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Biomedical subjects

R White

Publications and source records attributed to R White.

At least 73 records · Page 4Linked to original sources
PubMed2000

Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat.

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adult humans, results from expansion of a CTG repeat in the 3' untranslated region of the DMPK gene. The mutant DMPK messenger RNA (mRNA) contains an expanded CUG repeat and is retained in the nucleus. We have expressed an untranslated CUG repeat in an unrelated mRNA in transgenic mice. Mice that expressed expanded CUG repeats developed myotonia and myopathy, whereas mice expressing a nonexpanded repeat did not. Thus, transcripts with expanded CUG repeats are sufficient to generate a DM phenotype. This result supports a role for RNA gain of function in disease pathogenesis.

3' Untranslated Regions↗
PubMed2000

Mutations in the estrogen receptor ligand binding domain discriminate between hormone-dependent transactivation and transrepression.

The estrogen receptor (ER) suppresses transcriptional activity of the RelA subunit of nuclear factor-kappaB in a hormone-dependent manner by a mechanism involving both the receptor DNA binding domain and ligand binding domain (LBD). In this study we examine the role of the ER LBD in mediating ligand-dependent RelA transrepression. Both ERalpha and ERbeta inhibit RelA in response to 17beta-estradiol but not in the presence of antihormones. We have identified residues within the ERalpha LBD that are responsible for receptor dimerization and show that dimerization is necessary for transactivation and transrepression. Moreover we have generated mutant receptors that have lost their ability to inhibit RelA but retain their capacity to stimulate transcription and conversely mutants that are transcriptionally defective but capable of antagonizing RelA. Overexpression of p160 and cAMP-response element-binding protein-binding protein/p300 co-activators failed to relieve repression of RelA, which is consistent with the demonstration that RelA inhibition can occur independently of these co-activators. These findings suggest it is unlikely that sequestration of these cofactors required for ER transcriptional activation can account for hormone-dependent antagonism of RelA. The identification of ER mutants that discriminate between transactivation and transrepression implies that distinct surfaces within the LBD are involved in mediating these two receptor functions.

Animals↗
PubMed2000

Toxicity evaluation of petroleum blending streams: inhalation subchronic toxicity/neurotoxicity study of a light catalytic reformed naphtha distillate in rats.

A 13-wk whole-body inhalation study was conducted with Sprague-Dawley CD rats (16/sex/group) exposed to a light catalytic reformed naphtha distillate (LCRN-D, CAS number 64741-63-5) at target concentrations of 0, 750, 2500, and 7500 ppm for 6 h/d, 5 d/wk. Sixteen rats per sex in the control and high-dose groups were maintained after final exposure for a 4-wk recovery period. The highest exposure concentration was 75% of the lower explosive limit. Standard parameters of subchronic toxicity were measured throughout the study; at necropsy, organs were weighed and tissues processed for microscopic evaluation. Neurotoxicity evaluations consisted of motor activity (MA) and a functional operational battery (FOB) measured pretest, throughout exposure and after the recovery period. Neuropathology was evaluated at termination. No test-related mortality or effects on physical signs, body weight, food consumption, or clinical chemistry were observed. In males exposed to 7500-ppm LCRN-D, a statistically significant decrease in white blood cell counts and lymphocyte counts was observed at the termination of exposure that was not present in animals after the 4-wk recovery period. However, mean corpuscular volume was slightly decreased in high-dose males after the recovery period. Statistically significant increases in kidney weights relative to body weights in 7500-ppm male rats correlated with microscopically observed hyaline droplet formation and renal tubule dilation, indicative of light hydrocarbon nephropathy, a condition in male rats that is not toxicologically significant for humans. Statistically significant decrease in absolute and relative spleen weights in 7500-ppm male rats correlated with decreases in hematologic parameters but had no microscopic correlate and was not observed in animals after 4 wk of recovery. This mild, reversible effect in white blood cell populations may relate to the presence of aromatics in the distillate. The only effect of LCRN-D on neurobehavioral parameters was significantly higher motor activity counts among high-dose (7500 ppm) males after the 4-wk recovery period, suggesting a possible delayed effect of LCRN-D. However, there was no evidence of hyperactivity or abnormal behavior from the functional observational battery evaluations, and there were no microscopic changes in neural tissue to support this observation. The no-observed-adverse-effects level (NOAEL) for LCRN-D was 2500 ppm for both subchronic toxicity and neurotoxicity. The no-observed-effects level (NOEL) was 750 ppm.

Administration, Inhalation↗
PubMed2000

Interaction of cyclic AMP modulating agents with levcromakalim in the relaxation of rat isolated mesenteric artery.

The effect of cyclic AMP modulating agents on levcromakalim-induced relaxation was investigated in myograph-mounted rat mesenteric arteries. Forskolin (adenylyl cyclase activator), dibutyryl cyclic AMP (protein kinase A activator) and 5'-N-ethylcarboxamidoadenosine (NECA; adenosine receptor agonist) all potentiated the vasorelaxant effects of levcromakalim. The modulatory and relaxant effects of dibutyryl cyclic AMP, NECA and forskolin were sensitive to the protein kinase A inhibitor, Rp-cAMPS. However, relaxation to these three agents was unaffected by the K(ATP) inhibitor, glibenclamide. Dibutyryl cyclic AMP and NECA also caused levcromakalim to induce relaxation in the sub-nanomolar concentration range, however, this effect was Rp-cAMPS- and glibenclamide-insensitive. These results suggest that cyclic AMP modulating agents modulate K(ATP), even though this channel does not contribute to their relaxant effects.

Adenosine-5'-(N-ethylcarboxamide)↗
PubMed2000

Monitoring the AIDS epidemic using HIV prevalence data among young women attending antenatal clinics: prospects and problems.

OBJECTIVE: To assess the potential of antenatal surveillance data on HIV prevalence in young women as an indicator of trends in HIV incidence. DESIGN: Review of empirical data and discussion of problems encountered with surveillance systems, illustrated using cohort-component projection models. METHODS: Simple descriptive analyses are presented of prevalence and incidence data, with projection models used to explore aspects of the dynamic relationships between changes in HIV incidence and prevalence in young pregnant women for which empirical data are not yet available. Incidence changes due to change in risk among sexually active, and change in pattern of sexual debut are explored separately, and the resulting prevalence trends in pregnant women under age 25 years, and those expecting their first two births are described. RESULTS: HIV prevalence levels in young pregnant women categorized by age and by parity have different relationships to recent incidence levels. Age categorized prevalence data provide a reasonable indication of incidence under stable conditions, but may be very misleading if the age pattern of sexual debut changes. Prevalence levels categorized by parity are a reliable guide to incidence in the sexually active, but not necessarily to incidence in the population as a whole. CONCLUSIONS: Ante-natal surveillance systems should categorize prevalence data by both age and parity to aid in the interpretation of underlying incidence levels.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Toxicity evaluation of petroleum blending streams: reproductive and developmental effects of light catalytic reformed naphtha distillate in rats.

A distillate of light catalytic reformed naphtha (CAS number 64741-63-5, LCRN-D) administered by inhalation was tested for reproductive and developmental toxicity in Sprague-Dawley rats, following a modified OECD Guideline 421, Reproductive/Developmental Toxicity Screening protocol. LCRN-D was administered as a vapor, 6 h/d, 7 d/wk at target concentrations of 0, 750, 2500 or 7500 ppm to female rats for approximately 6 wk from 2 wk prior to mating, during mating through gestational d 19, and to males beginning 2 wk prior to mating for approximately 7 consecutive weeks. Dams and litters were sacrificed on postnatal d 4 and males were sacrificed within the week after the last litter was necropsied. Parental systemic effects observed at the 7500 ppm exposure level included slightly lower body weights for males throughout the study. Increased kidney to body weight and increased liver to body weight ratio in male rats exposed to 7500 ppm LCRN-D may be related to slightly lower final mean body weights. Body and organ weight data for female rats in all exposure groups were comparable to controls. No test-material-related microscopic changes were observed in the reproductive organs or nasal turbinate tissue of either sex. Reproductive performance was unaffected by exposure to LCRN-D. The mating and fertility indices were 100% in all groups. There were no significant exposure-related differences in implantation sites or live pups per litter, and no gross abnormalities were observed in pups from treated dams. Pups born from LCRN-D-exposed dams showed comparable body weights and weight gain to control pups. The viability index on postpartum d 4 was > or =97%. Under conditions of this study, the no-observed-adverse-effect level (NOAEL) for exposure to light catalytic reformed naphtha distillate for parental effects was 2500 ppm and the NOAEL for reproductive and developmental toxicity was 7500 ppm.

Alkanes↗
PubMed2000

Hyperpolarisation of rat mesenteric endothelial cells by ATP-sensitive K(+) channel openers.

Membrane potential responses of rat mesenteric endothelial cells were investigated in intact arteries using sharp electrodes. Levcromakalim, an activator of ATP-sensitive K(+) channels (K(ATP)) induced concentration-dependent hyperpolarisation of the endothelial cells, which was reversible by glibenclamide and ciclazindol, inhibitors of K(ATP). Another K(ATP) activator, diazoxide, also hyperpolarised the endothelial cells. Carbachol induced endothelial hyperpolarisation that was inhibited by combinations of apamin and charybdotoxin, but not Ba(2+) and ouabain. Prior stimulation with levcromakalim inhibited carbachol-induced responses, and this inhibitory effect was also sensitive to glibenclamide. 1, 3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl) -2H-benzimidazol-2-one (NS 1619), an activator of large conductance, Ca(2+)-activated K(+) channels (BK(Ca)), induced only small hyperpolarisations of the endothelial cells. Preincubation of tissues with 18 alpha- or 18 beta-glycyrrhetinic acid, inhibitors of gap junction communication, increased the input resistance and depolarised the endothelial cells, and inhibited the hyperpolarising effect of levcromakalim. It is concluded that activation of K(ATP) causes hyperpolarisation of rat mesenteric endothelial cells, probably through gap junctional transfer of smooth muscle hyperpolarisation, and that this may represent an important modulator of endothelial function.

Adenosine Triphosphate↗
PubMed2000

The social context of insight in schizophrenia.

BACKGROUND: Psychiatrists place great weight on impaired insight in schizophrenia, generally attributing it to pathological mental processes. However, denial of illness may be based on attitudes common in patients' social and cultural groups. Moreover, even where denial of illness has a pathological element, it may be affected by the social context. In this paper, we predicted that denial of illness would be associated with social distance between clinician and patient, and reduced by access to 'normalizing' social interaction. METHOD: One hundred and fifty patients with schizophrenia in the London arm of the European Schizophrenia cohort were assessed using the 'Awareness of Illness' (AI) subscale of David's Assessment of Insight. Clinical and social attributes were related to AI. RESULTS: There was little evidence for our social distance hypotheses: there was little variation in AI by social class, ethnicity, membership of a drug taking culture or the presence of strongly held religious beliefs. However, there were strong relations between AI and the size of primary group, consistent with our normalizing hypothesis. CONCLUSIONS: The normalizing function of social support is in line with modern psychological models of delusion formation. Longitudinal data will eventually be available from the current study that will assist in establishing the causal direction of this association.

Adult↗
PubMed2000

Mechanical strain activates estrogen response elements in bone cells.

The involvement of the estrogen receptor in the early responses of bone cells to mechanical strain was investigated by subjecting subconfluent monolayer cultures of ROS.SMER #14 cells (ROS 17/2.8 cells stably transfected with additional ER alpha) to 17 beta-estradiol or a single short period of dynamic mechanical strain (600 cycles, 1 Hz). The basal proliferation rate of ROS.SMER #14 cells was similar to ROS 17/2.8 cells, whose proliferative responsiveness to strain and estrogen is similar to that of primary cultures of rat long bone-derived osteoblasts. At peak strains of 3400 mu epsilon, strain-related proliferation in ROS.SMER #14 cells was 1.4 times that of ROS 17/2.8 cells. At 10(-8) mol/L, 17 beta-estradiol-related proliferation was nearly twice greater. The ROS.SMER #14 cells were transiently transfected with an estrogen-responsive reporter, 2ERE-pS2-CAT, containing two consensus estrogen response elements (ERE) linked to a chloroamphenicol acetyl transferase gene. Strain increased normalized ERE-CAT activity threefold and estradiol (10(-8) mol/L) sixfold. Both strain-related and estradiol-related increases in proliferation and ERE-CAT activity were blocked by the estrogen antagonist ICI 182,780 (10(-6) mol/L). These data show that strain as well as estrogen stimulates increased proliferation in ROS 17/2.8 cells and increased ER alpha-related ERE activity in ROS cells transfected with ER alpha. Proliferation is greater in the cells with more estrogen receptors. Both strain- and estrogen-related proliferation and ERE activity are blocked by the estrogen antagonist ICI 182,780. This indicates that ROS cells' early responses to mechanical strain involve ER alpha and estrogen-responsive genes.

Animals↗
PubMed2000

Partial hippocampal inactivation: effects on spatial memory performance in aged and young rats.

Changes in anatomical or functional connectivity during normal aging are thought to contribute to cognitive alterations over the lifespan. Neural network theories predict that synaptic loss in an aging brain could place the organism near the point of dysfunction in the nonlinear curve defining neural compromise versus performance. The present experiments examined whether aged rats are closer to this point of behavioral dysfunction by reversibly inactivating one or both hippocampal hemispheres. As expected, bilateral tetracaine inactivation of the hippocampus disrupted spatial memory in both age groups. Unilateral left hippocampal inactivation significantly increased errors only in aged rats; however, unilateral inactivation of the right hippocampus had no effect. The present outcome could reflect more extensive synaptic dysfunction in the aged right hippocampus or a greater involvement of the left hippocampus in spatial working memory problems.

Age Factors↗
PubMed2000

The nuclear receptor co-repressor nrip1 (RIP140) is essential for female fertility.

Ovulatory dysfunction is the commonest cause of female infertility. Here we show that the co-repressor nuclear-receptor-interacting protein 1 (Nrip1; encoded by the gene Nrip1) is essential for ovulation. Mice null for this protein are viable, but female mice are infertile because of complete failure of mature follicles to release the oocyte at ovulation. In contrast, luteinization proceeds normally, resulting in a phenotype closely resembling that of luteinized unruptured follicle syndrome, often associated with infertility in women. Therefore, whereas the pre-ovulatory surge of luteinizing hormone induces both ovulation and luteinization, the ability to suppress the action of nuclear receptors is essential for the coordinated control of ovarian function with the essential process of oocyte release dependent on the activity of the transcriptional co-repressor Nrip1 (RIP40).

Adaptor Proteins, Signal Transducing↗
PubMed2000

Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries.

The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC(50)=3.5+/-1.1 nM, R(max)=103+/-10% of control contraction induced by 60 mM KCl and 1 microM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 microM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC(50)=1.3+/-0.8 nM, R(max)=20.1+/-4.9% of control contraction induced by 10 microM 5-HT). The contractile response was significantly enhanced by removal of the endothelium (R(max)=55.4+/-16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HT-precontracted arteries, which was abolished by L-NAME or removal of the endothelium. No contractile effects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration- and endothelium-dependent relaxations of methoxamine-precontracted vessels. The relaxant responses were potentiated by L-NAME (300 microM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). The present study is the first to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.

Animals↗
PubMed2000

Dexamphetamine substitution in the treatment of amphetamine abuse: an initial investigation.

AIMS: Dexamphetamine substitution is a widely practised, yet under-researched and controversial treatment for amphetamine abusers. This study aimed to evaluate the usefulness of substitute prescribing, to both oral and intravenous users, and to find out which factors predict doing well in treatment. In the absence of more rigorous controlled trials, it was hoped that this study would help make some inroads into what is a hitherto unexplored area. DESIGN: The standardized records of 220 users receiving dexamphetamine prescriptions were examined retrospectively. Cross-sectional socio-demographic data, and longitudinal outcome data were obtained for 148 of them. SETTING: The amphetamine users had all attended and received treatment by Cornwall Community Drug Team, in the far South-West of England, during the period 1992-96. FINDINGS: Oral and intravenous users had remarkably similar outcomes, with intravenous users making more overall gains in treatment. Over half the injectors stopped injecting, and more than a third within 2 months of coming into treatment. Variables predicting a good outcome differed between oral and intravenous users; although for both groups being female was associated with a slower change in drug-use behaviours, but a longer period in treatment. CONCLUSIONS: Dexamphetamine prescribing appears to be reasonably safe, and is associated with improvements in drug-use. Randomized trials are warranted to determine the specific efficacy of the treatment.

Adolescent↗
PubMed2000

Dipyridamole-thallium/sestamibi before vascular surgery: a prospective blinded study in moderate-risk patients.

PURPOSE: This study assessed in a prospective, blinded fashion whether a reversible defect on dipyridamole-thallium (DTHAL)/sestamibi (DMIBI) can predict adverse cardiac events after elective vascular surgery in patients with one or more clinical risk factors. METHODS: Consecutive patients with one or more clinical risk factors underwent a preoperative blinded DTHAL/DMIBI. Patients with recent congestive heart failure (CHF) or myocardial infarction (MI) or severe or unstable angina were excluded. RESULTS: Eighty patients (78% men; mean age, 65 years) completed the study. Diabetes mellitus was the most frequent clinical risk factor (73%), followed by age older than 70 years (41%), angina (29%), Q wave on electrocardiogram (26%), history of CHF (7%), and ventricular ectopy (3%). The results of DTHAL/DMIBI were normal in 36 patients (45%); a reversible plus or minus fixed defect was demonstrated in 28 patients (36%), and a fixed defect alone was demonstrated in 15 patients (19%). Nine adverse cardiac events (11%) occurred, including three cases of CHF, and one case each of unstable angina, Q wave MI, non-Q wave MI, and cardiac arrest (successfully resuscitated). Two cardiac deaths occurred (2% overall mortality), one after a Q wave MI and one after CHF and a non-Q wave MI. The cardiac event rate was 14% for reversible defect and 9.8% without reversible defect (P =.71). The cardiac event rate was 12.5% (one of eight cases) for two or more reversible defects, versus 11.1% (eight of 72 cases) for fewer than two reversible defects (P = 1.0). The sensitivity rate of two or more areas of redistribution was 11% (95% CI, 0.3%-48%), the specificity rate was 90%, and the positive and negative predictive values were 12.5% and 89%, respectively. CONCLUSION: Our study demonstrated no association between reversible defects on DTHAL/DMIBI and adverse cardiac events in moderate-risk patients undergoing elective vascular surgery.

Aged↗
PubMed2000

Disruption of the pelvic ring in pediatric patients.

Pelvic ring disruptions are rare in children. Generally, nonoperative treatment has been recommended for children with these injuries. The authors retrospectively reviewed the medical records and radiographs of 189 patients with pelvic ring disruptions who were evaluated at a tertiary care children's hospital during a 10-year period. Of the 189 patients, 57 were identified with unstable pelvic fractures. These fractures were classified according to Tile, and Torode and Zieg. Forty-three of these patients were available to complete a subjective evaluation of their treatment at midterm followup. Thirteen patients were treated operatively and 30 were treated nonoperatively. There was no significant difference in subjective scoring between the two groups for pain at rest, pain with activity, limp, leg length discrepancy, and overall satisfaction with treatment. Overall, there were 92% good or excellent results in the patients who were treated operatively and 80% good or excellent results in the patients who were treated nonoperatively. Patients in both groups reported a high level of satisfaction with their outcome regardless of their fracture classification and treatment method.

Adolescent↗
PubMed2000

Cardiac hypertrophy and cardiac renin-angiotensin system in Dahl rats on high salt intake.

OBJECTIVE: On high salt intake, Dahl salt-sensitive rats develop cardiac hypertrophy disproportionate to the degree of hypertension. In the present studies, we assessed whether the cardiac hypertrophy induced by high salt depends on the development of hypertension per se, and leads to over-activity of the cardiac renin-angiotensin system (RAS). METHODS: Cardiac angiotensin converting enzyme (ACE) mRNA and activity, cardiac and plasma angiotensin I and II (AngI, II), as well as plasma renin activity (PRA) were assessed in Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats on high (1370 micromol/g food) or regular salt (120 micromol/g food) diet for 2-5 weeks. Cardiac ACE and hypertrophic response in Dahl S on high salt were also assessed after central blockade of sympathetic hyperactivity and hypertension. RESULTS: In Dahl S rats, ACE mRNA and activity of the left ventricle (LV) increased markedly after 4-5 weeks of high salt diet compared with Dahl S on the control diet and Dahl R on either diet Chronic intra-cerebroventricular treatment with Fab fragments blocking brain 'ouabain' prevented the hypertension by high salt in Dahl S rats but did not affect the salt-induced increases in LV weight or in LV ACE mRNA and activity. On regular salt diet, Dahl S rats demonstrated significantly lower cardiac AngI and AngII than Dahl R rats. However, high salt intake did not cause significant changes in cardiac AngI and II in either strain. On regular salt diet, PRA, plasma AngI and II were all significantly lower in Dahl S versus R. In Dahl S rats, high salt did not cause further decreases of the already low PRA or plasma AngI and II. CONCLUSIONS: These data indicate a low activity of both circulatory and cardiac RAS in Dahl S versus R rats. The marked cardiac hypertrophy and increase in cardiac ACE mRNA and activity induced by high salt in Dahl S do not depend on the increase in blood pressure. High salt intake did not increase cardiac AngII in Dahl S, suggesting that the increase in ACE mRNA and activity may be relevant for non-angiotensinergic mechanisms involved in cardiac hypertrophy.

Angiotensin I↗
PubMed2000

Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyltransferase gene.

Peptide deformylase, a bacterial enzyme, represents a novel target for antibiotic discovery. Two deformylase homologs, defA and defB, were identified in Staphylococcus aureus. The defA homolog, located upstream of the transformylase gene, was identified by genomic analysis and was cloned from chromosomal DNA by PCR. A distinct homolog, defB, was cloned from an S. aureus genomic library by complementation of the arabinose-dependent phenotype of a P(BAD)-def Escherichia coli strain grown under arabinose-limiting conditions. Overexpression in E. coli of defB, but not defA, correlated to increased deformylase activity and decreased susceptibility to actinonin, a deformylase-specific inhibitor. The defB gene could not be disrupted in wild-type S. aureus, suggesting that this gene, which encodes a functional deformylase, is essential. In contrast, the defA gene could be inactivated; the function of this gene is unknown. Actinonin-resistant mutants grew slowly in vitro and did not show cross-resistance to other classes of antibiotics. When compared to the parent, an actinonin-resistant strain produced an attenuated infection in a murine abscess model, indicating that this strain also has a growth disadvantage in vivo. Sequence analysis of the actinonin-resistant mutants revealed that each harbors a loss-of-function mutation in the fmt gene. Susceptibility to actinonin was restored when the wild-type fmt gene was introduced into these mutant strains. An S. aureus Deltafmt strain was also resistant to actinonin, suggesting that a functional deformylase activity is not required in a strain that lacks formyltransferase activity. Accordingly, the defB gene could be disrupted in an fmt mutant.

Amidohydrolases↗