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Biomedical subjects

I G Campbell

Publications and source records attributed to I G Campbell.

At least 19 recordsLinked to original sources
PubMed2001

The phosphatidylinositol 3'-kinase p85alpha gene is an oncogene in human ovarian and colon tumors.

Phosphatidylinositol 3'-kinases (PI3ks) are a family of lipid kinases that play a crucial role in a wide range of important cellular processes associated with malignant behavior including cell growth, migration, and survival. We have used single-strand conformational polymorphism/heteroduplex analysis to demonstrate the presence of somatic mutations in the gene for the p85alpha regulatory subunit of PI3k (PIK3R1) in primary human colon and ovarian tumors and cancer cell lines. All of the mutations lead to deletions in the inter-SH2 region of the molecule proximal to the serine608 autoregulatory site. Expression of a mutant protein with a 23 amino acid deletion leads to constitutive activation of PI3k providing the first direct evidence that p85alpha is a new oncogene involved in human tumorigenesis.

Aged↗
PubMed2001

Loss of heterozygosity at 7q22 and mutation analysis of the CDP gene in human epithelial ovarian tumors.

Many tumor types including that of the ovary show loss of heterozygosity (LOH) on chromosome arm 7q, which suggests the existence of at least one tumor suppressor gene (TSG) on this chromosome arm. We have studied the region surrounding the putative tumor suppressor gene CUTL1 at 7q22 in 127 epithelial ovarian tumors. LOH was found across 7q22 in 31% of malignant and 14% of benign ovarian tumors. In 16% of the tumors the LOH appeared to be centered on the CUTL1 gene. This gene has been implicated previously as a TSG in both uterine leiomyomas and breast carcinoma. However, mutation analysis of the CUTL1 gene in 47 tumors with 7q22 LOH failed to identify any somatic alterations in the coding regions. This finding suggests that CUTL1 may not be the target of the 7q22 LOH in ovarian cancers.

Adenocarcinoma, Mucinous↗
PubMed2001

A kinetic analysis of trained wheelchair racers during two speeds of propulsion.

The purpose of the study was to investigate the propulsion kinetics of wheelchair racers at racing speeds and to assess how these change with an increase in speed. It was hypothesised that propulsive force would increase in proportion to speed, to accommodate the additional work required. Six wheelchair racers volunteered to participate in this study which required each athlete to push a racing wheelchair at 4.70 and 5.64 m s(-1) on a wheelchair ergometer (WERG). Eight pairs (16 in total) of strain gauges, mounted on four bars attached to the hand-rim of a racing wheelchair wheel, measured the medio-lateral and tangential forces applied to the hand-rim. Kinetic data were sampled at 200 Hz while a single on-line (ELITE) infrared camera operating at 100 Hz was positioned perpendicular to the WERG to record the location of the hand with respect to the hand-rim. In general, peak tangential force occurred when the hand was positioned on the hand-rim between 140 and 180 degrees. With the increase in speed, the peak hand-rim forces applied tangentially increased from 132 to 158 N and those applied medio-laterally increased from 90 to 104 N. The ratio of tangential to total measured force was similar at both speeds (80 and 82%, respectively). In conclusion, these data indicate that wheelchair racers adopt a different propulsion strategy than that employed in everyday chairs and that the forces increase in proportion to propulsion speed.

Adult↗
PubMed2001

Internight reliability and benchmark values for computer analyses of non-rapid eye movement (NREM) and REM EEG in normal young adult and elderly subjects.

OBJECTIVE: To determine the reliability of computer measured non-rapid eye movement (NREM) and REM frequency bands in the 0.3-45 Hz range and to provide benchmark data for these measures in young normal (YN) and elderly normal (EN) subjects (Ss). METHODS: Sleep EEG was recorded in 19 YN and 19 EN Ss on 4 non-consecutive baseline nights and simultaneously quantified as fast Fourier transform (FFT) power and 3 zero-cross period-amplitude (PA) measures: integrated amplitude, time in band and average wave amplitude. RESULTS: The shapes of both the FFT and PA spectra differed among Ss but were highly consistent within individuals. Inter-night reliability of the separate frequency bands was correspondingly high. Despite substantial age effects, the reliability of computer-measured sleep EEG in the elderly equaled that of the YN Ss. Within both the YN and EN groups, the shapes of the NREM and REM spectral curves differed significantly. The NREM and REM also differed significantly in the two age groups. CONCLUSIONS: Computer-measured sleep EEG is highly reliable across non-consecutive nights in both young and elderly normal Ss. The trait-like stability of these measures suggests they are genetically determined. This possibility is supported by twin study data that show strong heritability for FFT-measured waking EEG. The different shapes of NREM and REM spectra add further evidence that these are fundamentally different states of brain organization. The age differences in spectral shape, along with PA data for wave incidence, demonstrate that age effects on sleep EEG are not caused by changes in skull impedance or other non-cerebral factors.

Adult↗
PubMed2001

A simple method for computer quantification of stage REM eye movement potentials.

We describe a simple method for computer quantification of eye movement (EM) potentials during REM sleep. This method can be applied by investigators using either period-amplitude (PA) or Fast Fourier Transform (FFT) spectral EEG analysis without special hardware or computer programming. It provides good correlations with visual ratings of EM in baseline sleep and after administration of GABAergic hypnotics. We present baseline data for both PA and FFT measures for 16 normal subjects, studied for 5 consecutive nights. Both visually rated and computer-measured EM density (EMD) showed high night-to-night correlations across baseline and drug nights and the computer measures detected the EMD suppression that is produced by GABAergic drugs. Measurement of EM in addition to stage REM provides biologically significant information and application of this simple computer method, which does not require pattern recognition algorithms or special hardware, could provide reliable data that can be compared across laboratories.

Computers↗
PubMed2001

GSTM1 null polymorphism and susceptibility to endometriosis and ovarian cancer.

It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer.

Case-Control Studies↗
PubMed2001

Polymorphic variation in CYP19 and the risk of breast cancer.

The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (cyp19). We have assessed the frequency of allelic variants of the CYP19 intron 4 [TTTA]n repeat in 327 breast cancer cases and 253 controls from southern England. Previous studies have suggested that the [TTTA](10) repeat and [TTTA](12) repeat variants represent low penetrance breast cancer susceptibility alleles. Compared with controls our breast cancer cases had a statistically significant positive association with the [TTTA](10) allele (1.5 versus 0.2%, P = 0.028) and the [TTTA](8) allele (13.5 versus 8.7%, P = 0.012). The frequency of the [TTTA](12) allele was not significantly elevated in our study group compared with controls (2.3 versus 2.2%, P = 1.00). The CYP19 intron 4 [TTTA]n repeat is unlikely to have a functional effect on aromatase activity and it is more likely that the [TTTA](8) and [TTTA](10) variants are in linkage disequilibrium with other functional CYP19 variants.

Adult↗
PubMed2001

The influence of recovery posture on post-exercise hypotension in normotensive men.

PURPOSE: Postexercise hypotension may be the result of an impaired vasoconstrictor response. This hypothesis was investigated by examining the central and peripheral hemodynamic responses during supine and seated recovery after maximal upright exercise. METHODS: After supine or seated baseline measurements, seven normotensive male volunteers completed a graded upright cycling protocol to volitional exhaustion. This was immediately followed by either supine or seated recovery. Measurements of pulsatile arterial blood pressure and central and peripheral hemodynamic variables recorded 30 min before exercise were compared with those taken throughout 60 min of recovery. RESULTS: Compared with baseline, mean arterial pressure (MAP) was reduced after exercise (P < 0.05) although the degree of change was not different between the supine (-9 +/- 4 mm Hg) and seated positions (-6 +/- 2 mm Hg). This change in MAP was associated with a reduction in diastolic blood pressure (DBP) (P < 0.05) and arterial pulse pressure (APP) (P < 0.01) for the supine and seated positions, respectively. The reduction in APP during seated recovery was accompanied by a decline in stroke volume (SV) (P < 0.05), not seen in the supine position, that limited the contribution of cardiac output (CO) to the maintenance of MAP. This effect of seated recovery was compensated by greater systemic (SVR) and regional vascular resistances in the forearm (FVR) and the forearm skin (SkVRA). There was also evidence of an augmented return of FVR and SkVRA to resting levels in the seated position after exercise. CONCLUSION: The lower peripheral resistance in the supine compared with seated recovery position suggests there is potential for greater vasoconstriction, although this is not evoked to increase blood pressure. This further suggests that the arterial baroreceptor reflex is reset to a lower operating pressure after exercise.

Adult↗
PubMed2000

High internight reliability of computer-measured NREM delta, sigma, and beta: biological implications.

BACKGROUND: Computer analysis of the sleep electroencephalogram (EEG) waveforms is widely employed, but there have been no systematic studies of its reliability. METHODS: The most commonly used computer methods are power spectral analysis with the fast-Fourier transform (FFT) and period amplitude analysis (PAA) with zero cross or zero first derivative half-wave measurement. We applied all three computer methods to the digitized EEG of 16 normal subjects who underwent 5 consecutive nights of baseline (placebo) recording. We evaluated the internight reliability of three non-rapid eye movement (NREM) frequency bands of special importance to sleep research: delta (0.3-3 Hz), sigma (12-15 Hz), and beta (15-23 Hz). RESULTS: Both FFT and the two methods of PAA gave excellent internight reliability for delta and sigma. Even a single night of recording correlated highly (r >.9) with the 5-night mean. Beta reliability was lower but still highly significant for both the PAA and the FFT measures. CONCLUSIONS: Computer-analyzed sleep EEG data are highly reliable. Period amplitude methods demonstrate that wave incidence and period as well as amplitude are reliable, indicating that the reliability of composite measures (FFT power, PAA integrated amplitude) is not solely based on individual differences in EEG amplitude. The high internight stability of NREM delta indicates that it possesses traitlike characteristics and is relatively independent of day-to-day variations in state.

Adult↗
PubMed2000

Refinement of an ovarian cancer tumour suppressor gene locus on chromosome arm 22q and mutation analysis of CYP2D6, SREBP2 and NAGA.

Loss of heterozygosity on chromosome 22q was detected in 53% of 123 ovarian carcinomas, suggesting the presence of at least one tumour suppressor gene. We have refined the location of one possible tumour suppressor gene to the region between the microsatellite markers D22S299 and CYP2D. Located within this region are the genes SREBP2 (sterol regulatory element binding protein 2) and NAGA (N-acetyl-alpha-D-galactosaminidase). Investigation of the coding exons of these genes by single stranded conformational polymorphism/heteroduplex analysis failed to identify any somatic genetic alterations in 57 ovarian tumours which exhibited LOH on 22q13. The CYP2D gene locus straddles the distal boundary of the candidate region. Germline variants of the active CYP2D6 gene with differing abilities to metabolise specific substrates have been implicated in the development of various cancers. Comparison of the frequency of the two common germline mutations among 258 ovarian tumours and 231 non-cancer controls did not reveal any significant differences between the two groups. This suggests that the known polymorphic variants of CYP2D6 are not involved in ovarian cancer predisposition. We also conclude that neither NAGA nor SREBP2 are likely to be mutated in ovarian carcinomas.

Chromosome Mapping↗
PubMed2000

Effect of push frequency on the economy of wheelchair racers.

PURPOSE: The aim of the study was to examine the effect of varying push frequency on pushing economy (oxygen uptake at a given speed). METHODS: Eight male wheelchair racers completed a series of exercise bouts on a wheelchair ergometer (Bromking Turbo Trainer, Bromakin, UK) at 6.58 m x s(-1). Initially, subjects self-selected their freely chosen push frequency (FCF); this was followed by 4 random trials pushing at 60, 80, 120, and 140% of this FCF. Steady state VO2 was determined using Douglas bags, and heart rate was recorded by telemetry. After each condition, a small capillary blood sample was obtained and analyzed for blood lactate concentration (BLa) and a rating of perceived exertion (RPE) was recorded. RESULTS: At 6.58 m x s(-1) oxygen uptake, RPE, and gross mechanical efficiency were nonlinearly related to push frequency. Analysis of variance showed a significant effect (P < 0.05) of cycle frequency on VO2. VO2 was 11% higher at the 140% FCF compared with the 100% FCF condition. Changes in push frequency had little effect on HR although BLa increased linearly and was higher at the 140% FCF condition compared with 60% FCF (P < 0.05). A two-dimensional sagittal plane video analysis showed large interindividual differences in propulsion style. Both cycle time and the propulsion phase (%) decreased as the push frequency increased. The start angle and end angle of hand contact were similar for conditions, whereas the range of trunk motion decreased with push frequency (P < 0.05). CONCLUSION: The results of this study showed that the push frequency had an effect on pushing economy, and that the athletes' FCF was the most economical.

Adolescent↗
PubMed2000

Evidence that endometriosis behaves in a malignant manner.

It is well known that certain aspects of endometriosis are similar to those of malignant disease. For example, like cancer, endometriosis can be both locally and distantly metastatic; it attaches to other tissues, invades, and damages them. Endometriosis is a common disease that does not create a cachectic or catabolic state, and is rarely fatal. There are, however, numerous reported cases of malignancy arising from endometriotic deposits and substantial histologic evidence that endometriosis is associated with endometrioid carcinoma and clear cell carcinoma of the ovary. A large review article by Mostoufizadeh and Scully investigated the association between endometriosis and endometrioid carcinoma, noting that women who had both diseases tended to be younger [1]. They found no association between endometriosis and serous or mucinous carcinoma of the ovary, and reported that malignant transformation of endometriosis was rare and associated with the use of exogenous estrogens. An epidemiological study of Swedish women reported a higher incidence of breast and ovarian cancer and non-Hodgkin's lymphoma in women with endometriosis compared with controls [2]. Vercellini and colleagues also reported a higher incidence of endometrioid and clear cell carcinoma in women with endometriosis compared with controls [3]. Mutations in genes associated with galactose metabolism have been identified as one possible mechanism for this association. These mutations are more common in ovarian cancer and have been reported to be more common in women with endometriosis. We compared 78 women with endometriosis with 248 controls and were unable to demonstrate an increased frequency of these mutations in any of these groups.

Animals↗
PubMed2000

Molecular genetic defects in endometriosis.

In a series of studies, we have hypothesised that endometriotic proliferation is, in part, precipitated by mutations in oncogenes or deletions in tumor suppressor genes that have been shown to be important steps in the transformation from a benign to a malignant epithelium. We reported previously that we could find no mutations in the TP53 and RASK genes in cases of endometriosis. However, having shown that endometriotic deposits were monoclonal, we showed loss of heterozygosity on chromosomes 9p (18%), 11q (18%), and 22q (15%) - in total 28% of endometriotic lesions showed loss of heterozygosity at one or more sites [1]. We could not demonstrate any loss of heterozygosity in normal endometrium. We examined adjacent endometriosis, atypical endometriosis, and endometrioid carcinoma of the ovary and showed common genetic alterations that are consistent with a common lineage. These common alterations were not seen in lesions that were distant from each other [2]. In endometrioid tumors, we reported an increased frequency of mutations in the PTEN/MMAC tumor suppressor genes that was not seen in clear cell or serous carcinoma, suggesting distinct developmental pathways for these tumors [3].

Carcinoma, Endometrioid↗
PubMed2000

The effect of aerobic exercise training on the lipid-lipoprotein profile of children and adolescents.

Longitudinal paediatric population studies have provided evidence that the risk factor theory may be extended to children and adolescents. These studies could assist in identifying individuals at increased coronary risk. Numerous studies have focused on the effects of regular exercise on the paediatric lipoprotein profile, a recognised primary risk factor, with equivocal results. Cross-sectional comparisons of dichotomised groups provide the strongest evidence of an exercise effect. 'Trained' or 'active' children and adolescents demonstrate 'favourable' levels of high density lipoprotein-cholesterol (HDL-C), triacylglycerol, total cholesterol (TC)/HDL-C and low density lipoprotein-cholesterol (LDL-C)/HDL-C, whilst TC is generally unaffected. The evidence regarding LDL-C in these studies is equivocal. A possible self-selection bias means that a cause-effect relationship between exercise and the lipoprotein profile cannot be readily established from this design. Correlational studies are difficult to interpret because of differences in participant characteristics, methods employed to assess peak oxygen uptake and habitual physical activity (HPA), and the statistical techniques used to analyse multivariate data. Directly measured cardiorespiratory fitness does not appear to be related to lipoprotein profiles in the children and adolescents studied to date, although there are data to the contrary. The relationship with HPA is more difficult to decipher. The evidence suggests that a 'favourable' lipoprotein profile may be related to higher levels of HPA, although differences in assessment methods preclude a definitive answer. While few prospective studies exist, the majority of these longitudinal investigations suggest that imposed regular exercise has little, if any, influence on the lipoprotein levels of children and adolescents. However, most prospective studies have several serious methodological design weaknesses, including low sample size, inadequate exercise training volume and a lack of control individuals. Recent studies have suggested that increases in HDL-C and reductions in LDL-C may be possible with regular exercise. The identification of a dose-response relationship between exercise training and the lipoprotein profile during the paediatric years remains elusive.

Adolescent↗
PubMed1999

Absence of PPP2R1B gene alterations in primary ovarian cancers.

The PPP2R1B gene has recently been implicated as a tumor suppressor based on the finding of somatic alterations in lung and colon cancers. PPP2R1B is located on chromosome 11q22-24 which coincides with the site of frequent loss of heterozygosity (LOH) in ovarian cancer. We investigated if the PPP2R1B gene was inactivated in ovarian cancer by single strand conformational polymorphism (SSCP) and heteroduplex (HD) analysis of 99% of the coding region. LOH at the PPP2R1B locus was detected in 32% of the malignant tumors but no somatic alterations were detected in any of 65 malignant, five borderline or six benign tumors. A germline G > A transition (GGC > GAC) in codon 90 was detected in 4/76 tumors. This alteration has previously been described as a mutation but on further investigation we found that the frequency of this variant among 167 ovarian cancers (4.2%) was not statistically significantly different from that observed in 247 non-cancer random controls (2.4%). We conclude that the PPP2R1B gene is not involved in the pathogenesis of ovarian cancer. The codon 90 Gly > Asp alteration may represent a non-pathological polymorphism and consequently the mutation frequency reported in lung cancers may have been overstated and the designation of PPP2R1B as a tumor suppressor gene should be regarded with caution.

Carcinoma↗
PubMed1999

Comparison of MK-801 and sleep deprivation effects on NREM, REM, and waking spectra in the rat.

In previous studies, we showed that blockade of the cation channel gated by NMDA glutamate receptors with ketamine or MK-801 massively stimulates NREM delta. We now test whether this NREM delta stimulation is physiological by comparing the EEG response following MK-801 to the EEG response following sleep deprivation (SD). Our previous studies measured only NREM 1-4 Hz EEG with period-amplitude analysis (PAA). Here we extended the analysis of MK-801 effects on sleep EEG by applying power spectral analysis (PSA) to examine delta and higher frequency spectra (.2-100 Hz) in NREM and by including REM and waking spectra. The changes in EEG spectra following MK-801 and SD were remarkably similar. Both SD and MK-801 produced their largest changes in NREM delta and REM 10-20 Hz power. There were some differences in the high frequency EEG, but the overall similarity of the PSA spectra in all three vigilance states after MK-801 and SD supports the possibility that MK-801 stimulated physiologic sleep, perhaps by increasing the need for homeostatic recovery from the metabolic effects of NMDA channel blockade.

Animals↗