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.

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)⇓ .

Nevner at betennelseshemmende midler kan hjelpe på tynnfibernevropati, kanskje spesielt post-operativ tynnfiber nevropati.

http://www.ncbi.nlm.nih.gov/pubmed/16519781

Small-fiber neuropathy is often idiopathic and commonly follows a chronic course. Treatment is often effective in treating the core symptom of pain, but it has no effect on the pathologic process. We describe four patients with acute small-fiber neuropathy who responded dramatically to steroid therapy. All patients had acute onset neuropathic pain, normal nerve conduction studies, and evidence of small-fiber dysfunction in quantitative sensory testing and skin biopsy. Symptoms were distal and symmetrical in three patients and generalized in one patient. In two cases, the neuropathy presented as an erythromelalgia-like syndrome. Marked clinical improvement occurred 1-2 weeks after oral prednisone therapy was initiated. Three patients remained symptom free, and one patient experienced recurrence of neuropathy after prednisone was tapered.

Nevner hvordan operasjoner kan gi betennelser i nervene og bidra til post-operative nevropatiske smerter. Dette er et underkjent tema, akkurat som all nevropati uten de vanlige nevrologiske funn er. Konkluderer med at immunoterapi er nyttig.

http://brain.oxfordjournals.org/content/early/2010/09/15/brain.awq252.full

Post-surgical neuropathies are usually attributed to mechanical factors, such as compression, stretch, contusion or transection. The role of inflammatory mechanisms in neuropathies occurring after surgeries is poorly appreciated and not well characterized, and may provide a rationale for immunotherapy. A total of 23 selected patients with post-surgical neuropathies received nerve biopsies, of which 21 demonstrated increased inflammation. Here we report the clinical features in these 21 cases of biopsy-confirmed and 12 cases of clinically suspected post-surgical inflammatory neuropathies, in whom no trauma to the nerves was documented. All neuropathies developed within 30 days of a surgical procedure. Of 33 patients, 20 were male and the median age was 65 years (range 24–83). Surgical procedures were orthopaedic (n = 14), abdominal/pelvic (n = 12), thoracic (n = 5) and dental (n = 2). Patients developed focal (n = 12), multifocal (n = 14) or diffuse (n = 7) neuropathies. Focal and multifocal neuropathies typically presented with acute pain and weakness, and focal neuropathies often mimicked mechanical aetiologies. Detailed analyses, including clinical characteristics, electrophysiology, imaging and peripheral nerve pathology, were performed. Electrophysiology showed axonal damage. Magnetic resonance imaging of roots, plexuses and peripheral nerves was performed in 22 patients, and all patients had abnormally increased T2nerve signal, with 20 exhibiting mild (n = 7), moderate (n = 12) or severe (n = 1) enlargement. A total of 21 patients had abnormal nerve biopsies that showed increased epineurial perivascular lymphocytic inflammation (nine small, five moderate and seven large), with 15 diagnostic or suggestive of microvasculitis. Evidence of ischaemic nerve injury was seen in 19 biopsies. Seventeen biopsies had increased axonal degeneration suggesting active neuropathy. Seventeen biopsied patients were treated with immunotherapy. In 13 cases with longitudinal follow-up (median 9 months, range 3–71 months), the median neuropathy impairment score improved from 30 to 24 at the time of last evaluation (P = 0.001). In conclusion: (i) not all post-surgical neuropathies are mechanical, and inflammatory mechanisms can be causative, presenting as pain and weakness in a focal, multifocal or diffuse pattern; (ii) these inflammatory neuropathies may be recognized by their spatio-temporal separation from the site and time of surgery and by the characteristic magnetic resonance imaging features; (iii) occasionally post-surgical inflammatory and mechanical neuropathies are difficult to distinguish and nerve biopsy may be required to demonstrate an inflammatory mechanism, which in our cohort often, but not exclusively, exhibited pathological features of microvasculitis and ischaemia; and (iv) recognizing the role of inflammation in these patients’ neuropathy led to rational immunotherapy, which may have resulted in the subsequent improvement of neurological symptoms and impairments.