The metabolic effects of intermittent versus continuous feeding in critically ill patients.

Intermittent (or bolus) feeding regimens in critically ill patients have been of increasing interest to clinicians and scientists. Changes in amino acid, fat and carbohydrate metabolites over time might yet deliver other benefits (e.g. modulation of the circadian rhythm and sleep, and impacts on ghrelin secretion, insulin resistance and autophagy). We set out to characterise these changes in metabolite concentration. The Intermittent versus Continuous Feeding in Critically Ill paitents study (NCT02358512) was an eight-centre single-blinded randomised controlled trial. Patients were randomised to received a continuous (control arm) or intermittent (6x/day, intervention arm) enteral feeding regimen. Blood samples were taken on trial days 1, 7 and 10 immediately before and 30 min after intermittent feeds, and at equivalent timepoints in the control arm. A pre-planned targeted metabolomic analysis was performend using Nuclear Resonance Spectroscopy. Five hundred and ninety four samples were analysed from 75 patients. A total of 24 amino acid-, 19 lipid based-, and 44 small molecule metabolite features. Across the main two axes of variation (40-60% and 6-8% of variance), no broad patterns distinguished between intermittent or continuous feeding arms, across intra-day sampling times or over the 10 days from initial ICU admission. Logfold decreases in abundance were seen in metabolites related to amino acids (Glutamine - 0.682; Alanine - 0.594), ketone body metabolism (Acetone - 0.64; 3-Hydroxybutyric Acid - 0.632; Acetonacetic Acid - 0.586), fatty acid (carnitine - 0.509) and carbohydrate metabolism ( Maltose - 0.510; Citric Acid - 0.485). 2-3 Butanediol, a by-product of sugar-fermenting microbial metabolism also decreased (- 0.489). No correlation was seen with change in quadriceps muscle mass for any of the 20 metabolites varying with time (all p > 0.05). Increasing severity of organ failure was related to increasing ketone body metabolism (3 Hydroxybutyric Acid-1 and - 3; p = 0.056 and p = 0.014), carnitine deficiency (p = 0.002) and alanine abundancy (p - 0.005). A 6-times a day intermittent feeding regimen did not alter metabolite patterns across time compared to continuous feeding in critically ill patients, either within a 24 h period or across 10 days of intervention. Future research on intermittent feeding regimens should focus on clinical process benefits, or extended gut rest and fasting.

Hyperpolarizabilities of hydrogenlike atoms in Debye and dense quantum plasmas.

The hyperpolarizabilities of the hydrogenlike atoms in Debye and dense quantum plasmas are calculated using the sum-over-states formalism based on the generalized pseudospectral method. The Debye-Hückel and exponential-cosine screened Coulomb potentials are employed to model the screening effects in, respectively, Debye and dense quantum plasmas. Our numerical calculation demonstrates that the present method shows exponential convergence in calculating the hyperpolarizabilities of one-electron systems and the obtained results significantly improve previous predictions in the strong screening environment. The asymptotic behavior of hyperpolarizability near the system bound-continuum limit is investigated and the results for some low-lying excited states are reported. By comparing the fourth-order corrected energies in terms of hyperpolarizability with the resonance energies using the complex-scaling method, we empirically conclude that the applicability of hyperpolarizability in perturbatively estimating the system energy in Debye plasmas lies in the range of [0,F_{max}/2], where F_{max} refers to the maximum electric field strength at which the fourth-order energy correction is equal to the second-order term.

Total haemoglobin mass, but not haemoglobin concentration, is associated with preoperative cardiopulmonary exercise testing-derived oxygen-consumption variables.

Background: Cardiopulmonary exercise testing (CPET) measures peak exertional oxygen consumption ( V˙O2peak ) and that at the anaerobic threshold ( V˙O2 at AT, i.e. the point at which anaerobic metabolism contributes substantially to overall metabolism). Lower values are associated with excess postoperative morbidity and mortality. A reduced haemoglobin concentration ([Hb]) results from a reduction in total haemoglobin mass (tHb-mass) or an increase in plasma volume. Thus, tHb-mass might be a more useful measure of oxygen-carrying capacity and might correlate better with CPET-derived fitness measures in preoperative patients than does circulating [Hb]. Methods: Before major elective surgery, CPET was performed, and both tHb-mass (optimized carbon monoxide rebreathing method) and circulating [Hb] were determined. Results: In 42 patients (83% male), [Hb] was unrelated to V˙O2 at AT and V˙O2peak ( r =0.02, P =0.89 and r =0.04, P =0.80, respectively) and explained none of the variance in either measure. In contrast, tHb-mass was related to both ( r =0.661, P <0.0001 and r =0.483, P =0.001 for V˙O2 at AT and V˙O2peak , respectively). The tHb-mass explained 44% of variance in V˙O2 at AT ( P <0.0001) and 23% in V˙O2peak ( P =0.001). Conclusions: In contrast to [Hb], tHb-mass is an important determinant of physical fitness before major elective surgery. Further studies should determine whether low tHb-mass is predictive of poor outcome and whether targeted increases in tHb-mass might thus improve outcome.

The future of UK healthcare: problems and potential solutions to a system in crisis.

The UK's Health System is in crisis, central funding no longer keeping pace with demand. Traditional responses-spending more, seeking efficiency savings or invoking market forces-are not solutions. The health of our nation demands urgent delivery of a radical new model, negotiated openly between public, policymakers and healthcare professionals. Such a model could focus on disease prevention, modifying health behaviour and implementing change in public policy in fields traditionally considered unrelated to health such as transport, food and advertising. The true cost-effectiveness of healthcare interventions must be balanced against the opportunity cost of their implementation, bolstering the central role of NICE in such decisions. Without such action, the prognosis for our healthcare system-and for the health of the individuals it serves-may be poor. Here, we explore such a new prescription for our national health.

Atomic vs. quantum dot open shell spectra.

Hund's rules apply to pairs of atomic states which, in the limit of weak interelectronic repulsion, belong to a common configuration. We examine the asymptotic behavior of the energy difference between states belonging to such pairs (ΔE) as a function of the nuclear charge (Z) at both Z→∞ (ignoring relativistic effects) and at Z→Zc, where Zc is the critical charge below which the outermost electron is not bound. We find that the ratio ΔEZ2 is non-monotonic, having a maximum at some intermediate value of Z. This non-monotonicity is shown to account for the sign reversal in the difference between the corresponding interelectronic repulsion energies. For analogous open shell systems with confining potentials (such as Hooke's atom or the infinite spherical well), the corresponding function of the energy difference, in terms of which the interelectronic repulsion energy is given as a first derivative with respect to the parameter that characterizes the strength of the one-body potential (such as the harmonic force constant or the well radius, respectively), is monotonic in this parameter. This implies that the relative magnitude of the interelectronic repulsion energies that characterizes the strong one-body limit (usually, the ordering naively expected on the basis of Hund's rule) remains valid along the whole isoelectronic sequence.

Caudwell Xtreme Everest: An Overview.

The Caudwell Xtreme Everest (CXE) expedition in the spring of 2007 systematically studied 222 healthy volunteers as they ascended from sea level to Everest Base Camp (5300 m). A subgroup of climbing investigators ascended higher on Everest and obtained physiological measurements up to an altitude of 8400 m. The aim of the study was to explore inter-individual variation in response to environmental hypobaric hypoxia in order to understand better the pathophysiology of critically ill patients and other patients in whom hypoxaemia and cellular hypoxia are prevalent. This paper describes the aims, study characteristics, organization and management of the CXE expedition.

The virial theorem for the smoothly and sharply, penetrably and impenetrably confined hydrogen atom.

Confinement of atoms by finite or infinite boxes containing sharp (discontinuous) jumps has been studied since the fourth decade of the previous century, modelling the effect of external pressure. Smooth (continuous) counterparts of such confining potentials, that depend on a parameter such that in an appropriate limit they coincide with the sharp confining potentials, are investigated, with an emphasis on deriving the corresponding virial and Hellmann-Feynman theorems.

Cardiopulmonary exercise testing predicts postoperative outcome in patients undergoing gastric bypass surgery.

BACKGROUND: For several types of non-cardiac surgery, the cardiopulmonary exercise testing (CPET)-derived variables anaerobic threshold (AT), peak oxygen consumption (VO2 peak), and ventilatory equivalent for CO(2) (VE/VCO2 ) are predictive of increased postoperative risk: less physically fit patients having a greater risk of adverse outcome. We investigated this relationship in patients undergoing gastric bypass surgery. METHODS: All patients (<190 kg) who were referred for CPET and underwent elective gastric bypass surgery at the Whittington Hospital NHS Trust between September 1, 2009, and February 25, 2011, were included in the study (n=121). Fifteen patients did not complete CPET. CPET variables (VO2 peak, AT, and VE/VCO2 ) were derived for 106 patients. The primary outcome variables were day 5 morbidity and hospital length of stay (LOS). The independent t-test and Fisher's exact test were used to test for differences between surgical outcome groups. The predictive capacity of CPET markers was determined using receiver operating characteristic (ROC) curves. RESULTS: The AT was lower in patients with postoperative complications than in those without [9.9 (1.5) vs 11.1 (1.7) ml kg(-1) min(-1), P=0.049] and in patients with a LOS>3 days compared with LOS ≤ 3 days [10.4 (1.4) vs 11.3 (1.8) ml kg(-1) min(-1), P=0.023]. ROC curve analysis identified AT as a significant predictor of LOS>3 days (AUC 0.640, P=0.030). The VO2 peak and VE/VCO2 were not associated with postoperative outcome. CONCLUSIONS: AT, determined using CPET, predicts LOS after gastric bypass surgery.

Preoperative exercise capacity in adult inflammatory bowel disease sufferers, determined by cardiopulmonary exercise testing.

BACKGROUND AND AIMS: Aerobic exercise capacity appears impaired in children with inflammatory bowel disease (IBD). Whether this holds true in adults with IBD is not known. Using cardiopulmonary exercise testing (CPET), we assessed anaerobic threshold (AT) in such patients comparing data with reference values and other elective surgical patients. We also sought to confirm whether the presence of a fistula further reduced AT. METHODS: CPET was performed between November 2007 and December 2010 on patients awaiting abdominopelvic surgery. Gender-specific normal reference values were used for comparison. Unadjusted comparison between two groups was made using Mann-Whitney U test and by unpaired t test. Data were adjusted by analysis of covariance, using age and sex as covariates. Differences between patients' observed values and reference values were tested using paired t tests. RESULTS: Four hundred and fourteen patients (234 male) were studied (mean ± SD age, 56.6 ± 16.4 years; weight, 74.2 ± 15.6 kg). Adjusted AT values in Crohn's disease (CD) were lower than colorectal cancer (11.4 ± 3.4 vs 13.2 ± 3.5 ml.kg(-1).min(-1), p = 0.03) and for all other colorectal disease groups combined (12.6 ± 3.5 ml.kg(-1).min(-1), p = 0.03). AT of Ulcerative colitis (UC) and CD patients together were reduced compared to population reference values (p < 0.05). CONCLUSION: After adjusting for age and sex, CD patients had a reduced AT compared to patients with colorectal cancer and other colorectal disease groups combined. The pathogenesis of this low AT remains to be defined and warrants further investigation.

Review article: pancreatic renin-angiotensin systems in health and disease.

BACKGROUND: In addition to the circulating (endocrine) renin-angiotensin system (RAS), local renin-angiotensin systems are now known to exist in diverse cells and tissues. Amongst these, pancreatic renin-angiotensin systems have recently been identified and may play roles in the physiological regulation of pancreatic function, as well as being implicated in the pathogenesis of pancreatic diseases including diabetes, pancreatitis and pancreatic cancer. AIM: To review and summarise current knowledge of pancreatic renin-angiotensin systems. METHODS: We performed an extensive PubMed, Medline and online review of all relevant literature. RESULTS: Pancreatic RAS appear to play various roles in the regulation of pancreatic physiology and pathophysiology. Ang II may play a role in the development of pancreatic ductal adenocarcinoma, via stimulation of angiogenesis and prevention of chemotherapy toxicity, as well as in the initiation and propagation of acute pancreatitis (AP); whereas, RAS antagonism is capable of preventing new-onset diabetes and improving glycaemic control in diabetic patients. Current evidence for the roles of pancreatic RAS is largely based upon cell and animal models, whilst definitive evidence from human studies remains lacking. CONCLUSIONS: The therapeutic potential for RAS antagonism, using cheap and widely available agents, and may be untapped and such roles are worthy of active investigation in diverse pancreatic disease states.

Prolongation of the corrected QT complex--a cause of sudden cardiac death in the mountain environment?

In the mountain environment sudden cardiac death (SCD) has been shown to be responsible for the deaths of up to 52% of downhill skiers and 30% of hikers. The majority of SCD's are precipitated by a ventricular arrhythmia. Although most are likely to result from structural abnormalities associated with conditions such as ischaemic heart disease, a small but significant number may be due to abnormalities in ion channel activity, commonly known as, "channelopathies". Channelopathies have the potential to lengthen the time between ventricular depolarisation and repolarisation that can result in prolongation of the corrected QT interval (QTc) and episodes of polymorphic ventricular tachycardia (PVT) and eventually, ventricular fibrillation. This review examines the factors that prolong the QTc interval in the mountain environment and outlines a practical framework for preventing the life threatening arrhythmias that are associated with this condition.

Mountain mortality: a review of deaths that occur during recreational activities in the mountains.

The growing popularity of activities such as hiking, climbing, skiing and snowboarding has ensured that the number of visitors to mountain environments continues to increase. Since such areas place enormous physical demands on individuals, it is inevitable that deaths will occur. Differences in the activities, conditions and methods of calculation make meaningful mortality rates difficult to obtain. However, it is clear that the mortality rate for some mountain activities is comparable to hang gliding, parachuting, boxing and other pastimes that are traditionally viewed as dangerous. Deaths in the mountains are most commonly due to trauma, high altitude illness, cold injury, avalanche burial and sudden cardiac death. This review describes the mortality rates of those who undertake recreational activities in the mountains and examines the aetiology that lies behind them.

Angiotensin-converting enzyme genotype and encephalopathy in Chernobyl cleanup workers.

BACKGROUND AND PURPOSE: To identify, using a genetic model, a key role for the renin-angiotensin system (RAS) in the development of dyscirculatory encephalopathy (DE) in Chernobyl cleanup workers (CCW). The insertion/deletion polymorphism of the angiotensin-converting enzyme (ACE) gene denotes a substantial individual variation in RAS activity with the D-allele being associated with higher ACE activity. METHODS: Ninety-three male, Caucasian CCW were recruited from those under regular review at the All-Russia Centre of Emergency and Radiation Medicine, St. Petersburg. The presence or absence of DE was determined using existing institutional guidelines. ACE genotype was determined using internationally accepted methodologies. RESULTS: Angiotensin-converting enzyme genotype distribution in 59 subjects with DE was II: 10 (17%), ID: 31 (53%), DD: 18 (30%), D-allele frequency 56.8%. Whereas in those without the condition the distribution was II: 12 (35%), ID: 19 (56%), DD 3 (9%) and D-allele frequency 35.9% (P = 0.02). CONCLUSIONS: These data are the first to identify an association between the ACE D-allele and DE in CCW. They provide evidence of a significant role for the RAS in the development of DE and suggest that clinical trials of ACE inhibition would be profitable in this group.

Angiotensin-converting enzyme genotype may predict survival following major trauma.

BACKGROUND: As a key component of the endocrine renin-angiotensin system (RAS), angiotensin-converting enzyme (ACE) regulates circulatory homeostasis. Meanwhile, the local RAS influences tissue growth, inflammatory and metabolic responses. The absence (deletion, D) rather than the presence (insertion, I) of a 287 base pair fragment in the ACE gene is associated with higher circulating and tissue ACE activity, with excess mortality in critical illness (including adult acute respiratory distress syndrome and paediatric meningococcal infection) and with worse functional outcome from traumatic brain injury. OBJECTIVE: To determine if the ACE genotype is associated with mortality following major trauma. METHODS: 41 subjects with major trauma admitted to the Royal London Hospital over a 2-year period via the Helicopter Emergency Medical Service were enrolled. ACE genotype was available in 36. Injury Severity Score (ISS), Revised Trauma Score (RTS), age, sex and outcome data were recorded for each. ACE genotype was determined from leucocyte DNA using well described techniques. RESULTS: The presence of one or more D alleles was associated with a mortality of 36.4% compared with 7.1% for II alleles (p = 0.048). Age (p = 0.044) also predicted mortality whereas RTS (p = 0.08) and ISS (p = 0.46) did not. ACE genotype was significantly associated with RTS but not age or ISS. CONCLUSION: The ACE D allele may be associated with mortality from major trauma. Replication of these findings in larger studies may aid definition of high-risk subgroups that would benefit from early intensive management. New therapeutic targets might also be suggested.

Level of ex vivo interleukin 6 expression in human peripheral fat compared with other tissues.

OBJECTIVES: Adipose tissue is able to secrete a variety of active mediators into the circulation. One of these is Interleukin 6 (IL6). IL6 may play a causal role in the development of atherosclerosis. It has therefore been suggested that IL6 may form part of the link between obesity and vascular disease. The aim of this study was to quantify the relative IL6 expression in adipose tissue compared to other tissues. METHODS: Tissue (vein, fat, muscle, blood) was collected from 32 patients undergoing varicose vein surgery. RNA was extracted and mRNA measured using RT-PCR relative quantification. The mean relative IL6 mRNA levels were compared between tissues using the Mann Whitney U test and the independent t-test. Tissue levels were compared for individuals using the Wilcoxon signed rank test. RESULTS: Mean relative IL6 mRNA levels (mean+/-SEM) were significantly greater in adipose tissue 44.8+/-16.1 than in other tissues (leukocytes 1.1+/-0.3, vein 2.0+/-0.8, muscle 0.06+/-0.03: p<0.001). mRNA expression levels were also significantly higher in fat than in all other tissue types in individuals (p<0.001). CONCLUSIONS: IL6 mRNA expression is significantly higher in adipose than in many other tissues known to express IL6.

Role of bacterial endotoxin in chronic heart failure: the gut of the matter.

Proinflammatory cytokines are now thought to play a key role in the pathophysiology of chronic heart failure, driving both symptomatic presentation and disease progression. We propose that this proinflammatory state, in turn, may be sustained through a chronic release of enterically derived bacterial endotoxin. Human trials have indicated that bacterial decontamination of the gut with concomitant decrease in lipopolysaccharide (LPS) has a positive outcome on heart disease patients. Antiendotoxin antibodies may thus represent therapeutic agents in this setting. Previously, antiendotoxin antibodies were targeted to the inner hydrophobic lipid A moiety of endotoxin in an attempt to neutralize its toxicity. These antibodies failed because they lacked specificity and bound to LPS weakly. In contrast, our studies on antiendotoxin antibodies have revealed that antibodies targeted to the hydrophilic oligosaccharides of the endotoxin have the potential to bind specifically with high affinity. Development of immunotherapeutics that can reduce systemic LPS or other agents, such as bactericidal/permeability-increasing protein that can neutralize LPS and limit inflammation safely, will enable the role of LPS in chronic heart failure to be elucidated and may pave the way to develop a new generation of effective therapeutic agents that may be directed to the treatment of chronic heart failure.

The impact of ACE genotype on serum ACE activity in a black South African male population.

The strong association between the angiotensin I-converting enzyme (ACE) gene I/D polymorphism with serum ACE activity appears lacking in Nigerians and Kenyans, but has not previously been well assessed in others of African origin. This study addressed this issue in an ethnically well defined black South African population. A putative association for the A22982G ACE gene variant, a QTL likely to impact on serum ACE activity, was also sought. Subjects were 200 healthy male black South African volunteers from the Xhosa ethnic group. Venous blood was obtained from all subjects for DNA extraction. ACE I/D and A22982G genotypes were determined and serum ACE activity measured. Age and blood pressure were recorded. For the group as a whole (mean +/- SD age 38.5 +/- 9.8 years, SBP 119.6 +/- 14.1 mmHg, DBP 78.2 +/- 10.1 mmHg) serum ACE activity was 38.2 +/- 11.2 nmol ml(-1)min(-1). ACE I/D genotype was not significantly associated with serum ACE activity. In contrast, the A22982G variant was significantly associated with serum ACE activity, being 35.9 +/- 9.6, 38.1 +/- 10.6 and 42.4 +/- 15.3 nmol ml(-1)min(-1) for AA, AG and GG genotypes respectively; p = 0.03 by ANOVA and p = 0.01 by linear trend. In keeping with the findings in some other African populations, the ACE I/D polymorphism is not strongly associated with serum ACE activity in Xhosa South Africans. As such, it cannot be used as a marker of ACE activity in these subjects. In this regard the use of the A22982G gene variant may be more appropriate.

Cognitive outcome and cyclo-oxygenase-2 gene (-765 G/C) variation in the preterm infant.

BACKGROUND: Cyclo-oxygenase (COX) inhibition by indomethacin does not result in an improvement in long-term neurocognitive outcome, despite reducing the incidence of both severe intraventricular haemorrhage and white matter injury visible on ultrasound. Diffuse brain injury after preterm birth may have inflammatory origins. These two points suggest that, in the preterm brain, COX inhibition may have a dominant proinflammatory or neuropathological role. The inducible form of the COX2 gene is polymorphic: the -765 C (rather than G) variant of the gene is associated with reduced COX2 activity. OBJECTIVE: To test the hypothesis that the C allele of COX2 is associated with worse neurodevelopmental outcomes after premature birth. OUTCOMES: Cerebral palsy, disability, Griffith's developmental quotient at 2 years and British Ability Scales-11 general cognitive ability and motor performance (movement assessment battery for children) at 5(1/2) years were compared with COX2 genotype. RESULTS: The C allele (GC 65 (31%), CC 3 (1%)) was independently associated with worse cognitive performance at 2 and 5(1/2) years: C allele mean (SEM) developmental quotient 92.7 (1.7), v GG 97.6 (1.5), p = 0.039; C allele mean (SEM) general cognitive ability, 94.3 (2.2) v GG 100.9 (1.7), p = 0.028. CONCLUSION: An antineuropathological role for COX2 in the preterm brain may help account for the lack of effect of indomethacin treatment in improving neurocognitive outcomes in children born preterm, despite reported reduction in apparent brain injury.

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.