Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.

Mitochondrial uncoupling proteins regulate angiotensin-converting enzyme expression: crosstalk between cellular and endocrine metabolic regulators suggested by RNA interference and genetic studies.

Uncoupling proteins (UCPs) regulate mitochondrial function, and thus cellular metabolism. Angiotensin-converting enzyme (ACE) is the central component of endocrine and local tissue renin-angiotensin systems (RAS), which also regulate diverse aspects of whole-body metabolism and mitochondrial function (partly through altering mitochondrial UCP expression). We show that ACE expression also appears to be regulated by mitochondrial UCPs. In genetic analysis of two unrelated populations (healthy young UK men and Scandinavian diabetic patients) serum ACE (sACE) activity was significantly higher amongst UCP3-55C (rather than T) and UCP2 I (rather than D) allele carriers. RNA interference against UCP2 in human umbilical vein endothelial cells reduced UCP2 mRNA sixfold (P < 0·01) whilst increasing ACE expression within a physiological range (<1·8-fold at 48 h; P < 0·01). Our findings suggest novel hypotheses. Firstly, cellular feedback regulation may occur between UCPs and ACE. Secondly, cellular UCP regulation of sACE suggests a novel means of crosstalk between (and mutual regulation of) cellular and endocrine metabolism. This might partly explain the reduced risk of developing diabetes and metabolic syndrome with RAS antagonists and offer insight into the origins of cardiovascular disease in which UCPs and ACE both play a role.

Review of cases of IgA nephropathy.

OBJECTIVES: A review of 26 years of British military renal pathology showed the commonest diagnosis to be immunoglobulin A (IgA) nephropathy affecting 115/346 (33%) of cases. It was possible to follow-up 50/115 military patients with this condition with the primary objective to determine whether initial observations enabled a confident prediction of prognosis. Additionally, unpublished observations have shown that the incidence of glomerulonephritis in an Indo-Asian British military racial group was fourfold that in the majority Caucasians although the nature of pathology (IgA vs non-IgA nephropathy) was not statistically significantly different. The present study secondarily sought to determine if prognosis of IgA nephropathy was different in this Indo-Asian military group. Finally, some conclusions concerning the traditionally restrictive policy towards applicants for military service with evidence of active nephritis were attempted. METHODS: An archive of military renal patients covering 1985-2011 was reviewed and clinical details of cases of IgA nephropathy were extracted and analysed. RESULTS: 95 cases (80 Caucasian, 15 Indo-Asian) were reviewed. There was no racial difference (p=0.2) in initial median estimated glomerular filtration rate (eGFR, 86 vs 83 ml/min/1.73 m(2)). Altogether, initial median of mean arterial pressure (MAP) was 96 mm Hg (IQR=87-103) and median proteinuria was 485 mg/24 h (IQR=195-925). There was an inverse correlation between initial eGFR and both MAP (p=0.0008) and proteinuria (p=0.0006). In the 50 patients who were followed up, the change in eGFR with time (ΔeGFR) was calculated. 10 of the 44 Caucasians and 3/6 Indo-Asians showed significant changes in eGFR but population proportions were not significantly different (p=0.2). Altogether, 11/50 (22%) showed deteriorating eGFR despite therapeutic interventions, compared with those without deterioration; this was not due to different duration of observation (p=0.08), initial MAP (p=0.23) or initial proteinuria (p=0.07). There was no statistically significant correlation between ΔeGFR and initial MAP (p=0.6) or proteinuria (p=0.7). CONCLUSIONS: The proportion of military cases of IgA nephropathy with deteriorating renal function (22%) was not different from that described in civilians, suggesting that military medical management (including operational restriction where necessary) was appropriate. Initial clinical observations, including racial group, did not permit confident prediction of prognosis thus mandating follow-up for all military cases. Relaxing current enlistment policy would be inadvisable given the inability to confidently predict prognosis in individual cases.

Renal function after trauma.

OBJECTIVE: The lack of need for immediate renal replacement treatment for military trauma victims suggests that the current policy of restricting operational deployment of those Service personnel with active inflammatory renal disease and significantly impaired renal function, combined with good prehospital care for all trauma casualties, is probably correct. No published estimates of renal function in civilian or military trauma victims in the earliest period following injury have been retrieved. The purpose of the present retrospective study was to assess the renal function of military trauma victims on arrival in the Emergency Department of the field hospital. METHODS: The case records of 287 military trauma casualties with severe injury (New Injury Severity Score, NISS≥16) were retrospectively reviewed to assess renal function by calculating estimated glomerular filtration rate (eGFR) using the serum creatine concentration obtained immediately on arrival in the Emergency Department of the field hospitals in Iraq and Afghanistan, 2005-2009. Correlations were attempted between eGFR and other clinical and laboratory variables. RESULTS: Hospital case notes recording management following repatriation were retrieved in 221/287 (77%) cases. None had required immediate renal support in the field. Serum creatine concentration on arrival in the field hospital with demographic data permitting calculation of eGFR was recorded in 158 cases. Median eGFR=76 ml/min/1.73 m(2) (range=43-144). Statistically significant correlations were found among eGFR and pulse rate (r=-0.3, p=0.0002), body temperature (r=0.24, p=0.01) and mean arterial pressure (r=0.2, p=0.02). No statistically significant correlation was found among eGFR and NISS, white cell count, or respiration rate. A stepwise multivariate regression analysis of 106 cases suggested that the best combination of clinical observations to predict renal function were pulse rate and body temperature but the prediction was overoptimistic at lower eGFR values. eGFR was statistically significantly different in those satisfying criteria for systemic inflammatory response syndrome (SIRS; eGFR with SIRS=76 and eGFR without SIRS=86 ml/min/1.73 m(2)). CONCLUSIONS: Prehospital resuscitative measures are effective in maintaining renal function at an adequate level until arrival in the field hospital. The combination of tachycardia and hypothermia predicts lower renal function, variables already employed in the assessment of injury severity. The observations in the present study support restriction of recruitment and operational deployment where renal problems exist.

Military nephrology: magnitude of rates of deterioration in renal function.

OBJECTIVE: To review military cases of renal disease seen between 1985 and 2011 to assess the magnitude of rates of deterioration in renal function according to diagnosis when therapeutic interventions were employed and to compare these with data from civilian patients. METHODS: A 26-year archive of out-patient consultations, discharge summaries and renal biopsies was reviewed according to diagnosis. Serum creatine concentration and demographic data permitted retrospective calculation of estimated glomerular filtration rate (eGFR) at presentation and follow-up. Calculation of an annualised rate of deterioration of eGFR (ΔeGFR, ml/min/1.73 m(2)/y) was undertaken when there were at least four follow-up values. RESULTS: Eight of 13 (61%) conditions included cases where eGFR deteriorated significantly with time and this was present in 40/161 (25%) individual cases. Those diseases where 10% or more of cases showed significant deterioration in eGFR were hypertensive/ischaemic nephropathy (10%), immunoglobulin A nephropathy (22%), Henoch-Schönlein nephritis (28%), focal and segmental glomerulosclerosis (30%), membranous nephropathy (57%), acquired single kidney status (60%) and adult polycystic kidney disease (68%). In the latter condition, frequency of significant deterioration was greater (p<0.0001) than in civilian patients. Median ΔeGFR values ranged from -1.8 to -9.1 ml/min/1.73 m(2)/y in military patients and were similar to those of civilian patients. CONCLUSIONS: Cases of renal disease discovered de novo in serving military personnel showed deterioration of renal function with time in a significant proportion despite interventions to maintain renal function. The magnitude of rates of deterioration was similar to that of civilian patients suggesting that military medical management strategy was appropriate. These results support a traditional restrictive policy concerning applicants with a history of renal disease.

Bone structure and geometry in young men: the influence of smoking, alcohol intake and physical activity.

BACKGROUND: The development of osteoporosis is influenced by peak bone mass attained in youth - the influence of lifestyle factors upon which is poorly described, especially amongst males. We sought to address this issue in a large scale study. METHODS: Hip bone mineral density (dual X-ray absorptiometry, DXA), bone microarchitecture (calcaneal quantitative ultrasound, QUS) and femoral geometry (magnetic resonance imaging, MRI) were characterised in 723 healthy male military recruits (mean ± S.E. age 19.92 ± 0.09 years [range 16-18 years], height 177.67 ± 0.24 cm, weight 73.17 ± 0.37 kg) on entry to UK Army training. Association was sought with prior physical activity, smoking status and alcohol intake. RESULTS: DXA measures were made in 651, MRI measures in 650, and QUS measures in 572 recruits. Increasing levels of weight-bearing physical activity enhanced periostial bone apposition, increases in both total hip and femoral neck bone mineral density (BMD; p ≤ 0.0001 in both cases), and cortical [p<0.0001] and periostial bone volumes [p=0.016]. Smoking habit was associated with preserved bone geometry, but worse BMD [p=0.0001] and QUS characteristics [p ≤ 0.0005]. Moderate alcohol consumption was associated with greater BMD [p ≤ 0.015]. CONCLUSIONS: Whilst exercise (and perhaps moderate alcohol intake) is beneficial to bone morphometry, smoking is detrimental to bone mineral density in young males notable for the likely short duration of smoking to influence skeletal properties. However, differences in socio-economic status, lifestyle and related environmental factors may to some extent confound our results.

Adult polycystic kidney disease: who needs hospital follow-up?

Clinical data from 120 adult patients with genetically undifferentiated polycystic kidney disease who had been followed up for more than 3 months (range 3-172) were reviewed in order to try to identify clinical indicators that might predict deterioration in renal function. They were split into two groups dependent on whether annualized fall in estimated glomerular filtration rate (ΔeGFR mL/min/1.73 m(2) /year) was statistically significant or not. Only 26 patients (22%) had a statistically significantly decreasing ΔeGFR with a median decrease of -2.6 mL/min/1.73 m(2) /year (range -6.2 to -0.7). There was no difference in initial age, gender, or racial distributions between the groups or in initial eGFR. Follow-up was longer (median 86, range 23-172 months vs. 46, range 3-161 months; P = 0.002) and initial blood pressure values tended to be lower (with mean systolic values of 128 vs. 148 mm Hg; P = 0.02) in the group with statistically significant fall in ΔeGFR, but this trend failed to achieve an a priori level of statistical significance. However, the proportion of patients with initial systolic blood pressure ≤ 144 developing a statistically significant fall in ΔeGFR was 0.26 (95% confidence interval = 0.13 to 0.45). No differences were found in initial hemoglobin or cholesterol concentrations. Overall, the annualized rate of decrease in eGFR tended to be greater in those with the higher initial eGFR (P = 0.04), but correlation was poor (rho(2) = 0.04) and failed to achieve an a priori level of statistical significance. No statistically significant correlation was found between ΔeGFR and any other variable. Only those patients with polycystic kidney disease with a statistically significant annualized decrease in eGFR may need to be referred for hospital follow-up in the renal clinic. This simple selection would reduce referrals by 78%.

Variation in the uncoupling protein 2 and 3 genes and human performance.

Uncoupling proteins 2 and 3 (UCP2 and UCP3) may negatively regulate mitochondrial ATP synthesis and, through this, influence human physical performance. However, human data relating to both these issues remain sparse. Examining the association of common variants in the UCP3/2 locus with performance phenotypes offers one means of investigation. The efficiency of skeletal muscle contraction, delta efficiency (DE), was assessed by cycle ergometry in 85 young, healthy, sedentary adults both before and after a period of endurance training. Of these, 58 were successfully genotyped for the UCP3-55C>T (rs1800849) and 61 for the UCP2-866G>A (rs659366) variant. At baseline, UCP genotype was unrelated to any physical characteristic, including DE. However, the UCP2-866G>A variant was independently and strongly associated with the DE response to physical training, with UCP2-866A allele carriers exhibiting a greater increase in DE with training (absolute change in DE of -0.2 ± 3.6% vs. 1.7 ± 2.8% vs. 2.3 ± 3.7% for GG vs. GA vs. AA, respectively; P = 0.02 for A allele carriers vs. GG homozygotes). In multivariate analysis, there was a significant interaction between UCP2-866G>A and UCP3-55C>T genotypes in determining changes in DE (adjusted R(2) = 0.137; P value for interaction = 0.003), which was independent of the effect of either single polymorphism or baseline characteristics. In conclusion, common genetic variation at the UCP3/2 gene locus is associated with training-related improvements in DE, an index of skeletal muscle performance. Such effects may be mediated through differences in the coupling of mitochondrial energy transduction in human skeletal muscle, but further mechanistic studies are required to delineate this potential role.

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, Ward's 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.

Military nephrology-what a civilian doctor should know.

This article provides some background on military nephrology in the UK. The primary objective of the Defence Medical Services is the maintenance of operational capability of military personnel. This includes exclusion of nephrological diseases that might reduce renal reserve to a critical level under field conditions, increasing susceptibility to trauma, burns, infection and adverse environmental conditions and increasing the need for renal support. Renal failure potentially compromises not only the patient but also his comrades through reduced staffing and inability to execute the military mission. Safety of weapon systems for which the patient is responsible may be reduced. At forward locations, need for evacuation may put aircraft or vehicles and their crew with medical attendants at unnecessary risk. Regular follow-up and continuity of care are difficult owing to the demands of military life that include frequent postings and deployments.

Mitochondrial complex activity in donor renal grafts, cold ischemia time, and recovery of graft function.

Indexed mitochondrial complex activities (MCAi) were determined in biopsies obtained from 52 donor kidneys at the end of cold ischemia (8-32 hr) to see if longer anoxia affected MCAi and accounted for the increased risk of delayed graft function (DGF) in recipients of grafts with longer cold ischemia time (CIT) or from non-heart-beating donors (NHBD). CITs were significantly different between those with and without DGF (P=0.02), being shorter in the latter, but MCAi were similar. CIT was correlated (r=0.43, P=0.003) with the time taken for creatinine concentration to fall to half the perioperative value (Crt(1/2)) but not with MCAi. Frequency of DGF, greater in NHBD, was significantly different from that of heart-beating donors (P=0.04), but CIT and MCAi were similar. However, Crt(1/2), was significantly different being longer in NHBD. Thus, the frequency of DGF increased and the speed of recovery diminished with longer CIT, whereas MCAi remained stable suggesting other factors determined tissue recovery.

Electrocardiographic (ECG) criteria for determining left ventricular mass in young healthy men; data from the LARGE Heart study.

BACKGROUND: Doubts remain over the use of the ECG in identifying those with increased left ventricular (LV) mass. This is especially so in young individuals, despite their high prevalence of ECG criteria for LV hypertrophy. We performed a study using cardiovascular magnetic resonance (CMR), which provides an in vivo non-invasive gold standard method of measuring LV mass, allowing accurate assessment of electrocardiography as a tool for defining LV hypertrophy in the young. METHODS AND RESULTS: Standard 12-lead ECGs were obtained from 101 Caucasian male army recruits aged (mean +/- SEM) 19.7 +/- 0.2 years. LV mass was measured using CMR. LV mass indexed to body surface area demonstrated no significant correlation with the Cornell Amplitude criteria or Cornell Product for LV hypertrophy. Moderate correlations were seen with the Sokolow-Lyon Amplitude (0.28) and Sokolow-Lyon Product (0.284). Defining LV hypertrophy as a body surface area indexed left ventricular mass of 93 g/m(2), calculated sensitivities [and specificities] were as follows; 38.7% [74.3%] for the Sokolow-Lyon criteria, 43.4% [61.4%] for the Sokolow-Lyon Product, 19.4% [91.4%] for Cornell Amplitude, and 22.6% [85.7%] for Cornell Product. These values are substantially less than those reported for older age groups. CONCLUSION: ECG criteria for LV hypertrophy may have little value in determining LV mass or the presence of LV hypertrophy in young fit males.

Iraq: the environmental challenge to HM land forces.

In 2003, occasional military patients with hyponatraemia, hypokalaemia and alkalosis were encountered in Iraq. Development of central pontine myelinolysis in one patient indicated treatment should be cautious. Two years later, heat illness continued to occur during the very hot summer months and 23 cases were admitted to a British military field hospital near Basra, Iraq. Incidence was < 0.15% of deployed personnel per summer month. Serum sodium and potassium concentrations were directly (r = 0.66, p = 0.0002) and serum sodium and bicarbonate concentrations inversely (r= -0.64, p = 0.002) correlated. The magnitude of these changes was unrelated to the glomerular filtered load of sodium. While blood pressure was undiminished, estimated glomerular filtration rate was reduced. These electrolyte changes were compatible with secondary hyperaldosteronism but field conditions constrained further investigation. Hyponatraemia was probably due to salt deficiency rather than overhydration. In some military personnel summer salt supplementation could be essential during operations in hot countries.

The association of left ventricular mass with blood pressure, cigarette smoking and alcohol consumption; data from the LARGE Heart study.

BACKGROUND: Left ventricular mass is a risk factor for cardiovascular morbidity and mortality. Although factors associated with elevated left ventricular mass have been sought and studied extensively in elderly and in diseased subjects, few studies have examined the young and healthy. The aim of this study was to examine the possible influence of lifestyle on left ventricular mass in a large group of young men. METHODS: Left ventricular mass was assessed using cardiovascular magnetic resonance in 541 healthy Caucasian male army recruits. Anthropometric, lifestyle and blood pressure data were collected. RESULTS: Mean unadjusted left ventricular mass and left ventricular mass indexed to body surface area were 163.8+/-24.9 g and 86.6+/-10.2 g m(-2) respectively. In univariate analysis, age, height, weight, alcohol consumption, systolic blood pressure, diastolic blood pressure and indices of physical activity were positively associated with unadjusted left ventricular mass (all P<0.02). By contrast, smoking was associated with lower mean left ventricular mass; never smoked 167.5+/-25.8 g vs ex-smokers 159.1+/-25.2 g vs current smokers 161.0+/-23.1 g (P=0.007). Multivariate analysis revealed weight, systolic blood pressure, smoking status and indices of physical activity to be independent predictors of left ventricular mass. CONCLUSIONS: Our data confirm an association of age, body weight, height, physical activity, diastolic and systolic blood pressure with left ventricular mass. In addition, unexpectedly, we have found smoking is associated with lower left ventricular mass in a large sample of young healthy men. Although the latter association may result from confounding effects, such an interesting observation deserves further investigation.

Variation in the lipoprotein lipase gene influences exercise-induced left ventricular growth.

The adult heart relies predominantly on fatty acids (FA) for energy generation, and defects in FA catabolism cause dramatic left ventricular (LV) growth in early age. Since lipoprotein lipase (LPL) is the key enzyme in plasma triglyceride catabolism and is highly expressed in the myocardium, we investigated an association between the functional LPL gene serine 447 stop (S447X) variant and exercise-induced LV growth. The S447X variant was genotyped in 146 British Army recruits undergoing a 10-week exercise programme. Over the training period, X447 allele carriers showed less LV growth than S447 homozygotes (SS, 5.8+/-0.7%; SX, 2.2+/-1.5%; P=0.03) and a decrease in systolic blood pressure (DeltaSBP: SS, 1.9+/-1.3 mmHg; SX, -5.7+/-2.2 mmHg; P=0.015). Although LPL genotype did not significantly predict LV growth with DeltaSBP in statistical modelling (LPL, P=0.14; DeltaSBP, P=0.06), regression analysis indicated that LPL S447X genotype effect on DeltaSBP accounted for only 20% of the effect on LV growth. In multivariate analysis, LPL, peroxisome-proliferator-activated receptor alpha and angiotensin-converting enzyme genotypes were independent predictors of cardiac growth. Thus, LPL S447X genotype influenced exercise-induced changes in LV mass and SBP. Change in blood pressure accounted for a proportion of LV growth. These data suggest that increased myocardial FA availability may reduce exercise-induced LV growth.

Bioterrorism: the need to be prepared.

Postal distribution of anthrax spores in October 2001 in the USA resulted in cases of pulmonary anthrax. In consequence, interest and concern about terrorist attacks on civilian populations using biological weapons have increased, particularly when one recent authoritative assessment suggested that an attack using some form of unconventional weapon on a Western city was 'inevitable'. This article reviews the steps necessary to minimise the probability of a successful attack. Despite best endeavours, the possibility remains that significant numbers of casualties will arise, emphasising the need to plan for reception, triage, decontamination and treatment of patients. The medical Royal Colleges could assist the education of the wider medical community about aspects of pathology hitherto considered to be primarily military but which have now become important for civilian physicians.

Bradykinin receptor gene variant and human physical performance.

Accumulating evidence suggests that athletic performance is strongly influenced by genetic variation. One such locus of influence is the gene for angiotensin-I converting enzyme (ACE), which exhibits a common variant [ACE insertion (I)/deletion (D)]. ACE can drive formation of vasoconstrictor ANG II but preferentially degrades vasodilator bradykinin. The ACE I allele is associated with higher kinin activity. A common gene variant in the kinin beta(2) receptor (B(2)R) exists: the -9 as opposed to +9 allele is associated with higher receptor mRNA expression. We tested whether this variant was associated with the efficiency of muscular contraction [delta efficiency (DE)] in 115 healthy men and women, or with running distance among 81 Olympic standard track athletes. We further sought evidence of biological interaction with ACE I/D genotype. DE was highly significantly associated with B(2)R genotype (23.84 +/- 2.41 vs. 24.25 +/- 2.81 vs. 26.05 +/- 2.26% for those of +9/+9 vs. +9/-9 vs. -9/-9 genotype; n = 25, 61, and 29, respectively; P = 0.0008 for ANOVA adjusted for sex). There was evidence for interaction with ACE I/D genotype, with individuals who were ACE II, with B(2)R -9/-9 having the highest DE at baseline. The ACE I/B(2)R -9 "high kinin receptor activity" haplotype was significantly associated with endurance (predominantly aerobic) event among elite athletes (P = 0.003). These data suggest that common genetic variation in the B(2)R is associated with efficiency of skeletal muscle contraction and with distance event of elite track athletes and that at least part of the associations of ACE and fitness phenotypes is through elevation of kinin activity.

Cortical bone resorption during exercise is interleukin-6 genotype-dependent.

The objective of this study was to examine the relationship between the interleukin-6 (IL-6) -174 G>C promoter polymorphism and exercise-induced femoral cortical bone resorption. Skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10-week period of basic physical training, and changes in cross-sectional cortical area were calculated. Recruits were genotyped for the -174 G>C IL-6 promoter polymorphism. Genotype frequencies (GG 36%, GC 47%, CC 22.17%) were in Hardy-Weinberg equilibrium. The mean percentage change in proximal femoral cross-sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 (3.82)% in cortical area, GC gaining+5.5 (4.88)% and CC gaining+17.3 (9.46)% (P=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (P=0.03). This study demonstrates an association between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans.

Left ventricular mass: reliability of M-mode and 2-dimensional echocardiographic formulas.

The study of left ventricular (LV) hypertrophy is hindered by problems with LV mass measurement by echocardiography. Both the M-mode and 2D area-length formulas for calculating LV mass assume a fixed geometric shape, which may be a source of error. We examined this hypothesis by using cardiovascular magnetic resonance images to eliminate the confounding effects of acoustic access and image quality. LV mass was measured directly in 212 healthy subjects by means of a standard 3D cardiovascular magnetic resonance technique. LV mass was also calculated by using the cube-function and area-length formulas with measurements from the magnetic resonance images. A comparison of serial measurements was made by examining the changes in LV mass by all 3 techniques in those completing an exercise program (n=140). The cube-function technique showed a consistent underestimation of LV mass of 14.3 g, and there were wide 95% limits of agreement (+/-57.6 g and +/-46.3 g for cube-function and area-length techniques, respectively) when compared with 3D measurement. There were similarly wide limits of agreement for the change in mass (+/-55.2 g and +/-44.8 g for cube-function and area-length, respectively). The assumption of geometric shape in the cube-function and area-length formulas resulted in significant variation in LV mass estimates from direct measurement by using a 3D technique. The technique cannot be recommended either at a single time point or for serial studies in small populations; 3D imaging techniques, such as cardiovascular magnetic resonance, are preferable.