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Biomedical subjects

J White

Publications and source records attributed to J White.

At least 235 records · Page 13Linked to original sources
PubMed1997

Production of the novel C-C chemokine MCP-4 by airway cells and comparison of its biological activity to other C-C chemokines.

Monocyte chemotactic protein-4 (MCP-4) is a newly identified C-C chemokine with potent eosinophil chemoattractant properties. We describe studies of its biological activity in vitro to induce chemotaxis of peripheral blood eosinophils and to induce histamine release from IL-3-primed peripheral blood basophils. MCP-4 and eotaxin caused a similar rise in eosinophil intracytoplasmic Ca2+ and complete cross-desensitization. MCP-4 also abolished the eosinophil Ca2+ response to MCP-3 and partially desensitized the response to macrophage inflammatory protein-1alpha. MCP-4 activated cell migration via either CCR2b or CCR3 in mouse lymphoma cells transfected with these chemokine receptors. MCP-4 inhibited binding of 125I-eotaxin to eosinophils and CCR3-transfected cells and inhibited 125I-MCP-1 binding to CCR2b-transfectants. MCP-4 mRNA was found in cells collected in bronchoalveolar lavage of asthmatic and nonasthmatic subjects and was prominently expressed in human lung and heart. MCP-4 mRNA was expressed in several human bronchial epithelial cell lines after cytokine stimulation. Pretreatment of BEAS-2B epithelial cells with the glucocorticoid budesonide inhibited MCP-4 mRNA expression. These features make MCP-4 a candidate for playing a role in eosinophil recruitment during allergic respiratory diseases.

Amino Acid Sequence↗
PubMed1997

Structure-based design of substituted diphenyl sulfones and sulfoxides as lipophilic inhibitors of thymidylate synthase.

Six new diphenyl sulfoxide and five new diphenyl sulfones were designed, synthesized, and tested for their inhibition of human and Escherichia coli thymidylate synthase (TS) and of the growth of cells in tissue culture. The best sulfoxide inhibitor of human TS was 3-chloro-N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4- (phenylsulfinyl)-N-(prop-2-ynyl)-aniline (7c) that had a Ki of 27 nM. No sulfone improved on TS inhibition by the previously reported 4-(N-((3,4-dihydro-2-methyl-6-quinazolinyl)methyl)-N-prop-2- ynylamino)phenyl phenyl sulfone (Ki = 12 nM). Nevertheless, one sulfone, 4-((2-chlorophenyl)sulfonyl)-N-((3,4-dihydro-2-methyl-4-oxo-6- quinazolinyl)methyl)-N-(prop-2-ynyl)aniline, was selected, on the basis of its inhibition of both TS and cell growth, for antitumor testing; it gave a 61% increase in life span to mice bearing the thymidino kinase-deficient L5178Y (TK-) lymphoma. A crystal structure of N-((3,4-dihydro-2-methyl-4-oxo-6-quinazolinyl)methyl)-4-((2- methylphenyl)sulfinyl)-N-(prop-2-ynyl)aniline complexed with E. coli TS was solved and revealed selective binding of one sulfoxide enantiomer. AMBER calculations showed that the enantioselection was due to asymmetric electrostatic effects at the mouth of the active site. In contrast, a similar crystal structure of the sulfoxide 7c, along with AMBER calculations, indicated that both enantiomers bound, but with different affinities. The side chain of Phe176 shifted in order to structurally accommodate the chlorine of the more weakly bound enantiomer.

Animals↗
PubMed1997

Hindlimb suspension and hind foot reversal in Varecia variegata and other arboreal mammals.

The foot, perhaps more than any other region of the primate body reflects the interaction of positional behaviors with the geometric properties of available supports. The ability to reverse the hind foot during hindlimb suspension while hanging from a horizontal support or descending a large diameter vertical trunk has been noted in many arboreal mammals, including primates. Observations of Varecia variegata in the wild and under seminatural conditions document hindlimb suspension in this lemurid primate. The kinematics and skeletal correlates of this behavior are examined. Analogy is made with the form and function exhibited by nonprimate mammalian taxa employing this behavior. Examples of carnivores and rodents display very similar adaptations of the tarsals while other mammals, such as the xenarthrans, accomplish a similar end by means of different morphologies. However, a suite of features is identified that is shared by mammals capable of hind foot reversal. Hindlimb suspension effectively increases the potential feeding space available to a foraging mammal and represents a significant, and often unrecognized, alternative adaptive strategy to forelimb suspension and prehensile-tail suspension in primates.

Adaptation, Physiological↗
PubMed1997

The influence of restraint on blood pressure in the rat.

We examined the influence of procedures used in blood pressure measurement on blood pressure and the effects of antihypertensive agents. Subjects were spontaneously hypertensive rats (SHR) and their Wistar/Kyoto (WKY) controls. Blood pressure was recorded by telemetry. Twenty-four h baseline pressure were measured, and the effect of minor handling on blood pressure and heart rate was examined. The influence of restraint such as is used for tail-cuff blood pressures was examined. The effects of three different antihypertensive drugs was also examined in the SHR. In the home-cage environment, the SHRs showed higher systolic blood pressures, but had similar hypertensive responses to minor handling as the WKYs. Both strains had elevated heart rate and blood pressure when restrained in the manner used for tail-cuff readings. The antihypertensive effects of captopril and losartan in the SHR were unchanged when the animals were restrained but the hypotensive effect of hydralazine was greater. These results confirm that significant changes in heart rate and blood pressure can occur as a result of the minor procedures frequently used in blood pressure recording in both SHR and WKY rats. This suggests that telemetry may have significant advantages as a method for continuous blood pressure monitoring. The pharmacological profile of antihypertensive drugs may well be different in animals where telemetry is employed and are not subject to the stresses involved in previous methods of monitoring blood pressure.

Animals↗
PubMed1997

Parental reporting of childrens' coughing is biased.

Assessment of cough in the clinical setting as well as in community-based studies of respiratory epidemiology has relied on self-reports. To examine the accuracy and potential for systematic bias in reported cough during a field study, questionnaires administered to parents about their childrens' coughing were compared to overnight cough recordings performed in 145 homes in the community of Wallaceburg, Canada. Percentage agreement between reported and recorded coughing was low, with kappa statistics ranging from 0.02-0.10. Compared to non-smoking parents, smokers under-reported their childrens' coughing (p = 0.01). The association found between parental smoking and recorded coughing was biased towards the null when reported coughing was substituted for recorded coughing: the odds ratio between parental smoking and recorded coughing was 3.1 (95% CI: 1.1-8.8) whereas for reported coughing it was 0.6 (95% CI: 0.2-1.7), the difference in the odds ratios being significant at p = 0.03. When carrying out field surveys, consideration should be given to measuring cough in a subsample of the population in order to estimate the degree of bias inherent in the questionnaire-based results.

Child↗
PubMed1997

The efficacy of doxorubicin microspheres for hepatic micrometastases in a rat tumour model.

The use of sustained-release microspheres is of potential benefit as an adjuvant treatment for patients with occult hepatic micrometastases. This study investigates the response of a model of implantable adenocarcinoma micrometastases in the livers of DA rats following the intraportal injection of doxorubicin-incorporated ion-exchange microspheres compared to free drug bolus administration. A point-counting technique was used to determine the percentage of liver consisting of tumour 13 days after treatment. This was used as an indicator of tumour response, as was the derived tumour mass. There was a significantly higher tumour response in animals treated with the microspheres compared to animals treated with free drug delivered at the same concentration. This effect, however, was shown to decrease with a delay in the time of treatment. The tumour response of the sustained-release microspheres was achieved in the absence of any detectable local or systemic toxicity. This study demonstrates the potential of sustained-release microspheres in the treatment of patients with hepatic micrometastases.

Animals↗
PubMed1997

Substrate induction and glucose repression of maltose utilization by Streptomyces coelicolor A3(2) is controlled by malR, a member of the lacl-galR family of regulatory genes.

malR of Streptomyces coelicolor A3(2) encodes a homologue of the Lacl/GalR family of repressor proteins, and is divergently transcribed from the malEFG gene cluster, which encodes components of an ATP-dependent transport system that is required for maltose utilization. Transcription of malE was induced by maltose and repressed by glucose. Disruption or deletion of malR resulted in constitutive, glucose-insensitive malE transcription at a level markedly above that observed in the parental malR+ strain, and overproduction of MalR prevented growth on maltose as carbon source. Consequently, MalR plays a crucial role in both substrate induction and glucose repression of maltose utilization. malR is expressed from a single promoter with transcription initiating at the first G of the predicted GTG translation start codon.

Amino Acid Sequence↗
PubMed1997

Parental HIV discordancy and its impact on the family.

There is little or no available information on the effect of HIV discordancy in heterosexual relationships on different family members. A review of case notes was carried out on all families who had a child referred to the paediatric HIV service/family clinic at St Mary's Hospital between January 1991 and March 1996. The children had been exposed to HIV infection because they were born to HIV-positive women. There was HIV discordancy in more than one-fifth of the parents' relationships. In over 46% of the relationships, the HIV status of the natural or birth father was not known because he was either untested or unavailable. It is likely that not all of these men are infected and the number of discordant couples is greater. There were more discordant couples where the man and woman came from different ethnic groups. Consideration of the potential impact of discordancy on individual men, women and children is discussed.

Adult↗
PubMed1997

Rapid classical conditioning of odor response in a physiological model for olfactory research, the tiger salamander.

In recent years there have been a number of important advances in the understanding of cellular mechanisms related to olfactory function. Hypotheses regarding the complex relationships among odorant structure, physiological activity and behavioral outcome generated by these findings, however, remain largely untested due to a paucity of psychophysical data on stimulus discrimination in the same experimental species. Comparisons between behavioral and physiological responses are essential for elucidating the critical aspects of stimulus coding in sensory systems. We have developed a method for generating psychophysical data in one of the primary model species used in olfactory research, the tiger salamander, Ambystoma tigrinum. These psychophysical experiments are carried out under the same conditions as physiological experiments in our laboratory. Using classical conditioning, individual salamanders are trained over a period of 2-3 h to show skin potential responses to odor and not air. Failure to train using backward pairing demonstrates that the response is not due to sensitization or pseudoconditioning. The conditioned response is mediated by the olfactory pathway, as it is blocked by olfactory nerve section. We show that salamanders detect three odorants that are commonly used stimuli in physiological experiments (butyl alcohol, butyl acetate and amyl acetate), but cannot detect a fourth common experimental odorant, camphor. This method should be a powerful tool for studying olfactory information processing by providing data on discriminability of stimuli used in salamander physiological studies.

Acetates↗
PubMed1997

Use of adoptive transfer of T-cell-antigen-receptor-transgenic T cell for the study of T-cell activation in vivo.

Adoptive transfer of TCR-transgenic T cells uniformly expressing an identifiable TCR of known peptide/MHC specificity can be used to monitor the in vivo behavior of antigen-specific T cells. We have used this system to show that naive T cells are initially activated within the T-cell zones of secondary lymphoid tissue to proliferate in a B7-dependent manner. If adjuvants or inflammatory cytokines are present during this period, enhanced numbers of T cells accumulate, migrate into B-cell-rich follicles, and acquire the capacity to produce IFN-gamma and help B cells produce IgG2a. If inflammation is absent, most of the initially activated antigen-specific T cells disappear without entering the follicles, and the survivors are poor producers of IL-2 and IFN-gamma. Our results indicate that inflammatory mediators play a key role in regulating the anatomic location, clonal expansion, survival and lymphokine production potential of antigen-stimulated T cells in vivo.

Adjuvants, Immunologic↗
PubMed1997

bldA dependence of undecylprodigiosin production in Streptomyces coelicolor A3(2) involves a pathway-specific regulatory cascade.

The production of the red-pigmented tripyrrole antibiotic undecylprodigiosin (Red) by Streptomyces coelicolor A3(2) depends on two pathway-specific regulatory genes, redD and redZ. RedD is homologous to several other proteins that regulate antibiotic production in streptomycetes; RedZ is a member of the response regulator family. redZ transcripts were detected during exponential growth and increased in amount during transition and stationary phases; transcription of redD was confined to the two latter stages of growth. Whereas mutation of redD had no effect on redZ transcription, transcription of redD was highly dependent on redZ, suggesting that RedZ is a transcriptional activator of redD. bldA, which encodes the only tRNA of S. coelicolor that can efficiently translate the rare leucine codon UUA, is required for Red production at higher phosphate concentrations. While the redD transcript contains no UUA codons, the redZ mRNA contains one. Transcription of redZ appeared to be unaffected in a bldA mutant; in contrast, redD transcription was undetectable, consistent with the translational dependence of redZ on bldA and the transcriptional dependence of redD on redZ. Red production in a bldA mutant was restored by multiple copies of redZ, presumably reflecting a low level of mistranslation of the redZ UUA codon, while multiple copies of redD had no effect, presumably a consequence of the severe dependence of redD transcription on RedZ. Transcription of redZ appears to be negatively autoregulated.

Anti-Bacterial Agents↗
PubMed1997

Paroxysmal limbic disorders in neuropsychiatry.

Patients who experience episodes with a transient disturbance in perception, memory, mood, and level of anxiety are frequently encountered by neurologists, psychiatrists, and psychologists. The possibilities for differential diagnosis of these episodes include partial complex epilepsy, psychogenic seizures, panic disorder, dissociative states, migraine, and transient global amnesia, among others. The clinical history may be vague and confusing, making it difficult to determine definitively the etiology of the events. This article describes a spectrum of paroxysmal disorders involving limbic structures, highlighting the clinical features and assessment techniques that aid in diagnosis and treatment. Clinical-anatomic correlations are provided whenever possible.

Adult↗
PubMed1997

Tubefeeding and mortality in children with severe disabilities and mental retardation.

OBJECTIVE: To study the contribution of tubefeeding to mortality for children with severe disabilities and mental retardation. Previous research has suggested an association between tubefeeding and mortality. However, risk has never been determined using population-based data or defined in regard to patient variables. METHODS: Retrospective analysis of a comprehensive statewide data set comprised of 4921 children with severe disabilities and mental retardation living in community and congregate care settings. The outcome measure was mortality; primary study variables included the presence of a feeding tube, measures of functional independence, type of residence, and medical comorbidity. RESULTS: There were four findings. First, the use of a feeding tube was associated with virtually every disability. Second, when no study variables were controlled, statistically significant differences in mortality rates were noted between children who were tubefed and those who were not. The relative risk of mortality associated with use of a feeding tube was 2.1. Third, the use of a feeding tube was associated with a reduction in relative risk of mortality in children with tracheostomy (relative risk of mortality: .55). However, this association did not achieve statistical significance. Fourth, when study variables were controlled in a multivariate analysis, feeding tube use was associated with no identifiable increase in mortality among children with very severe disabilities, but was associated with an approximated doubled mortality rate among those with less severe disabilities. CONCLUSIONS: We hypothesize that the increased mortality associated with tubefeeding may be attributable to a differential increase in pulmonary disease secondary to overly vigorous nutritional maintenance and subsequent aspiration after tube placement. For children with tracheostomy this risk may be reduced. If tracheostomy proves to be associated with a relatively more favorable outcome for tubefeeding, we hypothesize that it would reflect the benefits of tracheostomy in allowing access to the airway for suctioning and ventilation. Given the observed higher mortality rates among the less severely disabled children who are tubefed and the substantial costs associated with tubefeeding, a prospective, controlled study may be clinically indicated, ethically justifiable, and economically warranted.

Adolescent↗