Pharmacogenetic screening and therapeutic drugs.

BACKGROUND: Pharmacogenetics is the science of the influence of heredity on pharmacological response. ISSUES: The cost of severe adverse drug reactions in individuals has been estimated in the US alone to be in excess of US$4 billion. It has been argued that in a significant proportion of cases, the efficacy and toxicity profiles of drug therapy would be substantially improved in individuals if characteristics due to genetic variation were taken into account. Methods are now available, which make screening for susceptibility feasible. CONCLUSIONS: There are several therapeutic areas in which screening may give rise to significant improvements in outcome with cost-benefits to both the individual and the community. However, there is currently a lack of data on which cost-benefit analysis can be based. The challenge is to provide this information for new drugs, and for drugs with established therapeutic roles.     

Gliotoxin non-selectively induces apoptosis in fibrotic and normal livers.

BACKGROUND: Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis. Several lines of evidence indicate that inducing apoptosis of hepatic stellate cells (HSC) may lead to regression of liver fibrosis. Recently, it was shown that gliotoxin (GTX) induces apoptosis of HSC. However, the clinical use of GTX may be limited because of the lack of cell and tissue specificity, causing a high risk of potentially severe adverse effects. The aim of this study, therefore, was to study the effect of GTX on different cells of the liver. METHODS: We used normal and fibrotic precision-cut rat liver slices to study the effect of GTX on the various resident liver cell types. In these slices, the complex cell-cell interactions are preserved, which closely mimics the in vivo situation. RESULTS: GTX exhibited a potent apoptosis-inducing activity in these slices. Both immunohistochemical stainings and real-time mRNA techniques showed that this apoptosis-inducing effect was seen in HSC. However, Kupffer cells and liver endothelial cells were also affected by GTX, whereas hepatocytes were only mildly affected. CONCLUSIONS: This study indicates that the apoptosis-inducing strategy to treat liver fibrosis has high potential, but it will be necessary to develop an HSC-specific therapy to prevent adverse effects.     

Measurement of acceleration: a new method of monitoring neuromuscular function

A new method for monitoring neuromuscular function based on measurement of acceleration is presented. The rationale behind the method is Newton's second law, stating that the acceleration is directly proportional to the force. For measurement of acceleration, a piezo-electric ceramic wafer was used. When this piezo electrode was fixed to the thumb, an electrical signal proportional to the acceleration was produced whenever the thumb moved in response to nerve stimulation. The electrical signal was registered and analysed in a Myograph 2000 neuromuscular transmission monitor. In 35 patients anaesthetized with halothane, train-of-four ratios measured with the accelerometer (ACT-TOF) were compared with simultaneous mechanical train-of-four ratios (FDT-TOF). Control ACT-TOF ratios were significantly higher than control FDT-TOF ratios: 116 +/- 12 and 98 +/- 4 (mean +/- s.d.), respectively. In five patients not given any relaxant during the anaesthetic procedure (20-60 min), both responses were remarkably constant. In 30 patients given vecuronium, a close linear relationship was found during recovery between ACT-TOF and FDT-TOF ratios. It is concluded that the method fulfils the basic requirements for a simple and reliable clinical monitoring tool.     

Grundlagen des akuten Schmerzes: Voraussagbarkeit und Quantifizierung

Ohne Zusammenfassung     

Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Process, format, and clinimetric testing plan.

This article presents the revision process, major innovations, and clinimetric testing program for the Movement Disorder Society (MDS)-sponsored revision of the Unified Parkinson's Disease Rating Scale (UPDRS), known as the MDS-UPDRS. The UPDRS is the most widely used scale for the clinical study of Parkinson's disease (PD). The MDS previously organized a critique of the UPDRS, which cited many strengths, but recommended revision of the scale to accommodate new advances and to resolve problematic areas. An MDS-UPDRS committee prepared the revision using the recommendations of the published critique of the scale. Subcommittees developed new material that was reviewed by the entire committee. A 1-day face-to-face committee meeting was organized to resolve areas of debate and to arrive at a working draft ready for clinimetric testing. The MDS-UPDRS retains the UPDRS structure of four parts with a total summed score, but the parts have been modified to provide a section that integrates nonmotor elements of PD: I, Nonmotor Experiences of Daily Living; II, Motor Experiences of Daily Living; III, Motor Examination; and IV, Motor Complications. All items have five response options with uniform anchors of 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe. Several questions in Part I and all of Part II are written as a patient/caregiver questionnaire, so that the total rater time should remain approximately 30 minutes. Detailed instructions for testing and data acquisition accompany the MDS-UPDRS in order to increase uniform usage. Multiple language editions are planned. A three-part clinimetric program will provide testing of reliability, validity, and responsiveness to interventions. Although the MDS-UPDRS will not be published until it has successfully passed clinimetric testing, explanation of the process, key changes, and clinimetric programs allow clinicians and researchers to understand and participate in the revision process.     

Kardiovaskuläre Bildgebung

Ohne Zusammenfassung     

The effect of observation time and contrast on visual acuity

Background: Field studies of the duration of fixation during daytime driving find that it is about 0.2 seconds on average. Thus, the time available to read traffic signs is often limited. There are other circumstances where time to read alphanumeric messages is limited. Data relating time of observation are needed for purposes of ergonomic design as the data available in the literature are limited and uncertain. Method: Visual acuity was measured using Landolt rings in negative contrast, which were presented on a computer screen with a background luminance of 32 cd/m2 for durations that varied between two and 0.02 seconds at three different contrasts. Resulte: Visual acuity depends on the log of the light dose reduced by a factor that may be related to absorption of the light by the eye media. For young observers, it was found that: VA = 0.57 (log C t) + 1.705, where C is the contrast and is expressed as δL/L, where δL is the difference between target and background luminances in cd/m2 and t is the observation time in seconds. Conclusion: This formula or the functions fitted to the data obtained can be used to calculate the increase in target size needed to allow for short observation times.     

Brain perfusion territory imaging applying oblique-plane arterial spin labeling with a standard send/receive head coil.

A new method for the selective spin labeling of left- or right-sided supplying arteries of the brain without the need for additional RF coils is demonstrated. A clinical 1.5 T scanner was used. The spatial selectivity of the labeling process is based on the limited coverage of the excitation field of a standard send/receive head coil together with an oblique positioning of the labeling plane. A computer simulation was used to optimize key labeling parameters under the condition of laminar flow. The validity of the computer model results was confirmed by MRI measurements with a flow model. For human studies, a double-inversion continuous arterial spin labeling (CASL) sequence was modified to allow for arbitrary positioning of the labeling plane. The obtained perfusion-weighted images showed a clear delineation of the perfusion territories of the selected arteries in the anterior circulation of the brain and good gray/white matter contrast.