Estimating Potency for the E max-Model Without Attaining Maximal Effects

The most widely applied model relating drug concentrations to effects is the E_max model. In practice, concentration–effect relationships often deviate from a simple linear relationship but without reaching a clear maximum because a further increase in concentration might be associated with unacceptable or distorting side effects. The parameters for the E_max model can only be estimated with reasonable precision if the curve shows sign of reaching a maximum, otherwise both EC₅₀ and E_max estimates may be extremely imprecise. This paper provides a solution by introducing a new parameter (S₀ ) equal to E_max/EC₅₀ that can be used to characterize potency adequately even if there are no signs of a clear maximum. Simulations are presented to investigate the nature of the new parameter and published examples are used as illustration.     

Scalp electrical recording during paralysis: quantitative evidence that EEG frequencies above 20 Hz are contaminated by EMG.

OBJECTIVE: To identify the possible contribution of electromyogram (EMG) to scalp electroencephalogram (EEG) rhythms at rest and induced or evoked by cognitive tasks. METHODS: Scalp EEG recordings were made on two subjects in presence and absence of complete neuromuscular blockade, sparing the dominant arm. The subjects undertook cognitive tasks in both states to allow direct comparison of electrical recordings. RESULTS: EEG rhythms in the paralysed state differed significantly compared with the unparalysed state, with 10- to 200-fold differences in the power of frequencies above 20 Hz during paralysis. CONCLUSIONS: Most of the scalp EEG recording above 20 Hz is of EMG origin. Previous studies measuring gamma EEG need to be re-evaluated. SIGNIFICANCE: This has a significant impact on measurements of gamma rhythms from the scalp EEG in unparalysed humans. It is to be hoped that signal separation methods will be able to rectify this situation.     

Effects of preparation techniques on the porosity of acrylic cements

We investigated four acrylic cement preparation techniques for their effects on cement porosity: hand mixing, pressurization in a pneumatic pistol, centrifugation, and vacuum mixing. All the techniques were tested on three types of cement with different viscosity characteristics. The best results were obtained with vacuum mixing using a newly designed experimental system, yielding porosity reductions of 60-80 percent relative to hand mixing. Vacuum mixing with a commercial system was also effective, but to a somewhat lesser extent.

Pressurization and centrifugation had no substantial effect on the overall porosity. Centrifugation led to considerable nonuniformity in the distribution of pores and additives.     

Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material

The expression and cellular localization of angiotensin II (Ang II) and AT(1) receptor proteins were examined in the normal human prostate and benign prostatic hyperplasia (BPH) by immunohistochemistry. In the normal prostate, Ang II immunoreactivity was localized to the basal layer of the epithelium and AT(1) receptor immunostaining was found predominantly on stromal smooth muscle and also on vascular smooth muscle of prostatic blood vessels. Ang II immunoreactivity was markedly increased in hyperplastic acini in BPH compared with acini in the normal prostate (normal: 7.4+/-0.2%, n=5 vs. BPH: 22.7+/-1.9%, n=5, p<0.001). However, AT(1) receptor immunoreactivity was significantly decreased in BPH compared with the normal prostate [normal: 16.4+/-2.2%, n=4 vs. BPH: 9.4+/-1.3%, n=5, p<0.05 (p=0.025)]. The present study demonstrates the presence of Ang II peptide in the basal layer of the epithelium and AT(1) receptors on stromal smooth muscle, suggesting that Ang II may mediate paracrine functions on cellular growth and smooth muscle tone in the human prostate. Furthermore, AT(1) receptor down-regulation in BPH may be due to receptor hyperstimulation by increased local levels of Ang II in BPH. These data extend previous findings in support of the novel concept that overactivity of the renin-angiotensin system (RAS) may be involved in the pathophysiology of BPH.     

Monte Carlo simulations of a scintillation camera using GATE: validation and application modelling

Geant4 application for tomographic emission (GATE) is a recently developed simulation platform based on Geant4, specifically designed for PET and SPECT studies. In this paper we present validation results of GATE based on the comparison of simulations against experimental data, acquired with a standard SPECT camera. The most important components of the scintillation camera were modelled. The photoelectric effect. Compton and Rayleigh scatter are included in the gamma transport process. Special attention was paid to the processes involved in the collimator: scatter, penetration and lead fluorescence. A LEHR and a MEGP collimator were modelled as closely as possible to their shape and dimensions. In the validation study, we compared the simulated and measured energy spectra of different isotopes: 99mTc, 22Na, 57Co and 67Ga. The sensitivity was evaluated by using sources at varying distances from the detector surface. Scatter component analysis was performed in different energy windows at different distances from the detector and for different attenuation geometries. Spatial resolution was evaluated using a 99mTc source at various distances. Overall results showed very good agreement between the acquisitions and the simulations. The clinical usefulness of GATE depends on its ability to use voxelized datasets. Therefore, a clinical extension was written so that digital patient data can be read in by the simulator as a source distribution or as an attenuating geometry. Following this validation we modelled two additional camera designs: the Beacon transmission device for attenuation correction and the Solstice scanner prototype with a rotating collimator. For the first setup a scatter analysis was performed and for the latter design. the simulated sensitivity results were compared against theoretical predictions. Both case studies demonstrated the flexibility and accuracy of GATE and exemplified its potential benefits in protocol optimization and in system design.     

The effect of the extracorporeal shock wave lithotriptor on bone cement

For the purpose of studying its applicability for acrylic cement removal during total hip revision surgery, experiments with an extracorporeal shock wave lithotriptor were carried out. High-energy shock waves (HESW) were focussed on discs of polymethylmethacrylate bone cement. The average discharge was 18.1 kV; the number of shock waves 0, 100, 250, 500, 1000, and 2000; the application rate was 85 shocks/min. Macroscopic or radiographic effects were not in evidence. Microscopically, typical lesions in a small concentric focal area with a diameter of 8.5 (+/- 2.5) mm were found. The individual lesions were smaller than 0.1 mm, and displayed characteristic shapes. The area porosity increased with the number of shocks. The maximal area porosity caused by the HESW, measured by quantitative microscopy, was 4% after 2000 shock waves. The lesions were also studied by scanning electron microscopy. It can be concluded that HESW causes only microscopic lesions on the frontal surface of discs of bone cement, and that these lesions are small compared to the pores normally present in bone cement, when applied clinically.     

Molecular determinants of treatment response in human germ cell tumors.

PURPOSE: Germ cell tumors (GCTs) are highly sensitive to cisplatin-based chemotherapy. This feature is unexplained, as is the intrinsic chemotherapy resistance of mature teratomas and the resistant phenotype of a minority of refractory GCTs. Various cellular pathways may influence the efficacy of chemotherapy. Their impact has not been investigated in a comprehensive study of tumor samples from clinically defined subgroups of GCT patients. EXPERIMENTAL DESIGN: We investigated proteins involved in regulation of apoptosis (p53, BAX, BCL-2, and BCL-X(L)), cell cycle control [p21 and retinoblastoma protein (RB)], and drug export and inactivation [P-glycoprotein, multidrug resistance-associated protein (MRP) 1, MRP2, breast cancer resistance protein, lung resistance protein, metallothionein, and glutathione S-transferase pi] immunohistochemically in samples of unselected GCT patients (n = 20), patients with advanced metastatic disease in continuous remission after first-line chemotherapy (n = 12), and chemotherapy-refractory patients (n = 24). Mature teratoma components (n = 10) within tumor samples from all groups were analyzed separately. The apoptotic index was studied by terminal deoxynucleotidyl transferase-mediated nick end labeling assay. RESULTS: Invasive GCTs of all groups showed a correlation between wild-type p53 and apoptotic index (r(s) = 0.66; P < 0.001). The levels of the antiapoptotic proteins BCL-2 and BCL-X(L) were generally low. p21 was hardly detectable and did not correlate with p53 (r(s) = 0.29; P = 0.07). No significant differences among the three patient groups were identified regarding any of the investigated parameters (all Ps were >0.08), even though only individual samples from chemotherapy-resistant cases showed a strong staining for MRP2 and GSTpi. In contrast to other components, mature teratomas showed an intense p21 and RB staining and were mostly positive for MRP2, lung resistance protein, and GSTpi. CONCLUSIONS: Our results indicate a multifactorial basis for the chemosensitivity of GCTs with lack of transporters for cisplatin, of antiapoptotic BCL-2 family members, of p21 induction by p53, and of RB and an intact apoptotic cascade downstream of p53. These findings suggest a preference for apoptosis over cell cycle arrest after up-regulation of p53. None of the examined parameters offers a general explanation for the chemotherapy-resistant phenotype of refractory tumors. The up-regulation of various factors interfering with chemotherapy efficacy and ability for a p21-induced cell cycle arrest may explain the intrinsic chemotherapy resistance of mature teratomas.