heart failure (CHF) have been demonstrated repeatedly. It is not clear whether these differences arise entirely from patient characteristics or factors related to the country itself, such as health care systems or culture. We aim to assess the role of countries in this international variation, aside from the role of patient characteristics. METHODS: In this European primary care practice survey (from 1999/2000) 11062 CHF patients from 14 countries were included. The influence of country (corrected for patient characteristics) on prescribed drug regimes was assessed by multinomial logistical regression. RESULTS: Prescribing of guideline-recommended drug regimes ranged from 28.1% in Turkey to 61.8% in Hungary. Including additional regimes justifiable by patients' co-morbidities, increased overall 'rational' prescribing by 11%, but differences among countries remained similar. Multivariate analysis for one-drug and two-drug regimes explained between 35% and 42% of the total variance, country contributed 7%-8% (p < 0.005). Countries determined the number of drugs used and the likelihood of individual drug regimes. For example, in Czech Republic digoxin alone was more likely to be given than the recommended ACE-inhibitors (OR: 3.45; 95%CI: 2.56-4.64), while the combination of digoxin with ACE-inhibitors was as likely as the recommended combination of ACE-inhibitors and beta-blockers (OR: 1.17; 95%CI: 0.88-1.55). CONCLUSION: Country of residence clearly influenced prescribed drug volume and choice of drug regimes. Therefore, optimal CHF management cannot be achieved without considering country specific factors. It remains to be established which factors within health-care systems are responsible for these effects.