Occlusion and stability of synthetic femoral canal plugs used in cemented hip arthroplasty.

The occlusion and stability of five synthetic plugs used to restrict the femoral canal prior to cemented arthroplasty was assessed. A model was employed consisting of a hollow wooden dowel to simulate the canal, with adapters fixed to both ends to accommodate cement insertion and pressurization, and to produce a closed distal cavity. Three different canal diameters within the range accommodated by the plug selected were employed to assess insertion force, distal pressure during both insertion and pressurization of acrylic cement, and plug migration and leakage for each device. There was a wide variation among plugs in the magnitudes of the force and distal pressure upon plug insertion. During cement pressurization, cement leakage and/or plug migration was noted in all trials, and either of these events resulted in pressure rises in the distal cavity. Most notably, differences of only 0.5 mm in the diameter of the canal resulted in marked changes in the occlusion and stability achieved. It is concluded that for the range of canal sizes anticipated intraoperatively, these synthetic plugs appear deficient to varying extents in their ability to occlude or remain stable in the intramedullary canal.

Willardiines differentiate agonist binding sites for kainate- versus AMPA-preferring glutamate receptors in DRG and hippocampal neurons.

Concentration jump responses to 5-substituted (S)-willardiines were recorded from dorsal root ganglion (DRG) and hippocampal neurons under voltage clamp. After block of desensitization by concanavalin-A, dose-response analysis for activation of kainate-preferring receptors in DRG neurons gave the potency sequence trifluoromethyl > iodo > bromo approximately chloro > nitro approximately cyano > kainate > methyl > fluoro > (R,S)-AMPA >> willardiine; EC50 values for the most and least potent willardiine derivatives, 5-trifluoromethyl (70 nM) and 5-fluoro (69 microM), differed 1000-fold. The potency sequence for equilibrium responses at AMPA-preferring receptors in hippocampal neurons was strikingly different from that obtained in DRG neurons: fluoro > cyano approximately trifluoromethyl approximately nitro > chloro approximately bromo > (R,S)-AMPA > iodo > willardiine > kainate > methyl. In hippocampal neurons EC50 values for the most and least potent willardiine derivatives, 5-fluoro (1.5 microM) and 5-methyl (251 microM), differed only 170-fold. Consistent with equilibrium potency measurements, in DRG neurons the kinetics of deactivation for willardiines, recorded following a return to agonist-free solution, were rapid for 5-fluoro (tau off = 43 msec) but slow for 5-iodo (tau off = 4.2 sec), while the opposite sequence was observed for hippocampal neurons, slow for 5-fluoro (tau off = 2.1 sec) and rapid for 5-iodo (tau off = 188 msec). The kinetics of recovery from desensitization showed comparable agonist- and cell-dependent differences. Structure-activity analysis for agonist responses recorded from DRG and hippocampal neurons suggests that for both kainate-preferring and AMPA-preferring receptors the binding of willardiines involves interactions with polar groups such that potency is related to ionization of the uracil ring, and hence the electron-withdrawing ability of the 5-position substituent. However, kainate-preferring receptors differ from AMPA-preferring receptors in possessing a lipophilic pocket that further enhances agonist potency by hydrophobic bonding of the 5-substituent. In contrast, AMPA-preferring receptors lack such a lipophilic site, and for 5-position substituents of the same electron-withdrawing ability, potency decreases with increase in size.

Differential modulation by cyclothiazide and concanavalin A of desensitization at native alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid- and kainate-preferring glutamate receptors.

Concanavalin A, cyclothiazide, and aniracetam, ligands that modulate desensitization at glutamate receptors, were tested for their actions on responses at kainate-preferring receptors in dorsal root ganglion (DRG) neurons and at alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring receptors in hippocampal neurons. In DRG neurons concanavalin A blocked desensitization produced by either kainate or 5-chlorowillardiine and strongly potentiated the peak amplitude of responses to both agonists. However, in hippocampal neurons concanavalin A produced only weak potentiation of responses to kainate and 5-chlorowillardiine, and after treatment with lectin responses to 5-chlorowillardiine remained strongly desensitizing. In contrast, cyclothiazide completely blocked desensitization produced by 5-chlorowillardiine in hippocampal neurons and strongly potentiated responses to kainate; the action of aniracetam was similar but much weaker. In DRG neurons cyclothiazide and aniracetam had no effect on desensitization and instead produced weak inhibition of responses to kainate. The different sensitivities of native AMPA- and kainate-preferring glutamate receptors to cyclothiazide and concanavalin A should prove useful for the differentiation of glutamate receptor subtypes in other areas of the central nervous system.

Equal aspiration rates from postpylorus and intragastric-placed small-bore nasoenteric feeding tubes: a randomized, prospective study.

Postpylorus delivery of enteral feeding is perceived by many experts to be safer than intragastric delivery. To test this assumption, patients with similar Glasgow Coma Scores were given identical enteral formulas continuously via a 10-French nasoenteric tube, placed into the stomach or beyond the second portion of the duodenum. Observations were made for attainment of desired nutrition, bowel changes, and clinical signs of aspiration. Radiographs of the chest and abdomen were obtained every 3 days. If a tube migrated out of a chosen location, it was replaced. Thirty-three patients were studied. Seventeen patients were fed into the stomach and 16 patients were fed postpylorus. The mean duration of enteral feeding was 11.8 days for the gastric group and 10.9 days for the postpylorus group (p = NS). The time to deliver the desired kilocalories was 3.33 and 2.77 days (p = NS) for gastric and postpylorus-fed patients. Tubes displaced similarly in each group, gastric 0.647, postpylorus 0.750 per duration of feeding (p = NS). Chest radiographs met the criteria for aspiration pneumonia in 31.3% of gastric and 40% of postpylorus-fed patients (p = NS). Together, these data indicate that complications from enterally fed patients are equally common whether the distal port of the feeding tube is in the stomach or beyond the second portion of the duodenum.

Pharmacology of nicotinic receptor-mediated inhibition in rat dorsolateral septal neurones.

1. Intracellular electrophysiological techniques were employed to investigate the effects of nicotinic receptor stimulation on rat dorsolateral septal nucleus (DLSN) neurones in a submerged rat brain slice preparation. 2. Acetylcholine (in the presence of the muscarinic antagonist, atropine), nicotine or dimethylphenylpiperazinium (DMPP), applied either by pressure ejection or superfusion, produced predominantly a membrane potential hyperpolarization. 3. Following concentration-response comparisons, DMPP appeared to exhibit fewer desensitizing properties and greater efficacy than nicotine with half-maximal hyperpolarizing responses attainable at 3 and 10 microM, respectively. 4. Pharmacological analyses revealed that the agonist-induced membrane hyperpolarization was sensitive to antagonism by mecamylamine (50-100 microM) and neuronal bungarotoxin (0.2-0.3 microM), but not alpha-bungarotoxin (0.5-1.0 microM), curare (10-50 microM) or dihydro-beta-erythroidine (50-100 microM). 5. Hyperpolarizing responses to DMPP were found to reverse near the equilibrium potential for potassium and were sensitive to changes in extracellular potassium concentration as predicted by the Nernst equation. Under single-electrode voltage clamp, application of DMPP produced an outward current (75-100 pA) which approached reversal at around -88 mV. These findings indicated that the hyperpolarizing response to nicotinic receptor stimulation was mediated by changes in membrane permeability to potassium. 6. DMPP-induced membrane hyperpolarization resulted from a direct action on postsynaptic DLSN neurones since the response persisted under conditions of superfusion with calcium-free/high-magnesium media or tetrodotoxin; both conditions blocked orthodromically induced neurotransmission. The hyperpolarizing response remained unaltered in TTX but was diminished in calcium-free/high-magnesium media. Further studies revealed blockade of the DMPP response following intracellular injection of EGTA. This response was also sensitive to antagonism by various calcium-dependent potassium channel blockers including apamin, barium and tetraethylammonium. 7. Our studies reveal a novel class of CNS nicotinic receptor whose action upon stimulation by an agonist results in a membrane hyperpolarization via a calcium-dependent increase in potassium ion conductance.

Somatostatin induced hyperpolarization of septal neurons is not blocked by pertussis toxin.

The coupling of postsynaptic somatostatin receptors to pertussis toxin (PTX) sensitive guanine nucleotide regulatory proteins (G proteins) was investigated in dorsolateral septal nucleus (DLSN) neurons using a submerged brain slice preparation and intracellular recording techniques. Rats were pretreated with PTX i.c.v. and neuronal responsivity to somatostatin and baclofen, a selective GABAB receptor agonist, tested using a submerged brain slice preparation and intracellular recording techniques. In tissue obtained from rats pretreated with PTX (2.5 micrograms) for 2-5 days, somatostatin applied by superfusion (0.1 microM) produced membrane hyperpolarization and decreased the membrane resistance of DLSN neurons. Hyperpolarizing effects of somatostatin persisted in the presence of tetrodotoxin (0.3 microM) blocking synaptic transmission. Current-voltage relations of the somatostatin-induced, PTX-resistant hyperpolarization indicated a reversal potential close to the equilibrium potential for potassium ions. Membrane hyperpolarizations in PTX treated tissue were similar to those recorded in tissue from vehicle control or untreated rats. Hyperpolarizing responses to the selective GABAB receptor agonist baclofen, however, were blocked by the PTX treatment used in the present study. Our findings suggest that the postsynaptic inhibitory effects of somatostatin in the DLSN is not mediated by a somatostatin receptor coupled to PTX-sensitive G proteins. These G proteins, however, appear to be an essential link in the postsynaptic GABAB receptor-mediated response of DLSN neurons.

Redox modulation of NMDA receptor-mediated Ca2+ flux in mammalian central neurons.

NMDA receptor-mediated Ca2+ flux was studied in cultured rat retinal ganglion cells and neocortical neurons. Intracellular free calcium ([Ca2+]i was measured with fura-2 fluorescence imaging. Baseline [Ca2+]i was 59 +/- 5 nM. In low [Mg2+]o, 200 microM NMDA reversibly increased [Ca2+]i to 421 +/- 70 nM. This rise in [Ca2+]i was blocked by the NMDA antagonists APV (200 microM) or [Mg2+]o (1 mM), but only slightly inhibited by the non-NMDA antagonist CNQX (10 microM). Chemical reduction with dithiothreitol (DTT) had no effect on resting [Ca2+]i. However, DTT increased the NMDA-induced rise in [Ca2+]i approximately 1.6-fold; the oxidizing agent dithiobisnitrobenzoic acid (DTNB) reversed this effect. In patch-clamp experiments, DTT increased NMDA-activated whole-cell conductance approximately 1.7-fold in low and high [Ca2+]o. The Ca2+/Na+ permeability ratio of approximately 7 for NMDA channels remained unaltered by chemical reduction. Thus, redox modulation of the NMDA receptor/channel complex results in a dramatic alteration in current magnitude but no change in ionic permeabilities.

A direct nicotinic receptor-mediated inhibition recorded intracellularly in vitro.

Acetylcholine activates both nicotinic and muscarinic receptors in the central nervous system. Although the action of acetylcholine at muscarinic receptor has been well characterized, relatively little is known at the cellular level concerning nicotinic receptor stimulation in brain. Central nicotinic receptors have been implicated in Alzheimer's disease, seizure activity, the generation of slow-wave theta rhythm in the hippocampus and the potential abuse liability of nicotine. At the neuronal level, nicotinic agonists have been most often associated with postsynaptically mediated excitation and membrane depolarization at various sites, including Renshaw spinal motoneurons, locus coeruleus and the medial habenular nucleus. Nicotine acting presynaptically can produce either excitation or inhibition indirectly through the release of endogeneous transmitters or modulators. Whereas a direct inhibitory effect of nicotine has been suggested by one in vivo extracellular recording study in rat cerebellar Purkinje neurons, the mechanism(s) underlying this action is not yet known. We now report our findings obtained using in vitro intracellular methods in a submerged brain slice preparation in which application of nicotinic agonists to rat dorsolateral septal neurons reveal a direct membrane hyperpolarization mediated by an increase in potassium conductance.

Control of endotoxemia in burn patients by use of polymyxin B.

A group of patients with severe burns were entered into two sequential prospective randomized trials for reduction of endotoxemia by the use of intravenous polymyxin B. The first group underwent polymyxin administration during the first week after burn injury in a bell-shaped dosage form constructed to resemble the level of endotoxemia as previously documented. This group showed a statistically highly significant reduction in endotoxin levels and a suggestive, but not statistically significant, reduction in wound infection and mortality in the treated group compared with controls. The second group of patients underwent treatment with perioperative polymyxin B given in conjunction with an excisional procedure of the burn wound. In this group, polymyxin B also accomplished a reduction in endotoxemia from preoperative to postoperative cases, but there was no significant reduction in clinical complication rate or mortality. In the dosages used, polymyxin B is nontoxic and promises to be a useful part of the surgeon's armamentarium in dealing with severe complications of gram-negative sepsis.

Alterations in erythrocytes in hyperosmolar diabetic decompensation: a pathophysiological basis for impaired blood flow and for an improved design of fluid therapy.

In a study of 10 diabetic patients, each of whom was in a severely decompensated state, notable alteration of blood flow properties was observed in those six patients who were hyperosmolar. In this form of diabetic decompensation, whole blood filtration was distinctly impaired. The additional impairment was shown to be due to an accumulation of solute within the erythrocytes occurring as a consequence of hyperosmolarity. The alterations in erythrocytes were revealed by Coulter blood count abnormalities and confirmed by osmotic fragility studies. When biochemical improvement was achieved in these patients, rapid resolution of the erythrocyte abnormalities occurred. Microvascular ischaemia due to such erythrocyte alterations may be a possible explanation for the characteristic cerebral disturbances of the hyperosmolar diabetic state. Altered blood flow properties would also promote vascular thrombosis, a common terminal event in the hyperosmolar non-ketotic syndrome with associated 50 per cent mortality. An improved design of the insulin and fluid replacement therapy for patients in hyperosmolar diabetic coma might be based on the findings of these and further studies.

Raised Coulter mean corpuscular volume in diabetic ketoacidosis, and its underlying association with marked plasma hyperosmolarity.

An abnormal and transient increase of the Coulter mean red cell volume (MCV) was observed in four of 10 patients with diabetic decompensation. A sequential study of haematological and biochemical measurements in these patients revealed that this phenomenon was associated with the hyperosmolar state. The proposed mechanism and the clinical implications of this change are briefly discussed.

The mean red cell volume in diabetes mellitus.

The Coulter mean red cell volume was found to be significantly elevated in a sample of 100 diabetic patients compared with 200 normal subjects (p less than 0.01). There was no correlation between the mean red cell volume level and the type of diabetes, its method of treatment or degree of control as measured by random blood glucose and glycosylated haemoglobin levels.