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Biomedical subjects

M L Smith

Publications and source records attributed to M L Smith.

At least 19 recordsLinked to original sources
PubMed2007

Bcl-2 family proteins are essential for platelet survival.

Platelets are relatively short-lived, anucleated cells that are essential for proper hemostasis. The regulation of platelet survival in the circulation remains poorly understood. The process of platelet activation and senescence in vivo is associated with processes similar to those observed during apoptosis in nucleated cells, including loss of mitochondrial membrane potential, caspase activation, phosphatidylserine (PS) externalization, and cell shrinkage. ABT-737, a potent antagonist of Bcl-2, Bcl-X(L), and Bcl-w, induces apoptosis in nucleated cells dependent on these proteins for survival. In vivo, ABT-737 induces a reduction of circulating platelets that is maintained during drug therapy, followed by recovery to normal levels within several days after treatment cessation. Whole body scintography utilizing ([111])Indium-labeled platelets in dogs shows that ABT-737-induced platelet clearance is primarily mediated by the liver. In vitro, ABT-737 treatment leads to activation of key apoptotic processes including cytochrome c release, caspase-3 activation, and PS externalization in isolated platelets. Despite these changes, ABT-737 is ineffective in promoting platelet activation as measured by granule release markers and platelet aggregation. Taken together, these data suggest that ABT-737 induces an apoptosis-like response in platelets that is distinct from platelet activation and results in enhanced clearance in vivo by the reticuloendothelial system.

Animals↗
PubMed2006

Development of AFLP-derived, functionally specific markers for environmental persistence studies of fungal strains.

The ability to rapidly identify and quantify a microbial strain in a complex environmental sample has widespread applications in ecology, epidemiology, and industry. In this study, we describe a rapid method to obtain functionally specific genetic markers that can be used in conjunction with standard or real-time polymerase chain reaction (PCR) to determine the abundance of target fungal strains in selected environmental samples. The method involves sequencing of randomly cloned AFLP (amplified fragment length polymorphism) products from the target organism and the design of PCR primers internal to the AFLP fragments. The strain-specific markers were used to determine the fate of three industrially relevant fungi, Aspergillus niger, Aspergillus oryzae, and Chaetomium globosum, during a 4 month soil microcosm experiment. The persistence of each of the three fungal strains inoculated separately into intact soil microcosms was determined by PCR analyses of DNA directly extracted from soil. Presence and absence data based on standard PCR and quantification of the target DNA by real-time PCR showed that all three strains declined after inoculation (approximately 14-, 32-, and 4-fold for A. niger, A. oryzae, and C. globosum, respectively) but remained detectable at the end of the experiment, suggesting that these strains would survive for extended periods if released into nature.

Aspergillus niger↗
PubMed2006

A rare ganglioneuroblastoma secreting dopamine and the value of its measurement in diagnosis and prognosis.

A case is described of a patient with a ganglioneuroblastoma, initially located in the right adrenal, which produced an excess of dopamine (7646 and 7959 nmol/24 h), approximately two and a half times the upper limit of the normal daily urine output. The urinary excretion of noradrenaline, adrenaline and methylated derivatives was always within the normal reference ranges. The patient was generally well, with normal blood pressure and only mild flushes. Two years after surgical resection, recurrence was indicated by an increase in urinary dopamine (8507 nmol/24 h); it was located in the tumour bed and left side of the neck by CT and (123)I MIBG scans. The patient was treated with a high dose of (131)I MIBG, with subsequent reduction in dopamine production. This was repeated on four other occasions, the latest being in January 2005. The output of dopamine was thus used as a marker of tumour diagnosis and progression and it is recommended that the assay of dopamine be included in the screening of catecholamine-secreting tumours to avoid possible misdiagnosis.

Dopamine↗
PubMed2005

Optical spectra of lactoperoxidase as a function of solvent.

The iron of lactoperoxidase is predominantly high-spin at ambient temperature. Optical spectra of lactoperoxidase indicate that the iron changes from high-spin to low-spin in the temperature range from room temperature to 20 K. The transformation is independent of whether the enzyme is in glycerol/water or solid sugar glass. Addition of the inhibitor benzohydroxamic acid increases the amount of the low-spin form, and again the transformation is independent of whether the protein is in an aqueous solution or a nearly anhydrous sugar. In contrast to lactoperoxidase, horseradish peroxidase remains high-spin over the temperature excursion in both solvents and with addition of benzohydroxamic acid. We conclude that details of the heme pocket of lactoperoxidase allow ligation changes with temperature that are dependent upon the apoprotein but independent of solvent fluctuations. At low pH, lactoperoxidase shows a solvent-dependent transition; the high-spin form is predominant in anhydrous sugar glass, but in the presence of water, the low-spin form is also present in abundance. The active site of lactoperoxidase is not as tightly constrained at low pH as at neutrality, though the enzyme is active over a wide pH range.

Binding Sites↗
PubMed2005

Comparing language lateralization determined by dichotic listening and fMRI activation in frontal and temporal lobes in children with epilepsy.

We investigated the relationship between ear advantage scores on the Fused Dichotic Words Test (FDWT), and laterality of activation in fMRI using a verb generation paradigm in fourteen children with epilepsy. The magnitude of the laterality index (LI), based on spatial extent and magnitude of activation in classical language areas (BA 44/45, 21/22, 39) differed significantly for patients classified with unilateral left, compared to bilateral, language representation based on FDWT scores. Concordance with fMRI was higher for those classified with unilateral left, than bilateral language representation on the FDWT. Of note, asymmetry in temporal lobe, rather than frontal lobe, activation was more strongly related to the LI from the dichotic listening test. This study shows that the FDWT can provide a quick and valid estimate of lateralization in pre-surgical candidates, which can be readily adopted for other clinical or research purposes when an estimate of language dominance is desired.

Brain Mapping↗
PubMed2005

Regional hippocampal alteration associated with cognitive deficit following experimental brain injury: a systems, network and cellular evaluation.

Cognitive deficits persist in patients who survive traumatic brain injury (TBI). Lateral fluid percussion brain injury in the mouse, a model of human TBI, results in hippocampal-dependent cognitive impairment, similar to retrograde amnesia often associated with TBI. To identify potential substrates of the cognitive impairment, we evaluated regional neuronal loss, regional hippocampal excitability and inhibitory synaptic transmission. Design-based stereology demonstrated an approximate 40% loss of neurons through all subregions of the hippocampus following injury compared with sham. Input/output curves recorded in slices of injured brain demonstrated increased net synaptic efficacy in the dentate gyrus in concert with decreased net synaptic efficacy and excitatory postsynaptic potential-spike relationship in area CA1 compared with sham slices. Pharmacological agents modulating inhibitory transmission partially restored regional injury-induced alterations in net synaptic efficacy. Both evoked and spontaneous miniature inhibitory postsynaptic currents (mIPSCs) recorded in surviving dentate granule neurons were smaller and less frequent in injured brains than in uninjured brains. Conversely, both evoked and spontaneous mIPSCs recorded in surviving area CA1 pyramidal neurons were larger in injured brains than in uninjured brains. Together, these alterations suggest that regional hippocampal function is altered in the injured brain. This study demonstrates for the first time that brain injury selectively disrupts hippocampal function by causing uniform neuronal loss, inhibitory synaptic dysfunction, and regional, but opposing, shifts in circuit excitability. These changes may contribute to the cognitive impairments that result from brain injury.

Afferent Pathways↗
PubMed2005

Antifungal constituents of northern prickly ash, Zanthoxylum americanum mill.

Leaf, fruit, stem, bark and root of Zanthoxylum americanum were investigated for antifungal activity with 11 strains of fungi representing diverse opportunistic and systemic pathogens, including Candida albicans, Cryptococcus neoformans and Aspergillus fumigatus. All extracts demonstrated a broad spectrum of antifungal activity and inhibited at least eight fungal species in a disk diffusion assay (600 microg/disk). Antifungal activity was light-dependent, with fruit and leaf extracts most active in general. The presence of light-mediated compounds, such as psoralen, 8-methoxypsoralen and imperatorin in extracts of different organs was confirmed by RP-HPLC. A high furanocoumarin content was detected in fruit and leaf and low furanocoumarin levels were found in bark and wood. A high positive correlation was observed between total furanocoumarin content and fungal inhibition zones (r2=0.902, p<0.001). The results provide a phytochemical basis for the very widespread use of Z. americanum in indigenous North American ethnomedical tradition for conditions that may be related to fungal infections.

Antifungal Agents↗
PubMed2003

Carotid baroreflex function during and following voluntary apnea in humans.

Muscle sympathetic nerve activity (MSNA) and arterial pressure increase concomitantly during apnea, suggesting a possible overriding of arterial baroreflex inhibitory input to sympathoregulatory centers by apnea-induced excitatory mechanisms. Apnea termination is accompanied by strong sympathoinhibition while arterial pressure remains elevated. Therefore, we hypothesized that the sensitivity of carotid baroreflex control of MSNA would decrease during apnea and return upon apnea termination. MSNA and heart rate responses to -60-Torr neck suction (NS) were evaluated during baseline and throughout apnea. Responses to +30-Torr neck pressure (NP) were evaluated during baseline and throughout 1 min postapnea. Apnea did not affect the sympathoinhibitory or bradycardic response to NS (P > 0.05); however, whereas the cardiac response to NP was maintained postapnea, the sympathoexcitatory response was reduced for 50 s (P < 0.05). These data demonstrate that the sensitivity of carotid baroreflex control of MSNA is not attenuated during apnea. We propose a transient rightward and upward resetting of the carotid baroreflex-MSNA function curve during apnea and that return of the function curve to, or more likely beyond, baseline (i.e., a downward and leftward shift) upon apnea termination may importantly contribute to the reduced sympathoexcitatory response to NP.

Adult↗
PubMed2003

Bioassay-guided isolation and identification of antifungal compounds from ginger.

A bioassay-guided isolation of antifungal compounds from an African land race of ginger, Zingiber officinale Roscoe, led to the identification of [6], [8] and [10]-gingerols and [6]-gingerdiol as the main antifungal principles. The compounds were active against 13 human pathogens at concentrations of <1 mg/mL. The gingerol content of the African land race was at least 3 x higher than that of typical commercial cultivars of ginger. Therefore, ginger extracts standardized on the basis of the identified compounds, could be considered as antifungal agents for practical therapy.

Amphotericin B↗
PubMed2003

Inhibition of human pathogenic fungi by ethnobotanically selected plant extracts.

In this study, 36 extracts derived from 29 plant species selected using an ethnobotanical approach were tested for antifungal activity against a taxonomically diverse group of 13 human pathogenic fungi. We compared the inhibitory characteristics of these plant extracts with those of the commonly used antifungals, amphotericin B and ketoconazole, and the plant-derived antifungal, berberine. Several plant extracts, notably those from Zingiber officinale (ginger) and Juglans cinerea (butternut), had pronounced antifungal activity against a wide variety of fungi, including strains that were highly resistant to amphotericin B and ketoconazole. Further exploration of Z. officinale as an antifungal is warranted as this species is generally regarded as safe for human consumption.

Amphotericin B↗
PubMed2002

Review of Ge detectors for gamma spectroscopy.

A review is given of the use of germanium detectors for gamma spectroscopy. The advantages, principles of operation, and fabrication processes of semiconductor radiation detectors are described.

Equipment Design↗
PubMed2002

Assessing community child passenger safety efforts in three Northwest Tribes.

OBJECTIVE: To identify strengths and weaknesses in community based child passenger safety programs by developing a scoring instrument and conducting observations of child restraint use in three Native American communities. SETTING: The three communities are autonomous Tribal reservations in the Pacific Northwest. Their per capita incomes and rates of unemployment are comparable. METHODS: In each community, 100 children under 5 years old were observed for car seat use. A six item community assessment tool (100 points maximum) awarded points for such items as the type (primary or secondary) and enforcement of child restraint laws; availability of car seats from distribution programs; extent of educational programs; and access to data on vehicle injuries. RESULTS: For children from birth to 4 years, the car seat use rate ranged from 12%-21%. Rates for infants (71%-80%) far exceeded rates for 1-4 year old children (5%-14%). Community scores ranged from 0 to 31.5 points. There was no correlation between scores and observed car seat use. One reason was the total lack of enforcement of restraint laws. CONCLUSIONS: A community assessment tool can highlight weaknesses in child passenger efforts. Linking such a tool with an objective measure of impact can be applied to other injury problems, such as fire safety or domestic violence. The very process of creating and implementing a community assessment can enhance agency collaboration and publicize evidence based "best practices" for injury prevention. Further study is needed to address methodologic issues and to examine crash and medical data in relation to community child passenger safety scores.

Accidents, Traffic↗
PubMed2001

Potent inhibition of NFAT activation and T cell cytokine production by novel low molecular weight pyrazole compounds.

NFAT (nuclear factor of activated T cell) proteins are expressed in most immune system cells and regulate the transcription of cytokine genes critical for the immune response. The activity of NFAT proteins is tightly regulated by the Ca(2+)/calmodulin-dependent protein phosphatase 2B/calcineurin (CaN). Dephosphorylation of NFAT by CaN is required for NFAT nuclear localization. Current immunosuppressive drugs such as cyclosporin A and FK506 block CaN activity thus inhibiting nuclear translocation of NFAT and consequent cytokine gene transcription. The inhibition of CaN in cells outside of the immune system may contribute to the toxicities associated with cyclosporin A therapy. In a search for safer immunosuppressive drugs, we identified a series of 3,5-bistrifluoromethyl pyrazole (BTP) derivatives that block Th1 and Th2 cytokine gene transcription. The BTP compounds block the activation-dependent nuclear localization of NFAT as determined by electrophoretic mobility shift assays. Confocal microscopy of cells expressing fluorescent-tagged NFAT confirmed that the BTP compounds block calcium-induced movement of NFAT from the cytosol to the nucleus. Inhibition of NFAT was selective because the BTP compounds did not affect the activation of NF-kappaB and AP-1 transcription factors. Treatment of intact T cells with the BTP compounds prior to calcium ionophore-induced activation of CaN caused NFAT to remain in a highly phosphorylated state. However, the BTP compounds did not directly inhibit the dephosphorylation of NFAT by CaN in vitro, nor did the drugs block the dephosphorylation of other CaN substrates including the type II regulatory subunit of protein kinase A and the transcription factor Elk-1. The data suggest that the BTP compounds cause NFAT to be maintained in the cytosol in a phosphorylated state and block the nuclear import of NFAT and, hence, NFAT-dependent cytokine gene transcription by a mechanism other than direct inhibition of CaN phosphatase activity. The novel inhibitors described herein will be useful in better defining the cellular regulation of NFAT activation and may lead to identification of new therapeutic targets for the treatment of autoimmune disease and transplant rejection.

Amino Acid Sequence↗
PubMed2001

Caterpillar talk: acoustically mediated territoriality in larval Lepidoptera.

We provide evidence for conspecific acoustic communication in caterpillars. Larvae of the common hook-tip moth, Drepana arcuata (Drepanoidea), defend silk nest sites from conspecifics by using ritualized acoustic displays. Sounds are produced by drumming the mandibles and scraping the mandibles and specialized anal "oars" against the leaf surface. Staged interactions between a resident and intruder resulted in escalated acoustic "duels" that were typically resolved within minutes, but sometimes extended for several hours. Resident caterpillars generally won territorial disputes, regardless of whether they had built the nest, but relatively large intruders occasionally displaced residents from their nests. All evidence is consistent with acoustic signaling serving a territorial function. As with many vertebrates, ritualized signaling appears to allow contestants to resolve contests without physical harm. Comparative evidence indicates that larval acoustic signaling may be widespread throughout the Lepidoptera, meriting consideration as a principal mode of communication for this important group of insects.

Animal Communication↗