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Biomedical subjects

S L Thomas

Publications and source records attributed to S L Thomas.

At least 19 recordsLinked to original sources
PubMed2001

Malaria parasite Plasmodium gallinaceum up-regulates host red blood cell channels.

The properties of the malaria parasite-induced permeability pathways in the host red blood cell have been a major area of interest particularly in the context of whether the pathways are host- or parasite-derived. In the present study, the whole-cell configuration of the patch-clamp technique has been used to show that, compared with normal cells, chicken red blood cells infected by Plasmodium gallinaceum exhibited a 5-40-fold larger membrane conductance, which could be further increased up to 100-fold by raising intracellular Ca(2+) levels. The increased conductance was not due to pathways with novel electrophysiological properties. Rather, the parasite increased the activity of endogenous 24 pS stretch-activated non-selective cationic (NSC) and 62 pS calcium-activated NSC channels, and, in some cases, of endogenous 255 pS anionic channels.

Animals↗
PubMed2001

Stroke education by utility bill inserts.

To assess the usefulness of utility bill inserts in stroke education, a stroke fact sheet was included in the bills of 13,000 customers of a rural electric cooperative in eastern Arkansas. Recipients were asked to return their responses to four questions based on the fact sheet via a postage-paid postcard. Two hundred eleven people responded, for an overall 1.65% response rate. Seventy-seven percent responded correctly with all four "S" stroke symptoms. Hypertension was correctly identified by 88% and smoking by 72%. Fifty-seven percent said they would immediately dial 911 at the onset of symptoms, while 36% said they would contact their doctor.

Arkansas↗
PubMed2000

The role of anion and cation channels in volume regulatory responses in trout red blood cells.

(1) An outwardly rectifying chloride channel (ORCC) of large conductance has been detected under isotonic conditions (320 mosM 1(-1)) in the plasma membrane of trout red blood cells (RBCs) using the excised inside-out configuration. The channel, with a permeability ratio P(Cl)/Pcation of 12, was inhibited by the Cl- channel blockers 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) (50 microM), and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) (100 microM) in the bathing solution. (2) In hypotonic conditions (215 mosM 1(-1)), 44% of cell-attached patches showed spontaneous single channel activity identified as nonselective cationic (NSC) channels. A second group, corresponding to 7% of cell-attached patches, showed spontaneous activity corresponding to a channel type presenting outward rectification and anionic selectivity. Finally, 49% of patches displayed a complex spontaneous signal corresponding to the superimposition of inward and outward currents probably due to activation of different channel types. (3) Giga-seals obtained without suction in intact cells under isotonic conditions possessed NSC channels that were quiescent but which could be activated either by mechanical deformation of cell membrane or by hypotonic cell swelling. (4) Hypotonically swollen RBCs exhibited regulatory volume decrease (RVD) over 3 h, which was linked to a fivefold to sixfold increase in unidirectional fluxes of K+, a net loss of intracellular K+ and net gain of extracellular Na+. RVD and the hypotonically activated, unidirectional K+ influx continued after replacement of Cl- by methylsulfonate (MeSF) albeit more slowly. (5) The NSC channel inhibitor, barium, and the Cl- channel inhibitor, NPPB, both inhibited the RVD response by approximately 50% in Cl- containing saline. When Cl- was replaced by MeSF, the inhibition was > 90% suggesting that NSC channels and ORCC play key roles in the chloride-independent component of RVD.

Animals↗
PubMed1998

Gait in patients with cerebellar ataxia.

The gait pattern in 10 patients with cerebellar degenerations was studied and the results were compared with 10 matched normal subjects, seeking the principal patterns in this disorder. Gait at natural speed was studied in a biomechanics laboratory using a video-based kinematic data acquisition system for measuring body movements. Patients showed a reduced step and stride length with a trend to reduced cadence. Heel off time, toe off time, and time of peak flexion of the knee in swing were all delayed. Range of motion of ankle, knee, and hip were all reduced, but only ankle range of motion reached significance. Multijoint coordination was impaired, as indicated by a relatively greater delay of plantar flexion of the ankle compared with flexion of the knee and a relatively late knee flexion compared with hip flexion at the onset of swing. The patients also showed increased variability of almost all measures. Although some of the deviations from normal were simply the result of slowness of walking, the gait pattern of patients with cerebellar degeneration shows incoordination similar to that previously described for their multijoint limb motion.

Adult↗
PubMed1998

A review of hepatitis C virus (HCV) vertical transmission: risks of transmission to infants born to mothers with and without HCV viraemia or human immunodeficiency virus infection.

BACKGROUND: Hepatitis C virus (HCV) vertical transmission studies have reported conflicting findings, possibly due to differences in HCV transmission risk factors among maternal populations, or to methodological differences. METHODS: Systematic review of worldwide published and unpublished HCV vertical transmission studies. Standardized diagnostic criteria were applied to minimize methodological differences, and transmission rates recalculated according to maternal HCV viraemic and human immunodeficiency virus (HIV) infection status. RESULTS: In all, 976 eligible infants from 28 studies were followed up sufficiently for recalculation of transmission rates. Overall transmission rates were less than 10% in 8/12 studies of HIV negative mothers, compared with 2/7 studies comprising at least 50% HIV-coinfected mothers. Rates from 409 viraemic mothers in 15 studies ranged from 0% to 41%, being less than 10% from HIV negative mothers in 6/13 studies and from HIV positive mothers in 1/6 studies. Nine studies measured maternal viraemia levels, with only 2/30 transmitting mothers having < 10(6) copies/ml of HCV RNA. Eight transmissions were identified overall from non-viraemic mothers. Significant transmission rate variation remained after accounting for maternal viraemia and HIV coinfection, possibly due to differences in other vertical transmission risk factors, in frequencies of postnatal transmission, or residual differences in study methodologies. CONCLUSIONS: Overall, HCV transmission is largely restricted to infants born to HCV viraemic mothers, and low risks among most HIV negative mothers may be due to lower HCV viraemia levels. International agreement on standardized diagnostic criteria for HCV vertical transmission would facilitate pooling of individual findings, to allow more precise transmission estimates and further investigation of risk factors.

Adult↗
PubMed1998

Functional analysis of the human immunodeficiency virus type 1 Rev protein oligomerization interface.

The expression of human immunodeficiency virus type 1 (HIV-1) structural proteins requires the action of the viral trans-regulatory protein Rev. Rev is a nuclear shuttle protein that directly binds to its cis-acting Rev response element (RRE) RNA target sequence. Subsequent oligomerization of Rev monomers on the RRE and interaction of Rev with a cellular cofactor(s) result in the cytoplasmic accumulation of RRE-containing viral mRNAs. Moreover, Rev by itself is exported from the nucleus to the cytoplasm. Although it has been demonstrated that Rev multimerization is critically required for Rev activity and hence for HIV-1 replication, the number of Rev monomers required to form a trans-activation-competent complex on the RRE is unknown. Here we report a systematic analysis of the putative multimerization domains within the Rev trans-activator protein. We identify the amino acid residues which are part of the proposed single hydrophobic surface patch in the Rev amino terminus that mediates intermolecular interactions. Furthermore, we show that the expression of a multimerization-deficient Rev mutant blocks HIV-1 replication in a trans-dominant (dominant-negative) fashion.

Amino Acid Sequence↗
PubMed1997

Tissue-specific regulation of G-protein-coupled inwardly rectifying K+ channel expression by muscarinic receptor activation in ovo.

We investigated the effects of muscarinic acetylcholine receptor stimulation on the expression levels of the G-protein-coupled inwardly rectifying K+ channel (GIRK) subunits using solution hybridization and immunoblot analyses. We report here that treatment of chick embryos in ovo with muscarinic agonist causes decreases in mRNA levels encoding GIRK1 and GIRK4 in atria but does not alter GIRK1 expression in ventricles. In addition, GIRK1 protein levels also demonstrate a decrease in atria upon muscarinic acetylcholine receptor stimulation. Numerous receptors couple to the activation of the GIRK family of inwardly rectifying K+ channels; thus, these decreases represent a novel mechanism for regulating physiological responses to chronic agonist exposure.

Animals↗
PubMed1997

Flexibility of anticipatory postural adjustments revealed by self-paced and reaction-time arm movements.

In standing humans, it is not certain whether anticipatory postural adjustments associated with rapid, voluntary elbow flexion movements (focal movements) originate as a selection from preset synergies or as the result of specific planning of motor commands. We studied these muscle recruitment patterns when the same focal movement was made under behavioral conditions of a self-paced task (SPT) and a reaction-time task (RTT). While standing still, eight normal subjects performed focal movements under the SPT and RTT behavioral conditions and under three different biomechanical conditions: (1) unloaded-upright, (2) loaded-upright (holding a 3800-g metal bar), and (3) unloaded-forward leaning. Anticipatory postural adjustments were quantified using the latency and duration of electromyographic (EMG) data and the center of pressure (COP) displacement data. Postural-kinematic [joint and body center of gravity (COG) motion] data were used to quantify the anticipatory postural program's effectiveness at preventing postural movement. Focal movement kinematics and associated EMG activity differed due to biomechanical but not behavioral (SPT vs. RTT) conditions. The maximum and net displacement of the body COG measurements did not differ between the behavioral conditions. The amplitude, timing, and net movements of lower extremity joints were influenced by the behavioral conditions. However, the behavioral conditions significantly affected the phasing (including order of activation) and duration of anticipatory postural EMG activity and the phasing of COP displacements under certain biomechanical conditions. These findings support the theory that anticipatory postural adjustments are planned in detail.

Adolescent↗
PubMed1997

Use of polymerase chain reaction and antibody tests in the diagnosis of vertically transmitted hepatitis C virus infection.

Data on patterns of polymerase chain reaction (PCR) and antibody test results in infants born to hepatitis C virus (HCV)-infected mothers were systematically reviewed to aid development of optimum testing schedules and diagnostic criteria for vertically exposed infants and to facilitate early identification of infected infants. Survival and cross-sectional analyses were used to estimate the timing of initial PCR positivity and subsequent PCR negativity in infected infants, and maternal antibody loss in uninfected infants was estimated as a weighted average of individual study findings. Of 74 eligible infants with strong evidence of HCV infection, an estimated 89% (90% confidence interval, 80-95%) were first PCR positive by 3 months of age, and less than 10% had subsequent PCR negativity attributable to intermittent viraemia or resolved infection in the first 18 months of life. The negative predictive value of PCR at 3 months of age was greater than 98% at an assumed rate of 5% vertical transmission, but as low as 88% at 25% transmission. The inclusion of 22 infants, each with a single PCR-positive result, increased the estimated frequency of resolved infections but made little difference to other estimates. A minority of PCR-positive infants had periods of antibody negativity by second- or third-generation assays, and among 297 uninfected infants, maternal antibody was not detected beyond 18 months. Thus, the majority of infected infants may be persistently PCR positive from 3 months of age, and the negative predictive value of PCR at 3 months is generally high. However, poor repeatability of PCR, inadequate infant follow-up, and inclusion of postnatally infected infants limits interpretation of the pooled data. Further studies using standardised PCR methodologies are needed.

Cross-Sectional Studies↗
PubMed1997

Regulation of muscarinic receptor expression and function in cultured cells and in knock-out mice.

We have investigated the molecular and cellular basis for the regulation of expression and function of the muscarinic acetylcholine receptors. Treatment of cultured chick cardiac cells with the agonist carbachol results in decreased levels of mRNA encoding the m2 and m4 receptors. Treatment of chick embryos in ovo with carbachol results in decreased levels of mRNA encoding the potassium channel subunits GIRK1 and GIRK4 as well as the m2 receptor. There are thus multiple pathways for the regulation of mAChR responsiveness by long-term agonist exposure. Immunoblot, immunoprecipitation, and solution hybridization analyses have been used to quantitate the regulation of mAChR expression in chick retina during embryonic development. The m4 receptor is the predominant subtype expressed early in development, while the expression of the m3 and m2 receptors increases later in development. A cAMP-regulated luciferase reporter gene has been used to demonstrate that the m2 and m4 receptors have distinct specificities for coupling to G-protein subtypes to mediate inhibition of adenylyl cyclase. This system has also been used to demonstrate that beta-arrestin1 and beta-adrenergic receptor kinase-1 act synergistically to promote receptor desensitization. We have isolated the promoter region for the chick m2 receptor gene, identified regions of the promoter required to drive high level expression in cardiac and neural cells, and have identified a region which confers sensitivity of gene expression to neurally active cytokines. Finally, in order to determine the role of individual receptor subtypes in muscarinic-mediated responses in vivo, we have used the method of targeted gene disruption by homologous recombination to generate mice deficient in the m1 receptor.

Animals↗
PubMed1997

Probing the structure of the HIV-1 Rev trans-activator protein by functional analysis.

Human immunodeficiency virus type 1 (HIV-1) encodes a trans-acting regulatory protein, termed Rev, which is critically required for virus replication. Rev is a sequence-specific RNA binding protein which mediates the nuclear export of unspliced and incompletely spliced viral mRNAs encoding the viral structural proteins. While CD and fluorescence measurements have provided several possible structural models of Rev, all attempts employing X-ray crystallography and NMR techniques have so far failed to provide more accurate data. We present a new approach to validate alternative structural models of the N-terminal region of Rev which contains the nuclear localization/RNA binding domain. Points of contact between structural elements in a protein were determined by introduction of targeted amino acid substitutions and subsequent scoring of the biological activities. Our data resulted in the suggestion of a new and more refined model of HIV-1 Rev structure which to date has been impossible to obtain by other means.

Animals↗
PubMed1995

Differential coupling of m2 and m4 muscarinic receptors to inhibition of adenylyl cyclase by Gi alpha and G(o)alpha subunits.

We compared the G-protein requirements for coupling of human and chicken m2 and m4 muscarinic acetylcholine receptors (mAChRs) to inhibition of adenylyl cyclase, using a luciferase reporter gene under the transcriptional control of a cAMP response element as a sensitive monitor of intracellular cAMP levels. Previously, we used this system to demonstrate that the chick m4 receptor preferentially coupled to Gi alpha-2 and G(o)alpha over Gi alpha-1 and Gi alpha-3. We found that both the chick and human m2 mAChRs can couple to Gi alpha-1, Gi alpha-2, Gi alpha-3, and G(o)alpha, while the human m4 mAChR preferentially couples to Gi alpha-2 and G(o)alpha. Both the G(o)1 and G(o)2 forms of the G(o)alpha subunit were effective in reconstituting coupling of the m2 and m4 mAChRs to inhibit adenylyl cyclase activity. The m2 and m4 mAChRs thus couple to inhibition of adenylyl cyclase by overlapping but different sets of G-protein alpha subunits.

Adenylyl Cyclases↗
PubMed1995

Ultraviolet radiation reduces phagocytosis and intracellular killing of mycobacteria and inhibits nitric oxide production by macrophages in mice.

Exposure of mice to a single or multiple low doses of ultraviolet radiation (UVR) decreases the induction of the delayed-type hypersensitivity (DTH) response to Mycobacterium bovis BCG and Mycobacterium lepraemurium (MLM) and impairs the clearance of bacteria from the lymphoid organs. This study is an attempt to address the mechanism by which UV radiation impairs the clearance of bacteria from the lymphoid organs by determining whether alterations in macrophage function such as ingestion and intracellular killing of mycobacteria or production of reactive nitrogen intermediates might be responsible for these effects. BALB/c or C3H/HeN mice were exposed to a single dose of UVB (280-320 nm) radiation ranging from 0.35 to 45 kJ/m2, and at regular intervals after irradiation, the peritoneal and splenic macrophages were collected, cultured, and infected with live BCG or MLM. Phagocytosis was assessed at 6 h by counting the number of acid-fast bacteria per macrophage after Ziehl-Neelsen staining. The rate of intracellular killing was assessed by lysing the macrophages at 6, 12, 24, and 48 h after BCG infection, plating the suspension on 7H11 agar, and counting the number of colony-forming units 21 days later. Similarly, the nitric oxide production, as measured by nitrite, by macrophages obtained from UVB-irradiated and nonirradiated mice in response to BCG was assessed. There was a significant reduction in the uptake of organisms by both peritoneal and splenic macrophages collected from UV-irradiated mice. The intracellular killing of organisms was also significantly reduced, as was the production of nitric oxide by peritoneal macrophages infected with BCG in vitro. These results indicate that UVR affects macrophage functions and are consistent with our hypothesis that impaired clearance of bacteria in vivo results from an alteration in macrophage function.

Animals↗
PubMed1995

Molecular analysis of the regulation of muscarinic receptor expression and function.

Several systems are being used to determine the molecular and cellular basis for the regulation of expression and function of the muscarinic receptors. Treatment of chick heart cells in culture results in decreased levels of mRNA encoding the cm2 and cm4 receptors. This probably results from decreased gene transcription which requires concomitant mAChR-mediated inhibition of adenylyl cyclase and mAChR-mediated stimulation of phospholipase C. Site-directed mutagenesis was used to demonstrate that the single tyrosine residue in the carboxyl-terminal cytoplasmic tail of the m2 receptor is involved in agonist-induced down-regulation but not sequestration. Activation of heterologous receptors in chick heart cells can also regulate mAChR mRNA levels. A cAMP-regulated luciferase reporter gene, has been used to demonstrate that the m4 receptor preferentially couples to Gi alpha-2 or Go alpha over Gi alpha-1 or Gi alpha-3 to mediate inhibition of adenylyl cyclase activity. Finally, in order to determine the role of individual receptor subtypes in muscarinic-mediated responses in vivo, we are beginning to use the method of targeted gene disruption by homologous recombination to generate mice deficient in specific receptor subtypes.

Adenylate Cyclase Toxin↗
PubMed1995

Constipation and diarrhea: the neglected symptoms.

OBJECTIVE: To review the symptom experience of constipation and diarrhea related to cancer and its treatment. DATA SOURCES: Published articles and book chapters relating to constipation and diarrhea in patients with cancer. CONCLUSIONS: Constipation and diarrhea often represent a major concern and source of discomfort for the cancer patients. Research is needed to establish prevention and treatment protocols for patients at risk for constipation or diarrhea. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses are in an excellent position to recognize individuals who are at high risk for constipation and diarrhea. Preventive strategies and treatment protocols are of utmost importance.

Cathartics↗