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C Williams

Publications and source records attributed to C Williams.

At least 253 records · Page 14Linked to original sources
PubMed1997

Loss of Ref-1 protein expression precedes DNA fragmentation in apoptotic neurons.

Ref-1 is a bifunctional protein that has been implicated in the transcriptional regulation of AP-1 elements and in DNA repair. To investigate whether Ref-1 is involved in programmed cell death its expression was measured in the 21-day-old rat brain at various time-points following a moderate unilateral hypoxic-ischemic (HI) insult. The CA1 pyramidal cells, which are selectively vulnerable to HI injury, showed a significant decrease in Ref-1 immunoreactivity 48 h-7 days post-insult. This loss of Ref-1 immunoreactivity may contribute to a decrease in endogenous repair activity and the development of apoptosis in the CA1 pyramidal cells.

Animals↗
PubMed1997

Insulin improves survival in a canine model of acute beta-blocker toxicity.

STUDY OBJECTIVE: To compare the efficacy of a novel antidote, insulin, with standard treatments, glucagon and epinephrine, in a canine model of acute beta-blocker toxicity. METHODS: Anesthetized dogs were fitted with instruments by means of thoracotomy and vascular cutdown for multiple cardiodynamic, hemodynamic, metabolic, and electrical measures. After basal measurements were taken, animals received intravenous propranolol (.25 mg/kg/minute) continuously for the remainder of the experiment. Toxicity was defined as a 25% decrease in the product of heart rate times mean blood pressure. Thirty minutes after the development of toxicity, toxic measures were taken (treatment 0 minutes), and then the animals (n = 6 each group) received either sham (saline solution), insulin (4 IU/minute with glucose clamped), glucagon (50 micrograms/kg bolus, then 150 micrograms/kg/hour infusion), or epinephrine (1 microgram/kg/minute). Animals were monitored until death or for 240 minutes. RESULTS: Propranolol decreased contractility, left ventricular pressure, and systemic blood pressure, and resulted in death of all sham-treated animals by 150 minutes. Six of six insulin-treated, four of six glucagon-treated, and one of six epinephrine-treated animals survived. Survival was greater for insulin-treated animals, compared with either glucagon-treated (P < .05) or epinephrine-treated animals (P < .02) by the log-rank test. Insulin-treated animals were characterized by improved cardiodynamics and hemodynamics, increased myocardial glucose uptake, and decreased serum potassium. CONCLUSION: Insulin is a superior antidote compared with glucagon or epinephrine in an anesthetized canine model of acute beta-blocker toxicity.

Acute Disease↗
PubMed1997

Genomic analysis of single cells from human basal cell cancer using laser-assisted capture microscopy.

In this study, we show that direct mutational analysis of genomic DNA can be performed on single somatic cells extracted from a frozen, immunohistochemically stained tissue section using laser-assisted capture microscopy. Eighty-nine single tumor cells were separately dissected from one case of human basal cell cancer (BCC) and p53 mutations were analyzed by direct semi-automated sequencing of PCR fragments. Amplification was obtained for at least one of the two analyzed exons from approximately 50% of the single tumor cells. Identical p53 mutations were found in widely spread areas of the tumor, suggesting a clonal proliferation originating from one cell. Interestingly, comparison between results of immunohistochemistry and genetic analysis of the single cells revealed the same p53 mutations irrespective of the p53 immunoreactivity. We propose that this approach has a great potential to allow investigation of genotypic differences in single cells and more specifically to resolve important and fundamental questions determining cancer heterogeneity.

Aged↗
PubMed1997

Enhancement of bioreductive drug toxicity in murine tumours by inhibition of the activity of nitric oxide synthase.

Nitro-L-arginine inhibits the production of nitric oxide and can thereby cause vasoconstriction in vivo. One consequence of this is that nitro-L-arginine can increase hypoxia in a range of transplantable and spontaneous murine solid tumours. Bioreductive drugs such as RB6145 are more active under hypoxic conditions, and the combination of RB6145 with nitro-L-arginine in vivo shows greater anti-tumour activity than either agent individually. In mice given nitro-L-arginine at 10 mg kg(-1) i.p. up to 1 h before or after 300 mg kg(-1) i.p. RB6145, survival of KHT tumour cells was reduced by 3-4 logs when assessed by clonogenic assay 24 h after treatment. RB6145 or nitro-L-arginine alone caused no more than 20% cell kill. Similar effects were found in SCCVII tumours. The tumour response to the drug combination was tumour size dependent, with increased tumour cell sensitivity occurring when the tumour volume at the time of treatment was increased. Further, the response of KHT tumours to the combination of RB6145 and nitro-L-arginine was also dependent on the time interval between treatment and on when tumours were excised for determination of survival in vitro. The relative surviving fraction was about 0.3 for intervals less than 4 h but was reduced to 0.01 at 12 h and 0.001 at 24 h. These results were supported by histological examination of tumours, when necrosis at 2 h after treatment was less than 5% but increased to greater than 90% at 24 h. RB6145-induced normal tissue damage, as measured by CFU-A survival, was not altered by combining with nitro-L-arginine. Hence, this drug combination may provide therapeutic benefit. It is likely that the substantial anti-tumour effects are due to enhancement of bioreductive toxicity through increased tumour hypoxia, although additional mechanism(s) may also contribute to the overall response.

Animals↗
PubMed1997

Segregation analysis of ovarian cancer using diathesis to include other cancers.

Despite the recent cloning of BRCA1, BRCA2 and the mismatch repair genes, it will still be a long time before it is possible to specify any individual's risk for ovarian cancer based on her genotype. Most women concerned about their risk on the basis of one or two affected relatives do not belong to extensive ovarian cancer families. Risk calculations depend on a reliable genetic model for ovarian cancer derived, ideally, from the population from which an individual is drawn. We have carried out a segregation analysis using data collected from consecutive ovarian cancer patients in two different centres in the UK. Complex segregation analysis was carried out with the addition of diathesis as a separate parameter allowing other cancers, associated with ovarian cancer, to be taken into account. The use of diathesis in the derivation of this alternative model is described. Analysed under joint likelihood without diathesis, the gene frequency is 0.0028 and penetrance to age 70 years is 50%. This is in agreement with other published models. Incorporating diathesis into the model under joint likelihood gives similar parameters for a single locus model but gives the best fit with a two locus model where both genes are rare.

Adult↗
PubMed1997

Pre-exercise carbohydrate meal and endurance running capacity when carbohydrates are ingested during exercise.

This study examined whether combining a pre-exercise carbohydrate meal with the ingestion of a carbohydrate-electrolyte solution during exercise is better in improving endurance running capacity than a carbohydrate-electrolyte solution alone. Ten men completed three treadmill runs at 70% VO2max to exhaustion. They consumed 1.) a carbohydrate meal three hours before exercise and a carbohydrate-electrolyte solution during exercise (M + C), or 2.) a liquid placebo three hours before exercise and the carbohydrate-electrolyte solution during exercise (P + C), or 3.) a placebo three hours before exercise and placebo during exercise (P + P). When the meal was consumed (M + C) serum insulin concentrations were higher at the start of exercise, and carbohydrate oxidation rates were higher during the first 60 min of exercise compared with the values found in the P + C and P + P trials (p < 0.01). Exercise time was longer in the M + C (147.4+/-9.6 min) compared with the P + C (125.3+/-7 min) (p < 0.01). Also, exercise time was longer in M + C and P + C compared with the P + P (115.1+/-7.6 min) (p < 0.01 and p < 0.05 respectively). These results indicate that the combination of a pre-exercise carbohydrate meal and a carbohydrate-electrolyte solution further improves endurance running capacity than the carbohydrate-electrolyte solution alone.

Adult↗
PubMed1997

Haplotypes of angiotensinogen in essential hypertension.

The M235T polymorphism of the angiotensinogen gene (AGT) has been associated with essential and pregnancy-induced hypertension. Generation of haplotypes can help to resolve whether the T235 allele itself predisposes to the development of hypertension or acts as a marker of an unknown causal molecular variant. We identified 10 diallelic polymorphisms at the AGT locus and genotyped both a series of 477 probands of hypertensive families and 364 controls, all French Caucasians, as well as a series of 92 hypertensives and 122 controls from Japan. Despite a large ethnic difference in gene frequency, a significant association of T235 with hypertension was observed both in Cancasians (.46 vs. .38, P = .004) and in Japanese (.91 vs. .76, P = .002). In both groups, the G-->A substitution located at position -6 upstream of the initial transcription site occurred at the same frequency and in complete linkage disequilibrium with the T235 allele. No other polymorphism was found to be consistently associated with hypertension. Five informative haplotypes subdividing the T235 allele were generated. Whereas two of them were associated with hypertension in Caucasians, none of these two haplotypes (H3 and H4) reached statistical significance in Japanese. The analysis of the AGT-GT repeat revealed marked linkage disequilibriums between each of the diallelic polymorphisms and some (GT)n alleles, with similar patterns in the two populations. The strong disequilibrium between M235 and (GT)16 explained the increased frequency of that particular allele in French controls compared with hypertensives (.42 vs. .36, P < .01). The haplotype combining the M235T and G-6A polymorphisms appears as the ancestral allele of the human AGT gene and as the one associated with hypertension.

Age of Onset↗
PubMed1997

Harvest quality and factors affecting collection and engraftment of CD34+ cells in patients with breast cancer scheduled for high-dose chemotherapy and peripheral blood progenitor cell support.

The use of CFU-GM and CD34+ cell enumeration for assessing harvest quality and factors affecting peripheral blood progenitor cell (PBPC) harvest and engraftment were investigated in 45 women with high-risk and metastatic breast cancer scheduled for dose-intensive cyclophosphamide, thiotepa, and carboplatin (CTCb). PBPC were mobilized with standard breast cancer regimens or cyclophosphamide (1.5 g/m2) and 5 micrograms/kg/day G-CSF and used together with G-CSF for hematopoietic support post-CTCb. There was a significant correlation between peripheral blood CD34+ cells/microliter and harvest CD34+/kg (r = 0.73, p < 0.0001) and between harvest CFU-GM and CD34+ cells/kg (r = 0.5, p < 0.0001). CFU-GM clonogenic assays were of no clinical use beyond that of CD34+ cell enumeration, with the latter allowing for real-time decisions regarding harvesting. Multiple stepwise regression identified the number of prior chemotherapy cycles as the only significant clinical predictor of CD34+ cell yield. For 34 patients proceeding to CTCb with PBPC support, multiple stepwise regression identified as the best predictors for engraftment CFU-GM and CD34+ cells/kg for neutrophils and CFU-GM, CD34+ cells/kg, and the number of prior cycles of chemotherapy for platelets, respectively. A threshold dose of 1 x 10(6) CD34+ cells/kg, obtained in 87% of these heavily pretreated breast cancer patients, was adequate to ensure engraftment within 15 days. There was no significant difference in length of hospital stay or blood product use between patients receiving 1-2.5 x 10(6) CD34+ cells/kg and greater than 2.5 x 10(6) CD34+ cells/kg, although median time to engraftment of neutrophils (9 days versus 8 days, p = 0.007) and platelets (12 days versus 9 days, p = 0.006) was significantly longer. The established threshold of > or = 1 x 10(6) CD34+ cells/kg will allow for more confident consideration of using aliquots of this threshold dose for hematopoietic support in sequential high-dose regimens inclusive of CTCb.

Adult↗
PubMed1997

Risk factors for reported elder abuse and neglect: a nine-year observational cohort study.

To determine longitudinal risk factors for elder abuse and neglect, an established cohort of community-dwelling older adults (n = 2,812) was linked with elderly protective service records over a 9-year follow-up period. Protective services saw 184 (6.5%) individuals in the cohort for any indication, and 47 cohort members were seen for corroborated elder abuse or neglect for a sampling adjusted 9-year prevalence of 1.6% (95% CI 1.0%, 2.1%). In pooled logistic regression, age, race, poverty, functional disability, and cognitive impairment were identified as risk factors for reported elder mistreatment. Additionally, the onset of new cognitive impairment was also associated with elder abuse and neglect. Because the mechanism of elder mistreatment case-finding in this study was a social welfare system (protective services), the influence of race and poverty as risk factors is likely to be overestimated due to reporting bias.

Activities of Daily Living↗
PubMed1997

Neutralization of HIV-1 primary isolates by polyclonal and monoclonal human antibodies.

To examine antibody-mediated neutralization of HIV-1 primary isolates in vitro, we tested sera and plasma from infected individuals against four clade B primary isolates. These isolates were analyzed further for neutralization by a panel of several human anti-HIV-1 mAb in order to identify the neutralizing epitopes of these viruses. Each of the HIV-1+ serum and plasma specimens tested had neutralizing activities against one or more of the four primary isolates. Of the three individual sera, one (FDA-2) neutralized all of the four isolates, while the other two sera were effective against only one virus. The pooled plasma and serum samples reacted broadly with these isolates. Based on the neutralizing activities of the mAb panel, each virus isolate exhibited a distinct pattern of reactivity, suggesting antigenic diversity among clade B viruses. Neutralizing epitopes were found in the V3 loop and CD4-binding domain of gp120, as well as near the transmembrane region (cluster II epitope) of gp41. A mAb directed to the cluster I epitope of gp41 near the immunodominant disulfide loop weakly neutralized one primary isolate. None of the mAb in the panel affected one primary isolate, US4, although this virus was sensitive to neutralization by some of the polyclonal antibody specimens. This isolate was also resistant to neutralization by a cocktail of 10 mAb, most of which individually inhibited at least one of the other three viruses tested. These results suggest that neutralizing activity for this latter virus is present in certain HIV-1+ sera/plasma, but is not exhibited by the mAb in the panel. Thus, effective neutralizing antibodies against primary isolates can be generated by humans upon exposure to HIV-1, but not all of these antigenic specificities are represented in a large panel of human anti-HIV-1 mAb.

Antibodies, Monoclonal↗
PubMed1997

The influence of a high carbohydrate intake during recovery from prolonged, constant-pace running.

The present study examined the influence of ingesting 3.0 g CHO . kg-1 body mass . 2 hr-1 after prolonged exercise on recovery and running capacity 4 hr later. Nine men and 8 women completed two trials in a counterbalanced design. Each trial consisted of a 90-min run on a level treadmill at 70% VO2 max (R1) followed by 4 hr recovery (REC) and a further exhaustive run at 70% VO2 max (R2). During REC, subjects ingested either two feedings of a 6.9% glucosepolymer (GP) solution (D trial) or two feedings of a 19.3% GP solution (C trial). There were no differences in mean (+/- SE) R2 run times between the C and D trials or between the male and female subjects. More stable blood glucose concentrations were maintained during REC in the C trial, such that blood glucose was elevated in the C trial in comparison with the D trial after 210 min of REC. It was concluded that increasing postexercise carbohydrate intake from 1.0 to 3.0 g CHO . kg-1 body mass . 2 hr-1 does not improve endurance capacity 1 hr later.

Adult↗
PubMed1997

Carbohydrate intake and recovery of intermittent running capacity.

The purpose of the present study was to examine the influence of an increased carbohydrate intake on the recovery of endurance running capacity after exhaustive intermittent running. Six male subjects were randomly assigned to two dietary recovery conditions, each involving two running tests separated by 22 hr. The protocol comprised a prolonged, intermittent, high-intensity shuttle run test (I-HI). One week later subjects repeated the I-HI on consecutive days under different dietary conditions. During the 22-hr recovery, either the carbohydrate intake of the subjects was increased (CHO) or they ate an isocaloric diet by supplementing their normal diet with extra protein and fat (CON). Intermittent running capacity was improved when subjects increased their carbohydrate intake to 10 g.kg-1 bm during the 22-hr recovery between trials, but an isocaloric diet without additional carbohydrate did not bring about the same improvements.

Adult↗
PubMed1997

Physiological responses of wheelchair athletes at percentages of top speed.

OBJECTIVE: Wheelchair athletes often select a percentage of their top speed (%TS) to determine training intensity. The aim of the study was to determine whether choosing a %TS corresponds to the physiological concept of relative exercise intensity (% peak oxygen uptake: %VO2 peak) and to examine selected physiological and metabolic responses of a group of wheelchair athletes to 60 minutes' exercise at 80% TS. METHODS: 12 male wheelchair athletes (10 paraplegics and two tetraplegics) performed a series of tests on a motorised treadmill adapted for wheelchairs. The tests, which were undertaken on separate occasions, included the determination of VO2 peak, the determination of oxygen cost at a range of submaximal wheelchair propulsion speeds, and a 60 min exercise test at 80% TS. RESULTS: Wheelchair propulsion speeds equivalent to 60%, 70%, 80%, and 90% of each subject's TS were found to equate to 48.3 (SD13.8)%, 60.0(11.1)%, 70.6(9.8)%, and 82.7(9.6)% of VO2 peak, with a wide variation in the relative exercise intensities evident at each %TS. During the 1 h exercise test at 80% TS the physiological and metabolic responses measured were indicative of steady state exercise, with no signs of fatigue evident. CONCLUSIONS: The results of this study suggest that selecting a %TS is not an appropriate way of selecting a common relative exercise intensity. There may also be a need for the current training practises of some wheelchair road racers to be modified.

Exercise Test↗