Metabolic Weight Loss

Bodyweight Flow Program

Bodyweight Flow is a brand new fitness course developed by Tyler Bramlett and Sylvia Favela which comes with seven different flow routines for upper body, lower body and full body. There are seven routines in the beginner, intermediate and advanced levels of each of these areas of the body. The complete guide comes with a quick start manual that gives you a quick overview of how to start applying the program to ensure you start off immediately and get results from your first session. You are also presented with five bonus tools including a calendar to ensure you know exactly when to do what sequences. Bodyweight Flow is one incredible program finding which not only helps people burn up calories but also strengthens their core, improves posture and targets all of the major muscle groups, considered to be one of its best features. Another great feature is that sequences like the ones explicated inside this fitness course are found to increase the overall oxygen consumption during workouts by 21.4%. Read more...

Bodyweight Flow Overview

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I started using this ebook straight away after buying it. This is a guide like no other; it is friendly, direct and full of proven practical tips to develop your skills.

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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....

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...

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...

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...

The Spine in the Lateral Projection

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...

Complex Picture Emerges

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.

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.

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.

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

Physiological Regulation

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 .

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 thi-amine toxicity by oral administration 50 .

Analytical techniques

Size, which is referred to by both Barton (Chapter 7) and Lee (Chapter 5) is a case in point. It proposes that brain size depends on maternal investment during gestation, as measured by a combination of the mother's basal metabolic rate and gestation length. Increase in either variable would increase maternal investment, and so their combined effects must be investigated to test the hypothesis fully.

Substrates of methyltransferases

S-Methylation of thiol groups (Figure 10a) is documented for such drugs as 6-mercaptopurine (24, Figure 11) and captopril. More recently, it has been shown to be one of the major routes of human metabolism of the vasopeptidase inhibitor omapratilat (25, Figure 11).47 Other substrates are metabolites (mainly thiophenols) resulting from the S-C cleavage of (aromatic) glutathione and cysteine conjugates (see later). Once formed, such methylthio metabolites can be further processed to sulfoxides and sulfones before excretion (see 5.05 Principles of Drug Metabolism 1 Redox Reactions).

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...

Ischemic Stroke Cerebral Infarction

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-

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-

Monoamine oxidases MAOs EC 1434

(MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which causes Parkinson's disease. Within the neurons only MAO can metabolize MPTP, while in other tissues CYP- and FMO-catalyzed detoxification reactions compete with MAO for the substrate. This combination of selective uptake into cells possessing a selective pattern of drug-metabolizing enzymes causes the selective neurotoxicity. MPTP is an experimental chemical. Related compounds such as beta-carboline or tetrahydroisoquinoline are present at low concentrations in food. Whether they behave in a similar way to MPTP and therefore are neurotoxicologically important by...

Content Based Medical Image Retrieval by Physiologically Functional Features

This work, Kim et al. 161 recently developed a new VOI-based retrieval system for multidimensional dynamic functional 18F 2-fluoro-deoxy-glucose (FDG) brain PET images, which are widely used to determine the local cerebral metabolic rate of glucose (LCMRGlc) and depicts the glucose consumption and energy requirements of various structural and functional components in the human brain. In dynamic functional imaging studies, prior knowledge has the form of a tracer kinetic model to a time series of PET tracer uptake measurements. Such functional information can be defined in terms of a mathematical model m(t p) (where t 1,2, ,T are discrete sampling times of the uptake measurements, while the number of conventional scan time intervals T is 22, and p is a set of the model parameters), whose parameters describe the delivery, transport, and biochemical transformation of the tracer. The input function for the model is the plasma time activity curve (PTAC) obtained from serial blood samples....

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.

Dimension of the Nutritional Problem in the World

To identify the groups and individuals who are most affected by denutrition within a population, methods have been established that estimate chronic alimentary defects and long-term needs, with reference to basal metabolism and during working activity. The FAO World Food Survey has fixed the new limit of the minimum alimentary need at 1.54 times the basal metabolic rate (BMR), previously 1.2-1.4 times the BMR. The earlier value expressed a person's energy expenditure before meals and at complete rest, whereas the more recent index corresponds, in a more realistic manner, to the energy level required to maintain body weight and carry out light physical activity. Raising the value of the minimum amount of energy needed automatically increases the number of undernourished people in the world. Malnutrition, both under and over, can no longer be addressed without considering global food insecurity socioeconomic disparity, both globally and nationally and global cultural, social, and...

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...

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.

The Martin maternal energy hypothesis

Assuming that the majority of growth from neonate brain mass to adult brain mass occurs during lactation - a model that fits most of the nonhuman primates (Martin, 1983) and may apply to humans when an average duration of lactation is four years (Dettwyler, 1995) - then the change in brain mass should be a function of maternal energy capacity via the mother's metabolic rate and body mass relations (Martin, 1996). A relationship between brain mass and maternal mass has been noted for a variety of taxa (Martin, 1981 Gittleman, 1994), with further effects of brain mass on other life history parameters (e.g. age at first reproduction Harvey et al., 1987) for primates.

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 .

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,...

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...

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...

Overview of Secondary Central Nervous System Injury

The key players and the complex interrelationships involved in the secondary cascade of events occurring during the first minutes, hours, and days after traumatic CNS injury are shown in Figure 1.1-5 Most of the players involved in ischemic and hemorrhagic CNS insults are the same as for traumatic injury. For TBI and SCI the most immediate event is mechanically induced depolarization and the consequent opening of voltage-dependent ion channels (i.e., Na +, K +, Ca2 +). Similarly, the onset of ischemia is quickly followed by loss of ionic homeostasis in the affected tissue. In the case of intracerebral hemorrhage or SAH, this loss of normal ion distribution is more insidious, requiring time for the secondary ischemic events to manifest themselves. The depolarization leads to massive release of a variety of neurotransmitters, including glutamate, which can cause the opening of glutamate-receptor-operated ion channels (e.g., NMDA and AMPA). The most important consequence of these rapidly...

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...

Prevention of Mitochondrial Dysfunction

And disruption of synaptic homeostasis occur after TBI, implicating a pivotal role for mitochondrial dysfunction in the neuropathological sequalae that follow the mechanical trauma. This theory has been solidified by the demonstration that therapeutic intervention with the immunosuppressant, cyclosporine A (CsA) following experimental TBI reduces mitochondrial dysfunction and cortical damage, as well as cytoskeletal changes and axonal dysfunction.61-63 These neuroprotective effects of CsA result from the ability of the drug to bind to cyclophilin D, thus preventing binding of the latter to the adenine nucleotide translocator protein (ANT), blocking the interaction of ANT with the mitochondrial permeability transition (MPT) pore. In the absence of cyclophilin D ANT binding to the MPT pore, the MPT pore cannot open and MPT cannot occur the mitochondrion is protected from a catastrophic loss of its membrane potential (DC) and metabolic failure and the neuronal energy metabolism (ATP...

Neuroimaging and deficits of consciousness

A 33-year-old, right-handed male without prior history of neurological disorders suffered severe head trauma secondary to a blow in the right frontal region with a blunt object leading to bilateral sub-dural hematoma and brainstem compression injury (Hirsch et al., 2003 Schiff et al., 2005). Bedside examinations were consistent with the diagnosis of MCS (Giacino et al., 2002), and the functional imaging study was performed 24 months after the injury. Neurological examination at the time of the study revealed oculocephalic responses with intact visual tracking and saccades to both stimuli and to commands, marked increased motor tone bilaterally, and frontal release signs. The highest level of behavior observed in this patient was his ability to inconsistently follow complex commands including go, no-go, countermanding tasks, and occasional verbalization. Right frontal lobe encephalomalacia and paramedian thalamic infarction were present on the structural MRI and on the functional (T2*)...

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.

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 .

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...

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 .

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).

Pheochromocytoma and Weight Loss

Weight loss in PCC patients is usual, although obesity cannot exclude the diagnosis. The weight reduction is partly due to increased metabolic rate, excessive sweating, and heat intolerance. Fever may also be present 31-33 . Weight loss is sustained by an activation of lipolysis in white adipose tissue. An activation of brown fat is also evident in patients with PCC 34 . It is noteworthy that, while adipose tissue constitutes the bulk of body fat stores and primarily has as an energy storage function, brown adipose tissue functions principally to generate heat in humans and many other species 34 .

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.

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

Adaptive variation in brain size

Tend to have lower metabolic rates (Martin, 1996), shorter gestations, a different type of placentation and smaller neonates (Martin, 1990), and tend to be more nocturnal and live in smaller groups (Smuts et al., 1987 Kappeler and Heymann, 1996). Interspecific analysis of any of these variables with brain size would risk finding a spurious correlation as a result of the overall grade differences between the two suborders. The word 'spurious' is used here to mean a correlation that does not reflect a general adaptive association. In order to infer that two traits have such an association, it is necessary (though not sufficient) to show that they exhibit correlated evolution that is, they can be shown to have covaried in a consistent way across multiple evolutionary events. As an example, an interspecific analysis of relative brain size and activity timing (diurnal versus nocturnal habits) in primates shows a statistically significant difference with the effects of body weight...

Historical Context

Over time many unusual theories have been espoused regarding the diagnosis and treatment of mental illness. In the late 1700s, Philadelphia's Dr. Benjamin Rush, a signer of the Declaration of Independence and the Father of American Psychiatry, challenged demonic causation and believed moral treatment that controlled the environment would cure insanity in acute patients. Thinking brain arterial disease resulting from gluttony caused mental illness, he advocated a restricted diet, extensive bleeding, emetics to encourage vomiting, and hot or cold showers to slow metabolism. He also invented the gyrator, a spinning chair or plank upon which the patient was tied, designed to increase the brain's blood supply. Rush's Medical Inquiries and Observations upon the Diseases of the Mind made him a revolutionary authority on madness, and he became a popular lecturer. Much later, in the mid-1800s, Christian social reformer Dorothea Dix (1802-87) raised money to establish the first state mental...

Life histories maternal energetics and brain size

Perhaps differences in brain size reflect overall life history strategies or biological constraints (Sacher, 1959 Hofman, 1984 Shea, 1987 Harvey et al., 1987 Parker, 1990 Allman, McLaughlin and Hakeem, 1993 Martin, 1996), rather than ecologically related neural specialisation. One suggestion has been that brain size is linked to life span (Sacher, 1959 Hofman, 1984 Allman et al., 1993 see also Harvey and Read (1988) for a discussion). Sacher (1959) found that brain size and life span were more strongly correlated than either were with body size. Similarly, Allman et al. (1993) found that primate life spans and brain sizes were positively correlated even after the effects of body weight had been removed from each. Harvey et al. (1987) suggested that brain size is more directly related to age at maturity than to life span, because age at maturity reflects the amount of postnatal brain development and learning during the juvenile phase (see also Joffe, 1997). Others have suggested that...

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...

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...

Of Antidepressant Treatments

Taken together, this work provides evidence for a molecular and cellular hypothesis of depression and the action of antidepressants (see Fig. 1). In some forms of depression, stress and elevated levels of glucocorticoids could lead to atrophy, and in severe cases, it could lead to death of CA3 sensitive hippocampal neurons. This could occur via decreased energy metabolism, increased glutamate and calcium excitotoxicity, and decreased expression of BDNF. In addition, exposure to stress during early stages of development could reduce neurogenesis and thereby compromise the function of the granule cell mossy fiber pathway. The atrophy and loss of CA3 neurons and

Regulation of Appetite in the Elderly

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.

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...

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...

Role of Bone Tissue in Osteoarthritis Progression or Initiation

An elevated bone turnover rate can result from abnormal systemic regulation, from an altered response to normal signals, or from abnormal cell function. The latter is implied by the finding that osteocalcin, a marker of bone formation, is elevated in synovial fluid of patients whose knee scan showed abnormalities 215 . We have observed a higher than normal metabolic rate in osteoblasts that had been isolated from the bone of tibial plateaus of OA patients. These OA osteoblasts showed elevated levels of osteocalcin 101 and higher IGF-1 and TGF-P levels compared to normal 101,149,150 . Similarly, Gevers and Dequeker 80 have reported elevated serum osteocalcin levels in women with OA of the hand, and elevated osteocalcin in cortical bone explants. The levels of IGF-1, IGF-2, and TGF-P, were also found elevated in samples of iliac crest bone of patients with OA 53 . This is a site distant from weight-bearing joints. High TGF-P and IGF-1 activity in OA bone tissue would promote bone...

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...

Relationship Approaches to Absorption Distribution Metabolism and Excretion Predictions

The relevance of these studies lies in the major role of CYP enzymes in human metabolism understanding the basis of their activity is important to determine their role and predict effects on new substrates.108'109 Extensive analyses have been performed on CYP2B6 substrates using two 3D-QSAR approaches, namely WHIM and pharmacophore mapping.110 Both methods suggest the crucial relevance of three hydrophobic regions and one HBA, located at defined distances (Figure 8). These results are in agreement with classic QSAR studies that correlated binding affinities to CYP2B6 with log P and hydrogen-bonding descriptors.111 It is interesting to observe that both 3D-QSAR methods, even if conceptually different, yielded very similar results, suggesting some degree of mutual validation, although both methods failed to predict molecules not included in the training set. Docking analyses on homology-modeled CYP2B6 revealed that its binding site consists of three well-defined...

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 .

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

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...

Detection and characterization of unintended effects

Another key issue in the safety evaluation of GM foods is whether unexpected changes may have taken place in the transgenic crop plant as a result of the genetic modification process. If so, do these unintended (secondary) changes affect the safety or nutritional status of the modified organism Unexpected changes in agronomical traits or composition may result from insertional mutagenesis or from the metabolic effects of the new gene product(s). In order to identify such changes, a systematic comparison should be made between the genetically modified organism and its parent grown under conditions that are as near identical as possible, since environmental factors may interact with the genotype of the crop, possibly resulting in alterations in phenotypic traits and composition. Compositional analysis has until now been performed on single constituents, such as key nutrients and natural plant toxins, as a screening strategy for unintended effects. A subchronic animal feeding study of 90...

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...

Pharmacological treatments of OSA risk factors and morbidities

Orlistat alters fat metabolism by inhibiting pancreatic lipases with consequent increased fecal fat excretion. Long-term trials confirm orlistat's ability to promote approximately 10 weight loss 120,121 , and to help prevent weight regain 122 . Main side effects are discomforting gastrointestinal symptoms such as excessive borborygmi, cramps, flatus, etc. Orlistat also may produce an improvement in lipid profile unexplained by the degree of weight loss 123 . It is FDA approved for long-term use.

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

Relationship between systemic and intracranial hemodynamics

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)

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

Which Skeletal Sites Should Be Used for Monitoring

The area or size of the various regions of interest is relevant to rule 3. The PA spine is generally considered to be 66 trabecular bone. In the proximal femur, the regions of interest with the greatest percentage of trabecular bone are Ward's area and the trochanteric region. The exact percentage of trabecular bone in Ward's area is not defined but it is considered highly trabecular. The percentage of trabecular bone in the trochanteric region is approximately 50 . The greatest rates of change are usually seen in skeletal regions that contain higher percentages of trabecular bone. This is because trabecular bone has a much higher metabolic rate than cortical bone. Precision however, is often a function of the size of the area being measured. The larger the size, the better the precision tends to be. The greatest area is found in the PA spine by considering three or four of the lumbar vertebrae as one block. In the proximal femur, the greatest area is in...

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.

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).

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...

Diet and Physical activity

Study, Oeffinger et al. observed cardiovascular disease risk factors such as obesity, dyslipidemia, hypertension, and insulin resistance in 62 of a cohort of young adult survivors treated for ALL in association with sedentary activity levels 37 . The higher prevalence of obesity in survivors treated with cranial radiation has been attributed to lower physical activity and resting metabolic rate, and hormonal insufficiency 32 . In particular, hypothalamic insult may predispose to obesity through leptin insensitivity 39 and adult growth hormone deficiency, which is associated with higher rates of dyslipidemia, insulin resistance, and cardiovascular mortality 40, 41 .

Male and female energetic constraints

Male primates are often larger than female primates. Large differences in body size have significant energetic consequences. While metabolic rate increases with body size as around body weight0'75, commonly the rate of food intake may increase less rapidly with body weight (Clutton-Brock, 1994). Furthermore, heavier bodied animls are further constrained by their greater weight and size and are thus less able to exploit certain areas of food patches such as the outer branches of fruiting trees (Doran, 1993a, 1993b). Conversely, weaker, smaller animals are less able to exploit resources that require greater strength for their processing such as the stripping of bark. Smaller animals are also more likely to be displaced at food sources by larger ones (Wheatley, 1982).

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...

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

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.

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...

Mitochondrial Cytopathies

Mitochondrial disorders are caused by mutations of nuclear or mitochondrial DNA encoded genes involved in oxidative phosphorylation. Mutations in these critical genes are associated with specific clinical syndromes with diverse presentations (99,100). Because mitochondria are present in many of our organs and play a key role in energy metabolism, mitochondrial encephalomyopathies often present as multisystem disorders that may manifest with neurologic, cardiac, endocrine, gastrointestinal, hepatic, renal, and or hematologic involvement. Several laboratory studies may be useful to screen for impaired energy metabolism such as serum lactate, pyruvate, plasma amino acids, complete blood count, electrolytes, car-nitine, acylcarnitine profile, ammonia, and creatine phospho-kinase. Renal tubular acidosis as part of a Fanconi syndrome may be seen, especially in patients with complex IV defects. Renal disease is more common in pediatric presentations. Elevated lactate is suggestive but not...

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...

Pyrethrum and the Pyrethrins

Disrupts energy metabolism in mitochondria. Mammalian oral LD50s range from 25-3000, dermal > 1000. More acutely toxic to mammals and more persistent than many botanicals. Some chronic toxicity suspected. Extremely toxic to fish. Rotenone disrupts energy metabolism in cell mitochondria, either by inhibiting the electron transport system or by uncoupling the transport system from ATP production. Synthetic insecticides also known to act in one of these two ways include hydramethylnon, sulfuramid, and pyridaben. Reviews of the mode of action of rotenone and the synthetic insecticides that act similarly have been prepared by Haley (1978), Hayes (1982), Matsumura (1985), Hollingshaus (1987), Schnellmann and Manning (1990), and Hollingworth et al. (1994). In insects, rotenone is converted to metabolites that are highly toxic in mammals, metabolism results in detoxication (Ware 1988).

Extrapolation across Doses Routes of Exposure and Species

Species to Species PBPK modeling is a highly appropriate approach for species-to-species extrapolation because all mammals have the same compartment-scale circulatory anatomy, and much is known about the comparative dimensions of their blood flow rates, organ volumes, and clearances. In order to conduct such an extrapolation, estimates of physiological parameters, partition coefficients, and metabolic rate constants must be obtained for the species of interest 14 . Although several methods to obtain these parameters were described earlier, it is worth considering this issue in the context of species-to-species extrapolation. It has been observed that many anatomical and physiological variables can be empirically correlated to the body mass of a species 27,28 , and that the physiological function per unit of organ or body mass decreases as the size of the animal increases 29 . For those parameters used in the description of metabolism, the situation is generally much more complex. This...

Types Of Bioprocesses

Type 2 production process is due to primary metabolisms, but the reaction rates could be complex. The product may be an intermediate and not the end product of a metabolic pathway. It has something to do with catabolism energy metabolism. The production phase can be distinguished from the growth phase. Examples of type 2 classifications are alkaline protease (Bacillus lycheniformis), amylase (Aspergillus oryzae), pectinase (Aspergillus niger), cellulase (Trichoderma resii), citric acid (Aspergillus niger), amino acids (Corynebacterium glutamicum), and riboflavin (Eremothecium ashbyi). All these processes are aerobic and are operated in batch mode. The first four systems are operated in fed batch mode as well. One example of an anaerobic system is vitamin B12 (Pseudomonas nitrificans), which is operated in batch mode. Type 3 process is a nongrowth-associated production. Sometimes production only begins when the main carbon source is exhausted and a secondary carbon source is used. The...

Second Era 19241973 Initial Clinical Investigations Into CLL 221 Major Contributors

In the first comprehensive report on CLL in 1924, Minot (Fig. 11) and Isaacs (23) compared their series of 92 CLL patients with 84 CLL patients reported by Ward. Figures 12 and 13 are extracted from their report. They showed that most cases of CLL occurred at 45-54 yr of age. The male female ratio was 3 1, symptoms were usually present 9 mo before the patient presented, and another 6 mo more was required to confirm the diagnosis. Minot and Isaacs (23) further report on 50 patients who received irradiation and 30 patients who did not and who served as controls. The source of irradiation was radium, administered over the lymph nodes and spleen. They noted that there was no difference in the duration of life span for the two groups 3.45 yr (40 mo). We have taken the liberty of using their data to draw Fig. 14. However, they did note that individual patients did benefit if the irradiation was given at 1 or more years prior to death. Although there seemed to...

Summary

At present, conventional magnetic resonance imaging (MRI) shows no convincing structural changes in Parkinson's disease (PD) itself, but it may be useful in helping to distinguish PD from other neurodegenerative parkinsonian syndromes. Magnetic resonance spectroscopy (MRS) also may provide useful information in distinguishing PD from disorders such as multiple system atrophy. The general field of MRI and MRS is evolving rapidly, and a number of new developments may provide relevant information. Novel pulse sequences, for instance, may provide more information regarding substantia nigra pathology in PD. The use of MR technologies to measure regional concentrations of brain iron should provide more information regarding the relationship between iron accumulation and parkinsonian symptoms. MRS provides a sensitive tool to investigate the possible contribution of abnormal brain energy metabolism to the pathogenesis of PD. MRS also allows the assessment of other metabolite changes in PD,...

Tissue Metabolism

In contrast to uncomplicated starvation, where the energy expenditure is decreased as compensation, an elevated metabolic rate was recognised. Several symptoms such as tachycardia, hyperp-noea, sweating and a rise in body temperature indicated an increase of the metabolic rate that was in sharp contrast to the reduced energy supply in these patients 25 . In 1916, the increase in the basal metabolic rate was directly documented 26, 27 . Increased metabolic demands of several specific tissues were discussed as one underlying reason for this finding. Decreased efficiency of the respiratory system due to reduced compliance 28 and capacity of the lungs, together with hyperventilation, result in higher energy demands of the respiratory muscles 29 . In the case of patients with congestive heart failure it was also suggested that the hypertrophic myocardium may contribute to the hypermetabolism in chronic heart failure 30, 31 . The combination of an increase in total energy consumption of the...

Dietary Intake

Another question is the continuing debate about the use of reference parameters in nutritional studies in the elderly. In fact, the value of dietary intake data as an indicator of health status in an elderly population is debatable 32 . In a population with an increased number of physical and mental disabilities like the elderly, dietary assessment methods might be adapted or different methodologies might be developed 19 . An independent measure of the reliability of reported energy can be obtained by calculating the ratio of energy intake to the resting metabolic rate (RMR) 33 .

Energy

Energy requirements are defined by energy expenditure composed of RMR, physical activity and diet-induced thermogenesis 39 . With ageing there is a reduction in energy requirements related to a reduction in metabolic rate (due to the loss of lean body mass and the reduction of protein turnover) and to a diminution of physical activity 44 . However, some authors have stressed that the energy requirements to remain active are the same for the elderly as for younger adults walking, however, seems to require more energy in the elderly due to the loss of balance (diminution of neuro-muscular coordination) 45,46 .

Protein Requirements

An intake of 0.6 g kg day of well-balanced proteins is considered sufficient to achieve a zero (i.e. at equilibrium) nitrogen balance 6 (Table 3). A safety amount is considered to be 0.75 g kg day. These values represent the minimum recommended protein intake, derived also from studies investigating the metabolic response to a range of protein intakes between 0.75 and 2 g kg day.

Sleep traits

The phylogenetic context of mammalian sleep traits is well documented, and raises many interesting questions concerning the relationship between ecology, social behaviour, life history and physiology. For example, studies on mammals have shown that metabolic rate and body size account for much interspecies variability in sleep quotas (Zepelin, 1994 Berger and Phillips, 1995), and that precociality is positively correlated with paradoxical sleep levels (Elgar, Pagel and Harvey, 1988). This example does not attempt to recreate these studies, but simply to demonstrate a cladistic interpretation of some of this information for primates.

Conclusions

Nutritional status and specific nutrients may impact on the immune system. In addition, altered immune status can impact on nutritional status. For example, immune response to injury (infection, cancer, etc.) can change the efficiency of the body to adsorb and utilise nutrients, alter metabolic rate, modify hormone secretion, alter hepatic synthesis of proteins or lipids, change intracel-lular enzymes (gluconeogenesis, lipogenesis, etc.). Mediators of immune response such as proinflammatory cytokines and CRP are involved in the pathogenesis of several metabolic disorders (diabetes mellitus, insulin resistance, obesity, cachexia associated with different chronic diseases) and have a well-recognised role as prognostic factors of disease outcome and survival. So, the assessment of immunological parameters has to be included in an exhaustive global assessment of nutritional status, especially with the aim to develop and to monitor the effect of nutritional approaches. Another exciting...

Energy Signals

Similar to the changes in fat mass, changes in energy metabolism also influence energy intake in a leptin-independent manner via energy signals. Conceptually, energy signals differ from classic peripheral signals, since they are generated within hypothalamic neurons controlling energy intake. A number of studies have suggested that a metabolic control of food intake also exists, in which biochemical partitioning between fatty-acid oxidation and synthesis represents a key signal indicating catabolic or anabolic energy status 28 . Energy signals are independent from leptin pathway and they inform the brain on the metabolic switch occurring at a subcellular level between fatty-acid oxidation and synthesis 29 . Under physiological conditions, food intake is accompanied by increased intracellular levels of malonyl coenzyme A (malonyl-CoA) 30 , a potent signal reducing food intake, via inhibition of the synthesis of the prophagic factor neuropeptide Y (NPY) 29 . It is therefore tempting to...

Overview

In each neurodegenerative disease, there is selective neuronal vulnerability such that the primary neuronal population affected differs. Common factors that are potential mediators of the disease process include increased oxidative burden (reactive oxygen species) impaired energy metabolism lysosomal dysfunction protein aggregation inclusion-body formation inflammation excitoxicity necrosis and or apoptosis. Since many of these features underlie multiple CNS disease states, new chemical entities (NCEs) targeting these mechanisms may have general utility. As evidence of this, evaluation of antioxidants, antiinflammatory agents, glutamate receptor antagonists, and antiapoptotic agents for effects on neuronal survival has been conducted in animal models of neurodegeneration with some having been clinically evaluated in multiple neurodegenerative disease states (e.g., minocycline, riluzole).

Ki k2 k3 k4

Cerebral metabolic rate of glucose FIGURE 6.3 Flow chart of estimating cerebral metabolic rate of glucose (CMRGlc) using ROI. Parameter estimation is a discipline that provides tools for mathematically modeling phenomena and the estimation of the constants appearing in these models 10 . Diverse approaches are available for parameter estimation. These are optimized in terms of the tracer, compartment model, and imaging implementation. A compartment model for regional cerebral blood flow (rCBF) is used to demonstrate two basic methods of parameter estimation. In contrast to the indirect measurement of metabolic rate of glucose with FDG, kinetic modeling of blood flow directly measures rCBF transported into the tissue, as shown in Figure 6.5, based on the Kety-Schmidt single compartment model 11, 12 . Cerebral metabolic rate of glucose FIGURE 6.4 Flow chart of generating parametric image of cerebral metabolic rate of glucose (CMRGlc). Cerebral metabolic rate of glucose FIGURE 6.4 Flow...

Flowers

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

Glucose Metabolism

Changes in energy metabolism consisting of increased resting energy expenditure associated with alterations of glucose, lipid and protein metabolism are typical of cancer-related anorex-ia cachexia syndrome (CACS). In advanced cancer patients, energy metabolism is severely compromised by the occurrence during the disease progression of symptoms such as anorexia, nausea and vomiting, which do not allow for a normal nutrition and so a regular supply of carbohydrates, proteins, amino acids and vitamins. In addition to the reduced food intake, important changes of energy metabolism and bio

Leptin

We hypothesise that low serum leptin levels have a primary physiological role as a signal of depletion of energy stores rather than as a suppressor of body fat involved in the onset of cancer cachexia 43, 44 and they may be evidence of the alterations of energy metabolism occurring in CACS. The low serum leptin levels observed in advanced cancer patients are related to the increased energy expenditure induced by tumour during the progression of disease and to the appearance of anorexia with consequent reduced intake of energy substrates. In advanced cancer patients, and especially in cachectic patients, characterised by severe alterations of energy metabolism, impairment of energy utilisation and increased energy expenditure, the activation of leptin feedback may be a biological defence of the body that limits the use of energy when energy is scarce. Decrease of leptin synthesis and release should induce lowering of metabolic rate and a powerful drive to eat more, in an effort to...

Metabolic Factors

The involvement of other mechanisms of energy metabolism in brain responses such as uncoupling proteins needs to be characterised based on observations of up-regulation of uncoupling protein subtypes in various tumour-bearing animal models 4, 17 . The same applies to accumulating evidence on ubiquitin-proteasome-dependent proteolysis 5,6 .

Spinal Cord Injury

Interest in the LP hypothesis of secondary SCI evolved during parallel investigations of the effects of high-dose MP (15-90 mg kg 1 i.v.) on spinal cord electrophysiology in the context of improving impulse conduction and recovery of function in the injured spinal cord.39 A similar high dose of MP, which enhanced spinal neuronal excitability and impulse transmission, was tested for its ability to inhibit posttraumatic spinal cord LP. In an initial study in cats, an i.v. bolus of MP inhibited posttraumatic LP in spinal cord tissue, but the doses required were much higher (30mgkg_ 1) than those previously hypothesized, or those empirically employed in the clinical treatment of acute CNS injury or tested in the NASCIS trial. Additional studies in cat SCI models showed that at a dose of 30 mgkg 1 MP not only prevented LP but, in parallel, inhibited posttraumatic spinal cord ischemia, supported aerobic energy metabolism (i.e., reduced lactate and improved ATP and energy charge), improved...

Diagnosis

When smokers, adolescents as well as adults, stop smoking, they may experience nicotine withdrawal as defined by DSM-IV-TR (American Psychiatric Association, 2000). About 50 of adults who attempt to stop smoking will meet DSM-IV criteria for nicotine dependence (American Psychiatric Association, 1996), and young smokers show signs of addiction within several months of taking up the habit (DiFranza et al., 2002). Diagnostic criteria for nicotine withdrawal are presented in DSM-IV-TR. Associated features include craving, a desire for sweets, and impaired performance on tasks requiring vigilance (American Psychiatric Association, 2000). Depression and difficulty sleeping are not uncommon. Associated laboratory findings include a slowing on elec-troencephalograph, decreases in catecholamine and cortisol levels, rapid eye movement (REM) changes, impairment on neuropsychological testing, and decreased metabolic rate (American Psychiatric Association, 2000). Nicotine withdrawal also may be...

Alzheimers Disease

Weight loss is common in elderly people with dementia, particularly those with Alzheimer's disease (AD), and feeding difficulties are major issues in their care in the later stages of the disease. The aetiology is still uncertain and appears multifactorial. Hypotheses to explain the weight loss have been suggested (e.g. atrophy of the mesial temporal cortex, biological disturbances, and higher energy expenditure), but none has been proven. More than half of the AD patients of one recent study 5 developed body-weight loss overall, the AD patients were significantly thinner than non-demented subjects. Anthropometric and laboratory measures suggested a poorer nutritional status and fewer daily physical activities in AD patients. While most of them had poor appetite, their daily calorie intake was not significantly different from that of the control group. In fact, patients with body weight loss consumed more calories per body weight kilogram per day. In the food composition analysis, AD...

Glutamine

Glutamine is broken down to produce energy in many tissues in the body. It is especially important as an energy source for the cells lining the digestive tract and the white blood cells. Glutamine can be taken up by the liver and converted to glucose to maintain blood sugar levels.2

Brain allometry

Several authors have analysed brain to body size relationships in primates (e.g. Jerison, 1973 Martin, 1981). In theory, the slope of the best-fit line on a log-log plot of the two variables represents the rate at which brain size has to increase in order to maintain functional equivalence as body size increases. Early comparative analyses of mammals using individual species as data points gave slopes of around 0.67 (Jerison, 1973), whereas later studies put the slope at 0.75 (Martin, 1981). In each case, a fundamental biological reason for these slopes was suggested. The 0.67 slope suggested a connection with surface-to-volume ratios, because the surface area of a solid increases to the 2 3 power of its volume. The biological reason for this might be that numbers of sensory receptors and motor effectors must increase in direct proportion to the area of the body surfaces over which they are distributed. The more recently accepted 0.75 slope suggested a link with basal metabolic rate,...

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