James Skipworth

The ACE gene and human performance: 12 years on.

Some 12 years ago, a polymorphism of the angiotensin I-converting enzyme (ACE) gene became the first genetic element shown to impact substantially on human physical performance. The renin-angiotensin system (RAS) exists not just as an endocrine regulator, but also within local tissue and cells, where it serves a variety of functions. Functional genetic polymorphic variants have been identified for most components of RAS, of which the best known and studied is a polymorphism of the ACE gene. The ACE insertion/deletion (I/D) polymorphism has been associated with improvements in performance and exercise duration in a variety of populations. The I allele has been consistently demonstrated to be associated with endurance-orientated events, notably, in triathlons. Meanwhile, the D allele is associated with strength- and power-orientated performance, and has been found in significant excess among elite swimmers. Exceptions to these associations do exist, and are discussed.In theory, associations with ACE genotype may be due to functional variants in nearby loci, and/or related genetic polymorphism such as the angiotensin receptor, growth hormone and bradykinin genes. Studies of growth hormone gene variants have not shown significant associations with performance in studies involving both triathletes and military recruits. The angiotensin type-1 receptor has two functional polymorphisms that have not been shown to be associated with performance, although studies of hypoxic ascent have yielded conflicting results. ACE genotype influences bradykinin levels, and a common gene variant in the bradykinin 2 receptor exists. The high kinin activity haplotye has been associated with increased endurance performance at an Olympic level, and similar results of metabolic efficiency have been demonstrated in triathletes.Whilst the ACE genotype is associated with overall performance ability, at a single organ level, the ACE genotype and related polymorphism have significant associations. In cardiac muscle, ACE genotype has associations with left ventricular mass changes in response to stimulus, in both the health and diseased states. The D allele is associated with an exaggerated response to training, and the I allele with the lowest cardiac growth response. In light of the I-allele association with endurance performance, it seems likely that other regulatory mechanisms exist. Similarly in skeletal muscle, the D allele is associated with greater strength gains in response to training, in both healthy individuals and chronic disease states. As in overall performance, those genetic polymorphisms related to the ACE genotype, such as the bradykinin 2 gene, also influence skeletal muscle strength.Finally, the ACE genotype may influence metabolic efficiency, and elite mountaineers have demonstrated an excess of I alleles and I/I genotype frequency in comparison to controls. Interestingly, this was not seen in amateur climbers. Corroboratory evidence exists among high-altitude settlements in both South America and India, where the I allele exists in greater frequency in those who migrated from the lowlands. Unfortunately, if the ACE genotype does influence metabolic efficiency, associations with peak maximal oxygen consumption have yet to be rigorously demonstrated.The ACE genotype is an important but single factor in the determinant of sporting phenotype. Much of the mechanisms underlying this remain unexplored despite 12 years of research.

Genetic Influences in Sport and Physical Performance

The common inheritance of approximately 20 000 genes defines each of us as human. However, substantial variation exists between individual human genomes, including ‘replication’ of gene sequences (copy number variation, tandem repeats), or changes in individual base pairs (mutations if <1% frequency and single nucleotide polymorphisms if >1% frequency). A vast array of human phenotypes (e.g. muscle strength, skeletal structure, tendon elasticity, and heart and lung size) influences sports performance, each itself the result of a complex interaction between a myriad of anatomical, biochemical and physiological systems. This article discusses the role for genetic influences in influencing sporting performance and injury, offering specific exemplars where these are known. Many of these preferable genotypes are uncommon, and their combination even rarer. In theory, the chances of an individual having a perfect sporting genotype are much lower than 1 in 20 million — as the number of associated polymorphisms increase, the odds decrease correspondingly. Many recently discovered polymorphisms that may affect sports performance have been described in animal or other human based models, and have been included in this review if they may apply to athletic populations. Muscle performance is heavily influenced by basal muscle mass and its dynamic response to training. Genetic factors account for approximately 5080%of inter-individual variation in lean body mass, with impacts detected on both training-naive’ muscle mass and its growth response. Several cytokines such as interleukin-6 and -15, cilliary neurotrophic factor and insulin-like growth factor (IGF) have myoanabolic effects. Genotype-associated differences in endocrine function, necessary for normal skeletal muscle growth and function, may also be of significance, with complex interactions existing between thyroxine, growth hormone and the downstream regulators of the anabolic pathways (such as IGF-1 and IGF-2). Almost 200 polymorphisms are known to exist in the vitamin D receptor (VDR) gene. VDR genotype is associated with differences in strength in premenopausal women. VDR expression decreases with age and VDR genotype is associated with fatfree mass and strength in elderly men and women. Muscle fibre type determination is complex. Whilst initial composition is likely to be strongly influenced by genetic factors, training has significant effects on fibre shifts. Polymorphisms of the peroxisome proliferator-activated receptor a (PPARa) gene and R577x polymorphism of the ACTN3 gene are both associated with specific fibre compositions. Alterations in cardiac size have been associated with both increased performance and excess cardiovascular mortality. PPARa is a ligand-activated transcription factor that regulates genes involved in fatty acid uptake and oxidation, lipid metabolism and inflammation. Psychology plays an important role in training, competition, tolerance of pain and motivation. However, the role of genetic variation in determining psychological state and responses remains poorly understood; only recently have specific genes been implicated in motivational behaviour and maintenance of exercise. Thyroid hormone receptors exist within the brain and influence both neurogenesis and behaviour. With the current state of knowledge, the field of genetic influences on sports performance remains in its infancy, despite over a decade of research.

Marathon-induced ischemic colitis: why running is not always good for you

We present the case of a 31 year-old man who presented to the emergency department of University College Hospital London after collapsing upon finishing the London marathon. Contrast-enhanced multidetector computed tomography scanning revealed ischemic colitis of the cecum and ascending colon, which progressed to the development of clinical peritonism after 48 hours. This patient subsequently underwent a laparotomy and right hemicolectomy, with ileostomy formation, on the third day after admission. Operative and histologic findings confirmed ischemic colitis of the cecum and proximal colon. The postoperative recovery was uneventful, and he was discharged home well. Possible mechanisms of ischemia in marathon runners and those undergoing intense exercise include a combination of splanchnic vasoconstriction, dehydration, and hyperthermia, combined with mechanical forces. Most patients presenting with marathon-running-induced ischemic colitis respond to conservative treatment and the need for operative intervention is extremely rare.

Pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis in familial adenomatous polyposis

BACKGROUND Patients with familial adenomatous polyposis (FAP) develop duodenal and ampullary polyps that may progress to malignancy via the adenoma-carcinoma sequence. OBJECTIVE The aim of this study was to review a large series of FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary polyposis. METHODS A retrospective case notes review of all FAP patients undergoing pancreaticoduodenectomy for advanced duodenal and ampullary adenomatosis was performed. RESULTS Between October 1993 and January 2010, 38 FAP patients underwent pancreaticoduodenectomy for advanced duodenal and ampullary polyps. Complications occurred in 29 patients and perioperative mortality in two. Postoperative histology revealed five patients to have preoperatively undetected cancer (R = 0.518, P < 0.001). CONCLUSIONS Pancreaticoduodenectomy in FAP is associated with significant morbidity, but low mortality. All patients under consideration for operative intervention require careful preoperative counselling and optimization.

A Comparison of Woven Versus Nonwoven Polypropylene (PP) and Expanded Versus Condensed Polytetrafluoroethylene (PTFE) on Their Intraperitoneal Incorporation and Adhesion Formation

OBJECTIVE To compare known and novel synthetic materials useful for incisional hernia repair and to test independently, whether they justify common perceptions related to their use. METHODS Four types of synthetic materials were implanted in to 12 pigs to compare incorporation histology and adhesion formation 90 d after placement. Woven polypropylene (WPP), nonwoven polypropylene (NWPP), expanded polytetrafluoroethylene (ePTFE). and condensed polytetrafluoroethylene (cPTFE) were placed intraperitoneally (IP). RESULTS Intraperitoneally, WPP became fully peritonealized, but generated thick and plentiful adhesions. NWPP became fully peritonealized and generated filmy and far less numerous adhesions. ePTFE formed some filmy adhesions and did not peritonealize. cPTFE and WPP became fully peritonealized. However, bowel became adherent on raised edges of cPTFE and WPP. CONCLUSION We conclude that NWPP incorporates extremely well intraperitoneally, promotes few adhesions, and its use is likely to be suitable for hernia repair. cPTFE performs well and promotes few adhesions, but to minimize potentially serious complications, its edges must be secured around its entire circumference.

The role of 18FDG PET/CT in the management of colorectal liver metastases

INTRODUCTION Surgical resection remains the only potentially curative treatment for colorectal liver metastases (CLM). However, involvement of both the hepatic lobes or extrahepatic disease (EHD) can be a contra-indication for resection. The aim of the present study was to examine the addition of combined positron emission and computed tomography (PET/CT) to CLM staging to assess the effects upon staging and management. METHODS All CLM patients referred to a single centre between January 2005 and January 2009 were prospectively included. All underwent routine staging (clinical examination and computed tomography), followed by a whole body (18) fluoro-deoxy-glucose ((18)FDG)-PET/CT scan and Fong clinical risk score calculation. RESULTS Sixty-four patients were included [63% male with a median age of 63 years (age range 32-79 years)]. The addition of PET/CT led to disease upstaging in 20 patients (31%) and downstaging in two patients (3%). EHD was found in 24% of low-risk patients (Fong score 0-2) as compared with 44% of high-risk patients (Fong score 3-5) (P= 0.133). There was a trend towards a greater influence upon management in patients with a low score (44% vs. 17%; P= 0.080). CONCLUSION The addition of PET/CT led to management changes in over one-third of patients but there was no correlation between alterations in staging or management and the Fong clinical risk score; suggesting that PET/CT should be utilized, where available, in the pre-operative staging of CLM patients.

No evidence for a local renin-angiotensin system in liver mitochondria

The circulating, endocrine renin-angiotensin system (RAS) is important to circulatory homeostasis, while ubiquitous tissue and cellular RAS play diverse roles, including metabolic regulation. Indeed, inhibition of RAS is associated with improved cellular oxidative capacity. Recently it has been suggested that an intra-mitochondrial RAS directly impacts on metabolism. Here we sought to rigorously explore this hypothesis. Radiolabelled ligand-binding and unbiased proteomic approaches were applied to purified mitochondrial sub-fractions from rat liver, and the impact of AngII on mitochondrial function assessed. Whilst high-affinity AngII binding sites were found in the mitochondria-associated membrane (MAM) fraction, no RAS components could be detected in purified mitochondria. Moreover, AngII had no effect on the function of isolated mitochondria at physiologically relevant concentrations. We thus found no evidence of endogenous mitochondrial AngII production, and conclude that the effects of AngII on cellular energy metabolism are not mediated through its direct binding to mitochondrial targets.

The Lichfield bone study: the skeletal response to exercise in healthy young men

The skeletal response to short-term exercise training remains poorly described. We thus studied the lower limb skeletal response of 723 Caucasian male army recruits to a 12-wk training regime. Femoral bone volume was assessed using magnetic resonance imaging, bone ultrastructure by quantitative ultrasound (QUS), and bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA) of the hip. Left hip BMD increased with training (mean ± SD: 0.85 ± 3.24, 2.93 ± 4.85, and 1.89 ± 2.85% for femoral neck, Wards area, and total hip, respectively; all P < 0.001). Left calcaneal broadband ultrasound attenuation rose 3.57 ± 0.5% (P < 0.001), and left and right femoral cortical volume by 1.09 ± 4.05 and 0.71 ± 4.05%, respectively (P = 0.0001 and 0.003), largely through the rise in periosteal volume (0.78 ± 3.14 and 0.59 ± 2.58% for right and left, respectively, P < 0.001) with endosteal volumes unchanged. Before training, DXA and QUS measures were independent of limb dominance. However, the dominant femur had higher periosteal (25,991.49 vs. 2,5572 mm(3), P < 0.001), endosteal (6,063.33 vs. 5,983.12 mm(3), P = 0.001), and cortical volumes (19,928 vs. 19,589.56 mm(3), P = 0.001). Changes in DXA, QUS, and magnetic resonance imaging measures were independent of limb dominance. We show, for the first time, that short-term exercise training in young men is associated not only with a rise in human femoral BMD, but also in femoral bone volume, the latter largely through a periosteal response.

The role of 18fluoro‐deoxy glucose combined position emission and computed tomography in the clinical management of anal squamous cell carcinoma

Aim  Anal squamous cell carcinoma (SCC) is uncommon in the western world but continues to increase in incidence. Optimal treatment and outcome are dependent upon pretreatment staging strategies. We evaluate the role of 18fluoro‐deoxyglucose (18FDG) combined position emission and computed tomography (PETCT) in the management of anal SCC.

Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Objective Alcohol-related pancreatitis is associated with a disproportionately large number of hospitalisations among GI disorders. Despite its clinical importance, genetic susceptibility to alcoholic chronic pancreatitis (CP) is poorly characterised. To identify risk genes for alcoholic CP and to evaluate their relevance in non-alcoholic CP, we performed a genome-wide association study and functional characterisation of a new pancreatitis locus. Design 1959 European alcoholic CP patients and population-based controls from the KORA, LIFE and INCIPE studies (n=4708) as well as chronic alcoholics from the GESGA consortium (n=1332) were screened with Illumina technology. For replication, three European cohorts comprising 1650 patients with non-alcoholic CP and 6695 controls originating from the same countries were used. Results We replicated previously reported risk loci CLDN2-MORC4, CTRC, PRSS1-PRSS2 and SPINK1 in alcoholic CP patients. We identified CTRB1-CTRB2 (chymotrypsin B1 and B2) as a new risk locus with lead single-nucleotide polymorphism (SNP) rs8055167 (OR 1.35, 95% CI 1.23 to 1.6). We found that a 16.6 kb inversion in the CTRB1-CTRB2 locus was in linkage disequilibrium with the CP-associated SNPs and was best tagged by rs8048956. The association was replicated in three independent European non-alcoholic CP cohorts of 1650 patients and 6695 controls (OR 1.62, 95% CI 1.42 to 1.86). The inversion changes the expression ratio of the CTRB1 and CTRB2 isoforms and thereby affects protective trypsinogen degradation and ultimately pancreatitis risk. Conclusion An inversion in the CTRB1-CTRB2 locus modifies risk for alcoholic and non-alcoholic CP indicating that common pathomechanisms are involved in these inflammatory disorders.