Military nephrology: a review of cases 1985-2011.

OBJECTIVE: Evidence of the prevalence of renal pathology in military populations is rare, probably as a result of a traditionally cautious military medical attitude that limits applicants with evidence of renal disease joining the Armed Forces and the continued service of military personnel who develop this later. The aim of this paper is to provide the first comprehensive review of renal diseases in a British military population. METHODS: An archive of out-patient consultations, discharge summaries and renal biopsies between 1985 and 2011 was reviewed. Cases were classified according to diagnosis providing a frequency distribution over this 26-year period. Serum creatinine 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 (ml/min/1.73 m2/y) was undertaken when there were at least four follow-up values. In those cases where there was a statistically significant negative correlation with time, the probability of deterioration of renal function according to diagnosis was calculated. Where numbers of patients with a given diagnosis were sufficient for statistical purposes, correlations were also attempted between initial eGFR and both initial mean arterial pressure (MAP) and initial proteinuria. RESULTS: The most frequent condition was IgA nephropathy, present in 115/346 (33%) of cases. Follow-up data permitted analysis of change in eGFR in 50 of these and 11 (22%) deteriorated. In this condition, there were statistically significant negative correlations between initial eGFR and MAP (r = -0.35, p = 0.0008) and proteinuria (r = -0.4, p = 0.0006). Other conditions showing deterioration despite therapeutic interventions included adult polycystic kidney disease (15/2 2 = 68%) and membranous nephropathy (4/ 7 = 57%). Altogether, 8/13 (61%) conditions included cases where eGFR deteriorated and this was present in 40/161 (25%) individual cases. CONCLUSIONS: Cases of renal disease are discovered de novo in serving military personnel and, despite interventions to maintain renal function, a significant proportion deteriorate supporting the traditionally restrictive policy concerning applicants with evidence of renal disease.

Left ventricular growth response to exercise and cigarette smoking: data from LARGE Heart.

BACKGROUND: Increasing left ventricular mass is a risk factor for cardiovascular morbidity and mortality. OBJECTIVE: To examine the possible association of smoking with the left ventricular growth response in men. METHODS: Left ventricular mass was measured in 309 army recruits before and after an identical 12-week physical training programme. Left ventricular mass was determined using cardiovascular magnetic resonance. RESULTS: Left ventricular mass increased with training (mean (standard deviation (SD)) 3.83 (10.81) g, p<0.001). By univariate analysis, exercise-induced change in left ventricular mass was positively associated with cigarette smoking (mean (SD) 1.69 (11.10) g v 4.76 (10.23) g for non-smokers v ex- and current smokers, respectively; p = 0.026), whereas age, height, diastolic and systolic blood pressure (SBP), alcohol consumption or indices of physical activity were not significantly associated with change in left ventricular mass. Multivariate analysis showed body weight, smoking status and SBP to be independent predictors of left ventricular mass (incremental R(2) = 3.4%, p = 0.004; R(2) = 4.9%, p = 0.024; and R(2) = 1.7%, p = 0.041, respectively). CONCLUSIONS: Cigarette smoking and SBP are associated with exercise-induced left ventricular growth in young men. The positive association of smoking with changes in left ventricular mass is surprising, given the limited exposure of these subjects to smoking, and although these data do not prove causation, they are of great interest to those trying to uncover the drivers of left ventricular hypertrophy, as well as to those examining the possible ill-effects of smoking in the young.

Human CRP gene polymorphism influences CRP levels: implications for the prediction and pathogenesis of coronary heart disease.

OBJECTIVE: C-reactive protein (CRP) concentrations are predictive of cardiovascular disease, and levels are heritable, in part. We identified novel polymorphisms in the CRP gene and assessed their influence on CRP level. METHODS AND RESULTS: CRP was measured in 250 male army recruits before and after strenuous exercise and perioperatively in 193 coronary artery bypass graft (CABG) patients. Two novel polymorphisms were identified in the CRP gene, -717G>A in the promoter and +1444C>T in the 3'UTR. Among army recruits, CRP was higher in +1444TT homozygotes than +1444 C-allele carriers at baseline (1.04+/-0.38 versus 0.55+/-0.06, P=0.014) and at all time points after exercise (2.35+/-0.68 versus 1.07+/-0.12, 2.11+/-0.53 versus 0.88+/-0.09, and 1.77+/-0.44 versus 0.71+/-0.09, P=0.034, P=0.007, and P=0.013, at 2, 48, and 96 hours after exercise, respectively). In the CABG patients, mean CRP (mg/L) rose from 1.97+/-0.36 at baseline to 167.2+/-5.0 72 hours postoperatively. Genotype did not influence CRP at baseline; however, peak post-CABG CRP levels were higher in +1444TT homozygotes compared with +1444C-allele carriers (198+/-17 versus 164+/-5, P=0.03). CONCLUSIONS: The CRP gene +1444C>T variant influences basal and stimulated CRP level. These findings have implications both for the prediction and pathogenesis of coronary heart disease.

Endurance enhancement related to the human angiotensin I-converting enzyme I-D polymorphism is not due to differences in the cardiorespiratory response to training.

Human physical performance is strongly influenced by genetic factors. We have previously reported that the I variant of the human angiotensin I-converting enzyme (ACE) gene is associated with greater endurance performance in mountaineers and Olympic runners and improved performance in army recruits. In this study we examined whether this effect is mediated by improvements in cardiovascular fitness with training in 58 army recruits homozygous for the insertion (I, ACE genotype II) or deletion (D, ACE genotype DD) allele. A submaximal and maximal exercise protocol was used to calculate both the heart rate/oxygen uptake (VO2) relationship and changes in maximal oxygen uptake (VO2max), respectively. There was no significant intergroup difference in VO2max at baseline (P=0.19) or after training (P=0.22). There was no difference between genotypes with training in the heart rate/VO2 elevation (P = 0.79 for the mean difference in mean adjusted heart rates). However, VO2 at all exercise intensities in the submaximal test was lower for all subjects after training and at 80 W the reduction in VO2 was greater for the II subjects compared to DD subjects [mean(SEM)] [1.6 (0.27) and 0.68 (0.27) ml kg(-1) min(-1), respectively; P = 0.02 for mean difference]. The I/D polymorphism may play a role in enhanced endurance performance but this is not mediated by differences in VO2max or the heart rate/VO2 relationship in response to training.

The effect of fibrinogen genotype on fibrinogen levels after strenuous physical exercise.

We have examined the effect of two beta-fibrinogen gene promoter polymorphisms (-455G>A and -854G>A) on the fibrinogen response to severe exercise in a group of male army recruits undergoing basic training. Fibrinogen was measured pre-training and again serially after severe 48 h final military exercise (FME). Out of 884 subjects, 762 completed training of whom 250 were selected for post-FME study. Fibrinogen levels (g/l) were significantly elevated over baseline levels 2, 48 and 96 h after FME, representing increases of 15.7%, 3.4% and 7.6% (p <0.005; p = 0.05 and p <0.005 respectively), with higher levels in -455A allele carriers than genotype -455GG: 3.17+/-0.05 vs. 2.94+/-0.05 (p <0.001), 2.86+/-0.05 vs. 2.60+/-0.05 (p <0.0005) and 2.98+/-0.06 vs. 2.69+/-0.06 (p <0.0005) at 2, 48 and 96 h respectively. There was no effect of the -854G>A polymorphism on fibrinogen, even after taking into account beta-fibrinogen -455 genotype. Thus the fibrinogen -455G>A polymorphism influences fibrinogen levels following exercise. The effect of genotype might be clinically relevant at times of hyperfibrinogenaemia such as following an acute inflammatory response.

Bradykinin B2BKR receptor polymorphism and left-ventricular growth response.

Angiotensin-converting-enzyme (ACE) activity regulates left-ventricular growth. The deletion (D), rather than the insertion (I), ACE gene variant is associated with increased ACE activity and kinin degradation, and the absence (-) rather than the presence (+) of a 9 bp deletion in the gene encoding the bradykinin 2 receptor (B2BKR) is associated with greater gene expression. We determined the ACE and B2BKR genotype of 109 male army recruits, and measured their physiological left-ventricular growth response to a 10-week physical training programme. Mean left-ventricular growth was 15.7 g (SE 3.5) in those with ACE genotype D/D and B2BKR genotype +9/+9, but -1.37 g (4.1) in those with ACE genotype I/I and B2BKR genotype -9/-9 (p=0.003 for trend across genotypes). These results suggest that kinins regulate left-ventricular growth, mediating some of the effects of ACE in this regard.

Left ventricular hypertrophy with exercise and ACE gene insertion/deletion polymorphism: a randomized controlled trial with losartan.

BACKGROUND: Local cardiac renin-angiotensin systems may regulate left ventricular (LV) hypertrophic responses. The absence (deletion [D]) of a 287-bp marker in the ACE gene is associated with greater myocardial ACE levels and exercise-related LV growth than is its presence (insertion [I]), an effect potentially mediated through either increased activity of the cellular growth factor angiotensin II on the angiotensin type 1 (AT(1)) receptor or increased degradation of growth-inhibiting kinins. We sought to confirm ACE genotype-associated exertional LV growth and to clarify the role of the AT(1) receptor in this association. METHODS AND RESULTS: One hundred forty-one British Army recruits homozygous for the ACE gene (79 DD and 62 II) were randomized to receive losartan (25 mg/d, a subhypotensive dose inhibiting tissue AT(1) receptors) or placebo throughout a 10-week physical training program. LV mass, determined by cardiac magnetic resonance, increased with training (8.4 g, P:<0.0001 overall; 12.1 versus 4.8 g for DD versus II genotype in the placebo limb, P:=0.022). LV growth was similar in the losartan arm: 11.0 versus 3.7 g for DD versus II genotypes (P:=0.034). When indexed to lean body mass, LV growth in the II subjects was abolished, whereas it remained in the DD subjects (-0.022 versus 0.131 g/kg, respectively; P:=0.0009). CONCLUSIONS: ACE genotype dependence of exercise-induced LV hypertrophy is confirmed. Additionally, LV growth in DD (unlike II) subjects is in excess of the increase in lean body mass. These effects are not influenced by AT(1) receptor antagonism with the use of losartan (25 mg/d). The 2.4-fold greater LV growth in DD men may be due to the effects of angiotensin II on other receptors (eg, angiotensin type 4) or lower degradation of growth-inhibitory kinins.

Malaria remains a military medical problem.

OBJECTIVE: To bring military medical problems concerning malaria to the attention of the Defence Medical Services. METHOD: Seven military medical problems related to malaria are illustrated by cases referred for secondary assessment over the past five years. Each is discussed in relation to published data. RESULTS: The cases of failure of various kinds of chemoprophylaxis, diagnosis and treatment of malaria may represent just a fraction of the magnitude of the overall problem but in the absence of reliable published military medical statistics concerning malaria cases, the situation is unclear. CONCLUSION: Present experience suggests there are a number of persisting problems affecting the military population in relation to malaria. Only publication of reliable statistics will define their magnitude. Interim remedies are proposed whose cost-effectiveness remains to be established.

Adverse reactions to anthrax immunisation in a military field hospital.

OBJECTIVE: To determine the outcome of anthrax immunisation. METHODS: Adverse reactions (occurrence, nature, severity and incapacity) and immune responses to a voluntary programme of anthrax immunisation at 0, 3, 6, and 24 weeks were monitored by questionnaire and voluntary blood sampling in 129 members, including 24 immunised 7 years previously (immunes), of a military field hospital alerted for possible deployment. RESULTS: Follow-up was complete in 85%. Ninety-eight (76%) received the first anthrax immunisation. Uptake was greater (p = 0.015) in immunes. Initial prevalence of adverse reaction was 63%. Subsequent uptake and adverse reaction dwindled significantly (p < 0.001). Only 28 (22%) were immunised at 24 weeks. Proportions reporting adverse reactions following the initial immunisation were greater in immunes (p = 0.046) and officers (p = 0.02). There was no significant (p = 0.36) correlation between uptake of immunisation and prevalence of adverse reaction. Antecedent adverse reaction did not reduce the proportion of participants accepting immunisation subsequently. The nature of adverse reactions (47% local, 24% systemic and 27% both) and severity were the same throughout. Forty-five percent of adverse reactions caused incapacity. Seventy-four percent of these had pain in the injected arm (+/- systemic symptoms) which prevented lifting or driving for 48 hours in 63%. Immune responses were greater in immunes. CONCLUSIONS: It was concluded that anthrax immunisation results in a higher than expected prevalence of adverse reaction with initial incapacity of military significance affecting 18%. Greater immune responses may increase adverse reaction but this does not affect acceptance of anthrax immunisation. Poor completion rates necessitate development of a new anthrax immunisation strategy.

Exercise training enhances endothelial function in young men.

OBJECTIVES: The present study was designed to assess whether exercise training can enhance endothelium-dependent dilatation in healthy young men. BACKGROUND: Exercise has been shown to reduce cardiovascular morbidity and mortality, but the mechanisms for this benefit are unclear. Endothelial dysfunction is an early event in atherogenesis, and animal studies have shown that exercise training can enhance endothelial function. METHODS: We have examined the effect of a standardized, 10-week, aerobic and anaerobic exercise training program on arterial physiology in 25 healthy male military recruits, aged 17 to 24 (mean 20) years, of average fitness levels. Each subject was studied before starting, and after completing the exercise program. Baseline vascular reactivity was compared with that of 20 matched civilian controls. At each visit, the diameter of the right brachial artery was measured at rest, during reactive hyperemia (increased flow causing endothelium-dependent dilation) and after sublingual glyceryltrinitrate (GTN; an endothelium-independent dilator), using high-resolution external vascular ultrasound. RESULTS: At baseline, flow-mediated dilatation (FMD) and GTN-mediated dilatation were similar in the exercise and control groups (FMD 2.2+/-2.4% and 2.4+/-2.8%, respectively, p = 0.33; GTN 13.4+/-6.2 vs. 16.7+/-5.9, respectively, p = 0.53). In the military recruits, FMD improved from 2.2+/-2.4% to 3.9+/-2.5% (p = 0.01), with no change in the GTN-mediated dilation (13.4+/-6.2% vs. 13.9+/-5.8%, p = 0.31) following the exercise program. CONCLUSION: Exercise training enhances endothelium-dependent dilation in young men of average fitness. This may contribute to the benefit of regular exercise in preventing cardiovascular disease.

Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.

BACKGROUND: The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS: We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS: Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION: II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.

Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training.

BACKGROUND: The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. METHODS AND RESULTS: Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001). CONCLUSIONS: Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.

Side effects of mefloquine prophylaxis for malaria: an independent randomized controlled trial.

A prospective randomized double-'blind' trial was undertaken during a military exercise in East Africa to determine whether there was a significant difference in the incidence of side effects experienced by soldiers taking mefloquine 250 mg weekly compared with those taking chloroquine 300 mg weekly and proguanil 200 mg daily as chemoprophylaxis for malaria. Subject to their informed voluntary consent, male soldiers who were not aviators were included in the study. Identical questionnaires were completed voluntarily at the end of 2 and 8 weeks. Symptoms were classified by nature into-'all', 'neuropsychological', 'enteric' and 'other', and by severity into 'severe' and 'very severe'. The proportions of respondents experiencing side effects were compared to seek statistically significant differences between the chemoprophylactic groups. Questionnaire 1 was completed after 2 weeks by 183 of 317 subjects (58%) randomly assigned mefloquine and by 176 of 307 subjects (57%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was not significantly different between the groups (71/183 vs. 70/176), odds ratio 0.96 (95% confidence interval [CI] 0.63 to 1.47). Questionnaire 2 was completed after 8 weeks by 145 of 317 subjects (46%) randomly assigned mefloquine and by 142 of 307 subjects (46%) randomly assigned chloroquine-proguanil. The incidence of putative side effects was still not significantly different between the groups (95/145 vs. 103/142), odds ratio 0.72 (95% CI 0.43 to 1.19). None of the subjects developed a serious neuropsychological reaction. Among respondents, 12.8% and 38% admitted lack of full compliance at 2 and 8 weeks, respectively. Exclusion of these subjects during a secondary analysis did not affect the results. None of the subjects developed malaria in the 12 months following return to the UK. Subject to the limitations of a response rate that was smaller than desired and the fact that the study was conducted in fit male military personnel, these results support evidence which indicates that mefloquine is no more toxic than chloroquine-proguanil.