Bridget Wardley-Smith

Effect of excitatory amino acid antagonists on the high pressure neurological syndrome in rats

The onset pressures for the tremor, myoclonus and convulsions seen in the high pressure neurological syndrome (HPNS) are increased following cis-2,3-piperidine dicarboxylic acid 1 mmol/kg in the rat. Glutamic acid diethyl ester 1-3 mmol/kg has no effect on tremor or myoclonus, but increases the convulsion pressure when 3 mmol/kg is given immediately before compression. These and earlier data with 2-amino-7-phosphonoheptanoic acid suggest that excitation at the N-methyl-D-aspartate receptor is important in HPNS tremor, and that excitation at the quisqualate receptor contributes to HPNS convulsions.

Treatment with parathyroid peptides and estrogen replacement for severe postmenopausal vertebral osteoporosis: prediction of long-term responses in spine and femur

Abstract Fifteen women with severe vertebral osteoporosis were treated with daily parathyroid peptide (hPTH) plus hormone-replacement co-therapy (HRT) for 1 year. Eight other patients were randomized to HRT alone. Co-therapy with hPTH and HRT resulted in an impressive mean treatment response at the spine (dual-energy X-ray absorptiometry DXA) 15% above baseline; P < 0.015 compared with the HRT group) at 2 years, while at the proximal femur and radius there were smaller increases. hPTH co-therapy led to a significantly positive metabolic calcium balance at 1 year (by 2.13 mmol Ca/day, equivalent to a 5% annual increment in total body calcium; P = 0.015). The magnitude of the lumbar spine DXA response at 2 years depended statistically on the increase in bone formation rate, measured with 85Sr (r2 adjusted 0.48; P < 0.005) and patients with a large spine DXA response had larger calcium balance improvements (P < 0.03). Plasma osteocalcin changes tracked closely with increases in bone formation rate (r2 = 0.87). In seven patients treated throughout with HRT alone, and in eight hPTH-treated patients (three of whom switched to bisphosphonate therapy at year 4), DXA spine changes seen in years 3–5 were minimal, with no evidence of a statistically significant difference between groups. It is concluded that hPTH or comparable PTH receptor activators remain the most promising anabolic treatment for osteoporosis currently under clinical evaluation and a 6- or 12-month measurement of bone formation or a marker predicts the 2–5 year bone density outcome. Post-hPTH treatment, loss of bone appeared preventable with anti-resorptive therapy.

Dietary determinants of post-menopausal bone loss at the lumbar spine: a possible beneficial effect of iron

IntroductionPrevious studies suggesting different effects of diet on post-menopausal bone loss may have given conflicting results because they sometimes failed to exclude confounding conditions or used imprecise methodology.DesignTo identify dietary determinants of bone loss from the lumbar spine after menopause in women not taking hormone replacement who developed no evidence of spondylotic or sclerotic degenerative disease, forty-three women were followed with repeated (mean = 12) measurements of bone mineral density (BMD) at L2–4 for 11–14 years. Eleven developed evidence suggestive of degenerative disease and were excluded. Diet was assessed at the beginning of the study and 2.5 years later using 3-day and 7-day periods of weighed intakes. Nutrients estimated were: carbohydrate, fat, protein, fibre, calcium, magnesium, iron, phosphorus, copper, zinc and six vitamins. We tested the ability of diet to predict post-menopausal bone loss using stepwise regression.ResultsEach woman’s BMD change was described by a single coefficient after log transformation of the BMD data. The best model for BMD loss including dietary factors alone had two significant determinants: daily energy or protein (p=0.0003) intake was adverse, while dietary iron (p=0.002) was predictive of bone maintenance, an effect that persisted if iron was expressed as a ratio to energy intake. Adding body mass index to the model increased the goodness of fit (R2adj rose from 0.33 to 0.42) without affecting the statistical significance of the dietary determinants.ConclusionsDiet may influence bone loss after menopause, with dietary iron (or an associated factor) possibly having a protective effect on bone at the spine.

Mechanism of inhibition of bacterial luciferase by anaesthetics.

Abstract The effects of volatile anaesthetics on bacterial luciferase were studied in vitro . It was shown that the concentration of anaesthetic required to inhibit the reaction velocity by 50% was similar to that required to reduce light output by 50% in vivo and this concentration was also in the clinical range for each agent. A kinetic response suggestive of competitive inhibition is occuring at the aldehyde binding site on the luciferase and it is postulated that this is related to the very hydrophobic nature of this site.

Studies on the role of the NMDA receptor in the substantia nigra pars reticulata and entopeduncular nucleus in the development of the high pressure neurological syndrome in rats.

SummaryThe effect of the focal injection of N-methyl-D-aspartate (NMDA) and 2-amino-7-phosphonoheptanoate (APH) into the substantia nigra pars reticulata (SNR) and entopeduncular nucleus (EP) on behavioural signs of the high pressure neurological syndrome (HPNS) in rats was studied. Doses of 1, 5 and 10 nmoles of NMDA or APH were injected into the SNR or EP, 10–30 min prior to the exposure of animals to a high pressure. Injection of NMDA into either SNR or EP results in a lowering of the threshold pressure for tremor by about 30%. Injection of NMDA into the SNR has no significant effect on clonic seizures whereas its injection into the EP results in a decrease of threshold pressure for clonic seizures. NMDA also facilitates the occurrence of forelimb clonus when injected into the EP. Injection of the NMDA antagonist, APH, into the SNR or EP significantly increases the threshold pressure of tremor (32.8 and 48.2% respectively). Seizure threshold is also increased by the injection of APH into either area, but nigral injections (especially the higher doses) are more protective against seizures than the EP injections. Comparing the two sites blockade of NMDA receptors within the EP is more protective against tremor, whereas in the SNR NMDA blockade is more protective against seizures.

Regional Amino Acid Concentration in the Brains of Rats Exposed to High Pressures

Regional amino acid concentrations were measured in rat brain fixed by microwave irradiation at three levels of elevated atmospheric pressure corresponding to different phases of the high‐pressure neurological syndrome [20 atmospheres absolute (ATA), no clinical signs; 60 ATA, tremor; 85 ATA, severe tremor and myoclonic jerks]. No changes in amino acid content occurred at 20 or 60 ATA. At 85 ATA glutamine content increased in hippocampus, striatum, cerebellum, and substantia nigra, and γ‐aminobutyric acid content increased in hippocampus. It is suggested that enhanced glutamate release in various subcortical structures contributes to the myoclonic activity observed at 85 ATA.

Effect of NMDA and 2-amino-7-phosphonoheptanoate focal injection into the ventrolateral thalamic nucleus on the high pressure neurological syndrome in the rat

We report the effect of focal injections of N-methyl-D-aspartate (NMDA, 5 nmol) and 2-amino-7-phosphonoheptanoate (APH, 5 and 10 nmol) into the ventrolateral thalamic nucleus on behavioural symptoms of the high pressure neurological syndrome in rats. The injection of NMDA significantly lowers the threshold pressure for tremor and increases its intensity. The injection of APH significantly increases the threshold pressure for tremor and decreases its intensity. APH, 10 nmol, significantly increases the threshold pressure for myoclonus and convulsions. These protective effects are, however, less pronounced than those produced by either systemic injection of APH or its focal infusion into the basal ganglia output system.

The high pressure neurological syndrome in genetically epilepsy prone rats : protective effect of 2-amino-7-phosphono heptanoate

Genetically epilepsy prone rats (GEPR) are hypersensitive to various epileptogenic treatments and undergo characteristic generalized seizures when exposed to potent acoustic stimulation. We have studied the sensitivity of GEPR to high atmospheric pressure. Threshold pressures for behavioral symptoms of the high pressure neurological syndrome (HPNS) were recorded in normal Sprague-Dawley (SD) and GEPR (which originate from the SD strain) of both sexes. The threshold pressure (TP) for tremor and for convulsion was significantly lower in GEPR than in SD rats. The protective action of the NMDA receptor antagonist D-2-amino-7-phosphono-heptanoate (D-APH) was tested on both strains of rats. D-APH, 90 mg/kg ip was more protective against tremor in SD than in GEPR. Female GEPR were not protected against tremor. Protection against clonic seizures was similar in both sexes of GEPR and female SD rats while SD males were not significantly protected. None of the animals treated with D-APH developed the tonic phase of seizures. Blockade of the NMDA receptor with D-APH brought the threshold for convulsions in GEPR to a similar pressure to that obtained in SD vehicle-injected controls. This findings suggests the involvement of the excitatory amino acid system in the hypersensitivity of GEPR to high atmospheric pressure.

The effect of two novel dipeptide antagonists of excitatory amino acid neurotransmission on the high pressure neurological syndrome in the rat

Intracerebroventricular injection in the rat of beta-D-aspartyl aminomethylphosphonate (Asp-Amp) 1 mumol, or Y-D-glutamylaminomethylsulphonate (GAMS) 1 mumol, increases the onset pressure for the initial tremor phase of the high pressure neurological syndrome (HPNS) by 50%. Asp-Amp also significantly increases the onset pressures for myoclonus and for tonic-clonic seizures. GAMS did not significantly change the onset pressures for myoclonus or tonic clonic seizures, but it caused the appearance of brief clonic seizures prior to the onset of the HPNS.

Pressure reversal of alphaxalone/alphadolone and methohexitone in tadpoles: evidence for different molecular sites for general anaesthesia

1 Tadpoles were used to study quantitative interactions between high pressure and two intravenous anaesthetics, alphaxalone/alphadolone and methohexitone. 2 The potencies of the two agents were decreased by high pressure but to different extents. The maximum effect was seen in the pressure range 70–130 atmospheres absolute (ATA). The increases in the normobaric anaesthetizing concentration (ED50) required at 100 ATA were alphaxalone/alphadolone:405 ± 5 (s.d.)%; methohexitone:658 ± 80 (s.d.)%. 3 For both alphaxalone/alphadalone and methohexitone, the curves obtained when the increase in ED50 was plotted against increasing pressure showed plateaux at pressures above 70 ATA. 4 These data support the concept of the two intravenous drugs causing general anaesthesia by the occupation of separate molecular ‘sites’ with different but finite capacities.