Beat-by-beat changes of viscoelastic and inertial properties of the pulmonary arteries

We tested the hypothesis that pulmonary arterial input impedance varies during the ventilatory cycle due to alterations not only of the viscoelastic components of the pulmonary vasculature but also due to changes of the inertial components. A four-element lumped-parameter model was used to fit the pulmonary arterial pressure-flow recordings in the time domain in 10 anesthetized dogs. The four elements consisted of a resistor (R) that represents input resistance, a second resistor (R1) and a capacitor (C1) that represent the viscoelastic properties of the pulmonary vasculature, and an inductor (L1) that represents inertial properties of blood within the pulmonary vasculature. The parameters were evaluated at each heartbeat throughout the ventilatory cycle at three levels of positive end-expiratory pressure. All four parameters varied significantly during the ventilatory cycle. R, C1, L1, and R1 varied by up to 97, 33, 13, and 17%, respectively. Changes in parameter values were most apparent at the start of expiration when the most rapid changes of lung volume occur. This pattern of the results is consistent with the hypothesis that the time variation of pulmonary arterial impedance is due to dynamic shifts of blood volume between the extra-alveolar and alveolar arteries.     

Metrifonate benefits cognitive, behavioral, and global function in patients with Alzheimer's disease

OBJECTIVE: To evaluate the efficacy and safety of metrifonate, an acetylcholinesterase inhibitor, in patients clinically diagnosed with probable Alzheimer's disease (AD) of mild to moderate severity. METHODS: A prospective, 36-week, multicenter, double-blind, randomized, parallel group study of metrifonate in probable AD patients, including a 2-week screening period, a 26-week double-blind treatment period, and a follow-up visit at 8 weeks post-treatment. A total of 24 ambulatory clinics in the United States in a variety of settings, including contract research organizations, public health facilities, and universities. Patients met diagnostic criteria for probable AD as defined by the work group of the National Institute for Neurological and Communicative Diseases and Stroke and the Alzheimer's Disease and Related Disorders Association. Patients had Mini-Mental State Examination (MMSE) scores of 10 to 26 and Ischemic Scores (Rosen Modification) of <4. A total of 408 patients were enrolled. Percentages of patients completing double-blind treatment were 88% and 79% in the placebo and metrifonate groups, respectively. Rates of discontinuation due to adverse events were 4% in the placebo group and 12% in the metrifonate group. Placebo or metrifonate was administered once daily. Metrifonate-treated patients received a loading dose of 100 to 180 mg based on weight (2.0 mg/kg) for 2 weeks, followed by a maintenance dose of 30 to 60 mg based on weight (0.65 mg/kg) for 24 weeks. Primary efficacy variables were the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) and the Clinician's Interview-Based Impression of Change with Caregiver Input (CIBIC-plus). Secondary efficacy variables included the Neuropsychiatric Inventory (NPI), the Disability Assessment in Dementia, the Global Deterioration Scale (GDS), the ADAS-Noncognitive subscale (ADAS-Noncog), the MMSE, and the Clinician's Interview-Based Impression of Severity with Caregiver Input (CIBIS-plus). Outcome measures reflected changes from baseline at week 26 for all variables. Safety was assessed with incidences of premature termination, treatment-emergent events and mortality, and routine safety evaluations. RESULTS: After 26 weeks of metrifonate therapy, a 2.86-point treatment difference (p = 0.0001) was observed in the ADAS-Cog scores of the intent-to-treat AD patients. The treatment difference in the mean CIBIC-plus score at this time was 0.28 points (p = 0.0071). At week 26, treatment differences also were observed in the mean NPI total score (p = 0.0161). Analysis of the remaining secondary efficacy variables showed treatment differences that favored metrifonate but did not reach statistical significance. Metrifonate adverse events were predominantly mild in intensity. No hepatotoxicity was observed. CONCLUSIONS: Metrifonate was safe and well-tolerated. It enhanced not only the cognitive and global function, but also the behavioral function of patients diagnosed with mild to moderate AD. Therefore, metrifonate appears to be useful in the symptomatic treatment of AD.     

Increased levels of TrkA in the regenerating retinal ganglion cells of fish

Retinal ganglion cells of the fish have the spontaneous capacity to regenerate after nerve crush, a phenomenon known to be facilitated by nerve growth factor (NGF). We have studied the high-affinity NGF receptor TrkA, during the regeneration of the tench (Tinca tinca L.) optic nerve, using immunocytochemical techniques. TrkA-like immunoreactivity increased during the regeneration of the retinal ganglion cells. The increase is followed by a change in the subcellular distribution from perinuclear in control cells to cytoplasmic and perinuclear in regenerating ones. This increase was observed when antibodies against the extracellular domain of TrkA were used; no changes in TrkA-like immunoreactivity were observed with antibodies against the intracellular domain of TrkA. We thus conclude that modulation of TrkA is involved in the regeneration of fish retinal ganglion cells.     

Selective in vivo stimulation of stress-activated protein kinase in different rat tissues by immobilization stress

The quaternary structure of Lumbricus terrestris hemoglobin was investigated by small-angle x-ray scattering (SAXS). Based on the SAXS data from several independent experiments, a three-dimensional (3D) consensus model was established to simulate the solution structure of this complex protein at low resolution (about 3 nm) and to yield the particle dimensions. The model is built up from a large number of small spheres of different weights, a result of the two-step procedure used to calculate the SAXS model. It accounts for the arrangement of 12 subunits in a hexagonal bilayer structure and for an additional central unit of clylinder-like shape. This model provides an excellent fit of the experimental scattering curve of the protein up to h = 1 nm-1 and a nearly perfect fit of the experimental distance distribution function p(r) in the whole range. Scattering curves and p(r) functions were also calculated for low-resolution models based on 3D reconstructions obtained by cryoelectron microscopy (EM). The calculated functions of these models also provide a very good fit of the experimental scattering curve (even at h > 1 nm-1) and p(r) function, if hydration is taken into account and the original model coordinates are slightly rescaled. The comparison of models reveals that both the SAXS-based and the EM-based model lead to a similar simulation of the protein structure and to similar particle dimensions. The essential differences between the models concern the hexagonal bilayer arrangement (eclipsed in the SAXS model, one layer slightly rotated in the EM model), and the mass distribution, mainly on the surface and in the central part of the protein complex.