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Aim: To review the radiology-led ultrasound (US) surveillance programme for the detection of hepatocellular carcinoma (HCC) in cirrhotic patients in a UK tertiary-referral centre., Materials and Methods: The radiology information system was searched for patients who had undergone US for surveillance of cirrhosis from September 2009 to May 2013. Patient demographics and cirrhosis aetiology were documented. Data including numbers of surveillance scans, abnormal findings suspicious for HCC, subsequent radiological investigations, numbers of HCC and survival for HCC patients were recorded. Service performance data, such as rates of attendance and rebooking, were also recorded., Results: Eight hundred and four patients entered surveillance and 2,366 surveillance US examinations were performed; 368 (46%) underwent follow-up (6-monthly US). Abnormalities leading to further radiological investigations were found in 81 patients. Reasons for incomplete surveillance included non-attendance and radiology failure to re-book appointments. HCC was diagnosed in 22 patients. Fourteen had HCC diagnosed on a surveillance scan, eight had HCC diagnosed on a scan performed for other reasons. Patients diagnosed with HCC on a surveillance scan were more likely to be treated with curative intent and had longer survival., Conclusion: Even with a radiology-led recall service for HCC surveillance, the proportion of patients receiving scans 6-monthly was low, due in part to the lack of organisational support that is available for other screening programmes. This study gives a realistic representation of the implementation of surveillance in a UK hospital at the current time and of the rates of HCC proceeding to treatment., (Copyright © 2016. Published by Elsevier Ltd.)

Adams and Foley described asterixis in the 1940s in patients with hepatic encephalopathy, but it has since been associated with a wide range of potential causes, both in neurology and general medicine. Here, we review the history, characteristics and clinical significance of this important clinical sign., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

It is generally recommended that an esophageal balloon-catheter possess an adequate frequency response up to 15 Hz, such that parameters of respiratory mechanics may be quantified with precision. In our experience, however, we have observed that some commercially available systems do not display an ideal frequency response (<8-10 Hz). We therefore investigated whether the poor frequency response of a commercially available esophageal catheter may be adequately compensated using two numerical techniques: 1) an exponential model correction, and 2) Wiener deconvolution. These two numerical techniques were performed on a commercial balloon-catheter interfaced with 0, 1, and 2 lengths of extension tubing (90 cm each), referred to as configurations L0, L90, and L180, respectively. The frequency response of the balloon-catheter in these configurations was assessed by empirical transfer function analysis, and its "working" range was defined as the frequency beyond which more than 5% amplitude and/or phase distortion was observed. The working frequency range of the uncorrected balloon-catheter extended up to only 10 Hz for L0, and progressively worsened with additional tubing length (L90 = 3 Hz, L180 = 2 Hz). Although both numerical methods of correction adequately enhanced the working frequency range of the balloon-catheter to beyond 25 Hz for all length configurations (L0, L90, and L180), Wiener deconvolution consistently provided more accurate corrections. Our data indicate that Wiener deconvolution provides a superior correction of the balloon-catheter's dynamic response, and is relatively more robust to extensions in catheter tube length compared with the exponential correction method., (Copyright © 2016 the American Physiological Society.)

Study Objectives: To determine the impact of averaging window-length on the "desaturation" indexes (DIs) obtained via overnight pulse oximetry (SpO2) at high altitude., Design: Overnight SpO2 data were collected during a 10-day sojourn at high altitude. SpO2 was obtained using a commercial wrist-worn finger oximeter whose firmware was modified to store unaveraged beat-to-beat data. Simple moving averages of window lengths spanning 2 to 20 cardiac beats were retrospectively applied to beat-to-beat SpO2 datasets. After SpO2 artifacts were removed, the following DIs were then calculated for each of the averaged datasets: oxygen desaturation index (ODI); total sleep time with SpO2 < 80% (TST < 80), and the lowest SpO2 observed during sleep (SpO2 low)., Setting: South Base Camp, Mt. Everest (5,364 m elevation)., Participants: Five healthy, adult males (35 ± 5 y; 180 ± 1 cm; 85 ± 4 kg)., Interventions: N/A., Measurements and Results: 49 datasets were obtained from the 5 participants, totalling 239 hours of data. For all window lengths ≥ 2 beats, ODI and TST < 80 were lower, and SpO2 low was higher than those values obtained from the beat-to-beat SpO2 time series data (P < 0.05)., Conclusions: Our findings indicate that increasing oximeter averaging window length progressively underestimates the frequency and magnitude of sleep disordered breathing events at high altitude, as indirectly assessed via the desaturation indexes., (© 2015 Associated Professional Sleep Societies, LLC.)

Despite recent efforts to increase the global coverage of marine protected areas (MPAs), studies investigating the effectiveness of marine protected areas within temperate waters remain scarce. Furthermore, out of the few studies published on MPAs in temperate waters, the majority focus on specific ecological or fishery components rather than investigating the ecosystem as a whole. This study therefore investigated the dynamics of both benthic communities and fish populations within a recently established, fully protected marine reserve in Lamlash Bay, Isle of Arran, United Kingdom, over a four year period. A combination of photo and diver surveys revealed live maerl (Phymatolithon calcareum), macroalgae, sponges, hydroids, feather stars and eyelash worms (Myxicola infundibulum) to be significantly more abundant within the marine reserve than on surrounding fishing grounds. Likewise, the overall composition of epifaunal communities in and outside the reserve was significantly different. Both results are consistent with the hypothesis that protecting areas from fishing can encourage seafloor habitats to recover. In addition, the greater abundance of complex habitats within the reserve appeared to providing nursery habitat for juvenile cod (Gadus morhua) and scallops (Pecten maximus and Aequipecten opercularis). In contrast, there was little difference in the abundance of mobile benthic fauna, such as crabs and starfish, between the reserve and outside. Similarly, the use of baited underwater video cameras revealed no difference in the abundance and size of fish between the reserve and outside. Limited recovery of these ecosystem components may be due to the relatively small size (2.67 km(2)) and young age of the reserve (<5 years), both of which might have limited the extent of any benefits afforded to mobile fauna and fish communities. Overall, this study provides evidence that fully protected marine reserves can encourage seafloor habitats to recover, which in turn, can create a number of benefits that flow back to other species, including those of commercial importance., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The measurement of esophageal pressure allows for the calculation of several important and clinically useful parameters of respiratory mechanics. Esophageal pressure is often measured with balloon-tipped catheters. These catheters may be handmade from natural latex condoms and polyethylene tubing. Given the potential of natural latex to cause allergic reaction, it is important to determine whether esophageal catheter balloons can be fabricated, by hand, using nonlatex condoms as construction materials. To determine the static and dynamic response characteristics of esophageal balloon catheters handmade from latex and nonlatex materials, six esophageal catheter balloons were constructed from each of the following condom materials: natural latex, synthetic polyisoprene, and polyurethane (18 total). Static compliance and working volume range of each balloon catheter was obtained from their pressure-volume characteristics in water. The dynamic response of balloon catheters were measured via a pressure "step" test, from which a third-order underdamped transfer function was modeled. The dynamic ranges of balloon catheters were characterized by the frequencies corresponding to ±5% amplitude- and phase-distortion (fA5% and fφ5%). Balloon catheters handmade from polyurethane condoms displayed the smallest working volume range and lowest static balloon compliance. Despite this lower compliance, fA 5% and fφ5% were remarkably similar between all balloon materials. Our findings suggest that polyisoprene condoms are an ideal nonlatex construction material to use when fabricating esophageal catheter balloons by hand., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

The purpose of this study was to examine whether circulatory occlusion of the hand impacts on regional forearm muscle haemodynamics as determined by the near-infrared spectroscopy (NIRS) venous occlusion technique (NIRSVOT). Twenty-five young, healthy participants (18 males and 7 females; 28 ± 4 years; 71 ± 7 kg) completed two experimental protocols that were performed on the dominant arm: (1) a series of five venous occlusion trials with a suprasystolic cuff (>260 mmHg) applied to the wrist and (2) five venous occlusion trials without hand-occlusion. Both protocols were performed twice in a counterbalanced manner. NIRS data were obtained from the flexor digitorum superficialis (FDS) muscle using a dual wavelength, continuous-wave spectrophotometer. FDS muscle blood flow (Q(FDS)), vascular conductance (C(FDS)), O2 consumption (Vo(2FDS)), and venous O2 saturation (SvO2) were calculated from NIRS data during the initial 5 s of venous occlusion. Circulatory occlusion of the hand via wrist cuffing significantly (P < 0.05) reduced Q(FDS) (-36 ± 23%), CFDS (-37 ± 23%), Vo2(FDS) (-14 ± 31%) and SvO2 (-14 ± 12%). These findings indicate that hand-occlusion, via wrist cuffing, adversely impacts on regional forearm haemodynamics as determined by the NIRS-VOT. Consequently, it is recommended that future investigators avoid hand-occlusion when using the NIRS-VOT to quantify spontaneous haemodynamics of regional forearm muscle.

Purpose: The slow component of O2 uptake (V˙O2sc) represents a progressive decline in work efficiency during strenuous, constant work rate cycling. Although most of this "excess" O2 uptake can be explained by factors intrinsic to the exercising muscles, it has been proposed that respiratory muscle work rate may also contribute to the V˙O2sc response. To date, however, no study has provided a comprehensive analysis of the mechanical power of breathing (Pb) in relation to the V˙O2sc while performing strenuous exercise., Methods: The mechanical Pb was measured in 12 recreational cyclists (24 ± 1 yr, 70.9 ± 3.9 kg) during heavy- and severe-intensity cycling. The resistive and elastic components of Pb were quantified using the modified Campbell diagram., Results: Total Pb significantly increased (P < 0.05) over the V˙O2sc phase during both heavy (Δ13 ± 2 J·min) and severe work rate transitions (Δ219 ± 56 J·min). The magnitude of this increase was relatively greater during severe cycling trials (P < 0.05). The greater "slow component" rise in total Pb during severe work rate transitions was consequent to relatively larger increases in the inspiratory and expiratory resistive Pb and inspiratory elastic Pb (P < 0.05)., Conclusions: The findings of this investigation support the thesis that the energetic contribution from respiratory muscles to the V˙O2sc amplitude is disproportionately higher during severe- compared with that during heavy-intensity exercise.

Background: Eighty percent (80%) of patients with Autoimmune hepatitis (AIH) respond to a combination of prednisolone and Azathioprine (AZA). Choice of treatment is limited for those who do not respond to this standard therapy. We evaluated the role of Mycophenolate mofetil (MMF) as a second line therapy in AIH., Method: A retrospective observational study was carried out on all patients who received MMF for AIH., Results: Twenty out of 117 patients with AIH received MMF due to AZA intolerance (18 patients) or refractory disease (2 patients). Median age of the study patients was 56 (18-79) years, Male, n = 3 (15%) and Female, n = 18 (85%). After a median follow-up period of 47 (5-83) months, 14 (73.6%) patients were still on MMF with biochemical remission, including 4 out of 5 patients with cirrhosis. One patient was lost to follow-up. Three patients were intolerant of MMF due to adverse events, and two had disease refractory to MMF. Both these patients with refractory disease to MMF were initially unresponsive to AZA therapy., Conclusion: MMF is a safe second line agent in patients with autoimmune hepatitis including those with cirrhosis.

Liver transplantation (LT) is a lifesaving treatment. Because of the shortage of donor organs, some patients will not survive long enough to receive a transplant. The identification of LT candidates at increased risk of short-term mortality without transplantation may affect listing decisions. Functional capacity, determined with cardiopulmonary exercise testing (CPET), is a measure of cardiorespiratory reserve and predicts perioperative outcomes. This study examined the association between functional capacity and short-term survival before LT and the potential for CPET to predict 90-day mortality without transplantation. A total of 176 patients who were assessed for nonacute LT underwent CPET. Ninety days after the assessment, 10 of the 164 patients who had not undergone transplantation were deceased (mortality rate = 6.1%). According to a comparison of survivors and nonsurvivors, the Model for End-Stage Liver Disease score, UK Model for End-Stage Liver Disease (UKELD) score, age, anaerobic threshold, and peak oxygen uptake (VO(2)) were significant univariate predictors of 90-day mortality without transplantation, but only the UKELD score and peak VO(2) retained significance in a multivariate analysis. The mean peak VO(2) was significantly lower for nonsurvivors versus survivors (15.2 ± 3.3 versus 21.2 ± 5.3 mL/minute/kg, P < 0.001). According to a receiver operating characteristic (ROC) curve analysis, peak VO(2) performed well as a diagnostic test (area under the ROC curve = 0.84, 95% confidence interval = 0.76-0.92, sensitivity = 0.90, specificity = 0.74, P < 0.001). The optimal cutoff value for predicting mortality was ≤17.6 mL/minute/kg. The positive predictive value of a peak VO(2)  ≤ 17.6 mL/minute/kg for 90-day mortality was greatest for patients with high UKELD scores: 38% of the patients with a UKELD score ≥ 57 and a peak VO(2)  ≤ 17.6 mL/minute/kg died, whereas only 6% of the patients with a UKELD score ≥ 57 and a peak VO(2)  > 17.6 mL/minute/kg died (P = 0.03). In conclusion, patients assessed for LT with an impaired functional capacity have poorer short-term survival; this is particularly true for individuals with worse liver disease severity., (© 2014 American Association for the Study of Liver Diseases.)

Purpose: Critical power (CP), and the finite capacity to perform work above CP (W'), can be determined using a 3-min "all-out" cycling test (3MT). This protocol requires two laboratory visits: an incremental exercise test, followed by a 3MT on a separate day. The purpose of this study was to establish whether an incremental exercise test and a 3MT performed during a single laboratory visit can be used to accurately determine CP and W'., Methods: Twelve participants completed two experimental protocols: (1) Combined protocol: an incremental exercise test followed by a 3MT, with 20 min of recovery between exercise bouts; and (2) Independent protocol: the conventional 3MT protocol, performed on a separate day., Results: CP determined from the Combined (254 ± 117 W) and Independent (256 ± 118 W) protocols were not different (p = 0.40). Similarly, W' was not different (p = 0.96) between the Combined (13.7 ± 3.9 kJ) and Independent (13.7 ± 4.5 kJ) protocols. Linear regression revealed a strong level of measurement agreement between the protocols for CP and W', evidenced by high R(2) values (≥0.85) and marginal standard errors of the estimates (CP = 5 W; W' = 1.81 kJ)., Conclusion: A Combined protocol, consisting of an incremental exercise test followed by a 3MT, provides an accurate and valid method to determine an individual's CP and, to a lesser extent, W'. Furthermore, this protocol permits the measurement of the gas-exchange threshold and peak O2 uptake and, consequently, the moderate, heavy, and severe exercise-intensity domains may be defined within a single exercise-testing session.

The purpose of this study was to investigate hand-finger tremor dynamics when a load was applied to the finger in a group of healthy older adults. Moreover, we sought to determine if projecting a representation of the subject's finger tremor on a target was capable of overcoming the effects of loading so that hand-finger interactions returned to a state that was similar to normal tremor. Eight healthy older males (67 ± 1 year) performed a postural pointing task, where tremor was assessed using lightweight accelerometers attached to the hand and finger. Tremor was then assessed when a laser pointer was attached to the finger and switched off (the load), and then with the laser pointer attached and switched on pointing at targets of 40 mm and 20mm in diameter. The main findings of this study were that 1) loading the finger resulted in a reduction in finger tremor amplitude and increased finger tremor regularity, but no change in hand tremor, 2) loading caused increased hand-finger 8-12 Hz cross wavelet coherence and phase synchrony, and 3) pointing at different targets while the finger was loaded resulted in an increase in finger tremor amplitude, and changes in inter-segmental coupling to the extent that hand-finger dynamics reflected normal unloaded conditions. Overall, these results illustrate that the damping effects of limb loading can be offset, in part, by altering the accuracy demands of the task to make the pointing action more challenging., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Aims: To examine whether dynamic cerebral autoregulation is acutely impaired during maximal voluntary apnoea in trained divers., Methods: Mean arterial pressure (MAP), cerebral blood flow-velocity (CBFV) and end-tidal partial pressures of O2 and CO2 (PETO2 and PETCO2) were measured in eleven trained, male apnoea divers (28 ± 2 yr; 182 ± 2 cm, 76 ± 7 kg) during maximal "dry" breath holding. Dynamic cerebral autoregulation was assessed by determining the strength of phase synchronisation between MAP and CBFV during maximal apnoea., Results: The strength of phase synchronisation between MAP and CBFV increased from rest until the end of maximal voluntary apnoea (P<0.05), suggesting that dynamic cerebral autoregulation had weakened by the apnoea breakpoint. The magnitude of impairment in dynamic cerebral autoregulation was strongly, and positively related to the rise in PETCO2 observed during maximal breath holding (R (2) = 0.67, P<0.05). Interestingly, the impairment in dynamic cerebral autoregulation was not related to the fall in PETO2 induced by apnoea (R (2) = 0.01, P = 0.75)., Conclusions: This study is the first to report that dynamic cerebral autoregulation is acutely impaired in trained divers performing maximal voluntary apnoea. Furthermore, our data suggest that the impaired autoregulatory response is related to the change in PETCO2, but not PETO2, during maximal apnoea in trained divers.

Background: Anecdotally, liver size is important in determining prognosis in patients with end-stage liver disease (ESLD)., Aims: To assess if a ratio of liver area and abdominal area on cross-sectional imaging could accurately predict mortality in ESLD., Methods: A retrospective-prospective cohort study was performed on patients with ESLD in a training set. The censor point used was date of patient death or liver transplant (LT). The liver to abdominal area ratio (LAAR) was calculated using the formula {LAAR = [liver area (cm(2))/abdominal area (cm(2))] × 100}. A validation set was collected from a different institution., Results: Three hundred and sixteen patients were identified. Complete imaging and survival data were available in 158 subjects, 100 male (63%). The LAAR score detected progression to death/LT in our cohort (P < 0.003). Its prognostic accuracy at 90, 360 and 720 days, using the optimal cut-off (32.1), from baseline CT date to death/LT using the log-rank test was P = 0.28, P = 0.06 (OR 1.347, 95% CI 0.94-1.94) and P < 0.0001 (OR 1.89, 95% CI 1.25-2.85) respectively. On multivariate analysis, LAAR (P = 0.008), MELD (P = 0.004) and MELD-Na (P = 0.03) were independently associated with the primary study outcome measurement at 720 days. The validation set of 52 patients confirmed the utility of the LAAR to determine risk of death or need for LT, AUROC 0.89 (0.78-0.97), and P < 0.0001., Conclusions: The liver to abdominal area ratio (LAAR) score offers a new paradigm in disease modelling in end-stage liver disease (ESLD) and offers prognostic accuracy at 2 years from computer tomography (CT) imaging., (© 2013 John Wiley & Sons Ltd.)

The effects of involuntary respiratory contractions on the cerebral blood flow response to maximal apnoea is presently unclear. We hypothesised that while respiratory contractions may augment left ventricular stroke volume, cardiac output and ultimately cerebral blood flow during the struggle phase, these contractions would simultaneously cause marked 'respiratory' variability in blood flow to the brain. Respiratory, cardiovascular and cerebrovascular parameters were measured in ten trained, male apnoea divers during maximal 'dry' breath holding. Intrathoracic pressure was estimated via oesophageal pressure. Left ventricular stroke volume, cardiac output and mean arterial pressure were monitored using finger photoplethysmography, and cerebral blood flow velocity was obtained using transcranial ultrasound. The increasingly negative inspiratory intrathoracic pressure swings of the struggle phase significantly influenced the rise in left ventricular stroke volume (R (2) = 0.63, P<0.05), thereby contributing to the increase in cerebral blood flow velocity throughout this phase of apnoea. However, these contractions also caused marked respiratory variability in left ventricular stroke volume, cardiac output, mean arterial pressure and cerebral blood flow velocity during the struggle phase (R (2) = 0.99, P<0.05). Interestingly, the magnitude of respiratory variability in cerebral blood flow velocity was inversely correlated with struggle phase duration (R (2) = 0.71, P<0.05). This study confirms the hypothesis that, on the one hand, involuntary respiratory contractions facilitate cerebral haemodynamics during the struggle phase while, on the other, these contractions produce marked respiratory variability in blood flow to the brain. In addition, our findings indicate that such variability in cerebral blood flow negatively impacts on struggle phase duration, and thus impairs breath holding performance.

Introduction: We sought to characterize the patterns of active pressure development of the inspiratory and expiratory rib cage muscles (P(rcm,i) and P(rcm,e)), the diaphragm (P(di,i)), and the expiratory abdominal muscles (P(abm,e)) during maximal "dry" breath holding in trained apnea divers (n = 8)., Methods: Respiratory contractions were assessed via esophageal and gastric manometry. It was expected that inspiratory/expiratory pressures would progressively increase in both magnitude and frequency during the struggle phase, and that inspiratory rib cage muscle pressures would rise at a rate exceeding that of the diaphragm by the break point., Results: P(rcm,i), P(di,i), P(rcm,e), and P(abm,e) significantly increased from the beginning until the end of the struggle phase (P < 0.05). Moreover, P(di,i)/P(rcm,i) and P(abm,e)/P(rcm,e) ratios had declined by the break point (P < 0.05), indicating that rib cage muscles increased their contribution to net inspiratory/expiratory pressure development by the end of the breath hold, relative to that contributed by the diaphragm and abdominal muscles. The pressure-time indices of the diaphragm and inspiratory rib cage muscles continuously increased over the struggle phase (P < 0.05)., Conclusions: The "extradiaphragmatic" shift in inspiratory muscle recruitment, commensurate with increasing P(rcm,e) and P(abm,e), may reflect an extreme loading response to breathing against a heavy elastance (i.e., closed glottis). In addition, the relative intensity of diaphragmatic and inspiratory rib cage muscle contractions approaches potentially "fatiguing" levels by the break point of maximal breath holding.

Patients with heart failure (HF) display numerous derangements in ventilatory function, which together serve to increase the work of breathing (W(b)) during exercise. However, the extent to which the resistive and elastic properties of the respiratory system contribute to the higher W(b) in these patients is unknown. We quantified the resistive and elastic W(b) in patients with stable HF (n = 9; New York Heart Association functional class I-II) and healthy control subjects (n = 9) at standardised levels of minute ventilation (V'(E)) during graded exercise. Dynamic lung compliance was systematically lower for a given level of V'(E) in HF patients than controls (p<0.05). HF patients displayed slightly higher levels of inspiratory elastic W(b) with greater amounts of ventilatory constraint and resistive W(b) than control subjects during exercise (p<0.05). Our data indicates that the higher W(b) in HF patients is primarily due to a greater resistive, rather than elastic, load to breathing. The greater resistive W(b) in these patients probably reflects an increased hysteresivity of the airways and lung tissues. The marginally higher inspiratory elastic W(b) observed in HF patients appears related to a combined decrease in the compliances of the lungs and chest wall. The clinical and physiological implications of our findings are discussed.

The growing urge to breathe that occurs during breath-holding results in development of involuntary breathing movements (IBMs). The present study determined whether IBMs are initiated at critical levels of hypercapnia and/or hypoxia during maximal apnoea. Arterial blood gasses at the onset of IBM were monitored during maximal voluntary breath-holds. Eleven healthy men performed breath holds after breathing air, hyperoxic-normocapnia, hypoxic-normocapnia, and normoxic-hypercapnia. Pre-breathing of the gas mixtures facilitated the IBM onset, reducing the time-to-onset for ∼46% (hyperoxic condition) and for ∼80% (hypoxic condition) compared to the normoxic air breathing time. A strong correlation (R=0.83, P=0.002) between arterial partial pressure of CO₂ (PaCO₂) at IBM onset after pre-breathing hyperoxic and hypercapnic gas mixtures was observed, suggesting the existence of a possible IBM PaCO₂ threshold level of ∼6.5 ± 0.5 kPa. No clear "threshold" was observed for partial pressure of arterial O₂(PaO₂). However, we observed that IBM onset was influenced, in part, by an interaction between PaO₂ and PaCO₂ levels during maximal apnoea. This study demonstrated the complex interaction between arterial blood-gases and the physiological response to maximal breath holding., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The present study investigated whether 'break-points' in breathing pattern correspond to the first ([Formula: see text]) and second gas-exchange thresholds ([Formula: see text]) during incremental cycling. We used polynomial spline smoothing to detect accelerations and decelerations in pulmonary gas-exchange data, which provided an objective means of 'break-point' detection without assumption of the number and shape of said 'break-points'. Twenty-eight recreational cyclists completed the study, with five individuals excluded from analyses due to low signal-to-noise ratios and/or high risk of 'pseudo-threshold' detection. In the remaining participants (n = 23), two separate and distinct accelerations in respiratory frequency (f (R)) during incremental work were observed, both of which demonstrated trivial biases and reasonably small ±95% limits of agreement (LOA) for the [Formula: see text] (0.2 ± 3.0 ml O(2) kg(-1) min(-1)) and [Formula: see text] (0.0 ± 2.4 ml O(2) kg(-1) min(-1)), respectively. A plateau in tidal volume (V (T)) data near the [Formula: see text] was identified in only 14 individuals, and yielded the most unsatisfactory mean bias ±LOA of all comparisons made (-0.4 ± 5.3 ml O(2) kg(-1) min(-1)). Conversely, 18 individuals displayed V (T)-plateau in close proximity to the [Formula: see text] evidenced by a mean bias ± LOA of 0.1 ± 3.1 ml O(2) kg(-1) min(-1). Our findings suggest that both accelerations in f (R) correspond to the gas-exchange thresholds, and a plateau (or decline) in V (T) at the [Formula: see text] is a common (but not universal) feature of the breathing pattern response to incremental cycling.

Four novel peptides were isolated from the venoms of the solitary eumenine wasps Eumenes rubrofemoratus and Eumenes fraterculus. Their sequences were determined by MALDI-TOF/TOF (matrix assisted laser desorption/ionization time-of-flight mass spectrometry) analysis, Edman degradation and solid-phase synthesis. Two of them, eumenitin-R (LNLKGLIKKVASLLN) and eumenitin-F (LNLKGLFKKVASLLT), are highly homologous to eumenitin, an antimicrobial peptide from a solitary eumenine wasp, whereas the other two, EMP-ER (FDIMGLIKKVAGAL-NH(2)) and EMP-EF (FDVMGIIKKIAGAL-NH(2)), are similar to eumenine mastoparan-AF (EMP-AF), a mast cell degranulating peptide from a solitary eumenine wasp. These sequences have the characteristic features of linear cationic cytolytic peptides; rich in hydrophobic and basic amino acids with no disulfide bond, and accordingly, they can be predicted to adopt an amphipathic α-helix secondary structure. In fact, the CD (circular dichroism) spectra of these peptides showed significant α-helical conformation content in the presence of TFE (trifluoroethanol), SDS (sodium dodecylsulfate) and asolectin vesicles. In the biological evaluation, all the peptides exhibited a significant broad-spectrum antimicrobial activity, and moderate mast cell degranulation and leishmanicidal activities, but showed virtually no hemolytic activity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Autoimmune hepatitis (AIH) is an immune-mediated necroinflammatory condition of the liver. Presentation can vary from the asymptomatic individual with abnormal liver function test to fulminant liver failure. The diagnosis is based on the combination of biochemical, autoimmune, and histological parameters, and exclusion of other liver diseases. Standard therapy consists of a combination of corticosteroids and azathioprine, which is efficacious in 80% of patients. Alternative therapies are increasingly being explored in patients who do not respond to the standard treatment and/or have unacceptable adverse effects. This review examines the role of alternative drugs (second-line agents) available for AIH treatment non-responders. These agents include budesonide, mycophenolate mofetil, cyclosporin, tacrolimus, 6-mercaptopurine, 6-thioguanine, rituximab, ursodeoxycholic acid, rapamycin, and methotrexate. In addition, the risk of opportunistic infections and malignancies are discussed. A treatment algorithm is proposed for the management of patients with AIH treatment non-responders., (© 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.)

Clinical outcomes of recurrent hepatitis C virus after liver transplantation are difficult to predict. We evaluated collagen proportionate area (CPA), a quantitative histological index, at 1 year with respect to the first episode of clinical decompensation. Patients with biopsies at 1 year after liver transplantation were evaluated by Ishak stage/grade, and biopsy samples stained with Sirius red for digital image analysis were evaluated for CPA. Cox regression was used to evaluate variables associated with first appearance of clinical decompensation. Receiver operating characteristic (ROC) curves were also used. A total of 135 patients with median follow-up of 76 months were evaluated. At 1 year, median CPA was 4.6% (0.2%-36%) and Ishak stage was 0-2 in 101 patients, 3-4 in 23 patients, and 5-6 in 11 patients. Decompensation occurred in 26 (19.3%) at a median of 61 months (15-138). Univariately, CPA, tacrolimus monotherapy, and Ishak stage/grade at 1 year were associated with decompensation; upon multivariate analysis, only CPA was associated with decompensation (P = 0.010; Exp(B) = 1.169; 95%CI, 1.037-1.317). Area under the ROC curve was 0.97 (95%CI, 0.94-0.99). A cutoff value of 6% of CPA had 82% sensitivity and 95% specificity for decompensation. In the 89 patients with hepatic venous pressure gradient (HVPG) measurement, similar results were obtained. When both cutoffs of CPA > 6% and HVPG ≥ 6 mm Hg were used, all patients decompensated. Thus, CPA at 1-year biopsy after liver transplantation was highly predictive of clinical outcome in patients infected with hepatitis C virus who underwent transplantation, better than Ishak stage or HVPG., (Copyright © 2011 American Association for the Study of Liver Diseases.)

We examined the influence of operational lung volumes and mean inspiratory flow on the amplitude of the slow component of O₂uptake (V(O)₂(SC) ) during constant-load cycling performed below and above the respiratory compensation threshold (RCT) in young (24±1yr), healthy individuals (n=10). Subjects demonstrated a significantly greater rise in expiratory reserve volume (ERV) and mean inspiratory flow over the V(O)₂(SC) period during exercise performed above compared with below the RCT (P<0.05). Inspiratory reserve volume (IRV) was, on average, smaller for trials performed above relative to below the RCT (P<0.05). The difference in the magnitudes of change in ERV and mean inspiratory flow, but not IRV, were positively correlated with the increase in V(O)₂(SC) amplitude between work rates (R(2)=0.86, P<0.01). These findings suggest that dynamic hyperinflation and mean inspiratory flow (by increasing inspiratory resistive work) contribute to the development of the V(O)₂(SC') , particularly when exercise is performed above the RCT., (Copyright 2010 Elsevier B.V. All rights reserved.)

Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post-transplant. A retrospective study was performed assessing serial liver biopsies for post-transplant chronic hepatitis C infection. One hundred eighty-five patients were included in the analysis; median age 53 years (interquartile range 48-59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres' (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver-operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F >or= 2) was 0.78 (95% CI, 0.70-0.86; P < 0.0001), for advanced fibrosis (F4-6) was 0.80 (95% CI, 0.72-0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72-0.88; P < 0.0001). An optimal cut-off value of 6.3 distinguished patients with no or mild fibrosis (F

Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King's score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty-seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono-infection (HCV RNA-positive by RT-PCR), attending King's College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3-F6, and cirrhosis defined as Ishak fibrosis F5-F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43-54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3-F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (>or=F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut-off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3-F6.

The impact of steatosis on treatment response in chronic hepatitis C infection is controversial. The aim of this study was to determine whether steatosis +/- steatohepatitis on pre-treatment liver biopsy influenced sustained virological response (HCV RNA negative 6 months after completing therapy) in patients with chronic hepatitis C infection treated with pegylated interferon-alpha and ribavirin. One hundred and seventy-nine patients, median age 46 years (interquartile range 40-52), treated between 2001 and 2005. Histological evidence of steatosis was present in 93 patients (52%) and steatohepatitis in 33 patients (18%), 31 patients (17.3%) were cirrhotic. There were 106 (59%) responders, who were similar to non-responders in respect to gender, age, and pre-treatment ALT. On univariate analysis, infection with genotype 2 or 3 was associated with sustained virological response (odds ratio 6.5 (95% CI, 3.3-12.5); P < 0.0001), whereas cirrhosis and patient weight were associated with a reduced response (odds ratios 0.23 (95% CI, 0.11-0.48); P < 0.0001, and 0.97 (95% CI, 0.95-0.99); P < 0.01, respectively); steatohepatitis but not steatosis impacted on the likelihood of achieving sustained virological response (odds ratio 0.37 (95% CI, 0.17-0.77); P = 0.009, and P = 0.18, respectively). Multivariate analysis revealed that infection with genotype 1 or 4 (odds ratio 0.09 (95% CI, 0.03-0.32); P < 0.001) and pre-treatment weight (odds ratio 0.94 (95% CI, 0.90-0.98); P = 0.002) were the only variables associated independently with sustained virological response. In chronic hepatitis C infection, although steatosis was associated with steatohepatitis, neither was shown to affect sustained virological response, which was influenced by genotype, patient weight and the presence of cirrhosis., ((c) 2010 Wiley-Liss, Inc.)

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2- to 3-fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re-enforcing the concept that in patients with CHC, some have "metabolic steatosis", predominantly HCV genotype 1, and others "viral steatosis", mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro-fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies.

The contribution of respiratory muscle O2 uptake ((.)V(O2RM)) to the development of the slow component of O2 uptake kinetics ((.)V(O2SC)) is unclear. The aim of the present study was to examine the impact of respiratory muscle unloading (via breathing, a He-O2 mixture) on the amplitude of (.)V(O2SC) during exercise performed below (B-RCT) and above the respiratory compensation threshold (A-RCT). We hypothesized that breathing He-O2 would reduce the amplitude of the (.)V(O2SC) by a greater amount during exercise performed A-RCT than B-RCT. Eight healthy male recreational cyclists performed constant load cycling in four sets of conditions: (1) B-RCT breathing normal air; (2) B-RCT breathing He-O2; (3) A-RCT breathing normal air; and (4) A-RCT breathing He-O2. Breathing He-O2 did not significantly attenuate the (.)V(O2SC) during exercise performed B-RCT (-3+/-14%, P >0.05). However, breathing He-O2 significantly reduced the (.)V(O2SC) during exercise A-RCT(-45+/-6%, P <0.05). The attenuated (.)V(O2SC) while breathing He-O2 is likely to reflect a decreased (.)V(O2RM). Minute ventilation was not +/-different between normal air and He-O2 breathing trials either B-RCT or A-RCT. However, operating lung volume was significantly lower when breathing He-O2 during exercise performed A-RCT (-12+/-3%, P <0.05). These findings suggest that (.)V(O2RM) comprises a greater proportion of the (.)V(O2SC) when exercise is performed A-RCT compared with B-RCT. Therefore, the impact of breathing He-O2 was more pronounced during exercise A-RCT. Furthermore, changes in operating lung volume and the work of breathing appear to play an important role in the development of the (.)V(O2SC).

Mass spectrometry-based multiple reaction monitoring (MRM) quantitation of proteins can dramatically impact the discovery and quantitation of biomarkers via rapid, targeted, multiplexed protein expression profiling of clinical samples. A mixture of 45 peptide standards, easily adaptable to common plasma proteomics work flows, was created to permit absolute quantitation of 45 endogenous proteins in human plasma trypsin digests. All experiments were performed on simple tryptic digests of human EDTA-plasma without prior affinity depletion or enrichment. Stable isotope-labeled standard peptides were added immediately following tryptic digestion because addition of stable isotope-labeled standard peptides prior to trypsin digestion was found to generate elevated and unpredictable results. Proteotypic tryptic peptides containing isotopically coded amino acids ([(13)C(6)]Arg or [(13)C(6)]Lys) were synthesized for all 45 proteins. Peptide purity was assessed by capillary zone electrophoresis, and the peptide quantity was determined by amino acid analysis. For maximum sensitivity and specificity, instrumental parameters were empirically determined to generate the most abundant precursor ions and y ion fragments. Concentrations of individual peptide standards in the mixture were optimized to approximate endogenous concentrations of analytes and to ensure the maximum linear dynamic range of the MRM assays. Excellent linear responses (r > 0.99) were obtained for 43 of the 45 proteins with attomole level limits of quantitation (<20% coefficient of variation) for 27 of the 45 proteins. Analytical precision for 44 of the 45 assays varied by <10%. LC-MRM/MS analyses performed on 3 different days on different batches of plasma trypsin digests resulted in coefficients of variation of <20% for 42 of the 45 assays. Concentrations for 39 of the 45 proteins are within a factor of 2 of reported literature values. This mixture of internal standards has many uses and can be applied to the characterization of trypsin digestion kinetics and plasma protein expression profiling because 31 of the 45 proteins are putative biomarkers of cardiovascular disease.

MS-based proteomics has become an indispensable tool in system biology generating a need for accurate and precise quantitation of peptide standards. The presented method utilizes ultra performance LC-MS/MS (UPLC-MS/MS) to accurately quantify peptide standards at concentrations of 0.1-10 microM. The ability for accurate quantitation of micro-molar concentrations has the advantages that quantitation can be performed routinely with high precision and the high sensitivity of the method minimizes the amounts required.

Objectives: Histological assessment of patients with chronic hepatitis C infection is no longer performed routinely; consequently, a simple test is needed to identify patients with significant hepatic fibrosis., Methods: Data were collected, retrospectively, on 923 consecutive patients undergoing percutaneous liver biopsy for chronic hepatitis C at King's College Hospital between 1 January 2000 and 30 June 2006; 602 patients were accepted to form the training set and a further 105 patients to form the validation set., Results: On liver biopsy, 132 (22%) had cirrhosis (Ishak F5-6) in the training set and 19 (18%) in the validation set. Factors found by multivariate analysis to be associated with fibrosis in the training set were used to construct the King's Score: age x aspartate aminotransferase x international normalized ratio / platelets. Area under receiver operating characteristic curves for predicting cirrhosis and significant fibrosis (F3-6) were 0.91 and 0.79, respectively. A King's Score of greater than or equal to 16.7 predicted cirrhosis in 34% of patients (odds ratio 36.2, 95% confidence interval, 22.0-59.6; P<0.0001) with sensitivity 86%, specificity 80% and a high negative predictive value of 96%; a score greater than or equal to 12.3 predicted F3-6 (odds ratio 33.9, 95% confidence interval, 15.2-34.4; P<0.001). The validation set confirmed the utility of this index, area under receiver operating characteristic curves 0.94 and 0.89 for cirrhosis and F3-6, respectively., Conclusion: The King's Score is a simple and accurate index for predicting cirrhosis in chronic hepatitis C. Patients with a score of less than 16.7 have a low risk of cirrhosis.

Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39-51 years), who had two liver biopsies performed (median biopsy interval 50, 34-74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5-33% = S1, 33-66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n = 59), declined therapy (n = 48), or had co-existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3-16.7, P = 0.02). Twenty-three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by > or =1 stage. On univariate analysis, fibrosis progression was associated with older age (P = 0.004), higher AST (P = 0.04), and steatosis (P = 0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1-111.1, P = 0.006). Kaplan-Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak > or =F3) and cirrhosis (Ishak F5-6) (P = 0.001 and P = 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti-viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.

Background/aims: Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT., Methods: We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality., Results: One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2)., Conclusions: The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.