Swimming-Induced Pulmonary Edema: Pathophysiology and Risk Reduction With Sildenafil.

BACKGROUND: Swimming-induced pulmonary edema (SIPE) occurs during swimming or scuba diving, often in young individuals with no predisposing conditions, and its pathophysiology is poorly understood. This study tested the hypothesis that pulmonary artery and pulmonary artery wedge pressures are higher in SIPE-susceptible individuals during submerged exercise than in the general population and are reduced by sildenafil. METHODS AND RESULTS: Ten study subjects with a history of SIPE (mean age, 41.6 years) and 20 control subjects (mean age, 36.2 years) were instrumented with radial artery and pulmonary artery catheters and performed moderate cycle ergometer exercise for 6 to 7 minutes while submersed in 20°C water. SIPE-susceptible subjects repeated the exercise 150 minutes after oral administration of 50 mg sildenafil. Work rate and mean arterial pressure during exercise were similar in controls and SIPE-susceptible subjects. Average o2 and cardiac output in controls and SIPE-susceptible subjects were: o2 2.42 L·min(-1) versus 1.95 L·min(-1), P=0.2; and cardiac output 17.9 L·min(-1) versus 13.8 L·min(-1), P=0.01. Accounting for differences in cardiac output between groups, mean pulmonary artery pressure at cardiac output=13.8 L·min(-1) was 22.5 mm Hg in controls versus 34.0 mm Hg in SIPE-susceptible subjects (P=0.004), and the corresponding pulmonary artery wedge pressure was 11.0 mm Hg versus 18.8 mm Hg (P=0.028). After sildenafil, there were no statistically significant differences in mean pulmonary artery pressure or pulmonary artery wedge pressure between SIPE-susceptible subjects and controls. CONCLUSIONS: These observations confirm that SIPE is a form of hemodynamic pulmonary edema. The reduction in pulmonary vascular pressures after sildenafil with no adverse effect on exercise hemodynamics suggests that it may be useful in SIPE prevention. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00815646.

Hypercapnia in diving: a review of CO2 retention in submersed exercise at depth.

Carbon dioxide (CO2) retention, or hypercapnia, is a known risk of diving that can cause mental and physical impairments leading to life-threatening accidents. Often, such accidents occur due to elevated inspired carbon dioxide. For instance, in cases of CO2 elimination system failures during rebreather dives, elevated inspired partial pressure of carbon dioxide (PCO2) can rapidly lead to dangerous levels of hypercapnia. Elevations in PaCO2 (arterial pressure of PCO2) can also occur in divers without a change in inspired PCO2. In such cases, hypercapnia occurs due to alveolar hypoventilation. Several factors of the dive environment contribute to this effect through changes in minute ventilation and dead space. Predominantly, minute ventilation is reduced in diving due to changes in respiratory load and associated changes in respiratory control. Minute ventilation is further reduced by hyperoxic attenuation of chemosensitivity. Physiologic dead space is also increased due to elevated breathing gas density and to hyperoxia. The Haldane effect, a reduction in CO2 solubility in blood due to hyperoxia, may contribute indirectly to hypercapnia through an increase in mixed venous PCO2. In some individuals, low ventilatory response to hypercapnia may also contribute to carbon dioxide retention. This review outlines what is currently known about hypercapnia in diving, including its measurement, cause, mental and physical effects, and areas for future study.

The HO-1/CO system regulates mitochondrial-capillary density relationships in human skeletal muscle.

The heme oxygenase-1 (HO-1)/carbon monoxide (CO) system induces mitochondrial biogenesis, but its biological impact in human skeletal muscle is uncertain. The enzyme system generates CO, which stimulates mitochondrial proliferation in normal muscle. Here we examined whether CO breathing can be used to produce a coordinated metabolic and vascular response in human skeletal muscle. In 19 healthy subjects, we performed vastus lateralis muscle biopsies and tested one-legged maximal O2 uptake (V̇o2max) before and after breathing air or CO (200 ppm) for 1 h daily for 5 days. In response to CO, there was robust HO-1 induction along with increased mRNA levels for nuclear-encoded mitochondrial transcription factor A (Tfam), cytochrome c, cytochrome oxidase subunit IV (COX IV), and mitochondrial-encoded COX I and NADH dehydrogenase subunit 1 (NDI). CO breathing did not increase V̇o2max (1.96 ± 0.51 pre-CO, 1.87 ± 0.50 post-CO l/min; P = not significant) but did increase muscle citrate synthase, mitochondrial density (139.0 ± 34.9 pre-CO, 219.0 ± 36.2 post-CO; no. of mitochondrial profiles/field), myoglobin content and glucose transporter (GLUT4) protein level and led to GLUT4 localization to the myocyte membrane, all consistent with expansion of the tissue O2 transport system. These responses were attended by increased cluster of differentiation 31 (CD31)-positive muscle capillaries (1.78 ± 0.16 pre-CO, 2.37 ± 0.59 post-CO; capillaries/muscle fiber), implying the enrichment of microvascular O2 reserve. The findings support that induction of the HO-1/CO system by CO not only improves muscle mitochondrial density, but regulates myoglobin content, GLUT4 localization, and capillarity in accordance with current concepts of skeletal muscle plasticity.

Economic impact of a genetic test for cisplatin-induced ototoxicity.

Cisplatin is a widely used chemotherapy drug in the treatment of pediatric solid tumors, but it is associated with significant rates of ototoxicity (medication-induced hearing loss). A genetic test has recently been developed that can help predict the likelihood that a cisplatin-treated pediatric patient will develop ototoxicity. This study estimates the potential economic impact of this test. Assuming that an alternative, non-preferred, medication to cisplatin exists that it is as efficacious as cisplatin but without the risk of hearing loss, and that the alternative treatment is no more expensive than current practice, we have estimated that administering this genetic test to every pediatric cancer patient for whom cisplatin is first-line therapy could potentially avoid an average of $71,168 in societal costs per tested patient. This translates into a potential present value savings of over $2.4 million annually in British Columbia and over $19.6 million in Canada.

Challenges for Emergent Combined Cesarean Delivery and Type A Aortic Dissection Repair Including Bleeding Management in the Setting of Full Heparinization: A Case Report.

Type A aortic dissection is rare in young females; however, it is associated with a high mortality rate. This case report describes a 30-year-old female at 38 weeks of gestation who presented with acute onset chest pain and hypotension responsive to intravenous fluid therapy. Transthoracic echocardiogram and chest computed tomography angiography confirmed a type A aortic dissection. The patient was transported urgently to the operating room for a Cesarean section and aortic dissection repair. Following induction of general anesthesia, the baby was delivered, oxytocin infusion was started, and a Bakri balloon was placed in the uterus. On cardiopulmonary bypass with circulatory arrest, the ascending aorta and aortic valve were repaired. Multiple uterotonic agents were required intraoperatively to manage persistent uterine bleeding in the setting of full heparinization. Both mother and baby survived without major complications. Preoperative management should focus on maternal hemodynamic control while completing a diagnostic evaluation. Intraoperative considerations include minimizing fetal exposure to medication, maintaining hemodynamic stability, and managing intraoperative blood loss in the setting of full anticoagulation.

National trends and practices in breast MRI.

OBJECTIVE: The objective of our study was to report on the current practices of radiologists involved in the performance and interpretation of breast MRI in the United States. MATERIALS AND METHODS: We invited the 1,696 active physician members of the Society of Breast Imaging to participate in a survey addressing whether and how they performed and interpreted breast MRI. Respondents were asked to select one member of their practice to complete the survey. A total of 754 surveys were completed. Every respondent did not reply to every question. RESULTS: Contrast-enhanced breast MRI was offered at 557 of 754 (73.8%) practices. Of these, 346 of 553 (62.6%) performed at least five breast MRI examinations per week, and only 56 of 553 (10.1%) performed > 20 per week. Radiologists qualified under the Mammography Quality Standards Act supervised the performance of and interpreted breast MRI in the majority of facilities. Of 552 respondents, breast MRI was interpreted as soft copy with computer-aided detection (CAD) in 280 practices (50.7%), as soft copy without CAD in 261 (47.3%), and as hard copy in 11 (2.0%). Of 551 respondents, 256 (46.5%) never and 207 (37.6%) rarely interpreted breast MRI without correlating mammography or sonography findings. The majority of respondents never (269/561, 48.0%) or rarely (165/561, 29.4%) interpreted breast MRI performed at an outside facility. Screening breast MRI was offered at 359 of 561 (64.0%) practices. Of the practices performing contrast-enhanced examinations, 173 of 557 (31.1%) did not perform MRI-guided interventional procedures. CONCLUSION: Contrast-enhanced breast MRI is now widely used in the United States. The information gained from this survey should provide reasonable approaches for the development of professional practice guidelines.

DNA variation in the genes of the Na,K-adenosine triphosphatase and its relation with resting metabolic rate, respiratory quotient, and body fat.

The aim of this study was to investigate in 261 subjects from 58 families the association between DNA variation at the genes coding for the Na,K-ATPase peptides and resting metabolic rate (RMR), respiratory quotient (RQ), and percent body fat (%FAT). Five restriction fragment length polymorphisms (RFLP) at three Na,K-ATPase genes were determined: one at the alpha 1 locus (BglII), and two at the beta locus (beta MspI and beta PvuII). Haplotypes were determined from the two variable sites of the alpha 2 gene (alpha 2 haplotypes) and the beta gene (beta haplotypes). There was a strong trend for %FAT to be related to the RFLP generated by BglII at the alpha 2 exons 21-22 in males (P = 0.06) and females (P = 0.05). RQ was (a) associated with the BglII RFLP at the alpha 2 exon 1 (P = 0.02) and with the alpha 2 8.0 kb/4.3 kb haplotype (P = 0.04) and (b) linked with the beta gene MspI marker (P = 0.04) and with the beta 5.3 kb/5.1 kb haplotype (P = 0.008) based on sib-pair analysis. The present study suggests that the genes encoding Na,K-ATPase may be associated or linked with RQ and perhaps with %FAT but not with RMR.

The Trp64Arg mutation of the beta3 adrenergic receptor gene has no effect on obesity phenotypes in the Québec Family Study and Swedish Obese Subjects cohorts.

The beta adrenergic system plays a key role in regulating energy balance through the stimulation of both thermogenesis and lipid mobilization in brown and white adipose tissues in human and various animal models. Recent studies have suggested that a missense Trp64Arg mutation in the beta3 adrenergic receptor (ADRB3) gene was involved in obesity and insulin resistance. We have investigated the effect of this mutation on obesity-related phenotypes in two cohorts: the Québec Family Study (QFS) and the Swedish Obese Subjects (SOS). In QFS, no association was found between this mutation and body mass index (BMI), body fat including abdominal visceral fat, resting metabolic rate, various diabetes and cardiovascular risk factors, and changes in body weight and body fat over a 12-yr period. With the exception of RMR (P = 0.04), no evidence of linkage was detected between the mutation and phenotypes of QFS based on sib-pair data. In SOS, the frequency of the Trp64Arg allele was not significantly different between nonobese and obese female subjects and no association was found between the mutation and body weight gain over time. These findings do not support the view that there is an association between the Trp64Arg mutation in the ADRB3 gene and obesity.

Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.

Chromosomal synteny between the mouse model and humans was used to map a gene for the complex trait of obesity. Analysis of NZB/BINJ x SM/J intercross mice located a quantitative trait locus (QTL) for obesity on distal mouse chromosome 2, in a region syntenic with a large region of human chromosome 20, showing linkage to percent body fat (likelihood of the odds [LOD] score 3.6) and fat mass (LOD score 4.3). The QTL was confirmed in a congenic mouse strain. To test whether the QTL contributes to human obesity, we studied linkage between markers located within a 52-cM region extending from 20p12 to 20q13.3 and measures of obesity in 650 French Canadian subjects from 152 pedigrees participating in the Quebec Family Study. Sib-pair analysis based on a maximum of 258 sib pairs revealed suggestive linkages between the percentage of body fat (P < 0.004), body mass index (P < 0.008), and fasting insulin (P < 0.0005) and a locus extending approximately from ADA (the adenosine deaminase gene) to MC3R (the melanocortin 3 receptor gene). These data provide evidence that a locus on human chromosome 20q contributes to body fat and insulin in a human population, and demonstrate the utility of using interspecies syntenic relationships to find relevant disease loci in humans.

Sildenafil: Possible Prophylaxis against Swimming-induced Pulmonary Edema.

Swimming-induced pulmonary edema (SIPE) occurs during swimming and scuba diving, usually in cold water, in susceptible healthy individuals, especially military recruits and triathletes. We have previously demonstrated that pulmonary artery (PA) pressure and PA wedge pressure are higher during immersed exercise in SIPE-susceptible individuals versus controls, confirming that SIPE is a form of hemodynamic pulmonary edema. Oral sildenafil 50 mg 1 h before immersed exercise reduced PA pressure and PA wedge pressure, suggesting that sildenafil may prevent SIPE. We present a case of a 46-yr-old female ultratriathlete with a history of at least five SIPE episodes. During a study of an exercise submerged in 20°C water, physiological parameters before and after sildenafil 50 mg orally were as follows: O2 consumption 1.75, 1.76 L·min; HR 129, 135 bpm; arterial pressure 189/88 (mean 121.5), 172/85 (mean 114.3) mm Hg; mean PA pressure 35.3, 28.8 mm Hg; and PA wedge pressure 25.3, 19.7 mm Hg. She has had no recurrences during 20 subsequent triathlons while taking 50 mg sildenafil before each swim. This case supports sildenafil as an effective prophylactic agent against SIPE during competitive surface swimming.

Deaths in triathletes: immersion pulmonary oedema as a possible cause.

BACKGROUND/AIM: To address the question as to whether immersion pulmonary oedema (IPO) may be a common cause of death in triathlons, markers of swimming-induced pulmonary oedema (SIPO) susceptibility were sought in triathletes' postmortem examinations. METHODS: Deaths while training for or during triathlon events in the USA and Canada from October 2008 to November 2015 were identified, and postmortem reports requested. We assessed obvious causes of death; the prevalence of left ventricular hypertrophy (LVH); comparison with healthy triathletes. RESULTS: We identified 58 deaths during the time period of the review, 42 (72.4%) of which occurred during a swim. Of these, 23 postmortem reports were obtained. Five individuals had significant (≥70%) coronary artery narrowing; one each had coronary stents; retroperitoneal haemorrhage; or aortic dissection. 9 of 20 (45%) with reported heart mass exceeded 95th centile values. LV free wall and septal thickness were reported in 14 and 9 cases, respectively; of these, 6 (42.9%) and 4 (44.4%) cases exceeded normal values. 6 of 15 individuals (40%) without an obvious cause of death had excessive heart mass. The proportion of individuals with LVH exceeded the prevalence in the general triathlete population. CONCLUSIONS: LVH-a marker of SIPO susceptibility-was present in a greater than the expected proportion of triathletes who died during the swim portion. We propose that IPO may be a significant aetiology of death during the swimming phase in triathletes. The importance of testing for LVH in triathletes as a predictor of adverse outcomes should be explored further.

Failure rate and complications associated with the use of spinal catheters for the management of inadvertent dural puncture in the parturient: a retrospective comparison with re-sited epidural catheters.

Objective To report on the failure rate of spinal catheters placed following inadvertent dural puncture (IDP) compared with re-sited epidural catheters in the obstetric population. Research design and methods Patients who experienced IDP during epidural or combined spinal epidural placement with 17 or 18 gauge Tuohy needles for labor analgesia between 2003 and 2014 were identified using our post-dural puncture headache (PDPH) database. Patients were categorized into two groups: those who had spinal catheters inserted and those who had epidural catheters re-sited. Main outcome measure Failure rate associated with spinal or re-sited epidural catheters (defined as need for repeat block or alternative analgesic modality). Secondary outcomes were incidence of PDPH, need for epidural blood patch (EBP), and adverse events. Results A total of 109 patients were included in the final analysis; 79 ultimately had spinal catheters and 30 ultimately had re-sited epidural catheters. There were no differences between spinal catheters and re-sited epidural catheters in failure rate (22% vs. 13%, P = 0.33), incidence of PDPH (73% vs. 60%, P = 0.24), need for EBP (42% vs. 30%, P = 0.28), number of headache days, or maximum headache scores. There was also no difference in the rate of adverse events including high block levels, hypotension, and fetal bradycardia (9% vs. 7%, P = 1.0) between the two groups. Conclusions There were no differences in failure rates, PDPH outcomes, or adverse events between spinal catheters and re-sited epidural catheters following IDP in parturients receiving labor analgesia. Limitations of the study include its single-center retrospective non-randomized design, and the uneven number of patients in the two groups with a relatively small number in the re-sited epidural catheter group.

The apoB-100 gene EcoRI polymorphism influences the relationship between features of the insulin resistance syndrome and the hyper-apoB and dense LDL phenotype in men.

The aim of this study was to investigate whether the EcoRI polymorphism of the apolipoprotein B (apoB) gene influences the relationships between features of the insulin resistance syndrome and the dense LDL phenotype and apoB concentrations. A sample of 65 men was divided into two groups on the basis of the EcoRI genotype. Forty-four subjects were (+/+) homozygotes for the presence of the EcoRI restriction site that is associated with a glutamic acid at codon 4154. Twenty-one men were (+/-) heterozygotes for the absence of the restriction site resulting from a glutamic acid to a lysine substitution at codon 4154. In the (+/-) group, fasting plasma FFA levels were positively correlated with plasma apoB, LDL-apoB, and the LDL particle score that was calculated from the migration distances of LDL subspecies and their relative band intensities, reflecting the proportion of small dense LDL particles. However, these associations were not found among (+/+) subjects. The two genotypic groups were further divided into two subgroups on the basis of fasting FFA concentrations, and the LDL particle score and the LDL-apoB levels were compared. High FFA levels were associated with a higher proportion of small dense LDL particles, as reflected by a higher mean LDL particle score, irrespective of the genotype. However, the apoB-EcoRI polymorphism appeared to influence the association between high FFA levels and LDL-apoB concentrations because (+/-) heterozygotes with high FFA levels had higher LDL-apoB concentrations than (+/-) heterozygotes with low FFA levels. In addition, the integrated area under the curve of plasma insulin concentrations, measured in response to a 75-g oral glucose challenge, and the amount of visceral adipose tissue, measured by computed tomography, were positively associated with the LDL particle score only in (+/-) heterozygotes. When subjects were divided on the basis of insulin area (low vs. high) or visceral adipose tissue (low vs. high), (+/-) heterozygotes with high insulin area or with high levels of visceral adipose tissue had a higher mean LDL particle score than (+/-) heterozygotes with low insulin area or low visceral adipose tissue. However, among (+/+) homozygotes, low or high levels of insulin or visceral adipose tissue could not discriminate between men with large or small LDL particles. Therefore, (+/-) heterozygotes may be more susceptible to develop the dense LDL phenotype in presence of hyperinsulinemia and visceral obesity. Results of the present study suggest that the apoB-EcoRI polymorphism may exacerbate the alterations in the LDL particle (size and concentration) found among visceral obese-hyperinsulinemic men.

Immersion pulmonary edema and comorbidities: case series and updated review.

PURPOSE: Immersion pulmonary edema (IPE) occurs in swimmers (especially triathletes) and scuba divers. Its pathophysiology and risk factors are incompletely understood. This study was designed to establish the prevalence of preexisting comorbidities in individuals who experience IPE. METHODS: From 2008 to May 2010, individuals who had experienced IPE were identified via recruitment for a physiological study. Past medical history and subject characteristics were compared with those available in the current body of literature. RESULTS: At Duke University Medical Center, Durham, NC, 36 subjects were identified (mean age = 50.11 ± 10.8 yr), of whom 72.2% had one or more significant medical conditions at the time of IPE incident (e.g., hypertension, cardiac dysrhythmias or structural abnormality or dysfunction, asthma, diabetes mellitus, overweight or obesity, obstructive sleep apnea, hypothyroidism). Forty-five articles were included, containing 292 cases of IPE, of which 24.0% had identifiable cardiopulmonary risk factors. Within the recreational population, cases with identifiable risk factors comprised 44.9%. Mean age was 47.8 ± 11.3 yr in recreational divers/swimmers and 23.3 ± 6.4 yr in military divers/swimmers. CONCLUSIONS: Cardiopulmonary disease may be a common predisposing factor in IPE in the recreational swimming/diving population, whereas pulmonary hypertension due to extreme exertion may be more important in military cases. Individuals with past history of IPE in our case series had a greater proportion of comorbidities compared to published cases. The role of underlying cardiopulmonary dysfunction may be underestimated, especially in older swimmers and divers. We conclude that an episode of IPE should prompt the evaluation of cardiac and pulmonary function.

Progestin binding in testes from three siblings with the syndrome of male pseudohermaphroditism with testicular feminization.

We have found a specific binding protein for synthetic progestins 6,7-[3H]methyltrienolone (R1881) and 17,21-dimethyl-19-norpregna-4,9-diene-3,20-dione (R5020) and in the testis cytosol from three "sisters" with the complete form of the testicular feminization syndrome. The binding component sediments in the 8S region of sucrose gradients. It is saturable. The apparent affinity constant (Ka) for R5020 was determined in two cases and found to be 1.8 and 0.6 X 10(8) M-1. The number of binding sites calculated from Scatchard plots is relatively high: 572 and 826 fmol/mg protein. Competition studies indicate that this putative receptor is specific for natural and synthetic progestins but not for 5 alpha-dihydrotestosterone and cortisol. Similar progestin binding could not be found in normal human and rat testes.

Induction of acid phosphatase synthesis in canine prostatic epithelial cells in vitro.

The increase in acid phosphatase (AP) activity in cultured canine prostatic epithelial cells was investigated as a biochemical marker of in vitro cellular differentiation. The enzyme was studied in secretory and non-secretory epithelial cell populations obtained from control and cycloheximide-treated cultures over a period of 3 weeks and compared to the AP present in tissue and cellular extracts from normal canine prostates. The progressive increase in AP activity with the duration of culture was strongly inhibited by cycloheximide in both cell populations. The degree of inhibition was more pronounced late in the culture when AP activity increased at a faster rate in secretory cells. Cycloheximide inhibited protein biosynthesis by 70-80% as evidenced by a reduction in the incorporation of amino acids into acid-insoluble material. However, the specific activities of AP in the cellular extracts were similar in control and cycloheximide-treated cultures and increased sharply by 3-4-fold in the secretory cells after 12 days of culture. When extracts derived from control and cycloheximide-treated cells of various duration were submitted to electrophoresis in polyacrylamide gels (PAGE), a unique pattern of three bands of AP activity with Rf values of 0.18, 0.27 and 0.38 was obtained. In controls the AP activity in the band with an Rf of 0.18 increased preferentially during the culture period and was more important quantitatively in secretory cells. In cycloheximide-treated cultures the increase of AP activity associated with the band with an Rf of 0.18 was more strongly inhibited. The addition of tartrate to the staining mixture inhibited all three bands of AP activity. Similar results were obtained when extracts derived from freshly dispersed cells as well as from normal canine prostatic tissue were submitted to PAGE; the AP activity was resolved into 3 bands with Rf values of 0.15-0.18, 0.23-0.27 and 0.33-0.38; all three bands were inhibited by the addition of tartrate and the first band was predominant. Thus, the increase in AP activity in prostatic epithelial cells in a culture medium supplemented with serum and deprived of sex steroids is due to the de novo synthesis of a major form of the enzyme by the secretory cells.

Mitochondrial DNA sequence polymorphism, VO2max, and response to endurance training.

Mitochondrial DNA sequence variation was determined in 46 sedentary young adult males who took part in ergocycle endurance training programs in two laboratories to assess whether mitochondrial DNA variants were associated with individual differences in maximal oxygen uptake (VO2max) and its response to training. VO2max was obtained from a progressive ergocycle test to exhaustion. White blood cell mitochondrial DNA was characterized with the restriction fragment length polymorphism (RFLP) technique using 22 restriction enzymes and human mitochondrial DNA as a probe for hybridization. Multiple mitochondrial DNA variants were detected with 15 of the enzymes. Some subjects exhibited many RFLPs, while others showed no variation. These RFLPs (morphs) were generated by base substitutions located in gene regions coding for mitochondrial proteins as well as in the noncoding regions. Carriers of three mitochondrial DNA morphs, two in the subunit 5 of the NADH dehydrogenase gene and one in the tRNA for threonine, had a VO2max (ml.kg-1.min-1) in the untrained state significantly higher than noncarriers, while carriers of one mitochondrial DNA morph in subunit 2 of NADH dehydrogenase had a lower initial VO2max. Endurance training increased VO2max by a mean of 0.51 of O2, with individual differences ranging from gains of 0.06 to 1.03. After adjustment for training site and initial VO2max, a lower response was observed for three carriers of a variant in subunit 5 of the NADH dehydrogenase detected with HincII (mean gain of 0.28 I; P less than 0.05). These results suggest that sequence variation in mitochondrial DNA may contribute to individual difference in VO2max and its response to training.

Mitochondrial DNA sequence polymorphism, VO2max, and response to endurance training.

Mitochondrial DNA sequence variation was determined in 46 sedentary young adult males who took part in ergocycle endurance training programs in two laboratories to assess whether mitochondrial DNA variants were associated with individual differences in maximal oxygen uptake (VO2max) and its response to training. VO2max was obtained from a progressive ergocycle test to exhaustion. White blood cell mitochondrial DNA was characterized with the restriction fragment length polymorphism (RFLP) technique using 22 restriction enzymes and human mitochondrial DNA as a probe for hybridization. Multiple mitochondrial DNA variants were detected with 15 of the enzymes. Some subjects exhibited many RFLPs, while others showed no variation. These RFLPs (morphs) were generated by base substitutions located in gene regions coding for mitochondrial proteins as well as in the noncoding regions. Carriers of three mitochondrial DNA morphs, two in the subunit 5 of the NADH dehydrogenase gene and one in the tRNA for threonine, had a VO2max (ml.kg-1.min-1) in the untrained state significantly higher than noncarriers, while carriers of one mitochondrial DNA morph in subunit 2 of NADH dehydrogenase had a lower initial VO2max. Endurance training increased VO2max by a mean of 0.5 l of O2, with individual differences ranging from gains of 0.06 to 1.03. After adjustment for training site and initial VO2max, a lower response was observed for three carriers of a variant in subunit 5 of the NADH dehydrogenase detected with HincII (mean gain of 0.28 l; P < 0.05). These results suggest that sequence variation in mitochondrial DNA may contribute to individual difference in VO2max and its response to training.

A polymorphism in the alpha2a-adrenoceptor gene and endurance athlete status.

PURPOSE: In a case control study, we examined the allelic frequencies and genotype distributions of two restricted fragment length polymorphisms (RFLP) in the alpha-2A-adrenoceptor gene (ADRA2A) and beta-2-adrenoceptor gene (ADRB2) among elite endurance athletes (EEA) and sedentary controls (SC). METHODS: The EEA group included 148 Caucasian male subjects recruited on the basis that they had a VO2max > 74 mL O2 x kg(-1) x min(-1). The SC group comprised 149 unrelated sedentary male subjects, all Caucasians, from the Quebec Family Study. After digestion with the restriction enzymes Dra I (ADRA2A) and Ban I (ADRB2), Southern blotting and hybridization techniques were used to detect the mutations in the two ADR genes, which are encoded on chromosomes 10 (q24-26) and 5 (q31-32), respectively. RESULTS: For the Dra I ADRA2A RFLP, we observed a significant difference in genotype distributions between the two groups (P = 0.037). A higher frequency of the 6.7-kb allele was observed in the EEA group compared with the SC group (P = 0.013). No statistically significant difference was found between groups for the Ban I ADRB2 polymorphic site. Genotype frequencies for both genes in both groups were in Hardy-Weinberg equilibrium. CONCLUSIONS: In summary, we found evidence that ADRA2A gene variability detected with Dra I is weakly associated with elite endurance athlete status, and we conclude that genetic variation in the ADRA2A gene or a locus in close proximity may play a role in being able to sustain the endurance training regimen necessary to attain a high level of maximal aerobic power.

Muscle-specific creatine kinase gene polymorphisms in elite endurance athletes and sedentary controls.

The purpose of this study was to investigate the association between elite endurance athlete (EEA) status and two restriction fragment length polymorphisms (RFLPs) at the muscle-specific creatine kinase (CKMM) gene locus. Genomic DNA was extracted from white blood cells or lymphoblastoid cell lines of 124 unrelated Caucasian male EEA (VO2max > 73 mL.kg-1.min-1) and 115 unrelated Caucasian sedentary male controls (SCON). The genetic polymorphism at the CKMM locus was detected by the polymerase chain reaction and DNA digestion with the NcoI and TaqI restriction endonucleases. The allelic frequencies for the NcoI and TaqI RFLPs were not different (P > 0.05) between EEA and SCON subjects. The three expected genotypes for CKMM-NcoI (1170/1170 bp, 1170/985 + 185 bp, and 985 + 185/985 + 185 bp) and CKMM-TaqI (1170/1170 bp, 1170/1020 + 150 bp, and 1020 + 50/1020 + 150 bp) were observed in the EEA and SCON groups. These genotype frequencies were in Hardy-Weinberg equilibrium, but they were not significantly (P > 0.05) different between the EEA and SCON. A strong (P < 0.001) linkage disequilibrium was detected among the NcoI and TaqI RFLPs in both EEA and SCON. These findings indicate that the skeletal muscle CK-NcoI and CK-TaqI gene polymorphisms are not associated with the elite endurance athlete status.