The diagnostic significance of clinical signs of right ventricular insufficiency in patients with chronic obstructive bronchitis

A parasitologic investigation, realised between March and November 1993, among 532 pupils 6-15 years old living in N'Djamena's peripheric quarter and in 5 Chari Baguirmi's villages had showed urogenital schistosomiasis infection prevalence is 11.8%.     

Comparison of the pharmacological profile of S-nitrosothiols, nitric oxide and the nitrergic neurotransmitter in the canine ileocolonic junction

1. In organ bath experiments, hydroquinone (30-100 microM) and hydroxocobalamin (30-100 microM) concentration-dependently inhibited the relaxations induced by NO (0.3-30 microM) but not those by nitroglycerin (GTN, 1 microM) in the canine ileocolonic junction (ICJ). Hydroxocobalamin reduced the relaxation to low frequency (2 Hz) stimulation of the non-adrenergic, non-cholinergic (NANC) nerves, whereas hydroquinone only reduced the NANC nerve-mediated relaxations to electrical stimulation at 16 Hz, 0.5 ms. 2. Relaxations to S-nitroso-L-cysteine (CysNO, 1-30 microM), or S-nitroso-N-acetyl-D,L-penicillamine (SNAP, 1-30 microM) were not inhibited by hydroquinone (30-100 microM), hydroxocobalamin (30-100 microM), pyrogallol (30-100 microM) or L-cysteine (1-3 microM). Hydroquinone (100 microM) only reduced the relaxation to 10 microM CysNO. Hydroxocobalamin, but not hydroquinone, pyrogallol or L-cysteine, potentiated the relaxations to the lowest concentration (1 microM) of S-nitrosoglutathione (GSNO, 1-30 microM). 3. In the superfusion bioassay, hydroquinone (100 microM) and hydroxocobalamin (1 microM) concentration-dependently inhibited the biological activity of authentic NO (1-4 pmol) to the same extent as that of the transferable nitrergic factor, released from the canine ICJ in response to NANC nerve stimulation (8-16 Hz, 2 ms). Responses to GTN (10 pmol) or adenosine 5'-triphosphate (10 nmol) were not affected. 4. In conclusion, the nitrosothiols CysNO, SNAP and GSNO relax the canine ileocolonic junction, but these relaxations, pharmacologically, behave differently from the NANC nerve-mediated relaxations. From the bioassay experiments, we conclude that the nitrergic factor, released in response to NANCnerve stimulation of the canine ICJ, behaves pharmacologically like NO but not like a nitrosothiol.Therefore, we suggest NO, and not CysNO, SNAP or GSNO as the inhibitory NANC neurotransmitter in the canine ICJ.     

Transcranial Doppler ultrasound signals associated with prosthetic heart valves: an in vitro study

The application of transcranial Doppler (TCD) ultrasonography to asymptomatic prosthetic heart valve patients can result in detection of localized bursts of high intensity signals, similar to those caused by the passage of emboli. The origin of these signals is not known. In order to investigate this phenomenon in a simplified, more controllable environment, a TCD machine was used to record flow downstream from mechanical prosthetic heart valves in a mock circulatory loop. The model, which uses a saline solution seeded with silk particles (< 15 micrometers) as the circulatory fluid, recreates the principal hydrodynamic characteristics of the left heart and systemic circulation. Reproducibility of the system was established through repeated testing of a Monostrut valve. Three different mechanical valve types, (Monostrut, Medtronic Hall, St. Jude Medical) were tested over a range of simulated cardiac outputs, and the effect of valve size was investigated with four Omniscience tilting disc valves (21, 23, 25 and 29 mm). Average energy of the reflected Doppler signal was used to quantify the amount of high intensity Doppler signal, QTCD. TCD signals recorded in vitro were visually and aurally similar to those found in prosthetic heart valve patients. All valve types generated exponentially more QTCD with increasing simulated cardiac output. Differences amongst valve types were only significant at higher flow outputs, with the Monostrut valve producing the greatest QTCD. Larger valves consistently generated greater QTCD than smaller valves. In conclusion, TCD signals found in prosthetic heart valve patients can be reproduced, at least qualitatively, using a mock circulatory loop which does not incorporate the formed elements of blood.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of the resistance of C57BL/6 and C3H/He mice to infection with Mycobacterium paratuberculosis

Susceptibility of C57BL/6 (Bcgs) and C3H/HeN (Bcgr) mice to an intraperitoneal infection with Mycobacterium paratuberculosis strain 19698 was compared (by histopathology and the number of mycobacteria isolated from the spleen). Mycobacterial counts from the spleen of Bcgr mice progressively decreased over the course of infection but remained unchanged in Bcgs mice. Granulomatous lesions and acid-fast bacteria were consistently present in the liver and lymph nodes of Bcgs mice, whereas lesions were transient or absent in Bcgr mice. These results indicate that Bcgr mice are inherently resistant to M. paratuberculosis, whereas Bcgs mice are inherently susceptible. These differences may prove useful in elucidating the mechanisms of resistance and susceptibility to paratuberculosis and other mycobacterial infections.     

Evaluation of the protective efficacy of reshaped human monoclonal antibody RSHZ19 against respiratory syncytial virus in cotton rats

Reshaped human MAb RSHZ19, which is specific for the surface fusion protein of respiratory syncytial virus (RSV) is in clinical development for the prevention and treatment of RSV-induced disease in human infants. The current studies profile lung virus clearance and evaluate lung histopathology in MAb-treated, RSV-infected cotton rats, a well characterized model of RSV infection. The highest dose of this MAb (10 mg/kg) administered parenterally 24 h before infection decreased subgroup A or B RSV lung titers to below detectable levels (> or = 2.3 log10 reduction), and significantly reduced lung virus titers (> or = 2.0 log10 reduction) when administered 96 h postinfection. Prophylactic administration of 10 mg/kg RSHZ19 was significantly more protective than 1000 mg/kg conventional human immune serum globulin (HSIg), and protective serum-neutralizing titers in MAb-treated animals (1:32, which correlated with approximately 40 micrograms/ml determined by anti-idiotype ELISA) were significantly lower than those reported previously for HSIg or for convalescent human serum (1:200-1:400). MAb concentration in lung lavages was determined by ELISA to be approximately 1% of the serum MAb concentration, but was not detectable by neutralization assay. The degree of lung histopathology in MAb-treated cotton rats was proportional to lung virus titer, and inversely proportional to the RSHZ19 dose administered. There was no evidence of exacerbated disease in the lungs of MAb-treated animals. These studies thus support the potential clinical utility of RSHZ19 MAb in the prevention and treatment of RSV-induced disease in humans.     

Arteriovenous fistulas aggravate the hemodynamic effect of vein bypass stenoses: an in vitro study

PURPOSE: The purpose of this study was to assess the impact of arteriovenous fistulas combined with varying degrees of stenosis on distal bypass hemodynamics and Doppler spectral parameters. METHODS: In an in vitro flow model bypass stenoses causing 30%, 55%, and 70% diameter reduction were induced 10 cm upstream of a fistula with low outflow resistance. Flow and intraluminal pressure were measured proximal to the stenosis and downstream of the fistula. The waveform parameters peak systolic velocity, end-diastolic velocity, pulsatility index, and pulse rise time were determined from midstream Doppler spectra obtained 10 cm downstream of the fistula. All measurements were carried out with open and clamped fistula. RESULTS: At 30% diameter reducing stenosis opening of the fistula induced a 12% systolic pressure drop across the stenosis but had no adverse effect on the Doppler waveform parameters. At 55% stenosis the pressure drop increased from 16% to 31% after fistula opening. This increased pressure drop was associated with a further reduction in peak systolic velocity, a decrease in pulsatility index, and an enhanced pulse rise time prolongation. Fistula opening at 70% stenosis increased the systolic pressure drop from 31% to 48% and had significant impact on all waveform parameters. CONCLUSIONS: Distal arteriovenous fistulas enhance pressure loss across stenoses and affect downstream velocity waveform configuration. The presence of a combined fistula and a stenosis mimics the distal hemodynamic conditions of a more severe stenosis. Assessment of the hemodynamic impact of fistulas must be undertaken in the evaluation of in situ vein bypass stenoses.     

Biosynthesis of the unsaturated 14-carbon fatty acids found on the N termini of photoreceptor-specific proteins

In the vertebrate retina, a number of proteins involved in signal transduction are known to be N-terminal acylated with the unusual 14 carbon fatty acids 14:1n-9 and 14:2n-6. We have explored possible pathways for producing these fatty acids in the frog retina by incubation in vitro with candidate precursor fatty acids bearing radiolabels, including [3H]14:0, [3H]18:1n-9, [3H]18:2n-6, and [3H]18:3n-3. Rod outer segments were prepared from the radiolabeled retinas for analysis of protein-linked fatty acids, and total lipids were extracted from the remaining retinal pellet. Following saponification of extracted lipids, fatty acid phenacyl esters were prepared and analyzed by high pressure liquid chromatography (HPLC) with detection by continuous scintillation counting. Transducin, whose alpha-subunit (Gt alpha) is known to bear N-terminal acyl chains, was extracted from the rod outer segments and subjected to SDS-polyacrylamide gel electrophoresis and fluorography to detect radiolabeled proteins. Gt alpha was also subjected to methanolysis, and the resulting fatty acyl methyl esters were analyzed by HPLC. The identities of HPLC peaks coinciding with unsaturated species of both phenacyl esters and methyl esters were confirmed by reanalyzing them after catalytic hydrogenation. The results showed that 14:1n-9 can be derived in the retina from 18:1n-9 and 14:2n-6 from 18:2n-6, most likely by two rounds of beta-oxidation, but that neither is produced in detectable amounts from 14:0. Retroconversion of unsaturated 18 carbon fatty acids to the corresponding 14 carbon species showed specificity, in that 18:3n-3 was not converted to 14 carbon fatty acids in detectable amounts. Myristic acid (14:0), 14:1n-9, and 14:2n-6 were all incorporated into Gt alpha. A much less efficient incorporation of 18:1n-9 into Gt alpha was also observed, but no radiolabeling of Gt alpha was observed in retinas incubated with 18:3n-3. Thus, retroconversion by limited beta-oxidation of longer chain unsaturated fatty acids appears to be the most likely metabolic source of the unusual fatty acids found on the N termini of signal transducing proteins in the retina.     

A shape-based machine learning tool for drug design

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.