Effects of beta-adrenergic stimulation with dobutamine on isovolumic relaxation in the normal and failing human left ventricle.

BACKGROUND. We tested the hypothesis that beta-adrenergic receptor-stimulated acceleration of left ventricular (LV) isovolumic relaxation (i.e., positive lusitropic response) is attenuated in patients with severe congestive heart failure (CHF) compared with patients without LV dysfunction or CHF. METHODS AND RESULTS. The beta-adrenergic agonist dobutamine was infused by the intracoronary route in 14 subjects (normal group, six; CHF patients, eight) and by the intravenous route in a second group of 14 subjects (normal group, four; CHF patients, 10). The positive inotropic response to intracoronary or intravenous dobutamine was substantially and significantly reduced in the patients with CHF. LV isovolumic relaxation rate was determined by the methods of Weiss (TL), Mirsky (T1/2), and by a nonlinear regression technique (TNL). LV isovolumic relaxation assessed by all three methods was significantly prolonged in CHF patients compared with normal subjects. Intracoronary and intravenous infusions of dobutamine caused significant acceleration of LV isovolumic relaxation in both normal subjects and patients with CHF. The magnitude of the dobutamine-stimulated acceleration of isovolumic relaxation in patients with CHF was comparable with that in normal subjects. CONCLUSIONS. These data demonstrate that beta-adrenergic receptor stimulation causes significant acceleration of LV isovolumic relaxation in both normal subjects and patients with severe CHF. Coronary to our hypothesis, the lusitropic response to beta-adrenergic stimulation is well preserved in patients with severe CHF despite substantial attenuation of the beta-adrenergic positive inotropic response. These findings have potentially important implications regarding the physiology and pharmacology of adrenergically mediated LV relaxation in humans.     

Antibodies to a synthetic peptide from the preS 120-145 region of the hepatitis B virus envelope are virus neutralizing

Studies with synthetic peptides have provided evidence for the presence of preS coded sequences in the envelope (env) proteins of hepatitis B virus (HBV) and indicated that these sequences are involved in the specific attachment of HBV to liver cells. Scanning of the preS sequence for immunodominant continuous epitopes identifies the sequence within residues preS (120-145) as the most immunogenic in eliciting antibodies recognizing HBV and as the most efficiently binding antibodies from sera of rabbits and humans immunized with HBV env proteins. To assess the potential of preS (120-145) as a synthetic vaccine against hepatitis B, in vitro neutralization of the virus by rabbit antiserum to the peptide was assayed in chimpanzees. The animals, subsequently proven to be susceptible to HBV infection, did not develop hepatitis B as judged by negative serological tests for HBV-associated antigens and antibodies and by normal serum alanine aminotransferase levels and normal liver biopsies. These results establish the role of preS domains in the process of virus neutralization and the potential of synthetic preS analogues for hepatitis B vaccination.     

Synaptically evoked membrane potential oscillations induced by substance P in lamprey motor neurons.

Short-lasting application (10 min) of tachykinin neuropeptides evokes long-lasting (>24 h) modulation of N-methyl-D-aspartate (NMDA)-evoked locomotor network activity in the lamprey spinal cord. In this study, the net effects of the tachykinin substance P on the isolated spinal cord have been examined by recording from motor neurons in the absence of NMDA and ongoing network activity. Brief bath application of substance P (30 s to 2 min) induced irregular membrane potential oscillations in motor neurons. These oscillations consisted of depolarizing and hyperpolarizing phases and were associated with phasic ventral-root activity. The oscillations were blocked by the tachykinin antagonist spantide II. They were also blocked by tetrodotoxin (TTX), suggesting that they were not dependent on intrinsic membrane properties of the motor neurons but were synaptically mediated. Substance P could also have a direct effect, however, because a membrane potential depolarization persisted in the presence of TTX. Protein kinase agonists and antagonists were used to investigate the intracellular pathways through which substance P acted. The oscillations were blocked by the selective protein kinase C (PKC) antagonist chelerythrine. However, the TTX-resistant membrane potential depolarization was not significantly affected by blocking PKC. The protein kinase A and G antagonist H8 did not affect either the oscillations or the direct TTX-resistant membrane potential depolarization. The glutamate receptor antagonist kynurenic acid abolished the substance-P-evoked oscillations, suggesting that they were dependent on glutamate release. The oscillations were abolished or reduced by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione but were only reduced by the NMDA receptor antagonist D-AP5. The oscillations were thus mediated by glutamatergic inputs with a greater dependence on non-NMDA receptors. Blocking glycinergic inputs with strychnine resulted in large depolarizing plateaus and bursts of spikes. The glutamatergic and glycinergic inputs underlying the oscillations are apparently evoked through direct and indirect excitatory effects on inhibitory and excitatory premotor interneurons. Substance P thus has a distributed excitatory effect in the spinal cord. While it can activate premotor networks, this activation alone is not able to evoke a coordinated behaviorally relevant motor output.     

Immunomodulation of Delayed Hypersensitivity to Methylated Bovine Serum Albumin (MBSA) in Mice Using Subliminal and Normal Sensitization Procedures

Delayed hypersensitivity (DH) was induced in the footpads of mice sensitized to methylated bovine serum albumin (MBSA). The magnitude of this DH response increased with increasing sensitizing concentration of MBSA. Levamisole administered 1 hr prior to MBSA challenge stimulated the DH response and this was optimal using subliminal sensitizing concentrations of antigen. A number of antirheumatic agents, immunomodulators mediator antagonists and antiallergies were subsequently examined using the subliminal sensitizing concentration of MBSA. The same drugs were also evaluated using a normal sensitizing procedure. These studies indicate that the sensitizing concentration of antigen is critical in establishing whether a drug will stimulate or suppress a DH response.     

Retrorenal colon: implications for percutaneous diskectomy

It has been recommended that computed tomography (CT) with the patient prone be performed in every patient undergoing percutaneous diskectomy; this would enable detection of a retrorenal location of the colon, which could interfere with the percutaneous procedure. In this evaluation of 346 prone CT studies, only one patient (0.29%) was found to have retrorenal or retropsoas bowel that would have been perforated at diskectomy. Because of this extremely low prevalence, the performance of prone CT in every patient undergoing percutaneous lumbar diskectomy is not believed to be necessary.     

Off-the-shelf audit: is it feasible?

Increasing interest in audit in the health service has focused attention on the tools and methods used to achieve it. These can be extremely expensive, so a tendency to opt for off-the-shelf packages has developed. This article reviews how one such instrument, The Central Nottinghamshire Psychiatric Nursing Audit, has been used in two settings over the past three years, with particular emphasis on its cost-effectiveness.