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Meditation Programs for Psychological Stress and Well-being

En metaanalyse av studier på meditasjonsprogrammer. Konkluderer med at effekten er såpass stor og viktig at leger bør prate med sine pasienter om meditasjon.

http://archinte.jamanetwork.com/article.aspx?articleid=1809754

Mindfulness meditation programs had moderate evidence of improved anxiety (effect size, 0.38 [95% CI, 0.12-0.64] at 8 weeks and 0.22 [0.02-0.43] at 3-6 months), depression (0.30 [0.00-0.59] at 8 weeks and 0.23 [0.05-0.42] at 3-6 months), and pain (0.33 [0.03- 0.62]) and low evidence of improved stress/distress and mental health–related quality of life.

Clinicians should be aware that meditation programs can result in small to moderate reductions of multiple negative dimensions of psychological stress. Thus, clinicians should be prepared to talk with their patients about the role that a meditation program could have in addressing psychological stress.

Reviews to date report a small to moderate effect of mindfulness and mantra meditation techniques in reducing emotional symptoms (eg, anxiety, depression, and stress) and improving physical symptoms (eg, pain).7– 26

Among the 9 RCTs43,44,47,54,55,63,64,73,74 evaluating the effect on pain, we found moderate evidence that mindfulness-based stress reduction reduces pain severity to a small degree when compared with a nonspecific active control, yielding an ES of 0.33 from the meta-analysis. This effect is variable across painful conditions and is based on the results of 4 trials, of which 2 were conducted in patients with musculoskeletal pain,55,64 1 trial in patients with irritable bowel syndrome,43 and 1 trial in a population without pain.44 Visceral pain had a large and statistically significant relative 30% improvement in pain severity, whereas musculoskeletal pain showed 5% to 8% improvements that were considered nonsignificant.

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Magnesium: Novel Applications in Cardiovascular Disease – A Review of the Literature

En review studie fra 2012 som inneholder det meste om Magnesium, spesielt rettet mot betennelser i hjerte/kar og nervesystemet.

http://www.karger.com/Article/FullText/339380

Magnesium L-lactate and L-aspartate are the oral magnesium compounds that have the greatest bioavailability, are the most water-soluble and have the greatest serum and plasma concentrations [8].

After a mean follow-up of 9.8 years and adjusting for confounders, the authors concluded that women in the highest quintile (an intake of 400 mg/day of magnesium) had a decreased HTN (hypertension) risk (p < 0.0001) versus those in the lowest quintile (approx. 200 mg/day of magnesium) [20].

Because of magnesium’s anti-inflammatory, statin-like and anti-mineralizing effects, a role for it is emerging in cardiovascular and neurological medicine.

The potential impact of magnesium in cardiovascular and neurological health, the abundance and low cost of the supplement, the relatively low side effect profile and the paucity of information in the literature about this common mineral suggest that more studies should be conducted to determine its safety and efficacy. The majority of human trials with magnesium thus far have not been interventional, but based on food questionnaires which may not be accurate and are subject to a recall bias. Further work is also needed to determine the mechanism of action by which magnesium modulates the mineralization and inflammation of the cardiovascular and nervous systems.

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Co-administration of the health food supplement, bovine colostrum, reduces the acute non-steroidal anti-inflammatory drug-induced increase in intestinal permeability

Nevner at Colostrum reduserer problemer med lekk tarm fra overforbruk av betennelsesdempende medikamenter som NSAIDS. 5 dager med betennelsesdempende 3x daglig ga 3 ganger så mye lekk tarm. De sammenlignet Colostrum med Whey Protein for fant at colostrum gan ingen økning i lekk tarm selv om de gikk på betennelsesdempende.

http://www.clinsci.org/cs/100/0627/cs1000627.htm

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics but cause gastrointestinal injury. Present prophylactic measures are suboptimal and novel therapies are required. Bovine colostrum is a cheap, readily available source of growth factors, which reduces gastrointestinal injury in rats and mice. We therefore examined whether spray-dried, defatted colostrum could reduce the rise in gut permeability (a non-invasive marker of intestinal injury) caused by NSAIDs in volunteers and patients taking NSAIDs for clinical reasons. Healthy male volunteers (n = 7) participated in a randomized crossover trial comparing changes in gut permeability (lactulose/rhamnose ratios) before and after 5 days of 50 mg of indomethacin three times daily (tds) per oral with colostrum (125 ml, tds) or whey protein (control) co-administration. A second study examined the effect of colostral and control solutions (125 ml, tds for 7 days) on gut permeability in patients (n = 15) taking a substantial, regular dose of an NSAID for clinical reasons. For both studies, there was a 2 week washout period between treatment arms. In volunteers, indomethacin caused a 3-fold increase in gut permeability in the control arm (lactulose/rhamnose ratio 0.36±0.07 prior to indomethacin and 1.17±0.25 on day 5, P < 0.01), whereas no significant increase in permeability was seen when colostrum was co-administered. In patients taking long-term NSAID treatment, initial permeability ratios were low (0.13±0.02), despite continuing on the drug, and permeability was not influenced by co-administration of test solutions. These studies provide preliminary evidence that bovine colostrum, which is already currently available as an over-the-counter preparation, may provide a novel approach to the prevention of NSAID-induced gastrointestinal damage in humans.

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The nutriceutical bovine colostrum truncates the increase in gut permeability caused by heavy exercise in athletes

Studie som nevner at hard trening gir lekk tarm, og at Colostrum (hoppemelk) lukker tarmen. Dette kan forklare hvorfor så mange vektløftere og toppidrettsutøver har problemer med tarm og immunsystem. I studien brukte de 20g colostrum daglig, som er ganske mye.

http://ajpgi.physiology.org/content/300/3/G477

Heavy exercise causes gut symptoms and, in extreme cases, “heat stroke” partially due to increased intestinal permeability of luminal toxins. We examined bovine colostrum, a natural source of growth factors, as a potential moderator of such effects. Twelve volunteers completed a double-blind, placebo-controlled, crossover protocol (14 days colostrum/placebo) prior to standardized exercise. Gut permeability utilized 5 h urinary lactulose-to-rhamnose ratios. In vitro studies (T84, HT29, NCM460 human colon cell lines) examined colostrum effects on temperature-induced apoptosis (active caspase-3 and 9, Baxα, Bcl-2), heat shock protein 70 (HSP70) expression and epithelial electrical resistance. In both study arms, exercise increased blood lactate, heart rate, core temperature (mean 1.4°C rise) by similar amounts. Gut hormone profiles were similar in both arms although GLP-1 levels rose following exercise in the placebo but not the colostrum arm (P = 0.026). Intestinal permeability in the placebo arm increased 2.5-fold following exercise (0.38 ± 0.012 baseline, to 0.92 ± 0.014, P < 0.01), whereas colostrum truncated rise by 80% (0.38 ± 0.012 baseline to 0.49 ± 0.017) following exercise. In vitro apoptosis increased by 47–65% in response to increasing temperature by 2°C. This effect was truncated by 60% if colostrum was present (all P < 0.01). Similar results were obtained examining epithelial resistance (colostrum truncated temperature-induced fall in resistance by 64%, P < 0.01). Colostrum increased HSP70 expression at both 37 and 39°C (P < 0.001) and was truncated by addition of an EGF receptor-neutralizing antibody. Temperature-induced increase in Baxα and reduction in Bcl-2 was partially reversed by presence of colostrum. Colostrum may have value in enhancing athletic performance and preventing heat stroke.

SEVERAL STRESSES AFFECT the integrity of the intestinal barrier. These include prolonged strenuous exercise (10), heat stress (11), and drugs such as nonsteroidal anti-inflammatory agents. Loss of intestinal barrier integrity leading to increased intestinal permeability may result in passage of luminal endotoxins into the circulation. This, in turn, results in an inflammatory cascade, exacerbating the loss of barrier function and, in severe cases, resulting in severe systemic effects.

Gastrointestinal symptoms including cramps, diarrhea, nausea, and bleeding are commonly reported by long-distance runners (16). These symptoms are likely to be due to a combination of reduced splanchnic blood flow, hormonal changes, altered gut permeability, and increased body temperature.

Colostrum is the first milk produced after birth and is particularly rich in immunoglobulins, antimicrobial peptides (e.g., lactoferrin, lactoperoxidase), and other bioactive molecules including growth factors (20).

We have previously shown, using a combination of in vitro and in vivo studies, that a commercially available defatted bovine colostral preparation can reduce NSAID-induced upper intestinal gut injury in rats, mice, and humans (19, 21).

The total protein content of the colostrum was 80%. The concentrations of the various growth factors present in the colostrum preparation are incompletely defined but include IGF-I at 213 ng/g, TGF-β1 at 113 ng/g, and TGF-β2 at 441 ng/g.

In a double-blind crossover design, subjects received oral supplementation with 20 g/day bovine colostrum or the isoenergetic and isomacronutrient placebo.

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Magnesium attenuates chronic hypersensitivity and spinal cord NMDA receptor phosphorylation in a rat model of diabetic neuropathic pain

Magnesium gjør at nervesystemet blir mindre sensitivt i studie på rotter med nevropati. Dosen er beregnet til å være ca 147 mg pr dag (24t), som er veldig mye relativt til kroppsvekten på en mus på 10-20g. Om vi regner det om til menneskevekt blir det megadoser.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002451/

Neuropathic pain is a common diabetic complication affecting 8–16% of diabetic patients. It is characterized by aberrant symptoms of spontaneous and stimulus-evoked pain including hyperalgesia and allodynia. Magnesium (Mg) deficiency has been proposed as a factor in the pathogenesis of diabetes-related complications, including neuropathy. In the central nervous system, Mg is also a voltage-dependant blocker of the N-methyl-d-aspartate receptor channels involved in abnormal processing of sensory information. We hypothesized that Mg deficiency might contribute to the development of neuropathic pain and the worsening of clinical and biological signs of diabetes and consequently, that Mg administration could prevent or improve its complications. We examined the effects of oral Mg supplementation (296 mg l−1 in drinking water for 3 weeks) on the development of neuropathic pain and on biological and clinical parameters of diabetes in streptozocin (STZ)-induced diabetic rats. STZ administration induced typical symptoms of type 1 diabetes. The diabetic rats also displayed mechanical hypersensitivity and tactile and thermal allodynia. The level of phosphorylated NMDA receptor NR1 subunit (pNR1) was higher in the spinal dorsal horn of diabetic hyperalgesic/allodynic rats. Magnesium supplementation failed to reduce hyperglycaemia, polyphagia and hypermagnesiuria, or to restore intracellular Mg levels and body growth, but increased insulinaemia and reduced polydipsia. Moreover, it abolished thermal and tactile allodynia, delayed the development of mechanical hypersensitivity, and prevented the increase in spinal cord dorsal horn pNR1. Thus, neuropathic pain symptoms can be attenuated by targeting the Mg-mediated blockade of NMDA receptors, offering new therapeutic opportunities for the management of chronic neuropathic pain.

Diabetes is also the most common pathological state in which secondary magnesium (Mg) deficiency occurs. Indeed, Mg deficiency has been described in 25–30% and 13.5–47.7% of type 1 and type 2 diabetic patients, respectively (Garland, 1992Tossielo, 1996Corsonelloet al. 2000Engelen et al. 2000Rodriguez-Moran & Guerrero-Romero, 2003Pham et al.2007) and its incidence is correlated to diabetes complications (De Leeuw, 2001). Mg is an ATPase allosteric effector involved in inositol transport (Grafton et al. 1992) and the impaired Na+/K+-ATPase activity in peripheral nerves of diabetic animals (Garland, 1992) plays a role in the pathophysiology of diabetic neuropathy (Li et al. 2005).

In the central nervous system, Mg has voltage-dependent blocking properties that play an important role in pain processing at the N-methyl-d-aspartate (NMDA) receptor channel complex (Mayer et al. 1984Xiao & Bennett, 1994Begon et al. 2000). In vitro, this blockade operates at extracellular Mg concentrations of less than 1 mm (Mayer et al. 1984), i.e. within the ranges found in human and animal cerebrospinal fluid and plasma (Morris, 1992). The excess release of glutamate from central nociceptor terminals due to nerve damage releases Mg blockade and activates NMDA receptors known to trigger painful sensations (hyperalgesia, allodynia) and alter the sensitivity of postsynaptic cells, resulting in central sensitization (Bennett, 2000). This central sensitization involving the NMDA receptor can be induced in rats in vivo by Mg depletion (Alloui et al. 2003). Several studies suggest that phosphorylation of the NMDA receptor NR1 subunit is correlated to the presence of signs of neuropathy and to persistent pain following nerve injury (Gao et al.2005Ultenius et al. 2006Gao et al. 2007Roh et al. 2008).

One week after STZ or distilled water injection, the animals were assigned to the following three experimental groups:

  • MgSO4-supplemented STZ-D group: STZ-D rats receiving MgSO4 (296 mg l−1 of Mg) in drinking water for 3 weeks,
  • Non-supplemented STZ-D group: STZ-D rats given tap water,
  • Control non-diabetic group: rats given tap water.

Water intake was 10-fold and sixfold higher in non-supplemented and MgSO4-supplemented STZ-D rats, respectively, compared with non-diabetic rats. Water intake was significantly lower in MgSO4-supplemented STZ-D rats than non-supplemented STZ-D rats (Table 1). Consequently, urine excretion was 24-fold higher in non-supplemented STZ-D rats than non-diabetic rats. The MgSO4-supplemented STZ-D rats also developed polyuria corresponding to a 15-fold increase in urine excretion compared with non-diabetic rats, but which was nevertheless lower than the increase in non-supplemented STZ-D rats (Table 1). Polyuria in STZ-D rats was significantly correlated to water intake (P < 0.001).

Parameter Non-diabetic Non-suppl. STZ-D MgSO4-suppl. STZ-D
Water intake (ml (24 h)−1) 35.22 ± 2.36 376.6 ± 32.87*** 214.4 ± 30.87***,###
Urine excretion (ml (24 h)−1) 12.45 ± 1.51 300.1 ± 24.16*** 184.4 ± 25.23***,##
Food intake (g (24 h)−1) 30.7 ± 1.83 54.66 ± 3.67** 42.06 ± 6.21
Total Mg intake (mg (24 h)−1) 61.40 ± 3.66 109.32 ± 7.34*** 147.58 ± 1.58***,###

Figure 4: Time course of mechanical sensitivity measured by paw pressure-induced vocalization threshold (VT) variations in non-diabetic (Non-D), non-supplemented STZ-diabetic (Non-suppl. STZ-D) and MgSO4-supplemented (MgSO4-suppl. STZ-D) rats

Parameter Non-diabetic Non-suppl. STZ-D MgSO4-suppl. STZ-D
Tactile hypersensitivity
Week 2 0/10 3/10 0/10#
Week 4 0/10 6/10* 0/10#
Thermal hypersensitivity
Week 2 0/10 6/10* 0/10#
Week 4 0/10 6/10* 0/10#

This study clearly showed that Mg supplementation prevents tactile and thermal allodynia and attenuates and delays mechanical hyperalgesia in STZ-D rats. This effect was mediated, at least in part, by the prevention of NMDA receptor NR1 subunit phosphorylation in STZ-D rats. However, the study also showed that Mg supplementation did not improve most of the biological and clinical signs of diabetes despite restoration of normal insulin secretion.

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Inhibition of Respiration Extends C. elegans Life Span via Reactive Oxygen Species that Increase HIF-1 Activity

Om hvordan reduksjon i respirasjon øker livslengde pga aktivering an HIF-1.

http://www.cell.com/current-biology/abstract/S0960-9822(10)01374-6?switch=standard

  • A mild inhibition of mitochondrial respiration extends the life span of many organisms, including yeast, worms, flies, and mice [1,2,3,4,5,6,7,8,9,10], but the underlying mechanism is unknown. One environmental condition that reduces rates of respiration is hypoxia (low oxygen). Thus, it is possible that mechanisms that sense oxygen play a role in the longevity response to reduced respiration. The hypoxia-inducible factor HIF-1 is a highly conserved transcription factor that activates genes that promote survival during hypoxia [11, 12,11, 12]. In this study, we show that inhibition of respiration in C. elegans can promote longevity by activating HIF-1. Through genome-wide screening, we found that RNA interference (RNAi) knockdown of many genes encoding respiratory-chain components induced hif-1-dependent transcription. Moreover, HIF-1 was required for the extended life spans of clk-1and isp-1 mutants, which have reduced rates of respiration [1, 4, 13,1, 4, 13,1, 4, 13]. Inhibiting respiration appears to activate HIF-1 by elevating the level of reactive oxygen species (ROS). We found that ROS are increased in respiration mutants and that mild increases in ROS can stimulate HIF-1 to activate gene expression and promote longevity. In this way, HIF-1 appears to link respiratory stress in the mitochondria to a nuclear transcriptional response that promotes longevity.
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Impaired respiration is positively correlated with decreased life span in Caenorhabditis elegans models of Friedreich Ataxia

Nevner at respirasjonsrate styrer mer en 73% av livlengden. Respirasjonsrate er ikke det samme som pustefrekvens, men lavere pustefrekvens vil også påvirke respirasjonsraten i mitokondriene.

Den nevner to tilsynelatende motstridene teorier: den ene sier ROS aktivitet øker aldringshastighet, den andre sier at ROS akivitet setter igang forsvarsmekanismer som senker aldringshastighet.

Vi lever lengst om vi har høy respirasjonsrate og sterkt forsvar mot ROS.

I restitusjonspust, med høy CO2 som gir lav affinitet for O2 i blodcellene, vil mer O2 hoppe over til mitokondriene. Så selv om vi har lavere metabolisme får vi sannsynligvis både større utnyttelse av oksygen (høyere respirasjonsrate) og et sterkere forsvar mot ROS.

http://www.fasebj.org/content/21/4/1271.long

Moreover, we show that frh-1-inhibiting RNAi impairs oxygen consumption and that respiratory rate is positively correlated with life span in this multicellular eukaryote (r=0.8566), suggesting that >73% of life span variance in C. elegans is explained by changes in respiratory rate.

Not surprisingly, the underlying hypotheses are conflicting: one line of evidence suggests that down-regulation of mitochondrial metabolism causes decreased formation of reactive oxygen species (ROS), a mandatory by-product of mitochondrial electron transfer (20 , 21) . This hypothesis is essentially a modernized version of the rate-of-living theory (22) , which in later years was focused on detrimental effects of ROS by Harman (23). The other and conflicting line of evidence suggests that induction of mitochondrial metabolism might induce a positive response to increased formation of ROS and other stressors, leading to a secondary increase in stress defense following primary induction of stress, cumulating in reduced net stress levels (24 25 26 27) . The process has been named hormesis (28) . Whether it applies to processes extending life span is currently a matter of fierce debate (26) .

Moreover, a potential role of increased respiration to extend life span in eukaryotes has been suggested for the unicellular eukaryote S. cerevisae in states of caloric restriction (29) , a known regimen to extend life span in eukaryotes including mammals (30 , 31) . Recent evidence has questioned the role of increased respiration in regards to S. cerevisae (32) . It should be noted though that these observations are conflicting, but mechanistically not at all mutually exclusive, since both pathways (sirtuin-activation vs.mTOR) may coexist independently of each other.

We here have shown that life span in the multicellular eukaryote C. elegans is positively correlated to respiratory activity. Since increased respiration may cause increased formation of ROS, we tentatively assume that decreased life span due to reduced levels of respiration reflects a reduction of hormetic responses to systemic stressors. This assumption is supported by findings in fibroblasts where frataxin was overexpressed: these cells show increased respiration and increased oxidative phosphorylation (3) , while formation and accumulation of ROS in these cells are decreased due to induction of antioxidant defense capacity (33) .

 

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Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity

Omfattende gjennomgang om hvordan nevrogene betennelser fungerer fysiologisk. Nevner at betennelser ikke er problemet, men en funksjon kroppen benytter seg av for å håndtere problemer som giftstoffer og metabolsk problemer. Derfor nytter det ikke å dempe betennelsen. Man MÅ fjerne årsaken til betennelsen…

http://www.ncbi.nlm.nih.gov/pubmed/24281245

http://www.nature.com/nrn/journal/vaop/ncurrent/full/nrn3617.html

The CNS is endowed with an elaborated response repertoire termed ‘neuroinflammation’, which enables it to cope with pathogens, toxins, traumata and degeneration. On the basis of recent publications, we deduce that orchestrated actions of immune cells, vascular cells and neurons that constitute neuroinflammation are not only provoked by pathological conditions but can also be induced by increased neuronal activity. We suggest that the technical term ‘neurogenic neuroinflammation’ should be used for inflammatory reactions in the CNS in response to neuronal activity. We believe that neurogenic neuro-inflammation maintains homeostasis to enable the CNS to cope with enhanced metabolic demands and increases the computational power and plasticity of CNS neuronal networks. However, neurogenic neuroinflammation may also become maladaptive and aggravate the outcomes of pain, stress and epilepsy.

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Whatever next? Predictive brains, situated agents, and the future of cognitive science

Fantastisk interessant studie som nevner at hjernen ikke benytter seg av input fra omgivelsene til å skape et bilde av omgivelsene, men til å bekrefte det bildet den allerede har skapt, altså bekrefte sin «fantasi» om virkeligheten.

Klikk for å få tilgang til Whatever%20next.pdf

Brains, it has recently been argued, are essentially prediction machines. They are bundles of cells that support perception and action by constantly attempting to match incoming sensory inputs with top-down expectations or predictions. This is achieved using a hierarchical generative model that aims to minimize prediction error within a bidirectional cascade of cortical processing. Such accounts offer a unifying model of perception and action, illuminate the functional role of attention, and may neatly capture the special contribution of cortical processing to adaptive success. This target article critically examines this hierarchical prediction machineapproach, concluding that it offers the best clue yet to the shape of a unified science of mind and action. Sections 1 and 2 lay out the key elements and implications of the approach. Section 3 explores a variety of pitfalls and challenges, spanning the evidential, the methodological, and the more properly conceptual. The paper ends (sections 4 and 5) by asking how such approaches might impact our more general vision of mind, experience, and agency.

In this paradigm, the brain does not build its current model of distal causes (its model of how the world is) simply by accumulating, from the bottom-up, a mass of low-level cues such as edge-maps and so forth. Instead (see Hohwy 2007), the brain tries to predict the current suite of cues from its best models of the possible causes.

The Helmholtz Machine sought to learn new representations in a multilevel system (thus capturing increasingly deep regularities within a domain) without requiring the provision of copious pre-classified samples of the desired input/output mapping. In this respect, it aimed to improve (see Hinton 2010) upon standard back-propagation driven learning. It did this by using its own top-down connections to provide the desired states for the hidden units, thus (in effect) self-supervising the development of its perceptual recognition modelusing a generative model that tried  to create the sensory patterns for itself (in fantasy,as it was sometimes said).3 (For a useful review of this crucial innovation and a survey of many subsequent developments, see Hinton 2007a).

Transposed (in ways we are about to explore) to the neural domain, this makes prediction error into a kind of proxy (Feldman & Friston 2010) for sensory information itself. Later, when we consider predictive processing in the larger setting of information theory and entropy, we will see that prediction error reports the surpriseinduced by a mismatch between the sensory signals encountered and those predicted.

A good place to start (following Rieke 1999) is with what might be thought of as the view from inside the black box.For, the task of the brain, when viewed from a certain distance, can seem impossible: it must discover information about the likely causes of impinging signals without any form of direct access to their source. Thus, consider a black box taking inputs from a complex external world. The box has input and output channels along which signals flow. But all that it knows, in any direct sense, are the ways its own states (e.g., spike trains) flow and alter. In that (restricted) sense, all the system has direct access to is its own states. The world itself is thus off-limits (though the box can, importantly, issue motor commands and await developments). The brain is one such black box.