Biomedical subjects

Richard H Wilson

Publications and source records attributed to Richard H Wilson.

At least 19 recordsLinked to original sources

PubMed2006

Association analysis of the ACTN3 R577X polymorphism and complex quantitative body composition and performance phenotypes in adolescent Greeks.

The functional allele (577R) of ACTN3, which encodes human alpha-actinin-3, has been reported to be associated with elite athletic status and with response to resistance training, while the nonfunctional allele (577X) has been proposed as a candidate metabolically thrifty allele. In a study of 992 adolescent Greeks, we show that there is a significant association (P=0.003) between the ACTN3 R577X polymorphism and 40 m sprint time in males that accounts for 2.3% of phenotypic variance, with the 577R allele contributing to faster times in an additive manner. The R577X polymorphism is not associated with other power phenotypes related to 40 m sprint, nor with an endurance phenotype. Furthermore, the polymorphism is not associated with obesity-related phenotypes in our population, suggesting that the 577X allele is not a thrifty allele, and thus the persistence of this null allele must be explained in other terms.

Actinin↗

PubMed2006

Phase I study of STX 64 (667 Coumate) in breast cancer patients: the first study of a steroid sulfatase inhibitor.

PURPOSE: Inhibition of steroid sulfatase (STS), the enzyme responsible for the hydrolysis of steroid sulfates, represents a potential novel treatment for postmenopausal women with hormone-dependent breast cancer. Estrone and DHEA are formed by this sulfatase pathway and can be converted to steroids (estradiol and androstenediol, respectively), which have potent estrogenic properties. EXPERIMENTAL DESIGN: STX64 (667 Coumate), a tricylic coumarin-based sulfamate that irreversibly inhibits STS activity, was selected for entry into the first phase I trial of a STS inhibitor in postmenopausal women with breast cancer. STX64 was administered orally (nine patients at 5 mg and five patients at 20 mg) as an initial dose followed 1 week later by 3 x 2 weekly cycles, with each cycle comprising daily dosing for 5 days followed by 9 days off treatment. Blood and tumor tissue samples were collected for the assessment of STS activity and serum was obtained for steroid hormone measurements before and after treatment. RESULTS: The median inhibition of STS activity by STX64 was 98% in peripheral blood lymphocytes (PBL) and 99% in breast tumor tissue at the end of the 5-day dosing period. As expected, serum concentrations of estrone, estradiol, androstenediol, and DHEA all decreased significantly from pretreatment levels. Unexpectedly, androstenedione and testosterone concentrations also decreased. Four patients, all of whom had previously progressed on aromatase inhibitors, showed evidence of stable disease for 2.75 to 7 months. The drug was well tolerated with only minor drug-related adverse events recorded. CONCLUSION: STX64 is a potent, well-tolerated STS inhibitor. It inhibits STS activity in PBLs and tumor tissues and causes significant decreases in serum concentrations of steroids with estrogenic properties.

Administration, Oral↗

PubMed2006

The associations of ACE polymorphisms with physical, physiological and skill parameters in adolescents.

Genetic variation in the human Angiotensin I-Converting Enzyme (ACE) gene has been associated with many heritable traits, including physical performance. Herein we report the results of a study of several physical, physiological and skill parameters and lifestyle in 1,027 teenage Greeks. We show that there is a strong association (P < 0.001) between the ACE I/D (insertion/deletion) polymorphism and both handgrip strength and vertical jump in females, homozygotes for the I-allele exhibiting higher performance-related phenotype scores, accounting for up to 4.5% of the phenotypic variance. The association is best explained by a model in which the D-allele is dominant, with the mean phenotypic value in the I/D heterozygotes being close to that of the mean of the DD homozygotes. The association acts across the phenotype distribution in a classical polygenic manner. Other polymorphisms that define major ACE haplotypes in European populations (rs4424958, rs4311) show weaker associations with these performance-related phenotypes than does I/D. Similarly, diplotypes defined by these polymorphisms do not explain significantly larger amounts of the variance than I/D alone. As ACE I/D is the polymorphism most strongly associated with circulating ACE activity in European populations, we propose that the functional allelic differences that influence ACE activity also mediate the associations with the performance-related phenotypes studied here.

Adolescent↗

PubMed2006

Novel therapeutic developments other than EGFR and VEGF inhibition in colorectal cancer.

Developments that may improve existing cytotoxic therapy for colorectal cancer (CRC) include alternatives to 5-fluorouracil (5-FU) such as the liposomal Thymidylate Synthase inhibitor OSI-7904L and the multitargeted antifolate pemetrexed. Studies have explored means of reformulating irinotecan, modulating its pharmacokinetics, and enhancing its activity by maximizing DNA damage through poly(ADP-ribose) polymerase inhibition. Cell cycle inhibitors may offer an alternative to combination with 5-FU. However, as standard regimens become more complex, so do the clinical trials needed to develop new agents, and the path to registration becomes ever more tortuous. It is therefore likely that several drugs with promise in CRC will not be developed for this indication.

Antineoplastic Agents↗

PubMed2006

Homogeneity of the 18 QuickSIN lists.

The purpose of this study was to determine the list equivalency of the 18 QuickSIN (Quick Speech in Noise test) lists. Individuals with normal hearing (n = 24) and with sensorineural hearing loss (n = 72) were studied. Mean recognition performances on the 18 lists by the listeners with normal hearing were 2.8 to 4.3 dB SNR (signal-to-noise ratio), whereas the range was 10.0 to 14.3 dB SNR for the listeners with hearing loss. The psychometric functions for each list showed high performance variability across lists for listeners with hearing loss but not for listeners with normal hearing. For listeners with hearing loss, Lists 4, 5, 13, and 16 fell outside of the critical difference. The data from this study suggest nine lists that provide homogenous results for listeners with and without hearing loss. Finally, there was an 8.7 dB difference in performances between the two groups indicating a more favorable signal-to-noise ratio required by the listeners with hearing loss to obtain equal performance.

Acoustic Stimulation↗

PubMed2006

Dichotic word recognition in young and older adults.

Dichotic word recognition was evaluated in free-recall, directed-attention right, and directed-attention left response conditions. All participants were right-handed and included a group of young adults with normal hearing and two groups of older adults with sensorineural hearing loss. Dichotic word recognition performance was best for young adults and decreased for each older group. A right-ear advantage (REA) was observed for all groups. REAs observed in the older groups were larger than those for the young adults, resulting from a greater deficit in dichotic word recognition performance for words presented to the left ear. A subset of older adults exhibited few to no responses (< or = 3/100) for the left ear for all response conditions, which may relate to a compromise in auditory processing. The results support an age-related disadvantage in recognition performance for dichotic stimuli presented to the left ear not entirely accounted for by differences in hearing sensitivity between subject groups.

Adult↗

PubMed2006

Word recognition of digit triplets and monosyllabic words in multitalker babble by listeners with sensorineural hearing loss.

In an initial experiment (Wilson and Weakley, 2004), word recognition was assessed with six digit triplets presented at 14 signal-to-babble ratios (S/B) in 2 dB steps. An abbreviated version of the protocol was developed for clinic use involving three digit triplets at 7 S/Bs in 4 dB steps. The purpose of this experiment was to examine the relationship between the two digit protocols with comparisons made with other variables including age, pure-tone thresholds, subjective measures of understanding speech in quiet and in noise, and word recognition of monosyllabic words in quiet and in babble. Ninety-six listeners with sensorineural hearing loss participated. For equivalent performance, the short version of the digit triplets required (1) a 2.6 dB more favorable S/B than the long version and (2) a 15.1 dB less favorable S/B than the words. Age, hearing loss, and subjective evaluation of the ability to understand speech in quiet and in noise were not related to performance on digits or words in multitalker babble.

Acoustic Stimulation↗

PubMed2005

Phase I and pharmacologic study of 17-(allylamino)-17-demethoxygeldanamycin in adult patients with solid tumors.

PURPOSE: To determine the clinical toxicities of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG) given as a 1-hour infusion daily for 5 days every 3 weeks. PATIENTS AND METHODS: Nineteen patients received 17-AAG over six dose levels (10 to 56 mg/m(2)) using an accelerated titration scheme. Drug levels of 17-AAG were determined by high-performance liquid chromatography. Biologic effects of 17-AAG were monitored by changes in the content of target proteins by immunoblot analysis of lysates prepared from peripheral-blood mononuclear cells. RESULTS: Toxicity was acceptable at doses up to 28 mg/m(2). The cohort was expanded to three patients at 40 mg/m(2) because a second occurrence of grade 2 hepatic transaminitis occurred. Two of six assessable patients who received 56 mg/m(2) had reversible, grade 3 hepatic transaminitis. Five additional patients were enrolled at 40 mg/m(2); none had dose-limiting toxicity. The maximum plasma concentrations (C(max)) of 17-AAG at 40 and 56 mg/m(2) were 1,724 and 2,046 ng/mL, respectively; the average plasma exposures (AUC) were 2,809 and 6,708 hours.ng/mL, respectively. Less than 3% of the daily dose was excreted into the urine. Clearance did not correlate with body-surface area. Possible biologic activity was suggested by apparent increased protein content of either glucose-related 78 kd protein or heat shock protein 70 with >/= 14 mg/m(2) and decreased protein content of either Lck or Raf1 with >/= 28 mg/m(2) of 17-AAG. CONCLUSION: 17-AAG 40 mg/m(2) (median dose, 70 mg) was well tolerated when given daily for 5 days every 3 weeks.

Adult↗

PubMed2005

No association between Angiotensin Converting Enzyme (ACE) gene variation and endurance athlete status in Kenyans.

East African runners are continually successful in international distance running. The extent to which genetic factors influence this phenomenon is unknown. The insertion (I) rather than deletion (D) of a 287 bp fragment in the human angiotensin converting enzyme (ACE) gene is associated with lower circulating and tissue ACE activity and with endurance performance amongst Caucasians. To assess the association between ACE gene variation and elite endurance athlete status in an African population successful in distance running, DNA samples were obtained from 221 national Kenyan athletes (N), 70 international Kenyan athletes (I), and 85 members of the general Kenyan population (C). Blood samples were obtained from C and assayed for circulating ACE activity. ACE I/D (rs????--from NCBI SNPdb first time poly mentioned) genotype was determined, as was genotype at A22982GD (rs????--from NCBI SNPdb first time poly mentioned) which has been shown to associate more closely with ACE levels in African subjects than the I/D polymorphism. ACE I/D and A22982G genotypes explained 13 and 24% of variation in circulating ACE activity levels (P = 0.034 and <0.001 respectively). I/D genotype was not associated with elite endurance athlete status (df = 4, chi(2) = 4.1, P=0.39). In addition, genotype at 22982 was not associated with elite endurance athlete status (df = 4, chi(2) = 5.7, P = 0.23). Nor was the A allele at 22982, which is associated with lower ACE activity, more prevalent in N (0.52) or I (0.41) relative to C (0.53). We conclude that ACE I/D and A22982G polymorphisms are not strongly associated with elite endurance athlete status amongst Kenyans.

Female↗

PubMed2005

Mitochondrial DNA lineages of elite Ethiopian athletes.

Previous studies have hypothesised that mitochondrial DNA (mtDNA) polymorphisms may influence aerobic performance. The matrilineal inheritance and accumulation of polymorphisms in mtDNA means that mtDNA haplogroups, characterised by key polymorphisms, are often represented at different frequencies in different populations. The present study aimed to compare the mtDNA haplogroup distribution of elite Ethiopian athletes relative to the general Ethiopian population. The haplogroup distribution of 76 endurance athletes (E), members of the Ethiopian national athletics team, was compared to 108 members of the general Ethiopian population (C). DNA was extracted from buccal swabs and haplogroups assigned by sequencing part of the hypervariable sequence (HVS-I), followed by analysis of key coding-region polymorphisms. A high proportion of African 'L' haplogroups was found in athletes and controls (C=53%; E=55%). Haplogroup distribution of endurance runners did not differ from that of C (P=0.63). Elite Ethiopian athletes are not a mitochondrially distinct group relative to the Ethiopian population. It appears that environment and, perhaps, polymorphisms in the nuclear genome are more important determinants of Ethiopian running success than mtDNA polymorphisms.

Black People↗

PubMed2005

Effects of interaction between angiotensin I-converting enzyme polymorphisms and lifestyle on adiposity in adolescent Greeks.

Genetic variation in the human angiotensin I-converting enzyme (ACE) gene has been associated with many heritable traits, including obesity. Herein, we report the results of a study of obesity-related phenotypes and lifestyle in 1016 teen-aged Greeks. We show that there is a strong association (p = 0.001) between subcutaneous fat and the ACE insertion/deletion (I/D) polymorphism in females, possession of genotypes containing the D allele being associated with increased fat thickness. This association is strongest in females who participate in no extra exercise and accounts for 6.5% of the phenotypic variance in fat thickness by ANOVA. The association is additive, with the mean phenotypic values in heterozygotes intermediate between the means of the two homozygotes, and the association acts at both extremes of the fat thickness distribution in a classical polygenic manner. Other ACE polymorphisms (rs4424958, rs4311) that define major haplotypes in European populations fail to provide stronger associations with the subcutaneous fat phenotype. Because ACE I/D is the polymorphism most strongly associated with circulating ACE levels in European populations, we propose that the functional allelic differences that influence circulating ACE levels also mediate the associations with the obesity-related phenotypes studied here.

Adiposity↗

PubMed2005

Oxaliplatin induces hyperexcitability at motor and autonomic neuromuscular junctions through effects on voltage-gated sodium channels.

Oxaliplatin, an effective cytotoxic treatment in combination with 5-fluorouracil for colorectal cancer, is associated with sensory, motor and autonomic neurotoxicity. Motor symptoms include hyperexcitability while autonomic effects include urinary retention, but the cause of these side-effects is unknown. We examined the effects on motor nerve function in the mouse hemidiaphragm and on the autonomic system in the vas deferens. In the mouse diaphragm, oxaliplatin (0.5 mM) induced multiple endplate potentials (EPPs) following a single stimulus, and was associated with an increase in spontaneous miniature EPP frequency. In the vas deferens, spontaneous excitatory junction potential frequency was increased after 30 min exposure to oxaliplatin; no changes in resting Ca(2+) concentration in nerve terminal varicosities were observed, and recovery after stimuli trains was unaffected. In both tissues, an oxaliplatin-induced increase in spontaneous activity was prevented by the voltage-gated Na(+) channel blocker tetrodotoxin (TTX). Carbamazepine (0.3 mM) also prevented multiple EPPs and the increase in spontaneous activity in both tissues. In diaphragm, beta-pompilidotoxin (100 microM), which slows Na(+) channel inactivation, induced multiple EPPs similar to oxaliplatin's effect. By contrast, blockers of K(+) channels (4-aminopyridine and apamin) did not replicate oxaliplatin-induced hyperexcitability in the diaphragm. The prevention of hyperexcitability by TTX blockade implies that oxaliplatin acts on nerve conduction rather than by effecting repolarisation. The similarity between beta-pompilidotoxin and oxaliplatin suggests that alteration of voltage-gated Na(+) channel kinetics is likely to underlie the acute neurotoxic actions of oxaliplatin.

Action Potentials↗

PubMed2005

The WHO-DAS II: psychometric properties in the measurement of functional health status in adults with acquired hearing loss.

The World Health Organization's (WHO) Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument firmly grounded in the WHO's International Classification of Functioning, Disability and Health (WHO-ICF). As such, it assesses functioning for six domains: communication, mobility, self-care, interpersonal, life activities, and participation. Domain scores aggregate to a total score. Because the WHO-DAS II contains questions relevant to hearing and communication, it has good face validity for use as an outcome measure for audiologic intervention. The purpose of the present study was to determine the psychometric properties of the WHO-DAS II on a sample of individuals with adult-onset hearing loss, including convergent validity, internal consistency, and test-retest stability. Convergent validity was established by examining correlations between the WHO-DAS II (domain and total scores) and the Abbreviated Profile of Hearing Aid Benefit (APHAB) and the Hearing Aid Handicap for the Elderly (HHIE), two disease-specific measures, as well as with the Short Form-36 for veterans (SF-36V), a second generic measure. Data on all four measures were collected from 380 older individuals with adult-onset hearing loss who were not hearing aid users. The results of the convergent validity analysis revealed that the WHODAS II communication domain score was moderately and significantly correlated with scores on the APHAB and the HHIE. WHO-DAS II interpersonal and participation domain scores and the total scores were also moderately and significantly correlated with HHIE scores. These findings support the validity of using the WHO-DAS II for assessing activity limitations and participation restrictions of adult-onset hearing loss. Several WHO-DAS II domain scores and the total score were also significantly and moderately-markedly correlated with scores from the SF-36V. These findings support the validity of the WHO-DAS II as a generic health-status instrument. Internal consistency reliability for all the domain scores was adequate for all but the interpersonal domain. Test-retest stability for all the domain scores was adequate. Critical difference values were calculated for use in clinical application of the WHO-DAS II. From these findings, we concluded that the WHO-DAS II communication, participation, and total scores can be used to examine the effects of adult-onset hearing loss on functional health status. Further work examining the utility of the WHO-DAS II as an outcome measure for hearing aid intervention is warranted.

Activities of Daily Living↗

PubMed2005

The WHO-DAS II: measuring outcomes of hearing aid intervention for adults.

The World Health Organization's Disability Assessment Scale II (WHO-DAS II) is a generic health-status instrument that provides six domain scores and a total, aggregate score. Two of the domain scores, communication and participation, and the total score, have good validity, internal-consistency reliability, and test-retest stability in individuals with adult-onset hearing loss. As such, these two domain scores and the total WHO-DAS II score may be useful as generic outcome measures to assess the effectiveness of hearing aid intervention for this population. Before the use of the WHO-DAS II in hearing aid clinical trials, however, the responsiveness of the instrument and the short- and long-term outcomes to hearing aid intervention had to be determined. Responsiveness and outcomes were assessed in 380 veterans (approximately half received hearing aids and half served as controls) by examining group differences, effect-size estimates, and individual differences as a function of hearing aid intervention. For comparison, data also were obtained on two disease-specific measures, the APHAB and the HHIE. The WHO-DAS II communication domain and total scores were sufficiently responsive to hearing aid intervention for use in future studies in which group differences are to be detected. The WHO-DAS II participation domain was not sufficiently responsive to hearing aid intervention. The APHAB and HHIE, both disease-specific measures, were more sensitive to hearing aid intervention than the generic measure. The short- and long-term outcomes of hearing aid intervention were also examined in the present study. Group outcomes for hearing aid intervention can be expected to be stable for at least 6 months when measured by WHO-DAS II total score and for at least 12 months when measured by the WHO-DAS II communication domain scores. Effect-size estimates and examination of the number of individuals exhibiting change scores exceeding 90% critical differences for true changes in scores indicate that for clinical applications, disease-specific instruments are more useful than the WHO-DAS II. The findings of this study support the use of the WHO-DAS II as a generic measure in hearing aid trials research so as to allow for comparisons of health-status outcomes across different diseases or disorders.

Aged↗

PubMed2005

The 500 Hz masking-level difference and word recognition in multitalker babble for 40- to 89-year-old listeners with symmetrical sensorineural hearing loss.

The purpose of this study was to determine if performances on a 500 Hz MLD task and a word-recognition task in multitalker babble covaried or varied independently for listeners with normal hearing and for listeners with hearing loss. Young listeners with normal hearing (n = 25) and older listeners (25 per decade from 40-80 years, n = 125) with sensorineural hearing loss were studied. Thresholds at 500 and 1000 Hz were < or = 30 dB HL and < or = 40 dB HL, respectively, with thresholds above 1000 Hz < 100 dB HL. There was no systematic relationship between the 500 Hz MLD and word-recognition performance in multitalker babble. Higher SoNo and SpiNo thresholds were observed for the older listeners, but the MLDs were the same for all groups. Word recognition in babble in terms of signal-to-babble ratio was on average 6.5 (40- to 49-year-old group) to 10.8 dB (80- to 89-year-old group) poorer for the older listeners with hearing loss. Neither pure-tone thresholds nor word-recognition abilities in quiet accurately predicted word-recognition performance in multitalker babble.

Acoustic Stimulation↗

PubMed2005

Word recognition in multitalker babble measured with two psychophysical methods.

The purpose of this experiment was to determine the relationship between psychometric functions for words presented in multitalker babble using a descending presentation level protocol and a random presentation level protocol. Forty veterans (mean = 63.5 years) with mild-to-moderate sensorineural hearing losses were enrolled. Seventy of the Northwestern University Auditory Test No. 6 words spoken by the VA female speaker were presented at seven signal-to-babble ratios from 24 to 0 dB (10 words/step). Although the random procedure required 69 sec longer to administer than the descending protocol, there was no significant difference between the results obtained with the two psychophysical methods. There was almost no relation between the perceived ability of the listeners to understand speech in background noise and their measured ability to understand speech in multitalker babble. Likewise, there was a tenuous relation between pure-tone thresholds and performance on the words in babble and between recognition performance in quiet and performance on the words in babble.

Audiometry, Pure-Tone↗

PubMed2005

Speech recognition in multitalker babble using digits, words, and sentences.

The purpose of this mixed model design was to examine recognition performance differences when measuring speech recognition in multitalker babble on listeners with normal hearing (n = 36) and listeners with hearing loss (n = 72) utilizing stimulus of varying linguistic complexity (digits, words, and sentence materials). All listeners were administered two trials of two lists of each material in a descending speech-to-babble ratio. For each of the materials, recognition performances by the listeners with normal hearing were significantly better than the performances by the listeners with hearing loss. The mean separation between groups at the 50% point in signal-to-babble ratio on each of the three materials was approximately 8 dB. The 50% points for digits were obtained at a significantly lower signal-to-babble ratio than for sentences or words that were equivalent. There were no interlist differences between the two lists for the digits and words, but there was a significant disparity between QuickSIN lists for the listeners with hearing loss. A two-item questionnaire was used to obtain a subjective measurement of speech recognition, which showed moderate correlations with objective measures of speech recognition in noise using digits (r = .641), sentences (r = .572), and words (r = .673).

Adolescent↗

PubMed2004

Y chromosome haplogroups of elite Ethiopian endurance runners.

Favourable genetic endowment has been proposed as part of the explanation for the success of East African endurance athletes, but no evidence has yet been presented. The Y chromosome haplogroup distribution of elite Ethiopian athletes (n=62) was compared with that of the general Ethiopian population (n=95) and a control group from Arsi (a region producing a disproportionate number of athletes; n=85). Athletes belonged to three groups: marathon runners (M; n=23), 5-km to 10-km runners (5-10K; n=21) and other track and field athletes (TF; n=18). DNA was extracted from buccal swabs and haplogroups were assigned after the typing of binary markers in multiplexed minisequencing reactions. Frequency differences between groups were assessed by using contingency exact tests and showed that Y chromosome haplogroups are not distributed amongst elite Ethiopian endurance runners in the same proportions as in the general population, with statistically significant (P<0.05) differences being found in four of the individual haplogroups. The geographical origins and languages of the athletes and controls suggest that these differences are less likely to be a reflection of population structure and that Y chromosome haplogroups may play a significant role in determining Ethiopian endurance running success.

Chromosomes, Human, Y↗