Biomedical subjects

M C Brown

Publications and source records attributed to M C Brown.

At least 37 records · Page 2Linked to original sources

PubMed2000

Ejection from an aircraft following photorefractive keratectomy: a case report.

A 32-yr-old active duty United States Navy Lieutenant Naval Flight Officer (NFO), 6 mo status post photorefractive keratectomy (PRK) in both eyes performed as part of the first protocol to evaluate laser refractive surgery in aviators, ejected from a Navy S-3B Viking aircraft while performing field carrier landing practice. Neither the pilot nor the NFO suffered physical consequences as a result of the ejection. Coincidentally, the NFO had been examined just 1 wk before the mishap and was noted to have uncorrected visual acuity of 20/16 in each eye. Examination 1 wk following the mishap could not detect a change in vision. The NFO's vision status and his post-PRK status was not listed as a causal factor in the mishap. While this case report will not settle the debate regarding the appropriateness of refractive surgery in aviators, it does provide anecdotal evidence to support the safety of PRK in the aviation community.

Accidents, Aviation↗

PubMed1999

Activin A and TGF-beta stimulate phosphorylation of focal adhesion proteins and cytoskeletal reorganization in rat aortic smooth muscle cells.

Activin A and Transforming Growth Factor-beta (TGF-beta) are members of a common family of cytokines that bind to and stimulate serine/threonine kinase receptors. Activin A and TGF-beta are important during embryonic development exerting both positive and negative effects on cell growth. In the adult organism, they function in processes such as tissue repair, cellular proliferation, and differentiation. Although activin A and TGF-beta often induce opposite functional outcomes in specific cells; proliferation or differentiation, both were found to stimulate the formation of actin stress fibers and focal adhesions in serum-starved rat aortic smooth muscle (RASM) cells. These structural changes were accompanied by phosphorylation of the focal adhesion proteins, paxillin, and p130(cas). Similar cytoskeletal and biochemical changes were observed with the vasoactive agonist angiotensin II. Activation of the ERK/MAP kinase pathway has been implicated in the migration in certain cell types. However, while activin A, TGF-beta, and angiotensin II all stimulated ERK activity in RASM cells, only activin A and angiotensin II stimulated migration. TGF-beta failed to illicit a chemotactic response. Furthermore, pharmacologic inhibition of MEK activity failed to block migration in response to activin A and angiotensin II, indicating RASM migration can occur independent of ERK activity. These results suggest that TGF-beta and activin A share several signaling pathways with angiotensin II leading to cytoskeletal remodeling and ERK activation, but there are distinct differences regarding the effect of these agonists on cellular migration.

Actins↗

PubMed1999

Paxillin LD4 motif binds PAK and PIX through a novel 95-kD ankyrin repeat, ARF-GAP protein: A role in cytoskeletal remodeling.

Paxillin is a focal adhesion adaptor protein involved in the integration of growth factor- and adhesion-mediated signal transduction pathways. Repeats of a leucine-rich sequence named paxillin LD motifs (Brown M.C., M.S. Curtis, and C.E. Turner. 1998. Nature Struct. Biol. 5:677-678) have been implicated in paxillin binding to focal adhesion kinase (FAK) and vinculin. Here we demonstrate that the individual paxillin LD motifs function as discrete and selective protein binding interfaces. A novel scaffolding function is described for paxillin LD4 in the binding of a complex of proteins containing active p21 GTPase-activated kinase (PAK), Nck, and the guanine nucleotide exchange factor, PIX. The association of this complex with paxillin is mediated by a new 95-kD protein, p95PKL (paxillin-kinase linker), which binds directly to paxillin LD4 and PIX. This protein complex also binds to Hic-5, suggesting a conservation of LD function across the paxillin superfamily. Cloning of p95PKL revealed a multidomain protein containing an NH2-terminal ARF-GAP domain, three ankyrin-like repeats, a potential calcium-binding EF hand, calmodulin-binding IQ motifs, a myosin homology domain, and two paxillin-binding subdomains (PBS). Green fluorescent protein- (GFP-) tagged p95PKL localized to focal adhesions/complexes in CHO.K1 cells. Overexpression in neuroblastoma cells of a paxillin LD4 deletion mutant inhibited lamellipodia formation in response to insulin-like growth fac- tor-1. Microinjection of GST-LD4 into NIH3T3 cells significantly decreased cell migration into a wound. These data implicate paxillin as a mediator of p21 GTPase-regulated actin cytoskeletal reorganization through the recruitment to nascent focal adhesion structures of an active PAK/PIX complex potentially via interactions with p95PKL.

ADP-Ribosylation Factors↗

PubMed1999

The design of non-peptide human bradykinin B2 receptor antagonists employing the benzodiazepine peptidomimetic scaffold.

The Bradykinin B2 receptor antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) has been used as a template for the de novo design and synthesis of a small number of non-peptide lead compounds based on the 1,4-benzodiazepin-2-one framework. Two of the compounds have been found to exhibit moderate K(i) values of 8.9 and 9.2 microM at the human Bradykinin B2 receptor.

Bradykinin↗

PubMed1999

Characterization of paxillin LIM domain-associated serine threonine kinases: activation by angiotensin II in vascular smooth muscle cells.

Recently we reported a novel means of regulating LIM domain protein function. Paxillin LIM zinc-finger phosphorylation in response to cell adhesion regulates the subcellular localization of this cytoskeletal adaptor protein to focal adhesions, and also modulates cell adhesion to fibronectin (Brown et al. [1998] Mol. Biol. Cell 9:1803-1816). In the present study, we characterize further the protein kinases that phosphorylate paxillin LIM2 on threonine and LIM3 on serine. Analysis of the subcellular distribution of the LIM kinases demonstrated that the LIM3 protein kinase, but not the LIM2 kinase, resides within a detergent-insoluble fraction. The activities of the paxillin LIM domain kinases are differentially regulated during embryogenesis, and analysis of tissue distribution indicated a specificity in expression patterns between the LIM2 and LIM3 kinases. In addition, these protein kinases were refractory to inhibition by a panel of broad-spectrum serine/threonine kinase inhibitors, suggesting a novel derivation. The paxillin protein kinase activities were stimulated in serum-starved CHO.K1 cells by the mitogen phorbol myristate acetate (PMA), and by PMA and angiotensin II in rat aortic smooth muscle cells. In vivo labeling, phosphoamino acid analysis, and phosphopeptide mapping of paxillin immunoprecipitated from angiotensin II-stimulated smooth muscle cells confirmed an induction of paxillin serine/threonine phosphorylation and supports the contention that these newly identified paxillin kinases are dynamic components of growth factor signaling through the cytoskeleton.

Angiotensin II↗

PubMed1999

Policy-induced changes in Maori mortality patterns in the New Zealand economic reform period.

New Zealand's pro-market reform process commencing in 1984, while generally popular, did not represent a net social benefit for all socio-economic, cultural and ethnic groups. The reforms imposed hardships on groups heavily dependent on manual jobs in the manufacturing sector, on groups experiencing above average rates of unemployment, and on groups dependent on social programmes for stability in income flows. One group possessing all three characteristics, and adversely affected, was New Zealand's aboriginal population--the Maori. Previous statistical analyses have established that the Maori are a low income group that suffered a substantial decline in relative income from 1984 to 1987. The statistical research in this study establishes that Maori aged 30-79 years also experienced an increase in mortality ratios relative to the rest of the population, commencing in 1987. It is postulated that the decline in economic stability was a source of stress for middle-aged Maori, and that this was a contributing factor to the increase in observed relative mortality.

Adolescent↗

PubMed1999

The major brain isoform of kif1b lacks the putative mitochondria-binding domain.

Kinesin and kinesin superfamily proteins are molecular motors involved in important intracellular functions such as organelle transport and cell division. They are microtubule-activated ATPases composed of a motor domain that binds to microtubules and a cargo-binding domain that binds to specific organelles. While searching for the slow Wallerian degeneration mutation (WldS) on distal mouse Chromosome (Chr) 4, we have identified a member of the kinesin superfamily whose predicted gene product has the N-terminal motor domain of Kif1b and a novel C-terminal cargo-binding domain homologous to Kif1a. Kif1b is responsible for the movement of mitochondria along the axon, but the novel isoform containing the alternative C-terminal domain is likely to have a different cargo-binding specificity. cDNA library screening and Northern blot analysis indicate that the alternatively spliced form of Kif1b containing the novel 3'end accounts for the most part of Kif1b expression. We also found more alternatively spliced exons that can give rise to heterogeneous transcripts. Therefore, alternative splicing, as well as multiple genes, may contribute to the selective movement of diverse organelles by anterograde axonal transport. Kif1b maps on distal mouse Chr 4, within the Wld genetic candidate interval, but outside the recently identified triplication. There is, however, no evidence that Kif1b is the Wld gene.

Alternative Splicing↗

PubMed1999

Role of alpha9 nicotinic ACh receptor subunits in the development and function of cochlear efferent innervation.

Cochlear outer hair cells (OHCs) express alpha9 nACh receptors and are contacted by descending, predominately cholinergic, efferent fibers originating in the CNS. Mice carrying a null mutation for the nACh alpha9 gene were produced to investigate its role(s) in auditory processing and development of hair cell innervation. In alpha9 knockout mice, most OHCs were innervated by one large terminal instead of multiple smaller terminals as in wild types, suggesting a role for the nACh alpha9 subunit in development of mature synaptic connections. Alpha9 knockout mice also failed to show suppression of cochlear responses (compound action potentials, distortion product otoacoustic emissions) during efferent fiber activation, demonstrating the key role alpha9 receptors play in mediating the only known effects of the olivocochlear system.

Animals↗

PubMed1999

Cost-effectiveness of mirtazapine compared to amitriptyline and fluoxetine in the treatment of moderate and severe depression in austria.

This study estimated the cost-effectiveness of mirtazapine, compared to amitriptyline and fluoxetine, in the management of moderate and severe depression in Austria, as well as the costs related to the discontinuation of antidepressant treatment from the perspective of the Austrian Sick Funds (Gebietskrankenkassen). The economic analyses were based on a meta-analysis of four randomised clinical trials comparing mirtazapine with amitriptyline, and on a six week comparative trial of mirtazapine and fluoxetine which was extrapolated to six months using assumptions derived from the literature. Decision models of the treatment paths and associated resource use attributable to managing moderate and severe depression in Austria were developed from clinical trial data, information on Austrian clinical practice obtained from interviews with an Austrian Delphi panel (comprising psychiatrists and GPs), and from published literature. The models were used to estimate the expected costs to the Gebietskrankenkassen of managing a patient with moderate or severe depression, and the indirect cost per patient to Austrian society due to lost productivity. The expected cost to the Gebietskrankenkassen of healthcare resource use attributable to managing a patient suffering from moderate or severe depression who discontinues antidepressant treatment was estimated to be ATS 4,088 over five months, of which hospitalisations accounted for nearly 69% of the cost. Using mirtazapine instead of amitriptyline for 28 weeks increases the proportion of successfully treated patients by 21% (from 19.2 to 23.2%), and reduces the expected cost to the Gebietskrankenkassen by ATS 1,112 per patient (from ATS 31,411 to ATS 30,299). Patients treated with mirtazapine and amitriptyline for 28 weeks are expected to miss 4.76 and 5.01 weeks of work respectively, due to their depression. Hence, the expected indirect cost to Austrian society over this period was estimated to be ATS 58, 787 and ATS 61,851 per patient respectively. Using mirtazapine instead of fluoxetine for six months increases the proportion of successfully treated patients by 22% (from 15.6 to 19.1%), albeit for a negligible additional cost to the Gebietskrankenkassen of ATS 408 per patient (from ATS 29,205 to ATS 29,613). Patients treated with mirtazapine and fluoxetine for six months are expected to miss 4.53 weeks of work, due to their depression. Hence, the expected indirect cost to Austrian society due to lost productivity was estimated to be ATS 55,900 per patient with either antidepressant. In conclusion, this study suggests that despite the differences in acquisition costs, mirtazapine is a cost-effective antidepressant compared to amitriptyline and fluoxetine, supporting the adoption of this treatment in the management of moderate and severe depression in Austria.

Amitriptyline↗

PubMed1999

Magnetic field goniometry: a new method to measure the frequency of stomach contractions.

A system of magnetic field goniometry was developed for measuring the frequency of stomach contractions. This technique uses a handheld, electronic compass to measure the angular change in direction of a magnetic field generated by a small, ingested magnet. Measurements of gastric mechanical activity made by goniometry were validated with simultaneous measurements using manometry and electrogastrography. The agreement between these different modalities was excellent. In this pilot study, magnetic field goniometry provided an easy, minimally invasive, and accurate method to measure the frequency of gastric contractions.

Adult↗

PubMed1999

Eya1-deficient mice lack ears and kidneys and show abnormal apoptosis of organ primordia.

Haploinsufficiency for human EYA1, a homologue of the Drosophila melanogaster gene eyes absent (eya), results in the dominantly inherited disorders branchio-oto-renal (BOR) syndrome and branchio-oto (BO) syndrome, which are characterized by craniofacial abnormalities and hearing loss with (BOR) or without (BO) kidney defects. To understand the developmental pathogenesis of organs affected in these syndromes, we inactivated the gene Eya1 in mice. Eya1 heterozygotes show renal abnormalities and a conductive hearing loss similar to BOR syndrome, whereas Eya1 homozygotes lack ears and kidneys due to defective inductive tissue interactions and apoptotic regression of the organ primordia. Inner ear development in Eya1 homozygotes arrests at the otic vesicle stage and all components of the inner ear and specific cranial sensory ganglia fail to form. In the kidney, Eya1 homozygosity results in an absence of ureteric bud outgrowth and a subsequent failure of metanephric induction. Gdnf expression, which is required to direct ureteric bud outgrowth via activation of the c-ret Rtk (refs 5, 6, 7, 8), is not detected in Eya1-/- metanephric mesenchyme. In Eya1-/- ear and kidney development, Six but not Pax expression is Eya1 dependent, similar to a genetic pathway elucidated in the Drosophila eye imaginal disc. Our results indicate that Eya1 controls critical early inductive signalling events involved in ear and kidney formation and integrate Eya1 into the genetic regulatory cascade controlling kidney formation upstream of Gdnf. In addition, our results suggest that an evolutionarily conserved Pax-Eya-Six regulatory hierarchy is used in mammalian ear and kidney development.

Animals↗

PubMed1999

Economic impact of feeding a phenylalanine-restricted diet to adults with previously untreated phenylketonuria.

The aim of the present study was to estimate the direct healthcare cost of managing adults with previously untreated phenylketonuria (PKU) for one year before any dietary restrictions and for the first year after a phenylalanine- (PHE-) restricted diet was introduced. The resource use and corresponding costs were estimated from medical records and interviews with health care professionals experienced in caring for adults with previously untreated PKU. The mean annual cost of caring for a client being fed an unrestricted diet was estimated to be 83 996 pound silver. In the first year after introducing a PHE-restricted diet, the mean annual cost was reduced by 20 647 pound silver to 63 348 pound silver as a result of a reduction in nursing time, hospitalizations, outpatient clinic visits and medications. However, the economic benefit of the diet depended on whether the clients were previously high or low users of nursing care. Nursing time was the key cost-driver, accounting for 79% of the cost of managing high users and 31% of the management cost for low users. In contrast, the acquisition cost of a PHE-restricted diet accounted for up to 6% of the cost for managing high users and 15% of the management cost for low users. Sensitivity analyses showed that introducing a PHE-restricted diet reduces the annual cost of care, provided that annual nursing time was reduced by more than 8% or more than 5% of clients respond to the diet. The clients showed fewer negative behaviours when being fed a PHE-restricted diet, which may account for the observed reduction in nursing time needed to care for these clients. In conclusion, feeding a PHE-restricted diet to adults with previously untreated PKU leads to economic benefits to the UK's National Health Service and society in general.

Adult↗

PubMed1999

Equivalent analgesia and side effects during epidural and pharmacokinetically tailored intravenous infusion with matching plasma alfentanil concentration.

BACKGROUND: Recently, several clinical studies comparing intravenous and epidural infusions of fentanyl and its derivatives suggested that epidural infusions act primarily by systemic absorption to produce supraspinal analgesia. To evaluate this hypothesis, the authors used pharmacokinetically tailored intravenous infusions to produce matching plasma alfentanil concentrations during epidural and intravenous administration. The analgesia and side effects achieved with each mode of administration were compared. METHODS: Twelve volunteers participated in this placebo-controlled crossover study. The pain model was cutaneous electric stimulation of the finger and toe. The test battery included subjective rating of pain intensity; end-tidal carbon dioxide level; pupil size; ratings of alertness, nausea, and pruritus; and a plasma alfentanil assay. On one test day, the participants received epidural alfentanil (400 microg bolus + a 400-microg/h infusion for 2 h) and an intravenous saline infusion. The test battery was administered at regular intervals. On another test day, the participants received epidural saline and a computer-controlled intravenous infusion of alfentanil. The testing protocol was repeated as on the first test day. On the day the placebo was administered, the participants received epidural and intravenous saline infusions. The order of the placebo day was randomized. RESULTS: Plasma alfentanil concentration-time profiles were identical during epidural and intravenous infusions. A nearly equivalent analgesic response was observed with epidural and intravenous alfentanil at the upper and lower extremities. There were no differences in side effects for epidural and intravenous administration. CONCLUSIONS: The systemic redistribution of alfentanil accounts for most of the analgesia and effects produced by epidural infusion.

Adult↗

PubMed1999

Monocular and binocular depth discrimination thresholds.

BACKGROUND: Measurement of stereoacuity at varying distances, by real or simulated depth stereoacuity tests, is helpful in the evaluation of patients with binocular imbalance or strabismus. Although the cue of binocular disparity underpins stereoacuity tests, there may be variable amounts of other binocular and monocular cues inherent in a stereoacuity test. In such circumstances, a combined monocular and binocular threshold of depth discrimination may be measured--stereoacuity conventionally referring to the situation where binocular disparity giving rise to retinal disparity is the only cue present. A child-friendly variable distance stereoacuity test (VDS) was developed, with a method for determining the binocular depth threshold from the combined monocular and binocular threshold of depth of discrimination (CT). METHODS: Subjects with normal binocular function, reduced binocular function, and apparently absent binocularity were included. To measure the threshold of depth discrimination, subjects were required by means of a hand control to align two electronically controlled spheres at viewing distances of 1, 3, and 6m. Stereoacuity was also measured using the TNO, Frisby, and Titmus stereoacuity tests. BTs were calculated according to the function BT= arctan (1/tan alphaC - 1/tan alphaM)(-1), where alphaC and alphaM are the angles subtended at the nodal points by objects situated at the monocular threshold (alphaM) and the combined monocular-binocular threshold (alphaC) of discrimination. RESULTS: In subjects with good binocularity, BTs were similar to their combined thresholds, whereas subjects with reduced and apparently absent binocularity had binocular thresholds 4 and 10 times higher than their combined thresholds (CT). The VDS binocular thresholds showed significantly higher correlation and agreement with the TNO test and the binocular thresholds of the Frisby and Titmus tests, than the corresponding combined thresholds (p = 0.0019). CONCLUSION: The VDS was found to be an easy to use real depth (distance) stereoacuity test. The method described for calculating the BT provides one simple nonlinear solution for determining the respective contributions of binocular and monocular (MT) depth discrimination to the combined depth threshold.

Adolescent↗

PubMed1999

Inducible nitric oxide synthase in the lung and exhaled nitric oxide after hyperoxia.

The effect of hyperoxia on nitric oxide (NO) production in intact animals is unknown. We described the effects of hyperoxia on inducible nitric oxide synthase (iNOS) expression and NO production in the lungs of rats exposed to high concentrations of oxygen. Animals were placed in sealed Plexiglas chambers and were exposed to either 85% oxygen (hyperoxic group) or 21% oxygen (negative control group). Animals were anesthetized after 24 and 72 h of exposure and were ventilated via a tracheotomy. We measured NO production in exhaled air (E(NO)) by chemiluminescence. The lungs were then harvested and processed for detection of iNOS by immunohistochemistry and Western blotting analysis. The same experiments were repeated in animals exposed to hyperoxia for 72 h after they were infused with L-arginine. We used rats that were injected intraperitoneally with Escherichia coli lipopolysaccharide to induce septic shock as a positive control group. Hyperoxia and septic shock induced expression of iNOS in the lung. However, E(NO) was elevated only in septic shock rats but was normal in the hyperoxic group. Exogenous infusion of L-arginine after hyperoxia did not increase E(NO). To exclude the possibility that in the hyperoxic group NO was scavenged by oxygen radicals to form peroxynitrite, lungs were studied by immunohistochemistry for the detection of nitrotyrosine. Nitrotyrosine was found in septic shock animals but not in the hyperoxic group, further suggesting that NO is not synthesized in rats exposed to hyperoxia. We conclude that hyperoxia induces iNOS expression in the lung without an increase in NO concentration in the exhaled air.

Animals↗

PubMed1999

Gentamicin blocks both fast and slow effects of olivocochlear activation in anesthetized guinea pigs.

The medial olivocochlear (MOC) efferent system, which innervates cochlear outer hair cells, suppresses cochlear responses. MOC-mediated suppression includes both slow and fast components, with time courses differing by three orders of magnitude. Pharmacological studies in anesthetized guinea pigs suggest that both slow and fast effects on cochlear responses require an initial acetylcholine activation of alpha-9 nicotinic receptors on outer hair cells and that slow effects require additional intracellular events downstream from those mediating fast effects. Gentamicin, an aminoglycoside antibiotic, has been reported to block fast effects of sound-evoked OC activation following intramuscular injection in unanesthetized guinea pigs, without changing slow effects. In the present study, we show that electrically evoked fast and slow effects in the anesthetized guinea pig are both blocked by either intramuscular or intracochlear gentamicin, with similar time courses and/or dose-response curves. We suggest that sound-evoked slow effects in unanesthetized animals are fundamentally different from electrically evoked slow effects in anesthetized animals, and that the former may arise from effects of the lateral OC system.

Acoustic Stimulation↗

PubMed1998

An 85-kb tandem triplication in the slow Wallerian degeneration (Wlds) mouse.

Wallerian degeneration is the degeneration of the distal stump of an injured axon. It normally occurs over a time course of around 24 hr but it is delayed in the slow Wallerian degeneration mutant mouse (C57BL/Wlds) for up to 3 weeks. The gene, which protects from rapid Wallerian degeneration, Wld, previously has been mapped to distal chromosome 4. This paper reports the fine genetic mapping of the Wld locus, the generation of a 1.4-Mb bacterial artificial chromosome and P1 artificial chromosome contig, and the identification of an 85-kb tandem triplication mapping within the candidate region. The mutation is unique to C57BL/Wlds among 36 strains tested and therefore is a strong candidate for the mutation that leads to delayed Wallerian degeneration. There are very few reports of tandem triplications in a vertebrate and no evidence for a mutation mechanism so this unusual mutation was characterized in more detail. Sequence analysis of the boundaries of the repeat unit revealed a minisatellite array at the distal boundary and a matching 8-bp sequence at the proximal boundary. This finding suggests that recombination between short homologous sequences ("illegitimate" or "nonhomologous" recombination) was involved in the rearrangement. In addition, a duplication allele was identified in two Wlds mice, indicating some instability in the repeat copy number and suggesting that the triplication arose from a duplication by unequal crossing over.

Alleles↗

PubMed1998

General practitioner funding policy: from where to whither?

Six public policy objectives relating to general practitioner (GP) funding since 1938 have been identified. They concern national health insurance, rural GP shortages, care for the poor, health promotion, cost effectiveness and community control. Each of these objectives is examined in turn, focusing on the extent to which each has been met. In all cases past policies have been, at best, only partially successful in meeting their objectives and have required little in the way of dismantling prior to the introduction of new GP funding initiatives subsequent to 1993. Theoretical principles relating to the development of efficient and coherent public policy are discussed. New Zealand policy relating to funding of GP services has rarely conformed to such principles. There is an emerging consensus between social democrats and libertarians that targeted programmes for the poor is the equitable and efficient way to proceed. A key policy decision concerns the balance between planned primary care services for low income groups and more traditional market style arrangements for others.

Cost-Benefit Analysis↗