Biomedical subjects

J Philpot

Publications and source records attributed to J Philpot.

33 records · Page 2Linked to original sources

PubMed1995

Demyelinating peripheral neuropathy in merosin-deficient congenital muscular dystrophy.

It has recently been shown that merosin, a laminin variant, is deficient in a proportion of patients with congenital muscular dystrophy. Merosin is a heterotrimer composed of the alpha 2, beta 1, and gamma 1 subunits, and further studies have shown that it is the alpha 2 subunit that is deficient in these patients. Because the alpha 2 subunit is also expressed in S-merosin, found in Schwann cells, we have investigated whether peripheral nerve function is also affected in these patients. Motor nerve conduction velocities and sensory distal latencies were examined in 25 cases of congenital muscular dystrophy and the results correlated with the merosin expression in their muscle biopsies. All but two of the 10 merosin-deficient cases had reduced motor nerve conduction, whereas all the merosin-positive cases had normal results. Analysis of the biopsies of these two cases showed that they produced merosin in reduced amounts, in contrast to all other merosin-deficient patients that produced no or only traces of merosin. Sensory nerve studies showed no difference between the two groups. These results indicate that a peripheral demyelinating neuropathy is a feature of merosin-deficient congenital muscular dystrophy. The fact that the alpha 2 subunits is also expressed in Schwann cells supports the idea that the alpha 2 gene, located on chromosome 6, is the candidate gene for merosin-deficient congenital muscular dystrophy.

Adolescent↗

PubMed1994

Localization of merosin-negative congenital muscular dystrophy to chromosome 6q2 by homozygosity mapping.

Congenital muscular dystrophies (CMD) are autosomal recessive, heterogeneous disorders. The commonest forms are the Fukuyama CMD (FCMD), associated with mental retardation and structural brain anomalies, and classical (occidental) CMD, with pure muscle expression. FCMD has been localized to chromosome 9q31-q33. Following the discovery of merosin deficiency in some CMD cases, we have localized, by homozygosity mapping and linkage analysis (Zmax = 5.6; theta = 0.0 for marker AFM127xb2) in four merosin-negative families a CMD gene in a 16 cM region of chromosome 6q2 in the region of the laminin M chain gene. In three consanguineous, merosin-positive, CMD families there was no linkage to either chromosome 6q2 or 9q31-q33.

Chromosome Mapping↗

PubMed1987

A study of the possible influence of central 5-HT function on clonidine-induced hypoactivity responses in mice.

Administration of the alpha 2-adrenoceptor agonist clonidine (0.1 mg/kg) produces hypoactivity in mice. This sedation response was unaltered by pretreatment with either the 5-HT reuptake inhibitor zimeldine (1 or 10 mg/kg) or the 5-HT agonist quipazine (0.25 or 2.5 mg/kg). The 5-HT1B agonist RU 24969 (0.2 or 1 mg/kg) enhanced hypoactivity responses at the higher dose. The non-selective 5-HT antagonists methysergide (1 or 10 mg/kg) and metergoline (0.2 or 1 mg/kg) potentiated clonidine-induced hypoactivity. However, the marked enhancement produced by metergoline may have been due to its potent action as a alpha 1-adrenoceptor antagonist. Nevertheless, the 5-HT2 antagonists ritanserin (0.1 or 1 mg/kg) and ketanserin (0.1 or 1 mg/kg) both potentiated clonidine hypoactivity in a dose-dependent manner. beta-Adrenoceptor antagonists also inhibit 5-HT1 receptors at high dose. Pindolol (10 mg/kg) had no effect on sedation, but [-]-propranolol (20 mg/kg) caused some attenuation. This latter effect was probably not due to inhibition of 5-HT1 receptors, because this reduction also occurred at low dose (2 mg/kg). Destruction of 5-HT neurones by intracerebroventricular injection of 5,7-dihydroxytryptamine (50 micrograms) resulted in a marginal increase in hypoactivity. In conclusion, these data shown that central 5-HT function can influence alpha 2-adrenoceptor-mediated hypoactivity responses. However, since these effects were usually only apparent after severe manipulation of 5-HT function, it suggests that while these interactions may be of pharmacological interest, they are probably not of physiological importance.

5,7-Dihydroxytryptamine↗

PubMed1986

The influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice: possible implications for the actions of antidepressant drugs.

This study has investigated the influence of central noradrenergic function on 5-HT2-mediated head-twitch responses in mice. Central injection of low doses of the alpha 1-adrenoceptor agonists phenylephrine or methoxamine, or peripheral administration of the antagonist prazosin had no effect on the head-twitches induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT). High doses of both alpha 1-adrenoceptor agonists and antagonists markedly inhibited this response. Head-twitches induced by 5-MeODMT were potently inhibited by low doses of the alpha 2-adrenoceptor agonist clonidine, and potentiated by the antagonists idazoxan and yohimbine. Clonidine also potently inhibited this response when produced by 5-hydroxytryptophan (5-HTP) and carbidopa. The action of the beta-adrenoceptor agonist clenbuterol on head-twitches was paradoxical, this drug enhancing the responses to precursor loading (5-HTP/carbidopa) but inhibiting those induced by direct agonists (5-MeODMT, quipazine). Lesioning noradrenergic neurons by central injection of 6-hydroxydopamine (6-OHDA) or peripheral administration of DSP-4 resulted in enhanced head-twitch behaviour. 6-Hydroxydopamine lesioning did not alter the inhibition of head-twitch responses by clonidine but prevented their enhancement following withdrawal from repeated desmethylimipramine (DMI) administration. It is therefore suggested that head-twitch behaviour may be under tonic control by a population of alpha 2-adrenoceptors which are not on presynaptic noradrenergic terminals, but are postsynaptic and located "down-stream" of the 5-HT2 receptor. In addition, the enhancement of this behaviour produced by withdrawal from repeated DMI administration probably also resulted from alterations in central noradrenergic function.

Animals↗

PubMed1985

Intracerebroventricular administration of 5,7-dihydroxytryptamine to mice increases both head-twitch response and the number of cortical 5-HT2 receptors.

5-Hydroxytryptamine-containing (5-HT) neurones in brain of the mouse were selectively destroyed by intracerebroventricular injection of 5,7-dihydroxytryptamine (5,7-DHT, 50 micrograms). Sham-lesioned controls received vehicle (2 microliters, i.c.v.). Two weeks later the head-twitch response induced by 5-methoxy-N,N-dimethyltryptamine (2.0 mg/kg) and mediated by 5-HT2 receptors was markedly enhanced in the lesioned mice. Furthermore, lesioning also increased 5-HT2 binding sites in the cortex, assessed by the binding of [3H]ketanserin in these animals, and decreased levels of 5-HT in the cortex (70%) and mid/hindbrain (64%) regions. A second group of mice, lesioned with less 5,7-DHT (5-20 micrograms, i.c.v.) showed unaltered head-twitch responses to 5-methoxy-N, N-dimethyltryptamine (2.0 mg/kg) and did not have increased 5-HT2 receptor binding in the cortex. Depletions of 5-HT were 32 and 40% in the cortex and mid/hindbrain, respectively. Comparison of the extent of depletion of 5-HT in the mid/hindbrain after lesioning, with the increase in head-twitch response, suggested that depletions of less than 40% did not affect this behaviour. However, depletions greater than 40% produced marked increases in this response and there was a good correlation between these two variables (r=0.701, P less than 0.01). In conclusion, these data suggest that enhanced head-twitch responses occurring after lesioning with 5,7-DHT may result from increased 5-HT2 receptors in brain. Moreover, the magnitude of the observed behavioural enhancement was dependent upon the extent of depletion of 5-HT produced by the lesioning.

5,7-Dihydroxytryptamine↗

PubMed1985

Postmortem evaluation of Alzheimer's disease.

Postmortem evaluation of ten individuals with a diagnosis of Alzheimer's disease (AD) confirmed the clinical diagnostic accuracy at our institution and showed significant ventricular dilatation with reduced brain mass, increased neuritic plaques, neurofibrillary tangles, vascular amyloid, and Lewy bodies in these individuals. A matched control group had no or fewer cortical neuritic plaques and neurofibrillary tangles, and two of the four control patients with rare neuritic plaques had terminal dementia. Cancer and cardiovascular disease occurred more often in the control group, but pneumonia and respiratory failure were more prevalent in the patients with AD. Thorough clinical assessment can accurately indicate Alzheimer's disease, as shown in this study.

Aged↗

PubMed1985

Infantile hematomyelia complicating electrocardioversion.

A premature male infant survived for eight months with significant cardiorespiratory problems. He developed a sudden, unexplained cardiorespiratory arrest that required vigorous resuscitation with apparent electrical cardioversion. Subsequent postmortem examination demonstrated focal and confluent hemorrhages in the thoracic and lumbar cord. Care is advised in administering electrical cardioversion due to the potential hazard of hematomyelia.

Autopsy↗

PubMed1977