Anatomy and biomechanics of gluteus maximus and the thoracolumbar fascia at the sacroiliac joint.

Biomechanical models predict that recruitment of gluteus maximus (GMax) will exert a compressive force across the sacroiliac joint (SIJ), yet this muscle requires morphologic assessment. The aims of this study were to document GMax's proximal attachments and assess their capacity to generate forces including compressive force at the SIJ. In 11 embalmed cadaver limbs, attachments of GMax crossing the SIJ were dissected and their fascicle orientation, length and attachment volume documented. The physiological cross-sectional area (PCSA) of each attachment was calculated along with its estimated maximum force at the SIJ and lumbar spine. GMax fascicles originated from the gluteus medius fascia, ilium, thoracolumbar fascia, erector spinae aponeurosis, sacrum, coccyx, dorsal sacroiliac and sacrotuberous ligaments in all specimens. Their mean fascicle orientation ranged from 32 to 45° below horizontal and mean length from 11 to 18 cm. The mean total PCSA of GMax was 26 cm(2) (range 16-36), of which 70% crossed the SIJ. The average maximum force predicted to be generated by GMax's total attachments crossing each SIJ was 891 N (range 572-1,215), of which 70% (702 N: range 450-1,009) could act perpendicular to the plane of the SIJ. The capacity of GMax to generate an extensor moment at lower lumbar segments was estimated at 4 Nm (range 2-9.5). GMax may generate compressive forces at the SIJ through its bony and fibrous attachments. These may assist effective load transfer between lower limbs and trunk.

alpha7 nicotinic acetylcholine receptor agonist properties of tilorone and related tricyclic analogues.

BACKGROUND AND PURPOSE: The alpha7 nicotinic acetylcholine receptor (nAChR) has attracted considerable interest as a target for cognitive enhancement in schizophrenia and Alzheimer's Disease. However, most recently described alpha7 agonists are derived from the quinuclidine structural class. Alternatively, the present study identifies tilorone as a novel alpha7-selective agonist and characterizes analogues developed from this lead. EXPERIMENTAL APPROACH: Activity and selectivity were determined from rat brain alpha7 and alpha4beta2 nAChR binding, recombinant nAChR activation, and native alpha7 nAChR mediated stimulation of ERK1/2 phosphorylation in PC12 cells. KEY RESULTS: Tilorone bound alpha7 nAChR (IC(50) 110 nM) with high selectivity relative to alpha4beta2 (IC(50) 70 000 nM), activated human alpha7 nAChR with an EC(50) value of 2.5 microM and maximal response of 67% relative to acetylcholine, and showed little agonist effect at human alpha3beta4 or alpha4beta2 nAChRs. However, the rat alpha7 nAChR maximal response was only 34%. Lead optimization led to 2-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-xanthen-9-one (A-844606) with improved binding (alpha7 IC(50) 11 nM, alpha4beta2 IC(50)>30 000 nM) and activity at both human and rat alpha7 nAChR (EC(50)s 1.4 and 2.2 microM and apparent efficacies 61 and 63%, respectively). These compounds also activated native alpha7 nAChR, stimulating ERK1/2 phosphorylation in PC12 cells. CONCLUSIONS AND IMPLICATIONS: Tilorone, known as an interferon inducer, is a selective alpha7 nAChR agonist, suggesting utility of the fluorenone pharmacophore for the development of alpha7 nAChR selective agonists. Whether alpha7 stimulation mediates interferon induction, or whether interferon induction may influence the potential anti-inflammatory properties of alpha7 nAChR agonists remains to be elucidated.

Social isolation and delayed discovery of bodies in houses: the value of forensic pathology, anthropology, odontology and entomology in the medico-legal investigation.

The bodies of socially isolated people may remain undiscovered in their own houses for prolonged periods. Occasionally the body is in situ for sufficient time to become skeletonised, or partially so. Medico-legal investigation of these cases is complicated by degradation and contamination of evidence. Thus, a multidisciplinary forensic investigation is recommended. The potential contributions of forensic pathology, anthropology, odontology and entomology are outlined here with reference to two cases that occurred in Victoria, Australia, in 2003. Forensic pathologists are often unable to determine the cause of death in skeletonised bodies, however, they may find evidence to support either a natural or unnatural mode of death, and they may describe skeletal pathology or trauma, and identify skeletal features to support radiological identification of the deceased. Anthropologists can provide supplementary evidence of skeletal trauma. Additionally, they can assess age, sex, stature and racial affiliation from skeletal remains. Odontologists can identify individuals through comparison with ante-mortem dental records; however, potential difficulties exist in identifying the treating dentist of a socially isolated person. Odontologists may also examine the teeth and oro-facial skeleton for trauma. Entomologists may estimate minimum death time and/or season of death. Entomological examination of insect remains may also confirm that a body has lain in situ for a considerable period.

Effect of MK-801 at the human alpha 7 nicotinic acetylcholine receptor.

Responses of the human alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) expressed in Xenopus laevis oocytes were quantified in the presence of barium (10 mM) to prevent secondary activation of Ca(2+)-dependent Cl- currents and atropine (2 microM) to block endogenous muscarinic receptors. Acetylcholine (ACh) elicited responses with EC50 values of 177 +/- 32 microM to 272 +/- 26 microM in different experiments. Responses to ACh (200 microM) were blocked by the nAChR antagonists alpha-bungarotoxin (IC50 = 0.54 +/- 0.04 nM), methyllycaconitine (IC50 = 0.64 +/- 0.08 nM) and mecamylamine (IC50 = 1.8 +/- 02 microM). Additionally, MK-801, a non-competitive blocker of N-methyl-D-aspartate (NMDA) sensitive glutamate receptor channels, inhibited the human alpha 7 nAChR. This effect was not stereoselective; the IC50 for (+)-MK-801 was 15 +/- 3 microM while that for (-)-MK-801 was 14 +/- 3 microM. The inhibition by MK-801, in contrast to methyllycaconitine, was dependent upon cell potential, consistent with a mechanism involving channel blockade. The inhibition by MK-801 reversed slowly (time constant approximately 20 min) compared to that by methyllycaconitine (100% recovery within 10 min). However, MK-801 did not appear to be trapped in the channel because the recovery from inhibition showed little dependence upon stimulation rate or cell potential. Thus, MK-801 acted as a non-stereoselective alpha 7 nAChR inhibitor that was only about 8-fold less potent than the nAChR antagonist mecamylamine and probably acted through channel blockade.

Activation and inhibition of the human alpha7 nicotinic acetylcholine receptor by agonists.

To better understand the effects of weak as well as strong agonists at the human alpha7 nicotinic acetylcholine receptor (human alpha7 nAChR), the abilities of several classic nAChR agonists to both activate and inhibit (desensitize) the human alpha7 nAChR expressed in Xenopus oocytes were quantified and compared. Activation was measured during 0.2-20 s agonist application, as required to elicit a peak response. Inhibition was measured as the reduction in the agonist response to 200 microM ACh in the presence of inhibitor during a 5-20 min incubation. Acetylcholine (ACh), (-)-nicotine, (+)-nicotine, and 1,1-dimethyl-4-phenylpiperazinium (DMPP) were 62- to 130-fold more potent as inhibitors than as activators, with excellent correlation between the IC50 and EC50 values (r2 = 0.924). Agonist concentrations that elicited only 0.6-1.2% nAChR activation were sufficient to inhibit the response to ACh by 50%. Thus, even a very weak agonist could appear to be a potent and effective inhibitor through receptor desensitization. (-)-Lobeline, in contrast, acted as an antagonist at the human alpha7 nAChR, eliciting no detectable agonist-like response at concentrations up to 1 mM, but inhibiting the response to ACh with an IC50 value of 8.5 microM. (-)-Cotinine and the novel ligand ABT-089 [2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine] acted as weak agonists at the human alpha7 nAChR (1 and 1.5% response at 1 mM, respectively) and inhibited the response to ACh with IC50) values of 175 and 48 microM, respectively. These effects could be explained by receptor desensitization, at least in part.

Human alpha 7 nicotinic acetylcholine receptor responses to novel ligands.

Responses of the human alpha 7 nicotinic acetylcholine receptor (nAChR) in Xenopus laevis oocytes were quantified using two-electrode voltage clamp in the presence of barium (10 mM) to block secondary activation of Ca(2+)-dependent chloride currents. The effect of (S)-3-methyl-5-(1-methyl-2-pyrrolidinyl) isoxazole (ABT-418) and (2,4)-dimethoxybenzylidene anabaseine (GTS-21), two potential compounds for the treatment of Alzheimer's Disease, and of the natural product (+/-)epibatidine were compared to (-)nicotine. (+/-)Epibatidine acted as an agonist and was 64-fold more potent than (-) nicotine (EC50s = 1.30 +/- 0.11 microM and 83 +/- 10 microM, respectively). ABT-418 also was an agonist, 3-fold less potent and 75% as efficacious as (-)nicotine (EC50 = 264 +/- 34 microM). GTS-21, in contrast, inhibited the response to (-)nicotine at concentrations < or = 10 microM and itself elicited only a small response at higher concentrations (12% of the (-)nicotine response at 1 mM). Reversible blockade by methyllycaconitine (10 nM) corroborated the responses as due to activation of alpha 7 nAChR. This represents the first characterization of human alpha 7 nAChR responses to these novel nicotinic agonists.

A-85380 [3-(2(S)-azetidinylmethoxy) pyridine]: in vitro pharmacological properties of a novel, high affinity alpha 4 beta 2 nicotinic acetylcholine receptor ligand.

The in vitro pharmacological properties of a novel cholinergic channel ligand, A-85380 [3-(2(S)-azetidinylmethoxy)pyridine], were examined using tissue preparations that express different putative nAChR subtypes. In radioligand binding studies, A-85380 is shown to be a potent and selective ligand for the human alpha 4 beta 2 nAChR subtype (Ki = 0.05 + 0.01 nM) relative to the human alpha 7 (Ki = 148 +/- 13 nM) and the muscle alpha 1 beta 1 dg subtype expressed in Torpedo electroplax (Ki = 314 +/- 12 nM). The R-enantiomer of A-85380, A-159470, displays little enantioselectivity towards the alpha 4 beta 2 and alpha 1 beta 1 delta gamma subtypes but does not display 12-fold enantioselectivity towards the alpha 7 subtype (Ki = 1275 +/- 199 nM). (+)- and(-)-Epibatidine display similar potencies at the human human alpha 4 beta 2 (Ki = 0.04 +/- 0.02 nM and 0.07 +/- 0.02 nM, respectively), human alpha 7 (Ki = 16 +/- 2 nM and 22 +/- 3 nM, respectively) and muscle alpha 1 beta 1 delta gamma g (Ki = 2.5 +/- 0.9 nM and 5.7 +/- 1.0 nM, respectively) nAChRs. Functionally, A-85380 is a potent activator of cation efflux through the human alpha 4 beta 2 (EC50 = 0.7 +/- 0.1 microM) and ganglionic (EC50 = 0.8 +/- 0.09 microM) subtypes, effects that are attenuated by pretreatment with mecamylamine (10 microM). Further, A-85380 can activate (EC50 = 8.9 +/- 1.9 microM) currents through channels formed by injection of the human alpha 7 subunit into Xenopus oocytes, effects that are attenuated by pretreatment with the alpha 7 nAChR antagonist, methyllycaconitine (10 nM). In all cases, A-85380 is more potent than (-)-nicotine but less potent than (+/-)-epibatidine. In neurotransmitter release studies, A-85380 stimulates the release of dopamine with an EC 50 value of 0.003 +/- 0.001 microM which is equipotent to (+/-)-epibatidine, and 20-fold more potent than (-)-nicotine (EC50 = 0.04 +/- 0.009 microM). Thus, A-85380 displays a profile of robust activation of a number of nAChR subtypes with substantially less affinity for [125I] alpha-BgT sites than [3H](-)-cytisine sites, suggesting that it may serve as a more selective pharmacologic probe for the alpha 4 beta 2 subtype relative to the alpha 7 and alpha 1 beta 1 delta g nAChRs than (+/-)-epibatidine.

Identification and initial structure-activity relationships of (R)-5-(2-azetidinylmethoxy)-2-chloropyridine (ABT-594), a potent, orally active, non-opiate analgesic agent acting via neuronal nicotinic acetylcholine receptors.

New members of a previously reported series of 3-pyridyl ether compounds are disclosed as novel, potent analgesic agents acting through neuronal nicotinic acetylcholine receptors. Both (R)-2-chloro-5-(2-azetidinylmethoxy)pyridine (ABT-594, 5) and its S-enantiomer (4) show potent analgesic activity in the mouse hot-plate assay following either intraperitoneal (i.p.) or oral (p.o.) administration, as well as activity in the mouse abdominal constriction (writhing) assay, a model of persistent pain. Compared to the S-enantiomer and to the prototypical potent nicotinic analgesic agent (+/-)-epibatidine, 5 shows diminished activity in models of peripheral side effects. Structure-activity studies of analogues related to 4 and 5 suggest that the N-unsubstituted azetidine moiety and the 2-chloro substituent on the pyridine ring are important contributors to potent analgesic activity.

Long-term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP.

1. Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response. 2. The beta-adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz. 3. The adenosine receptor agonist 2-chloroadenosine inhibited ACh release and the postganglionic response by about 35%. 4. Tetanic preganglionic stimulation for a few seconds induced a long-term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani. 5. Forskolin and analogues of cyclic AMP also caused a long-lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl- and bromo-purine nucleotides. 6. The effects of forskolin and 8-bromo-cyclic AMP did not appear to be dependent upon extracellular Ca2+. 7. The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors--AH 21-132, papaverine and SQ 20-006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22-536. 8. The neurogenic long-term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin-induced potentiation--papaverine and SQ 20-006. 9. It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long-term potentiation induced by tetanic preganglionic stimulation.

Activation of the 5-HT1C receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393.

1. A cloned 5-HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1-selective benzazepines at the 5-HT1C receptor. Additionally, the apparent binding of the D1-selective benzazepines to 5-HT1C receptors was measured in the choroid plexus of the pig. 2. In voltage-clamped oocytes expressing the cloned 5-HT1C receptor, 5-hydroxytryptamine (5-HT) elicited a characteristic inward current response with an EC50 of 13 nM. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nM. SKF 38393 (1 microM-1 mM), SKF 77434 (100 microM), and SKF 82958 (100 microM) also acted as agonists (or partial agonists) at the cloned 5-HT1C receptor. SKF 38393 was not stereoselective at the 5-HT1C receptor. 3. The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike-like response seen routinely in response to 5-HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5-HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5-HT to each individual oocyte expressing the cloned 5-HT1C receptor. 4. Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5-HT1C receptors in the choroid plexus of the pig (Ki = 6.3 nM), and SKF 38393 bound non-stereoselectively with lower affinity (Ki = 2.0-2.2 microM).5. It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5-HT1c receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5-HTic receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5-HT receptors should be of interest in modelling the interactions of ligands with these G-protein coupled receptors, and in the testing of such models through receptor mutagenesis.

Effect of carbohydrate ingestion on exercise metabolism.

Five male cyclists were studied during 2 h of cycle ergometer exercise (70% VO2 max) on two occasions to examine the effect of carbohydrate ingestion on muscle glycogen utilization. In the experimental trial (CHO) subjects ingested 250 ml of a glucose polymer solution containing 30 g of carbohydrate at 0, 30, 60, and 90 min of exercise; in the control trial (CON) they received an equal volume of a sweet placebo. No differences between trials were seen in O2 uptake or heart rate during exercise. Venous blood glucose was similar before exercise in both trials, but, on average, was higher during exercise in CHO [5.2 +/- 0.2 (SE) mmol/l] compared with CON (4.8 +/- 0.1, P less than 0.05). Plasma insulin levels were similar in both trials. Muscle glycogen levels were also similar in CHO and CON both before and after exercise; accordingly, there was no difference between trials in the amount of glycogen used during the 2 h of exercise (CHO = 62.8 +/- 10.1 mmol/kg wet wt, CON = 56.9 +/- 10.1). The results of this study indicate that carbohydrate ingestion does not influence the utilization of muscle glycogen during prolonged strenuous exercise.

The role of neuronal nicotinic acetylcholine receptors in antinociception: effects of ABT-594.

ABT-594, a nicotinic acetylcholine receptor agonist, has antinociceptive effects in rat models of acute thermal, persistent chemical, and neuropathic pain. Direct injection of ABT-594 into the nucleus raphe magnus (NRM) is antinociceptive in a thermal threshold test and destruction of serotonergic neurons in the NRM attenuates the effect of systemic ABT-594. However, lidocaine-inactivation of the NRM prevents the antinociceptive effect of systemic (-)-nicotine but not that of systemic ABT-594.

Potentiation of nicotinic transmission in the rat superior cervical sympathetic ganglion: effects of cyclic GMP and nitric oxide generators.

The efficacy of nicotinic transmission in the rat superior cervical ganglion in vitro (24-26 degrees C) was estimated by extracellular recording of the postganglionic compound action potential response to stimulation of the preganglionic nerve at a slow rate (one shock every 60 s). Atropine (2 microM) was included to block muscarinic transmission, and hexamethonium (200-250 microM) was used to produce a submaximal response sensitive to potentiation and inhibition of nicotinic transmission. Upon exposure to 1-100 microM 8-bromo-guanosine 3',5'-cyclic monophosphate (8-Br-cGMP), nicotinic transmission was potentiated by 6 +/- 1% (n = 4) to 89 +/- 5% (n = 5) in a dose-dependent manner. 8-Bromo-adenosine 3',5'-cyclic monophosphate (8-Br-cAMP, 10-100 microM) also potentiated nicotinic transmission (3.8 +/- 0.3% (n = 3) to 43 +/- 4% (n = 3)). However, 8-Br-cGMP was at least 2-fold more effective than 8-Br-cAMP. Sodium nitroprusside (0.1 microM to 1 mM) and sodium azide (0.1-100 microM) were used to stimulate the formation of endogenous cGMP52. Nicotinic transmission was potentiated by these substances also. The response was increased by 3.4 +/- 0.7% (n = 4) to 32 +/- 2% (n = 5) upon exposure to 0.1-100 microM sodium nitroprusside, and by 5.5 +/- 0.9% (n = 3) to 18 +/- 4% (n = 4) upon exposure to 0.1-100 microM sodium azide. Ferricyanide ion (10-100 microM) appeared to be ineffective, as would be expected if the effect of nitroprusside was due to the nitric oxide rather than the cyanide or ferric moieties.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence that nitric oxide mediates the cyclic GMP response to synaptic activity in the rat superior cervical ganglion.

Preganglionic nerve stimulation in the rat superior cervical ganglion (SCG) caused an increase in guanosine 3':5'-cyclic monophosphate (cyclic GMP) in a Ca(2+)-dependent manner. This increase was inhibited by oxyhaemoglobin, and blocked stereoselectively by an inhibitor of nitric oxide synthase, NG-nitro-L-arginine. Thus, nitric oxide or a similar substance appears to mediate the neuronal cyclic GMP response to synaptic activity in the rat SCG.

Epibatidine, a nicotinic acetylcholine receptor agonist, inhibits the capsaicin response in dorsal root ganglion neurons.

In patch-clamp recordings from small-medium diameter dorsal root ganglion neurons in culture, (+/-)-epibatidine (1 microM) was able to inhibit the capsaicin response (IC(50)=0.32 microM) in neurons where there was no detectable direct nicotinic response. Thus, (+/-)-epibatidine may inhibit the vanilloid receptor in a manner that is not dependent upon nicotinic current activation, representing another mechanism by which such ligands could modulate vanilloid receptor signaling.

Gain of function mutation of the alpha7 nicotinic receptor: distinct pharmacology of the human alpha7V274T variant.

In the human alpha7 nicotinic receptor, valine-274 in the pore-lining transmembrane-2 region was mutated to threonine to produce the variant human alpha7V274T, which was evaluated electrophysiologically following expression in Xenopus laevis oocytes. Inward current rectification was strong in human alpha7V274T as in the human alpha7 wild type nicotinic receptor. However, human alpha7V274T was 100-fold more sensitive to the nicotinic receptor agonists acetylcholine, (-)-nicotine and 1,1-dimethyl-4-phenylpiperazinium. Choline also activated human alpha7V274T (EC50 = 12 microM) and was 82-fold more potent than at human alpha7 wild type nicotinic receptor. (-)-Cotinine, (2,4)-dimethoxybenzylidene anabaseine (GTS-21) and 2-methyl-3-(2-(S)-pyrrolidinylmethoxy)pyridine (ABT-089), weak partial agonists at human alpha7 wild type, were much stronger agonists at human alpha7V274T with EC50 values of 70 microM, 4 microM and 28 microM and fractional activation values of 93%, 96% and 40%, respectively. However, (-)-lobeline, a human alpha7 wild type nicotinic receptor antagonist, and dihydro-beta-erythroidine, which activates chick mutagenized alpha7 nicotinic receptors, had only weak agonist-like activity at human alpha7V274T (< or = 4% of the maximal acetylcholine response). Methyllycaconitine, mecamylamine, d-tubocurarine and dihydro-beta-erythroidine retained antagonist activity and, indeed, appeared to be at least as potent at human alpha7V274T as at human alpha7 wild type. These results support and extend the concept that human nicotinic receptor pharmacology can be profoundly altered by single amino acid changes in the pore-lining segment.

Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo.

(2.4)-Dimethoxybenzylidene anabaseine dihydrochloride (GTS-21), a compound that interacts with rat neuronal nicotinic acetylcholine receptors (nAChRs), was evaluated using human recombinant nAChRs in vitro and various pharmacokinetic and behavioral models in rodents, dogs and monkeys. GTS-21 bound to human alpha 4 beta 2 nAChR (K1-20 nM) 100-fold more potently than to human alpha 7 nAChR, and was 18- and 2-fold less potent than (-)-nicotine at human alpha 4 beta 2 and alpha 7 nAChR, respectively. Functionally. GTS-21 stimulated [5H]dopamine release from rat striatal slices with an EC50 of 10 +/- 2 microM (250-fold less potent and 70% as efficacious as (-)-nicotine), an effect blocked by the nAChR antagonist dihydro-beta-erythroidine. However, GTS-21 did not stimulate human alpha 4 beta 2 nor human ganglionic nAChRs significantly. In vivo, GTS-21 had no adverse effect on dog blood pressure (< or = 2.5 micromol/kg i.v. bolus infusion), in marked contrast with (-)-nicotine, GTS-21 (-62 micromol/kg.s.e.) also did not cross-discriminate significantly with (-)-nicotine in rats and did not reduce temperature or locomotion in mice. Neither was it active in the elevated plus maze anxiety model (0.19-6.2 micromol/kg.IP) in normal mice. However, GTS-21 did improve learning performance of monkeys in the delayed matching-to-sample task (32-130 nmol/kg.i.m.).

Attachments of the posterior layer of lumbar fascia.

STUDY DESIGN: Superficial and deep laminae of the posterior layer of lumbar fascia were dissected. The lumbar portion was measured for evidence of segmental thickenings. Superior attachments were dissected, documented, and photographed. OBJECTIVES: To verify the existence of posterior accessory ligaments and establish the superior attachments and fiber angles of the posterior layer of lumbar fascia. SUMMARY OF BACKGROUND DATA: There have been two small dissection studies on the posterior layer. Their findings are conflicting in several areas of clinical significance. Thickenings in the lumbar region were described in one study, but have not been verified. The superior attachments of the posterior layer have not been formally documented. METHODS: Study 1: In 21 embalmed cadavers, the lumbar region of the posterior layer was dissected. The lumbar spinous processes and adjacent fascia were marked. The fascia was removed and examined, and its thickness measured with a manual micrometer. Results were statistically analyzed. Study 2: Superior attachments of the posterior layer in 20 cadavers were dissected and photographed. Capacity to transmit tension was estimated and documented photographically, and fiber angles measured in situ. RESULTS: Study 1: There was no evidence of macroscopic segmental thickening in the posterior layer. Study 2: The superficial lamina was continuous superiorly with the rhomboids, and the deep lamina with the tendons of splenius cervices and capitis. These previously undocumented attachments were of variable thickness and fibrosity, and capable of transmitting tension. CONCLUSIONS: Both superficial and deep laminae of the posterior layer are more extensive superiorly than previously thought. This may have implications for certain tests used in assessment and management of low back pain such as the slump and "nonorganic" tests. The thickness of the superior attachments is variable. Their capacity for load bearing is yet to be quantified.

Histology of the fascial-periosteal interface in lower limb chronic deep posterior compartment syndrome.

OBJECTIVE: To describe the histological features of the fascial-periosteal interface at the medial tibial border of patients surgically treated for chronic deep posterior compartment syndrome and to make statistical comparisons with control tissue. METHODS: Nineteen subjects and 11 controls were recruited. Subject tissue was obtained at operation, and control tissue from autopsy cases. Tissue samples underwent histological preparation and then examination by an independent pathologist. Samples were analysed with regard to six histological variables: fibroblastic activity, chronic inflammatory cells, vascularity, collagen regularity, mononuclear cells, and ground substance. Collagen regularity was measured with respect to collagen density, fibre arrangement, orientation, and spacing. The observed changes were graded from 1 to 4 in terms of abnormality. Mann-Whitney U test, Spearman correlation coefficients, and intraobserver reliability scores were used. RESULTS: With regard to collagen arrangement, control tissue showed greater degrees of irregularity than subject tissue (p = 0.01). Subjects with a symptom duration of greater than 12 months (as opposed to less than 12 months) showed greater degrees of collagen irregularity (p = 0.043). Vascular changes approached significance (p = 0.077). With regard to the amount of fibrocyte activity, chronic inflammatory cell activity, mononuclear cells, or ground substance, there were no significant differences between controls and subjects. Good correlation was seen in scores measuring chronic inflammatory cell activity and mononuclear cells (r = 0.649), and moderate correlation was seen between fibrocyte activity and vascular changes (r = 0.574). Intraobserver reliability scores were good for chronic inflammatory cell activity and moderate for vascular changes, but were poor for collagen and fibrocyte variables. Individual cases showed varying degrees of fibrocyte activity, chronic inflammatory cellular infiltration, vascular abnormalities, and collagen fibre disruption. CONCLUSIONS: Statistical analysis showed no histological differences at the fascial-periosteal interface in cases of chronic deep posterior compartment syndrome, except for collagen, which showed less irregularity in subject samples. The latter may indicate a remodelling process, and this is supported by greater collagen irregularity in subjects with longer duration of symptoms.

Informed refusal and patient autonomy: using reflection to examine how nursing knowledge and theory affect attitudes.

Reflection is a medium increasingly being used in nursing to explore critical incidents, promote learning and integrate theory and practice. In this paper reflection is used to explore the influences of different types of nursing knowledge and theory upon reactions to informed refusal of treatment and the concept of patient autonomy. The paper contains consideration of the care of a Jehovah's Witness and her family who refused a badly-needed blood transfusion.