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Biomedical subjects

T L Brown

Publications and source records attributed to T L Brown.

At least 19 recordsLinked to original sources
PubMed2006

Can alcohol-based hand-rub solutions cause you to lose your driver's license? Comparative cutaneous absorption of various alcohols.

We assessed cutaneous ethanol (ETOH) and isopropanol (ISOP) absorption after intensive (30 times per h) use of alcohol-based hand-rub solutions by healthcare workers (HCWs). ETOH was detectable in the breath of 6/20 HCWs (0.001 to 0.0025%) at 1 to 2 min postexposure and in the serum of 2/20 HCWs at 5 to 7 min postexposure. Serum ISOP levels were unrecordable at all time points.

2-Propanol↗
PubMed2003

Q-VD-OPh, a broad spectrum caspase inhibitor with potent antiapoptotic properties.

In recent years, several inhibitors that prevent caspase activation and apoptosis have emerged. At high doses, however, these inhibitors can have nonspecific effects and/or become cytotoxic. In this study, we determined the effectiveness of broad spectrum caspase inhibitors to prevent apoptosis. A carboxy terminal phenoxy group conjugated to the amino acids valine and aspartate (Q-VD-OPh) potently inhibited apoptosis. Q-VD-OPh was significantly more effective in preventing apoptosis than the widely used inhibitors, ZVAD-fmk and Boc-D-fmk, and was also equally effective in preventing apoptosis mediated by the three major apoptotic pathways, caspase 9/3, caspase 8/10, and caspase 12. In addition to the increased effectiveness, Q-VD-OPh was not toxic to cells even at extremely high concentrations. Our data indicate that the specificity, effectiveness, and reduced toxicity of caspase inhibitors can be significantly enhanced using carboxyterminal o-phenoxy groups and may have important uses in vivo.

Amino Acid Chloromethyl Ketones↗
PubMed2003

Identification of the primary caspase 3 cleavage site in alpha II-spectrin during apoptosis.

Alpha II-spectrin is one of the major proteins responsible for maintaining the cytoskeletal integrity of the cell. The caspase 3-mediated cleavage of alpha II-spectrin during apoptotic cell death may play an important role in altering membrane stability and the formation of apoptotic bodies. In this study, we identified the primary caspase 3 cleavage site in alpha II-spectrin. We found that the transcriptional inhibitor, actinomycin D, induced caspase 3 activation and that caspase 3 activation is coincident with the cleavage of alpha II-spectrin protein at a primary cleavage site. Deletion analysis and site directed mutagenesis identified the primary cleavage site in alpha II spectrin at amino acid 1185 (DETD). The primary caspase 3 cleavage site in alpha II spectrin is conserved in immature and mature B cells. Our results indicate that alpha II-spectrin is initially cleaved at a caspase 3 consensus site and this primary event likely alters the structural conformation of the protein exposing subsequent cleavage sites and altering cytoskeletal integrity. Identification of the primary cleavage site for caspase 3 may help to elucidate the role of alpha II-spectrin in membrane stability and apoptosis as well as provide new insights into alpha II-spectrin autoantibody formation associated with the autoimmune disease, Sjögren's syndrome.

Animals↗
PubMed2003

MTS-conjugated-antiactive caspase 3 antibodies inhibit actinomycin D-induced apoptosis.

Caspase 3 is critically involved in the pathway of apoptosis. We have conjugated a MTS-transport-peptide to monoclonal and polyclonal anti-caspase-3 antibodies to suppress Actinomycin D-induced apoptosis in human lymphoma T cells. The advantage of using trans-membrane antibodies compared to conventional apoptosis inhibitors is their specific target recognition in the living cell and their lower toxicity compared to conventional apoptosis inhibitors. We could show that a MTS-transport-peptide modified monoclonal anti-caspase-3 antibody reduces Actinomycin D induced apoptosis, as shown by DNA ladder electrophoresis and cell death ELISA. These results indicate that antibodies have a therapeutic potential to inhibit apoptosis in a variety of diseases.

Antibodies↗
PubMed2002

A study of transcallosal inhibition in schizophrenia using transcranial magnetic stimulation.

A considerable body of imaging research has demonstrated morphological changes in the corpus callosum (CC) of patients with schizophrenia. Transcranial magnetic stimulation (TMS) allows the possibility for the in vivo investigation of a variety of aspects of brain function including the spread of information across the CC. We aimed to investigate whether patients with schizophrenia demonstrate abnormalities of transcallosal inhibition (TCI), a TMS parameter measured with both single and paired pulse experiments. 25 patients with DSM-IV schizophrenia and 20 normal volunteers participated in the study. Electromyographic (EMG) recordings from the bilateral abductor pollicis brevis (APB) muscle were made during focal TMS stimulation to the motor cortex. Experimental paradigms were utilised to measure both the timing and degree of the effect of TCI. The patient group demonstrated a reduction in the degree of TCI at rest and during a sustained muscle contraction. TCI commenced at the same time in the patient and the control group but was of prolonged duration in the patient group although the length of TCI correlated with medication dose. Patients with schizophrenia demonstrate a reduction in the degree of TCI that appeared independent of medication dose. The latency of TCI is not altered in the patient group suggesting that cortical inhibitory mechanisms, rather than corpus callosal ones, are likely to be the cause of these TCI alterations.

Adult↗
PubMed2002

The application of transcranial magnetic stimulation in psychiatry and neurosciences research.

OBJECTIVE: Over recent years transcranial magnetic stimulation (TMS) has become widely applied in the study of neuropsychiatric disorders. The aim of this article is to review the application of TMS as an investigative tool and as a potential therapeutic modality in psychiatric disorders. METHOD: A comprehensive literature review. RESULTS: When applied as an investigative tool, TMS provides innovative ways to directly study the excitability of the cortex, cortical regional connectivity, the plasticity of brain responses and cognitive functioning in illness and disease states. A number of studies suggest the potential of treatment with TMS in disease states, especially in patients with depression, although difficulties exist with the interpretation of the published literature. CONCLUSION: TMS has a considerable role in neuropsychiatric research. It appears to have considerable potential as a therapeutic tool in depression, and perhaps a role in several other disorders, although widespread application requires larger trials and establishment of sustained response.

Animals↗
PubMed2001

'VIT1', a novel gene associated with vitiligo.

To define genes associated with the pigmentary disorder vitiligo, gene expression was compared in non-lesional melanocytes cultured from three vitiligo patients and from three control melanocyte cultures by differential display. A basic local alignment search tool search did not reveal homology of six differentially expressed cDNA fragments to previously identified expressed sequence tags; thus, one was used to screen a melanocyte cDNA library. The underlying VIT1 gene maps to chromosome 2p16. The 3' portion of the VIT1 message is complementary to the 3' end of hMSH6 mRNA, enabling the formation of RNA-RNA hybrids, which may interfere with G/T mismatch repair function. Moreover, the aligned cDNA sequence revealed an open reading frame identical to a hypothetical protein expressed in brain, with a similarity to Drosophila calmodulin, and containing a zinc-finger motif partially identical to N-recognin. Expression of ORF mRNA was confirmed for multiple skin cell types, suggesting its importance for skin physiology.

Adult↗
PubMed2001

Characterization of a TGFbeta-responsive human trophoblast-derived cell line.

The placenta is formed by developing trophoblast cells to facilitate fluid, gas and nutrient exchange with the mother. Inappropriate trophoblast responsiveness can lead to life threatening complications during pregnancy including intrauterine growth retardation, pre-eclampsia, spontaneous abortion and malignancy that could lead to fetal loss. Transforming growth factor beta (TGFbeta) is a multifunctional cytokine required for embryonic development and is an important regulator of human trophoblast function. Although TGFbeta is critical for placental and embryonic development, there are currently no established TGFbeta-responsive human trophoblast-derived cell lines available to study the mechanisms by which TGFbeta regulates trophoblast function. Our studies have examined the transformed human trophoblast-derived cell line, ED27, to determine if it is responsive to TGFbeta. Our data indicate that TGFbeta dose responsively and reversibly inhibits cell growth in ED27 cells and induces classic TGFbeta response genes, fibronectin and plasminogen activator inhibitor 1 (PAI-1). TGFbeta also induces an inhibitor of trophoblast invasion, tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in ED27 cells. Our studies have identified a human trophoblast-derived cell line that parallels isolated primary human trophoblasts in their responses to TGFbeta. This cell line may provide us with the opportunity to determine TGFbeta-mediated responses on human trophoblast functions not previously possible.

Apoptosis↗
PubMed2001

A randomized double-blind, placebo-controlled trial of the EMLA patch for the reduction of pain associated with intramuscular injection in four to six-year-old children.

UNLABELLED: The effectiveness of a eutectic mixture lidocaine-prilocaine topical anaesthetic cream (EMLA) patch compared with a placebo patch in the reduction of pain associated with intramuscular immunization was evaluated. As part of the study, 161 children (aged 4-6-y) undergoing routine diphtheria, pertussis, tetanus and polio (DPTP) immunization in five urban and five rural private office settings were randomly assigned to an EMLA patch (n = 83) or a placebo patch control group (n = 78). Pain measurements included: child's self-report on a Faces Pain Scale; facial action on the Child Facial Coding System; the Children's Hospital of Eastern Ontario Pain Scale and parent and technician ratings on a Visual Analogue Scale. Parents also rated their own and their child's immunization-related anxiety on a Visual Analogue Scale. The EMLA patch group had significantly less pain on all four pain measures compared with the placebo group. Of the children in the placebo group, 43% had clinically significant pain, compared with 17% of children in the EMLA patch group. No severe adverse symptoms occurred as a result of either EMLA or placebo patch application. CONCLUSION: The EMLA patch reduced immunization pain in 4 to 6-y-old children during needle injection.

Anesthetics, Combined↗
PubMed2001

Speech-based interaction with in-vehicle computers: the effect of speech-based e-mail on drivers' attention to the roadway.

As computer applications for cars emerge, a speech-based interface offers an appealing alternative to the visually demanding direct manipulation interface. However, speech-based systems may pose cognitive demands that could undermine driving safety. This study used a car-following task to evaluate how a speech-based e-mail system affects drivers' response to the periodic braking of a lead vehicle. The study included 24 drivers between the ages of 18 and 24 years. A baseline condition with no e-mail system was compared with a simple and a complex e-mail system in both simple and complex driving environments. The results show a 30% (310 ms) increase in reaction time when the speech-based system is used. Subjective workload ratings and probe questions also indicate that speech-based interaction introduces a significant cognitive load, which was highest for the complex e-mail system. These data show that a speech-based interface is not a panacea that eliminates the potential distraction of in-vehicle computers. Actual or potential applications of this research include design of in-vehicle information systems and evaluation of their contributions to driver distraction.

Attention↗
PubMed2001

Human performance models and rear-end collision avoidance algorithms.

Collision warning systems offer a promising approach to mitigate rear-end collisions, but substantial uncertainty exists regarding the joint performance of the driver and the collision warning algorithms. A simple deterministic model of driver performance was used to examine kinematics-based and perceptual-based rear-end collision avoidance algorithms over a range of collision situations, algorithm parameters, and assumptions regarding driver performance. The results show that the assumptions concerning driver reaction times have important consequences for algorithm performance, with underestimates dramatically undermining the safety benefit of the warning. Additionally, under some circumstances, when drivers rely on the warning algorithms, larger headways can result in more severe collisions. This reflects the nonlinear interaction among the collision situation, the algorithm, and driver response that should not be attributed to the complexities of driver behavior but to the kinematics of the situation. Comparisons made with experimental data demonstrate that a simple human performance model can capture important elements of system performance and complement expensive human-in-the-loop experiments. Actual or potential applications of this research include selection of an appropriate algorithm, more accurate specification of algorithm parameters, and guidance for future experiments.

Accidents, Traffic↗
PubMed2001

The role of religion in predicting adolescent alcohol use and problem drinking.

OBJECTIVE: There are racial differences in adolescents' propensity to consume alcohol--with white adolescents tending to consume more alcohol than black adolescents--but there is no clear explanation for why such differences exist. The purpose of this study was to examine the relationship between religiosity, a cultural factor that is not well understood currently, and racial differences in adolescent alcohol use. METHOD: Participants were white and black ninth-grade adolescents (N = 899; 54% female, 57.5% white) involved in a 3-year longitudinal study of ways to reduce alcohol use and sexual risk-taking behavior among adolescents in Ohio and Kentucky. RESULTS: Findings indicate that religiosity is differentially associated with alcohol use and problem drinking for white and black adolescents. Religious service attendance was the most significant predictor of alcohol use for black adolescents, whereas religious fundamentalism was most important for white adolescents. In contrast, frequency of prayer was the significant predictor of problem drinking for black adolescents, whereas the level of importance placed on religion was the significant predictor for white adolescents. Important gender differences also emerged in both prediction models and are discussed. CONCLUSIONS: Since there is great heterogeneity among adolescents (in terms of race and gender) in their alcohol use and misuse, the "one-size-fits-all" approach to alcohol treatment and prevention is likely inappropriate. Moreover, conceptualizations of alcohol use and misuse, and its prevention and treatment, should include the consideration of such key cultural factors as religiosity.

Adolescent↗
PubMed2001

The Alaska Native diabetes program.

OBJECTIVES: To provide optimum health care to indigenous people with diabetes, to prevent diabetes, and to monitor the epidemiology of diabetes and selected complications. The purposes of this paper are to describe the program and to present data that highlights the major problems and successes. STUDY DESIGN: Descriptive epidemiology report of diabetes and population service program based on yearly chart review data. METHODS: Almost half of Alaska Natives with diabetes have no direct access to physicians or hospitals. Health care delivery is now managed by the tribes themselves. Program emphases include maintenance of a population-based registry, formal training for village health aides, physical activity programs, patient education, primary prevention activities and adherence to standards of care to prevent complications. A centralized registry is maintained to assure that epidemiological data is available and patients are not lost to follow-up. Each year a random sample of charts at each major facility is audited against nationally standardized care guidelines. RESULTS: The prevalence of diabetes among Alaska Natives increased 80% over the 13 years from 1985 to 1998 (15.7/1000 to 28.3/1000, age adjusted to U.S. 1980 population). For the years 1986-1998 the incidence rates of lower extremity amputation and end stage renal disease were 6.1/1000 and 2.0/1000 respectively. The level of care provided to Alaska Native patients is comparable to that provided to the general diabetic patient population seen in Alaskan urban clinics. CONCLUSIONS: In spite of logistic challenges, care provided to Alaska Native people with diabetes compares favorably to that provided in other settings. Incidence rates of lower extremity amputation and end stage renal disease also remain comparable to or lower than those in other U.S. populations. Many aspects of our system could be extended to other chronic disease programs serving isolated indigenous populations. Primary prevention of diabetes remains a major challenge as life styles change.

Alaska↗
PubMed2000

Smad7 is induced by CD40 and protects WEHI 231 B-lymphocytes from transforming growth factor-beta -induced growth inhibition and apoptosis.

Transforming growth factor-beta (TGF-beta) is a potent inducer of apoptosis in B-lymphocytes and is essential for immune regulation and maintenance of self-tolerance. Here we show that concomitant signaling through CD40 sustains proliferation and rescues the premature B cell line WEHI 231 from both TGF-beta-induced and anti-IgM-induced apoptosis. The anti-apoptotic effect of CD40 is associated with the transcriptional activation of the inhibitory Smad7 protein. The transactivation of Smad7 by CD40 is NFkappaB-dependent in that pharmacological inhibitors of this pathway, N-tosyl-l-phenylalanine chloromethyl ketone and pyrrolidine dithiocarbamate, abrogate CD40-induced Smad7 expression. Ectopic overexpression of Smad7 inhibited Smad2 activation, TGF-beta-mediated growth inhibition, and apoptosis in WEHI 231 cells. Consistent with this result, dominant negative interference with Smad2 and Smad3 function also inhibited TGF-beta-induced apoptosis. The inhibitory effects of Smad7 overexpression were specific to TGF-beta-induced apoptosis and were without effect on anti-IgM-induced cell death. These results suggest a mechanism of suppression of TGF-beta-induced apoptosis by CD40, mediated through activation of NF-kappaB and, consequently, induction of Smad7 expression.

Antigens, CD↗
PubMed2000

Cases of cat-associated human plague in the Western US, 1977-1998.

Exposure to cats infected with Yersinia pestis is a recently recognized risk for human plague in the US. Twenty-three cases of cat-associated human plague (5 of which were fatal) occurred in 8 western states from 1977 through 1998, which represent 7.7% of the total 297 cases reported in that period. Bites, scratches, or other contact with infectious materials while handling infected cats resulted in 17 cases of bubonic plague, 1 case of primary septicemic plague, and 5 cases of primary pneumonic plague. The 5 fatal cases were associated with misdiagnosis or delays in seeking treatment, which resulted in overwhelming infection and various manifestations of the systemic inflammatory response syndrome. Unlike infections acquired by flea bites, the occurrence of cat-associated human plague did not increase significantly during summer months. Plague epizootics in rodents also were observed less frequently at exposure sites for cases of cat-associated human plague than at exposure sites for other cases. The risk of cat-associated human plague is likely to increase as residential development continues in areas where plague foci exist in the western US. Enhanced awareness is needed for prompt diagnosis and treatment.

Adolescent↗
PubMed2000

Effects of fexofenadine, diphenhydramine, and alcohol on driving performance. A randomized, placebo-controlled trial in the Iowa driving simulator.

BACKGROUND: Sedating antihistamines may impair driving performance as seriously as alcohol. OBJECTIVE: To compare the effects of fexofenadine, diphenhydramine, alcohol, and placebo on driving performance. DESIGN: Randomized, double-blind, double-dummy, four-treatment, four-period crossover trial. SETTING: The Iowa Driving Simulator. PARTICIPANTS: 40 licensed drivers with seasonal allergic rhinitis who were 25 to 44 years of age. INTERVENTION: One dose of fexofenadine (60 mg), diphenhydramine (50 mg), alcohol (approximately 0.1% blood alcohol concentration), or placebo, given at weekly intervals before participants drove for 1 hour in the Iowa Driving Simulator. MEASUREMENTS: The primary end point was coherence, a continuous measure of participants' ability to match the varying speed of a vehicle that they were following. Secondary end points were drowsiness and other driving measures, including lane keeping and response to a vehicle that unexpectedly blocked the lane ahead. RESULTS: Participants had significantly better coherence after taking alcohol or fexofenadine than after taking diphenhydramine. Lane keeping (steering instability and crossing the center line) was impaired after alcohol and diphenhydramine use compared with fexofenadine use. Mean response time to the blocking vehicle was slowest after alcohol use (2.21 seconds) compared with fexofenadine use (1.95 seconds). Self-reported drowsiness did not predict lack of coherence and was weakly associated with minimum following distance, steering instability, and leftlane excursion. CONCLUSIONS: Participants had similar performance when treated with fexofenadine or placebo. After alcohol use, participants performed the primary task well but not the secondary tasks; as a result, overall driving performance was poorer. After participants took diphenhydramine, driving performance was poorest, indicating that diphenhydramine had a greater impact on driving than alcohol did. Drowsiness ratings were not a good predictor of impairment, suggesting that drivers cannot use drowsiness to indicate when they should not drive.

Adult↗
PubMed2000

Effect of experimental parameters on the ESI FT-ICR mass spectrum of fulvic acid.

Fulvic acid (FA) is a heterogeneous mixture of organic macromolecules found in the waters, soils, and sediments of the earth's surface. The ability of electrospray ionization (ESI) to effectively transfer large ions from the solution phase to the gas phase and the coupling of ESI to the high-mass-resolution capabilities of Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) provide a potential method for the mass spectrometric analysis of FA. Positive- and negative-ion ESI FT-ICR MS analyses of four reference International Humic Substances Society FAs were performed. The spray solution composition was found to have a dramatic effect on the ion distributions, with high-mass aggregates (m/z approximately 2000-4000) being formed in less polar spray solutions. Positive-ion spectra for each FA obtained under optimum conditions resulted in number-average molecular weights ranging from 1700 to 1900. The mass spectra were extremely complex, with ion distributions on the order of m/z approximately 500-3000. The presence of more than one ion at each nominal mass was routinely observed. Negative-ion ESI analysis of the FA samples resulted in the observation of multiply charged ions whose distributions could be affected by the acidification of the spray solution. Solution parameters which have been reported to affect molecular weight distributions of FA such as pH, ionic strength, and concentration of multivalent cations were found to have little or no effect on the observed m/z distributions.

Benzopyrans↗