How To Improve Your Metabolism

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Xpress Fat Loss Workouts Summary


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Metabolic Effects of Immune Response Mediators

When the organism is stressed by an injury, infection or illness, the daily swing of insulin- and glucagon-mediated metabolic shifts between fed and fasted states is disturbed. The organ system charged with recognising and responding to an injury is the immune system, which has the capacity to radically change body protein and energy metabolism and thus body composition 5 . The antigen-presenting cell (APC) of the immune system is typically a macrophage, tissue monocyte or skin dendritic cell. The APC contacts an antigen, phagocytoses it, processes an antigenic determinant, and brings it to its surface in an HLA-restricted manner in order to trigger an immune response. This immune response requires both the presence of a specific epitope from the antigen and the elaboration of one or more non-specific signals, chiefly via secretion of the cytokine IL-1. IL-1 secretion triggers activation of T cells and other portions of the immune response. The subsequent APC-initiated signals include...

Perturbation of Energy Metabolism

The mechanism of radiosensitization by modulators of energy metabolism is not clear. No radiosensitization was observed when low concentrations of 2-deoxyglucose and rote-none were used in combination to achieve a steady-state decrease in the adenylate energy charge of Chinese hamster ovary cells, even though very low energy levels were maintained for up to 4 h and DNA repair was inhibited (594). This result suggests that a complete collapse of energy metabolism may be required to achieve radiosensitization, and that the mechanism may involve secondary events, such as failure to maintain ionic ho-meostasis, rather than simply a lack of ATP to carry out repair. It could be that the processes that result in damage fixation are equally inhibited by a low energy state, and that both damage fixation and damage repair recover when the ATP is restored. It is possible that under certain conditions, the balance could be shifted the other way, inhibiting damage fixation while permitting repair....

Brain activity energy metabolism and neurotransmitter cycling

Epidemiological, cross-sectional and prospective associations between T2DM and moderate cognitive impairment of memory and executive functions have been discovered and were reviewed by Pasquier et al. (2006). Both vascular and non-vascular factors were found to be the reasons for dementia in diabetes (Stewart & Liolitsa 1999). Direct study using functional BOLD MRI of brain activation has shown that hypoglycaemia induced impairment of brain function is associated with task specific localised reduction in brain activation (Rosenthal et al. 2001). Higher increase of deoxygenation, depicted as higher BOLD signal in active brain areas, can help to overcome the energy shortage caused by hypoglycaemia (Rosenthal et al. 2001) or micovascular damage in type 1 diabetic patients (Wessels et al. 2006) with retinopathy. Certain overcompensation mechanisms can be observed in 31P and 1H MR spectroscopic observation of energy metabolism in type 1 diabetic patients, where, in contrast to healthy...

A labelled glucose analogue an indirect probe to measure energy metabolism

How does FDG work Using similar pathways to glucose, once FDG is intracellu-larly transported it can be phosphorylated to FDG-6-phosphate by the enzyme hexokinase (Figure 13.3). However, in contrast to phosphorylated glucose, FDG-6-phosphate is not a significant substrate for further reactions. Hence, the phosphory-lated FDG is accumulated in cells, reflecting hexokinase activity and providing regional information on energy metabolism. Since FDG gives information on the activity of the enzyme and not the concentration of the specific macromolecule, it can be categorized as an indirect imaging probe.

Brain Energy Metabolism In Bipolar Depression

Bipolar disorder as manifested by its opposite poles of depression and mania is characterized by decreased or increased motoric and mental energy expenditure. Does such a unique presentation suggest altered states of brain energy metabolism in this disorder Although the brain makes up about 2 of our total body weight, it consumes about 20 and 25 of total body dioxide and glucose, respectively. Neural activity is dependent upon energy metabolism mainly for the active transport of ions and other molecules through cellular membranes needed for neural excitation. Energy consumption is particularly high for Na+ K+-ATPase and Ca2+-ATPase in plasma and endoplasmic membranes. Brain energy metabolism is reflected in ade-nosine-triphosphate (ATP) turnover. ATP, an energy-rich molecule with two high-energy phosphoanhydride bonds, is the energy donor in most energy-consuming processes, and its production in the brain is highly regulated. Another energy-rich molecule with high-energy phosphate is...

Energy Metabolism In Pd

The rate of intracellular energy metabolism is reflected by the ratio of inorganic phosphate (Pi) to phosphocreatine (PCr), readily measured with 31P-MRS. The measurement of this ratio in resting muscle has been shown to be a useful diagnostic test for mitochondrial disease (78). Penn et al. have used 31P-MRS to investigate energy metabolism in muscle in patients with PD. The Pi PCr ratio was significantly increased in PD, suggesting a small, generalized mitochondrial defect (79). Further studies are needed to determine whether these changes are limited to a clinically definable subset of parkinsonian individuals. 31P-MRS studies of brain have recently been reported in MSA and PD (80). In these studies, patients with MSA showed significantly increased Pi content and reduced PCr content, whereas those with PD showed significantly increased Pi but unchanged PCr, suggesting abnormal energy metabolism in both disorders. An alternate approach to study energy metabolism is with 1H-MRS....

Energy Metabolism

Ferent components, with the basal metabolic rate usually being the largest component. Physical-activity-induced thermogenesis can vary substantially between different individuals. Other components of TEE are diet-induced thermogenesis (DIT), drug-induced thermogenesis, and the thermoregulatory component. Gas-exchange measurements made in patients in the awake-relaxed condition after an overnight fast allow determination of the so-called resting energy expenditure (REE). Under those conditions, the thermic effect of food is considered insignificant and it is assumed that the ambient temperature is within the thermoneu-tral zone for the individual. REE thus comprises the sleeping basal metabolic rate and the energy cost of arousal. Based on the assumption that REE is the major component of TEE in sedentary persons, several studies have measured REE in COPD patients. After adjustment for the metabolically active fat-free mass, REE was found to be elevated in COPD 25 . While in healthy...

Nutrition of the heart and myocardial protein turnover

The recent interest in healthy nutrition for the heart has almost exclusively focused on cholesterol because of its role in the development of coronary artery disease. There is little appreciation of the fact that, in terms of general descriptors of energy metabolism, heart muscle functions not simply as a conformer in response to substrate availability,65 but that substrate utilisation is controlled by the physiological demands on the system. Likewise, there is little appreciation of the fact that the heart stores endogenous substrates such as glycogen and triglycerides, and it does so in response to changes in the dietary state.66 67 In contrast to skeletal muscle, starvation increases the tissue content of both glycogen and triglycerides in heart muscle, an observation consistent with a biologist's definition of true hibernation.

Substrate competition

Lactate, fatty acids, ketone bodies, and amino acids. Subsequent work by Keul et al.2 has established that the contribution of fuels to the fuel of respiration for the heart depends on the physiological state of the whole body, which can vary greatly. The data from Keul's work are of interest, because they show glucose uptake to be relatively constant (16-31 ), whereas the uptake of fatty acids plus ketone bodies and the uptake of lactate vary considerably (from 25 to 63 , and from 5 to 61 , respectively). This observation is of relevance with respect to fatty acids and ketone bodies. Although fatty acid oxidation can be almost completely suppressed when lactate and pyruvate are abundant, there is a consistent rate of carbohydrate use. The need for glucose or lactate is most probably the result of the need for pyruvate carboxylation and the anaplerosis of the citric acid cycle. In keeping with this hypothesis we have shown that lactate (40 mmol l) suppresses glucose uptake by the...

Origin and Nutrient Determinants

Since the time of Lavoisier, it has been known that the ingestion of foods by animals and humans produces an increase in oxygen consumption. This increase in metabolic rate, originally called 'specific dynamic action' (SDA) is now widely referred to as the 'thermic effect' (TE) of food or 'diet-induced thermogenesis' (DIT) 1 . This effect starts generally 1 h after ingestion, reaches a maximum after 3 h later, and continues at this level for several hours 2 . The DIT is a component of the total energy expenditure, which includes energy expenditure required for performance of cellular and organ functions (basal metabolism BM ), physical activity, and thermoregulation of body temperature. Supplementary energy is required for metabolic processes taking place during growth, pregnancy, and lactation 3 . In quantitative terms DIT represents about 10 of total energy expenditure (15

The Metabolic Processes

The many forms of cytochrome P450 enzymes (called isoenzymes19) are grouped into families denoted by the letters CYP (from cytochrome P450) followed by numerals. The majority of enzymes concerned with human metabolism belong to familes CYP1,2 and 3. Within these families, are subdivisions denoted by a capital letter followed by a numeral. The family CYP3A is numerically the most important, being involved in the biotransformation of the majority of all drugs indeed CYP3A4 is expressed outside the liver and may be an important factor that explains poor oral availability of many drugs. Over 100 drugs are known substrates for CYP2D6, > 60 for CYP2C9 and > 50 for CYP2C19.20 Another isoenzyme CYP 2E1, catalyses a reaction involved in the metabolism of alcohol, paracetamol, oestradiol and ethynyloestradiol.

Summary And Conclusions

Opments to provide relevant information. Novel pulse sequences may provide more information regarding substantia nigra pathology in PD. The use of MR as a tool to measure regional iron concentrations should provide more information regarding the relationship between iron accumulation and parkinsonian symptoms. MRS provides a sensitive tool for the researcher to investigate in vivo the possible contribution of abnormalities in brain energy metabolism to the pathogenesis of PD. MRS also allows the assessment of other metabolite changes in PD, for example, providing for the evaluation of the potential importance of changes in regional brain glutamate content. Lastly, fMRI provides the potential to evaluate, in a noninvasive fashion, the role played by the basal ganglia in motor control and in cognition in normal individuals as well as in PD.

Mixed Venous Oxygen Saturation

At the resting metabolic state the Sv02 is normally 75 . Under anesthesia the Sv02 may rise to 85 as oxygen consumption substantially diminishes. Decreases in Sv02 during surgery can be due to low cardiac output, as tissue supply is reduced in relation to demand, or to insufficient anesthesia, where the oxygen consumption increases relative to supply.

Physical Activity Level

But the raw materials and analytical equipment are expensive and considerable expertise is required 52 . Stable isotopes 2H and 18O are used to enrich the body water pool. These are then lost from this pool as water (in the breath, urine and sweat) and additionally in the case of 18O, as CO2 in the breath. Samples of urine or blood are collected at the beginning and end of the study period, which is typically of the order of 2 weeks. These are then analysed using mass spectrometry. The washout curve for 18O is steeper than for 2H and the difference represents CO2 production - an indirect measure of metabolic rate.

Structure Activity Relationships

A-Melanotropin (a-MSH), was one of the first peptide hormones isolated from the pituitary gland (131-135). This hormone plays an important role in skin pigmentation. Other effects ascribed to this hormone include (l)regulation of the release of pituitary and peripheral hormones, such as somatostatin and corticotropin (2) sebotro-phic effects, adrenal steroidogenesis, immune response, cardiovascular and metabolic effects and (3) important roles in the CNS such as (a)control over learning, memory, motivation, sleep, sexuality, and food intake (associated with obesity) (b) effects on neurotransmission such as cholinergic and dopaminergic systems (c) neurochemical effects (d) hypothermic and antipyretic effects (e) effects on nerve regeneration and (f) interactions with other neuroactive compounds such as opiates.

Protection by Anoxia or Hypoxia

Other metabolic effects observed after thiol administration include hypotension, hypothermia, and hypoxia (271). An increase in serotonin level has also been noted in rats after injection of amino thiols (272). Release of endogenous thiols is another metabolic effect of he radioprotective thiols. This has been sed not only by amino thiols but also by serotonin and hypoxia-causingcompounds, as well as by the anoxic state (273). This increase in cellular thiol content is often 30- to 40-fold greater than the amount of thiol supplied by the protective agent. Protective effects of the amino thiols in Ehrlich ascites (274) and other turner cells (275), as well as in mice (276), show direct correlations with the levels of nonprotein thiols. The natural radiosensitivity of mice was related to the concentration of thiol ups in the blood-forming tissues of the spleen (277), and development of radioresistance in cells was attributed to increased concentration of non-protein-bound thiols (278)....

Differences in Physical Responses to Exercise in Health and Disease

As a result of peripheral intrinsic alterations associated with certain forms of cardiovascular disease (i.e. chronic heart failure), the ability of the skeletal muscle to respond to an overload by muscle hypertrophy and improved oxidative energy metabolism may be impaired.

The Normal Adult Brain

Insulin and glucose energy metabolism Acute stimulation of the cerebral insulin receptor was achieved through a single intracerebroventricular injection of insulin. This procedure led to a dose-dependent stimulation of the glycolytic key enzymes hexokinase and phosphofructokinase in the cerebral cortex. Also, acute stimulatory effects of the hormone in the brain have been demonstrated for pyruvate dehydrogenase and choline acetyltransferase. These data may indicate that both glycolytic flux and pyruvate oxidation in the brain are stimulated by insulin paralleling the hormone's effect in non-nervous tissue. Short-term (1 day) or long-term (7 and 21 days) intracerebroventricular infusion of insulin have been found to exhibit a discrete anabolic effect on energy metabolism in the hippocampus as can be concluded from an 11 increase in the concentration of creatine phosphate, the storage form of ATP (Henneberg and Hoyer 1994). Figure 1. Schematic survey on the normal function of the...

Impairment of the Immune System

Stress, which in turn is an effect of the cell's impaired glucose metabolism. In advanced cancer patients, the altered energy metabolism and particularly the defective glucose utilisation are responsible for the reduced synthesis of reducing compounds by the pentose-phosphate pathway. However, the correct immune cell functioning requires adequate concentrations of intracellular reducing compounds and particularly GSH. In fact, several studies have widely demonstrated that GSH is essential for the progression of activated lymphocytes into the cell cycle from G1 to S phase the supplementation of GSH to the medium of cultured T cells increases the IL-2 receptor expression as well as its internalisation and degradation and ameliorates the blastic response of lymphocytes to PHA, anti-CD3 and recombinant IL-2. These findings confirm that impairment of energy metabolism, by inducing oxidative stress, is responsible for defective immune functions shown in advanced cancer patients and that...

Changes in Intermediary Metabolism During the Acute Phase Response

The acute-phase response includes coordinated adaptations in intermediary metabolism, which differ from those of starvation. A major difference is an increase in protein degradation in skeletal muscle. Recent studies have partially defined the mechanisms by which cellular protein turnover is regulated. Turnover rates vary for individual proteins. Regulatory proteins, such as those that control the cell cycle, have extremely rapid turnover for others, such as myofibrillar proteins in skeletal muscle, turnover is slower. Of the various cellular proteolytic pathways, the adenosine triphosphate-dependent ubiquitin-proteasome pathway has the predominant role in the regulation of protein turnover 3 . Cachexia is also characterised by changes in fat metabolism, including hypertriglyc-eridaemia, increased hepatic secretion of very-

Cytokine Regulation of the Acute Phase Response

The realisation that the response to illness and injury is an endogenous, not exogenous, process was a milestone in the understanding of cachexia. Our understanding that cytokines regulate the acute-phase response and cachexia resulted from several observations. For example, studies of hypertriglyceridaemia in experimental infections suggested indirect, or endogenous, control the degree of hypertriglyceridaemia was not necessarily correlated with infectious or tumour burden, and metabolic effects of infection could be reproduced with dead organisms or even with supernatants of macrophage cultures stimulated in vitro. The responsible protein was sought, isolated, and named cachectin, and its sequence was found to be identical to that reported for tumour necrosis factor (TNF) 5 . These studies concluded that this molecule was the mediator of cachexia. At approximately the same time, other investigators demonstrated that proteolysis in animals occurred after infusion of a...

Porcine Cardiac Valve Leaflet Studies

Initial studies noted that clinical harvesting of allograft heart valves necessitates a time period of warm ischemia, corresponding to the time from cessation of donor heartbeat to the time of transport. Leaflet cell metabolic response to varying warm ischemic time intervals was characterized in porcine aortic valve leaflets by magnetic resonance spectroscopy (Figure 18.1).4 Two hours following donor death, aerobic metabolism ceased, as evidenced by total depletion of adenosine triphosphate (ATP), no phosphorus production, and signifi Figure 18.1. Progression of porcine aortic valve leaflet metabolic state in response to increasing ischemic time. Phosphorus accumulates significantly following 40 minutes post harvest warm ischemia. Metabolism becomes anaerobic after two hours, as shown by depletion of ATP reserves and accumulation of lactate. Viable cells persist with anaerobic metabolism, up to 24-36 hours. A subsequent series of experiments was performed to separate out further the...

Radionuclide Approaches

In patients experiencing a major acute cardiac event (MACE), urgent catheterization defines the location and extent of the problem and delivers local therapy. Although the event is usually caused by a culprit lesion, where an occlusive thrombus formed on a ruptured plaque, coronary angioscopy has demonstrated there are typically a large number of lesions at other sites in the coronary tree (9) that have characteristics similar to the culprit lesion prior its acute rupture. This observation suggests a pancoronary arteritis (10). These lesions remain clinically silent, unless the thrombus propagates, leading to occlusion of the vessel. Since these lesions are difficult or impossible to identify angiographically, other approaches are under development. The metabolic rate of atheroma varies, but lesions with large amounts of lipid, especially oxidized low density lipoprotein, have a high metabolic rate. The high metabolic rate leads to increased vasa vasorum. The vasa vasorum are thin...

Exercise pathophysiology in cardiac diseases

Be recognised that, according to the laws of diffusion, there must be, and there is, some oxygen flow below the value of 2.39 kPa. However, in an incremental exercise test, this flow is not enough to guarantee sufficient oxygen delivery for the increasing metabolic rate over the entire WR range. It should also be recognised that the measured femoral venous PO2 represents a mean value of a large number of muscle fibres whose local ratio of blood flow to metabolic rate vary significantly. Indeed, lower values of femoral venous Po2 have been reported during submaximal exercise performed with inhalational hypoxia 12 . Furthermore, the nadir in femoral venous Po2 is more variable in CHF 11 . In some heart failure patients, femoral venous PO2 actually increases with further increases in WR up to peak exercise, which is suggestive of an intramuscular mismatching of perfusion to metabolic rate. In the current authors' experience, this happens in at least 20 of patients and, more frequently in...

Leptin and Energy Expenditure

Increasing evidence from human studies suggests that leptin predominantly influences the human energy balance through appetite changes, but it appears not to be involved in regulating energy expenditure 72 . None of the expected factors, such as resting metabolic rate, total diurnal energy expenditure or dietary-induced thermogenesis, was related to blood leptin concentrations 73 .

Chromatin Versus Other Determinants Of Aging

That cellular senescence may function, at least in part, as a second effector program. Consistent with this, cell senescence or senescence-like phenotypes can be induced through oxidative stress, a variety of DNA-damaging agents, activated oncogene expression, or agents known to disrupt higher order chromatin structure (29-34). Here as well, the suggestion has been made that mitochondrial nuclear interactions play an important role (28). As for the genome, it presumptively influences the progression and pattern of senescence at the organismal level in several ways. It sets the metabolic rate as well as levels of oxidative defense and DNA repair pathways. It encodes determinants of signaling pathways and a variety of gene products that protect the integrity of the genome or that trigger either check-point(s), apoptosis, or senescence in response to severe lesions (24,33). In addition, its structure may determine what aspect of chromosomal stability is likely to be critical for a given...

Thyroid Disorders Thyrotoxicosis

Weight loss is a common manifestation of hyperthyroidism and is present in about 90 of such patients (Table 2). TS-induced weight loss is the result of the effects of thyroid hormones on different organs and on metabolism, particularly on the cardiovascular system, the sympathetic nervous system, the alimentary system, muscle, and energy metabolism 18 . Interestingly, a direct effect of thyroid hormones on adipocytes is unknown, while an indirect effect mediated by catecholamines has been identified. In fact, by affecting local norepinephrine (NE) levels and adrenergic postreceptor signalling, thyroid hormones may influence the lipolysis rate in abdominal subcutaneous (sc) adipose tissue 19 .

Effects on Metabolism and Energy Expenditure

As already mentioned, most of the effects of thyroid hormones (TH) are exerted on energy metabolism, including protein, carbohydrate, and lipid metabolism 18 . The stimulation of energy metabolism and heat production is reflected by the increased basal metabolic rate (BMR), increased appetite, heat intolerance and slightly elevated basal body temperature that occur during TS. Despite the increased food intake, a state of chronic caloric and nutritional inadequacy often ensues, depending on the degree of the TS-induced increase of metabolism.

Hypothyroidism and Weight Loss

The effect of hypothyroidism on energy metabolism is opposite to that of hyperthyroidism and is characterised by a general decrease of energy metabolism and heat production. This is reflected in a reduced BMR, decreased appetite, cold intolerance, and slightly lower basal body temperature 18 .

Structural abnormalities

Cytochrome C release may follow the MPT or occur independently. In a recent study of cisplatin toxic-ity 27 decrease in oxidative phosphorylation was due to the inhibition of mitochondrial F0-F1-ATPase activity, but the decrease in oxidative phosphorylation was accompanied by hyperpolarization of the mitochon-drial membrane rather than a decrease in membrane potential that is usually associated with the MPT 28 . The studies also demonstrate a marked decrease in active Na transport and Na-K-ATPase activity that paralleled the decrease in F0-F1-ATPase activity and preceded increases in membrane potential in cisplatin treated renal proximal tubular cells. These studies would suggest that cytochrome C release into the cytoplasm and the subsequent formation of the apoptosome (see below) may occur independently of the MPT and that the initiation of cell death by disruption of energy metabolism can directly engage the caspase cascade.

Protein Energy Malnutrition

It has also been proposed that weight loss in patients with Crohn's disease is caused by increased resting caloric needs 15 . Actually, active inflammation, infection, sepsis, and accelerated mucosal turnover may result in increased nutritional requirements however, Chan and Stokes showed that total energy expenditure was not high in patients with Crohn's disease 16,17 . Thus, there is a lack of consensus as to whether the basal metabolic rate is increased in these patients.

Chronic Liver Disease

In patients with chronic liver disease, malnutrition is commonly seen regardless of whether its aetiology is alcohol or not 55, 56 , and it is known that the severity of liver disease correlates with the severity of malnutrition 57 . Mechanisms of malnutrition in chronic liver disease are multifactorial and include inadequate diet, impaired digestion or absorption of nutrients, metabolic disorders, and altered energy metabolism (Table 5). One of the most important factors of malnutrition in chronic liver diseases is poor dietary intake, especially in advanced stages. Dietary restriction of sodium, liquid, and or protein, recommended in order to prevent ascites, oedema, and encephalopathy, often results in malnutrition. Altered energy metabolism

Newer Emerging Technologies

One very effective use of genetic engineering is to remove the off-flavour caused in beers by the accumulation of diacetyl, and thereby reduce the beer maturation time required for the slow metabolism of the diacetyl by the maturing yeast which converts it into acetoin. The diacetyl is formed from a-acetolactate, and its formation can either be prevented or it can be rapidly removed before it can be converted into diacetyl. In order to prevent its formation, acetolactate decarboxylase (ALDC) can be cloned into the yeast. Thus yeasts transformed with the Acetobacter aceti ssp. xylinum ALDC gene have been used for beer production at the pilot scale and produce much less diacetyl during fermentation than their untransformed parents, resulting in a significant saving in maturation time and therefore production costs 42 (Fig 15).

Rosmediated Cytotoxicity Of Antitumor Drugs

ROS plays a significant role in the cytotoxicity of bleomycins since bleomycins form a complex with Fe2+ and molecular oxygen, and produce ROS to cleave DNA.4243 In addition, metallo-bleomycins can be activated by NADPH-cytochrome P-450 reductase,44 which results in activated ROS formation in the cells. Bleomycin-induced lung fibrosis is caused by elevated ROS level, and can be moderated by antioxidants.4546 Furthermore, it is also known that mitomycin C and 5-fluorouracil increase ROS levels in different tissues,47 48 which can contribute to their side effects. These data show that several anticancer drugs activate ROS formation both in normal tissues and tumors, and elevated ROS level can cause serious damage in well-oxygenated normal tissues. Since elevated ROS level can cause single-strand DNA breaks, anticancer drug treatment can activate PARP and, therefore, induce NAD+ catabolism, defective energy metabolism, and finally cell death. The PARP activation and PARP-related cell...

The Remarkable Value of Lysine

Within the group of essential amino acids, lysine plays a similarly important role as vitamin C does within the vitamin group. The daily requirement of lysine surpasses that of all other amino acids. Among its many functions, lysine is also the basic building block of the amino acid carnitine, which is important for energy metabolism in every cell.

What Experiments Determine That The Molecular Probe Is Binding To The Target Site

Flow developed by Kety, including the quantitative autoradiographic procedure using inert diffusible tracers for measuring local metabolic rates. This laid the groundwork for the crucial development the determination of glucose utilization as a measure of energy metabolism and functional activity. Since the use of radiolabeled glucose necessitated very short measurement times, the metabolically trapped 2-deoxyglucose was studied. This substrate, like glucose, was phos-phorylated by hexokinase, but the product could not be converted to fructose-6-phosphate, the next step in the glycolytic pathway. Therefore, 2-deoxyglucose-6-phosphate accumulates in brain to high levels because it is a poor substrate for downstream enzymes present and because glucose-6-phosphatase activity is very low in brain. Thus, 2-deoxyglucose could be used as a tracer for glucose with the autoradiographic technique that had been devised for the local cerebral blood flow method. Drawing on his experience with...

Tuber Storage Parenchyma Ultrastructure

The dormant parenchyma cells contain plastids (Gerola and Dassu, 1960 Tulett et al., 1969), mitochondria, dictyosomes (Kaeser, 1988), a nucleus, and nucleoli (Williams and Jordon, 1980). The cells have high levels of arginine, glutamine, and asparagines, very low metabolism of DNA and RNA, low amounts of polysomes, and low levels of polyamines (Favali et al, 1984). They are highly vacuolated, causing the nuclei and other organelles to be adjacent to the cell walls. The vacuoles are the storage site for fructans, and vesicles are formed in the cytoplasm, facilitating fructan synthesis from sucrose entering the cell (Kaeser, 1983). There is a close association of the plastids with mitochondria and the nucleus (Figure 4.6A) (Ishikawa and Yoshida, 1985). The nuclei display regions of condensed chromatin and contain several nucleoli (Figure 4.6C) (Jordan and Chapman, 1971). The plastids vary in structure and are found both scattered in the peripheral

Vitaminrelated Macrocytic Anemia

Vitamin B12 is a water-soluble vitamin that functions as a coenzyme for several enzyme reactions in human metabolism, including the conversion of methyl-malonyl coenzyme A (CoA) to succinyl-CoA and the conversion of homocysteine to methionine. Vitamin B12 is a required cofactor for DNA synthesis. Impaired DNA synthesis results in ineffective red, white, and platelet blood cell production. Deficiency of this coenzyme affects production of blood cells, resulting in anemia, and myelination of the central nervous system, resulting in the neurological symptoms, such as dementia, that are typical of the disease.13

Cachexia Cytokinesand Lipid Metabolism

Observed in the inhibition of lipogenesis and LPL by TNF-a 28 . The ability of IFN-y to mimic the effects of TNF-a on fat metabolism, and its apparent synergy with TNF-a suggest that IFN-y plays a prominent role in cancer cachexia. In cultured adipocytes, IL-1, TNF-p (lymphotoxin), IFN-y, and lipid mobilising factor (LIF) were all shown to decrease LPL activity 29 . Similarly, IL-1 and IFN-a, p, and y increased lipolysis in adipocytes in culture 30 .

Regulation of Appetite in the Elderly

Adaptive Relaxation Stomach

The hormone leptin is released from adipose tissue 18 and exerts its effects by decreasing food intake and increasing the metabolic rate. Circulating leptin levels increase in older men and decrease in older women 19 . The increase in lep-tin levels in men is related to the decrease in testosterone that occurs with aging 1 , which, in turn, is associated with muscle loss 20 and an increase in body fat 21 . Testosterone replacement in older men leads to a decline in leptin levels 1 . The increase in leptin with aging in men is considered a major factor in the increased anorexia of aging that occurs in males compared to females.

Nutrigenomics Research on Dietary Beef

In the experiments described in this chapter, we fed flies a diet containing 95 lean ground beef in order to determine the metabolic effects of consuming beef. Surprisingly, to our knowledge, 95 lean beef diets have not yet been used for nutrigenomics studies in animal models. As described below, our findings suggest that diets rich in 95 lean ground beef, soy, or palmitic acid prolong the larval period, but decrease the mean and maximal life span. However, only beef was able to significantly decrease triglyceride levels in adult flies. In the final section, we will discuss the implications of these findings, if any, in terms of human health and life span.

Complex Picture Emerges

Cardiac Cachexia Pathophysiology

At the same time, an increased metabolic rate due to increased energetic demands of specific tissues and general calorie-consuming factors such as increased body temperature may further contribute to an unfavourable balance of the body energy metabolism. As a result, the catabolic drive may chronically dominate the anabolic pathways. The constant drain of the body's energy reserves may eventually lead to a pathological tissue degradation.

An Alternative Hypothesis

The reduced survival in MHD patients with a low BMI has recently been explained by a novel hypothesis 7 . Briefly, both in healthy and MHD subjects, visceral organ mass (i.e. high metabolic rate compartment, HMRC) relative to whole body mass (HMRC BW) is inversely related to weight and urea distribution volume (V). V, as determined by urea kinetic modeling, is closely related to MM (fig. 1), whereas fat mass contributes only marginally. Viscera are the most likely source of uremic toxins, and their mass and metabolic activity may be related to uremic toxin generation. According to this hypothesis the concentration of uremic toxins in V is higher in subjects with a low V (and thus low MM and low BMI), resulting in an under-dialysis in low BMI patients when dosed by Kt V. Dialysis dose is currently pre-

Lipid Metabolism and Fat Loss in Cancer Patients

The pathophysiology of cancer cachexia is multi-factorial and involves many different mediators producing various metabolic effects that could be categorised as metabolic effects of the tumour on the host, and metabolic effects of the host's response to the tumour 1 . As previously mentioned, cachexia is characterised by profound changes in intermediary metabolism, particularly

LMF as a Pleiotropic Mediator

Energy metabolism is profoundly deranged during tumour growth. The mitochondrial uncoupling proteins (UCP)-1, -2, and -3 likely play essential roles in energy dissipation and disposal Glucose metabolism is also affected by LMF. Treatment of ex-breeder male NMRI mice with LMF isolated from the urine of cachectic cancer patients caused a significant increase in glucose oxidation to CO2, compared with control mice receiving phosphate-buffered saline 25 . Glucose utilisation was elevated in brain, heart, BAT, and gastrocnemius muscle. The tissue glucose metabolic rate was increased almost threefold in brain, accounting for the ability of LMF to decrease blood glucose levels. LMF also increased overall lipid oxidation. There was a significant increase in lipid accumulation in plasma, liver, and white and brown adipose tissue after administration of LMF. These results provide further evidence that changes in carbohydrate metabolism and loss of adipose tissue, together with increased...

Ischemic Stroke Cerebral Infarction

Inferior Cerebellar Cortical Stroke

The brain requires a constant and adequate blood flow to supply oxygen and glucose essential for its high energy metabolism. A constant blood flow is assured by an autoregulatory mechanism of arteries and arterioles they constrict in response to rising systemic blood pressure and dilate in response to falling systemic blood pressure. This mechanism operates while the arterial pressure remains between 50 and 160 mm Hg. One-

The Brain GutBrain Axis in the Regulation of Food Intake

The hypothalamic mechanisms regulating food intake and energy metabolism occur via interaction of the monoaminergic and the neuropeptidergic systems at various levels in the nervous system. The important components of these interactions include (1) early satiety signals from the gut relayed via gastrointestinal afferent vagal fibres to

Structure Of Biguanides

Structure Nateglinide

At the molecular level, precise target recep-tor( have not been identified. Metformin has been reported to activate the AMP-activated protein kinase system (AMPK) in primary hepatocytes (131). AMPK has been proposed as a key regulatory enzyme of carbohydrate and fat metabolism (132).This kinase is activated through an allosteric mechanism by binding 5'-AMP and also by phosphorylation. Activation of AMPK by phosphorylation is 5'-AMP dependent because the binding of AMP to the enzyme makes it a better substrate for AMPK kinase, which phosphorylates AMPK, and a poorer substrate for protein phosphatase 2C, which dephosphorylates it. AMPK kinase is also activated by 5'-AMP. These actions of 5'-AMP are antagonized by high concentrations of ATP, and thus the system

Primary Hyperparathyroidism

Lating calcium concentrations, PTH exerts metabolic effects, including a stimulatory effect on lipolysis. This effect has been demonstrated both in animal and in human adipose tissue 44, 45 . However, PHPT is not commonly characterised by significant weight loss and there is contrasting evidence in the literature concerning this effect. For instance, it has been reported that PTH excess may promote weight gain by impeding cate-cholamine-induced lipolysis 46 . In a study by Grey et al., it was reported that post-menopausal women with mild untreated PHPT are markedly heavier than age-matched controls 47 . Thus, PHPT cannot be definitively considered as an endocrine cause of weight loss, although a lipolyt-ic effect of PTH has been described.

Historical Perspectives

Interest in tumor metabolism has been stimulated once again by modern techniques such as position emission tomography (PET), sensitive mass spectrometry (MS), and high-resolution nuclear magnetic resonance spectroscopy (NMR). PET uses fluorine-18 labeled fluorodeoxyglucose (FdG) to detect tissue regions of high glucose uptake, which is indicative of up-regulated glycolysis and increased metabolic rate. FdG PET imaging has shown that most primary and metastatic human cancers have increased glucose uptake.17 This finding is indicative of a ''glycolytic switch'' in cancer cells and may be a precursor of tumor angiogenesis and metastasis.17

Functional Imaging Using Radiopharmaceuticals

Nuclear medicine provides several techniques for the detection of inflammation. Studies demonstrating inflammatory lesions were reported as early as in 1959, when Athens et al. (44) labeled leukocytes by intravenous injection of diisopro-pylfluoro-phospate labeled with 32P and demonstrated skin blisters in volunteers . Classically, scintigraphic imaging of inflammation has been done with 67Gallium-citrate, radiolabeled leukocytes, nanocolloids, nonspecific human immuno-globulins (HIGs), and 18F-deoxyglucose (FDG). Uptake mechanisms included direct binding to relevant inflammatory cells or proteins (radiolabeled leukocytes, 67Gallium-citrate, HIG) over hyperemia, and binding to lactoferrin excreted in loco by leukocytes or to siderophores produced by microorganisms (67Gallium-citrate). In addition, nonspecific local increases in blood supply, extravasation through vessels with increased permeability may give rise to expansion of the local interstitial fluid space (67Gallium-citrate,...

Malate-aspartate Shuttle

Citrate Malate Pyruvate Shuttle

As can be observed, the glutamine metabolism can be diverted to a number of different possible pathways that in turn share a number of intermediate metabolites and transport systems around the mitochondria. From the energy yield perspective, the GDH pathway is more efficient than TA (27 ATP instead of 9) (57), and usually is the favored pathway when glutamine metabolism must be accelerated in the cell, for example, as a consequence of glucose depletion (58). Also, glutamine and glucose metabolism are related to each other, as will be discussed specifically in the section on flexibility of animal cell metabolism. As a consequence of this metabolic flexibility, different cell lines will adjust the metabolic rates through GDH, alaTA, or aspTA pathways, depending on the specific culture conditions. Similar to glucose, glutamine is also consumed by most mammalian cell lines at high rates, normally associated with the general use of excess glutamine concentrations in the culture media. As...

Expression Pattern in Mammals

In keeping with the housekeeping gene characteristics of the mammalian ACBP gene, ACBP appears to be ubiquitously expressed from early stages of mammalian embryogenesis 24 as well as in adult tissues (reviewed in Ref. 25 ). However, the level of ACBP differs markedly among different cell types. High concentrations are found in steroid-producing cells (glomerulosa and fasciculate cells of adrenal cortex, leydig cells of testis) 26 , keteratinocytes, and cells from sweat and sebaceous glands 27 . Lower concentrations are found in epithelial cells involved in water and electrolyte transport (intestinal mucosa, distal convoluted tubules of kidney) 26 . Interestingly, fruit fly ACBP is also highly expressed in potassium-transporting cells in the urine-secreting Malpighian tubules 28 . Hepatocytes contain moderate amounts of ACBP, however, the total amount of ACBP in liver is relatively high due to the diffuse presence of ACBP in all hepatocytes. Also brain exhibits differential expression...

Alveolararterial oxygen difference

To date, there are few published arterial blood-gas data sets that allow direct comparison of pulmonary gas exchange between sexes. A recent review has discussed in detail sex and pulmonary gas exchange during exercise 136 . In the review by Hopkins et al. 136 , data compiled from previously published studies of 57 females (VO2,peak 3270 mL kg-1 min-1) and 135 males (VO2,peak 30-83 mL kg-1 min-1) showed that PA-a,O2 during heavy to peak exercise is greater in females than males for the same metabolic rate. Furthermore, 12 of the females with a VO2,peak of < 50 mL kg-1 min-1 had evidence of gas exchange impairment. In males of the same fitness level, < 2 had evidence of gas exchange impairment. It should be kept in mind that when lung size and fitness levels are controlled for, many of the gas exchange differences between sexes seem to be lost.

The Spine in the Lateral Projection

Dxa Lumbar Spine

The effect on BMD measured in the AP or PA projection from aortic calcification, facet sclerosis, osteophytes, and other degenerative changes in the spine can be nullified by quantifying the bone density of the spine in the lateral projection as shown in Fig. 2-15B. In addition, the highly cortical posterior elements and a portion of the cortical shell of the vertebral body can be eliminated from the measurement, resulting in a more trabecular measure of bone density in the spine. The measurement is not a 100 trabecular measure as portions of the cortical vertebral body shell will still be included in the measurement. In addition to the elimination of artifact or confounding degenerative changes, the lateral spine BMD measurement is desirable in those circumstances in which a trabecular measure of bone density is indicated and particularly in circumstances in which changes in trabecular bone are being followed over time. The higher metabolic rate of trabecular bone compared to...

Flowmetabolism coupling

Increases in local neuronal activity are accompanied by increases in regional cerebral metabolic rate (rCMR). Until recently, the increases in rCBF and oxygen consumption produced during such functional activation were thought to be closely coupled to the cerebral metabolic rate of utilisation of (CMRo2) and glucose (CMRglu). However, it

Expression Profile in Other Eukaryotes

Expression profiles of ACBP from other eukaryotes support the notion that ACBP could be involved in lipid metabolism, water and ion transport, energy metabolism, and membrane remodeling or all of these. Determination of ACBP expression profiles in different tissues of the fruit fly, using rabbit-rat anti-ACBP, show that the expression is high in cardia, in part of the potassium-secreting Malpigian tubules, in the fat body, and in the gametes of both sexes 28 . However, these results should be treated with caution because fruit flies express five short and three long ACBP isoforms (our unpublished data). Interestingly, the mRNA level of one of these isoforms, (gene product CG15829 with the potential to encode an 82-residue protein) is specifically induced for 1.5 hours after bacterial infection 47 . After 6 hours the mRNA level is still increased 3-fold and after 12 hours the mRNA level is back to normal. No change in mRNA level of this particular ACBP isoform is seen during fungal...

PaO2 and PaCO2 and the alveolararterial PO2 difference

It is important that the Pet,co2 should not be used as a direct index of either the level or pattern of change of Pa,co2. This is because Pet,co2 is, typically, less than or equal to Pa,cO2 at rest however, it becomes systematically greater than Pa,cO2 during incremental exercise, by an amount that depends upon both the metabolic rate and the pattern of breathing 61, 63 . The arterial blood is normally sampled over several, and ideally a whole number of, respiratory cycles the syringe value, therefore, represents the mean level of Pa,co2. Pet,co2, however, is an index of the peak of the intra-breath Alternatively, mean PA,co2 (estimated from the mid-point of the expiratory PA,co2 profile (fig. 9)) also provides a more appropriate index of Pa,cO2 during exercise than does Pet,co2 in normal subjects 2, 63 . Blood sampled from the dorsum of an appropriately hyperaemic hand, however, (i.e. providing a high blood flow through a region of very low metabolic rate) has been shown to provide a...

Regulation of Longchain Acyl CoA Concentrations in vivo

In order to evaluate the physiological relevance of the regulatory effects of LCACoA esters, it is of great importance to consider the intracellular concentration of these esters. The total cellular concentration of LCACoA esters has been reported to be in the range of 5-160 M, depending on the tissue and its metabolic state (Ref. 56 and references therein). The size of the intracellular pool of LCACoA esters is determined by the rates of fatty acyl-CoA synthesis and utilization. While acyl-CoA synthesis is largely determined by the rate of activation by acyl-CoA synthe-tases of either imported fatty acids, endogenously synthesized fatty acids, or fatty acids from lipolysis of cellular lipids, utilization is determined by the rate of degradation by -oxidation, incorporation into cellular lipids, acyl-CoA hydrolysis, and protein acylation. While the total cellular concentrations of LCACoA esters have been determined (see Ref. 56 for a review), the concentration of free unbound LCACoA...

Dose Calculation By Body Weight And Surface Area

Correlates better with many physiological phenomena, e.g. metabolic rate. The relationship between body surface area and weight is curvilinear but a reasonable approximation is that a 70 kg human has a body surface area of 1.8 m2. A combination of body weight and height gives a more precise value for surface area (which can be obtained from standard nomograms) and there are several more sophisticated methods.24

Proinflammatory Cytokines

Proinflammatory cytokine peptides were originally studied for their effect on immunological homeostasis in several areas, but they also exert potent activity towards regulation of metabolic responses 12 . During early post-injury or infectious conditions, the initial cytokine response to such insults likely mediates beneficial protective signalling of the immune system. Nevertheless, prolonged production of cytokines sustains some metabolic effects of the hypercatabolic state. Proinflammatory cytokines may function by autocrine (acting on the same cell), paracrine (acting on cells in the immediate area), or systemic mechanisms of action. They produce local tissue responses by cell-to-cell interaction at very low concentrations but also exert systemic effects at higher concentrations. Among cytokines, the proinflammatory ones (IL-1, IL-6, TNF-a, interferon IFN -a and IFN-y) have been more widely studied from a metabolic perspective 13 . solid tumours 15 , this cytokine has been...

Vitamin B1 or Thiamine

The active form of thiamine, thiamine pyrophosphate, is a coenzyme involved in energy metabolism reactions the requirement for thiamine is therefore related to energy expenditure 56 . Patients at risk for vitamin B1 deficiency include alcoholics, those on chronic peritoneal dialysis, those re-fed after starvation, and thiamine-deplet-ed persons who are given glucose 64 . The RDA of vitamin B1 is 1.1 mg per day for women over 50 years and 1.2 mg per day for men over 50 years (Table 3) 54 . Patients at high risk, such as alcoholics, may benefit from supplementation 54 . Excessive amounts of ingested thiamine are rapidly cleared by the kidneys. No evidence exists of thiamine toxicity by oral administration 50 .

CPET indices of relevance for cardiac patients

In 1985, Weber and Janicki 27 reported a still frequently utilised classification of heart failure severity, based on Vo2,peak. The value of Vo2,peak is reported as normalised for body weight, but does not take age, sex or fitness into account. Fitness is an important determinant of exercise capacity in CHF patients. Furthermore, although the study by Weber and Janicki 27 reports Vo2 normalised for body weight, it does not take obese subjects into account. By recognising that fat has a very low metabolic rate, V -kg1 will, therefore, underestimate the true Vo2 a better strategy would be to normalise to fat-free mass. This is an important issue for CHF, as obesity is frequently a comorbidity of CHF patients and also CHF can be misdiagnosed in obese subjects.

Processes Activated by Cytosolic Calcium Are Extremely Diverse

In skeletal muscle cells (page 14) a transmitter released from nerve axon terminals leads to the escape of calcium from the endoplasmic reticulum (Fig. 16.4). This activates several processes. First, calcium ions bind to a protein called troponin that is attached to the cytoskeleton. This causes the cytoskeleton to contract, using the energy released by ATP hydrolysis to do mechanical work (page 393). Second, the calcium binds to the protein calmodulin, which in turn activates glycogen phosphorylase kinase and hence glycogen breakdown as part of the feedforward control of energy metabolism (page 305).

DNA Microarray Analysis of Bacterial Pathogens

Brospinal fluid (CSF), and bacteria attached to a pharyngeal epithelial cell (ECC) line in vitro. Gene expression levels at these three sites were compared with levels when S. pneumoniae was grown in semisynthetic casein liquid medium. Such in vivo studies are limited by the difficulties of obtaining sufficient quantities of pure and relatively intact bacterial RNA from infected tissues. Interestingly, the majority of the genes (92 in the blood, 85 in CSF, and 90 after ECC) were expressed in a similar fashion as growth in culture medium. However, distinct patterns of gene expression in each anatomical site can be identified. Amazingly, only eight genes showed similar alterations in gene expression during bacterial growth in blood, in CSF, or during ECC (25). Two of the eight genes encode pspA (26) and prtA (27) previously characterized as virulence factors, three involved in manganese acquisition and transport (psa operon), two in energy metabolism and one transporter. Orihuela et al....

Mark A Lane George S Roth and Donald K Ingram Summary

Caloric restriction remains the only nongenetic intervention that has been consistently and reproducibly shown to extend both average and maximal lifespan in a wide variety of species. If shown to be applicable to human aging, it is unlikely that most people would be able to maintain the 30-40 reduction in food intake apparently required for this intervention. Therefore, an alternative approach is needed. We first proposed the concept of caloric restriction (CR) mimetics in 1998. Since its introduction, this research area has witnessed a significant expansion of interest in academic, government, and private sectors. CR mimetics target alteration of pathways of energy metabolism to potentially mimic the beneficial health-promoting and anti-aging effects of CR without the need to reduce food intake significantly. To date, a number of candidate CR mimetics including glycolytic inhibitors, antioxidants and specific gene-modulators have been investigated and appear to validate the...

Oxygen Delivery Oxygen Uptake And The Critical Oxygen

Critical Do2

As the hematocrit is reduced in 5 per cent steps, VO2 is maintained by a combination of rising cardiac output and falling PvO2, resulting in a larger fractional oxygen extraction. When these compensations no longer suffice to satisfy tissue oxygen requirements, metabolic work cannot be maintained, and VO2 falls resulting in an oxygen debt, rising lactic acid and deepening base deficit. Figure 4.4 The critical DO2. As the hematocrit is reduced in 5 per cent steps, VO2 is maintained by a combination of rising cardiac output and falling PvO2, resulting in a larger fractional oxygen extraction. When these compensations no longer suffice to satisfy tissue oxygen requirements, metabolic work cannot be maintained, and VO2 falls resulting in an oxygen debt, rising lactic acid and deepening base deficit.

Dietary Recommendations

Obesity has numerous adverse hemodynamic, cardiac structure and function effects, as well as a propensity for more ventricular arrhythmias. Almost one-third of morbidly obese patients have clinical evidence of HF and a significant increase in NYHA functional class can be achieved with weight reduction.31 On the other hand, it has been documented that obese chronic HF patients have similar or improved prognosis compared to normal or underweight patients32 although these results are subject to debate, a lower body weight is likely to be associated with heightened metabolic state, and an involuntary weight loss, as in the cardiac cachexia syndrome, is associated with a poor outcome.19 A liberalized fat intake is allowed for weight maintenance and adequate caloric intake in poorly nourished chronic HF patients, with normal or low levels of total and LDL cholesterol.

Experimental Models of Caloric Restriction and Applicability to Humans

Metabolic rate (short-term) Metabolic rate (long-term) Metabolic rate (long-term nighttime) Body temperature Thriiodothyronine (T3) Thyroxin (T4) To achieve the maximum benefit from CR, presuming its applicability, humans would need to reduce their caloric intake by about 30 or from approx 2500 calories per day to 1750 (in men). The tremendous popularity of diet books, pills, and associated weight-loss products illustrates the challenge that use of such a regimen on a wide scale would present. Thus, to achieve the potential benefits of CR, an alternative approach is needed. In considering possible biological mechanisms of CR, we hypothesized that, by targeting alteration of cellular energy metabolism, it might be possible to trick the body into shifting to a CR-like survival mode (9) without actually reducing food intake, and in this way mimic the effects of CR.

Caloric Restriction Mimetics

We first proposed the idea of CR mimetics in 1998 (10) and further expanded on this potential approach in a subsequent article in Scientific American (11). In our initial study, we reported that disruption of cellular glucose metabolism (e.g., glycolysis) using the glucose analogue 2-deoxy-D-glucose (2DG) fed in the diet to rats lowered body temperature and fasting insulin levels without significantly reducing food intake over a 6-mo period at the selected dose (10). The 6-mo duration of this study was insufficient to assess indices of biological aging or longevity, but did validate that it may be possible to mimic metabolic effects of CR without reducing food intake. A follow-up survival study in rats unfortunately indicated that the window between efficacy and toxicity was too narrow to make this particular compound useful. The concept of CR mimetics has been further validated in other experiments. For example, similarly to CR, 2DG has been shown to be neuroprotective in rodent...

Relationship between systemic and intracranial hemodynamics

Icp Waveform Interpretation

An advantage to the use of Sjvo2 is the ability to calculate additional intracranial oxygenation values, including cerebral metabolic rate (CMR02) and global cerebral oxygen extraction ratio (02ER). Table 4.3 provides the formulas used for oxygenation calculations that may be used to fine-tune systemic flow parameters to enhance brain tissue oxygenation. Figure 4.10 provides an example of systemic augmentation measures that may be used to enhance brain tissue oxygenation based on Sivo2 and ICP data. Cerebral metabolic rate (CMR02)

Possible Metabolic Targets for CR Mimetics

CR mimetics have been proposed that target a number of pathways related to energy metabolism such as glycolysis inhibitors, antioxidants, sirtuin regulators, and insulin sensitizers. As summarized previously, inhibition of glycolysis remains a promising target despite our disappointing results with 2DG. Given the popularity and general acceptance of the Free Radical Theory of Aging, antioxidants have been the focus of many studies in biogerontology (15).

Molecular imaging in drug discovery and development

It has already been pointed out that in drug discovery and development it is also very important to be able to study the absorption and metabolism of the therapeutic agent in the body. Although most of the pharmacokinetic and pharmacodynamic studies needed for clinical approval of a drug are first carried out in animal models, there is increasing interest in doing such studies directly in humans since this would reduce considerably the failure rate associated to the inappropriate human metabolism of drug candidates. To tackle this, a new method known as microdosing has been developed in which human metabolism data on new potential drugs can be obtained. This approach comprises administration of sub-pharmacological or sub-therapeutic dose of a novel drug candidate to a human volunteer. The potential drug can be labelled with a radioisotope and hence PET can be used to monitor its absorption and metabolism.

Pathophysiology of Lipodystrophy Mechanisms of Lipodystrophy The Effects of Protease Inhibitors


Different hypotheses have been put forward to explain the putative mechanism of HAART drugs in the development of lipodystrophy syndrome 116-120,122-124,126,134,141,147-152 . The first postulates that PIs primarily block cytochrome P450, which is involved in fat metabolism. The second postulates an interaction between PIs and human proteins. HIV protease has a sequence homology of 12 amino acids with two human proteins playing an important role in fat metabolism, namely, LDL-receptor-related protein (LRP) and cytoplasmic retinoic-acid-binding protein type-1 (CRABP-1). PIs inhibit both HIV protease and these two proteins. Inhibition of LRP leads to a reduction in the absorption of fatty acids by capillary endothelium and liver cells. This causes elevated serum triglycerides, visceral fat accumulation, buffalo humps, bull neck, insulin resistance, type II diabetes, breast hypertrophy, etc. Inhibition of CRABP-1 and cytochrome P450 3A isoform results in decreased cell differentiation and...

Mechanical Cardiac Pacing

Percussion Pacing

The myocardial response to external mechanical pacing depends on the duration of bradyasystolic arrest and the metabolic state of the myocardium. Percussion pacing is most successful very early in the course of witnessed arrests in this setting it usually elicits a single myocardial depolarization for each blow delivered. As myocardial hypoxia and ischemia intervene, the evoked QRS

Metabolism and Excretion of Ethanol

Small amounts of ethanol are metabolized in the gastric lining before absorption. Of the remaining ethanol, 90 is metabolized in the liver to acetaldehyde by hepatic alcohol dehydrogenase (ADH). The resulting acetaldehyde is converted to acetic acid by aldehyde dehydrogenase. In small or moderate amounts, the metabolites are nontoxic and readily excreted. Food contents in the stomach can slow absorption of alcohol, allow for more gastric metabolism of ethanol, and help to maintain lower blood alcohol concentrations. However, aspirin and gastric hyperacidity medication such as cimetidine can inhibit gastric ADH activity and thereby slow metabolism. ADH is not 100 specific for ethanol and can also metabolize other alcohols, including methyl alcohol.

Tyrosine Kinase Inhibitors

Oral imatinib is well absorbed, with a bioavailability of nearly 100 .12 Peak plasma concentration occurs within 4 h of administration, regardless of whether or not the dose is taken with food.13 Following oral administration, the elimination half-lives of imatinib and its major active metabolite are approximately 18 and 40 h, respectively.13 Repeat dosing does not have a significant impact on the drug's pharmacokinetics and accumulation is 1.5 to 2.5fold with daily administration.1213 In-vitro models have established that at clinically relevant concentrations, imatinib is approximately 95 protein bound, primarily to albumin and a1-acid glycoprotein.12 Hepatic enzymes, predominantly the cytochrome P450-3A4 isoenzyme, are responsible for the drug's metabolism.13 Other cytochrome enzymes, such as CYP1A2, CYP2D6, CYP 2C9, and CYP 2C19, also contribute to imatinib's degradation.13 Because many other medications can affect this metabolic system, imatinib is susceptible to alterations in...

Exercise testing as a metabolic stress model to investigate altered control of intermediary metabolism

Basic knowledge of skeletal muscle intermediary metabolism during exercise may be important to establish whether there is a potential role for some specific substrates in modulating skeletal muscle wasting. Skeletal muscle energy metabolism is impaired in patients with COPD during exercise. For example, some studies have revealed prematurely early increases in blood lactate levels in exercise in COPD 92, 93 . Steiner et al. 94 demonstrated that this lower energy status in COPD is reflected in changes in intramuscular metabolites during exercise. Thus, the authors observed significant adenine nucleotide loss, activation of substrate level phosphorylation and inosine monophosphate accumulation in the muscles of COPD patients during a short constant WR exercise test at 80 of the predetermined peak WR. This suggests that significant metabolic stress occurs in the skeletal muscle of COPD patients during whole-body exercise at low-work rates similar to those required for activities of daily...

Other Androgens Dehydroepiandrosterone

Welle et al. 54 reported that the administration of 5.5 mmol dehydroepiandrosterone (DHEA) day for 4 weeks had no significant effect on body weight or lean body mass, as measured via two methods. Furthermore, there was no effect of DHEA on resting metabolic rate, total energy expenditure, or the rate of incorporation of leucine into muscle protein. Morales et al. 55 gave 50 mg DHEA day of over 6 months to men and women age 40-70 and found an increase in the bioavailability of IGF-1. In a subsequent study 56 , the same authors examined the effects of 6 months of treatment of 100 mg of DHEA to men and women age 50-65 years. In men, there was a 15 increase in knee muscle strength and a 13.9 increase in lumbar back strength but no improvement in women. Flynn et al. 57 administered 100 mg DHEA day to men age 60-84 for 9 months, but found no significant change in lean body mass or

LXRs in Adipose Tissue

Ing factors that regulate whole body energy metabolism 95 . Understanding this cell type is becoming increasingly important because of the rising incidence of obesity and its associated disorder, type II diabetes. The function of LXRa in adipocytes is unknown, however, adipocytes contain the largest pool of non-esterified cholesterol in the body 96 , and this transcription factor may be important for cholesterol regulation in adipocytes.

Correlations Of Oxidative Stress And Aging

Much work has been done correlating the differential production of ROS from mitochondria with life spans of different species (28-36). Although there are broad correlations in the level of ROS produced from isolated mitochondria relative to the maximum and mean life span, there are a number of notable exceptions to this generalization (37,38). Perhaps the best-known example is the comparison of nonpasserine birds to rats (39). Pigeons and rats have high metabolic rates that are approximately equivalent, yet pigeons live about three to five times longer than the rats. Mitochondria isolated from each species and compared for ROS production do not show equivalence, as might be expected based on the metabolic rate (38). Instead, isolated mitochondria from a variety of tissues of the pigeon have approximately two- to four-fold lower levels of ROS production than the rat (38). Hence, ROS production and its effects must be taken into account in addition to the metabolic rate in testing the...

Effects of anaesthesia on the heart

Artificial the physiological environment. For instance, isolated working heart preparations are deprived of any basic sympathetic drive, and coronary oxygen supply is often limited because of asanguineous crystalloid perfusion. Papillary muscle preparations are devoid of a blood supply, and the experiments are often performed at room temperature in order to decrease metabolic rate and to facilitate sufficient oxygen supply by diffusion. Cultured myocytes or skinned muscle fibres are obviously very artificial models and far from clinical reality.

Which particular form of test should be requested

Laboratory-based exercise tests allow evaluation of therapeutic interventions primarily by detecting improvements of exercise capacity, as well as characterising any associated changes in the ventilatory, gas exchange, circulatory and metabolic response patterns, but they are limited by the setting and expensive equipment. However, walking tests can be readily used in a field setting and are inexpensive, but provide considerably less information regarding the specific physiological responses underlying an alteration in exercise capacity. Nonetheless, while a wide variety of tests are available, each being more or less suitable as a stressor of a particular component of a patient's pathophysiology, the appropriateness of the integrated physiological system response to exercise is best studied, certainly for any initial exercise evaluation, by means of a symptom-limited incremental test with a relatively rapid work-rate (WR) incrementation rate. That is, WR is progressively increased by...

Soluble Proteinpattern Changes Induced by AZC Treatment

Based on our statistical tests, AZC treatment altered the abundance of 36 proteins from cytosol and mitochondria. Mass spectrometry allowed identification of 23 proteins (Table 10.1). Caspase 10 D, IF2A, tubulin-folding cofactor B, BET3, malate dehydrogenase, lactate dehydrogenase H-chain, two isoforms of transaldo-lase, and GARS protein were up-regulated. GARS was only known as a gene until now, and its function remains unknown. The cellular response to AZC treatment included key enzymes regulating energy metabolism. Transaldolase is an enzyme that catalyzes the reversible transfer of a three-carbon ketol unit from sedoheptu-lose 7-phosphate to glyceraldehyde 3-phosphate to form erythrose 4-phosphate and fructose 6-phosphate. Malate dehydrogenase is an oxidoreductase. It adds NAD to S-malate to product oxaloacetate. It also oxidizes some other 2-hydroxydi-carboxylic acids. It is implicated in different pathways such as pyruvate metabolism, glyoxylate, and dicarboxylate metabolism,...

Applications in Substance Abuse Research

Using such techniques, investigations haven fallen broadly into two areas as relates to substance abuse, including both the acute effects of drug administration and the long-term consequences of addiction on neuronal activity (e.g., during states of drug abstinence and or treatment). Among the first to exploit such techniques for studies of human drug abusers, London and colleagues (London et al., 1990) examined the effects of intravenous cocaine (30 mg) on rCGM using 18F FDG and PET. Cocaine induced global reductions in brain metabolism that were inversely correlated with ventricular size. These investigators posited that reductions in brain metabolism may be one mechanism whereby drugs are reinforcing rewarding. In addition, Volkow and colleagues have attempted to understand the metabolic correlates of both acute (i.e., < 1 wk) and sustained (i.e., 1-4 mo) drug abstinence in chronic cocaine abusers (Volkow et al., 1991, 1993). The latter studies have indicated patterns of...

Caloric Restriction

The available evidence suggests that the capacity of an organism to maintain steady state is a prime determinant of longevity. Senescence-related loss of function is due to impairment of a homeostatic state and CR enhances longevity by increasing metabolic stability 161 . Evidence suggests that metabolic stability is a better predictor of longevity than metabolic rate, and an organism's ability to maintain stable levels of free radicals may be more important than how fast it produces them 162, 163 . CR delays deleterious consequences of aging by inducing a stable state of biological parameters that normally demonstrate aging-related declines 164, 165 . Moreover, in the presence of continued CR, a stable state in those parameters is maintained across the lifespan 161, 164 . Thus, it may be that changes in critical biological parameters result in functional decline in the aging brain, and CR may eliminate such changes by inducing a stable state in those parameters.

H pylori Functional Genomics

Information about H. pylori energy metabolism and biosynthetic pathways was also gained from the genome sequence, including identification of the membrane-embedded F0 and catalytic Fj components of ATP synthase, dehydrogenases, menaquinone, cytochromes, and a terminal oxidase for respiration-coupled oxidative phosphorylation. Fumarate reductase, which may play a role in anaerobic and or aerobic respiration, as well as superoxide dismutase, catalase, and two peroxidases, presumably to detoxify oxygen species, are also present. Nonetheless, the genetic basis of microaerophily remains incompletely understood. Genes encoding enzymes for nitrogen assimilation, the tricar-boxylic acid cycle, and nucleotide metabolism have also been identified, and a metabolic model has been constructed from genomic information that provides an in silico network of almost 400 H. pylori enzymatic and transport reactions (70). More recently, a global transposon mutagenesis approach has been used to identify...

Alphaglucosidase inhibitor blocks hydrolysis of an

Obstruction of the airway atherosclerosis - fatty accumulation causing hardening and plugging in blood vessels atrophy - decrease in size or function automation - ability of an instrument to perform a laboratory test with minimal human involvement azotemia - an elevated level of urea in the blood basal metabolic rate - baseline rate of metabolism homeostasis - the state of dynamic equilibrium of the internal environment of the body that is maintained by processes of feedback and regulation in response to external or internal changes homogeneous assay - immunoassay in which bound and free antibody need not be separated before label is measured human chorionic gonadotropin (hCG) - classic hormone marker of pregnancy produced by the placenta after the fertilized ooctye implants human placental lactogen (hPL) - hormone produced by the placenta and involved in maternal glucose and fat metabolism and mammary gland function

Physiological Regulation

Brown Adipose Tissue And Thermogenesis

The amount of energy expenditure above BM after a meal from the energetic cost due to physical activity related to sitting, eating, and digesting. In practical terms, DIT is determined by measuring the metabolism of subjects after a meal, without limiting small movements. The value so obtained represents the resting metabolic rate (RMR), which is higher than the BM since it includes the energy expenditure for digestion and metabolism and for the increase in muscle tone and small movements. From measurements made in the morning, afternoon, and evening, it is possible to obtain an average value of the RMR 7 .

Chemical Transduction Metabolism

Biomacromolecules participate directly or catalytically in various intracellular (e.g. chemical transduction) as well as intercellular (e.g. signal transduction) activities. Chemical transductions are collectively known as metabolism. Metabolism represents the sum of the chemical changes that convert the raw materials necessary to nourish living organisms, into energy and the chemically complex finished products of cells. Metabolism consists of a large number of enzymatic reactions organized into discrete reaction sequences pathways (Dagley and Nicholson, 1970 Saier, 1987). The metabolic pathways that are common to all living organisms, are sometimes referred to as primary metabolism (or simply metabolism). The synthesis and degradation of biomolecules termed intermediary metabolism comprises all reactions concerned with storing and generating metabolic energy and with using that energy in biosynthesis of biochemical compounds and energy storage compounds. Energy metabolism is that...

Comparative Genomics and Virulence

The majority of these orthologs encode proteins involved in housekeeping functions, including transcription, translation, energy metabolism, and biosynthetic processes. All three organisms possess a small genome, similar coding capability, and a relatively low number of copies of ribosomal RNA genes. The high degree of homology among their genome contents is consistent with their similar morphology and growth requirements (Table 1). It has been proposed that these three organisms, along with W. succinogenes, are derived from a common ancestor with a larger genome, and have been subject to reductive evolution leading to reduced genome sizes (84). Subsequent to diverging from the common ancestor, each organism has acquired distinct genome features that contribute to their individual lifestyle and physiology. There are 544, 810, and 585 species-specific genes for H. pylori, H. hepaticus, and C. jejuni, respectively (84). In addition, a total of 109 H....

See also Biological Fuel Heart Metabolism Figure 234

Note that breakdown products of fat metabolism (glycerol, propionyl-CoA), protein degradation (alanine, other amino acids), and anaerobic glycolysis (lactate) are substrates for gluconeogenesis. Notably, the primary breakdown product of fat, acetyl-CoA , is not shown, because it cannot be effectively used by animals in gluconeogenesis. Some of the substrates are summarized as follows

See also Biological Fuel Figure 234

Glycolysis in the erythrocyte is the most prominent pathway in the energy metabolism of blood. Blood cells constitute nearly half the volume of blood, and erythrocytes constitute more than 99 of blood cells. Mammalian erythrocytes contain no mitochondria and depend exclusively upon anaerobic glycolysis to meet their energy needs.

Future Strategies And Developments In Mrbased In Vivo Metabolic Imaging

In conclusion, advanced MR techniques, with proton MRS playing a prominent role, provide an important adjunctive means of evaluated the patient with suspected leukodystrophy or metabolic white matter disease. Spectroscopic imaging allows for in vivo metabolic interrogation. Future developments in MRI and nonimaging technologies will likely allow us to advance from the metabolic to the metabolomic evaluation of patients. These exciting possibilities may allow for not only for reliable and efficient diagnosis of these diseases, but as a means to directly evaluate the metabolic effects of treatment and diet alteration, and the temporal evaluation of metabolic profiles as a whole.

Physiological Control of Ghrelin Secretion

In both anorexia and obesity, ghrelin secretion is normalised by recovery of ideal body weight 18,34,35 . These changes are opposite to those of leptin, suggesting that both ghrelin and leptin are hormones signalling the metabolic balance and managing the neuroendocrine and metabolic response to starvation 3,35,36 .

Lipid Mobilising Factor

In vitro studies showed that LMF-induced lipolysis is attenuated by the p-adrenergic receptor blocker propranolol 8 , and propranolol was shown to reduce the basal metabolic rate of cancer patients 16 . These findings and the evidence showing that LMF stimulates BAT oxygen consumption indicates that a p3-adrenergic receptor is involved in this action. p3-Adrenergic agonists up-regulate uncoupling protein-1, leading to a net increase in energy utilisation 17 . Resting energy expenditure, whole-body oxygen uptake, and carbon dioxide production were found to be increased in cancer patients with progressive weight loss after p-adrenoreceptor blockage 18 . Therefore, it was concluded that wasting of body tissues can be explained in part by increased p-adrenoreceptor activity leading to elevated cardiovascular activity, and that production of LMF by cachectic tumours accounts for the loss of body fat and the increase in energy expenditure. This reasoning is supported by more recent evidence...

Cachexia and Infectious Diseases

Most opportunistic infections and many lymphomas in AIDS patients are accompanied by cachexia. In such patients, weight loss is rapid (3-5 pounds per week or 5 per month). While the metabolic rate is extremely elevated,food intake is diminished. There is often extreme weakness and lethargy.

What are the Dietary Protein Requirements of Cancer Patients

If one were to accept the arguments presented by Millward and Jackson, then a healthy 60- to 70-year-old man or woman weighing 70 kg with a low physical activity level of 1.5 times the basal metabolism value would require a dietary P E ratio of at least 0.12 to maintain N balance. This might be considered to be a minimum amount, for the following reasons. The calculations by Millward are based on the assumption of energy balance, and do not take into account that at low energy intakes amino acids are diverted to energy-yielding reactions. The average energy intakes of advanced pancreatic cancer patients are in the vicinity of determined basal metabolic rate (22-25 kcal kg body weight per day) and thus a significant fraction of individuals are not taking in enough energy even to match basal metabolism requirements 16, 27 . Also, the definition used by Millward and Jackson for calculation of the P E ratio of sedentary persons is a physical activity level of 1.5 times basal metabolism...

Energy Expenditure in Diabetes Mellitus

Urinary glucose loss may be a more important cause of negative energy balance and weight loss in diabetic patients. However, the basal metabolic rate (BMR) of diabetic patients without glycosuria is higher than that of normal subjects. Increased resting energy expenditure may be another mechanism contributing to weight loss in diabetic subjects, in addition to caloric losses due to glyco-suria. The basal energy expenditure of obese subjects with type 2 diabetes was also found to be higher than that of obese subjects with normal glucose tolerance. The mean resting metabolic rate (RMR) of diabetic subjects (32.9 Kcal day kg fat-free mass) was 5 higher than that of nondiabetic subjects (31.4 Kcal day kg fat-free mass). A 5 higher resting energy expenditure can result in a net daily caloric deficit of about 100 Kcal day, or 3000 Kcal month 8 . However, resting energy expenditure accounts for only about 70 of the 24-h energy expenditure, which includes other factors, such as the thermic...

Presently available shortterm toxicological tests

An example of the use of a highly specialised cell type to study targeted toxic effects on the cellular metabolism is the recently developed boar spermatozoon motility inhibition test (Andersson et al., 1998). The motility of a spermatozoon depends on the integrity of mitochondrial functions, and thus the action of toxins affecting the energy metabolism is very rapidly detected as reduction of motility. Other end points that can be measured are plasma membrane integrity, astrodome function, and total cellular ATP and NAD reduction. This test has been particularly useful in the detection of certain types of bacterial toxins from various environmental and food sources.

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