Pharmacokinetic and pharmacodynamic effects of the novel benzodiazepine antagonist 2-phenylpyrazolo[4,3-c]quinolin-3(5H)-one in humans

2-Phenylpyrazolo[4,3-c]quinolin-3(5H)-one (CGS 8216) is pharmacologically characterized as benzodiazepine antagonist with low inverse agonistic effects. Single oral doses up to 650 mg and subchronic doses up to 100 mg daily for seven days are well tolerated by young healthy volunteers. Plasma concentrations of CGS 8216 are variable, not dose-related and relatively low considering the doses administered. A high plasma concentration ratio of metabolite vs. parent compound (3:1) points to an extensive gastrointestinal first-pass metabolism. CGS 8216 influences the human electroencephalogram similar to anxiolytic and vigilance enhancing drugs in doses which do not change performance of psychometric tests. CGS 8216 antagonizes the diazepam-induced impairment of alertness.     

The relation between conduction velocity and axonal length

Motor evoked potentials (MEPs) obtained by electrical root stimulation and F waves were used to examine the proximal nerve conduction velocity (CV) to tibialis anterior (TA), extensor digitorum brevis (EDB), flexor carpi radialis (FCR), and abductor pollicis brevis (APB) muscles in 40 humans. By subtracting motor latencies obtained by stimulating the peripheral nerve at the same point from the F-wave and MEP latencies, we could measure the CV over identical proximal segments. It was found that proximal CV to TA and FCR was significantly higher than to EDB and APB, respectively. Combining the data of the proximal CV to all four muscles in relation with axonal length resulted in a highly significant inverse relationship (r² = 0.77). Thus the axonal length explained to a large extent the higher CV of the arm nerves and also the inverse relation between body height and CV. The distal CV was always lower than proximal CV; however, there was no support for an additional effect of this gradient in explaining the relationship between CV and height since it was constant for all body heights. © John Wiley & Sons, Inc.     

The α1β1 and α2β1 Integrins Provide Critical Support for Vascular Endothelial Growth Factor Signaling, Endothelial Cell Migration, and Tumor Angiogenesis

Angiogenesis is a complex process, involving functional cooperativity between cytokines and endothelial cell (EC) surface integrins. In this study, we investigated the mechanisms through which the alpha(1)beta(1) and alpha(2)beta(1) integrins support angiogenesis driven by vascular endothelial growth factor (VEGF). Dermal microvascular EC attachment through either alpha(1)beta(1) or alpha(2)beta(1) supported robust VEGF activation of the Erk1/Erk2 (p44/42) mitogen-activated protein kinase signal transduction pathway that drives EC proliferation. Haptotactic EC migration toward collagen I was dependent on alpha(1)beta(1) and alpha(2)beta(1) as was VEGF-stimulated chemotaxis of ECs in a uniform collagen matrix. Consistent with the functions of alpha(1)beta(1) and alpha(2)beta(1) in supporting signal transduction and EC migration, antibody antagonism of either integrin resulted in potent inhibition of VEGF-driven angiogenesis in mouse skin. Moreover, combined antagonism of alpha(1)beta(1) and alpha(2)beta(1) substantially reduced tumor growth and angiogenesis of human squamous cell carcinoma xenografts. Collectively, these studies identify critical collaborative functions for the alpha(1)beta(1) and alpha(2)beta(1) integrins in supporting VEGF signal transduction, EC migration, and tumor angiogenesis.     

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Seven novel and four recurrent point mutations in the factor VIII (F8C) gene

Haemophilia A is a X‐linked bleeding disorder, caused by deficiency in the activity of coagulation factor VIII due to mutations in the corresponding gene. The most common defect in patients is an inversion of the factor VIII gene that accounts for nearly 45% of individuals with severe hemophilia A. Point mutations and small deletions/insertions are responsible for the majority of cases with moderate to mild clinical course and for half of the severe hemophilia A occurrences. The majority of these mutations are “private”, because of the high mutation rate for this particular gene. We report on eleven pathological changes in the factor VIII sequence detected in male patients with haemophilia A or in female obligate carriers. Seven of these mutations are novel [E204N, E265X, M320T, F436C, S535C, N2129M and R2307P] and four have been previously identified [V162M, R527W, R1966X, and R2159C]. Genotype‐phenotype correlations and computer prediction analysis on the effect of missense mutations on the secondary structure of the factor VIII protein are performed and the relationships evaluated. © 2001 Wiley‐Liss, Inc.     

Laparoscopic surgical staging for uterine malignancies using harmonic shears (UltraCision) in comparison to electrosurgery: operative technique, feasibility and complications

This retrospective study assesses and compares perioperative parameters in two groups of patients treated by different operative techniques of laparoscopic surgical staging (LASS) for uterine cancer. Between April 1996 and May 2005, 119 consecutively selected women with cervical cancer (n=30) or clinical stage I endometrial cancer (n=89) underwent laparoscopic assisted vaginal hysterectomy (LAVH), total laparoscopic hysterectomy (TLH) or radical laparoscopic assisted vaginal hysterectomy (RALVH) plus bilateral salpingo-oophorectomy (BSO) and/or lymph node dissection (LND) during a primary surgical procedure using an electrosurgery (ELC, n=37) or ultrasonic (US, n=82) operative technique (harmonic shears, UltraCision). The UltraCision was used as a primary method of dissection and hemostasis from 1999. We were unable to perform prompt and thorough hemostasis in 2 patients from the US group (successful procedure rate 97.5%) because of ineffective post-ultrasonic coagulation of venous paravaginal varices (RALVH procedure) and of vena ovarica varices (LAVH, BSO procedure). The UltraCision was effective in all cases of lymphadenectomy. Successful procedure rate of the ELC operative technique was 100%. There were no statistically significant differences between the groups with regard to operation time, blood loss, hospital stay, and complications. There was a significant difference (P<0.001) in the number of lymph nodes harvested: a mean of 18.1 in the US group and 13.7 in the ELC group. We think that the difference was influenced by an increase in experience with laparoscopic lymph node dissection. The UltraCision operative technique ensures efficient dissection, coagulation, cutting, and grasping for LASS in women with cervical and endometrial cancer.     

A Procedure to Measure the in-Situ Hygrothermal Behavior of Earth Walls

Rammed earth is a sustainable material with low embodied energy. However, its development as a building material requires a better evaluation of its moisture-thermal buffering abilities and its mechanical behavior. Both of these properties are known to strongly depend on the amount of water contained in wall pores and its evolution. Thus the aim of this paper is to present a procedure to measure this key parameter in rammed earth or cob walls by using two types of probes operating on the Time Domain Reflectometry (TDR) principle. A calibration procedure for the probes requiring solely four parameters is described. This calibration procedure is then used to monitor the hygrothermal behavior of a rammed earth wall (1.5 m × 1 m × 0.5 m), instrumented by six probes during its manufacture, and submitted to insulated, natural convection and forced convection conditions. These measurements underline the robustness of the calibration procedure over a large range of water content, even if the wall is submitted to quite important temperature variations. They also emphasize the importance of gravity on water content heterogeneity when the saturation is high, as well as the role of liquid-to-vapor phase change on the thermal behavior.     

Prophylactic Cranial Irradiation for Limited-Stage Small-Cell Lung Cancer Patients: Secondary Findings From the Prospective Randomized Phase 3 CONVERT Trial

Introduction

The impact of the dose and fractionation of thoracic radiotherapy on the risk of developing brain metastasis (BM) has not been evaluated prospectively in limited stage SCLC patients receiving prophylactic cerebral irradiation (PCI).