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Biomedical subjects

B W Jones

Publications and source records attributed to B W Jones.

At least 19 recordsLinked to original sources
PubMed2006

Population structure between environmentally transmitted vibrios and bobtail squids using nested clade analysis.

Squids from the genus Euprymna (Cephalopoda: Sepiolidae) and their symbiotic bacteria Vibrio fischeri form a mutualism in which vibrios inhabit a complex light organ within the squid host. A host-mediated daily expulsion event seeds surrounding seawater with symbiotically capable V. fischeri that environmentally colonize newly hatched axenic Euprymna juveniles. Competition experiments using native and non-native Vibrio have shown that this expulsion/re-colonization phenomenon has led to cospeciation in this system in the Pacific Ocean; however, the genetic architecture of these symbiotic populations has not been determined. Using genetic diversity and nested clade analyses we have examined the variation and history of three allopatric Euprymna squid species (E. scolopes of Hawaii, E. hyllebergi of Thailand, and E. tasmanica from Australia) and their respective Vibrio symbionts. Euprymna populations appear to be very genetically distinct from each other, exhibiting little or no migration over large geographical distances. In contrast, Vibrio symbiont populations contain more diverse haplotypes, suggesting both host presence and unidentified factors facilitating long-distance migration structure in Pacific Vibrio populations. Findings from this study highlight the importance of how interactions between symbiotic organisms can unexpectedly shape population structure in phylogeographical studies.

Animals↗
PubMed2002

A systematic review of tegaserod for the treatment of irritable bowel syndrome.

AIM: To assess the clinical effectiveness of tegaserod for the treatment of irritable bowel syndrome (IBS). DESIGN: Systematic review. SETTING: Six placebo-controlled, randomized controlled trials (RCTs) retrieved from electronic searches (Medline, Embase, FDA website) and hand-searching. MAIN OUTCOME MEASURES: Any outcome was accepted. RESULTS: In a small pharmacodynamic study, tegaserod 4 mg/day accelerated orocecal transit compared with placebo, but did not affect gastric emptying rate and colonic transit. Five placebo-controlled studies evaluated Subject's Global Assessment of gastrointestinal (GI) symptoms in predominantly female patients who fulfilled Rome criteria for constipation-predominant IBS. Responder rates were higher with tegaserod 1-24 mg/day than with placebo, although it was not possible in this review to evaluate the consistency of this effect, to fully quantify the effect size, or identify patients who may gain most benefit from this treatment. CONCLUSION: Currently published data on tegaserod for IBS are limited (two of six RCTs published in full, four as abstracts). Tegaserod may be an appropriate treatment for occasional use for relief of GI symptoms associated with constipation-predominant IBS. Further research, comparing tegaserod with alternative treatments for GI symptoms of IBS, should help define the place of this drug in therapy.

Adolescent↗
PubMed2001

Differential effects of a Toll-like receptor antagonist on Mycobacterium tuberculosis-induced macrophage responses.

We previously showed that viable Mycobacterium tuberculosis (Mtb) bacilli contain distinct ligands that activate cells via the mammalian Toll-like receptor (TLR) proteins TLR2 and TLR4. We now demonstrate that expression of a dominant negative TLR2 or TLR4 proteins in RAW 264.7 macrophages partially blocked Mtb-induced NF-kappa B activation. Coexpression of both dominant negative proteins blocked virtually all Mtb-induced NF-kappa B activation. The role of the TLR4 coreceptor MD-2 was also examined. Unlike LPS, Mtb-induced macrophage activation was not augmented by overexpression of ectopic MD-2. Moreover, cells expressing an LPS-unresponsive MD-2 mutant responded normally to Mtb. We also observed that the lipid A-like antagonist E5531 specifically inhibited TLR4-dependent Mtb-induced cellular responses. E5531 could substantially block LPS- and Mtb-induced TNF-alpha production in both RAW 264.7 cells and primary human alveolar macrophages (AM phi). E5531 inhibited Mtb-induced AM phi apoptosis in vitro, an effect that was a consequence of the inhibition of TNF-alpha production by E5531. In contrast, E5531 did not inhibit Mtb-induced NO production in RAW 264.7 cells and AM phi. Mtb-stimulated peritoneal macrophages from TLR2- and TLR4-deficient animals produced similar amounts of NO compared with control animals, demonstrating that these TLR proteins are not required for Mtb-induced NO production. Lastly, we demonstrated that a dominant negative MyD88 mutant could block Mtb-induced activation of the TNF-alpha promoter, but not the inducible NO synthase promoter, in murine macrophages. Together, these data suggest that Mtb-induced TNF-alpha production is largely dependent on TLR signaling. In contrast, Mtb-induced NO production may be either TLR independent or mediated by TLR proteins in a MyD88-independent manner.

Animals↗
PubMed2001

Glial cell development in the Drosophila embryo.

Glial cells play a central role in the development and function of complex nervous systems. Drosophila is an excellent model organism for the study of mechanisms underlying neural development, and recent attention has been focused on the differentiation and function of glial cells. We now have a nearly complete description of glial cell organization in the embryo, which enables a systematic genetic analysis of glial cell development. Most glia arise from neural stem cells that originate in the neurogenic ectoderm. The bifurcation of glial and neuronal fates is under the control of the glial promoting factor glial cells missing. Differentiation is propagated through the regulation of several transcription factors. Genes have been discovered affecting the terminal differentiation of glia, including the promotion glial-neuronal interactions and the formation of the blood-nerve barrier. Other roles of glia are being explored, including their requirement for axon guidance, neuronal survival, and signaling.

Animals↗
PubMed2001

Differential roles of Toll-like receptors in the elicitation of proinflammatory responses by macrophages.

BACKGROUND: Mammalian Toll-like receptor (TLR) proteins are pattern recognition receptors for a diverse array of bacterial and viral products. Gram negative bacterial lipopolysaccharide (LPS) activates cells through TLR4, whereas the mycobacterial cell wall glycolipids, lipoarabinomannan (LAM) and mannosylated phosphatidylinositol (PIM), activate cells through TLR2. Furthermore, short term culture filtrates of M. tuberculosis bacilli contain a TLR2 agonist activity, termed soluble tuberculosis factor (STF), that appears to be PIM. It was recently shown that stimulation of RAW264.7 murine macrophages by LPS, LAM, STF, and PIM rapidly activated NF-kappaB, AP1, and MAP kinases. RESULTS: This study shows that signalling by TLR2 and TLR4 also activates the protein kinase Akt, a downstream target of phosphatidylinositol-3'-kinase (PI-3-K). This finding suggests that activation of PI-3-K represents an additional signalling pathway induced by engagement of TLR2 and TLR4. Subsequently, the functional responses induced by the different TLR agonists were compared. LPS, the mycobacterial glycolipids, and the OspC lipoprotein (a TLR2 agonist) all induced macrophages to secrete tumour necrosis factor alpha (TNFalpha), whereas only LPS could induce nitric oxide (NO) secretion. Human alveolar macrophages also exhibited a distinct pattern of cellular response after stimulation with TLR2 and TLR4 agonists. Specifically, LPS induced TNFalpha, MIP-1beta, and RANTES production in these cells, whereas the TLR2 agonists induced only MIP-1beta production. CONCLUSION: Together, these data show that different TLR proteins mediate the activation of distinct cellular responses, despite their shared ability to activate NF-kappaB, AP1, MAP kinases, and PI-3-K.

Animals↗
PubMed2001

Different Toll-like receptor agonists induce distinct macrophage responses.

We previously reported that gram-negative bacterial lipopolysaccharide (LPS) activates cells via Toll-like receptor (TLR) 4, whereas the mycobacterial cell wall glycolipid lipoarabinomannan (LAM) activates cells via TLR2. We also identified a secreted TLR2 agonist activity in short-term culture filtrates of Mycobacterium tuberculosis bacilli, termed soluble tuberculosis factor (STF). Here we show that STF contains mannosylated phosphatidylinositol (PIM) and that purified PIM possesses TLR2 agonist activity. Stimulation of RAW 264.7 macrophages by LPS, LAM, STF, and PIM rapidly activated nuclear factor (NF)-kappaB, activator protein-1 (AP-1), and mitogen-activated protein (MAP) kinases. These TLR agonists induced similar levels of NF-kappaB and AP-1 DNA-binding activity, as well as trans-activation function. Unexpectedly, these TLR agonists induced tumor necrosis factor alpha secretion, whereas only LPS was capable of inducing interleukin-1beta and nitric oxide secretion. Thus, different TLR proteins are still capable of activating distinct cellular responses, in spite of their shared capacities to activate NF-kappaB, AP-1, and MAP kinases.

Animals↗
PubMed1998

Isolation and characterization of mammalian homologs of the Drosophila gene glial cells missing.

The glial cells missing (gcm) gene in Drosophila encodes a transcription factor that determines the choice between glial and neuronal fates. We report here the isolation of two mammalian gcm homologs, Gcm1 and Gcm2, and the characterization of their expression patterns during embryonic development. Although Gcm2 is expressed in neural tissues at a low level, the major sites of expression for both of the mammalian genes are nonneural, suggesting that the functions of the mammalian homologs have diverged and diversified. However, when expressed ectopically, Gcm1 can substitute functionally for Drosophila gcm by transforming presumptive neurons into glia. Thus, certain biochemical properties, although not the specificity of the tissue in which the gene is expressed, have been conserved through the evolution of the Gcm gene family.

Amino Acid Sequence↗
PubMed1998

Ad HoC conferences of hospital and community professionals in cases of hospitalized physically abused children.

OBJECTIVE: Although community interagency child protection teams are common and well described in the literature, they may not meet the needs of investigating agencies when children are hospitalized in tertiary medical facilities some distance from their homes. Sometimes, the communities in which they live do not have effective teams, or the information to be conveyed is highly technical. This report describes and assesses ad hoc multi-agency conferences with varying hospital and community agency participants, each conference devoted to a single hospitalized child suspected of having been abused. METHOD: A questionnaire devised by the authors was administered by telephone to 22 former conference participants from state social agencies, law enforcement units, and prosecuting attorney's offices. RESULTS: Most of the surveyed participants reported the case-specific conferences to have been helpful, meeting their goals and affecting the outcomes of their cases. CONCLUSION: The conferences appear to have been worthwhile. Although they were associated with some disadvantages for the involved professionals and the sponsoring hospital, the disadvantages appeared to have been offset by the potential benefits for the children, families, participants, and hospital.

Child↗
PubMed1996

Pharmacokinetics of the individual enantiomers of cis-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]-benzamide monohydrochloride (U-54494A) in the dog.

U-54494A, a racemic mixture of two enantiomers, is being developed in racemic form as an anticonvulsant drug candidate. A comparative pharmacokinetic study with intravenous and oral administration of the two individual enantiomers to the dog was conducted to evaluate the potential enantioselective pharmacokinetics of U-54494. Following i.v. administration, the (-)- and (+)-enantiomers showed no significant differences in plasma clearance (0.84 +/- 0.11 versus 0.86 +/- 0.06 l/hr/kg) and terminal elimination half-life (11.2 +/- 2.7 versus 8.0 +/- 2.6 hr) for the parent drug. However, the AUC of intact drug was two-fold lower with two-fold shorter elimination half-life following the oral administration for the (+)-enantiomer as compared to the (-)-enantiomer. Higher plasma levels of the four metabolites were also observed for the (+)-than for the (-)-enantiomer, particularly after oral administration. These results suggested that the (+)-enantiomer appeared to be more extensively metabolized by first-pass effect than the (-)-enantiomer after oral dosing, and as a result, oral bioavailability for the (+)-enantiomer is only one half of that for its antipode (12.0 +/- 1.5% versus 26 +/- 9%).

Administration, Oral↗
PubMed1995

glial cells missing: a genetic switch that controls glial versus neuronal fate.

The glial cells missing (gcm) gene in Drosophila encodes a novel nuclear protein that is transiently expressed early in the development of nearly all glia. In loss-of-function gcm mutant alleles, nearly all glia fail to differentiate, and, where we can follow them in the PNS, are transformed into neurons. In gain-if-function gcm conditions using transgenic constructs that drive ectopic gcm expression, many presumptive neurons are transformed into glia. Thus, gcm appears to function as a binary genetic switch for glia versus neurons. In the presence of gcm protein, presumptive neurons become glia, while in its absence, presumptive glia become neurons.

Amino Acid Sequence↗
PubMed1994

Identification and biological characterization of an epidermal growth factor-related protein: cripto-1.

The human and mouse cripto-1 (CR-1) genes can code for proteins related in structure to epidermal growth factor (EGF). A specific 36-kDa immunoreactive protein was detected by Western blot analysis in human cell lines that express CR-1 mRNA but not in cell lines that fail to express this transcript. Immunoprecipitation of GEO colon carcinoma or mouse embryonal carcinoma cells detected 27-29-kDa and 24-kDa proteins, respectively. Cell lysates and conditioned medium that were prepared from several CHO clones and were expressing either a recombinant human or mouse CR-1 cDNA contained immunospecific 27-29-kDa and 24-kDa proteins, respectively. Monensin or tunicamycin treatment resulted in a shift of the 27-29-kDa human CR-1 protein to 24 kDa and 20 kDa, respectively. The 20-kDa protein was also observed after digestion of the 27-29-kDa human CR-1 protein with N-glycosidase F. Using two CR-1 synthetic refolded peptides that correspond to the EGF-like domain of the human CR-1 sequence or conditioned medium obtained from human CR-1 expressing CHO cells, growth stimulatory activity could be detected on non-transformed human mammary epithelial cells and on two human breast cancer cell lines. EGF receptor-blocking antibody did not inhibit the growth stimulatory action of the CR-1 protein. Likewise, the CR-1 refolded peptides or conditioned medium from the human CR-1-expressing CHO cells failed to inhibit the binding of 125I-EGF in an EGF-radioreceptor assay. These data demonstrate that the CR-1 is a glycoprotein that can function as a growth factor through an EGF receptor-independent pathway.

Amino Acid Sequence↗
PubMed1994

First-pass effect of cis-3,4-dichloro-N-methyl-N-(2-(1-pyrrolidinyl)- cyclohexyl)-benzamide (U-54494) in rats--a model with multiple cannulas for investigation of gastrointestinal and hepatic metabolism.

A multiple cannulated rat model was utilized to investigate the relative contribution of the gut and liver as sites of first-pass metabolism of orally administered U-54494A, an anticonvulsant drug candidate. Each rat received a dose of U-54494A by oral, intraportal, and intravenous routes on three separate occasions. Intraportal and intravenous doses were administered through chronic cannulas surgically implanted in the portal vein and superior vena cava, respectively. Blood samples were collected over a 6-hr period from the superior vena cava cannula. The mean (n = 3) bioavailability of orally dosed U-54494A was 4.5 +/- 1.1%, while that dosed intraportally was 19.1 +/- 3.0%. The relative contribution of the gut and liver as sites of first-pass extraction and/or metabolism of orally administered drug was 69.9 +/- 14.0% and 24.5 +/- 12.2%, respectively. Approximately 35 to 40% of the total plasma clearance was attributeds to the liver. The plasma concentrations of the four known metabolites of U-54494A were apparently higher for the oral and intraportal routes compared to that after intravenous administration. This investigation confirms that the low oral bioavailability of U-54494A in the rat can be primarily attributed to both extensive intestinal and hepatic first-pass metabolism.

Administration, Oral↗
PubMed1992

Drug-induced hepatic microgranulomatosis in cynomolgus monkeys.

This report discusses a unique drug-induced hepatotoxicity in cynomolgus monkeys treated orally with a novel potassium sparing experimental diuretic, [2,6-bis(4-chlorophenyl)-4-pyridinecarboxylic acid]. Groups of 6 adult male and female monkeys were treated orally with vehicle diluent, modified vehicle #122 or a suspension of the drug at 5.0, 12.5, or 32.0 mg/kg/day for 2 weeks. Another group of 5 monkeys were treated orally with 25.0 mg/kg/day of the drug for 2 weeks. Disposition of the drugs was evaluated in 2 monkeys in the later group that received 27.4 mg/kg of radiolabelled drug on the 1st and last day of dosing. Hepatic toxicity was characterized biochemically, light and electron microscopically, histochemically, immunocytochemically, and toxico-kinetically. Conjugated serum bilirubin, alanine transaminase, and aspartate transaminase levels were increased in monkeys treated with over 12.5 mg/kg/day of the diuretic. The periacinar hepatic plates of monkeys treated with 25.0 or 32.0 mg/kg/day were distorted by accumulation of PAS and oil red-O positive multinucleated Kupffer cells. The cytosol of these cells was expanded by phagolysosomes containing granular materials of varying electron densities. Granular electron dense materials were also in endothelial cells and bile canaliculi. Fatty change, cholestasis, and rare piecemeal hepatic necrosis were minimal. The drug was primarily excreted through urine. Plasma concentration and half life of the drug were increased with multiple dosing. The highest concentration of unexcreted parent drug was in the liver. Drug-induced noninflammatory hepatic microgranulomatosis, apparently caused by sequestered drug-lipid/mucopolysaccharide complex in the phagocytic cells of the liver, can occur in any species, including humans, if orally administered xenobiotics are presented to the liver in particulate form.

Animals↗
PubMed1990

Diagnostic problem caused by an atypical creatine kinase isoenzyme in a patient with myocardial infarction.

This report describes the diagnostic problem caused by an atypical immunoglobulin-bound creatine kinase isoenzyme in a patient who had a myocardial infarction. In the presence of this atypical isoenzyme, creatine kinase isoenzyme electrophoresis was of no help in determining whether myocardial infarction had occurred. A diagnosis of myocardial infarction was confirmed by carrying out lactate dehydrogenase isoenzyme electrophoresis and finding the characteristic increase in LD1/LD2 ratio and by following the total creatine kinase, aspartate aminotransferase and lactate dehydrogenase activities over a 5-day period. Further investigations were carried out which characterized the atypical isoenzyme as an uncommon type: creatine kinase-BB bound to immunoglobulin A lambda.

Aged↗
PubMed1989

Mechanism of exercise-induced hypoxemia in horses.

Arterial hypoxemia has been reported in horses during heavy exercise, but its mechanism has not been determined. With the use of the multiple inert gas elimination technique, we studied five horses, each on two separate occasions, to determine the physiological basis of the hypoxemia that developed during horizontal treadmill exercise at speeds of 4, 10, 12, and 13-14 m/s. Mean, blood temperature-corrected, arterial PO2 fell from 89.4 Torr at rest to 80.7 and 72.1 Torr at 12 and 13-14 m/s, respectively, whereas corresponding PaCO2 values were 40.3, 40.3, and 39.2 Torr. Alveolar-arterial PO2 differences (AaDO2) thus increased from 11.4 Torr at rest to 24.9 and 30.7 Torr at 12 and 13-14 m/s. In 8 of the 10 studies there was no change in ventilation-perfusion (VA/Q) relationships with exercise (despite bronchoscopic evidence of airway bleeding in 3) and total shunt was always less than 1% of the cardiac output. Below 10 m/s, the AaDO2 was due only to VA/Q mismatch, but at higher speeds, diffusion limitation of O2 uptake was increasingly evident, accounting for 76% of the AaDO2 at 13-14 m/s. Most of the exercise-induced hypoxemia is thus the result of diffusion limitation with a smaller contribution from VA/Q inequality and essentially none from shunting.

Animals↗
PubMed1988

O2 transport in the horse during rest and exercise.

We studied mechanisms of O2 transport in 6 adult (2-5 year old) horses at rest and during steady-state exercise on a treadmill (0% slope) at 12 m/s (a submaximal gallop). Oxygen consumption was measured using an open-flow system. Arterial and mixed venous blood samples were simultaneously obtained for measurement of O2 content and hemoglobin concentration. VO2 increased from 1.5 +/- 0.2 L/min at rest to 46.2 +/- 4.8 L/min during exercise. HR increased from a resting value of 36.9 +/- 2.5 bpm to 196.5 +/- 10.9 bpm and the arterio-venous O2 content difference (a-v O2) increased from 4.2 +/- 0.8 ml O2/100 ml blood to 20.3 +/- 1.6 ml O2/100 ml blood. The 30.4-fold increase in oxygen consumption in the horse at submaximal VO2 versus only a 10-fold increase in man at VO2 max demonstrates the marked ability of the horse to transfer O2 at each step in the O2 transport pathway.

Animals↗
PubMed1985

Gingival and bacterial plaque response to instrumentation, oral hygiene instruction and nutritional therapy.

Thirty-three male subjects participated in a study to examine the effect of supplements of multiple vitamins and minerals, local therapy (periodontal instrumentation and oral hygiene instruction) and a combination of both on gingival inflammation and bacterial plaque formation. Subjects were given either multivitamin and mineral supplements or placebos on a double-blind basis for 21 days. On Day 7, the mandibular incisors were instrumented, and each subject was instructed in brushing and flossing. Observations were taken at Days 0, 7 and 21. There was a significant (P = 0.004) effect from micronutrient supplementation at Day 7 on the gingival index but no significant effect on the plaque index. On Day 21 there was no statistical superiority noted for the supplemented group in respect to either the gingival or plaque index, although the gingival index approached significance (P = 0.062).

Adult↗