Adrenergic regulation of macrophage-derived tumor necrosis factor-alpha generation during a chronic polyarthritis pain model.

Increases in the levels of proinflammatory cytokines, such as TNF alpha, have been intricately linked with arthritis and the pathogenesis of several models of neuropathic pain. In addition, arthritis (as well as other types of persistent pain) is associated with increased sympathetic activity and alterations of other responses in autonomic nervous activity. Adrenergic regulation of LPS-stimulated TNF production by M phi isolated from rats with streptococcal-cell-wall (SCW)-induced arthritis has been examined. Serum TNF levels and the cellular composition of peritoneal exudates have also been assessed. M phi were obtained from: (1) normal control rats, (2) animals injected with complete Freund's adjuvant (CFA), 3 rats injected with SCW and arthritic, and (4) those injected with SCW, which failed to develop arthritis. Serum levels of TNF alpha in rats that develop arthritis are significantly greater (2.4 fold) than levels from the other groups. The proportion of OX19-positive T cell subpopulations are the same in peritoneal exudates from all groups. Immunocytochemical staining also reveals differences between M phi subgroups in the degree of activation. Peritoneal exudates from rats that develop arthritis contain a greater proportion of the high TNF producing subclass of M phi, as identified by positive ED3 staining (p < 0.001). In contrast, Ia antigen presenting M phi (OX6-positive) in the peritoneal exudate cells are only elevated in rats administered CFA. The selective blockade of adrenergic receptors by idazoxan or propranolol demonstrates that the constitutive involvement of either alpha 2 or beta-adrenergic regulation of M phi-derived TNF production is pronounced in rats with arthritis (p < 0.001). These investigations demonstrate a distinctive pattern of peripheral M phi populations in rats that develop chronic polyarthritic pain. We believe that identification of interactions between the adrenergic responses and proinflammatory cytokines will lead to the development of improved strategies to treat patients with chronic pain.

Hyperoxia exacerbates microvascular lung injury following acid aspiration.

OBJECTIVES: To examine the effects of an increase in ambient oxygen (O2) concentrations on the extent of inflammatory pulmonary damage following acid aspiration. DESIGN: Prospective, controlled laboratory study. SETTINGS: University-affiliated animal research facility. SUBJECTS: Male, Long Evans rats weighing 250 to 300 g. INTERVENTION: Rats were injured by instillation of 1.2 mL/kg normal saline solution/HCl, pH= 1.25 (acid), into the lungs via a tracheotomy. Animals were allowed to awaken and were exposed to 21%, 50%, or 98% O2 for 0 to 5 h (n/group > or = 10). In a separate set of experiments, injured rats exposed to 98% O2 were treated with different doses of deferoxamine, just prior to injury. Uninjured rats and rats injured with normal saline solution, pH = 5.3, were used as the control group. MEASUREMENTS: Injury was determined by assessing lung function (lung compliance and arterial blood gases) and alveolar-capillary wall integrity (wet/dry weight, lung albumin permeability index [PI], and intrapulmonary hemorrhage [HI]). RESULTS: Intrapulmonary instillation of acid increased PI, HI, and decreased static lung compliance compared to uninjured control animals. Increased ambient oxygen following acid aspiration decreased lung compliance, 1.06+/-0.03 mL/kg/cm H2O, in oxygen-exposed lungs when compared to the lungs exposed to air, 1.26+/-0.04, following a low pH aspirate (p<0.05). An increase in protein leakage into the lung tissue was noted in oxygen-exposed animals, PI=1.33+/-0.10, vs air-exposed rats, 0.89+/-0.07 (p<0.05). The hyperoxia-induced increase in lung injury was prevented by 30 mg/kg or higher deferoxamine treatment, 0.78+/-0.05 (p<0.05). Exposure of animals to 98% O2 for 2 h was sufficient to produce the same increase in microvascular protein leakage as 5-h exposure to O2 following low pH aspirate. CONCLUSION: Hyperoxia increases acid aspiration-induced inflammatory microvascular lung injury. This appears to be mediated by production of reactive species of O2.

Brain-derived TNFalpha: involvement in neuroplastic changes implicated in the conscious perception of persistent pain.

The pleiotropic cytokine tumor necrosis factor-alpha (TNFalpha) is implicated in the development of persistent pain through its actions in the periphery and in the central nervous system (CNS). Activation of the alpha(2)-adrenergic receptor is associated with modulation of pain, possibly through its autoregulatory effect on norepinephrine (NE) release in the CNS. The present study employs a chronic constriction nerve injury (CCI) pain model to demonstrate the interactive role of presynaptic sensitivity to TNFalpha and the alpha(2)-adrenergic autoreceptor in the pathogenesis of neuropathic pain. Accumulation of TNFalpha is increased initially in a region of the brain containing the locus coeruleus (LC) at day 4 post-ligature placement, followed by an increase in TNFalpha in the hippocampus at day 8 post-ligature placement, coincident with hyperalgesia. Levels of TNFalpha in the thoraco-lumbar spinal cord are also increased at day 8 post-ligature placement. Concurrently, alpha(2)-adrenergic receptor and TNFalpha-induced inhibition of NE release are increased, and stimulated NE release is decreased in superfused hippocampal slices isolated at day 8 post-ligature placement. Stimulated NE release is also decreased in spinal cord slices (lumbar region) from animals undergoing CCI, although in contrast to that which occurs in the hippocampus, alpha(2)-adrenergic receptor inhibition of NE release is not changed. These results indicate an important role that TNFalpha plays in adrenergic neuroplastic changes in a region of the brain that, among its many functions, appears to be a crucial link in the conscious perception of pain. We predict that neuroplastic changes, involving increased functional responses of alpha(2)-adrenergic autoreceptors and increased presynaptic sensitivity to TNFalpha, culminate in decreased NE release in the CNS. These neuroplastic changes provide a mechanism for the role of CNS-derived TNFalpha in the pathogenesis of persistent pain.

Brain-derived TNFalpha mediates neuropathic pain.

Neuropathic pain is a chronic pain state that develops a central component following acute nerve injury. However, the pathogenic mechanisms involved in the expression of this central component are not completely understood. We have investigated the role of brain-associated TNF in the evolution of hyperalgesia in the chronic constriction injury (CCI) model of neuropathic pain. Thermal nociceptive threshold has been assessed in rats (male, Sprague-Dawley) that have undergone loose, chromic gut ligature placement around the sciatic nerve. Total levels of TNF in regions of the brain, spinal cord and plasma have been assayed (WEHI-13VAR bioassay). Bioactive TNF levels are elevated in the hippocampus. During the period of injury, hippocampal noradrenergic neurotransmission demonstrates a decrease in stimulated norepinephrine (NE) release, concomitant with elevated hippocampal TNF levels. Continuous intracerebroventricular (i.c.v.) microinfusion of TNF-antibodies (Abs) starting at four days, but not six days, following ligature placement completely abolishes the hyperalgesic response characteristic of this model, as assessed by the 58 degrees C hot-plate test. Antibody infusion does not decrease spinal cord or plasma levels of TNF. Continuous i.c.v. microinfusion of rrTNF alpha exacerbates the hyperalgesic response by ligatured animals, and induces a hyperalgesic response in animals not receiving ligatures. Likewise, field-stimulated hippocampal adrenergic neurotransmission is decreased upon continuous i.c.v. microinfusion of TNF. These results indicate an important role of brain-derived TNF, both in the pathology of neuropathic pain, as well as in fundamental pain perception.

Hyperbaric pressure of 51 atmospheres is without effect on the depression of oxygen uptake in kidney tissue culture produced by halothane.

Although anesthetized animals are awakened when subjected to increased pressure, compression does not result in antagonism of all phenomena associated with these drugs. It has recently been demonstrated that halothane's inhibition of respiration of isolated rat liver mitochondria is not reversed by hydraulic compression to 51 atmospheres. In order to determine whether this phenomenon can be extrapolated to the whole cell, we have investigated the effect of hydraulic compression of intact renal cells equilibrated with halothane, and conclude that pressure does not overcome the inhibitory effect of this anesthetic.

Atelectatic tympanic membrane reversal by nitrous oxide supplemented general anesthesia and polyethylene ventilation tube insertion. A preliminary report.

In certain instances an adherent atelectatic tympanic membrane (Sade Stage IV) may be successfully elevated off the promontory and ossicles by the use of nitrous oxide anesthesia and restored to a normal position and configuration by polyethylene ventilation tube insertion. Criteria of reversibility and long term follow-up of the tympanic membranes so restored remain to be elucidated.

The influence of trimethaphan (Arfonad)-induced hypotension with and without spine distraction on canine spinal cord blood flow.

Controlled hypotension is used in scoliosis surgery to reduce the need for transfusion and to improve operating conditions, but there is concern that deliberate hypotension may decrease spinal cord blood flow (SCBF) and predispose the spinal cord to injury, particularly when it is distracted during Harrington instrumentation. To study the effect of deliberate hypotension on SCBF, the mean arterial pressure (MAP) was reduced to 50% of its normotensive value with trimethaphan (Arfonad) in dogs and the SCBF measured using the hydrogen washout technique with and without spine distraction. The SCBF was significantly reduced to half its normotensive value of 23.2 ml/min/100 gm to 11.4 ml/min/100 gm after hypotension was established. The SCBF remained significantly decreased compared with controls when measured at 30, 45, and 60 minutes following the induction of hypotension and also when hypotension was terminated. SCBF was not further reduced when 2 cm of spine distraction was added. These results show that induction of hypotension with trimethaphan is associated with a similar decrease in SCBF, which is maintained as long as the drug is used and that this effect continues after the drug is terminated and the MAP increases. Cautiously extrapolating these findings clinically would suggest that trimethaphan may not be the drug of choice for controlled hypotension during scoliosis surgery, despite its apparently favorable hemodynamic and hormonal responses.

The effect of trimethaphan-induced hypotension on canine spinal cord blood flow. Measurement at different cord levels using radiolabelled microspheres.

Controlled hypotension which is used during scoliosis surgery to improve operating conditions and minimize transfusion requirements may decrease spinal cord blood flow (SCBF). Previous studies using hydrogen washout, an invasive technique, have shown that trimethaphan-induced hypotension is associated with a decrease in SCBF, whereas hypotension induced with sodium nitroprusside or nitroglycerin is not. To determine whether the decrease seen with trimethaphan represented a generalized rather than regional spinal cord phenomenon, SCBF was measured at three separate cord levels (T2-3, 7-8, L2-3) using a noninvasive radionuclide-labelled microsphere technique. When the mean arterial pressure was reduced by 50%, SCBF decreased 35 to 45% at all levels of the cord examined, and remained at this reduced level during the period of hypotension. The results confirm that trimethaphan-induced hypotension is associated with a significant reduction in SCBF and that this occurs throughout the spinal cord during the period of hypotension.

The influence of induced hypotension and spine distraction on canine spinal cord blood flow.

Deliberate hypotension is used in scoliosis surgery to reduce the need for blood transfusion and to improve operating conditions. There are concerns, however, that hypotension may decrease spinal cord blood flow (SCBF) and thereby predispose the spinal cord to ischemic injury, particularly when it is distracted during Harrington instrumentation. In a canine model, the mean arterial pressure (MAP) was reduced to 50% of the normotensive value with sodium nitroprusside and halothane to study its effects, with and without spinal distraction, on spinal cord blood flow measured by the hydrogen clearance technique. The induction of systemic hypotension resulted in a significant decrease in spinal cord blood flow from 15.7 +/- 1.1 ml/min/100 g (control) to 10.7 +/- 4.7 ml/min/100 g. This initial decrease in spinal cord blood flow returned to normotensive values by 35 minutes following the induction of hypotension, suggesting an autoregulatory effect. This indicates that the induction of deliberate hypotension to half its normotensive mean arterial pressure is associated with a significant decrease in spinal cord blood flow that returns to normotensive levels by 35 minutes. One and two centimeters of longitudinal distraction applied during systemic hypotension did not reduce spinal cord blood flow when it was applied at least 45 minutes after the hypotension was induced. Thus, when longitudinal stretch of a magnitude approximating that used clinically during Harrington instrumentation is applied in the presence of systemic hypotension, the normal SCBF is not reduced when the autoregulating system is functioning.(ABSTRACT TRUNCATED AT 250 WORDS)

What is the relationship between paresthesia and nerve stimulation for axillary brachial plexus block?

BACKGROUND AND OBJECTIVES: To quantify the motor threshold current of a needle following elicitation of paresthesia during axillary brachial plexus block (ABPB). METHODS: This is a prospective, observational study of ABPB in 72 patients. Having elicited paresthesia, the minimum current required to produce a motor response was noted. The development and success of the block were subsequently followed. RESULTS: Nineteen blocks were excluded (18 because of arterial puncture and 1 blocked needle). Of the remaining 53 blocks, 41 (77%) produced a motor response at 0.5 mA or less. The median current was 0.17 mA (range, 0.03 to 3.3 mA). The site of initial paresthesia and subsequent motor response were related in 43 (81%) of cases. CONCLUSIONS: A needle position causing paresthesia produced a motor response at 0.5 mA or less in 77% of cases studied. This current may, therefore, be a reasonable threshold to aim for when performing an ABPB.

Observations and predictions of secondary neutrons on Space Shuttle and aircraft.

The Cosmic Radiation Effects and Activation Monitor has flown on six Shuttle flights between September 1991 and February 1995 covering the full range of inclinations as well as altitudes between 220 and 570 km, while a version has flown at supersonic altitudes on Concorde between 1988 and 1992 and at subsonic altitudes on a SAS Boeing 767 between May and August 1993. The Shuttle flights have included passive packages in addition to the active cosmic ray monitor which comprises an array of pin diodes. These are positioned at a number of locations to investigate the influence of shielding and local materials. Use of both metal activation foils and scintillator crystals enables neutron fluences to be inferred from the induced radioactivity which is observed on return to Earth. Supporting radiation transport calculations are performed to predict secondary neutron spectra and the energy deposition due to nuclear reactions in silicon pin diodes and the induced radioactivity in the various scintillator crystals. The wide variety of orbital and atmospheric locations enables investigation of the influence of shielding on cosmic ray, trapped proton and solar flare proton spectra.