homeostatic functions of the brain

The activation of pro-inflammatory pathways, such as the interleukin-1/Toll-like receptor (IL-1R/TLR) pathway, appear to be involved in the precipitation and recurrence of seizures in rodent models of epilepsy (Vezzani et al., 2011a). The Pituitary Gland. Drug News Perspect. Adenosine kinase: exploitation for therapeutic gain. 6), 53–59. Increased levels of synaptic glutamate may in part be attributed to reduced expression of glutamate transporters within reactive astrocytes. Res. (2003). Intriguingly, activation of the IL-1R/TLR pathway may alter the permeability properties of the BBB via the production of cytokines and prostaglandins, promoting brain extravasation of albumin (Cacheaux et al., 2009). Pflugers Arch. Thereby adenosine assumes a unique role as homeostatic network regulator. The purine ribonucleoside adenosine has early evolutionary origins and likely played already a role in prebiotic evolution (Oro and Kimball, 1961). 31, 162–268. Homeostatic Control of Brain Function offers a broad view of brain health and diverse perspectives for potential treatments, targeting key areas such as mitochondria, the immune system, epigenetic changes, and regulatory molecules such as ions, neuropeptides, and neuromodulators. Distribution of CNT2 and ENT1 transcripts in rat brain: selective decrease of CNT2 mRNA in the cerebral cortex of sleep-deprived rats. J. Neurol. (2012). Inv. Localization of equilibrative nucleoside transporters in the rat brain. doi: 10.1111/j.1528-1167.2007.00988.x, Maroso, M., Balosso, S., Ravizza, T., Liu, J., Aronica, E., Iyer, A. M., et al. Astrocytic regulation of glutamate homeostasis in epilepsy. Your current browser may not support copying via this button. Brain Divisions . 28, 17–23. Int. Importantly, the increased activation of A2ARs by an injury-associated surge in adenosine can increase astrocyte proliferation and activation, whereas the blockade of A2ARs prevented the induction of astrogliosis by BDNF, which is a known transactivator of the A2AR (Hindley et al., 1994; Brambilla et al., 2003; Rajagopal et al., 2004). Glia 43, 190–194. (Wien) 89, 122–129. doi: 10.1016/j.tips.2005.08.004, Hassan, A. M., Keene, D. L., Whiting, S. E., Jacob, P. J., Champagne, J. R., and Humphreys, P. (1999). doi: 10.1097/00019052-200204000-00009, Kurzwelly, D., Herrlinger, U., and Simon, M. (2010). Neurology 65, 529–534. 79, 463–484. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Sleep affects almost every type of tissue and system in the body – from the brain, heart, and lungs to metabolism, immune function, mood, and disease resistance. Imaging inflammation in a patient with epilepsy due to focal cortical dysplasia. Brain Res. U.S.A. 95, 15735–15740. I. Adenine from hydrogen cyanide. Glia 52, 25–35. In our prior work we provided the following evidence linking expression levels of ADK to seizure propensity: during epileptogenesis increased ADK expression and emergence of spontaneous electrographic seizures coincided both temporally as well as spatially (Li et al., 2008). Biochim. Glial adenosine kinase – a neuropathological marker of the epileptic brain. The reduced methylation of CpG rich promoter regions could induce the transcription of epileptogenesis genes, suggesting a novel mechanism whereby an acute injury-induced surge in adenosine could trigger epileptogenesis. Blood-brain barrier dysfunction, TGF-beta signaling and astrocyte dysfunction in epilepsy. Neurosci. Biochem. Albumin is a potent astroglial activator through stimulation of transforming growth factor beta (TGF-β) signaling and activation of the SMAD-2/5 pathway (Ivens et al., 2007; Cacheaux et al., 2009). Neurol. Biol. Brain-derived neurotrophic factor (BDNF)-induced synthesis of early growth response factor 3 (Egr3) controls the levels of type A GABA receptor alpha 4 subunits in hippocampal neurons. Exp. doi: 10.1016/j.bbi.2011.03.018, Vining, E. P., Freeman, J. M., Ballaban-Gil, K., Camfield, C. S., Camfield, P. R., Holmes, G. L., et al. Biol. Adenosine-releasing silk might be an attractive therapeutic candidate due to the bioresorbable properties of this biopolymer. The first randomized, controlled study of the ketogenic diet clearly demonstrated a beneficial effect (Neal et al., 2008). Neurochem. Epilepsia 52(Suppl. Neurol. Peripheral changes in the transmethylation pathway are conserved within the brain. Thus, the ketogenic diet became a rare treatment, until a slow resurgence began in the 1990s in its use mostly for drug-refractory pediatric epilepsy. 62, 668–700. While ATP reflects the energy pool in the environment, RNA reflects the metabolic activities of a cell. The epigenetic drift hypothesis suggests that a gradual shift in the ratio of active DNA demethylation and de novo methylation, triggered by a precipitating injury and modified by environmental and intrinsic factors leads to increased DNA methylation, altered gene expression, and an altered (e.g., seizure) phenotype (Feil and Fraga, 2011). Adv. Exp. doi: 10.1172/JCI62378, Shepel, P. N., Ramonet, D., Stevens, P., and Geiger, J. D. (2005). Thus, if adenosine levels are raised sufficiently, synaptic transmission can be blocked altogether. 222, 127–134. Tuberous sclerosis: a primary pathology of astrocytes? Epilepsy Behav. Sci. Brain Dev. Interestingly astrocytes express all types of ATP-releasing proteins and are capable of releasing ATP from these pathways simultaneously (Garre et al., 2010). Insect Biochem. J. Neurosci. 32, 618–624. Research with transgenic mice further implicates deregulation of astrocyte-mediated glutamate uptake as a contributing factor to epilepsy. Experimental blockade of TGF-β signaling following BBB disruption decreased those transcriptional responses and prevented epileptogenesis. Conversely, reduction of DNA methylation through therapeutic adenosine augmentation may provide a rational therapeutic approach for the prevention of epileptogenesis. Importantly, components of these pathways were found to be overexpressed in surgically resected specimens from human TLE (Ravizza et al., 2008). Stand. Each receptor presents a distinct pharmacology, and each has a particular distribution in tissues and cell types. Similar to ECS volume, changes in the K+ concentration influence neuronal excitability with millimolar increases in ECS K+ exacerbating epileptiform activity (Feng and Durand, 2006). doi:10.1517/17460441.2011.575777, Wong, M., Ess, K. C., Uhlmann, E. J., Jansen, L. A., Li, W., Crino, P. B., et al. Glia 60, 1258–1268. How do seizures stop? Homeostasis has long been recognized as a core physiological principle, and the CNS depends critically on maintaining its milieu, including ion gradients, temperature, pH, and cell energy, as well as also regulating transcription and translation to ensure proper function. PhD, Legacy Research Institute, Susan A. Masino, Rev. (2010). U.S.A. 95, 11981–11986. Neurochem. 4, pii:a003608. As an obligatory endproduct of transmethylation, the adenosine tone non-specifically drives the transmethylation pathway by regulating substrate availability; with site specific DNA methylation mediated by DNMT1, 3a or 3b complexes (Goll and Bestor, 2005; Caiafa et al., 2009; Feng et al., 2010; Zampieri et al., 2012). doi: 10.1111/j.1552-6569.2010.00572.x, Cacheaux, L. P., Ivens, S., David, Y., Lakhter, A. J., Bar-Klein, G., Shapira, M., et al. doi: 10.1523/JNEUROSCI.5048-07.2008, Kawamura, M. Jr., Ruskin, D. N., and Masino, S. A. Dietary therapies for epilepsy can be useful in cases where medications and other treatments are ineffective. In a simplistic model, resident macrophages are responsible for the basic developmental and homeostatic functions of phagocytes, while recruited macrophages would mediate inflammatory responses. doi: 10.1523/JNEUROSCI.2323-09.2009, Delaney, S. M., and Geiger, J. D. (1996). Rev. (2012). 219, 126–135. (2000). Microglia: key innate immune cells of the brain. Four members of the P1 class have been cloned in mammals: A1R, A2aR, A2bR, and A3R (Fredholm et al., 2011), and not surprisingly, given the ancient biological origin of adenosine, homologous genes have been found in numerous other animal groups (Sazanov et al., 2000; Petersen et al., 2003; Dolezelova et al., 2007; Boehmler et al., 2009; Malik and Buck, 2010). The methylation hypothesis: do epigenetic chromatin modifications play a role in epileptogenesis? 24, 6650–6658. However, HMGB1 can be released into the ECS following either cell damage or neuronal hyperexcitability. Loss of homeostasis becomes expressed as a diverse array of neurological disorders. Adv. Adenosine tone regulates the transmethylation pathway. 17. Glia 59, 1635–1642. doi: 10.1073/pnas.1120997109, Lu, S. C. (2000). Reduced DNA methylation permits the transcription of early epileptogenesis genes. The hypothalamus is the link between the endocrine and nervous systems. doi: 10.1111/j.1528-1167.2012.03610.x, Marchi, N., Angelov, L., Masaryk, T., Fazio, V., Granata, T., Hernandez, N., et al. Through this mechanism, astrogliosis and associated overexpression of ADK could contribute to continued epileptogenesis through maintenance of a hypermethylated state of hippocampal DNA. Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. (1997). Likewise, engineered mice with defects in the IL-1R/TLR signaling pathway are intrinsically resistant to seizures (Vezzani et al., 2011b). These data demonstrate that ADK provides a molecular link between astrogliosis and increased neuronal excitability. paraplegia: Definition. Loss of homeostasis becomes expressed as a diverse array of neurological disorders. Ca2+ waves within astrocytes have also been linked to glutamate and D-serine release. Similarly, conditions that can precipitate epilepsy – such as traumatic brain injury, and diseases in which epilepsy can be comorbid – such as Alzheimer’s disease, are accompanied by a chronic loss of homeostatic function. Butler, T., Ichise, M., Teich, A. F., Gerard, E., Osborne, J., French, J., et al. 1 Brain function, homeostasis, and the regulation of behavior: a three tier nested hierarchy with cerebellum and cerebrum as cognitive components in hybrid control. Since dietary interventions have been shown to increase adenosine signaling in the brain (Masino et al., 2011), dietary manipulations such as the ketogenic diet might likewise hold promising therapeutic potential for the prevention of epileptogenesis. Epilepsia 41(Suppl. Lett. (2012). Neuroprotective effects of an adenoviral vector expressing the glucose transporter: a detailed description of the mediating cellular events. Nat. 121, 2679–2683. 17(Suppl. doi: 10.1111/j.1469-8749.1989.tb03973.x. Methods 64, 151–156. B., Almonte, A. G., Wainer, B. H., et al. Cyclooxygenase-2 expression in rat microglia is induced by adenosine A2a-receptors. (2011). Actions of adenosine at its receptors in the CNS: insights from knockouts and drugs. Sci. Adenosine kinase deficiency disrupts the methionine cycle and causes hypermethioninemia, encephalopathy, and abnormal liver function. Myocardiol. The list of transmitters proposed to be released by astrocytes includes glutamate, D-serine, ATP, adenosine, and GABA (Devinsky et al., 2013). doi: 10.1002/ana.410320504, Dworkin, J. P., Lazcano, A., and Miller, S. L. (2003). An astrocytic basis of epilepsy. B., Chen, J. F., Masino, S. A., and Vaugeois, J. M. (2005). Therefore, zinc homeostasis in the brain is closely related to neuronal activity. Ann. doi: 10.1523/JNEUROSCI.2294-04.2004, Bjursell, M. K., Blom, H. J., Cayuela, J. HMGB1 is the endogenous ligand of TLR4 and normally bound to chromatin. In 1932, Joseph Barcroft a British physiologist, was the first to say that higher brain function required the most stable internal environment. doi: 10.1111/j.1528-1167.2011.03145.x, Kobow, K., and Blumcke, I. doi:10.1001/archpedi.1927.04130240092013, Meshorer, E., Biton, I. E., Ben-Shaul, Y., Ben-Ari, S., Assaf, Y., Soreq, H., et al. doi: 10.1038/sj.jcbfm.9600499, Raatikainen, M. J., Peuhkurinen, K. J., Kiviluoma, K. T., Hiltunen, J. K., and Hassinen, I. E. (1992). Here we will further review the supporting data from human epilepsy and rodent models of epilepsy that pertain to astroglial-mediated disruptions in synaptic transmission as a mechanism for epileptogenesis, with a more thorough discussion of adenosine homeostasis in epilepsy to follow. Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. Nomenclature and classification of adenosine receptors–an update. J. Biol. Increased reelin promoter methylation is associated with granule cell dispersion in human temporal lobe epilepsy. LXXXI. Neuropathology. editor The efficacy of the ketogenic diet-1998: a prospective evaluation of intervention in 150 children. Overexpression of adenosine kinase in epileptic hippocampus contributes to epileptogenesis. doi: 10.1124/pr.110.003046, Lovatt, D., Xu, Q., Liu, W., Takano, T., Smith, N. A., Schnermann, J., et al. breathing function homeostatic control of brain function new approaches to understand epileptogenesispdf fncel 07 0 0 1 09 20 13 7 16 1228 pag e1 beyond the influence of rygb on brain areas involved in the homeostatic reward and executive control of eating behavior human t 1 weighted mri studies suggest widespread structural adaptations throughout the gray and white matter regions of all brain … doi: 10.1111/j.1528-1167.2006.00499.x, Fiebich, B. L., Biber, K., Lieb, K., Van Calker, D., Berger, M., Bauer, J., et al. Therefore, changes in extracellular adenosine due to adenosine and/or ATP release can alter adenosine receptor signaling described above, and experimentally increasing intracellular adenosine or ATP concentration can increase the activity of adenosine receptors (Brundege and Dunwiddie, 1996; Kawamura et al., 2010). Biosph. It becomes clear that complex neurologica… • Examples of homeostatic therapies in preventing and delaying dysfunction. Bull. Drug Discov. doi: 10.1172/JCI57813, McQuarrie, I., and Keith, H. M. (1927). The body’s temperature regulation is controlled by a region in the brain called the hypothalamus. Miyata, H., Hori, T., and Vinters, H. V. (2013). Gene promoters from mTLE patients are characterized by altered DNA methylation patterns and decreased DNA methyltransferase (Dnmt) gene expression (Kobow et al., 2009; Zhu et al., 2012). (2012). Metabolic autocrine regulation of neurons involves cooperation among pannexin hemichannels, adenosine receptors, and KATP channels. Epilepsia 33, 1132–1136. Nat. (2008). PRINTED FROM OXFORD MEDICINE ONLINE (www.oxfordmedicine.com). Nat. Neuroanat. Homeostatic Control of Brain Function offers a broad view of brain health and diverse perspectives for potential treatments, targeting key areas such as mitochondria, the immune system, epigenetic changes, and regulatory molecules such as ions, neuropeptides, and neuromodulators. doi: 10.1523/JNEUROSCI.0010-04.2004, Rash, J. E., Yasumura, T., Hudson, C. S., Agre, P., and Nielsen, S. (1998). The hypothalamus regulates homeostasis by producing hormones that thereby influence the production of other hormones that then control the internal milieu of the body. The brain barrier system, i.e., the blood-brain and blood-cerebrospinal fluid barriers, is important for zinc homeostasis in the brain. Invest. Consequently, DNA methylation inhibitors might be of therapeutic value to either treat epilepsy by restoring non-pathological epigenetic homeostasis. Stimulation of reactive astrogliosis in vivo by extracellular adenosine diphosphate or an adenosine A2 receptor agonist. Brain Res. doi: 10.1038/nrd2638, Hasko, G., Pacher, P., Vizi, E. S., and Illes, P. (2005). Neuroscience 88, 1083–1091. (2008). (2011). Baborka, C. J. Transactivation of Trk neurotrophin receptors by G-protein-coupled receptor ligands occurs on intracellular membranes. Trends Neurosci. Acta 1099, 238–246. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. doi: 10.1073/pnas.95.26.15735, Coulter, D. A., and Eid, T. (2012). J. Neurol. Genet. J. Neurosci. 44, 1038–1055. The roads to and from the RNA world. Intracellular formation and release of adenosine from rat hippocampal slices evoked by electrical stimulation or energy depletion. Loss of homeostasis becomes expressed as a diverse array of neurological disorders. Initially, the homeostatic responses would be controlled by the brain stem and cerebellum. 45, 385–412. We conclude that reconstruction of homeostatic functions in the brain offers a new conceptual advance for the treatment of neurological conditions which goes far beyond current target-centric treatment approaches. Neurol. Increased brain-derived neurotrophic factor (BDNF) in particular has been linked to epileptogenesis (Grabenstatter et al., 2012). Rev. (2012). FASEB J. loss of motor function: Term. doi: 10.1111/j.1471-4159.2004.02204.x. The emerging role of DNA methylation in epileptogenesis. impulse moves from the receiving region of the neuron down the axon to the sending region. Cell. The limbic system is a part of the brain that’s involved … Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. doi: 10.1179/016164105X21832, Sommerschild, H. T., and Kirkeboen, K. A. In addition, the epileptogenic hippocampus is characterized by increased DNA methylation. 497, 223–230. Adenosine and cardioprotection during ischaemia and reperfusion–an overview. 80, 224–232. These combined A1R effects strongly dampen the synaptic network, and undoubtedly play a major role in the efficacious anticonvulsant effect of adenosine and A1R agonists (Boison, 2007). J. Neurosci. Chem. Homeostatic Control of Brain Function offers a broad view of brain health and diverse perspectives for potential treatments, targeting key areas such as mitochondria, the immune system, epigenetic changes, and regulatory molecules such as ions, neuropeptides, and neuromodulators. Adv. Adenosine in synapses of CA1 pyramidal neurons can be generated in response to high frequency stimulation that induces a Ca2+-mediated release of ATP from astrocytes through either vesicular transport or hemichannels (Cotrina et al., 1998; Zhang et al., 2003; Pascual et al., 2005; Kang et al., 2008) or the direct release of adenosine from neurons (Lovatt et al., 2012). doi: 10.1016/j.expneurol.2009.05.018, Tanaka, K., Watase, K., Manabe, T., Yamada, K., Watanabe, M., Takahashi, K., et al. Each disorder has multiple comorbidities - with some crossing over several conditions – and often disease-specific treatments remain elusive. Using an independent therapeutic approach, the transient delivery of adenosine by intraventricular silk for only 10 days provided long-lasting (beyond adenosine release) antiepileptogenic effects in the rat kindling model of epilepsy (Szybala et al., 2009). J. Chem. As a consequence, disruptions to normal glial cell function as observed in neurological disorders with a gliotic pathology has widespread deleterious ramifications that contribute to disease progression and maintenance through changes in synaptic activity, BBB permeability, brain immunity, and inflammation (Carmignoto and Haydon, 2012; Coulter and Eid, 2012; Kovacs et al., 2012). Mol. (in press). 26, 511–516. doi: 10.1016/j.ymgme.2011.02.001, Haj-Yasein, N. N., Jensen, V., Vindedal, G. F., Gundersen, G. A., Klungland, A., Ottersen, O. P., et al. Identification of zebrafish A2 adenosine receptors and expression in developing embryos. Multiple mechanisms by which reactive astrocytes may directly modulate neuronal activity at the synaptic cleft have been proposed. doi: 10.1523/JNEUROSCI.4781-03.2004, Grabenstatter, H. L., Russek, S. J., and Brooks-Kayal, A. R. (2012). The nervous system plays a critical role in the regulation of vascular homeostasis. 23, 329–344. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. doi: 10.1111/j.1528-1167.2008.01669.x, Lahav, N. (1993). Unfortunately, the use of DNMT inhibitors for treating epileptic patients must be approached with caution due to target related complications or side effects. Epigenetic changes induced by adenosine augmentation therapy prevent epileptogenesis. Blood-brain barrier disruption in post-traumatic epilepsy. Chronic cholinergic imbalances promote brain diffusion and transport abnormalities. Homeostatic Control of Brain Function offers a broad view of brain health and diverse perspectives for potential treatments, targeting key areas such as mitochondria, the immune system, epigenetic changes, and regulatory molecules such as ions, neuropeptides, and neuromodulators. Multiple inflammatory processes, which have been linked to epileptogenesis (Ravizza et al., 2011) could be triggered by an injury-induced surge in adenosine. Acad. Importantly, adenosine is not only part of the energy metabolite ATP but also of RNA, the nucleic acid thought to be at the origin of life (Lahav, 1993; Dworkin et al., 2003; Robertson and Joyce, 2012). Nucleoside transporter expression and function in cultured mouse astrocytes. Immun. Transcriptome profiling reveals TGF-beta signaling involvement in epileptogenesis. A substantial decrease in both astrocyte glutamate transporters, EAAT-1 and EAAT-2, has also been identified in resected mTLE hippocampi (Sarac et al., 2009). 12th Grade. Ketogenic diet in the treatment of refractory epilepsy in childhood. Achetez et téléchargez ebook Homeostatic Control of Brain Function (English Edition): Boutique Kindle - Neurology : Amazon.fr Akin to seizures themselves, which have negative acute and chronic effects, restoring homeostasis can benefit acute brain function and avert the progressive process of epileptogenesis. 118, 1461–1468. This interpretation is supported by a severe mitochondrial pathology in ADK knockout mice (Boison et al., 2002). 29, 8927–8935. Received: 30 April 2013; Accepted: 22 June 2013; Published online: 16 July 2013. U.S.A. 107, 22659–22664. Therefore, improving mitochondrial bioenergetics has the potential to offer dual benefits of improving metabolic dysfunction and restoring adenosine homeostasis. Injuries to the brain such as trauma, stroke, or SE trigger an acute surge in adenosine, which is accompanied by transient downregulation of ADK (Clark et al., 1997; Pignataro et al., 2008). Click here to study/print these flashcards. 68, 356–364. Brain Res. Temporal and mechanistic dissociation of ATP and adenosine release during ischaemia in the mammalian hippocampus. doi: 10.1016/j.neuropharm.2008.09.016, Eulenburg, V., and Gomeza, J. Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? Human Anatomy, diseases, traumas, and conditions in the brain. In the brain, epileptic seizures cause a rapid drop in energy, which results in the generation of adenosine levels that can exceed the baseline level more than 40 times (During and Spencer, 1992); it is this rise in adenosine that acts as endogenous terminator of seizures and which is responsible for the postictal refractoriness that normally follows a seizure (Lado and Moshe, 2008). Research in AD drug discovery has historically focused on the Amyloid Hypothesis, based primarily on findings from early-onset AD, which is caused by mutations in amyloid-β (Aβ) pathway proteins and which accounts for <2% of all AD cases. Loss of glutamine synthetase in the human epileptogenic hippocampus: possible mechanism for raised extracellular glutamate in mesial temporal lobe epilepsy. Williams-Karnesky, R. L., Sandau, U. S., Lusardi, T. A., Lytle, N. K., Farrell, J. M., Pritchard, E. M., et al. axon. At any given time it contains 15 percent of the body’s blood supply and consumes 20 percent of the body’s oxygen and glucose. Adenosine is cleared by ADK-mediated phosphorylation to AMP, and HCY is converted to methionine in a folate-dependent manner. 63, 103–112. During epileptogenesis the adenosine/ADK system undergoes biphasic changes that might be instrumental in epileptogenesis and seizure generation (Figure 2). Neurol. Hello Roksana, The portion of the brain that maintains the body’s internal balance (homeostasis). Both adenosine A1- and A2-receptors are required to stimulate microglial proliferation. Pascual, O., Casper, K. B., Kubera, C., Zhang, J., Revilla-Sanchez, R., Sul, J. Y., et al. 30, 3886–3895. 371, 137–145. homeostatic control of brain function Dec 17, 2020 Posted By Seiichi Morimura Public Library TEXT ID 6370e042 Online PDF Ebook Epub Library control of brain function offers a broad view of brain health and diverse perspectives for potential treatments targeting … doi: 10.1523/JNEUROSCI.0055-10.2010, Kim, J. H., Roberts, D. S., Hu, Y., Lau, G. C., Brooks-Kayal, A. R., Farb, D. H., et al. On the postsynaptic side, A1Rs hyperpolarize membranes by opening inwardly rectifying K+ channels. Aquaporin-4 and epilepsy. Proc. Natural course of glutamine synthetase deficiency in a 3 year old patient. Often the diet now is supplemented with medium-chain triglycerides, which are absorbed quickly and metabolized easily to ketones.

Numbers 5 11-31 Meaning, Kfc Venezuela Caracas, Role Of Natural Selection In Microevolution, Getit Changi Recommends Review, Lax Terminal 6 Directions, Maugi Meaning In English,