Maximum Metabolic Capacity Research Articles

LiMAx Prior to Radioembolization for Hepatocellular Carcinoma as an Additional Tool for Patient Selection in Patients with Liver Cirrhosis.

Simple SummaryRadioembolization is a well-established therapeutic option for patients with advanced hepatocellular carcinoma. However, patients with advanced tumor disease and presence of liver cirrhosis often present a borderline liver function and are at risk for post-interventional hepatic decompensation. The aim of our study was to evaluate the ability of the LiMAx®, a non-invasive test for liver function assessment, in predicting post-therapeutic hepatic deterioration and thus improve patient selection prior radioembolization.Background and Aims: Radioembolization (RE) has recently demonstrated a non-inferior survival outcome compared to systemic therapy for advanced hepatocellular carcinoma (HCC). Therefore, current guidelines recommend RE for patients with advanced HCC and preserved liver function who are unsuitable for transarterial chemoembolization (TACE) or systemic therapy. However, despite the excellent safety profile of RE, post-therapeutic hepatic decompensation remains a serious complication that is difficult to predicted by standard laboratory liver function parameters or imaging modalities. LiMAx® is a non-invasive test for liver function assessment, measuring the maximum metabolic capacity for 13C-Methacetin by the liver-specific enzyme CYP 450 1A2. Our study investigates the potential of LiMAx® for predicting post-interventional decompensation of liver function. Patients and methods: In total, 50 patients with HCC with or without liver cirrhosis and not amenable to TACE or systemic treatments were included in the study. For patients prospectively enrolled in our study, LiMAx® was carried out one day before RE (baseline) and 28 and 90 days after RE. Established liver function parameters were assessed at baseline, day 28, and day 90 after RE. The relationship between baseline LiMAx® and pre-and post-interventional liver function parameters, as well as the ability of LiMAx® to predict hepatic decompensation, were analyzed. Results: We observed a strong association between baseline LiMAx® and bilirubin, albumin, ALBI grade, and MELD score. Patients presenting with Child–Pugh score B 28 days after RE or with a deterioration in Child–Pugh score by at least one point had a significantly lower baseline LiMAx® compared to those with Child–Pugh score A or with stable Child–Pugh score. The ability of LiMAx® to predict hepatic decompensation after RE was determined using ROC curve analysis and was compared to MELD score and ALBI grade. LiMAx® achieved a substantial AUC of 0.8117, comparable to MELD score and ALBI grade. Conclusion: Patients with lower LiMAx® values at baseline have a significantly increased risk for hepatic decompensation after RE, despite being categorized as Child–Pugh A. Therefore, LiMAx® can be used as an additional tool to identify patients at high risk of post-interventional hepatic failure.

The Role of Metabolism in Migraine Pathophysiology and Susceptibility.

Migraine is a highly prevalent and disabling primary headache disorder, however its pathophysiology remains unclear, hindering successful treatment. A number of key secondary headache disorders have headaches that mimic migraine. Evidence has suggested a role of mitochondrial dysfunction and an imbalance between energetic supply and demand that may contribute towards migraine susceptibility. Targeting these deficits with nutraceutical supplementation may provide an additional adjunctive therapy. Neuroimaging techniques have demonstrated a metabolic phenotype in migraine similar to mitochondrial cytopathies, featuring reduced free energy availability and increased metabolic rate. This is reciprocated in vivo when modelling a fundamental mechanism of migraine aura, cortical spreading depression. Trials assessing nutraceuticals successful in the treatment of mitochondrial cytopathies including magnesium, coenzyme q10 and riboflavin have also been conducted in migraine. Although promising results have emerged from nutraceutical trials in patients with levels of minerals or vitamins below a critical threshold, they are confounded by lacking control groups or cohorts that are not large enough to be representative. Energetic imbalance in migraine may be relevant in driving the tissue towards maximum metabolic capacity, leaving the brain lacking in free energy. Personalised medicine considering an individual’s deficiencies may provide an approach to ameliorate migraine.

The additive effects of oil exposure and hypoxia on aerobic performance in red drum (Sciaenops ocellatus)

Aerobic scope, the difference between standard metabolic requirements and maximum metabolic capacity, is considered a particularly important metric influencing ecological success in fishes. Crude oil exposure can impair cardiorespiratory function in fishes, which reduces maximum metabolic rate, aerobic scope, and may impair ecological performance. Oil exposure is not the only environmental stressor that can affect aerobic scope, especially in areas affected by crude oil spills. Hypoxia (low dissolved oxygen) is also known to constrain maximum metabolic rate, yet there has been little effort to explore how hypoxia may influence the magnitude of metabolic injury following oil exposure. Therefore, our goal was to investigate the effects of acute oil exposure and hypoxia on the metabolic performance of red drum (Sciaenops ocellatus), an economically important fish common in the Gulf of Mexico. Here, sub-adult red drum were exposed to crude oil for 24 h before being exposed to hypoxic conditions following exhaustive exercise. Our results show that hypoxia exposure combined with crude oil exposure results in significantly reduced aerobic scope, which was additive compared to the reductions caused by each stressor alone. We also quantified hypoxia tolerance among treatments following exposure, and our results showed no changes to hypoxia tolerance among individuals, regardless of exposure to hypoxia or oil. These data offer insight into the metabolic constraints facing fishes exposed to oil while concurrently subjected to hypoxia, a notable climate change stressor.

Effects of different predator stress on vulnerability to predation and the underlying physiological and behavioral mechanisms of this vulnerability in juvenile qingbo (Spinibarbus sinensis)

Differences in the early life history would have a profound influence on the survival of the animal during the later life stages. We aimed to examine the effect of predator stress on vulnerability to predation in fish and the possible underlying behavioral and physiological mechanisms of this vulnerability. For this, we selected juvenile qingbo (Spinibarbus sinensis) as the prey and its natural predator, the southern catfish (Silurus meridionalis), as the predator. The juvenile qingbo were reared together with free predators (lethal group), caged predators (non-lethal group), and without predators (control group) for 4weeks at 25±0.5°C. After predator acclimation, predation mortality was evaluated to understand the potential difference in vulnerability to predation among these treatments when prey fish from each treatment group was cultured together with the predator. To investigate the possible physiological and behavioral mechanisms of this vulnerability, we measured the following parameters under the same environmental conditions: metabolic response parameters such as routine metabolic rate (RMR), maximum metabolic rate (MMR), and metabolic scope (MS=MMR−MS); routine activity level determined by measuring the total movement distance, percentage of time spent moving or hiding, and average velocity while moving; fast-start escape performance determined by measuring the response latency, maximum swimming speed (Vmax), and maximum acceleration (Amax). Both the lethal and non-lethal group fish exhibited significantly lower predation mortality, greater boldness (as suggested by the percentage of time spent hiding), and shorter response latency of fast-start response compared to those of the control group. Furthermore, the lethal group exhibited higher activity level, as evidenced by the increased amount of time spent moving at higher average speed and higher RMR. However, neither the fast-start parameters (Vmax and Amax) nor the maximum metabolic capacity (MMR and MS) of the two predator-stress groups differed from those of the control group. These results suggest that the S. sinensis cultured under predation stress was less vulnerable to predators because of shorter response latency and more explorative routine activities. However, the increase in spontaneous activity and enhanced alertness resulted in further energy expenditure in qingbo. Thus, the plasticity in physiology and behavior in qingbo may be one of the main anti-predator strategies that can increase the survival rate of this fish species under predator stress conditions.

Acclimatization of seasonal energetics in northern cardinals (Cardinalis cardinalis) through plasticity of metabolic rates and ceilings

Northern cardinals (Cardinalis cardinalis) are faced with energetically expensive seasonal challenges that must be met to ensure survival, including thermoregulation in winter and reproductive activities in summer. Contrary to predictions of life history theory that suggest breeding metabolic rate should be the apex of energetic effort, winter metabolism exceeds that during breeding in several temperate resident bird species. By examining whole-animal, tissue and cellular function, we ask whether seasonal acclimatization is accomplished by coordinated phenotypic plasticity of metabolic systems. We measured summit metabolism (V(O(2),sum)), daily energy expenditure (DEE) and muscle oxidative capacity under both winter (December to January) and breeding (May to June) conditions. We hypothesize that: (1) rates of energy utilization will be highest in the winter, contrary to predictions based on life history theory, and (2) acclimatization of metabolism will occur at multiple levels of organization such that birds operate with a similar metabolic ceiling during different seasons. We measured field metabolic rates using heart rate telemetry and report the first daily patterns in avian field metabolic rate. Patterns of daily energy use differed seasonally, primarily as birds maintain high metabolic rates throughout the winter daylight hours. We found that DEE and V(O(2),sum) were significantly greater and DEE occurred at a higher fraction of maximum metabolic capacity during winter, indicating an elevation of the metabolic ceiling. Surprisingly, there were no significant differences in mass or oxidative capacity of skeletal muscle. These data, highlighting the importance of examining energetic responses to seasonal challenges at multiple levels, clearly reject life history predictions that breeding is the primary energetic challenge for temperate zone residents. Further, they indicate that metabolic ceilings are seasonally flexible as metabolic effort during winter thermoregulation exceeds that of breeding.

The effect of exercise training on the metabolic interaction between feeding and locomotion in the juvenile southern catfish (Silurus meridionalis Chen)

The southern catfish exhibits the largest decrease in critical swimming speeds (U(crit)) during digestion among the fish species that have been investigated. To test whether the maximum metabolic capacity of the southern catfish was improved after exercise training to alleviate the competitive interaction between digestion and swimming, we measured postprandial metabolic responses, U(crit) and oxygen consumption rates (MO(2)) during swimming in both fasting and digesting fish. Twenty-one days of training (50 min swimming at 60% U(crit) followed by 10 min chasing) did not produce significant differences in resting MO(2) (MO(2rest)) or postprandial peak MO(2) (MO(2peak)). However, it did result in a significant decrease in energy expenditure during digestion. Feeding caused a significant decrease in U(crit) and an increase in active MO(2) (MO(2active)), whereas training caused a significant increase in U(crit) but no significant change in MO(2active). Neither digestion nor training had a significant effect on metabolic scope (MO(2active)-MO(2rest)). Training had no interactive effect on postprandial changes in any measured variable, so we conclude that training did not alleviate the competitive interaction between digestion and swimming. Our results suggest that: (1) the metabolic capacity of nontrained fish cannot support the metabolic demands of both digestion and locomotion simultaneously, and swimming metabolism, therefore, is sacrificed to sustain digestion when feeding and locomotion are combined (digestion-prioritization mode); (2) the metabolic capacity and metabolic mode of competition did not change after training, but trained fish did exhibit improved swimming performance, possibly due to their increased rate of O(2) extraction.

Differences in Michaelis–Menten kinetics for different cultivars of maize during cyanide removal

Knowledge of the kinetic parameters, the half-saturation constant ( K m) and the maximum metabolic capacity ( v max), is very useful for the characterization of enzymes and biochemical processes. Little is known about rates of which vegetation metabolizes environmental chemicals. It is known, however, that vascular plants possess an enzyme system that detoxifies cyanide by converting it into the amino acid asparagine. This study investigated the differences in Michaelis–Menten kinetics of cyanide removal by different cultivars of maize. Detached leaves (1.0 g fresh weight) of seven different cultivars of maize ( Zea mays L.) were kept in glass vessels with 100 mL of aqueous solution spiked with potassium cyanide at 25±0.5 °C for 28 h. Four treatment concentrations of cyanide were used, ranging from 0.43 to 7.67 mg CN L −1. The disappearance of cyanide from the aqueous solution was analyzed spectrophotometrically. Realistic values of K m and v max were estimated by a computer program using non-linear regression treatment. Lineweaver–Burk plots were also used to estimate the kinetic parameters for comparison. Using non-linear regression treatments, values of v max and K m were found to be between 10.80 and 22.80 mg CN kg −1 h −1, and 2.57 and 7.09 mg CN L −1, respectively. The highest v max was achieved by the cultivars HengFen 1, followed by NongDa 108. The lowest v max was demonstrated by JingKe 8. The highest K m was found in NongDa 108, followed by HengFen 1. The lowest K m was associated with JingKe 8. Results from this study indicated that significant removal of cyanide from an aqueous solution was observed in the presence of plant materials without apparent phytotoxicity, even at the high concentration of cyanide used in this study. All maize cultivars used in this study were able to metabolize cyanide efficiently, although with different metabolic capacities. Results also showed a small variation of metabolic rates between the different cultivars. This leads to the conclusion that plants can be used as a phytoremediation agent in the detoxification of cyanide, presenting a feasible option for cleaning up soils and water contaminated with cyanide.

Cyanide Removal by Chinese Vegetation. Quantification of the Michaelis-Menten Kinetics (6 pp)

Little is known about metabolism rates of environmental chemicals by vegetation. A good model compound to study the variation of rates among plant species is cyanide. Vascular plants possess an enzyme system that detoxifies cyanide by converting it to the amino acid asparagine. Knowledge of the kinetic parameters, the half-saturation constant (Km) and the maximum metabolic capacity (vmax), is very useful for enzyme characterization and biochemical purposes. The goal of this study is to find the enzyme kinetics (K(M) and vmax) during cyanide metabolism in the presence of Chinese vegetation, to provide quantitative data for engineered phytoremediation, and to investigate the variation of metabolic rates of plants. Detached leaves (1.0 g fresh weight) from 12 species out of 9 families were kept in glass vessels with 100 mL of aqueous solution spiked with potassium cyanide at 23 degrees C for 28 h. Four different treatment concentrations of cyanide were used, ranging from 0.44 to 7.69 mg CN/L. The disappearance of cyanide from the aqueous solution was analyzed spectrophotometrically. Realistic values of the half-saturation constant (KM) and the maximum metabolic capacity (vmax) were estimated by a computer program using non-linear regression treatments. As a comparison, Lineweaver-Burk plots were also used to estimate the kinetic parameters. The values obtained for K(M) and vmax varied with plant species. Using non-linear regression treatments, values of vmax and K(M) were found in a range between 6.68 and 21.91 mg CN/kg/h and 0.90 to 3.15 mg CN/L, respectively. The highest vmax was by Chinese elder (Sambucus chinensis), followed by upright hedge-parsley (Torilis japonica). The lowest Vmax was demonstrated by the hybrid willow (Salix matssudana x alba). However, the highest K(M) was found in the water lily (Nymphea teragona), followed by the poplar (Populus deltoides Marsh). The lowest K(M) was demonstrated by corn (Zea mays L.). The values of vmax were normally distributed with a mean of 13 mg CN/kg/h. Significant removal of cyanide from aqueous solution was observed in the presence of plant materials without phytotoxicity, even at high doses of cyanide. This gives rise to the conclusion that the Chinese plant species used in this study are all able to efficiently metabolize cyanide, although with different maximum metabolic capacities. A second conclusion is that the variation of metabolism rates between species is small. All these plants had a similar K(M), indicating the same enzyme is active in all plants. Detoxification of cyanide with trees seems to be a feasible option for cleaning soils and water contaminated with cyanide. For phytoremediation projects, screening appropriate plant species adapted to local conditions should be seriously considered. More chemicals should be investigated to find common principles of the metabolism of environmental chemicals by plants.

Removal of cyanide by woody plants

Hydrogen cyanide is a high volume production chemical that causes severe environmental problems. The toxicity of potassium cyanide (KCN) to basket willow trees ( Salix viminalis) was tested. In aqueous solution, 2 mg CN l −1 as KCN depressed the transpiration after 72 h about 50%. Trees exposed to 0.4 mg CN l −1 in aqueous solution showed initially a depression of transpiration, but recovered. Doses of 8 and 20 mg CN l −1 in aqueous solution were quickly mortal to the trees. At the end of the test, almost all cyanide had disappeared from the solutions. Levels of cyanide in plants were related to the toxicity, with no elevated levels of cyanide in plants exposed to 0.4 mg CN l −1. Willows grown in sand survived 423.5 h irrigation with 20 mg CN l −1. Willows grown in sand irrigated with 50 mg CN l −1 died within a few days. The roots of the surviving willows were able to consume about 10 mg CN kg fresh weight −1 h −1. Vascular plants possess the enzymes beta-cyanoalanine synthase and beta-cyanoalanine hydrolase, which convert free cyanide to the amino acid asparagine. The in vivo capacity of woody plants (willow, poplar, elder, rose, birch) to remove cyanide was evaluated. Tests were performed with detached leaves and roots in KCN solutions of different concentrations. The highest removal capacity was obtained for basket willow hybrids ( Salix viminalis x schwerinii). The Michaelis–Menten kinetics was determined. Realistic values of the half-saturation constant, K M, were between 0.6 and 1.7 mg CN l −1; the maximum metabolic capacity, v max, was around 9.3 mg CN kg fresh weight −1 h −1. The removal of cyanide by plants might be useful in phytoremediation and treatment of wastewater from gold mining.

Localization of metabolic restriction point in cows of differing genetic merit

AbstractMilk synthesis and secretion have a high priority in the metabolism of the lactating cow. At peak lactation the nutrient needs of the mammary gland are of such magnitude relative to total metabolism that the udder has been compared with a parasite. The question arises: has the udder taken control of the cow? The aim of this study was to investigate whether the metabolic restriction point determining maximum milk output is localized at the level of the mammary gland itself or elsewhere in the body. The results indicate that the restriction point determining the maximum metabolic capacity is not localized in the udder as indicated by the ability of the mammary tissue to increase further its rate of milk secretion and therefore the maximum capacity is determined at the level of the whole body.

Pharmacokinetic factors affecting antidepressant drug clearance and clinical effect: evaluation of doxepin and imipramine--new data and review.

The selection of a starting dose for an antidepressant, and subsequent clinical titration to an appropriate therapeutic dosage, should be based on pharmacokinetic and pharmacodynamic principles. In the past decade, therapeutic monitoring of antidepressant drugs and use of pharmacokinetic principles have been shown to be an improvement over the dose-response approach. Endogenous (e.g., genetic metabolic phenotype, hepatic blood flow, and protein binding) and exogenous factors (e.g., smoking, dietary habits, concurrent medications) are capable of influencing physiological and pharmacokinetic variables in patients, accounting for the marked interindividual differences in the clearance rates of cyclic antidepressants. Interpatient variability for steady-state concentrations in plasma (Cpss) greater than 20-fold are observed at a fixed dose of imipramine (r2 = 0.525, df = 346, t = 19.541, P less than 0.0001) or doxepin (r2 = 0.506, df = 128, t = 11.403, P less than 0.0001). Analysis of doxepin in plasma vs estimated in oral clearance for 61 patients demonstrates a significant decline in oral clearance as a function of Cpss. At doses approaching the upper range recommended for the treatment of depression, Cpss appear to approach, in at least a few individuals, the maximum metabolic capacity of the patient (Vmax), leading to greater-than-expected increases in concentrations for a given dosage increment. Significant alterations in oral clearance are observed when medications are administered concomitantly. A greater-than-threefold difference in mean oral doxepin clearance rates is observed between two groups of patients receiving additional medications that are either inducers or inhibitors (P less than 0.0001, df = 32, t = 6.687). Pharmacokinetic principles defining and explaining the determinants of oral clearance can provide the clinician with a greater insight into the reasons for therapeutic failure and toxicity.

Norepinephrine thermogenesis in seasonally acclimatized and cold acclimated red-backed voles in Alaska.

The calorigenic response (millilitres O2 per gram pre hour) to injected norepinephrine (NE) was compared as an index of nonshivering thermogenesis (NST) in the following groups of the Alaska red-backed vole (Clethrionomys rutilus): (1) summer, (2) fall acclimatized, (3) winter acclimatized, (4) 20 degrees C acclimated and (5) 5 degrees C acclimated. The metabolic response was tested at thermoneutrality (25 degrees C) and during cold exposure (5 degrees C). Winter acclimatized voles showed a significantly greater metabolic response to NE than summer voles at both 25 degrees C and 5 degrees C. In summer or winter voles the total metabolic rate after NE (Mne) was similar at 25 degrees C and 5 degrees C but the fraction of the total caused by exogenous NE was lower at 5 degrees C. Thus, thermogenesis during cold exposure and resulting from exogenous NE appear to be based on the same mechanism, and NE has thermoregulatory significance in these voles. The magnitude of the NE response in winter voles was comparable to he highest values reported for bats and exceeded levels reported for other adult small mammal species. Summer acclimatized voles and those acclimatized to 20 degrees C in the laboratory were comparable in their response to NE but winter acclimatized voles were significantly more sensitive to NE than voles acclimated to 5 degrees C. The seasonal winter peak in MNE coincided with peaks previously found for maximum metabolic capacity (MMAX), maximum brown fat, and the period of coldest temperature in December-January. the ratio of MNE to Mmax was similar throughout the year. The results suggest that small arctic-subarctic rodents have a greater capacity for NE stimulated NST than rodents from temperate latitudes probably because they are acclimatized to colder seasonal condtions.

Estimation of maximal aerobic power using stairclimbing--a simple method suitable for industry.

Data on the energy cost and heart rate of diverse Indian and U.S. subjects for stair-climbing, with or without external loads in both paced and unpaced manners, have been used to establish relations between metabolic costs, speeds of ascent and heart rates. A technique for estimating the maximum metabolic capacity from the heart rate of an indvidual climbing stairs at his own free pace has been presented. Formulae for deriving the maximum work capacity from the heart rate for different age groups are given.