Search PubMed⌕ Search

Biomedical subjects

A M Brown

Publications and source records attributed to A M Brown.

At least 145 records · Page 8Linked to original sources
PubMed1997

Vernier acuity in human infants: rapid emergence shown in a longitudinal study.

BACKGROUND: Vernier acuity was measured longitudinally for comparison with published results on early stereopsis development. METHODS: Thirty-seven human infants were tested using forced-choice preferential looking. These included 29 pilot infants (9 or 12 weeks of age) and eight infants tested longitudinally (9 weeks to 11 to 15 weeks of age). RESULTS: At 9 weeks, Vernier acuity was about 40 minutes of visual angle, compared with a typical adult value of less than 10 arc sec of visual angle. Vernier acuity improved rapidly immediately after emergence, doubling within about 10 days. After age 11 weeks, Vernier acuity remained constant, at 1000 arc sec (17 min) of visual angle, until testing ended. CONCLUSION: Vernier acuity developed over a time course different from published data on stereoacuity. Vernier acuity emerged significantly sooner, whereas stereopsis improved most quickly at an age when Vernier acuity was changing most slowly. It is unlikely that a single critical immaturity limits infant performance on both visual tasks.

Adult↗
PubMed1997

The occurrence of cancer in a cohort of New South Wales coal miners.

To describe the incidence of cancer in coal miners in New South Wales (NSW) between 1973 and 1992, an inception cohort of all male coal industry employees who entered the industry between 1 January 1973 and 31 December 1992 was constructed from the medical examination records of the Joint Coal Board. This cohort was matched with the NSW State Cancer Registry to determine the occurrence and type of cancer. In the cohort of 23,630 men, 297 developed 301 primary cancers in the 20-year period of observation. The standardised incidence ratio (SIR) for all cancers was 0.82. Stomach cancer has been reported to be common in coal miners but the SIR for stomach cancer was not higher than average in this cohort. A cluster of non-Hodgkin's lymphoma has been reported in a NSW coal mine but an increased risk of this cancer was not evident in the industry as a whole. Similarly a cluster of cases of brain tumour has been reported. In this cohort, the SIR for brain tumour was 1.05 (95 per cent confidence interval (CI) 0.57 to 1.76) and a risk for brain tumour remains unconfirmed. The SIR for malignant melanoma was 1.13 (CI 0.90 to 1.39) together and 2.02 (CI 1.31 to 2.98) for those workers who started in an open-cut mine. Overall, there does not appear to be a general risk of cancer in the NSW coal industry. Open-cut miners have an increased risk of malignant melanoma, which may be related to their exposure to the sun at work.

Adult↗
PubMed1997

Parotid gland metastases of two uncommon neoplasms with low metastatic potential.

Oligodendrogliomas are uncommon intracranial glial tumours in which extracranial spread is only rarely reported. Similarly, both intracranial and ocular medulloepitheliomas are also rare, with metastatic spread from the ocular neoplasm being less common than its intracranial counterpart. We report cases of an intracranial oligodendroglioma and an ocular medulloepithelioma both of which metastasised to the parotid gland. To our knowledge these are only the second oligodendroglioma and the third ocular medulloepithelioma to be reported as metastasising to this site.

Adolescent↗
PubMed1997

Pharmacological activity of feverfew (Tanacetum parthenium (L.) Schultz-Bip.): assessment by inhibition of human polymorphonuclear leukocyte chemiluminescence in-vitro.

The bioactivity of feverfew (Tanacetum parthenium) leaf extracts has been analysed, by use of a human polymorphonuclear leukocyte (PMNL) bioassay, to assess the relative contributions of solvent extraction and parthenolide content to the biological potency of the extract. Extracts prepared in acetone-ethanol (system 1) contained significantly more parthenolide (mean +/- s.d. 1.3 +/- 0.2% dry leaf weight) than extracts in chloroform-PBS (phosphate-buffered saline; system 2; 0.1 +/- 0.04% dry leaf weight) or PBS alone (system 3; 0.5 +/- 0.1% dry leaf weight). Extract bioactivity, measured as inhibition of phorbol 12-myristate 13-acetate-induced, 5-amino-2,3-dihydro-1,4-phthalazinedione (luminol)-enhanced PMNL, chemiluminescence, followed a similar trend. Extracts inhibited phorbol 12-myristate 13-acetate-induced oxidative burst by amounts which, if solely attributable to parthenolide, indicated parthenolide concentrations for the respective solvent systems of 2.2 +/- 0.6%, 0.2 +/- 0.1% and 0.9 +/- 0.1% dry leaf weight. The mean ratio of parthenolide concentration to the parthenolide equivalent/PMNL-bioactivity value, for acetone-ethanol and PBS extracts were both 1:1.7. Parthenolide, although a key determinant of biological activity for T. parthenium leaf extracts based on the PMNL-bioassay, seems not to be the sole pharmacologically-active constituent. The identical and elevated bioactivity-parthenolide ratios for both organic and aqueons-phase leaf extracts suggest that a proportion of the other bioactive compounds have solubilities similar to that of parthenolide.

Chromatography, High Pressure Liquid↗
PubMed1997

Contribution of the NH2 terminus of Kv2.1 to channel activation.

Opening and closing of voltage-operated channels requires the interaction of diverse structural elements. One approach to the identification of channel domains that participate in gating is to locate the sites of action of modifiers. Covalent reaction of Kv2.1 channels with the neutral, sulfhydryl-specific methylmethanethiosulfonate (MMTS) caused a slowing of channel gating with a predominant effect on the kinetics of activation. These effects were also obtained after intracellular, but not extracellular, application of a charged MMTS analog. Single channel analysis revealed that MMTS acted primarily by prolonging the latency to first opening without substantially affecting gating transitions after the channel first opens and until it inactivates. To localize the channel cysteine(s) with which MMTS reacts, we generated NH2- and COOH-terminal deletion mutants and a construct in which all three cysteines in transmembrane regions were substituted. Only the NH2-terminal deletion construct gave rise to currents that activated slowly and displayed MMTS-insensitive kinetics. These results show that the NH2-terminal tail of Kv2.1 participates in transitions leading to activation through interactions involving reduced cysteine(s) that can be modulated from the cytoplasmic phase.

Amino Acid Sequence↗
PubMed1997

Changes in fatty acid metabolism in rat hepatocytes in response to dietary n-3 fatty acids are associated with changes in the intracellular metabolism and secretion of apolipoprotein B-48.

Cultured hepatocytes from rats fed a low fat, chow diet (LF) or diets rich in fish oil (FO, 20% v/w) or olive oil (OO, 20%, v/w) were used to determine how the intracellular metabolism and secretion of apolipoproteins (apo)B-100 and B-48 respond to in vivo and in vitro manipulations of fatty acid esterification, storage, secretion, and oxidation. Hepatocytes from the FO- and OO-fed rats had higher initial triacylglycerol (TAG) contents and higher rates of fatty acid oxidation and ketogenesis than hepatocytes from the LF-fed group. However, only in the cells from the FO-fed animals was there any decrease in the rate of TAG synthesis and in the secretion of VLDL TAG. Decreased secretion of TAG by the FO hepatocytes was accompanied by a decreased synthesis and degradation of apoB, particularly apoB-48, and a decreased secretion of apoB-48 VLDL. In all dietary groups a substantial proportion of the apoB-48 and apoB-100 secreted into the medium was associated with small, lipid-poor particles of density > 1.006. FO feeding had no effect on the amounts of apoB-48 and apoB-100 that appeared in this fraction. Dietary composition affected the channelling of exogenous oleate in the culture medium into the oxidative and esterification pathways. While exogenous fatty acid increased the secretion of VLDL TAG in the FO-fed group, VLDL TAG secretion remained lower than that observed in the hepatocytes from the LF- and OO-fed groups cultured under identical conditions. Exogenous oleate did not significantly increase the secretion of either newly-synthesized apoB-48 or apoB-100 by hepatocytes in either of the dietary groups. We conclude that, in rat liver, a decreased capacity to transport TAG out of the hepatocyte after consumption of a diet rich in fish oil is associated with a decreased synthesis and presecretory degradation of apoB-48, and with a decreased secretion of VLDL apoB-48.

Animals↗
PubMed1997

A new species of Loma (Microsporea) in shiner perch (Cymatogaster aggregata).

Loma embiotocia n. sp. is described from the gills of shiner perch (Cymatogaster aggregata) from waters off Vancouver Island, British Columbia, Canada. Highest prevalence at a site was 15% and greatest intensity was 583 xenomas per fish. Xenomas averaged 0.13 mm in diameter (0.06-0.16 mm) and contained ovoid spores 4.8 x 2.6 (4.0-5.0 x 2.0-3.0) microns. Sporogonic stages were dispersed throughout the xenomas. The xenoma wall was smooth lacking invaginations into the cyto plasm: sporoblasts were not highly vacuolated, and the sporophorous vesicle formed before sporogony. In addition to differences in host and geographic location the new species is distinguished from Loma salmonae, the only other species in the genus known from British Columbia, by its internal transcribed spacer (ITS) ribosomal DNA sequence.

Animals↗
PubMed1997

Transformation by Wnt family proteins correlates with regulation of beta-catenin.

Several members of the Wnt family of secreted factors are strongly implicated as regulators of mammary cell growth and differentiation. To investigate Wnt signaling in mammary cells, we have assessed the abilities of 10 different Wnt genes to cause transformation of C57MG mammary epithelial cells and in parallel studied their effects on beta-catenin, a component of the Wnt-1 signaling pathway. Autocrine transforming potential was tested by expression of Wnt proteins in C57MG cells, and paracrine effects were evaluated by coculture of C57MG cells with fibroblasts secreting different Wnt proteins. Western blotting confirmed the expression of each Wnt protein in the relevant cell lines. Activities of the 10 Wnts tested were divisible into three groups. Wnt-1, Wnt-2, Wnt-3, and Wnt3a induced strong transformation and an elongated refractile cell morphology. Wnt-6 and Wnt-7a produced weak morphological changes. Wnt-4, Wnt-5a, Wnt-5b, and Wnt-7b had no effect at all on C57MG morphology. Analysis of beta-catenin levels showed that the transforming Wnts induced accumulation of cytosolic beta-catenin, whereas nontransforming Wnts did not. These result demonstrate that several Wnt family members are capable of elevating beta-catenin levels and suggest that their signaling pathways share intracellular signaling components. The correlation between increased cytosolic beta-catenin levels and C57MG transformation supports a role for beta-catenin in transformation of these cells. These data also imply the existence of receptors that respond to certain Wnt proteins but not to others.

Animals↗
PubMed1996

Kv2.1 and electrically silent Kv6.1 potassium channel subunits combine and express a novel current.

Heteromultimer formation between Kv potassium channel subfamilies with the production of a novel current is reported for the first time. Protein-protein interactions between Kv2.1 and electrically silent Kv6.1 alpha-subunits were detected using two microelectrode voltage clamp and yeast two-hybrid measurements. Amino terminal portions of Kv6.1 were unable to form homomultimers but interacted specifically with amino termini of Kv2.1. Xenopus oocytes co-injected with Kv6.1 and Kv2.1 cRNAs exhibited a novel current with decreased rates of deactivation, decreased sensitivity to TEA block, and a hyperpolarizing shift of the half maximal activation potential when compared to Kv2.1. Our results indicate that Kv channel subfamilies can form heteromultimeric channels and, for the first time, suggest a possible functional role for the Kv6 subfamily.

Animals↗
PubMed1996

Felbamate inhibits cloned voltage-dependent Na+ channels from human and rat brain.

The novel antiepileptic and neuroprotective drug felbamate (1 mM) caused a marked inhibition of voltage-dependent Na+ currents expressed in Xenopus oocytes upon injection of the cRNA encoding alpha-subunits from rat and human brain. This inhibition was present only if felbamate was perfused on the intracellular side of the membrane. In addition, felbamate seems to preferentially bind to and stabilize the inactivated state of the channel, resembling the action of local anesthetics. This study provides an additional mechanism by which felbamate might exert its wide-spectrum anticonvulsant and neuroprotective action.

Animals↗
PubMed1996

Rho guanine nucleotide dissociation inhibitor protein (RhoGDI) inhibits exocytosis in mast cells.

Introducing non-hydrolysable analogues of GTP into the cytosolic compartment of mast cells results in exocytotic secretion through the activation of GTP binding proteins. The identity and mechanism of action of these proteins are not established. We have investigated the effects of Rho GDP dissociation inhibitor (RhoGDI) on exocytosis induced by guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma-S) in rat mast cells, introducing the protein into cells by means of a patch pipette and recording the progress of exocytosis by monitoring cell capacitance. To allow time for the protein to enter the cells and find its correct location, stimulation was provided 5-10 min after patch rupture by photolysing caged GTP-gamma-S included in the pipette solution. When bovine RhoGDI was introduced into mast cells, exocytosis was inhibited at concentrations of 200-400 nM for native protein and 800 nM to 8 microM for the recombinant form. Protein denatured by heat or N-ethylmaleimide treatment did not inhibit. In permeabilized cells, recombinant RhoGDI increased the rate at which cells lose their ability to respond to GTP-gamma-S. These data demonstrate that one or more small GTP binding proteins of the Rho family has a central role in the exocytotic mechanism in mast cells.

Animals↗
PubMed1996

Molecular physiology and pharmacology of HERG. Single-channel currents and block by dofetilide.

BACKGROUND: The human ether-a-go-go-related gene (HERG) is one locus for the hereditary long-QT syndrome. A hypothesis is that HERG produces the repolarizing cardiac potassium current IKr with the consequence that mutations in HERG prolong the QT interval by reducing IKr. The elementary properties of HERG are unknown, and as a test of the hypothesis that HERG produces IKr, we compared their elementary properties. METHODS AND RESULTS: We injected HERG cRNA into Xenopus oocytes and measured currents from single channels or current variance from the noise produced by ensembles of channels recorded from macro patches. Single-channel conductance was dependent on the extracellular potassium concentration ([K]o). At physiological [K]o, it was 2 picosiemens (pS), and at 100 mmol/L [K]o, it was 10 pS. Openings occurred in bursts with a mean duration of 26 ms at -100 mV. Mean open time was 3.2 ms and closed times were 1.0 and 26 ms. In excised macro patches, HERG currents were blocked by the class III antiarrhythmic drug dofetilide, with an IC50 of 35 nmol/L. Dofetilide block was slow and greatly attenuated at positive potentials at which HERG rectifies. CONCLUSIONS: The microscopic physiology of HERG and IKr is similar, consistent with HERG being an important component of IKr. The pharmacology is also similar; dofetilide appears to primarily block activated channels and has a much lower affinity for closed and inactivated channels.

Animals↗
PubMed1996

Comparison of binding and block produced by alternatively spliced Kvbeta1 subunits.

Voltage-gated K+ (Kv) channels consist of alpha subunits complexed with cytoplasmic Kvbeta subunits. Kvbeta1 subunits enhance the inactivation of currents expressed by the Kv1 alpha subunit subfamily. Binding has been demonstrated between the C terminus of Kvbeta1.1 and a conserved segment of the N terminus of Kv1.4, Kv1.5, and Shaker alpha subunits. Here we have examined the interaction and functional properties of two alternatively spliced human Kvbeta subunits, 1.2 and 1.3, with Kvalpha subunits 1.1, 1.2, 1.4, and 1.5. In the yeast two-hybrid assay, we found that both Kvbeta subunits interact specifically through their conserved C-terminal domains with the N termini of each Kvalpha subunit. In functional experiments, we found differences in modulation of Kv1alpha subunit currents that we attribute to the unique N-terminal domains of the two Kvbeta subunits. Both Kvbeta subunits act as open channel blockers at physiological membrane potentials, but hKvbeta1.2 is a more potent blocker than hKvbeta1.3 of Kv1.1, Kv1.2, Kv1.4, and Kv1. 5. Moreover, hKvbeta1.2 is sensitive to redox conditions, whereas hKvbeta1.3 is not. We suggest that different Kvbeta subunits extend the range over which distinct Kv1alpha subunits are modulated and may provide a variable mechanism for adjusting K+ currents in response to alterations in cellular conditions.

Alternative Splicing↗
PubMed1996

Novel sites of N-glycosylation in ROMK1 reveal the putative pore-forming segment H5 as extracellular.

Inwardly rectifying K+ channels (IRKs) maintain resting membrane potential, excitability, and K+ exchange. The proposed topological model of IRKs consists of intracellular amino and carboxyl termini and two transmembrane segments (M1 and M2) linked by a pore-forming segment (H5). Structure-function studies have identified critical pore determinants in M2 and the carboxyl terminus but not as expected by analogy with voltage-dependent K+ channels, in H5. We investigated the topology of the IRK ROMK1 by substituting novel N-glycosylation sites which act as markers for extracellular segments. N-Glycosylation, before and after an N-glycosylation inhibitor, tunicamycin, was measured directly by gel shift assays and changes in membrane currents. Tunicamycin produced gel shifts and changes in membrane currents that correlated exactly. N-Glycosylation sites substituted into the amino and carboxyl termini and the M1 segment gave results consistent with the proposed model. N-Glycosylation sites were distributed throughout H5 and its flanking regions indicating that H5 is mainly extracellular. Thus, the linker between M1 and M2 has little or no intramembranous component.

Animals↗
PubMed1996

HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.

BACKGROUND: Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K+ current (Ikur) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go-related gene that expresses a delayed rectifier current (IKr) in human ventricle and produces hereditary long QT syndrome when defective. METHODS AND RESULTS: We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range. CONCLUSIONS: Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.

Animals↗
PubMed1996

m-Chlorophenylpiperazine (mCPP) is an antagonist at the cloned human 5-HT2B receptor.

The behavioural effects of m-chlorophenylpiperazine (mCPP) in rats and its clinical effects in man are thought to be related to its action at 5-HT2B/2C receptors. However, although mCPP is a partial agonist at these subtypes in rat, its efficacy at human 5-HT2B/2C receptors is unknown. We therefore investigated the activity of mCPP at cloned human 5-HT2B and 5-HT2C receptors. mCPP was a partial agonist at the human 5-HT2C receptor but antagonized the human 5-HT2B receptor. Therefore, while supporting the proposal that at least some of the clinical effects of mCPP are likely to be mediated via stimulation of the 5-HT2C receptor, this study also suggests that any 5-HT2B receptor-mediated effects are more likely to result from receptor blockade than from receptor activation.

Animals↗