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Product Description
The first book in the incredible new series from the author of Percy Jackson, the Kane Chronicles and Heroes of Olympus.
Magnus Chase has always been a troubled kid. Since his mother's mysterious death, he's lived alone on the streets of Boston, surviving by his wits, keeping one step ahead of the police and the truant officers. One day, he's tracked down by an uncle he's never met - a man his mother claimed was dangerous. His uncle tells him an impossible secret: Magnus is the son of a Norse god. The Viking myths are true. The gods of Asgard are preparing for war. Trolls, giants and worse monsters are stirring for doomsday. To prevent Ragnarok, Magnus must search the Nine Worlds for a weapon that has been lost for thousands of years.
When an attack by fire giants forces him to choose between his own safety and the lives of hundreds of innocents, Magnus makes a fatal decision.
Sometimes, the only way to start a new life is to die . . .
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Comments about Magnus Chase And The Sword of Summer:
Bought this for my 15 year old daughter she loved it. I even read it myself what a great book. A book that would appeal to both boys and girls. Would make a great gift.
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Comments about Magnus Chase And The Sword of Summer:
Magnus Chase and the Sword of Summer by Rick Riordon
(A Review by Sam, aged 9)
What is the Book About?unknown
A boy finds out his father is a norse god, he dies and is sent on a quest to save the world along with a dwarf, an elf and a valkyrie.
Who is your favourite character and why?
My favourite character would be Blitzen the dwarf because he has a very good imagination for building.
What was your favourite part of the book and why?
The part when the sword talks for the first time. It is funny because he just pops up and has a chat while they are running from the bad guys. He talks all through the book after that.
Why is this book better than other books you have read?
Rick Riordon writes about myths and I like myths, but it is still modern. When I read them I really want to find out what happens next. Each series he writes is better than the last one, and this is the best.
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Comments about Magnus Chase And The Sword of Summer:
I have borrowed all Rick Riordan's books from my niece's son, so I gave him this latest for Christmas. He says it's as good as the others - I can't wait to borrow it from him
Comments about Magnus Chase And The Sword of Summer:
My 12 year old son read this book in less than a week despite school and sporting commitments. he literally couldn't put it down. He has read all the Percy Jackson, Kane Chronicles and Lost Heroes of Olympus series and has loved them all. Very much looking forward to the next Magnus Chase adventure....
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Comments about Magnus Chase And The Sword of Summer:
This book was well writing with all the things you need in a book, action, humour, twist and more import Mangus. Great read can't wait till second
Series: Magnus Chase
Audience: Children
Format: Paperback
Language: English
Number Of Pages: 576
Published: 6th October 2015
Publisher: Penguin Books Ltd
Country of Publication: GB
Dimensions (cm): 21.5 x 13.7 x 4.2
Weight (kg): 0.59
Edition Number: 1


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Williams lands Robins trial
Tom Williams has been handed the chance to prove himself at Bristol City.
Last Updated: 21/07/10 4:55pm
Tom Williams has been handed the chance to prove himself at Bristol City.
The defender was released by League One outfit Peterborough in the close-season following their demotion from the Championship.
It meant the 30-year-old was without a club going into the new campaign but manager Steve Coppell has stepped in to take a look at the stopper on trial.
The former West Ham, Birmingham, QPR, Barnsley, Gillingham, Swansea, Wycombe and Preston man will now to look earn a deal at the Ashton Gate club.
City currently only have one established left-back on their books in the form of Jamie McAllister, and Robins chief Coppell reckons Williams could add vital back-up.
Coppell told the club's official website: "Tom has asked to come on board and as we only have one senior left-back in Jamie McAllister, it's an opportunity to look at him.
"He'll get a chance to impress over the next couple of games."
Williams will now go into the squad as a substitute for City's friendly trip to Torquay on Wednesday evening.

subset: commoncrawl


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Neuronal excitability of the brain and ongoing homeostasis depend not only on intrinsic neuronal properties, but also on external environmental factors; together these determine the functionality of neuronal networks. Homeostatic factors become critically important during epileptogenesis, a process that involves complex disruption of self-regulatory mechanisms. Here we focus on the bioenergetic homeostatic network regulator adenosine, a purine nucleoside whose availability is largely regulated by astrocytes. Endogenous adenosine modulates complex network function through multiple mechanisms including adenosine receptor-mediated pathways, mitochondrial bioenergetics, and adenosine receptor-independent changes to the epigenome. Accumulating evidence from our laboratories shows that disruption of adenosine homeostasis plays a major role in epileptogenesis. Conversely, we have found that reconstruction of adenosine's homeostatic functions provides new hope for the prevention of epileptogenesis. We will discuss how adenosine-based therapeutic approaches may interfere with epileptogenesis on an epigenetic level, and how dietary interventions can be used to restore network homeostasis in the brain. 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.
Epileptogenesis is a complex process that not only involves changes in neuronal excitability and circuitry, but also changes in glial physiology and in the homeostatic environment in which neurons need to survive and to function properly (Kunz, 2002; Borges et al., 2003; David et al., 2009; Ravizza et al., 2011; Devinsky et al., 2013). Characterized by abnormal and excessive neuronal firing, each seizure represents a rapid loss of homeostatic equilibrium, with altered energy and molecular gradients, and a corresponding interruption of normal behavior and consciousness. Because having a seizure can increase the likelihood of future seizures, seizures themselves contribute to epileptogenesis. 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. Therefore, the loss of homeostasis associated with epilepsy is found acutely during the seizure or precipitating event, and also during the chronic process of epileptogenesis.
Unfortunately, the pursuit of neurocentric therapeutic targets did not yield any antiepileptogenic therapies to date (Loscher and Brandt, 2010). In contrast, a revised understanding of epilepsy as a complex syndrome of disrupted network homeostasis may yield novel therapeutic avenues to halt, disrupt, or even reverse the process of epileptogenesis. Key elements to consider with the goal of restoring network homeostasis are glial function and metabolism. 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.
Glial cells play a major role in the homeostatic state of the brain by regulating the ambient concentration of synaptic neurotransmitters; modulating the permeability of the blood brain barrier (BBB) through astrocyte–endothelial interactions; regulating cerebral blood flow; and microglial control of brain immunity. Thereby, glial cells directly influence brain function on multiple levels including neuronal excitability and synaptic transmission; delivering energy substrates from the periphery; and recovery from injury or infection (Eulenburg and Gomeza, 2010; Kofler and Wiley, 2011; Petzold and Murthy, 2011; Santello et al., 2012). 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).
Within human epileptic foci the most prominent pathological finding is gliosis, with reports of reactive astrocytes, microglia, glial scars, and/or gliomas being present (Kallioinen et al., 1987; Kurzwelly et al., 2010; Butler et al., 2013). Pathological glial cells have been associated with a spectrum of different neurological diseases that result in epilepsy including mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE), focal cortical dysplasia (FCD), tuberous sclerosis complex (TSC), and Rasmussen's encephalitis (Sosunov et al., 2008; Malmgren and Thom, 2012; Butler et al., 2013). Concurrent with a gliotic pathology, studies from both epileptic patients and rodent models for epilepsy have identified abnormal glial cell activity as a contributing factor to seizures and/or epileptogenesis.
Alongside gliosis, it is increasingly appreciated that epilepsy is a global dysregulation involving metabolic dysfunction (DiMauro et al., 2002; Kunz, 2002), and, furthermore, that metabolic dysfunction is common in neurological disorders including neurodegenerative (Sas et al., 2007) and psychiatric disorders (Rezin et al., 2009). The ketogenic diet, developed as a treatment for epilepsy nearly 100 years ago, is a highly successful metabolic strategy now moving broadly into translational work for a variety of neurological disorders. Multiple lines of evidence suggest that key mechanisms underlying the acute anticonvulsant effects of a ketogenic diet may be adenosine acting via KATP channels. These findings highlight the potential for altered metabolism restoring and maintaining homeostasis in the central nervous system (CNS), and have implications for exploring the prevention and treatment of neurological disorders using strategies other that traditional neurocentric approaches.
Here we outline homeostatic therapeutic strategies with a focus on adenosine, an endogenous bioenergetic homeostatic regulator; multiple lines of evidence suggest that adenosine homeostasis is a key factor in preventing and stopping seizures. This review will first discuss glial mechanisms of epileptogenesis with emphasis on disruptions of adenosine homeostasis. Based on these mechanisms, we identify glia-centric therapeutic strategies that treat epilepsy through restoring normal brain homeostasis. We then highlight recent evidence regarding the role of adenosine in the process of epileptogenesis and describe metabolic therapy via a ketogenic diet, which may restore adenosine homeostasis.
Historically epilepsy research has predominantly focused on disruptions to normal neuronal function as the primary etiology. However, there is a substantial amount of evidence that implicate glial dysfunction as a major contributing factor to epileptogenesis (Figure Figure11). Astrocytes regulate or modulate a number of neuronal functions including excitability, synaptic transmission, and plasticity. As a consequence, the presence of reactive astrocytes, as found in patients with mTLE, FCD, and TSC, disrupts normal neuronal activity that either promotes epileptogenesis or decreases seizure threshold (Sosunov et al., 2008; Miyata et al., 2013). Multiple mechanisms by which reactive astrocytes may directly modulate neuronal activity at the synaptic cleft have been proposed. These include, but are not limited to (i) increases in neuronal excitability caused by decreased adenosine tone; increased synaptic glutamate levels; changes in the extracellular space (ECS) volume and K+ ion concentration; and (ii) modulation of synaptic transmission through glutamate, adenosine triphosphate (ATP), adenosine, gamma-aminobutyric acid (GABA), or D-serine from astrocytes (Devinsky et al., 2013). While multiple glial mechanisms of epileptogenesis have been investigated, disruption of adenosine homeostasis has consistently been identified as sufficient for seizure generation and has proven to be an effective therapeutic target for seizure suppression and stopping disease progression (Boison, 2013). 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.
Reactive astrocytes cause neuronal hyperexcitability through increased synaptic glutamate and K+ levels and decreased ECS volume. Decreased astrocyte-mediated glutamate uptake and glutamate to glutamine conversion have been proposed to increase synaptic glutamate in the gliotic hippocampus (Cavus et al., 2005). Increased levels of synaptic glutamate may in part be attributed to reduced expression of glutamate transporters within reactive astrocytes. High affinity glutamate transporters (2–90 μM) are concentrated on the astrocyte membrane and are integral to maintaining a low glutamate tone within the synaptic cleft. Thus, a decrease in astrocyte glutamate transporters may increase neuronal hyperexcitability and decrease seizure threshold. A patient diagnosed with spontaneous seizures was found to have a mutation in the human gene SLC1A3, resulting in decreased EAAT-1 protein expression and reduced capacity for glutamate uptake (Jen et al., 2005). 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). However, this finding has not been reproduced in other studies (Tessler et al., 1999; Eid et al., 2004). Research with transgenic mice further implicates deregulation of astrocyte-mediated glutamate uptake as a contributing factor to epilepsy. A mouse model of TSC with progressive epilepsy was found to have decreased glutamate/aspartate transporter (GLAST) and glial glutamate transporter 1 (GLT-1) protein levels (genetic equivalents to EEAT-1 an EAAT-2, respectively) and glutamate transporter currents (Wong et al., 2003). In addition, GLT-1 and GLAST knockout mice have a decreased pentylenetetrazol (PTZ) seizure threshold. The GLT-1 knockouts also exhibit spontaneous lethal seizures and have increased levels of synaptic glutamate (Tanaka et al., 1997; Watanabe et al., 1999). Downregulation of glutamine synthetase (GS) within reactive astrocytes has also been postulated as a potential cause for the increased synaptic glutamate tone observed in the epileptic hippocampus (Eid et al., 2004). GS primarily resides in the astrocyte cytoplasm and is responsible for the ATP-dependent conversion of glutamate to glutamine. GS protein and enzymatic activity are profoundly decreased, 40 and 38%, respectively, in the hippocampus of mTLE patients with the greatest reduction observed in proliferating astrocytes (Eid et al., 2004). Causative evidence that reduced GS activity is sufficient for epileptogenesis is from a pharmacological study with rats that developed seizures and neuropathology reminiscent of mTLE when chronically infused with the GS in inhibitor methionine sulfoximine (Wang et al., 2009). Furthermore, a mutation in the gene encoding GS has been linked to child with epilepsy (Haberle et al., 2011).
The state of neuron excitability is also tightly coupled to the ECS volume and associated K+ homeostasis (Schwartzkroin et al., 1998). More specifically, hypoosmolarity treatment reduces the ECS volume and increases neuron excitability and epileptiform activity; while hyperosmolarity treatment has the reverse effect. Aquaporin 4 (AQP4) is a water transport channel that is expressed within glial cells and which is integral to regulating ECS volume and implicated in epileptogenesis (Binder et al., 2012). AQP4 is normally localized to both the perivascular endfeet and within perisynaptic processes of astrocytes where it permits the bidirectional flow of water from the ECS to the blood (Nielsen et al., 1997; Rash et al., 1998; Nagelhus et al., 2004). In human mTLE brain specimens, AQP4 is redistributed primarily to the perisynaptic processes, which has been hypothesized to be a contributing factor of hyperexcitability through dysregulating water and K+ homeostasis (Eid et al., 2005). Research with transgenic AQP4 knockout mice support this hypothesis as they have increased ECS volume and are less susceptible to PTZ-induced seizures (Binder et al., 2004a,b). Glial-mediated water flow is also tightly coupled to K+ transport from the ECS through the inward rectifying K+ channel, Kir4.1, that is colocalized with AQP4 on the astrocyte membrane (Hsu et al., 2011). 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). Human polymorphisms in KCNJ10, the gene that encodes Kir4.1, are associated with epilepsy and a glial specific deletion of Kir4.1 in mice reduces K+ clearance from the synaptic cleft (Heinemann et al., 2000; Haj-Yasein et al., 2011). Dysregulation of AQP4 might also be linked to cholinergic imbalances in epilepsy, since overexpression of synaptic acetylcholinesterase has been associated with overexpression of AQP4 (Meshorer et al., 2005)
Aside from increasing neuronal excitability, astrogliosis disrupts synapse homeostasis through dysregulation of transmitter release from astrocytes. The list of transmitters proposed to be released by astrocytes includes glutamate, D-serine, ATP, adenosine, and GABA (Devinsky et al., 2013). In regards to adenosine homeostasis, astrocytes express two types of equilibrative nucleoside transporters, which mediate transport based on the concentration gradient of adenosine (Baldwin et al., 2004; Gray et al., 2004; Guillen-Gomez et al., 2004; Peng et al., 2005; Alanko et al., 2006). 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). Once in the synaptic cleft ATP is rapidly converted to adenosine by a series of ectonucleotidases (Zimmermann, 2000). Ca2+ waves within astrocytes have also been linked to glutamate and D-serine release. Within the epileptic brain Ca2+ signaling may regulate the glutamate-induced paroxysmal deporalization shift, which is the intracellular analog to the interictal spike (Tian et al., 2005). However, results from a separate study suggest that astrocytes may initiate seizures and not contribute to interictal activity (Gomez-Gonzalo et al., 2010).
Status epilepticus (SE) can induce a wide range of growth factors, neurotrophins, and transcription factors (Grabenstatter et al., 2012). Increased brain-derived neurotrophic factor (BDNF) in particular has been linked to epileptogenesis (Grabenstatter et al., 2012). In neurons, BDNF was shown to activate the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, cyclic adenosine monophosphate (cAMP) response element binding protein (CREB), inducible cAMP early repressor (ICER), and early growth response factors (Egrf) that induce a shift in the expression of specific subunits of the GABAAR as well as the expression levels of N-methyl-D-aspartate receptors (NMDARs; Roberts et al., 2006; Lund et al., 2008; Kim et al., 2012). In astrocytes, activation of the trkB receptors by BDNF has been linked to the development of astrogliosis, a mechanism that is also influenced by transactivation of the TrkB receptor through the adenosine A2AR (Brambilla et al., 2003). Whereas the role of growth factors on neuronal function is well documented, growth factor-dependent mechanisms that contribute to epileptogenesis via the disruption of glial homeostatic functions are not well established.
The breakdown of the BBB leading to albumin extravasation has directly been linked to epileptogenesis (Heinemann et al., 2012). 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). BBB disruption also triggered expression changes of genes associated with the TGF-β pathway, early astrocyte activation, inflammation, and reduced buffering for glutamate and K+ (Cacheaux et al., 2009; David et al., 2009). The reduced buffering capacity of transformed astrocytes for glutamate and K+ appears to be most critical during repetitive activation. Experimental blockade of TGF-β signaling following BBB disruption decreased those transcriptional responses and prevented epileptogenesis. BBB disruption has been demonstrated in patients with posttraumatic epilepsy (Tomkins et al., 2008) and in patients with brain tumors who developed epilepsy (Marchi et al., 2007). Thus, pathogenetic neurovascular interactions which involve astroglial dysfunction, changes in the immune response, and gene expression changes that promote neuronal hyperexcitability may play a critical role in epileptogenesis. Consequently, BBB disruption might constitute a valuable biomarker for the prediction of epileptogenesis following an insult to the brain.
Inflammatory processes play important roles in the pathogenesis of epilepsy (Aronica et al., 2012). Molecules linked to inflammatory reactions, such as TNF-α or prostaglandins, control the release of glutamate from astrocytes (Rossi and Volterra, 2009). 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). Importantly, components of these pathways were found to be overexpressed in surgically resected specimens from human TLE (Ravizza et al., 2008). Activation of the IL-1R/TLR pathway can increase excitability of the brain by the induction of post-translational changes in voltage- and ligand-gated ion channels. Among the endogenous ligands are danger signals, such as high mobility group box 1 (HMGB1), which can be released from injured or activated cells (Vezzani et al., 2011b). HMGB1 is the endogenous ligand of TLR4 and normally bound to chromatin. However, HMGB1 can be released into the ECS following either cell damage or neuronal hyperexcitability. The pro-epileptogenic role of HMGB1 is supported by recent data showing that blockade of the TLR4 pathway significantly delays seizure onset (Maroso et al., 2010). Likewise, engineered mice with defects in the IL-1R/TLR signaling pathway are intrinsically resistant to seizures (Vezzani et al., 2011b). 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). Thus, inflammatory processes and disruption of the BBB might form a self-perpetuating vicious cycle supporting chronic hyperexcitability of the brain via compromised astrocyte function on multiple levels.
The purine ribonucleoside adenosine has early evolutionary origins and likely played already a role in prebiotic evolution (Oro and Kimball, 1961). 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). While ATP reflects the energy pool in the environment, RNA reflects the metabolic activities of a cell. Thus, adenosine assumes a central place between energy availability and metabolic demands and has therefore been termed a retaliatory metabolite (Newby et al., 1985). It is fair to assume that adenosine played an early evolutionary role as key bioenergetic network regulator central to the energy homeostasis of a cell. The early evolutionary principle to conserve energy was likely a rise in adenosine as a consequence to ATP depletion and to use the increase in adenosine as a negative feedback regulator to attenuate all cellular activities that consume energy. This early evolutionary principle is omnipresent in all living systems and in every human organ. 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). Consequently, adenosine augmentation therapies constitute a promising avenue for seizure control (Boison, 2007). Seizure suppression by adenosine depends on the activation of G-protein coupled adenosine A1 receptors (Fredholm et al., 2005); however, new evidence suggests that adenosine retains important adenosine receptor-independent regulatory functions, which are based on interactions with mitochondrial bioenergetics, interference with biochemical enzyme reactions, and epigenetic functions. Thereby adenosine assumes a unique role as homeostatic network regulator.
A number of adenosine's actions are mediated by a group of specific receptors, G protein-linked transmembrane proteins of the P1 family, distinguished from the P2 ATP receptor family. 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). These receptors have biochemical specificity as each acts through a particular set of G proteins to influence second messengers: for the classical second messenger cAMP, A1R and A3R activation inhibits its production, whereas A2aR and A2bR activation are stimulatory (Fredholm et al., 2011). Other second messengers such as diacylglycerol, inositol triphosphate, and Ca2+ are also modulated. Each receptor presents a distinct pharmacology, and each has a particular distribution in tissues and cell types. For instance, A1Rs are expressed most highly in brain, whereas A2bRs and A3Rs have their highest expression in the periphery (Dixon et al., 1996). Within the brain, A1Rs are widespread with particularly high levels in the limbic system, whereas A2aRs are expressed mostly in the basal ganglia (Dixon et al., 1996).
Adenosine can have powerful receptor-mediated effects on synaptic transmission in the brain (Fredholm et al., 2011). Presynaptic A1Rs inhibit synaptic release of most, if not all, neurotransmitters, with an apparently greater effect on excitatory transmission. Thus, if adenosine levels are raised sufficiently, synaptic transmission can be blocked altogether. On the postsynaptic side, A1Rs hyperpolarize membranes by opening inwardly rectifying K+ channels. 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). The effect of A2aRs on network excitability is less clear, and more anatomically restricted, but if seizures reflect brain network imbalance, then one seizure model suggests that A1Rs and A2aRs may cooperate to promote homeostasis (De Sarro et al., 1999).
Mitochondria generate ATP via oxidative phosphorylation, and this is the main pathway for generating this critical cell energy molecule. Regarding the relationship between adenosine and ATP, intracellular adenosine is dephosphorylated from AMP by cytosolic 5′-nucleotidase and is converted back to AMP via adenosine kinase (ADK). The adenosine-AMP cycle is linked to ADP and ATP with adenylate kinase. Thus, adenosine is linked tightly to energy metabolism. Whereas mitochondrial uncouplers decrease ATP and increase adenosine (via net dephosphorylation of ATP), mitochondrial enhancers, or other strategies, which enhance ATP also appear to increase adenosine. Therefore, improving mitochondrial bioenergetics has the potential to offer dual benefits of improving metabolic dysfunction and restoring adenosine homeostasis.
Adenosine triphosphate is released from various pathways including vesicular release (Coco et al., 2003; Pascual et al., 2005), gap junction hemichannels (Kang et al., 2008) and chloride channels (Anderson et al., 2004), and hydrolyzed to adenosine by a series of ectonucleotidases (Zimmermann, 2000). Interestingly astrocytes express all types of ATP-releasing proteins and are capable of releasing ATP from these pathways simultaneously (Garre et al., 2010). After ATP is dephosphorylated, extracellular adenosine is salvaged into the intracellular space by equilibrative nucleoside transporters and/or concentrative nucleoside transporters (Latini and Pedata, 2001). However, it has also been reported that these nucleoside transporters release adenosine with various types of metabolic stress (Lloyd et al., 1993; Frenguelli et al., 2007). Adenosine-AMP cycles and bidirectional adenosine uptake and release via nucleoside transporters maintain adenosine homeostasis. 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).
Taken together, adenosine's role in maintaining homeostasis interacts directly with mitochondrial bioenergetics and energy metabolism (Newby, 1984; Newby et al., 1985; Sommerschild and Kirkeboen, 2000). The intracellular concentration of ATP is nearly 50 times higher than that of AMP (Arch and Newsholme, 1978) and about 10,000 times higher than that of adenosine (Pazzagli et al., 1995; Delaney and Geiger, 1996). Thus, minor decreases in intracellular ATP leads to a large rise of intracellular adenosine level. Thus, various excitatory stimuli cause decreased brain energy and a subsequent increase in adenosine (Shepel et al., 2005). It has been reported that increases in intramitochondrial AMP cause adenosine production in the purified mitochondria, and thus extramitochondrial adenosine levels increase in a time-dependent manner, suggesting a concentration-dependent adenosine output from mitochondria by diffusion or facilitated diffusion (Raatikainen et al., 1992). Conversely, the cytosolic adenosine formation with a balance of cytoplasmic ADK and cytosolic 5′-nucleotidase might influence mitochondrial adenosine production and affect mitochondrial bioenergetics. This interpretation is supported by a severe mitochondrial pathology in ADK knockout mice (Boison et al., 2002). As a "retaliatory metabolite" adenosine is thought to be one of the key links between neuronal network homeostasis and mitochondrial bioenergetics with both adenosine receptor-dependent and -independent pathways.
Modifications to the epigenome that include changes in DNA methylation, histone tail modifications, and incorporation of histone variants are mechanisms by which network homeostasis can be dramatically altered and consequently change the entire gene expression profile of a tissue. There are a number of epilepsy-associated neurological diseases that are directly attributed to primary genetic mutations and result in secondary deregulation of the epigenome (Kobow and Blumcke, 2011). 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).
Biochemically, DNA methylation is intricately linked to S-adenosylmethionine (SAM)-dependent transmethylation reactions (Figure Figure22). SAM donates a methyl group to unmethylated cytosines in DNA. Following methyl group donation, SAM is converted to S-adenosylhomocysteine (SAH). SAH is further hydrolyzed to adenosine and homocysteine (HCY). Adenosine is cleared by ADK-mediated phosphorylation to AMP, and HCY is converted to methionine in a folate-dependent manner. Importantly, DNA methylation is dependent on the continuous removal and subsequent equilibrium constants of SAH, adenosine and HCY (Lu, 2000; Boison et al., 2002). Thus, an accumulation of adenosine prevents the biochemical conversion of SAM to SAH and therefore inhibits DNA methylation.
Humans with ADK deficiency caused by a missense mutation in the ADK gene have disruptions to the transmethylation pathway with increased methionine and SAH levels. Furthermore, they have abnormal liver function; encephalopathy; and severe progressive neurological deficits (Bjursell et al., 2011). Transgenic mice with an ADK knockout also have disruptions in the transmethylation pathway with decreased blood adenine levels and increased HCY levels and the fatal liver disease neonatal hepatic steatosis (Boison et al., 2002). Peripheral changes in the transmethylation pathway are conserved within the brain. We recently found that hippocampal adenosine levels regulate the global DNA methylation status by shifting the equilibrium constant of the transmethylation pathway; thereby either increasing (high ADK and low adenosine) or decreasing (low ADK and high adenosine) methylation. These adenosine dependent changes in DNA methylation are receptor-independent and can be evoked by either a single pharmacological bolus of adenosine (icv) or in response to endogenous changes in ADK expression or activity (Williams-Karnesky et al., 2013). 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). Consequently, the adenosine tone does not regulate site specific DNA methylation, but instead the homeostasis of the DNA-methylome.
As outlined above, glial pathologies play important roles in epileptogenesis. Astrocytes form the major metabolic reuptake route for synaptic adenosine and control the availability of extracellular adenosine via expression changes of the astrocyte-based enzyme ADK, which phosphorylates adenosine to AMP and thereby drives the influx of adenosine into the astrocyte through equilibrative transporters (Boison, 2013). Using transgenic approaches and adenosine microelectrode biosensors we previously demonstrated that ADK expression levels in astrocytes directly control the levels of tissue adenosine under baseline conditions (Etherington et al., 2009). During epileptogenesis the adenosine/ADK system undergoes biphasic changes that might be instrumental in epileptogenesis and seizure generation (Figure Figure22).
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). The initial injury and the associated surge in adenosine can trigger several mechanisms possibly implicated in epileptogenesis, among which the induction of A2AR expression in glial cells appears to play a prominent role. In primary cultures of glial cells lipopolysaccharide (LPS) was found to induce A2AR mRNA and protein expression with a peak at 48 h after treatment (Saura et al., 2005). Likewise, in microglial cells and astrocytes of the mouse substantia nigra 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced the expression of A2ARs within 24 h after intoxication. The proliferation of astrocytes and thereby the development of astrogliosis is in part regulated by the ratio of the different adenosine receptors expressed on the astrocyte membrane. 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). In addition, important immune functions of the brain are under the control of adenosine homeostasis (Hasko et al., 2005, 2008). Via simultaneous activation of A1 and A2A receptors adenosine was shown to stimulate the proliferation of naïve microglial cells (Gebicke-Haerter et al., 1996), whereas the A2A receptor-dependent upregulation of cyclooxygenase 2 (COX-2) and the release of prostaglandin E2 (PGE2) were shown to mediate additional pro-inflammatory effects of adenosine (Fiebich et al., 1996). Multiple inflammatory processes, which have been linked to epileptogenesis (Ravizza et al., 2011) could be triggered by an injury-induced surge in adenosine. Recent findings also demonstrate that increased levels of adenosine induce hypomethylation of hippocampal DNA as described previously by shifting the equilibrium constant of the transmethylation pathway (Williams-Karnesky et al., 2013). 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.
Astrogliosis is a pathological hallmark of the human and experimental epileptic brain and has consistently been associated with overexpression of ADK resulting in adenosine deficiency (Li et al., 2008; Aronica et al., 2013). Adenosine deficiency in human epilepsy has directly been identified via the analysis of microdialysis samples. A 25% reduction of adenosine in the epileptogenic versus the contralateral control hippocampus was found (During and Spencer, 1992). 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). The transgenic overexpression of ADK (40% increase) in the brain of mice triggered spontaneous electrographic seizures (Li et al., 2008), whereas a transgenic approach that reduced ADK expression in cortex and hippocampus of mice (40% reduction) rendered those animals resistant to seizures and resistant to epileptogenesis (Li et al., 2008). These data demonstrate that ADK provides a molecular link between astrogliosis and increased neuronal excitability.
In addition, the epileptogenic hippocampus is characterized by increased DNA methylation. This hypermethylated state forms the basis of the methylation hypothesis of epileptogenesis, which suggests that seizures by themselves can induce epigenetic chromatin modifications and thereby aggravate the epileptogenic condition (Kobow and Blumcke, 2011). Hypermethylation of DNA can be triggered by a variety of mechanisms, however, the mechanisms underlying the gradual increase in DNA methylation status during the course of epileptogenesis are not well characterized and largely the subject of speculation (Kobow and Blumcke, 2012). 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). We propose that overexpression of ADK in the epileptogenic hippocampus and resulting adenosine deficiency drives the biochemical transmethylation pathway and thereby increases the methylation rate of the hippocampal DNA. It is important to note that adenosine affects DNA methylation in a non-cell-autonomous manner and thereby is uniquely positioned to effect homeostasis of the DNA-methylome on a global scale within the hippocampal formation (Williams-Karnesky et al., 2013). Through this mechanism, astrogliosis and associated overexpression of ADK could contribute to continued epileptogenesis through maintenance of a hypermethylated state of hippocampal DNA. Conversely, reduction of DNA methylation through therapeutic adenosine augmentation may provide a rational therapeutic approach for the prevention of epileptogenesis.
Several lines of evidence suggest that adenosine might prevent epileptogenesis. Transgenic mice with an engineered reduction of ADK expression in forebrain were found to be resistant to the development of epilepsy, even when the epileptogenesis-triggering SE was coupled with transient blockade of the A1R (Li et al., 2008). Similarly, adenosine-releasing stem cells – implanted into the hippocampal formation after triggering epileptogenesis – dose-dependently attenuated astrogliosis, suppressed ADK increases, and attenuated development of spontaneous seizures (Li et al., 2008). 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). More recent findings, as will be discussed in more detail below, suggest that the antiepileptogenic effects of adenosine are based on an epigenetic mechanism. 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.
As mentioned previously, DNA methylation has been highlighted as a component of the methylation hypothesis of epileptogenesis (Kobow and Blumcke, 2011). Consequently, DNA methylation inhibitors might be of therapeutic value to either treat epilepsy by restoring non-pathological epigenetic homeostasis. Unfortunately, the use of DNMT inhibitors for treating epileptic patients must be approached with caution due to target related complications or side effects. As an alternative to conventional pharmacological DNMT inhibitors focal adenosine therapy may serve as an effective epigenetic medicine. Recently, we described a novel antiepileptogenic role for adenosine; whereby a transient adenosine augmentation therapy administered to epileptic rats after the onset of spontaneous recurrent seizures not only suppressed seizures during active adenosine release, but also prevented further disease progression that lasted long after the therapy was suspended. Adenosine-dependent changes in DNA methylation were pinpointed as an underlying mechanism for the antiepileptogenic properties of this adenosine therapy. Adenosine treatment was found to restore normal DNA methylation levels in the otherwise hypermethylated hippocampus of the epileptic rat. More specifically, genome wide analysis using a methylated DNA immunoprecipitation (MeDIP) array revealed that out of the 125 genes which showed increased DNA methylation in epilepsy, 66 also showed reduced DNA methylation after adenosine therapy in treated epileptic rats. Interestingly, multiple targets that function to either interact with DNA or play a role in gene transcription and translation (PolD1, Polr1e, Rps6kl1, Snrpn, Znf524, Znf541, Znf710) responded to adenosine therapy with a decrease in the DNA methylation status of their respective promoters. Consequently, these targets are poised as likely candidates to mediate adenosine-dependent changes in major homeostatic functions (Williams-Karnesky et al., 2013).
Dietary therapies for epilepsy can be useful in cases where medications and other treatments are ineffective. The most obvious application is for epilepsies associated with specific inborn errors of metabolism that can be treated by removing or adding specific dietary components. Such disorders include dysfunctions of the enzymes phenylalanine hydroxylase, argininosuccinate synthetase, guanidinoacetate methyltransferase, 3-methylcrotonyl-CoA carboxylase, antiquitin, or various enzymes and transporters for metabolizing different classes of lipids (Papetti et al., 2012). Such disorders range from somewhat to extremely rare.
For more common forms of epilepsy, one effective dietary treatment is also the simplest: no diet at all. Fasting has been known to alleviate convulsions since antiquity. Some of the first work in the modern era on this topic was done by Geyelin in the 1910s (Geyelin, 1921). In working with grand mal and petit mal patients of various ages, he found that 22 out of 26 subjects were seizure-free after 10 days of fasting, with many experiencing beneficial effects after just 2 days of fasting. Furthermore, two subjects remained seizure-free for a year after the end of fasting, suggesting the potential for epigenetic and antiepileptogenic effects. Yet fasting has a number of problems, including the difficulty of maintaining a fast and being necessarily time-limited. Also, fasting would be contraindicated in patients that have other health problems besides epilepsy, growing children, and adults with very low body mass index.
Fasting forces a metabolic shift in which the liver metabolizes fatty acids into ketone bodies, which in the absence of sufficient glucose can be used as fuel by other tissues, particularly the brain, which is glucose-dependent. Hypothesizing that the antiseizure effects of fasting were due to this state of ketosis, in the 1920s Wilder began to use in his epileptic patients a strict modified diet which also produces ketosis (Wilder, 1921; Wilder and Winter, 1922). This ketogenic diet, low in carbohydrate, high in fat, with moderate-to-low protein, thus reproduces a major metabolic effect of fasting while still allowing food and was found to be an effective anticonvulsant in children and adults (McQuarrie and Keith, 1927; Baborka, 1930). Similar to fasting, initial reports also suggested an antiepileptogenic potential of a dietary approach, but there has been little research to follow up on using controlled studies.
The ketogenic diet was a fairly common epileptic treatment until the synthesis of phenytoin and other effective anticonvulsant drugs in the 1930s, which were easier to implement than a strict diet. Notably, anticonvulsant drugs often have sedative and cognitive side effects that the ketogenic diet lacks (Gupta et al., 2001; Drane and Meador, 2002). 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. Often the diet now is supplemented with medium-chain triglycerides, which are absorbed quickly and metabolized easily to ketones. Good success rates were reported in retrospective (Kinsman et al., 1992; Hassan et al., 1999) and prospective studies (Freeman et al., 1998; Vining et al., 1998).
The first randomized, controlled study of the ketogenic diet clearly demonstrated a beneficial effect (Neal et al., 2008). These studies often showed efficacy equal to anticonvulsant drugs and while seizures worsened as a whole in patients on anticonvulsant medications they improved as a whole in the group on the diet. While a subset of the children on the ketogenic diet became seizure-free, this did not occur in the group receiving standard therapy with anticonvulsants. Even though this study was randomized and controlled, blinded studies of the ketogenic diet present obvious difficulties; one attempt, with mixed results, has been published (Freeman et al., 2009).
Multiple lines of evidence suggest that a ketogenic diet can increase ATP or mitochondrial biogenesis (Bough et al., 2006), and that it may exert anticonvulsant effects via adenosine (Masino et al., 2011). Further validation of these findings could identify the metabolic shift, which accompanies a ketogenic diet (or fasting), as a key strategy to increase adenosine and restore homeostasis. Along those lines, and as noted above, the potential for the ketogenic diet to restore homeostasis and offer antiepileptogenic activity deserves additional research, particularly as this dietary therapy is pursued for diverse neurological indications in which epilepsy is often comorbid.
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. Chronic disruption of either its environment (the milieu) or its adaptive response to its environment (transcription and translation) results in a loss of CNS homeostasis and pathological dysfunction. It becomes clear that complex neurological syndromes, such as epilepsy, which are not only defined by a dominant symptom (i.e., a seizure), but also by a growing number of associated comorbidities, can best be explained by the disruption of network homeostasis. Disruption of network homeostasis will lead to the dysregulation of several molecular pathways (e.g., those dependent on K+, glutamate, and adenosine homeostasis) simultaneously. It becomes clear that conventional drugs with a mode of action that is restricted to only one target or pathway might be sufficient to block a symptom (e.g., a seizure), but are unlikely to affect a neurological condition on the network level. Novel therapeutic interventions based on adenosine, epigenetic mechanisms, or dietary interventions might hold promise to affect network homeostasis as a novel conceptual strategy to treat and prevent epilepsy on the network level. For future therapy development it is important to note that adenosine augmentation has no known adverse effects. In preclinical toxicity studies of intrathecal adenosine in dogs, no side effects were observed with intrathecal adenosine infused chronically for 26 days (Chiari et al., 1999). Likewise, intrathecal adenosine was tested in humans in escalating doses of up to 2 mg without any adverse effects (Eisenach et al., 2002a,b). Importantly, suprahippocampal implants of adenosine-releasing cells demonstrated a robust pro-cognitive effect in mice (Shen et al., 2012), suggesting that therapeutic adenosine augmentation might combine anticonvulsant with cognition-enhancing effects. Whereas seizure suppression in chronic epilepsy would require continuous long-term augmentation of adenosine, e.g., by gene therapy, cell grafts, or dietary intervention, preventing disease progression in the early stages of epilepsy might require only the transient delivery of adenosine. Adenosine-releasing silk might be an attractive therapeutic candidate due to the bioresorbable properties of this biopolymer. Those and related approaches are currently in preclinical development and molecular pathways stimulated by adenosine augmentation are currently under intense investigation.
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.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Murder at the Chase: A Locked Room Mystery Set in 1950s England Hardback
by Eric Brown
Part of the A Langham and Dupre Mystery series
Crime writer sleuth Donald Langham is faced with the classic locked-room conundrum in this engaging historical mystery July, 1955.
Donald Langham has interrupted his romantic break in rural Suffolk with the delectable Maria Dupre to assist a fellow writer.
Alastair Endicott has requested Langham's help in discovering what's happened to his father, Edward, who seems to have disappeared without trace from inside his locked study.
Before he vanished, the elder Endicott had been researching a book on the notorious Satanist Vivian Stafford.
Could the proposed biography have something to do with his disappearance?
Does local resident Stafford really possess supernatural powers, as some believe?
As Langham and Dupre question those around them, it becomes clear that there have been strange goings-on in the sleepy village of Humble Barton.
But is the village really haunted - or does someone merely want it to look that way?
With a further shocking discovery, the case takes a disturbing new twist.
- Format: Hardback
- Pages: 224 pages, black & white illustrations
- Publisher: Severn House Publishers Ltd
- Publication Date: 30/07/2014
- Category: Historical mysteries
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Showing 1 - 2 of 2 reviews.
Review by iansales
This is the second of Brown's 1950s-set murder mysteries featuring thriller writer Donald Langham and his fiancée literary agent Maria Dupré. In this book, they're invited to unravel a locked-room disappearance of another mystery writer, and it turns out it's all to do with a satanist who may or may not have been born over one hundred years earlier. Brown evokes his period well, and his two protagonists are eminently likeable. He even manages a nicely liberal view of humanity that wasn't common in 1955 – two of the secondary characters are gay, and despite it being illegal at the time, pretty much everyone seems surprisingly tolerant when confronted with it. The locked-room puzzle is disposed of disappointingly quickly, but then there's a murder and what looks like a suicide… And it all gets wrapped a little quickly and tidily for comfort. I suspect these are not written to be cosy mysteries, but they're beginning to resemble them. They need to be a bit edgier – Brown is capable of it, he handles his period with aplomb and his characters with assuredness. But the plot is all a bit rushed, and the ending is far too tidy.
Review by BookDivasReads
Donald Langham, mystery-thriller writer, and Maria Dupré, literary agent, are recuperating from the emotional trauma and physical wounds from their last encounter with a blackmailer (Murder by the Book). They are also in an established romantic relationship and looking forward to spending some time together in the country away from the hustle and bustle of the city. Unfortunately, their weekend in the country quickly becomes a hunt for a missing person, an investigation into a purported centenarian occultist, and more. All the while Donald is looking for the perfect opportunity to propose to Maria as Maria obsesses over whether or not he's actually interested in a permanent relationship. Will murder and mayhem keep these two off-balance? Can they ascertain the truth about the Satanist and the village's hauntings? I found Murder at the Chase to be a fast-paced and enjoyable read. I did have a few issues with the male Vivian character as I usually enjoy reading about characters that share my first name, but sharing it with a guy?! (Okay, it wasn't that big a deal but it was a little strange at first to read about Vivian the guy.) Donald and Maria are in an established relationship, so there isn't as much about the romance as there is intrigue in the storyline. Their weekend in the countryside is interrupted by a request to investigate a missing person with the classic locked-room scenario. As their attention turns toward the investigation of the missing person, they are introduced to a host of characters: an aging ex-Hollywood movie star with a secret past, an eccentric and lascivious artist, a lovable and young bumbling country vicar, the shy son of the missing person with a secret, the purported centenarian Satanist, and a crafty private investigator. This missing person case becomes a murder investigation when the Satanist's body is found with his head bashed in. The only problem I had with this book was the expectation of a locked room murder because there isn't an actual murder victim in a locked room. Murder at the Chase does provide murder, mystery, mayhem, and a hint of the macabre with the occult storyline. If you enjoy old-fashioned whodunits, then you'll definitely want to read Murder at the Chase. (No, I won't tell you if Donald pops the question . . . you'll have to read the book to find out for yourself!)
Also by Eric Brown | View all
Also in the A Langham and Dupre Mystery series | View all


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Pacamara Boutique Coffee Roasters Singapore15:40
Wednesday morning, hopped out of bed, craving for some poached eggs.
The weather's crazy, I can't find my way, where is Pacamara?
That was exactly what ran through my mind that Wednesday.
Finally, with the help of my trusty GoogleMaps, and after a 10-minute walk getting roasted under the horrendous sun, I found Pacamara.
It was little white-washed cafe, one of many shops nestled along the Upper Thomson neighbourhood stretch of road.
On a weekday morning, at around 11am, it was rather empty.
Sunlight was streaming through the floor-to-ceiling glass windows but it was a comfortable kind of brightness. The clean and minimalistic design was easy on the eyes.
They had a brunch and dinner menu. In the middle of the cafe, there was a water dispenser for free flow of citrus-flavoured water.
I ordered a Truffle Benedict ($18) with brioche, smoked ham, spinach, truffle hollandaise and free range poached eggs from the brunch menu.
Despite looking divine, the taste itself was off-the-mark.
For starters, what are poached eggs if their yolks weren't runny? Imagine my disappointment when I prodded the egg with my fork, and all I saw was a yellow lump of almost-solid yolk. The other egg at least, had a teeny bit of yolk oozing out, but still, it wasn't a good rendition of Eggs Benny.
When they include "Truffle" in the name, I had expected more of the rich, earthy, unique taste of truffle. It was barely discernible.
Thank goodness the brioche was decent and its crisp-edge-fluffy-inside combination cheered me up a little.
However wonderful the smoked ham and spinach tasted, it could never quite erase my memory of the lacklustre poached eggs, if you could call it poached at all.
Brunch wasn't as gratifying as expected, and nope, the price wasn't justifiable.
Celline had the Salmon Royale and Earl Grey.
As Pacamara is more well-known for their coffee and blends, I suppose I should brush that disappointing brunch off my mind and focus more on their coffee instead.
A cuppa in hand and a laptop in front - Pacamara has the perfect ambience for you to do your work in peace.
Post-brunch, I decided to stay on a little while more to get some work done, and ordered a $6 cup of Mocha. The latte art was... hmm. Nice try. I was hoping for something more instagram-worthy. At least the smooth mocha redeemed it.
Their coffee would probably be worth a visit, but not the food.
185 Upper Thomson Road, Singapore 574333
Nearest train station: Marymount (near Thomson Community Club)
Opening Hours:Tues – Sun: 9:00 am – 10:00 pm


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Dog Day Afternoon
It's a dog's life they say. Well, tomorrow it's certainly their afternoon at Graff Dairy. May 6th is Ice Cream Cones-Forever Homes event from 1-4pm.
I'm happy to report I've been to Graff Dairy. I know it's a local landmark and last weekend I made it by to sample some of their world-class ice cream. It was great. I had the peach flavor with cheesecake chunks on top. Yum!
Tomorrow looks to be another beautiful day for the Roice-Hurst Humane Society fundraising/adoption event. If you're looking for a pet, don't miss this! Dogs will be on site for adopting at a discounted price!
Graff Dairy too will be donating a portion of their proceeds that day to Roice-Hurst Humane Society. Graff Dairy will also be rolling out their new Vienna Beef Hot Dogs and Chicago Dogs! Sounds yummy! Graff will now be offering these world-class hot dogs to compliment their awesome ice cream!
So come on out. Graff Dairy is at 581 29 Road. Just look for this cool ride out front. It's all for a great cause and spring is the perfect time to adopt a pet. We'll see you there!


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Contact Info / Websites
Recent Movie Reviews
Fallen Angel Ep. 1 (Pt1)
Rated 5 / 5 stars
I Remember
I also remember seeing that trailer a while back, I enjoyed it to hell. Seriously, if the other episdoes are as good as this, I think this may be one of the best things ever on newgrounds.
All that I can say is, you have worked so hard for so long. Now enjoy, this is something I would have expected to see on T.V, its quality is a new level for that of a flash artist, well done, now go treat yourself to a nice cuppa tea and relax ;D.
I would rate this higher than 10 if I could
Angry Dog - Pheromones
Rated 5 / 5 stars
So original and great sense of humour, animation and graphics are not superb but fantastic for this type of series.
Tweed and Luc PART 3
Rated 3 / 5 stars
Really poor in terms of graphics, quality and quantity. But it actually made me laugh so I give a 6 =).
Recent Game Reviews
Ching Chong Beautiful
Rated 5 / 5 stars
Incredible, Addicting
Great great artwork and fluid feeling gameplay. My one issue with it is hard mode being almost impossible, took me a good 20 goes to beat the first level on it... best I could manage was the last level on the first stage for it.
Ownage Burst demo
Rated 5 / 5 stars
Really, Really Good
Fantastic gameplay, imaginative enemies, perfect difficulty. Great amount of skill needed, excellent graphics and fluid animation.
Brawl Royale
Rated 4.5 / 5 stars
Level Select System
I agree with the person below, you should be able to start from where you last lost, that way you might actually be able to beat the game o_0.
I loved the graphics and the animation was very clever with nice little bits of humour in between levels. I loved how I would kill (or be killed) differently and imaginativly every time.
Recent Audio Reviews
*++*(Link to the Past)*++
Rated 5 / 5 stars
That was great =). Needless to say that melody is just so enchantingly good, I cold listen to this for days...
The only thing that really bothers me is the end, I know this is a remix of a song and all, but I really am not sure about the sort of video game, organ-like ending. Of course the catchy tune throughout makes up for that and I love how you add in complimenting elements of hi-hats etc. that just keep the song nice and relaxing.
Excellent job
but as im sure you've noticed there are those that LOVE the ending - some hate the hihats, some hate the beginning - I can't please everyone - so in the end I settle with pleasing myself, because that's who matters the most is that "I" like it :P
thanks for the review!


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Cover Girl Models Trailer (1975)
"The Girls with the Centerfold Spreads." 01 July 1975 Drama, Action 98 mins
A fashion photography assignment teams three American models and inadvertently pitches them into the mystery and danger of international espionage, when an invaluable roll of microfilm secreted into one of the girls' fashion gowns, draws them into the violence and intrigue of a spy-vs-counterspy conspiracy.
Watch the official Cover Girl Models 1975 trailer in HD below or find more Cover Girl Models videos on Vidimovie.


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Send This Job to a Friend
Full Time
Graduate of an Accredited Nursing Program
RN Required
I am at least 18 years of age
I am authorized to work in the United States
I meet the job requirements as described
The Cancer Center at The University of Kansas Hospital is nationally known for innovative and compassionate cancer care. As a member of our team, you will be part of the latest advances in medicine and technology, backed by the expertise of the region's premier academic medical center. The Cancer Center's unique multidisciplinary team approach brings together nurses, physicians, social workers, nutrition experts and other clinical and administrative staff in an environment of mutual support and respect. Our commitment to quality care and patient satisfaction means every member of our staff plays a vital role in a patient's journey towards healing. We currently have an opening for an Oncology Nurse. Responsibilities: * Assesses patient status utilizing physical assessments, laboratory and diagnostic results, and a patient interview to provide patient care. * Demonstrates knowledge and skill in all aspects of IV Therapy. * Manages care based on knowledge of cancer, treatment and side effects. * Provides education to the patient and family regarding disease and treatment plan. Requirements: * Associate's Degree in Nursing. Bachelor's degree is preferred. * Kansas RN license * 2 years of oncology experience with IV Therapy skills. * Treatment Room RN or Office Practice RN in Oncology and BMT required.* OCN certification preferred* ONS Chemo/Bio Certification preferred* Must have an American Heart Association basic life support (BLS) or an American Red Cross CPR for the Professional Rescuer certification.
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text:
Crappy situation, need advice!
View Single Post
Scooby Specialist
Join Date:
Jan 2009
2004 WRX Wagon, WRB
06 Triumph Speed Triple
Crappy situation, need advice!
Hey guys. Let me start off by saying that yes, I have used the search function and I can't seem to come up with anything relevent to my particular issue. I'm just hoping for some honest advice here...
My scoob is a 95 Legacy L wagon. AWD, 2.2, manual...blah blah blah. Served me without fail or any major difficulties for the last 2 years in spite of its 207k and some change miles and being driven about 90 miles a day just commuting to work. And now it's broke...
I'll make a long story as short as possible. Started getting an intermittent knocking sound at idle from under the hood. Went away when the rev's were raised. Ended up finding out the outside of my harmonic balancer was wobbling around. The rubber in the balancer looked all dry/cracked/hard so I ordered up a nice lightweight crank pulley from Perrin.
Went to install it Friday evening after it came in the mail and ran into some BIG problems. I've had this car for the last 2 years and I've never had to really touch anything under the hood with the exception of a set of valve cover gaskets. But it looks like the place that did the t-belt before I bought the car did a real hack job. As we were backing out one of the bolts that holds the cooling fan in place on the driver's side, it came out wet and coolant started leaking on the ground. Some jerkoff used a bolt that was too long and drilled it right into the side tank of the radiator!!
Where it gets bad is when we went to take the old crank pulley off. The bolt that holds it in place was only like hand tight!! Someone forgot to use proper torque specs and/or Locktite! The keyway on the old pulley is MANGLED. Then we were worried about the crank. Removed the timing covers and found the end of the crank is equally destroyed. So...now I need an engine it seems, or a new car.
Thankfully, it's summer and I was able to scramble around yesterday and swap my registration and insurance over to my project truck so I at least have wheels while I figure out what I'm going to do. I've got a few options on the table...and I have about 6 months I figure before snow starts flying and renders my 2-wheel drive, lowered Nissan pickup useless.
1) New car.
2) Used 2.2 with lower miles. Pop in a new t-belt kit and all the trimmings, a new clutch and radiator and drive into the sunset.
3) A DOHC EJ25 swap.
4) A WRX EJ20 swap. (This is just one of those "That would be freakin' cool!" moments...not something I'm really taking under SERIOUS consideration.)
5) Haul my engine out, put it on a stand and rebuild it.
Here's where I have questions:
1) If I'm going to go through the trouble of tearing my motor down and rebuilding it, I'd like to squeeze some extra power out of it. No need to be a rocketship...just parts that are better than stock that'll give me a little extra grunt. Is it possible to pull off on an EJ22 without major Frankenstein modification? Higher compression pistons? Camshaft regrind?
2) The DOHC EJ25 swap seems the most doable as long as I can find a viable engine with a complete harness and ECU. However...Are the gains worth the expense and hastle of performing the swap? Or would I be better off to just go out and find a GT wagon?
If you've read this far: Thanks!
Just need some opinons so I can get myself moving in a direction. I'm having a really hard time digging up any relevent information anywhere...so hopefully some voices of experience can chime in.
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(to the tune of Uprising)
Bad reviews
Are in bloom
My reign of terror shall resume
I'll review Pokémon and give ground
They will never see the truth around
So type on!
They will never see the actual show
Thanks to me, Nell Minow!
So, type on!
And accuracy wrapped
In thick vines
To keep the truth
Forever confined
(electric guitar plays)
They can't see past us
They will stop flattering us
They will not believe us
We will be notorious
Lies! Lies! Lies! Lies!
We will see the brainwashed kids
Proud as heck of what we did
I'd think logically I could spill it out
I deserve to have vines from my body sprout
Give a speech on Google's sources
That awkward moment when you hold your noses
These are Harry Potter memes we thought were really...
Do you dislike twilight? If so, this is the book for...
Some Star Wars pics we found hilarious!
The title says it all
Dark magic is one of the most powerful things in all...
Miley talks to Bryan every week on Skype. He lives...
Cami Fezzeral has a cold. As everyone around her turns...


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Independent Alternate Boom Operation Services
Delivered in April 2015 to a Kent vegetable grower, this 1,500-litre Sprayranger with 60in track is a good example of how we can build to any specification a customer requires. It features an 18m boom with 5m inner and 4m outer sections, and is designed so that one boom half can be working while the other remains folded in its rest.
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POWAY —— While Escondido officials and residents bicker over whether that city's hospital should be rebuilt or replaced, people in Poway are poised to become the first beneficiaries of a $496 million hospital bond measure passed in November.
Palomar Pomerado Health submitted plans to the city of Poway last month for the first phase of a two-part $140 million expansion project at Poway's Pomerado Hospital. If all goes well, the district will break ground on the project by late spring, hospital officials said last week.
The $24 million phase one will add an outpatient services pavilion and parking garage to the hospital, which is the smaller of the two hospitals the district operates. Phase two, with construction scheduled to start in 2007, would add a new patient tower and a second parking structure.
The upcoming project will bring the first tangible result of a $753 million construction plan for several Palomar Pomerado Health district facilities.
A majority of area voters demonstrated support for the districtwide expansion in November, when they approved Proposition BB, the bond measure that will help pay for the projects: expanding Pomerado Hospital, building a new hospital in Escondido and turning Palomar Medical Center into a specialty hospital, and building at least two urgent-care centers in outlying communities.
On Thursday, Poway Mayor Mickey Cafagna said city officials, local doctors and patients alike will benefit from the plan to enlarge Pomerado Hospital.
"One of the complaints we hear about Pomerado from time to time is, 'It's a great hospital, but I can't get this (treatment) done or that done there,' " he said. "A lot of times, they have to make it a two-step process where people go to Pomerado for one part of a treatment and then to Palomar (Medical Center) for the other part. The one-stop shop, I just think, is better for our patients and our community."
Part of multifaceted plan
The district's expansion plan is a multifaceted one designed to help Palomar Pomerado Health adhere to new earthquake-proofing standards for hospitals as well as meet the needs of a rapidly growing population. The public hospital district serves residents in an 800-square-mile area that stretches from San Marcos east to Borrego Springs, and from the Riverside County line south to Poway.
Pomerado Hospital, at which the buildings were built in 1975 and 1984, already meets the seismic standards.
Palomar Medical Center, which is near Escondido's downtown, does not. The hospital is the district's flagship and North County's only trauma center.
The health district's construction plan calls for a new medical center in Escondido, after which Palomar will serve psychiatric patients and those needing outpatient care. Pomerado Hospital's size will be doubled, under the plan.
Palomar Pomerado Health also plans to build satellite medical centers, first in Ramona and Rancho Penasquitos, and later in Valley Center, Pauma Valley and San Marcos.
Escondido project faces multiple issues
An expansion timeline released by Palomar Pomerado Health showed the district intended to start construction for both the new Escondido hospital and Pomerado's expansion around the middle of this year.
The Escondido project has bogged down, though, over questions about whether the new hospital should be built and, if so, where.
District officials have said they need at least 30 acres for the facility. The list of undeveloped parcels in Escondido that could accommodate the project is small, numbering at about a half-dozen.
Palomar Pomerado Health President and Chief Executive Officer Michael Covert said last week that the district is negotiating a potential land purchase in the Escondido Research and Technology Center industrial park.
But some Escondido City Council members have publicly stated their opposition to the idea of the new medical center going in that location.
Other officials and some residents are lobbying hospital officials to nix the new-hospital plan in favor of retrofitting and expanding Palomar. Their arguments are based on concerns that relocating the city's main hospital would destroy the vitality of the city's downtown area and the medical offices adjacent to the existing hospital.
Another potential hitch is that if the industrial park site negotiations don't work out, Palomar Pomerado Health could end up competing for land with the Escondido Union High School District —— which is looking for a site for a new high school —— or re-evaluating its aversion to the use of condemnation to acquire land for either a new hospital or an expansion at Palomar.
Pomerado expansion unopposed
The issues related to Pomerado Hospital's expansion are much simpler.
Opened in 1975, the facility occupies 55 acres at the foot of a mountain along Pomerado Road. Nearly half the site is undeveloped, leaving the 117-bed hospital with plenty of room to grow.
That extra space is unusual for a major health-care facility and a distinct advantage, said Jim Flinn, its chief administrative officer.
The expansion plan also enjoys full support in Poway. The only obvious hurdle to getting the city's go-ahead to begin turning dirt is the City Council's stated desire to see the hospital's natural setting maintained.
That setting includes buildings that feature an architectural style that is modern but that blends into its surroundings. Pomerado Hospital's buildings are painted in desert hues and surrounded by native plants and trees, boulders and curving walkways. Mike Shanahan —— director of facilities, planning and development for the health district —— described the facility's look as "almost indigenous."
"It looks like it grew right out of the rocks," he said.
Palomar Pomerado Health officials share city officials' desire to maintain that image, for their own reasons, said Shanahan.
"It seems like a lot of what's evolving in health-care construction today, a lot of it has to do with stress reduction," he said. "(Hospitals are) just stressful environments anyway —— not just for the patients but also for the staff."
Designs submitted to the city therefore incorporate the same design themes, Shanahan said. "Healing gardens" that patients and visitors can walk through are also shown on the plans.
Transition to full service
The designs show the 144,000-square-foot, five-story outpatient services pavilion going up at the southern end of the hospital, next to its emergency department.
The pavilion will house a women's center that will offer obstetric, gynecological and breast care as well as other services geared toward women. Pomerado Hospital's radiology and imaging departments will be moved to the new structure, and plans call for outpatient surgery, wound care and urgent care centers to be added there, Flinn and Shanahan said.
The outpatient services pavilion will be connected to the rest of the hospital by pedestrian bridges. By building the pavilion, in-patient services can be expanded in Pomerado Hospital's existing buildings.
The expanded areas include the emergency and surgical departments, which now are plagued by cramped quarters and a lack of beds during peak periods, said Flinn. When phase one of the expansion is finished, the hospital's entire array of inpatient services will be consolidated in the existing buildings, while outpatient services will all be housed in the new structure, he said.
"It makes us much more competitive on an outpatient basis," Flinn said. "Secondly, it makes us able to expand our inpatient treatment capability without a lot of costly expansion of (inpatient) facilities."
Shanahan, who is overseeing the development of architectural designs for the expansion, agreed.
"It's a very different dynamic than what (exists at the hospital) today," he said. "What you're seeing Pomerado grow to is truly a full-service medical campus."
Contact staff writer Andrea Moss at (760) 739-6654 or firstname.lastname@example.com .


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Saturday, December 31
Bolton Wanderers v Wolverhampton Wanderers
Reebok Stadium
Kick-off: 15.00 GMT
TV: Highlights BBC1 Match of the Day.
Bolton (4-4-2): Jaaskelainen; Steinsson, Wheater, Knight, Robinson; M Davies, Reo-Coker, Muamba, Petrov; Klasnic, Ngog.
Out: Alonso (foot), Davis, Holden, Gardner (knee), Lee, Mears (both broken leg).
Test: Pratley (virus).
Wolves (Probable, 4-2-3-1): Hennessey; Stearman, Johnson, Berra, Ward; Henry, Edwards; Forde, Hunt, Jarvis; Fletcher.
Out: Craddock (hamstring), Foley (ankle).
Test: Edwards (illness), Zubar (knee).
Suspended: Milijas.
Referee: Mark Clattenburg (Matches 12, R4 Y41).
Team News
Bolton manager Owen Coyle has a trio of defenders back in first team contention for tomorrow's clash with Wolves at the Reebok Stadium.
Coyle indicated after the 2-0 home defeat to Newcastle on Boxing Day that he would make some changes to his struggling side and the Scot will be able to call on Sam Ricketts, who returned to the squad in that game as an unused substitute after a lengthy spell out with an Achilles injury.
In addition, Gretar Steinsson and Joe Riley, recently sidelined by illness and a hamstring problem respectively could also feature.
Midfielder Darren Pratley is a doubt, having picked up a virus, while it remains to be seen whether or not Gary Cahill will play after Coyle confirmed a fee for the centre-back had been agreed with Chelsea.
Wolves midfielder Nenad Milijas starts a three-match ban for his sending off against Arsenal, missing this game after failing with an appeal to the Football Association.
He could be replaced by Dave Edwards if he has shaken off the illness which ruled him out of the 1-1 draw at the Emirates Stadium.
Full-back Ronald Zubar is a major doubt with the knee injury suffered against at the Emirates Stadium and likely to be replaced by Richard Stearman.
Match Notes
After their 2-1 victory at Blackburn, Bolton's hopes of resurgence were hit by a 2-0 home loss to Newcastle on Boxing Day, their eighth home defeat in nine games.
They are still just four points behind Wolves, who will be sucked deep into trouble if Owen Coyle's men can improve their miserable form at the Reebok Stadium but at least Mick McCarthy's side can take heart from their 1-1 draw at Arsenal last time out.
Betting: Home 21-20, Away 12-5, Draw 13-5.
Stat of the game: Bolton have gone 28 games since they were last involved in a score draw.
Graham Chase's prediction: Bolton Wanderers 1 Wolverhampton Wanderers 1.


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World Market for Connectors Used in Mobile Infrastructure Equipment 2017 to 2022
The growth of mobile Internet users is undeniable. One million new mobile Internet users are added to the network every single day. While the wireless network still supports 2G and 3G, 4G will be the dominant access technology worldwide by 2018. By 2022, there will be nearly 500 million subscriptions of 5G globally.
The wireless infrastructure market is evolving. While mobile operators must maintain their 2G and 3G networks, they are also busy upgrading as much of them as they can to LTE and LTE-A now and 5G in the next few years. Thus we are now starting to see entirely new types of equipment.
The World Market for Connectors Used in Mobile Network Infrastructure Equipment report covers connectors used in telecommunications network equipment that supports mobile communications. The specific purpose of this report is to highlight likely new business opportunities for connector manufacturers. It will also discuss the various technologies being used in mobile infrastructure systems, the equipment involved and the connectivity products needed to support all of them.
Top 100 Connector Manufacturers
Did you know? In 2016, the Top 100 Connector Manufacturers Accounted for More Than 93% of the Total Electronic Connector Market!
- Who were the top 10 connector manufacturers in total sales?
- What percentage of sales did the top 10 connector manufacturers account for, the top 50 connector manufacturers?
- Which connector manufacturers had the greatest sales in the automotive sector, the industrial sector or the computer and peripherals sector?
- Who was the leader in fiber optic connector sales, RF connector sales or circular connector sales?
- By location of headquarters, in which region do the largest connector manufacturers reside?
- Which connector manufacturers showed the greatest year-over-year growth, the greatest year-over-year decline?
Providing answers to these questions and many more is Bishop & Associates newest research report, Top 100 Connector Manufacturers for 2016. A report that analyses by region, market sector and product type the top 100 connector manufacturers of 2016, this report provides detailed statistics that benchmark the leading connector manufacturers. Know the connector companies that made the greatest impact in 2016, order your copy of the Top 100 Connector Manufacturers.
Connector Industry Forecast
- How has the connector industry performed in 2016?
- How is the connector industry anticipated to perform in 2017 and beyond?
- Which markets and sub-sectors will show the most growth in 2017, in 2022?
- What outside factors affected connector growth in 2016? What factors may affect growth in 2017 and beyond?
- Historically, how did 2016's performance affect demand?
- What market trends will prevail in 2017 and beyond and why?
Bishop & Associates research report, Connector Industry Forecast, reviews total world connector sales in 2016 and provides a comprehensive analysis by region and market sector of projected connector sales for 2017 through 2022. With connector sales broken down by region, market sector and sub-sector, this report provides a detailed analysis in US dollars of the world connector industry. Be attuned to the markets and sub-sectors that will drive connector sales in 2017 and beyond, order your copy of the Connector Industry Forecast.
The High-Speed Datacom Communications and Connectivity Market 2017 and Beyond
Is Your Company Prepared As 100G Expands in the Gigabit Market?
Is your company prepared for the changes in the Gigabit and above market? The High-Speed Data Communications Connectivity Market – 2017 and Beyond – focuses on the key issues and trends that will drive these changes.
This report analyses:
- What the shift to 40/100G means to the data center operator and the role that Fibre Channel and InfiniBand will play in this shift.
- How top-of-rack (ToR) switching is affecting the network infrastructure.
- Provides a detailed assessment of the key connector and cable assemblers in this market – Bel Connectivity, CommScope, Corning, Telegärtner, and many others – their current and anticipated products and how they compare with mega connector and cable assembler's like Amphenol, Molex and TE Connectivity.
World Cable Assembly Market
What are the growth markets and regions for cable assemblies in the next five years?
- Which regions, markets, and cable assembly types have the highest growth prospects?
- What technical and economic trends are affecting the cable assembly industry?
- What cable assembly types are being used by market sector and region?
- Where should business investments be focused?
2017 World Cable Assembly Market, a new research report from industry leader Bishop & Associates, addresses these questions and many more. This 17-chapter, 220-page report provides a detailed analysis in US dollars for the years 2016 through 2022, by region, end-use equipment sector, and cable assembly type. Our analysis is provided numerically and graphically, allowing the reader to easily view and understand upcoming trends.
Constantly evolving technology is having a profound effect on the design and implementation of cable assemblies. Discover which cable assemblies will benefit most from this evolution and where to focus investments. Order your copy of 2017 World Cable Assembly Market now.
World Connector Market Handbook
In 2016, connectors used in the automotive end-use equipment sector accounted for 23.6% of all electronic connectors.
- How does this compare to five years ago? Ten years ago?
- How have other end-use equipment sectors performed over the last decade? How does this relate to the overall growth of the connector industry?
- Which product types gained the greatest market share and which product types lost market share?
- Which regions, product types, and end-use equipment sectors are aligned to show the most growth in 2017?
Analyzing the connector industry from 2007 through 2016, with a preliminary 2017 and 2022 forecast, Bishop & Associates newest research report, The Connector Market Handbook, details the connector industry by region, end-use equipment sector, and product type. Utilizing tables and graphs, key statistics are provided for total world, as well as by individual region. Growing 4.1% in 2016, the connector industry has gone through a number of very profitable growth years and a number of declining years.How have these changes effected the growth of individual market sectors, individual product types, and individual regions? Track and monitor the ways in which the connector industry has changed and grown over the last decade – order your copy of The World Connector Market Handbook.
Digital Transformation – Industrial IoT and the Connector Market
After the first (mechanization), second (mass production), and third (automation) industrial revolutions, the fourth industrial revolution has arrived on our doorstep and is dubbed the "Internet of Things" (IoT). The IoT will impact every aspect of our lives and the world we live in.
- What does the Industrial Internet of Things mean for the connector market?
- Which (communication) technologies are leading the way?
- Which market sub-sectors are experiencing substantial growth due IoT implementation? Can we quantify the impact of the Industrial IoT on the connector market?
- What are regional shares and growth rates by IIoT sub-sector, for the IIoT market?
Bishop & Associates newest research report, Digital Transformation – Industrial IoT and the Connector Market; Industrial IoT as the Driver of Connectivity – Smart Factory – Smart Grid – Smart City examines the Industrial IoT, with a detailed analysis of three key sub-sectors of the Industrial IoT. The report provides information on available communication technologies, applications within the Industrial IoT, and current and potential opportunities for connectors. Tables are included detailing connector potential by sub-sector, region, and connector type. Like previous industrial revolutions, the Industrial IoT has the potential to bring about profound changes. Be ready for the next industrial revolution, order your copy of Digital Transformation – Industrial IoT and the Connector Market.
Medical Electronics Market for Connectors
- What trends are driving growth in the medical equipment sector? What role will demographics play in this growth and how will it affect product design and marketing? What role will technologies like robotics, 5G Ethernet, mobile health (mHealth), or artificial intelligence play in the growth of the medical equipment sector?
- Who are the major connector suppliers to the medical equipment sector and what types of connector products are they supplying? Who are the major medical equipment manufacturers? What role do government regulations play in the design, marketing, and sale of medical equipment? How do regulations affect export and import demands?
- How important are design features such as low insertion force, non-magnetic materials, polarization capabilities, and the ability to handle a variety of contact types, including power, signal, fiber, and fluid?
Bishop & Associates newest research report, Medical Electronics Market for Connectors analyzes the many aspects involved in the design, development, approval, and marketing of connectors used in the medical market. Tables are included detailing medical connector market sales by region, by medical equipment sub-sector, and by connector product type for the years 2015 through 2021, including a five-year CAGR. A market sector where failure can literally be the difference between life and death, the medical market for connectors may offer designers and manufactures numerous challenges, but the rewards will generally outweigh the challenges.
The World Market for Terminal Blocks
Terminal block sales are anticipated to exceed $3B in sales by 2021.
- When selecting a terminal block for a specific application, a particular set of differentiators make this selection easier. What are those differentiators and how do they affect the selection?
- In industrial control applications, what are some of the advantages of using DIN rail mount terminal blocks?
- What terminal block style/type is most prevalent in China, North America, or the Asia Pacific region? In what applications are terminal blocks most predominate?
- Where are terminal blocks used in automotive applications? In computer/peripheral, consumer and instrumentation applications?
- A variety of methods exist for terminating wire to a terminal block or terminating a terminal block to a printed circuit board. What criterion determines the best termination method for an application? Which method, or methods, offer the most secure termination? Which offer the quickest termination, or the most economical termination?
Be prepared for the opportunities ahead, order your copy of The World Market for Terminal Blocks today.
Impact of Disruptive Innovations on Electronic Interconnects
What potential effect will new and innovative technologies have on electronic interconnects in the years to come?
- What does the future hold for copper, fiber, and wireless interconnects? Will one outpace the other?
- Which innovative technologies have the potential to drastically change the traditional process for new electronic interconnect development?
- Can existing connector design and manufacturing technology produce connectors that will satisfy future application requirements via sustaining innovation?
- Will the convergence of potentially disruptive technologies appearing on the horizon begin to obsolete many traditional interconnects as we know them?
- What new technical requirements may spur the interconnect industry to take a more proactive role in the development of interconnect technology?
The evolution of connector design has traditionally followed a well-developed path. A need is recognized, a product designed, and the growth cycle begins. Will new innovations, their rate of adoption, and the technologies they represent change this path? Examining 10 potentially disruptive technologies, and their effect on traditional copper, fiber and wireless interconnect, is Bishop & Associates newest research report, Impact of Disruptive Innovations on Electronic Interconnects. Don't let the past define your path to the future, order your copy of the Impact of Disruptive Innovations on Electronic Interconnects today.