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.     

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.     

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.     

A comparison of presenting characteristics of patients with intracapsular and extracapsular proximal femoral fractures.

The presenting characteristics of 1423 consecutive admissions with proximal femoral fractures were prospectively studied, to determine any differences that may exist between patients, dependent on the radiological site of the fracture. Patients with intracapsular fractures were of a lower average age, more mobile, less likely to use walking aids or live in residential accommodation, they also had a considerably shorter length of hospital stay than for those patients with extracapsular fractures. Comparison against previous series shows that the average age of hip fracture patients and the proportion of trochanteric fractures is increasing.     

Through a glass darkly: the disutility of the DSM nosology of depressive disorders.

OBJECTIVE: To demonstrate that the dimension-weighted DSM-IV model for classifying the depressive disorders lacks utility. METHOD: The logical flaws in classifying the depressive disorders with any severity-based model (which underpin both the DSM-IV and ICD-10 systems) are noted. Integral definitional limitations to the DSM-IV definition of key depressive disorders are identified. It is argued that the DSM-IV classificatory system lacks utility for providing information on etiology and preferential management strategies. An alternative subtyping model is considered. RESULTS: It is asserted that, in practice, the DSM-IV model and criteria lack explanatory power and compromise research and clinical practice. CONCLUSIONS: It is hoped that this article evokes wider debate about modelling and classifying the depressive disorders.     

Activated, HTLV-1-specific cytotoxic T-lymphocytes are found in healthy seropositives as well as in patients with tropical spastic paraparesis.

In human T cell lymphoma/leukemia virus (HTLV-1)-infected people with tropical spastic paraparesis (TSP), there are activated HTLV-1-specific cytotoxic T lymphocytes (CTL) in the circulation and lymphocytic infiltrates in spinal cord lesions that are rich in CD8+ T cells. These observations suggest a role for virus-specific CTL in the pathogenesis of TSP. We have examined the anti-HTLV-1 cytotoxic activity of freshly isolated CD8+ T cells from peripheral blood lymphocytes of eight subjects seropositive for HTLV-1. Four of five subjects with TSP had circulating activated anti-Tax CTL. However, two of three seropositive subjects without TSP also had activated anti-Tax CTL. These observations show that such activated CTL are not confined to patients with TSP and raise some uncertainty about their significance in the pathogenesis of the disease. In cultures of CD8+ T cells from two TSP subjects, we detected CTL with other HTLV-1 specificities, without exogenous antigenic stimulation. A CTL epitope in the middle region of Tax and one in the C terminus of Pol have been mapped at the peptide level and the HLA Class 1 molecules restricting their recognition have been defined.