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J M Barnes

Publications and source records attributed to J M Barnes.

At least 55 records · Page 3Linked to original sources

The actions of (-)N-n-propylnorapomorphine and selective dopamine D1 and D2 receptor agonists to modify the release of [3H]dopamine from the rat nucleus accumbens.

The ability of (-)N-n-propylnorapomorphine and selective D1 and D2 dopamine receptor agonists and antagonists to modify the release of [3H]dopamine, induced by potassium from the nucleus accumbens, was studied using an in vitro superfusion technique. (-)N-n-Propylnorapomorphine, in picomolar concentrations, inhibited the release of [3H]dopamine, the inhibition being antagonised by fluphenazine and the selective D2 receptor antagonist sulpiride; the selective D1 receptor antagonist SCH 23390 was ineffective. The selective D1 receptor agonist SKF 38393 and the selective D2 agonist quinpirole, both inhibited the potassium-induced release of [3H]dopamine; no synergistic effect was observed to a combined treatment with SKF 38393 and quinpirole. The effects of SKF 38393 and quinpirole were selectively antagonised by SCH 23390 and sulpiride, respectively, although both antagonists failed to modify the release of [3H]dopamine when administered alone. Receptor antagonists for other transmitter sites, e.g. noradrenaline, 5-hydroxytryptamine and acetylcholine, failed to modify potassium-induced release of [3H]dopamine, when administered alone or to prevent the inhibition of the release caused by (-)N-n-propylnorapomorphine. It is concluded that the action of dopamine agonists on both dopamine D1 and D2 receptors in the nucleus accumbens can reduce the release of [3H]dopamine in the in vitro system. Comparable actions in vivo may contribute to the ability of dopamine agonists to moderate locomotor responding.

2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗

Characterisation and autoradiographic localisation of 5-HT3 receptor recognition sites identified with [3H]-(S)-zacopride in the forebrain of the rat.

The pharmacological characterisation and topographical distribution of [3H]-(S)-zacopride recognition sites in the forebrain of the rat was studied using homogenate and autoradiographic radioligand binding techniques. [3H]-(S)-Zacopride labelled a single, saturable, specific binding site (defined by 10.0 microM granisetron) in homogenates prepared from the entorhinal cortex of the rat (pKD = 9.51 +/- 0.08; Bmax = 104 +/- 7 fmol mg-1 protein; mean +/- SEM, n = 8). Pharmacological characterisation of the recognition site, within the entorhinal cortex, suggested that [3H]-(S)-zacopride selectively labelled the recognition site of the 5-HT3 receptor. Specific binding of [3H]-(S)-zacopride (defined by 1.0 microM granisetron) was differentially distributed throughout the forebrain of the rat; highest densities were located within sub-nuclei of the amygdala (cortical amygdaloid nucleus, amygdalohippocampal area, posterior medial cortical amygdaloid nucleus, posterior lateral amygdaloid nucleus), cortical areas (primary olfactory cortex, entorhinal cortex) and hippocampus. Non-specific binding was distributed homogeneously, although lower in myelinated structures. It is concluded that [3H]-(S)-zacopride selectively labels 5-HT3 receptor recognition sites within the forebrain of the rat; the topographical distribution of these sites, within the limbic nuclei, is consistent with the behavioural actions in animal models of the selective 5-HT3 receptor antagonists.

Animals↗

The effects of ondansetron, a 5-HT3 receptor antagonist, on cognition in rodents and primates.

The selective 5-HT3 receptor antagonist, onansetron, has been assessed in three tests of cognition in the mouse, rat and marmoset. In a habituation test in the mouse, ondansetron facilitated performance in young adult and aged animals, and inhibited an impairment in habituation induced by scopolamine, electrolesions or ibotenic acid lesions of the nucleus basalis magnocellularis. Arecoline failed to improve basal performance in young adult mice but inhibited the impairment caused by scopolamine and lesions of the nucleus basalis magnocellularis. In the T-maze reinforced alternation task in rats, ondansetron and arecoline antagonised a scopolamine-induced impairment. In an object discrimination and reversal learning task in the marmoset, assessed using a Wisconsin General Test Apparatus, ondansetron improved performance in a reversal learning task. We conclude that ondansetron potently improves basal performance in rodent and primate tests of cognition and inhibits the impairments in performance caused by cholinergic deficits.

Aging↗

The differential activities of R (+)- and S(-)-zacopride as 5-HT3 receptor antagonists.

R(+)- and S(-)-zacopride were assessed as potential 5-HT3 receptor antagonists in behavioural and biochemical tests. The S(-)isomer was more potent than the R(+)isomer to antagonise the hyperactivity induced by the injection of amphetamine or the infusion of dopamine into the nucleus accumbens in the rat. In contrast, the R(+)isomer was more potent to reduce the aversive behaviour of mice to a brightly illuminated environment and in a marmoset human threat test, to facilitate social interaction in rats, to increase performance in a mouse habituation test and prevent a scopolamine-induced impairment, and to antagonise the inhibitory effect of 2-methyl-5-hydroxytryptamine to reduce [3H]acetylcholine release in slices of the rat entorhinal cortex. In binding assays, [3H]S(-)-zacopride and [3H]R(+)-zacopride labelled homogenous populations of high-affinity binding sites in the rat entorhinal cortex, R(+)-zacopride compete for a further 10 to 20% of the binding of [3H]R(+)/S(-)-zacopride or [3H]R(+)-zacopride in excess of that competed for by (S)(-)-zacopride. It is concluded that both isomers of zacopride have potent but different pharmacological activities, with the possibility of different recognition sites to mediate their effects.

Animals↗

Neurochemical consequences following injection of the substance P analogue, DiMe-C7, into the rat ventral tegmental area.

The effect on forebrain catecholamine- and indoleamine-related neurochemical levels was investigated following stimulation of the rat ventral tegmental area with the substance P analogue, DiMe-C7. DiMe-C7 (6.0 micrograms) induced a marked hyperactivity in rats with maximal response between 15 and 30 min following the injection. Fifteen min following the DiMe-C7 injection levels of dopamine and/or its metabolites (3,4-dihydroxyphenylacetic acid, homovanillic acid) were significantly increased in the nucleus accumbens, amygdala, entorhinal cortex and striatum relative to vehicle-injected animals. Although the increase in dopamine metabolism in the nucleus accumbens is consistent with the behavioural hyperactivity, it is concluded that other forebrain nuclei may also be involved in the mediation of the hyperactivity response.

Animals↗

Biochemical models for cognition enhancers.

Although the etiology of Alzheimer's disease includes a wide range of dysfunction, the most essential dysfunction is probably in the mesolimbic acetylcholine (ACh) system. Three novel approaches to modulating ACh function were considered, somatostatin, serotonin (5-HT) and modulation of cortical ACh tone through angiotension II. Concerning somatostatin there is no correlation between the decrease in somatostatin binding sites in brain and choline-acetyl-transferase activity suggesting that modulating somatostatin is not a promising therapeutic approach to Alzheimer's disease. With 5-HT, evidence suggests that 5-HT receptors (in particular 5HT1A) are located on cholinergic projections and behavioral evidence suggests 5-HT modulation of memory function. This area could therefore develop rapidly, particularly in view of the recent discovery of numerous subtypes of 5-HT receptor. Concerning the third approach, recent evidence has shown that angiotensin converting enzyme (ACE) inhibitors can facilitate ACh release and also possess cognition enhancing activity. The possibility was also evoked that drugs such as piracetam might prevent age-related decreases in ACh receptor density. Concerning trophic factors (e.g. glutamate-induced neuronal sprouting) most approaches have induced amnesia but the search for partial glutamate agonists may have potential. Finally, a neuronal transplant approach was considered but was thought to be very difficult in view of the global brain shrinkage associated with aging and Alzheimer's disease.

Alzheimer Disease↗

Angiotensin II inhibits cortical cholinergic function: implications for cognition.

In the present studies we have shown that angiotensin II (AT II), in a concentration-dependent manner in rat tissue (10(-9)-10(-5) M) or at a single concentration in human tissue (10(-6) M), can inhibit potassium-stimulated release of [3H]acetylcholine ( [3H]Ach) from slices of rat entorhinal cortex and human temporal cortex preloaded with [3H]choline for the biochemical analyses. The inhibitory effects of AT II (10(-6) M) were antagonised by the specific AT II receptor antagonist [1-sarcosine, 8-threonine]AT II in a concentration-dependent manner in rat tissue (10(-11)-10(-8) M) and at the single concentration employed in the human studies (10(-7) M). Also demonstrated were other components of the angiotensin system in the human temporal cortex; ACE activity was present (1.03 nmol min-1 mg-1 protein), as were AT II recognition sites (Bmax = 8.6 fmol mg-1 protein). It is hypothesised that the potential cognitive enhancing properties of ACE inhibitors may reflect their action to prevent the formation of AT II and so remove an inhibitory modulator of cholinergic function.

Acetylcholine↗

Angiotensin II inhibits the release of [3H]acetylcholine from rat entorhinal cortex in vitro.

The effects of angiotensin I and II on basal potassium-induced release of [3H]acetylcholine were investigated in slices of rat entorhinal cortex. Potassium (10-25 mM) produced a concentration-dependent increase in the release of [3H]acetylcholine in the presence of extracellular calcium. Angiotensin II (10(-9)-10(-5) M) (but not angiotensin I) reduced the potassium-induced release of [3H]acetylcholine in a concentration-related manner to 60% of control levels, but did not effect basal tritium release. The effect of angiotensin II was antagonised by [1-sarcosine, 8-threonine] angiotensin II, an angiotensin II receptor antagonist, but not by agents acting on alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine or 5-hydroxytryptamine receptors nor by the angiotensin converting enzyme (ACE) inhibitor SQ 29852. The results indicate that angiotensin II acting via an angiotensin II receptor can inhibit the release of [3H]acetylcholine in slices of the rat entorhinal cortex. It is hypothesised that the ability of ACE inhibitors to facilitate cognitive processes may be related to a reduced availability of angiotensin II.

Acetylcholine↗

Results of the United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies.

The United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies were undertaken to establish standard protocols for investigating, staging, and treating children, and to study the efficacy of new drug combinations and the value of serial measurement of serum alphafetoprotein (AFP) and human chorionic gonadotrophin (HCG). Boys with Stage I testicular tumors were treated by orchidectomy alone, whereas, after appropriate surgery, chemotherapy was recommended for children with more advanced testicular tumors or with tumors at other sites. From 1979 to 1987, 126 children aged 0 to younger than 16 years with malignant germ cell tumors were registered. They were similar to patients in other large pediatric series with respect to sites of origin, age at presentation in relationship to primary site, histology, female predominance for sacrococcygeal site, and presence of associated malformations (present in 17%). Serum AFP was measured in 123 patients and was elevated in 115, whereas HCG was raised in 19 of 77. Monitoring by serial AFP measurement proved valuable in assessing response to therapy and in early detection of tumor recurrence. When treatment results were assessed in February 1988, 101 of 122 patients were alive (four who received nonprotocol chemotherapy were excluded). Forty-four patients had been cured by surgery alone (41 with testicular tumors, two with ovarian tumors, and one with sacrococcygeal tumor). All of the remaining 78 children received chemotherapy. The initial low dose vincristine, actinomycin, and cyclophosphamide (LDVAC) regimen proved ineffective, actuarial survival at 5 years followup being 8% (12 patients), and a regimen of cisplatin, vinblastine, and bleomycin (PVB) caused unacceptable toxicity, with actuarial survival at 5 years follow-up being 67% (nine patients). Five-year actuarial survival was 87% for 17 children given high dose VAC with or without doxorubicin and 84% for 33 given bleomycin, etoposide, and cisplatin (BEP). All 7 children given various combinations of these regimens survived. Excluding the 12 LDVAC cases, patient survival by site was as follows: testis (59 patients, 100%); vagina, uterus, and prostate (four patients, 100%); ovary (25 patients, 88%); thorax (five patients, 40%), and other (four patients, 67%). Similarly, patient survival by stage was Stage I (62,97%), Stage II (14,86%); Stage III (18,83%); and Stage IV (16,72%). Survival by histology was analysed only in cases for which histologic review had been done the LDVAC cases were excluded.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

5-HT3 receptors mediate inhibition of acetylcholine release in cortical tissue.

The release of cerebral acetylcholine from terminals in the cerebral cortex has been shown to be regulated by 5-hydroxytryptamine (5-HT) but it is not known which subtype of the 5-HT receptor is involved. 5-HT receptor agonists increase acetylcholine levels in vivo, indicating a reduced turnover, and reduce release of acetylcholine from striatal slices in vitro. Depleting 5-HT by inhibiting synthesis or by destroying the neurons containing 5-HT potentiates acetylcholine release, and increases acetylcholine turnover in the cerebral cortex and hippocampus. Selective antagonists for the 5-HT3 receptor subtypes which seem to have effects on mood and activity may exert their effect through the regulation of acetylcholine release in the cortex and limbic system. Radioligand binding studies show a high density of 5-HT3 receptors in the cholinergic-rich entorhinal cortex and we provide evidence that a reduction in cortical cholinergic function can be effected in vitro by 5-HT3 receptors.

Acetylcholine↗

Histomorphometry of fresh frozen iliac crest bone biopsies.

Although methods are well established for the rapid histological preparation of fresh frozen soft tissues, they remain inadequate for the preservation of hard tissues. A recent technique for sectioning fresh frozen bone, in which sections can be prepared within an hour, has been applied to undecalcified human iliac crest bone biopsies. Quantitative analysis has shown that the static remodeling variables deduced from frozen sections closely resemble those derived from plastic-embedded sections prepared for routine use by established laboratory procedures. It is concluded that the rapid method is reliable for immediate diagnostic and histomorphometric purposes.

Biopsy↗

Prognostic relevance of DNA content in childhood renal tumours.

The DNA content of paraffin embedded tumour specimens from 100 children with kidney tumours was studied by flow cytometry. Data of adequate quality were obtained from 93 cases comprising 67 Wilms' tumours with a favourable histology (FH), 12 Wilms' tumours with unfavourable histology (UH) (pleomorphic), 8 bone-metastasising renal tumours of childhood (BMRTC) and 6 rhabdoid renal tumours. Only 4.5% FH compared with 75% UH Wilms' were aneuploid (P less than 0.001). Although BMRTC and rhabdoid tumours are associated with poor prognosis, there were no examples of aneuploidy in these tumours. The proliferation index was found to be of no prognostic value. Staging and ploidy were not correlated with each other in any of the various histological types of renal tumours studied.

Child↗

Identification and characterisation of 5-hydroxytryptamine 3 recognition sites in human brain tissue.

[3H]Zacopride displayed regional saturable specific binding to homogenates of human brain tissues, as defined by the inclusion of BRL43694 [endo-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1-methylindazole-3- carboxamide] in the incubation media. Scatchard analysis of the saturation data obtained from amygdaloid and hippocampal tissues identified the binding as being of high affinity and to a homogeneous population of binding sites (KD = 2.64 +/- 0.75 and 2.93 +/- 0.41 nmol/L and Bmax = 55 +/- 7 and 44 +/- 9 fmol/mg of protein in the amygdala and hippocampus, respectively). 5-Hydroxytryptamine 3 (5-HT3) receptor agonists and antagonists competed for the [3H]zacopride binding site, competing with up to 40% of total binding with a similar rank order of affinity in both tissues; agents acting on various other neurotransmitter receptors failed to inhibit binding. Kinetic data revealed a fast association that was fully reversible (k+1 = 6.61 X 10(5) and 7.65 X 10(5)/mol/L/s and k-1 = 3.68 X 10(-3) and 3.45 X 10(-3)/s in the amygdala and hippocampus, respectively). It is concluded that [3H]zacopride selectively labels with high affinity 5-HT3 recognition sites in human amygdala and hippocampus and, if these binding domains represent 5-HT3 receptors, may provide the opportunity for 5-HT3 receptor antagonists to modify 5-HT function in the human brain.

Adult↗

Selection of medical students at a medical faculty in South Africa.

The selection procedure at one medical faculty in the RSA was investigated. Students were admitted to the M.B. Ch.B. course on the basis of school results. Four groups were studied: matriculants; those selected after completing the 1st year of a B.Sc. course; those who had completed a full B.Sc. course; and those who had experience and other qualifications after leaving school. The matriculants were by far the largest group and the analysis of their marks received emphasis. Students who registered for their 1st year in 1980-1983 were followed up until the middle of their 3rd year. In total 635 students were assessed. The students' school results were compared with their preclinical marks. Chi-square tests for independence, multiple regression analysis, Pearson correlation coefficients and canonical correlation analysis were carried out. Although the results reflected a significant relationship between good selection marks and preclinical achievement, the strength of the association was too small for selection marks to have any reliable predictive value for an individual student. There was a low drop-out rate (5.4%) during the 1st year of study, but this rate increased threefold to 17.2% during the remaining preclinical period. This may indicate that the selection criteria were not specific enough to avoid this relatively large loss of students.

Educational Measurement↗

Glomerular basement membrane thickness in children. A morphometric study.

Measurements of glomerular basement membrane (GBM) thickness in children with minimal change nephrotic syndrome were made on electron micrographs of 43 biopsy specimens obtained from 35 children aged 1-13 years, of whom 13 were in remission at the time of biopsy. Measurements were also made in 2 children with non-glomerular disorders. A mean of 189 measurements per biopsy were made, using prints of x6,400-12,000 magnification. Quadratic curves were fitted by regression analysis to the mean GBM thickness for each of the 35 initial nephrotic biopsies, plotted against age for the whole group and separately for sex, race and the presence or absence of proteinuria at the time of biopsy. There were no significant differences in race or proteinuria, but there was a trend towards a thicker GBM in young males which disappeared by 9 years of age. From the mean +/- 2 SD of GBM thickness for each of the 35 initial nephrotic biopsies the calculated thickness ranged from 100-340 nm at 1 year of age to 190-440 nm at 9 years of age and older. The growth curve for GBM thickness increases steeply initially, reaching a plateau at 9 years of age. Because there was no significant difference between proteinuric patients and those in remission, while measurements in the nephrotic syndrome and non-glomerular disorders closely agreed, we believe that our results demonstrate the normal GBM thickness and growth pattern.

Adolescent↗

Reserpine, para-chlorophenylalanine and fenfluramine antagonise cisplatin-induced emesis in the ferret.

The involvement of 5-hydroxytryptamine (5-HT) with cisplatin-induced emesis in the ferret was investigated using reserpine, para-chlorophenylalanine and fenfluramine. Pretreatment with reserpine (5 mg/kg, 24 hr), fenfluramine (5 mg/kg, 4 days) or para-chlorophenylalanine (100 or 400 mg/kg, 4 days) antagonised cisplatin-induced emesis. All treatments reduced the levels of 5-HT in the area postrema and at other cerebral sites, but whilst this action was relatively selective for small doses of para-chlorophenylalanine [only modest effects on noradrenaline (NA) and no change in the content of dopamine (DA) in the area postrema], other treatments reduced levels of dopamine and noradrenaline. Data are discussed in terms of an involvement of 5-HT/catecholamines in the area postrema with the mediation of emesis induced by cisplatin.

Animals↗

The internship year in the RSA--a need for change.

A survey of all interns doing their compulsory internship year in the RSA during 1982 and 1983 was carried out by means of a questionnaire (978 interns responded, a response rate of about 85%). Various problem areas were identified, most notably long working hours, insufficient opportunities to practice required procedures, heavy clerical duties leaving little time for training, lack of formal training, and negative attitudes engendered towards the medical profession. The significance and impact of the internship year is evaluated and the way in which South African Medical and Dental Council regulations are applied is examined. Recommendations for improvements in the effectiveness of interns' training are made.

Attitude↗