Inhalation efficacy of RFI-641 in an African green monkey model of RSV infection.

Human respiratory syncytial virus (RSV) is a major cause of acute upper and lower respiratory tract infections. RFI-641 is a novel RSV fusion inhibitor with potent in vitro activity. In vivo efficacy of RFI was determined in an African green monkey model of RSV infection involving prophylactic and therapeutic administration by inhalation exposure. Inhalation was with an RFI-641 nebulizer reservoir concentration of 15 mg/ml for 15 minutes (short exposure) or 2 hours (long exposure). Efficacy and RFI-641 exposure was determined by collection of throat swabs, nasal washes and bronchial alveolar lavage (BAL) on selected days. The short-exposure group (15 minutes) exhibited no effect on the nasal, throat or BAL samples. The throat and nasal samples for the long-exposure group failed to show a consistent reduction in viral titers. RFI-641 2 hours exposure-treated monkeys showed a statistically significantly log reduction for BAL samples of 0.73-1.34 PFU/ml (P-value 0.003) over all the sampling days. Analysis indicates that the long-exposure group titer was lower than the control titer on day 7 and when averaged across days. The results of this study demonstrate the ability of RFI-641 to reduce the viral load of RSV after inhalation exposure in the primate model of respiratory infection.

Radiation-induced apoptosis in microvascular endothelial cells.

The response of the microvasculature to ionizing radiation is thought to be an important factor in the overall response of both normal tissues and tumours. It has recently been reported that basic fibroblast growth factor (bFGF), a potent mitogen for endothelial cells, protects large vessel endothelial cells from radiation-induced apoptosis in vitro. Microvessel cells are phenotypically distinct from large vessel cells. We studied the apoptotic response of confluent monolayers of capillary endothelial cells (ECs) to ionizing radiation and bFGF. Apoptosis was assessed by identifying changes in nuclear morphology, recording cell detachment rates and by detecting internucleosomal DNA fragmentation. Withdrawal of bFGF alone induces apoptosis in these monolayers. The magnitude of this apoptotic response depends upon the duration of bFGF withdrawal. Irradiation (2-10 Gy) induces apoptosis in a dose-dependent manner. Radiation-induced apoptosis occurs in a discrete wave 6-10 h after irradiation, and radiation-induced apoptosis is enhanced in cultures that are simultaneously deprived of bFGF. For example, 6 h after 10 Gy, 44.3% (s.e. 6.3%) of cells in the monolayer simultaneously deprived of bFGF exhibit apoptotic morphology compared with 19.8% (s.e. 3.8%) in the presence of bFGF. These studies show that either bFGF withdrawal or ionizing radiation can induce apoptosis in confluent monolayers of capillary endothelial cells and that radiation-induced apoptosis can be modified by the presence of bFGF.

Effect of cell cycle stage, dose rate and repair of sublethal damage on radiation-induced apoptosis in F9 teratocarcinoma cells.

There are at least two different modes of cell death after treatment with ionizing radiation. The first is a failure to undergo sustained cell division despite metabolic survival, and we refer to this end point as "classical reproductive cell death." The second is a process that results in loss of cell integrity. This second category includes cellular necrosis as well as apoptosis. Earlier studies in our laboratory showed that the predominant mechanism of cell death for irradiated F9 cells is apoptosis, and there is no indication that these cells die by necrosis. We have therefore used cells of this cell line to reassess basic radiobiological principles with respect to apoptosis. Classical reproductive cell death was determined by staining colonies derived from irradiated cells and scoring colonies of less than 50 cells as reproductively dead and colonies of more than 50 cells as survivors. Cells that failed to produce either type of colony (detached from the plate or disintegrated) were scored as having undergone apoptosis. Using these criteria we found that the fraction of the radiation-killed F9 cells that died by apoptosis did not vary when cells were irradiated at different stages of the cell cycle despite large variations in overall survival. This suggests that the factors that influence radiation sensitivity throughout the cell cycle have an equal impact on apoptosis and classical reproductive cell death. There was no difference in cell survival between split doses and single doses of X rays, suggesting that sublethal damage repair is not a factor in radiation-induced apoptosis of F9 cells. Apoptosis was not affected by changes in dose rate in the range of 0.038-4.96 Gy/min.

[Ambulatory angiologic diagnosis using the Doppler c.w. (continuous wave) method]. / Diagnostica angiologica ambulatoriale nel territorio con Doppler c.w.

A one year clinical activity of instrumental angiological diagnostics (doppler c.w. examinations) was evaluated and analysed. 970 outpatient continuous wave doppler have been performed: 37% examinations of epiaortic vessels (TSA), 31% examinations of lower limb veins, 28% examinations of lower limbs arteries. The question has been inappropriate (normal exam) in 81% of TSA, in 67% of AIA and in 52% of AIV. The authors think that the reasons for these results are a large misinformation from the physicians postulant and a consequent abuse of the instrumental method. It's therefore necessary to put a clinical filter to regulate the access to the instrumental (high technological) examinations, too often unnecessary.

[Cardiovascular adjustments in hypertensive patients. An echocardiographic study]. / Adattamenti cardiovascolari in ipertesi. Studio ecocardiografico.

Echocardiography was used to asses parameters of cardiovascular function in order to identify the main cardiac adjustment mechanisms to arterial hypertension. In addition to morphological parameters of septal and parietal thickness and diameter, telesystolic (Ses) and telediastolic (Spk) stress, EF, Vcfm, the index of left ventricular mass (ILVM), hypertrophy ratio (h/r), contractility index (Do), peripheral resistances (RPT) and Tarazi's index (SAC) were evaluated. In comparison to control subjects, higher levels of PwTs, h/r, SAC, RPT and ILVM (at the limit of significance) were found in hypertensive patients, which were reflected by higher Spk and Do values. From the further analysis of data to identify patients with signs of left ventricular hypertrophy (h/r greater than 0.40 and/or ILVM greater than 140) it was concluded that the hypertrophy ratio (h/r) is the functional parameter which most closely reveals the type of myocardial adjustment. Irrespective of absolute values of ILVM, the adequacy of myocardial hypertrophy to the dimensions of the cavity is accompanied by the normalisation of stress and the return of Do values close to normal levels. Hearts with low h/r those with the highest stress levels, as well as preesting the lowest EF and the highest Do values.