Rectal diazepam in the treatment of absence status: a pharmacodynamic study

Rectal administration of diazepam is highly effective in terminating absence status as judged by reduction of spike-wave activity in the EEG. Pharmacokinetic studies indicate that diazepam can have antiepileptic properties at serum levels well below those previously reported as being necessary to achieve a therapeutic effect.     

A review of the invasive mosquitoes in Europe: ecology, public health risks, and control options

There has been growing interest in Europe in recent years in the establishment and spread of invasive mosquitoes, notably the incursion of Aedes albopictus through the international trade in used tires and lucky bamboo, with onward spread within Europe through ground transport. More recently, five other non-European aedine mosquito species have been found in Europe, and in some cases populations have established locally and are spreading. Concerns have been raised about the involvement of these mosquito species in transmission cycles of pathogens of public health importance, and these concerns were borne out following the outbreak of chikungunya fever in Italy in 2007, and subsequent autochthonous cases of dengue fever in France and Croatia in 2010. This article reviews current understanding of all exotic (five introduced invasive and one intercepted) aedine species in Europe, highlighting the known import pathways, biotic and abiotic constraints for establishment, control strategies, and public health significance, and encourages Europe-wide surveillance for invasive mosquitoes.     

Positive feedbacks of coagulation: their role in threshold regulation

Tissue factor (TF), the initiator of coagulation, continuously circulates in the plasma, and the clotting system "idles," generating very low levels of active clotting enzymes, clotting products, and by-products. Given the enormous amplification potential of the clotting cascade, rigorous control is required to ensure that such low-level stimulation does not cause massive system amplification and response. We propose that among the various mechanisms of regulation, activation thresholds may play a major role. These arise when positive-feedback reactions, of which there are several in the clotting system, are regulated by inhibitors. Such thresholds act like switches, so that small stimuli and/or nonproductive local conditions will generate no response, whereas larger stimuli or the existence of local prothrombotic conditions will produce a full, explosive response. We review here the evidence for system idling, the structures of the various feedback mechanisms of clotting, the mechanisms by which they can produce threshold behavior, and the possible role of thresholds in system regulation.     

Platelet activation in a circulating flow loop: combined effects of shear stress and exposure time

Measurement of small changes in platelet activation state (PAS) in circulating stenotic systems in vitro has been problematic because of a paucity of real-time assay methods and circulation systems of low platelet-activating potential. PAS was measured by a modified prothrombinase assay in which activated platelets provide the essential cofactors in the activation of prothrombin by factor Xa. Chemical modification of the prothrombin ensures that the thrombin produced, while assayable, does not activate platelets. Human platelets were circulated in loops in which exposure to shear stress was adjusted by independently varying flow rate, viscosity, and the time of exposure to shear. Although with some differences in platelet response to different conditions of stress, the PAS directly increased with time of circulation, shear stress, and time of exposure to shear. The results show that low-level platelet activation caused by shear stress in a circulation loop can be quantitatively assessed in near-real time in a system of tube geometry. They confirm previous results obtained in non-circulating systems that exposure of platelets to shear conditions on the same order as found in the vasculature causes significant platelet activation, and that this activation is dependent on both shear stress and time of exposure.     

Next generation pharmaceutical impactor (a new impactor for pharmaceutical inhaler testing). Part II: Archival calibration.

A new seven-stage cascade impactor, the Next Generation Pharmaceutical Impactor (NGI), has been developed for the pharmaceutical industry. A calibration following "good laboratory practice (GLP)" procedures has been performed on a specific archival NGI, deemed to be representative of all NGIs. Thus, this impactor had nozzle dimensions for each stage manufactured close to the middle of the tolerance band for the design specification, and therefore the average nozzle diameter was equal to the nominal value for that stage. An essential feature of the NGI is that it is designed to operate at any flow rate between 30 and 100 L/min. Thus, the calibration was made at inlet flow rates of 30, 60 and 100 L/min representing the lower bound, mid-region and upper bound of the specified range of operation for the impactor. The calibration data were then used to develop equations that predict the particle cut size for all components of the impactor at any flow rate from 30 to 100 L/min.     

Deterministic rather than stochastic factors explain most of the variation in the expression of skin telangiectasia after radiotherapy.

BACKGROUND: The large patient-to-patient variability in the grade of normal tissue injury after a standard course of radiotherapy is well established clinically. A better understanding of this individual variation may provide valuable insights into the pathogenesis of radiation damage and the prospects of predicting the outcome. PURPOSE: To estimate the relative importance of the stochastic vs. patient-related components of variability in the expression of radiation-induced normal tissue damage. METHODS AND MATERIALS: The study data were selected from the dose fractionation studies of Turesson in Gothenburg. Patients treated with bilateral internal mammary fields, who completed at least 10 years of follow-up, were included. The material included 22 different fractionation schedules (11 on each side). Telangiectasia was graded on an arbitrary 6-point scale using clinical photographs of the irradiated fields. For each field, in each patient, a curve showing the grade of telangiectasia as a function of time was constructed. A measure of radioresponsiveness was obtained from the difference between the area under the curve (AUC) for a specific field in an individual patient minus the mean AUC of fields receiving the same dose fractionation schedule. As a confirmatory procedure, the same analysis was repeated with a weighted area under the curve (WAUC) approach, in which the time spent at or above each of the 5 nonzero grades was calculated for each field in each patient. These times were used as explanatory variables in a linear regression analysis of biological equivalent dose to establish statistically the weight of each grade providing the optimal relationship between dose and effect. Using these regression coefficients, the weighted area under the grade-time curve (WAUC) was estimated. RESULTS: The AUC was significantly correlated with the isoeffective dose in 2-Gy fractions (ID2). An analysis of variance components, using the maximum likelihood method, showed that 90% (with 95% confidence limits 65% and 100%) of the variance in radioresponsiveness in the right-sided field was explained by the radioresponsiveness on the left-sided field. Through the linear regression analysis between the AUC and the ID2, it was estimated that patients with a reaction that is 1 SD from the population mean would require a dose modification of approximately 23 Gy (from the group mean of 56 Gy) to give them a level of reaction similar to the group average. Similarly, the WAUC was significantly correlated with the ID2, and 81% (with 95% confidence limits 49% and 100%) of the variance in radioresponsiveness in the right-sided field was explained by the radioresponsiveness on the left-sided field. Patients with a reaction that is 1 SD from the population mean would require a dose modification of approximately 21 Gy (from the group mean of 56 Gy) to give them a level of reaction similar to the group average. CONCLUSION: For a given fractionation schedule, patient-related factors explain 81-90% of the patient-to-patient variation in telangiectasia level seen after radiotherapy. The remaining 10-19% are explained by stochastic effects. This observation encourages further research into genetic or phenotypic assays of normal tissue radioresponsiveness.