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T Bennett

Publications and source records attributed to T Bennett.

At least 37 records · Page 2Linked to original sources
PubMed1998

The Saccharomyces cerevisiae RAD9 checkpoint reduces the DNA damage-associated stimulation of directed translocations.

Genetic instability in the Saccharomyces cerevisiae rad9 mutant correlates with failure to arrest the cell cycle in response to DNA damage. We quantitated the DNA damage-associated stimulation of directed translocations in RAD9+ and rad9 mutants. Directed translocations were generated by selecting for His+ prototrophs that result from homologous, mitotic recombination between two truncated his3 genes, GAL1::his3-delta5' and trp1::his3-delta3'::HOcs. Compared to RAD9+ strains, the rad9 mutant exhibits a 5-fold higher rate of spontaneous, mitotic recombination and a greater than 10-fold increase in the number of UV- and X-ray-stimulated His+ recombinants that contain translocations. The higher level of recombination in rad9 mutants correlated with the appearance of nonreciprocal translocations and additional karyotypic changes, indicating that genomic instability also occurred among non-his3 sequences. Both enhanced spontaneous recombination and DNA damage-associated recombination are dependent on RAD1, a gene involved in DNA excision repair. The hyperrecombinational phenotype of the rad9 mutant was correlated with a deficiency in cell cycle arrest at the G2-M checkpoint by demonstrating that if rad9 mutants were arrested in G2 before irradiation, the numbers both of UV- and gamma-ray-stimulated recombinants were reduced. The importance of G2 arrest in DNA damage-induced sister chromatid exchange (SCE) was evident by a 10-fold reduction in HO endonuclease-induced SCE and no detectable X-ray stimulation of SCE in a rad9 mutant. We suggest that one mechanism by which the RAD9-mediated G2-M checkpoint may reduce the frequency of DNA damage-induced translocations is by channeling the repair of double-strand breaks into SCE.

Cell Cycle Proteins↗
PubMed1998

Successful isolation of a rat chromosome 1 blood pressure quantitative trait locus in reciprocal congenic strains.

Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the Sa gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an Sa gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-Sa), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-Sa). WKY.SHR-Sa contains at least approximately 26 cM of SHR chromosome 1, between markers mD7mit206 and D1Mit2 (and including the SHR allele of the Sa gene), and SHR.WKY-Sa carries at least approximately 15 cM of WKY chromosome 1, between mD7mit206 and D1Wox34 (and including the WKY allele of the Sa gene). Blood pressure of WKY.SHR-Sa rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-Sa rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-Sa and WKY were +11.5 mm Hg (P=0.001) and +11.6 mm Hg mm Hg (P<0.001), respectively. The corresponding differences between SHR.WKy-Sa and SHR were -11.3 mm Hg (P=0.002) and -9.1 mm Hg (P=0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal Sa mRNA levels in the congenic strains reflected their Sa allele with a high level in WKY. SHR-Sa and a low level in SHR.WKY-Sa, consistent with previous data suggesting that the level of Sa expression is primarily determined by cis-acting elements in or near the Sa gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the Sa gene in reciprocal congenic strains derived from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHRxWKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome.

Animals↗
PubMed1998

US health journal editors' opinions and policies on research in race, ethnicity, and health.

Health research on race and ethnicity has been criticized for lacking rigor in conceptualization, terminology, and analysis. Scientific journals' editorial processes help determine research quality. This survey assessed editors' awareness of current debates, attitudes toward recent recommendations, and involvement in developing editorial policies. Twenty-nine editors of health journals with impact factors of > or = 1 (based on citation ratings) were sent a questionnaire including four key problems identified in research literature and recommendations from federal agencies; 23 (79%) responded. Seven editors relevant policies. Two had read the federal directive on racial and ethnic classification; one was aware of its current review. Most perceived the four key problems as uncommon. The majority agreed with Public Health Service recommendations on race and ethnicity research, except for analyzing effects of racism. Approximately 20% had discussed issues with co-editors, editorial boards, or reviewers. About 40% saw further discussion as beneficial; four planned to draft guidelines. Editors' potential for helping resolve problems in race/ethnicity research is not being realized. Greater participation would be beneficial to public health research and practice.

Decision Making↗
PubMed1997

Regulation of CD28 costimulation in human CD8+ T cells.

Optimal stimulation and prevention of anergy in T cells requires signaling through the CD28 molecule. During HIV disease progression, CD28 expression is lost, particularly on CD8+ T cells. Because alterations in cytokine production patterns occur during HIV infection, we determined whether CD8+ T cell phenotype or function was affected by cytokine environment. Treatment of CD8+ T cells with IL-4 decreased levels of both CD28 surface expression and message and increased CD8 expression. Furthermore, CD8+ T cells that had down-regulated CD28 had reduced proliferative capacity. The inhibitory effects of CD28 reduction could be compensated either by increased anti-CD3 or by exogenous IL-2, suggesting that the strength of T cell signaling necessary for the production of IL-2 and subsequent proliferation is negatively regulated by IL-4. CD8+ subpopulations with differential CD28 expression produced different patterns of cytokines, particularly IL-2 and IFN-gamma. Furthermore, CD8+ T cells that had reduced CD28 levels but made their own IL-2 were able to proliferate in response to TCR stimulation. These results suggest that loss of CD28 expression and CD8 T cell function can be regulated by the cytokine environment, which may be altered during HIV disease progression. Whether the dysfunction of CD8+ T cells in HIV infection occurs by such a mechanism is the subject of future investigation.

Antibodies, Monoclonal↗
PubMed1997

Enhanced cardiac preconditioning in the isolated heart of the transgenic ((mREN-2) 27) hypertensive rat.

OBJECTIVE: Cardiac preconditioning represents an important cardioprotective mechanism which limits myocardial ischaemic damage. The aim of this investigation was to assess the impact of preconditioning in hypertension, which is a major risk factor for ischaemic heart disease. METHODS: Hearts isolated from male transgenic ((mREN-2)27) hypertensive (TGH) rats, and their normotensive controls (Hannover Sprague-Dawley; SD rats), were perfused at constant flow using the Langendorff technique, and were subjected to either ischaemic preconditioning (3 x 4 min ischaemia) or continuous perfusion. Global ischaemia was then induced for 30 min, followed by 60 min of reperfusion, during which time mechanical performance was assessed (left ventricular developed pressure (LVDP), heart rate, and end-diastolic pressure). RESULTS: In the absence of preconditioning, mechanical performance was substantially depressed on reperfusion, and there was no difference between TGH hearts and SD hearts (area under the curve (AUC) for the LVDP (LVDP0-60) plot against time for reperfusion = 356 +/- 115 and 296 +/- 206 mmHg.min, respectively). Cardiac preconditioning caused significant protection in both groups, but this was significantly (P < 0.05) greater (3-fold) in the TGH hearts (AUC for LVDP0-60 = 3349 +/- 610 mmHg.min) compared to the SD hearts (AUC for LVDP0-60 = 1153 +/- 527 mmHg.min). In both groups, preconditioning induced significant protection of diastolic function. The enhanced effects of preconditioning on mechanical performance in the TGH hearts were unaffected by the angiotensin AT1-receptor antagonist, losartan (3 microM). However, losartan did partially reverse the beneficial effects of preconditioning on post-ischaemic diastolic function in the TGH hearts. CONCLUSIONS: The results of the present investigation clearly show that cardiac preconditioning is substantially enhanced in hearts from TGH rats. Furthermore, the beneficial effects of preconditioning on diastolic function, but not mechanical performance, in TGH hearts is partially mediated by AT1-receptors.

Animals↗
PubMed1997

Long-term psychological adjustment to witnessing interparental physical conflict during childhood.

A retrospective survey of undergraduate students was used to examine the long-term psychological impact of witnessing interparental physical aggression during childhood. Two hundred and three of 1,452 young adults surveyed (14%) reported witnessing as children at least one incident of physical aggression between their parents. Both men and women who witnessed interparental physical conflict reported higher levels of current psychological distress than a comparison group of young adults who never observed physical aggression between their parents. This group difference remained even after controlling for parental divorce, parental SES, physical abuse of the child, parental alcoholism, and nonphysical discord witnessed between parents. Additional analyses found that the negative effect of witnessing interparental aggression was intensified when the aggression was serious enough to warrant some type of outside assistance for the victim and when the parent of the same-sex was seen being victimized. Although these findings provided support for the theory that witnessing interparental physical aggression is a traumatic experience that may have long-term psychological ramifications, we also found that a substantial proportion of the variance accounted for in adult adjustment by interparental physical conflict was mediated through decreased parental caring and warmth during childhood. Implications for these results, limitations of the present study, and directions for further research are discussed.

Adolescent↗
PubMed1997

Employment status and high blood pressure in women: variations by time and by sociodemographic characteristics.

PURPOSE: The association between employment status and high blood pressure in women was examined at two time periods to determine if associations between employment status and high blood pressure varied by time period or by age, race, education, marital status, or parental status. METHODS: Women participants from the National Health Examination Survey (1960) and the Second National Health and Nutrition Survey (1976-1980) between the ages of 25 and 64 and currently employed or keeping house were included. Logistic regression analysis was used to examine the cross-sectional association between employment status and high blood pressure in each survey, taking into account potential effect modifiers and covariates. RESULTS: In 1960 employment was associated with a slight, but not statistically significant, elevation in odds of high blood pressure. In 1976-1980, it was associated with a modest but significant reduction in odds of high blood pressure. Variations in associations occurred by marital status (protective associations were limited to unmarried women) and race (associations were of stronger magnitude among African-American women). CONCLUSIONS: The employment status-high blood pressure relationship shifted across surveys. Changes in the composition of the employed and nonemployed groups account for at least part of the varying relationships.

Adult↗
PubMed1997

Regulation of the taurine transporter gene in the S3 segment of the proximal tubule.

Traditionally, bulk amino acid reabsorption in the kidney has been thought to be localized to the early portions of the proximal nephron. Adult Sprague-Dawley rats were fed diets with low, normal, and high taurine content for two weeks. Kidneys were hybridized with an 35S-radiolabeled complementary RNA probe to the rB16a subclone encoding the extracellular and transmembrane domains of the rat brain taurine transporter. Identical fragments were generated by RT-PCR from rat brain and kidneys as confirmed by DNA sequencing. Hybridization was localized to the outer zone of the medulla of all the kidneys. In the normal diet animals, taurine transporter mRNA was localized to the S3 segment of the proximal tubule, to the loop of Henle in the medulla, and to the glomerular epithelial cell layer. With taurine restriction, taurine transporter mRNA expression was up-regulated predominantly in the S3 segment and was virtually absent in this segment in animals supplemented with taurine. These experiments have precisely localized the rat kidney taurine transporter gene, demonstrating regulation that is limited to the S3 segment of the proximal tubule.

Animals↗
PubMed1997

Effects of the dual metallopeptidase inhibitor, MDL 100,240, on regional haemodynamic responses to vasoactive peptides in conscious rats.

1. The effects of combined inhibition of neutral endopeptidase 24.11 and angiotensin-converting enzyme, with the dual metallopeptidase inhibitor, MDL 100,240 (3 mg kg-1 bolus, 3 mg kg-1, h-1 infusion), on baseline haemodynamics and on responses to a variety of vasoactive peptides were studied in conscious Long Evans rats (350-450 g: n = 9) chronically instrumented for the assessment of regional haemodynamics. 2. The experiments ran over 4 consecutive days. On the first 2 days the animals received the vehicle for MDL 100,240, and were given bolus i.v. injections of angiotensin I (AI; 250 pmol kg-1), angiotensin II (AII; 125 pmol kg-1), bradykinin (BK: 3 nmol kg-1) and endothelin-1 (ET-1; 250 pmol kg-1) on one day and AI (as above), atrial natriuretic peptide (ANP: 500 pmol kg-1) and big endothelin-1 (big ET-1; 500 pmol kg-1) on the other day in a random manner. On the third and fourth experimental days the vasoactive peptides were given in the same order as before, but in the presence of MDL 100,240. 3. Thirty minutes after onset of administration of vehicle, on the first or second experimental day, there were no consistent cardiovascular changes. However, at the same time following onset of MDL 100,240 administration on the third experimental day, there was a significant, but slight, reduction in mean arterial blood pressure (MAP; -5 +/- 2 mmHg) together with tachycardia (41 +/- 12 beats min-1) and increases in renal and mesenteric flows (17 +/- 3 and 13 +/- 4%, respectively) and vascular conductances (23 +/- 4 and 19 +/- 5%, respectively). The mesenteric vasodilator effect of MDL 100,240 was still present on the fourth experimental day before administration of the drug on that day, but otherwise the pattern of response to MDL 100,240 was similar to that on the previous day. 4. In the presence of vehicle, AI caused hypertension, bradycardia, and reductions in renal mesenteric and hindquarters vascular conductances; all these effects were abolished by MDL 100,240. 5. In the presence of vehicle, AII caused effects similar to those of AI. MDL 100,240 did not affect the pressor, bradycardic or hindquarters vasoconstrictor effects of AII. However, in the presence of MDL 100,240, the overall renal and mesenteric vasoconstrictor effects of AII were enhanced, probably because of the renal and mesenteric vasodilatation caused by MDL 100,240. 6. In the presence of vehicle, BK had a slight pressor effect, accompanied by tachycardia and transient increases in conductances in renal, mesenteric and hindquarters vascular beds. In the presence of MDL 100,240 BK caused marked hypotension, but an attenuated tachycardia; renal, mesenteric and hindquarters vasodilator responses were enhanced. 7. In the presence of vehicle, ANP caused slight hypotension and tachycardia, together with reductions in renal and mesenteric vascular conductances, and transient increases in hindquarters conductance. MDL 100,240 enhanced the hypotensive effect of ANP and promoted a delayed hindquarters vasoconstriction. 8. Big ET-1, in the presence of vehicle, caused a marked and prolonged increase in MAP, accompanied by bradycardia and reductions in renal, mesenteric and hindquarters vascular conductances. Although MDL 100,240 significantly attenuated the magnitude of the pressor effect of big ET-1, its bradycardic and renal, mesenteric and hindquarters haemodynamic actions were not reduced significantly. 9. In the presence of vehicle, ET-1 caused an initial hypotension, tachycardia and vasodilatation in the hindquarters, but reductions in renal and mesenteric vascular conductances; thereafter there was a rise in MAP and bradycardia with vasoconstriction in all three vascular beds. MDL 100,240 had no effect on the initial hypotensive, tachycardic or hindquarters haemodynamic effects of ET-1. Moreover the subsequent pressor and bradycardic actions of ET-1 were unchanged, but its renal and mesenteric vasoconstrictor effects were enhanced, possibly because of the dilatation

Angiotensin I↗
PubMed1997

Comparative effects of the dual metallopeptidase inhibitor, MDL 100,240 and of enalaprilat on regional and on cardiac haemodynamics in conscious, hypertensive, transgenic ((mRen-2)27) rats.

1. Heterozygous, male, hypertensive, transgenic ((mRen-2)27) rats (350-450 g) were instrumented for the measurement of regional or cardiac haemodynamics (n = 16, in both groups). Animals were given continuous i.v. infusions of the angiotensin-converting enzyme inhibitor, enalaprilat, or the dual metallopeptidase inhibitor, MDL 100,240 (both at 3 mg kg-1, 3 mg kg-1 h-1; n = 8 for regional and cardiac haemodynamics), for 32 h. Twenty four hours after the onset of infusion of enalaprilat or MDL 100,240, the bradykinin (B2)-receptor antagonist, Hoe 140 (1 mg kg-1, i.v.), was given and measurements were continued for a further 8 h, to assess any possible involvement of bradykinin. 2. Over the first 8 h of infusion, both enalaprilat and MDL 100,240 had significant antihypertensive effects, accompanied by similar regional vasodilatations. However, the blood pressure lowering effect of MDL 100,240 (-54 +/- 9 mmHg) was greater than that of enalaprilat (-38 +/- 4 mmHg), because the former caused a significantly greater reduction in cardiac index. 3. Between 8-24 h after the onset of infusion, there was a reduction in the effect of enalaprilat on blood pressure, because cardiac index rose, with no further increase in total peripheral conductance. In contrast, the antihypertensive effect of MDL 100,240 persisted, in spite of a recovery in cardiac index, because there was further vasodilatation, particularly in the mesenteric and hindquarters vascular beds. 4. There were no apparent haemodynamic changes associated with the injection of Hoe 140, and over the following 8 h, the difference between the haemodynamic effects of enalaprilat and MDL 100,240 persisted; there was little evidence of suppression of the effects of either drug. 5. These results are more consistent with the antihypertensive effects of enalaprilat or MDL 100,240 in transgenic ((mRen-2)27) rats being due to suppression of angiotensin II production, than due to inhibition of bradykinin degradation. The additional effects of MDL 100,240 may be accounted for by inhibition of the degradation of natriuretic peptides reducing cardiac output, initially, and decreasing vascular tone, subsequently. Alternatively, the additional increase in vascular conductance following treatment with MDL 100,240 may represent an autoregulatory response to the reduced pressure.

Adrenergic beta-Antagonists↗
PubMed1997

Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels.

AIMS: The haemodynamic effects of adrenomedullin and calcitonin gene-related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers. METHODS: Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3-30 pmol min(-1). Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3-10 pmol min(-1) into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction. RESULTS: Adrenomedullin and CGRP at a dose of 30 pmol min(-1), produced an increase in forearm blood flow of 288 +/- 42% and 252 +/- 30% respectively (mean +/- s.e. mean, P<0.001). At doses between 3 and 10 pmol min(-1) adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half-life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84 +/- 2% (P<0.001) at a dose of 10 pmol min(-1). CGRP produced a similar effect reversing constriction by 72 +/- 12% at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min(-1). CONCLUSIONS: The lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.

Adrenomedullin↗
PubMed1997

Insulin-like growth factor (IGF) and IGF binding protein gene expression in multicystic renal dysplasia.

Multicystic dysplastic kidney disease is the most common form of renal dysplasia that leads to ESRD in children. This study describes the histopathological changes of multicystic dysplasia that occur from early fetal life to the postnatal period. At 14 wk gestation, early cystic enlargement of various segments of the nephron have been identified, in addition to a displaced metanephric blastema adjacent to zones of normal nephrogenesis. At later stages, the predominant features include cyst enlargement with marked fibromuscular collars, architectural disorganization, and replacement of the interstitium with a disarray of mesenchymal tissue. This study investigated the expression of the mRNA encoding the insulin-like growth factors (IGF) and IGF binding proteins (IGFBP) and have demonstrated IGF-II, IGFBP-2, and IGFBP-3 to be altered. Apart from their expression in the displaced metanephric blastema, both IGF-II and IGFBP-2 were overexpressed in abnormal tissue elements in all kidneys from fetal to postnatal life. IGF-II gene expression was localized to mesenchymal tissue, specifically in the periductal fibromuscular collars. IGFBP-2 mRNA was found to be expressed exclusively in the cyst epithelia of all cysts at all ages studied, whereas IGFBP-3 mRNA was absent from these epithelia. This study details the failure of normal IGF expression in the development of multicystic renal dysplasia and suggests a role for the IGF system in the progressive histopathological changes of this disorder.

Child, Preschool↗