Search PubMed⌕ Search

Biomedical subjects

C Bouchard

Publications and source records attributed to C Bouchard.

At least 271 records · Page 15Linked to original sources

Segregation analysis of abdominal visceral fat: the HERITAGE Family Study.

A major gene hypothesis for abdominal visceral fat (AVF) level, both before and after adjustment for total body fat mass, was investigated in 86 white families who participated in the HERITAGE Family Study. In this study, sedentary families were tested for a battery of measures (baseline), endurance exercise trained for 20 weeks, and then remeasured again. The baseline measures reported here are unique in that the variance due to a potentially important environmental factor (activity level) was limited. AVF area was assessed at L4 to L5 by the use of computerized tomography scan, and total body fat mass was assessed with underwater weighing. For fat mass, a putative locus accounted for 64% of the variance, but there was no evidence of a multifactorial component (i.e., no polygenic and/or common familial environmental effects). For AVF area, both a major gene effect accounting for 54% of the variance and a multifactorial component accounting for 17% of the variance were significant. However, after AVF area was adjusted for the effects of total level of body fat, the support for a major gene was reduced. In particular, there was a major effect for fat mass-adjusted AVF area, but it was not transmitted from parents to offspring (i.e., the three transmission probabilities were equal). The importance of this study is twofold. First, these results confirm a previous study that suggested that there is a putative major locus for AVF and for total body fat mass. Second, the findings from the HERITAGE Family Study suggest that the factors underlying AVF area in sedentary families may be similar to those in the population at large, which includes both sedentary and active families. Whether the gene(s) responsible for the high levels of AVF area is the same as that which influences total body fat content remains to be further investigated.

Abdomen↗

Regional variation in adipose tissue insulin action and GLUT4 glucose transporter expression in severely obese premenopausal women.

Insulin action and GLUT4 expression were examined in adipose tissue of severely obese premenopausal women undergoing gastrointestinal surgery. Fat samples were taken from three different anatomical regions: the subcutaneous abdominal site, the round ligament (deep abdominal properitoneal fat), and the greater omentum (deep abdominal intraperitoneal fat). The stimulatory effect of insulin on glucose transport and the ability of the hormone to inhibit lipolysis were determined in adipocytes isolated from these three adipose depots. Insulin stimulated glucose transport 2-3 times over basal rates in all adipocytes. However, round ligament adipose cells showed a significantly greater responsiveness to insulin when compared to subcutaneous and omental adipocytes. Round ligament fat cells also displayed the greatest sensitivity and maximal antilipolytic response to insulin. We also investigated whether regional differences in fat cell insulin-stimulated glucose transport were linked to a differential expression of the GLUT4 glucose transporter. GLUT4 protein content in total membranes was 5 and 2.2 times greater in round ligament adipose tissue than in subcutaneous and omental fat depots, respectively. Moreover, GLUT4 mRNA levels were 2.1 and 3 times higher in round ligament than in subcutaneous or omental adipose tissues, respectively. Adipose tissue GLUT4 protein content was strongly and negatively associated (r = -0.79 to -0.89, p < 0.01) with the waist-to-hip ratio but not with total adiposity. In conclusion, these results demonstrate the existence of site differences in adipose tissue insulin action in morbidly obese women. The greater insulin effect on glucose transport in round ligament adipocytes was associated with a higher expression of GLUT4 when compared to subcutaneous abdominal and omental fat cells. Moreover, despite the regional variation in GLUT4 expression, an increased proportion of abdominal fat was found to be associated with lower levels of GLUT4 in all adipose regions investigated.

Adipocytes↗

Plasma leptin concentrations: gender differences and associations with metabolic risk factors for cardiovascular disease.

The cloning of the obese gene and the characterization of its protein product, leptin, has permitted the study of a new hormone potentially involved in the regulation of adipose tissue mass. The present study examined the gender differences in fasting plasma leptin concentration and its relationship to body fatness, adipose tissue distribution and the metabolic profile in samples of 91 men (mean age +/- SD: 37.3 +/- 4.8 years) and 48 women (38.5 +/- 6.8 years). Plasma leptin concentrations were strongly associated with body fat mass measured by underwater weighing [men: r = 0.80, p < 0.0001; women: r = 0.85, p < 0.0001]. In both genders, plasma leptin levels were also strongly correlated with waist girth as well as cross-sectional areas of abdominal subcutaneous and visceral adipose tissue measured by computed tomography. Women had, on average, plasma leptin concentrations that were three times higher than men. Furthermore, this gender difference remained significant when comparing men and women matched for similar levels of body fat mass. The associations between plasma leptin and lipoprotein concentrations were dependent of adiposity. In both men and women, elevated fasting plasma leptin levels were associated with higher plasma insulin concentrations, but only in women was the association maintained after correction for fat mass. Thus, results of the present study show that women have higher plasma leptin levels compared to men, independent of the concomitant variation in total body fat mass. Furthermore, our results also suggest that, in women, the association between plasma leptin and insulin concentrations is independent of adiposity, a finding which provides further support to the observation that adipose tissue leptin secretion may be upregulated by insulin.

Adipose Tissue↗

Relationships between endogenous steroid hormone, sex hormone-binding globulin and lipoprotein levels in men: contribution of visceral obesity, insulin levels and other metabolic variables.

Excess visceral adipose tissue (AT) and hyperinsulinemia are important correlates of an altered lipoprotein profile. It has also been reported that testosterone, adrenal C19 steroids and sex hormone-binding globulin (SHBG) concentrations are associated with plasma lipoprotein levels. The aim of the present study was to investigate the relative contributions of endogenous steroid hormone and SHBG levels, of visceral AT accumulation measured by computed tomography, and of fasting insulin and free fatty acid (FFA) concentrations to the variation of plasma lipoprotein levels in men. For this purpose, plasma concentrations of testosterone, dehydroepiandrosterone (DHEA), androstene-3beta,17beta-diol (delta5-DIOL), androstenedione (delta4-DIONE), estrone and estradiol, as well as SHBG levels were determined in a sample of 76 men covering a wide range of body fatness values. Higher testosterone levels were associated with a more favorable lipoprotein profile as it showed significant correlations with triglyceride (TG), total cholesterol and LDL-cholesterol (LDL-C) concentrations (r= -0.25, -0.25 and -0.27, respectively; P < 0.05). Higher plasma adrenal C19 steroid levels were also associated with a favorable lipoprotein profile as DHEA, delta4-DIONE and delta5-DIOL levels were negatively correlated with total cholesterol (r = -0.24, -0.33 and -0.24, respectively; P < 0.05) and LDL-C (r = -0.23, -0.31 and -0.28, respectively; P < 0.05). SHBG levels were negatively correlated with TG concentrations (r = -0.33; P < 0.005) whereas delta5-DIOL, testosterone and SHBG were negatively correlated with apolipoprotein B levels (-0.32 < or = r < or = -0.43; P < 0.005). Statistical adjustment for visceral AT area, fasting insulin, fasting free fatty acid (FFA) levels and total body fat mass eliminated most of the correlations between steroid and lipoprotein levels, while SHBG remained significantly correlated with lipoprotein concentrations after such adjustments. Multivariate analyses revealed that SHBG, delta4-DIONE, delta5-DIOL and metabolic variables all contributed to the variance in plasma lipoprotein concentrations (from 10 to 29% of explained variance). Visceral AT, fasting FFA and insulin levels as well as SHBG concentrations appeared to be independent correlates of lipoprotein concentrations. Thus, metabolic and anthropometric variables examined in the present study could have represented important confounding factors in previous studies which have examined the relationship of steroid hormones to plasma lipoprotein concentrations.

Adipose Tissue↗

Relationship between changes in physical activity and plasma insulin during a 2.5-year follow-up study.

The association between changes in physical activity, body weight, and diet and fasting plasma insulin was analyzed in a 2.5-year follow-up study of 146 men aged 50 to 60 years. Physical activity was assessed by a 7-day physical activity recall interview, diet by a 4-day food record, and plasma insulin radioimmunologically. Total physical activity decreased from (mean +/- SD) 45.1 +/- 10.1 to 39.0 +/- 6.1 metabolic equivalent (MET) hours (METh).d-1 and conditioning physical activity (> 5.0 METs) from 8.0 +/- 11.2 to 2.7 +/- 5.0 METh.d-1, whereas plasma insulin increased from 8.2 +/- 5.8 to 9.2 +/- 6.7 mU.L-1 and body weight from 80.5 +/- 12.0 to 81.6 +/- 11.6 kg during the follow-up period (P < or = .001 for all). The change in conditioning physical activity correlated inversely (r = -.34, P < .001) and change in body weight positively (r = .42,P < .001) with the change in plasma insulin level. With data adjusted for the baseline insulin level, cardiovascular health status, alcohol intake, change in body weight, smoking, age, and follow-up time, the odds ratio for an increase in fasting plasma insulin was 8.9 (95% CI, 2.1 to 37.1; P = .003) for men with the greatest decrease in conditioning physical activity (< -7 METh) compared with men who reported an increase in conditioning physical activity. The same logistic regression model showed an odds ratio of 9.9 (95% CI, 2.1 to 45.4; P = .003) for the increase in plasma insulin for subjects who gained more than 3.3 kg body weight compared with subjects who lost at least 0.6 kg. Men who consumed at least 12 g.d-1 alcohol at both examinations had an odds ratio of 12.8 (95% CI, 1.7 to 94.5; P = .012) compared with nondrinkers. These data suggest that in middle-aged men, a reduction in physical activity increases the risk for increased plasma insulin independently of alcohol intake and changes in body weight.

Aging↗

Endurance training with constant energy intake in identical twins: changes over time in energy expenditure and related hormones.

The effects of exercise training and of its interaction with the genotype on components of energy expenditure and related hormones were examined in young male monozygotic twins. Energy intake was maintained at the pretraining level for a 93-day training period. The estimated net energy deficit induced by training was 244 MJ and was associated with a 5-kg body weight loss that was almost entirely explained by body fat loss. Resting metabolic rate (RMR) was significantly decreased by 8% after training despite the preservation of fat-free mass (FFM). Accordingly, plasma norepinephrine (NE) concentrations, NE appearance rate, and plasma levels of triiodothyronine (T3), free T3, and total thyroxine (T4) were lower after training. The energy cost of standardized exercise was also reduced after the training program. A modest to significant within-twin-pair resemblance was observed for absolute changes in the RMR, thermic effect of food, energy cost of exercise, NE clearance, and plasma concentrations of thyroid hormones. These results suggest that when exercise training is associated with a substantial negative energy balance, energy expenditure and levels of related hormones are decreased, and this effect is partly accounted for by heredity.

Adult↗

Fat gain in female swimmers.

The association between diet and body composition was investigated in 6 elite female swimmers subjected to a 13-month nutritional supervision and in 11 female untrained subjects matched for fat-free mass. The impact of a 2-month interruption of training on diet and body composition was also studied in the swimmers. A positive correlation was observed between the percentage of dietary energy as fat and percent body fat in the untrained subjects (r = 0.68, p < 0.05). When values of the swimmers were incorporated in the regression analysis, the correlation coefficient remained the same. Following detraining for 2 months, a 4.8-kg body weight gain, including 4.3 kg fat mass, was observed. The energy equivalent of these morphological changes was 170 MJ and corresponded to about the amount of energy that would have been normally expended during this detraining period. In conclusion, these results suggest that the association between diet and body composition is not altered by exercise training, and that body fat gain occurs in response to detraining, perhaps to promote the restoration of energy and fat balance.

Adolescent↗

Adenovirus-mediated gene transfer to the brain: methodological assessment.

The purpose of this short review is to analyse major advantages and limitations of the adenovirus (Ad), specifically with relevance to its use as a vector for gene transfer to the brain. The characteristics of Ad transduction include: the relative absence of cell type specificity; the limited spatial spread of the virus; and the long-term expression of the transgene. In the central nervous system, in contrast to that which occurs in other organs, Ad transduction in the adult does not systematically provoke cell death. Nevertheless, a proportion of the transduced cells do die, and this represents a conspicuous problem. Mechanisms leading to cell death in the brain may include immune rejection and inflammation-related toxicity, although this would not explain all of the results, and direct toxicity related to either inappropriate preparation or the transduction itself. Taking into account uncertainties concerning the innocuousness of Ad transduction, it may seem unwise to envisage Ad gene therapy for diseases that are not life-threatening and/or benefit from adequate drug or surgical treatments (e.g. Parkinson's disease or epilepsy). Ad vectors may not be easily used either in diseases displaying major immune dysfunction (e.g. multiple sclerosis). In contrast, malignant brain tumors and numerous neurodegenerative diseases (such as Huntington's, Alzheimer's diseases or amyotrophic lateral sclerosis) are directly life-threatening and deprived of any adequate treatment. They may be appropriate targets for Ad-mediated gene therapy, once both the vector and the gene of interest have been defined and optimized.

Adenoviridae↗

In the early stage of major burns, is there a correlation between survival, interleukin-6 levels and oxygen delivery and consumption?

The correlation between haemodynamic and oxymetric parameters, and circulating cytokines has been little studied for the early phase of extensive burns. The aim of this prospective study was to evaluate survival, looking at variations in cardiac index (CI), oxygen delivery (DO2I) and consumption (VO2I) indexed to the body surface area (BSA), and circulating interleukin-6 (IL6) levels in the acute stage of major burns. Over a 12-month period, all patients admitted within 6 h of extensive thermal injury with total burn surface area (TBSA) of over 60 per cent, necessitating standardized resuscitation and mechanical ventilation, were included. Routine intensive care monitoring, including pulmonary and femoral artery catheters, was set up. During the first 3 days post-injury haemodynamic and oxymetric profiles were recorded every 6 h. Circulating IL6 samples were taken within 6 h of admission, then daily (at 24, 48 and 72 h). A comparison of the results in survivors (S) and non-survivors (NS) at those previously determined times was made. Ten consecutive patients were studied. Six patients survived (Age = 33 +/- 10 years; TBSA = 76 +/- 11 per cent) and four died (Age = 40 +/- 14 years; TBSA = 77 +/- 13 per cent). Similar initial hypovolemic profiles were found in both groups. From 24 h, a hyperdynamic status was observed which increased until 72 h. This hyperkinetic evolution was more marked in the survivors (CI: 4.6 +/- 2.0 for NS and 6.9 +/- 1.51 min-1 m-2 for S; SVRI: 2125 +/- 1288 for NS and 918 +/- 232 dyne s cm-5 m2 for S at 72 h). DO2I and VO2I were always higher in the survivors. DO2I and VO2I increased from admission to 72 h in the survivors whereas a significant drop in DO2I and VO2I occurred in the non-survivors at 48 h (DO2I:536 +/- 222 for NS and 1228 +/- 268 ml min-1 m-2 for S; VO2I:120 +/- 50 for NS and 251 +/- 56 ml min-1 m-2 for S (P < 0.01)). Plasma IL6 revealed abnormal values with consistent peaks at 24-48 h in the survivors (respectively 17,411 +/- 24,542 and 10,746 +/- 11,802 pg ml-1) and only moderate peaks in the non-survivors (865 +/- 652 and 912 +/- 485 pg ml-1). Finally, CI, DO2I, VO2I and circulating IL6 were always higher, and SVRI lower, in the survivors than in the non-survivors. The ability to increase DO2 and to optimize VO2 during the 'turning point' of 48 h seems to improve the prognosis of critically burned patients: the role of IL6 in this systemic inflammatory response is discussed.

Adult↗

Reproducibility of the HERITAGE Family Study intervention protocol: drift over time.

PURPOSE: The primary goal of the HERITAGE Family Study was to document the role of the genotype in the response to aerobic exercise training. Toward this end, nuclear families were enrolled in a 20-week exercise training program, with a large variety of tests performed before and after the training. Since study drift has the potential to adversely affect the results, reproducibility and potential bias over six consecutive 4-month periods were examined for selected test. METHODS: Intraclass correlations (ICC), technical errors (TE), coefficients of variation within subject (CV), and means were calculated with use of the pretraining test results for each of the six time periods. To check for homogeneity, hypothesis tests were performed on the intraclass correlations and means. If homogeneity was not found across all six periods, further tests were performed to assess differences between pairs of time periods. RESULTS: There was little evidence for real drifts in reproducibility, with most tests having ICCs of 0.8 or better. Only a few tests showed any change over time, and in no case was there evidence of a systematic drift in mean values. CONCLUSIONS: Overall, the reproducibility of the HERITAGE Family Study tests and assays considered in this paper was found to be very good, with no evidence of any systematic drift over time.

Adolescent↗

Energy and macronutrient balances for humans in a whole body metabolic chamber without control of preceding diet and activity level.

OBJECTIVE: To examine the relationships between 24 h energy and macronutrient balances in a whole body metabolic chamber subsequent to periods when subjects maintained their normal food intake and physical activity levels. SUBJECTS: Thirteen males and 17 females were studied for two 24 h sessions while consuming an estimated isocaloric diet with a food quotient of 0.85. MEASUREMENTS: Energy expenditure and macronutrient oxidation rates were measured twice for 24 h in whole body indirect calorimeter. RESULTS: Positive and significant correlations were evident between energy and lipid balances (r = 0.38, P < 0.05 and r = 0.54, P < 0.01, respectively) and differences between the two sessions for energy and lipid balances were also significantly correlated (r = 0.40, P < 0.05). Accounting for carbohydrate or protein balances improved the strength of each of these associations. CONCLUSION: These results indicate that for subjects in a small but significant positive energy balance, with uncontrolled diet and activity preceding their metabolic chamber sessions, that 24 h energy balance is positively correlated with lipid balance. Accounting for associations between lipid, carbohydrate, protein and energy balances, improved the strength of the association between 24 h lipid and energy balances. The implications of these results are that in these conditions modifications to lipid balance are important for weight maintenance.

Adult↗

Reproducibility of anthropometric and body composition measurements: the HERITAGE Family Study.

OBJECTIVE: To determine the reproducibility of anthropometric and body composition measures using the HERITAGE Family Study protocol. DESIGN: Anthropometric and body composition measures were obtained on three separate days within a 3-wk period at each of the four HERITAGE Clinical Centers. SUBJECTS: Sixty men and women representative of the HERITAGE subject population, 15 from each of four Clinical Centers. MEASUREMENTS: Anthropometric measures included eight skinfolds, three girths and one length; and body composition measures included stature, mass, hydrostatic weight, residual volume, and body density, from which relative fat, fat mass and fat-free mass were estimated. RESULTS: Reproducibility as determined by technical error, coefficient of variation, and intraclass correlations was very high for the total sample. For example, intraclass correlations for the total sample generally ranged from 0.95-0.99 for the anthropometric measures, and from 0.97-1.00 for the body composition measures. The results across Clinical Centers were in close agreement with each other and with the pooled data. CONCLUSIONS: The reproducibility of anthropometric and body composition measures using the HERITAGE Family Study protocol is sufficiently high that it should be possible to detect small changes in any of these measures and to determine the genetic basis of these changes consequent to a 20 wk endurance training program.

Adult↗

Visceral fat in relation to health: is it a major culprit or simply an innocent bystander?

The aim of this review is to look critically at the widely accepted notion that visceral fat accumulation is the main determinant of obesity related diseases. Most of the epidemiological evidence is based on anthropometric indicators of fatness and fat distribution and their implications for visceral fat accumulation may not be unequivocal. In most cross-sectional studies in which visceral fat is associated with the level of risk factors or presence of disease, no adjustment is made for potential confounders. There are potential confounders at different levels of the causal chains linking visceral fat to health. Firstly, there are aspects of body composition or fat depots associated with visceral fat accumulation such as total body fat or total subcutaneous fat. Total and subcutaneous fat are, by themselves, potentially strong determinants for metabolic disturbances and disease. Secondly, there are behavioural factors (for example smoking, alcohol consumption, physical activity, dietary habits) which have been found to be associated with both the amount of visceral fat and health outcomes. Thirdly, there are hormonal mechanisms (adrenal and gonadal steroids as well as growth hormone) which may affect both the accumulation of visceral fat as well as the development of diseases. Finally, even if associations between visceral fat and risk factors or presence of diseases would be firmly established, the causality of the observed associations may not always be easy to interpret. Prospective studies are needed with appropriate control of potential confounding variables. It is concluded that, based on the current evidence, it is difficult to quantify the independent contribution of visceral fat to the development of a variety of chronic diseases.

Adipose Tissue↗

Familial resemblance for abdominal visceral fat: the HERITAGE family study.

OBJECTIVES: Abdominal visceral fat (AVF) is considered a risk factor for diabetes, atherogenic lipid profiles and hypertension. However, little is known about the genetic contribution to AVF as compared to total body fat. DESIGN: AVF was assessed by computerized tomography, and total body fat (fat mass) was assessed by underwater weighing in 86 families participating in the Heritage Family Study. All family members were sedentary at baseline examination. The familial factors underlying the variability in age-adjusted AVF, age-fat mass-adjusted AVF and age-adjusted fat mass, were assessed using a familial correlation model. RESULTS: The maximal heritability (including genetic and familial environmental effects) for AVF was comparable before (47%) and after (48%) adjusting for fat mass, and was 55% for fat mass itself in these sedentary families. Spouse correlations were significant for fat mass and for AVF prior to, but not after, adjustment for fat mass. CONCLUSIONS: These results confirm the only previous study which investigated the familial aggregation of AVF (both in pattern and magnitude), suggesting that the factors underlying AVF in these sedentary families may be similar to those in the population at large. Although both genetic and familial environmental factors probably influence each of fat mass and AVF, there appears to be a predominantly genetic etiology for the visceral component which is independent of total body fat. These findings imply that some individuals are more at risk then others because of an inherited tendency to store abdominal fat viscerally rather than subcutaneously.

Abdomen↗

Time course of training-induced changes in maximal exercise of short duration in men and women.

The purpose of the present study was to test the hypothesis that gender differences are present in the extent and time course of exercise training-induced changes in maximal 10- and 90-s performance test. Thirty-six sedentary subjects (19 women and 17 men) were submitted to 15 weeks of training involving both continuous and interval ergocycle exercise sessions, while 13 other subjects (5 women and 8 men) served as a control group. Maximal power output after 10 s (P10) and 90s (P90) of cycling exercise was measured before and at each 5-week interval of the 15-week training period in both groups. Significant (p < 0.01) training-induced increases in performance were noted after 5 weeks, 10 weeks and 15 weeks of training for P10, and after 5 and 10 weeks for P90 in both genders. P10 and P90 were significantly increased in both genders (about 25% in men and 35% in women) following the 15-week training program and overall absolute increases were not statistically different between men and women. Slight increases (about 5%) in performance tests were observed in control subjects, but only during the first 5-week interval. P10 and P90 of women expressed as a percentage of that of men remained the same throughout the 15-week program. No significant relationship between pre-training values of P10 and their responses to training was found in men and women. In conclusion, results of the present study indicate that women have the same capacity to increase maximal short-term performance in response to training in comparison to men.

Adult↗

The surgical treatment of vulvar vestibulitis syndrome: a follow-up study.

This study evaluated the effectiveness of vestibulectomy in relieving coital pain and improving sexual function in women diagnosed with vulvar vestibulitis. Vulvar vestibulitis syndrome, a chronic, nonspecific inflammation of the vulvar vestibule, probably represents the most frequent subtype of premenopausal dyspareunia. Participants were 38 women who underwent vestibulectomy at a university hospital between 1986 and 1994. Telephone interviews were conducted to assess whether vestibulectomy or other subsequent treatments affected coital pain and sexual functioning. Length of postoperative follow-up ranged from 1.1 to 10 years, with a mean of 3.3 years. Vestibulectomy yielded a positive outcome for 63.2% of the participants and moderate to no improvement for the other 36.8%. The surgery was linked to a significant increase in intercourse frequency for the entire sample and to an increase in oral and manual stimulation for the women with successful surgical outcomes. No other factors were significantly associated with treatment outcome.

Adult↗

Linkage between markers in the vicinity of the uncoupling protein 2 gene and resting metabolic rate in humans.

The recent cloning of a gene that codes for a novel uncoupling protein, UCP2, which is expressed in a wide range of adult human tissues, has raised the possibility that it may be involved in regulation of energy balance. To explore this concept we have investigated potential linkage relationships between three microsatellite markers which encompass the UCP2 gene location on 11q13 with resting metabolic rate (RMR), body mass index, percentage body fat (%FAT) and fat mass (FM) in 640 individuals from 155 pedigrees from the Québec Family Study. Using a linkage analysis strategy based on sibling, avuncular, grandparental and cousin pairs, strong evidence of linkage was found between the marker D11S911 (P = 0.000002) and RMR, with more moderate evidence for D11S916 (P = 0.006) and D11S1321 (P = 0.02). Suggestive evidence of linkage was also observed between D11S1321 and %FAT (P = 0.04) and FM (P = 0.02). It is concluded that the three markers encompassing the UCP2 locus and spanning a 5 cM region on 11q13 are linked to resting energy expenditure in adult humans. The evidence is strong enough to warrant a search for DNA sequence variation in the gene itself.

Adult↗