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Nathan Goodyear

Diet-induced obesity and low testosterone increase neuroinflammation and impair neural ... - 0 views

www.ncbi.nlm.nih.gov/...PMC4190446

Testosterone neuroinflammation glia insulin resistance obesity diabetes brain CNS PNS inflammation low T low Testosterone TNF-alpha IL-1beta

shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • both obesity and low testosterone are also risk factors for neural dysfunction, including cognitive impairment [58–61] and development of AD
  • Levels of obesity and testosterone are often inversely correlated
  • diet-induced obesity causes significant metabolic disturbances and impairs central and peripheral nervous systems.
  • ...23 more annotations...
  • both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems
  • In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation
  • fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet
  • testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation
  • fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.
  • testosterone status did not significantly affect body weight
  • testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis
  • Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone
  • it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth
  • Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β
  • Testosterone status also affected metabolic and neural measures
  • many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression
  • neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation
  • testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions
  • glia are the primary sources of proinflammatory molecules in the CNS
  • poorer survival of neurons grown on glia from mice maintained on high-fat diet
  • Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group
  • significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice
  • testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions
  • IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons
  • Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration
  • testosterone prevented and/or restored thermal nociception in both diet groups
  • a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS
  • Nathan Goodyear on 28 Apr 15
     
    Study points to obesity and low Testosterone contribution of neuroinflammation.  No effect of body weight was seen with TRT.  This animal model found similar positive effects of TRT in insulin sensitivity.  Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line.  Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol.  Testosterone's effect on glial survival was positive but not significant.  Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta.   Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.
Nathan Goodyear

Safety of Combined Treatment With Monoclonal Antibodies and Viscum album L Preparations - 0 views

www.ncbi.nlm.nih.gov/...PMC5950938

VAE mistletoe cancer monoclonal antibodies mAB IL-12 NK cells

shared by Nathan Goodyear on 06 Jun 18 - No Cached
  • Among the most encouraging mAb is trastuzumab, which targets the human epidermal growth factor receptor 2 and is indicated in the treatment of breast cancer
  • bevacizumab, which inhibits vascular endothelial growth factor and is indicated in the treatment of a range of diseases, including colorectal, lung, and ovarian cancer3; and cetuximab, which blocks the epidermal growth factor receptor and is indicated in the treatment of colorectal and lung cancer
  • Viscum album L (VA or European mistletoe) preparations are widely used as additive cancer therapy in Europe, especially in German-speaking countries, and have been associated with a reduction in chemotherapy-related adverse drug reactions and increased HRQL
  • ...6 more annotations...
  • leading to enhancement of interleukin-12 secretion and natural killer cell function
  • Helixor VA preparations
  • A multivariable GEE model indicated that the odds for patients experiencing an AE following mAb therapy were nearly 5 times higher compared with that for mAb plus VA
  • VA preparations (Iscador Ltd) did not inhibit chemotherapy-induced cytostasis or cytotoxicity and showed an additive inhibitory effect at higher concentrations of VA.
  • previous in vitro investigations have shown that VA preparations have either no or minor effects on a range of CYPs, suggesting that VA-drug interactions based on drug metabolism are unlikely
  • mAb do not undergo hepatic metabolism but undergo proteolytic catabolism throughout the body
  • Nathan Goodyear on 06 Jun 18
     
    VAE therapy found to reduce adverse events in those receiving monoclonal Ab therapy.
fitspresso

https://www.thefastleanpro.us/ - 0 views

www.thefastleanpro.us

the fast lean pro us usa fastlean fastleanpro caps drops uk buy jar get customer benefits 2023 work scam pros ebay pro2023 drop price

shared by fitspresso on 27 Sep 23 - No Cached
  • fitspresso on 27 Sep 23
     
    Fast Lean Pro™ (official) | weight lose Formula thefastleanpro.us · by Fast Lean Pro Fast Lean Pro Only $49/Bottle Limited Time Offer! Fast Lean Pro Special Deal + Special 51% Discount Save $300 + 180 Days Money Back Guarantee FastLeanPro The #1 Solution To natural metabolism booster helps you lose weight quickly without starving yourself. Fast Lean Pro is a natural powder supplement for weight loss that has recently been developed by Japanese scientists. Regular Price: $99/per bottle Only for: $49/per bottle What Is Fast Lean Pro? Fast Lean Pro is a powdered dietary powdery supplement designed to aid in weight loss. It contains a unique combination of ingredients that are believed to activate the body's "fasting switch" to optimize results. This product focuses not only on weight loss but also on promoting cellular rejuvenation, fasting, and a healthy metabolism. The concept behind Fast Lean Pro is that incorporating fasting into one's lifestyle can lead to positive outcomes irrespective of individual food choices and eating habits. To comprehend the mechanism of the Fast Lean Pro process, it is necessary to delve into its specific details. One of the few weight loss pills on the market that contains Fibersol is Fast Lean Pro. This safe, specialized fiber adds bulk to its weight when combined with water, curbing your appetite before it throws off your meal plan. If you're trying to lose weight or curb your appetite, Fast Lean Pro can help. Supporting substances such as niacin and chromium contribute to this. The body can further benefit from these nutrients, such as through improved metabolic regulation. Fast lean Pro is non-GMO, vegan friendly, and contains no artificial ingredients or stimulants. Fast Lean Pro is a weight loss product that promotes the body's natural self-feeding process. The body naturally removes old, damaged cells through a process known as autophagy to encourage cell regeneration and repair. Recent studies by a group
Jadibuti jadibuti.net

Ashwagandha - 0 views

jadibuti.net/ashwagandha

Ashwagandha Withania Somnifera Indian Ginseng

shared by Jadibuti jadibuti.net on 29 May 16 - No Cached
  • Jadibuti jadibuti.net on 29 May 16
     
    Ashwagandha, one of the most powerful herbs in Ayurvedic healing, has been used since ancient times for a wide variety of conditions. In Sanskrit Ashwagandha means “the smell of a horse,” indicating that the herb imparts the vigor ...
  • Jadibuti jadibuti.net on 29 May 16
     
    Ashwagandha, one of the most powerful herbs in Ayurvedic healing, has been used since ancient times for a wide variety of conditions. In Sanskrit Ashwagandha means “the smell of a horse,” indicating that the herb imparts the vigor ...
Nathan Goodyear

Metabolic Effects of Liothyronine Therapy in Hypothyroidism: A Randomized, Double-Blind... - 0 views

press.endocrine.org/...jc.2011-1329

T4 T3 hypothyroid hypothyroidism thyroid lipids weight loss metabolism cholesterol hormones

shared by Nathan Goodyear on 24 Sep 14 - No Cached
  • tissue euthyroidism is the net result of multiple steps including conversion of the prohormone T4 into its active metabolite T3, which is ultimately responsible for signaling at the end-organ target level
  • The circulating and intracellular pools of T3 of treated hypothyroid patients (i.e. devoid of endogenous TH production) depend entirely on the conversion of exogenous l-T4 into T3
  • TH is the major regulator of basal metabolic rate
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  • The substitution of l-T3 for l-T4 caused a significant weight loss
  • The substitution of l-T3 for l-T4 caused a significant reduction in lipid parameters
  • TH action is increased in the liver, and the SHBG increase supports this hypothesis
  • The changes in serum lipid metabolism parameters are similar to the effects observed with drugs approved for the treatment of dyslipidemia
  • This differential response appears to be limited to the lipid metabolism and SHBG, whereas no differences in indices of insulin resistance were detected. This is remarkable because hyperthyroid states are associated with an increase in hepatic gluconeogenesis (37), and overt thyrotoxicosis is a known cause of secondary diabetes.
  • Despite the increase in serum T3, the l-T3 treatment did not cause major changes in cardiovascular or musculoskeletal function, as indicated by the echocardiographic and maximal exercise tolerance tests and DXA studies.
  • Similarly, no significant differences were observed in blood pressure, heart rate, or endothelial vascular function
  • In conclusion, the results of this pharmacology, proof-of-concept study indicate that replacement therapy of hypothyroidism with l-T3, compared with l-T4 causes weight loss and favorable changes in the lipid profile without appreciable side effects
  • Nathan Goodyear on 24 Sep 14
     
    Crossover study finds T3 versus T4 results in more weight loss, improved lipid management and increased SHBG without any adverse cardiovascular effects.   The T3 was dosed 3 x daily due to its short half life compared to T4.
Nathan Goodyear

PLOS ONE: Probiotic Microbes Sustain Youthful Serum Testosterone Levels and Testicular ... - 0 views

journals.plos.org/...article

hormone hormones low T low Testosterone hypogonadism Testosterone probiotic L reuters probiotics Lactobacillus lactobacillus reuteri male aging

shared by Nathan Goodyear on 29 Apr 15 - No Cached
  • Studies in both humans and rodents, however, suggest that low testosterone is due to age-related lesions in testes rather than irregular luteinizing hormone metabolism
  • Various dietary factors and diet-induced obesity have been shown to increase the risk for late onset male hypogonadism and low testosterone production in both humans and mice
  • Testosterone deficiency and metabolic diseases such as obesity appear to inter-digitate in complex cause-and-effect relationships
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  • dietary supplementation of aged mice with the probiotic bacterium Lactobacillus reuteri makes them appear to be younger than their matched untreated sibling mice
  • These results indicate that gut microbiota induce modulation of local gastrointestinal immunity resulting in systemic effects on the immune system which activate metabolic pathways that restore tissue homeostasis and overall health
  • all these studies we consistently observed that young and aged mice consuming purified L. reuteri organisms had particularly large testes and a dominant male behavior.
  • The testes of probiotic-fed aged mice were rescued from both seminiferous tubule atrophy and interstitial Leydig cell area reduction typical of the normal aging process. Preservation of testicular architecture despite advanced age or high-fat diet coincided with remarkably high levels of circulating testosterone. The beneficial effects of probiotic consumption were recapitulated by the depletion of the pro-inflammatory cytokine Il-17.
  • feeding of L. reuteri consistently increased the gonadal weights, consumption of a non-pathogenic strain of Escherichia coli (E. coli) K12 organisms did not affect testicular weight
  • mice with dietary L. reuteri supplements were rescued from diet-induced obesity and had normal body weight and lean physique
  • Despite the comparable numbers of ST profiles, we determined that testes from L. reuteri-treated mice had increased ST cross-sectioned profiles
  • the probiotic organism induced prominent Leydig cell accumulations in the interstitial tissue between the ST's
  • The probiotic-associated increase of interstitial Leydig cell areas was sustained with advancing age at 7 (CD vs CD+LR, P = 0.0025; CD+E.coli vs CD+LR, P = 0.0251) and 12 months
  • mice eating L. reuteri had profoundly increased levels of circulating testosterone regardless of the type of diet they consumed
  • blocking pro-inflammatory Il-17 signaling entirely recapitulates the beneficial effects of probiotics
  • previous studies we found that dietary probiotics counteract obesity [19] and age-related integumentary pathology [18] at least in part by down-regulating systemic pro-inflammatory IL-17A-dependent signaling
  • Testes histomorphometry and serum androgen concentration data were both suggestive of a probiotic-associated up-regulation of spermatogenesis in mice
  • Lactobacillus reuteri we discovered that aging male animals had larger testes compared to their age-matched controls
  • xamined testes of probiotic microbe-fed mice and found that they had less testicular atrophy coinciding with higher levels of circulating testosterone compared to their age-matched controls
  • Similar testicular health benefits were produced using systemic depletion of the pro-inflammatory cytokine Il-17 alone, implicating a chronic inflammatory pathway in hypogonadism
  • One specific aspect of this paradigm is reciprocal activities of pro-inflammatory Th-17 and anti-inflammatory Treg cells
  • Feeding of L. reuteri organisms was previously shown to up-regulate IL-10 levels and reduce levels of IL-17 [19] serving to lower systemic inflammation
  • insufficient levels of IL-10 may increase the risk for autoimmunity, obesity, and other inflammatory disease syndromes
  • Westernized diets are also low in vitamin D, a nutrient that when present normally works together with IL-10 to protect against inflammatory disorders
  • Physiological feedback loops apparently exist between microbes, host hormones, and immunity
  • The hormone testosterone has been shown to act directly through androgen receptors on CD4+ cells to increase IL-10 expression
  • studies in both humans and rodents suggest that hypogonadism is due to age-related lesions in testes rather than irregular LH metabolism
  • We postulate that probiotic gut microbes function symbiotically with their mammalian hosts to impart immune homeostasis to maintain systemic and testicular health [34]–[35] despite suboptimal dietary conditions.
  • Dietary factors and diet-induced obesity were previously shown to increase risk for age-associated male hypogonadism, reduced spermatogenesis, and low testosterone production in both humans and mice [2]–[4], [8]–[11], [14]–[17], phenotypic features that in this study were inhibited by oral probiotic therapy absent milk sugars, extra protein, or vitamin D supplied in yogurt.
  • Similar beneficial effects of probiotic microbes on testosterone levels and sperm indices were reported in male mice that had been simultaneously supplemented with selenium
  • L. reuteri-associated prevention of age- and diet-related testicular atrophy correlates with increased numbers and size of Leydig cells
  • the initial changes of testicular atrophy begin to occur in mice from the age of 6 moths onwards [7] and indicates that the trophic effect of L. reuteri on Leydig cells is a key event which precedes and prevents age-related changes in the testes of mice. This effect is reminiscent of earlier studies describing Leydig cell hyperplasia and/or hypertrophy in the mouse and the rat testis that were achievable by the administration of gonadotropins, including human chorionic gonadotropin, FSH and LH
  • Nathan Goodyear on 29 Apr 15
     
    Fascinating study on how the addition of Lactobacillus reuteri increased Testicular size, prevented testicular atrophy, increased serum Testosterone production and protected against diet-induced/obesity-induced hypogonadism.  This was a mouse model
Nathan Goodyear

Dietary Strategy to Repair Plasma Membrane After Brain Trauma - 0 views

nnr.sagepub.com/...75.long

curcumin DHA TBI traumatic brain injury brain injury neuroinflammation BDNF brain derived neurotrophic factor brain

shared by Nathan Goodyear on 31 Aug 15 - No Cached
  • concussive brain injury is a major cause of neuropsychological disability in spite of no obvious neuronal death
  • TBI elicits oxidative damage to plasma membrane phospholipids
  • DHA is the most abundant polyunsaturated fatty acid (PUFA) in the brain, where the DHA-containing phospholipids contribute to plasma membrane biogenesis and receptor signaling
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  • curcumin has potent anti-inflammatory and antioxidant activities that can function to reduce oxidative damage and cognitive deficits associated with neurological disorders
  • Curcumin provided in the diet before TBI can reduce oxidative damage and counteract TBI-related cognitive dysfunction
  • Our previous study indicated that n-3 fatty acids supplemented in the diet counteracted learning disability after TBI
  • curcumin contributes to enhance the effects of DHA on TBI by promoting phosphorylation of the BDNF receptor TrkB in the hippocampus
  • previous evidence indicates that curcumin10 and DHA5 counteract TBI-related learning disability by involving BDNF
  • Our findings indicate that curcumin counteracted the TBI-related reduction in n-3 DPA.
  • curcumin may promote the conversion of n-3 DPA to DHA
  • the combination of both nutrients has been reported to produce anti-inflammatory action
  • the enhanced actions of curcumin and DHA in reducing cholesterol levels could be interpreted as preservation of levels of phospholipids in the plasma membrane
  • curcumin and DHA may contribute to reduce inflammation associated with the action of cholesterol in the pathology of TBI.
  • Nathan Goodyear on 31 Aug 15
     
    Curcumin and DHA shown to protect against TBI through a reduction in inflammation and maintenance of brain phospholipid membranes.  BDNF is increases also.
Nathan Goodyear

Stuck at the bench: Potential natural neuroprotective compounds for concussion - 0 views

www.ncbi.nlm.nih.gov/...PMC3205506

concussions concussion natural therapies brain curcumin omega 3 resveratrol green tea EGCG EPA DHA vitamin E vitamin c vitamin D

shared by Nathan Goodyear on 20 Feb 16 - No Cached
  • Long-chain polyunsaturated fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are highly enriched in neuronal synaptosomal plasma membranes and vesicles
  • The predominant CNS polyunsaturated fatty acid is DHA
  • effective supplementation and/or increased ingestion of dietary sources rich in EPA and DHA, such as cold-water fish species and fish oil, may help improve a multitude of neuronal functions, including long-term potentiation and cognition.
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  • multiple preclinical studies have suggested that DHA and/or EPA supplementation may have potential benefit through a multitude of diverse, but complementary mechanisms
  • pre-injury dietary supplementation with fish oil effectively reduces post-traumatic elevations in protein oxidation
  • The benefits of pre-traumatic DHA supplementation have not only been independently confirmed,[150] but DHA supplementation has been shown to significantly reduce the number of swollen, disconnected and injured axons when administered following traumatic brain injury.
  • DHA has provided neuroprotection in experimental models of both focal and diffuse traumatic brain injury
  • potential mechanisms of neuroprotection, in addition to DHA and EPA's well-established anti-oxidant and anti-inflammatory properties
  • Despite abundant laboratory evidence supporting its neuroprotective effects in experimental models, the role of dietary DHA and/or EPA supplementation in human neurological diseases remains uncertain
  • Several population-based, observational studies have suggested that increased dietary fish and/or omega-3 polyunsaturated fatty acid consumption may reduce risk for ischemic stroke in several populations
  • Randomized control trials have also demonstrated significant reductions in ischemic stroke recurrence,[217] relative risk for ischemic stroke,[2] and reduced incidence of both symptomatic vasospasm and mortality following subarachnoid hemorrhage
  • Clinical trials in Alzheimer's disease have also been largely ineffective
  • The clinical evidence thus far appears equivocal
  • curcumin has gained much attention from Western researchers for its potential therapeutic benefits in large part due to its potent anti-oxidant[128,194,236] and anti-inflammatory properties
  • Curcumin is highly lipophilic and crosses the blood-brain barrier enabling it to exert a multitude of different established neuroprotective effects
  • in the context of TBI, a series of preclinical studies have suggested that pre-traumatic and post-traumatic curcumin supplementation may bolster the brain's resilience to injury and serve as a valuable therapeutic option
  • Curcumin may confer significant neuroprotection because of its ability to act on multiple deleterious post-traumatic, molecular cascades
  • studies demonstrated that both pre- and post-traumatic curcumin administration resulted in a significant reduction of neuroinflammation via inhibition of the pro-inflammatory molecules interleukin 1β and nuclear factor kappa B (NFκB)
  • no human studies have been conducted with respect to the effects of curcumin administration on the treatment of TBI, subarachnoid or intracranial hemorrhage, epilepsy or stroke
  • studies have demonstrated that resveratrol treatment reduces brain edema and lesion volume, as well as improves neurobehavioral functional performance following TBI
  • green tea consumption or supplementation with its derivatives may bolster cognitive function acutely and may slow cognitive decline
  • At least one population based study, though, did demonstrate that increased green tea consumption was associated with a reduced risk for Parkinson's disease independent of total caffeine intake
  • a randomized, placebo-controlled trial demonstrated that administration of green tea extract and L-theanine, over 16 weeks of treatment, improved indices of memory and brain theta wave activity on electroencephalography, suggesting greater cognitive alertness
  • Other animal studies have also demonstrated that theanine, another important component of green tea extract, exerts a multitude of neuroprotective benefits in experimental models of ischemic stroke,[63,97] Alzheimer's disease,[109] and Parkinson's disease
  • Theanine, like EGCG, contains multiple mechanisms of neuroprotective action including protection from excitotoxic injury[97] and inhibition of inflammation
  • potent anti-oxidant EGCG which is capable of crossing the blood-nerve and blood-brain barrier,
  • Epigallocatechin-3-gallate also displays neuroprotective properties
  • More recent research has suggested that vitamin D supplementation and the prevention of vitamin D deficiency may serve valuable roles in the treatment of TBI and may represents an important and necessary neuroprotective adjuvant for post-TBI progesterone therapy
  • Progesterone is one of the few agents to demonstrate significant reductions in mortality following TBI in human patients in preliminary trials
  • in vitro and in vivo studies have suggested that vitamin D supplementation with progesterone administration may significantly enhance neuroprotection
  • Vitamin D deficiency may increase inflammatory damage and behavioral impairment following experimental injury and attenuate the protective effects of post-traumatic progesterone treatment.[37]
  • emerging evidence has suggested that daily intravenous administration of vitamin E following TBI significantly decreases mortality and improves patient outcomes
  • high dose vitamin C administration following injury stabilized or reduced peri-lesional edema and infarction in the majority of patients receiving post-injury treatment
  • it has been speculated that combined vitamin C and E therapy may potentiate CNS anti-oxidation and act synergistically with regards to neuroprotection
  • one prospective human study has found that combined intake of vitamin C and E displays significant treatment interaction and reduces the risk of stroke
  • Pycnogenol has demonstrated the ability to slow or reduce the pathological processes associated with Alzheimer's disease
  • Pcynogenol administration, in a clinical study of elderly patients, led to improved cognition and reductions in markers of lipid peroxidase
  • One other point of consideration is that in neurodegenerative disease states like Alzheimer's disease and Parkinson's disease, where there are high levels of reactive oxygen species generation, vitamin E can tend to become oxidized itself. For maximal effectiveness and to maintain its anti-oxidant capacity, vitamin E must be given in conjunction with other anti-oxidants like vitamin C or flavonoids
  • These various factors might account for the null effects of alpha-tocopherol supplementation in patients with MCI and Alzheimer's disease
  • preliminary results obtained in a pediatric population have suggested that post-traumatic oral creatine administration (0.4 g/kg) given within four hours of traumatic brain injury and then daily thereafter, may improve both acute and long-term outcomes
  • Acutely, post-traumatic creatine administration seemed to reduce duration of post-traumatic amnesia, length of time spent in the intensive care unit, and duration of intubation
  • At three and six months post-injury, subjects in the creatine treatment group demonstrated improvement on indices of self care, communication abilities, locomotion, sociability, personality or behavior and cognitive function when compared to untreated controls
  • patients in the creatine-treatment group were less likely to experience headaches, dizziness and fatigue over six months of follow-up
  • CNS creatine is derived from both its local biosynthesis from the essential amino acids methionine, glycine and arginine
  • Studies of patients with CNS creatine deficiency and/or murine models with genetic ablation of creatine kinase have consistently demonstrated significant neurological impairment in the absence of proper creatine, phosphocreatine, or creatine kinase function; thus highlighting its functional importance
  • chronic dosing may partially reverse neurological impairments in human CNS creatine deficiency syndromes
  • Several studies have suggested that creatine supplementation may also reduce oxidative DNA damage and brain glutamate levels in Huntington disease patients
  • Another study highlighted that creatine supplementation marginally improved indices of mood and reduced the need for increased dopaminergic therapy in patients with Parkinson's disease
  • Nathan Goodyear on 20 Feb 16
     
    great review of natural therapies in the treatment of concussions
Nathan Goodyear

Transfusion of Blood and Blood Products: Indications and Complications - - American Fam... - 0 views

www.aafp.org/...p719.html

Transfusion platelets anemia Thrombocytopenia "red blood cells" plasma cryoprecipitate

shared by Nathan Goodyear on 13 Nov 18 - No Cached
  • Nathan Goodyear on 13 Nov 18
     
    Good review of transfusion indications and complications
Nathan Goodyear

American Journal of Obstetrics & Gynecology Home Page - 0 views

www.ajog.org/...fulltext

"Vaginal mesh" immune system

shared by Nathan Goodyear on 31 Aug 18 - No Cached
  • M1 macrophages are characterized by the secretion of reactive oxygen species and proinflammatory cytokines and chemokines and can be identified via the cell surface marker CD86
  • M2 macrophages secrete growth factors and antiinflammatory immune modulators and can be identified by the cell surface marker CD206
  • an overzealous M2 response can also lead to excess tissue deposition and fibrosis
  • ...14 more annotations...
  • Studies of similar meshes that are used in hernia repair have demonstrated that all polypropylene meshes induce a prolonged inflammatory response at the site of implantation
  • the long-term presence of activated inflammatory cells, such as macrophages at the mesh tissue interface, can impact negatively the ability of the mesh to function as intended.
  • All M1 proinflammatory and M2 proremodeling cytokines and chemokines were increased in mesh explants as compared with nonmesh tissue (Table 3Table 3), which indicated a robust, active, and ongoing host response to polypropylene long after implantation
  • Comparison of the ratio of the M2 proremodeling cytokines (IL-10+IL-4) with the M1 proinflammatory cytokines (TNF-α+IL-12p70) revealed a decrease in mesh explants as compared with controls (P = .003), which indicated a shift towards a proinflammatory profile.
  • Mesh explants contained a higher number of total cells/×200 field when compared with controls (682.46 ± 142.61 cells vs 441.63 ± 126.13 cells; P < .001) and a lower ratio of M2:M1 macrophages (0.260 ± 0.161 cells vs 1.772 ± 1.919; P = .001), which supported an ongoing proinflammatory response.
  • the host response was proportional to the amount of material in contact with the host
  • A persistent foreign body response was observed in mesh-tissue complexes that were excised from women who required surgical excision of mesh months to years after mesh implantation
  • The host response was characterized by a predominance of macrophages with an increase in both proinflammatory and proremodeling cytokines/chemokines along with increased tissue degradation, as evidenced by increased MMP-2 and -9
  • Mesh-tissue complexes removed for mesh exposure had increased pro–MMP-9 that indicated a proinflammatory and tissue destruction–type response
  • The presence of macrophages, elevated cytokines, chemokines, and MMPs in tissue-mesh complexes that were excised from patients with exposure or pain suggests that polypropylene mesh elicits an ongoing host inflammatory response
  • In the presence of a permanent foreign body, the implant is surrounded with a fibrotic capsule because it cannot be degraded
  • For hernia meshes, if the fibers are too close (<1 mm), the fibrotic response to neighboring fibers overlaps, or “bridges,” and results in “bridging fibrosis” or encapsulation of the mesh
  • Gynemesh PS has a highly unstable geometry when loaded that resulted in pore collapse and increasing stiffness of the product
  • mesh shrinkage (50-70%) has been described to occur after transvaginal insertion of prolapse meshes
  • Nathan Goodyear on 31 Aug 18
     
    Mesh and the abnormal immune response.
Nathan Goodyear

Press-pulse: a novel therapeutic strategy for the metabolic management of cancer | Nutr... - 0 views

nutritionandmetabolism.biomedcentral.com/...s12986-017-0178-2

ketogenic diet ketogenic press-pulse hyperbaric oxygen therapy HBOTnutrition diet cancer HBOT IVC IV vitamin C DCA dichloracetic acid cancer therapy cancer treatment alternative cancer treatment

shared by Nathan Goodyear on 09 Jul 17 - No Cached
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  • A “press” disturbance was considered a chronic environmental stress on all organisms in an ecological community
  • “pulse” disturbances were considered acute events that disrupted biological communities to produce high mortality
  • Neoplasia involving dysregulated cell growth is the biological endpoint of the disease
  • ...84 more annotations...
  • Data from the American Cancer Society show that the rate of increase in cancer deaths/year (3.4%) was two-fold greater than the rate of increase in new cases/year (1.7%) from 2013 to 2017
  • cancer is predicted to overtake heart disease as the leading cause of death in Western societies
  • cancer can also be recognized as a metabolic disease.
  • glucose is first split into two molecules of pyruvate through the Embden–Meyerhof–Parnas glycolytic pathway in the cytosol
  • Aerobic fermentation, on the other hand, involves the production of lactic acid under normoxic conditions
  • persistent lactic acid production in the presence of adequate oxygen is indicative of abnormal respiration
  • Otto Warburg first proposed that all cancers arise from damage to cellular respiration
  • The Crabtree effect is an artifact of the in vitro environment and involves the glucose-induced suppression of respiration with a corresponding elevation of lactic acid production even under hyperoxic (pO2 = 120–160 mmHg) conditions associated with cell culture
  • the Warburg theory of insufficient aerobic respiration remains as the most credible explanation for the origin of tumor cells [2, 37, 51, 52, 53, 54, 55, 56, 57].
  • The main points of Warburg’s theory are; 1) insufficient respiration is the predisposing initiator of tumorigenesis and ultimately cancer, 2) energy through glycolysis gradually compensates for insufficient energy through respiration, 3) cancer cells continue to produce lactic acid in the presence of oxygen, and 4) respiratory insufficiency eventually becomes irreversible
  • Efraim Racker coined the term “Warburg effect”, which refers to the aerobic glycolysis that occurs in cancer cells
  • Warburg clearly demonstrated that aerobic fermentation (aerobic glycolysis) is an effect, and not the cause, of insufficient respiration
  • all tumor cells that have been examined to date contain abnormalities in the content or composition of cardiolipin
  • The evidence supporting Warburg’s original theory comes from a broad range of cancers and is now overwhelming
  • respiratory insufficiency, arising from any number mitochondrial defects, can contribute to the fermentation metabolism seen in tumor cells.
  • data from the nuclear and mitochondrial transfer experiments suggest that oncogene changes are effects, rather than causes, of tumorigenesis
  • Normal mitochondria can suppress tumorigenesis, whereas abnormal mitochondria can enhance tumorigenesis
  • In addition to glucose, cancer cells also rely heavily on glutamine for growth and survival
  • Glutamine is anapleurotic and can be rapidly metabolized to glutamate and then to α-ketoglutarate for entry into the TCA cycle
  • Glucose and glutamine act synergistically for driving rapid tumor cell growth
  • Glutamine metabolism can produce ATP from the TCA cycle under aerobic conditions
  • Amino acid fermentation can generate energy through TCA cycle substrate level phosphorylation under hypoxic conditions
  • Hif-1α stabilization enhances aerobic fermentation
  • targeting glucose and glutamine will deprive the microenvironment of fermentable fuels
  • Although Warburg’s hypothesis on the origin of cancer has created confusion and controversy [37, 38, 39, 40], his hypothesis has never been disproved
  • Warburg referred to the phenomenon of enhanced glycolysis in cancer cells as “aerobic fermentation” to highlight the abnormal production of lactic acid in the presence of oxygen
  • Emerging evidence indicates that macrophages, or their fusion hybridization with neoplastic stem cells, are the origin of metastatic cancer cells
  • Radiation therapy can enhance fusion hybridization that could increase risk for invasive and metastatic tumor cells
  • Kamphorst et al. in showing that pancreatic ductal adenocarcinoma cells could obtain glutamine under nutrient poor conditions through lysosomal digestion of extracellular proteins
  • It will therefore become necessary to also target lysosomal digestion, under reduced glucose and glutamine conditions, to effectively manage those invasive and metastatic cancers that express cannibalism and phagocytosis.
  • Previous studies in yeast and mammalian cells show that disruption of aerobic respiration can cause mutations (loss of heterozygosity, chromosome instability, and epigenetic modifications etc.) in the nuclear genome
  • The somatic mutations and genomic instability seen in tumor cells thus arise from a protracted reliance on fermentation energy metabolism and a disruption of redox balance through excess oxidative stress.
  • According to the mitochondrial metabolic theory of cancer, the large genomic heterogeneity seen in tumor cells arises as a consequence, rather than as a cause, of mitochondrial dysfunction
  • A therapeutic strategy targeting the metabolic abnormality common to most tumor cells should therefore be more effective in managing cancer than would a strategy targeting genetic mutations that vary widely between tumors of the same histological grade and even within the same tumor
  • Tumor cells are more fit than normal cells to survive in the hypoxic niche of the tumor microenvironment
  • Hypoxic adaptation of tumor cells allows for them to avoid apoptosis due to their metabolic reprograming following a gradual loss of respiratory function
  • The high rates of tumor cell glycolysis and glutaminolysis will also make them resistant to apoptosis, ROS, and chemotherapy drugs
  • Despite having high levels of ROS, glutamate-derived from glutamine contributes to glutathione production that can protect tumor cells from ROS
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      reason to eliminate glutamine in cancer patients and even GSH with cancer patients
  • It is clear that adaptability to environmental stress is greater in normal cells than in tumor cells, as normal cells can transition from the metabolism of glucose to the metabolism of ketone bodies when glucose becomes limiting
  • Mitochondrial respiratory chain defects will prevent tumor cells from using ketone bodies for energy
  • glycolysis-dependent tumor cells are less adaptable to metabolic stress than are the normal cells. This vulnerability can be exploited for targeting tumor cell energy metabolism
  • In contrast to dietary energy reduction, radiation and toxic drugs can damage the microenvironment and transform normal cells into tumor cells while also creating tumor cells that become highly resistant to drugs and radiation
  • Drug-resistant tumor cells arise in large part from the damage to respiration in bystander pre-cancerous cells
  • Because energy generated through substrate level phosphorylation is greater in tumor cells than in normal cells, tumor cells are more dependent than normal cells on the availability of fermentable fuels (glucose and glutamine)
  • Ketone bodies and fats are non-fermentable fuels
  • Although some tumor cells might appear to oxidize ketone bodies by the presence of ketolytic enzymes [181], it is not clear if ketone bodies and fats can provide sufficient energy for cell viability in the absence of glucose and glutamine
  • Apoptosis under energy stress is greater in tumor cells than in normal cells
  • A calorie restricted ketogenic diet or dietary energy reduction creates chronic metabolic stress in the body
  • . This energy stress acts as a press disturbance
  • Drugs that target availability of glucose and glutamine would act as pulse disturbances
  • Hyperbaric oxygen therapy can also be considered another pulse disturbance
  • The KD can more effectively reduce glucose and elevate blood ketone bodies than can CR alone making the KD potentially more therapeutic against tumors than CR
  • Campbell showed that tumor growth in rats is greater under high protein (>20%) than under low protein content (<10%) in the diet
  • Protein amino acids can be metabolized to glucose through the Cori cycle
  • The fats in KDs used clinically also contain more medium chain triglycerides
  • Calorie restriction, fasting, and restricted KDs are anti-angiogenic, anti-inflammatory, and pro-apoptotic and thus can target and eliminate tumor cells through multiple mechanisms
  • Ketogenic diets can also spare muscle protein, enhance immunity, and delay cancer cachexia, which is a major problem in managing metastatic cancer
  • GKI values of 1.0 or below are considered therapeutic
  • The GKI can therefore serve as a biomarker to assess the therapeutic efficacy of various diets in a broad range of cancers.
  • It is important to remember that insulin drives glycolysis through stimulation of the pyruvate dehydrogenase complex
  • The water-soluble ketone bodies (D-β-hydroxybutyrate and acetoacetate) are produced largely in the liver from adipocyte-derived fatty acids and ketogenic dietary fat. Ketone bodies bypass glycolysis and directly enter the mitochondria for metabolism to acetyl-CoA
  • Due to mitochondrial defects, tumor cells cannot exploit the therapeutic benefits of burning ketone bodies as normal cells would
  • Therapeutic ketosis with racemic ketone esters can also make it feasible to safely sustain hypoglycemia for inducing metabolic stress on cancer cells
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      Ketones are much more than energy adaptabilit, but actually are therapeutic.
  • ketone bodies can inhibit histone deacetylases (HDAC) [229]. HDAC inhibitors play a role in targeting the cancer epigenome
  • Therapeutic ketosis reduces circulating inflammatory markers, and ketones directly inhibit the NLRP3 inflammasome, an important pro-inflammatory pathway linked to carcinogenesis and an important target for cancer treatment response
  • Chronic psychological stress is known to promote tumorigenesis through elevations of blood glucose, glucocorticoids, catecholamines, and insulin-like growth factor (IGF-1)
  • In addition to calorie-restricted ketogenic diets, psychological stress management involving exercise, yoga, music etc. also act as press disturbances that can help reduce fatigue, depression, and anxiety in cancer patients and in animal models
  • Ketone supplementation has also been shown to reduce anxiety behavior in animal models
  • This physiological state also enhances the efficacy of chemotherapy and radiation therapy, while reducing the side effects
  • lower dosages of chemotherapeutic drugs can be used when administered together with calorie restriction or restricted ketogenic diets (KD-R)
  • Besides 2-DG, a range of other glycolysis inhibitors might also produce similar therapeutic effects when combined with the KD-R including 3-bromopyruvate, oxaloacetate, and lonidamine
    • Nathan Goodyear
      Nathan Goodyear on 08 Feb 18
       
      oxaloacetate is a glycolytic inhibitor, as is doxycycline, and IVC.
  • A synergistic interaction of the KD diet plus radiation was seen
  • It is important to recognize, however, that the radiotherapy used in glioma patients can damage the respiration of normal cells and increase availability of glutamine in the microenvironment, which can increase risk of tumor recurrence especially when used together with the steroid drug dexamethasone
  • Poff and colleagues demonstrated that hyperbaric oxygen therapy (HBOT) enhanced the ability of the KD to reduce tumor growth and metastasis
  • HBOT also increases oxidative stress and membrane lipid peroxidation of GBM cells in vitro
  • The effects of the KD and HBOT can be enhanced with administration of exogenous ketones, which further suppressed tumor growth and metastasis
  • Besides HBOT, intravenous vitamin C and dichloroacetate (DCA) can also be used with the KD to selectively increase oxidative stress in tumor cells
  • Recent evidence also shows that ketone supplementation may enhance or preserve overall physical and mental health
  • Some tumors use glucose as a prime fuel for growth, whereas other tumors use glutamine as a prime fuel [102, 186, 262, 263, 264]. Glutamine-dependent tumors are generally less detectable than glucose-dependent under FDG-PET imaging, but could be detected under glutamine-based PET imaging
  • GBM and use glutamine as a major fuel
  • Many of the current treatments used for cancer management are based on the view that cancer is a genetic disease
  • Emerging evidence indicates that cancer is a mitochondrial metabolic disease that depends on availability of fermentable fuels for tumor cell growth and survival
  • Glucose and glutamine are the most abundant fermentable fuels present in the circulation and in the tumor microenvironment
  • Low-carbohydrate, high fat-ketogenic diets coupled with glycolysis inhibitors will reduce metabolic flux through the glycolytic and pentose phosphate pathways needed for synthesis of ATP, lipids, glutathione, and nucleotides
  • Nathan Goodyear on 09 Jul 17
     
    Cancer is a mitochondrial disease? So says the well published Dr Seyfried. Glucose and glutamine drive cancer growth.
Nathan Goodyear

Ascorbic acid: Chemistry, biology and the treatment of cancer - 0 views

www.ncbi.nlm.nih.gov/...PMC3608474

Fenton reaction ferritin vitamin C Fe cancer

shared by Nathan Goodyear on 07 Jul 19 - No Cached
  • iron and ascorbate has long been used as an oxidizing system; the combination of these two reagents is referred to as the Udenfriend system
  • ascorbate serves as a reducing cofactor for many enzymes
  • uptake of ascorbate from the intestinal tract is very tightly controlled
  • ...11 more annotations...
  • pharmacokinetic data indicate that intravenous administration of ascorbate can bypass this tight control resulting in highly elevated plasma levels
  • ascorbate readily oxidizes to produce H2O2, pharmacological ascorbate has been proposed as a prodrug for the delivery of H2O2 to tumors
  • Ascorbate is an excellent reducing agent and readily undergoes two consecutive, one-electron oxidations to form ascorbate radical (Asc•−) and dehydroascorbic acid (DHA)
  • Ascorbate oxidizes readily. The rate of oxidation is dependent on pH and is accelerated by catalytic metals
  • In near-neutral buffers with contaminating metals, the oxidation and subsequent loss of ascorbate can be very rapid
  • Ascorbate is required for maintaining iron in the ferrous state
  • In the presence of catalytic metal ions, ascorbate can also exert pro-oxidant effects
  • Ascorbate is an excellent one-electron reducing agent that can reduce ferric (Fe3+) to ferrous (Fe2+) iron, while being oxidized to ascorbate radical
  • In a classic Fenton reaction, Fe2+ reacts with H2O2 to generate Fe3+ and the very oxidizing hydroxyl radical
  • e presence of ascorbate can allow the recycling of Fe3+ back to Fe2+, which in turn will catalyze the formation of highly reactive oxidants from H2O2
  • Depending on concentrations, the effects of ascorbate on models of lipid peroxidation can be pro- or antioxidant
  • Nathan Goodyear on 07 Jul 19
     
    ferritin released enhanced pharmacologic ascorbate induced-cytotoxicity, indicating that ferritin with high iron-saturation could be a source of catalytic iron. Consistent with this, ascorbate has also been shown to be capable of releasing iron from cellular ferritin
Nathan Goodyear

Availability of evidence of benefits on overall survival and quality of life of cancer ... - 0 views

www.bmj.com/bmj.j4530

cancer cancer treatment survival quality of life

shared by Nathan Goodyear on 20 Dec 17 - No Cached
  • Although the goal of cancer treatment is to improve the quantity and quality of life,123 clinical trials designed to gain regulatory approval for new drugs often evaluate indirect or “surrogate” measures of drug efficacy. These endpoints show that an agent has biological activity, but they are not reliable surrogates for improved survival4567891011 or quality of life46111213
  • two recent systematic reviews suggest that the strength of association between surrogates in cancer clinical trials and life extension is generally low
  • Available data from the US show that only a small proportion of cancer treatments approved by the US Food and Drug Administration (FDA) unequivocally show benefits on survival or quality of life.30
  • ...16 more annotations...
  • We sought to systematically evaluate the evidence base for all new drugs and new indications for the treatment of solid tumours and haematological malignancies approved by the EMA in the five year period 2009-13
  • Three investigators (AP, EP, and EG) independently extracted data on and descriptively analysed the following trial features: characteristics of the participant population, study design (randomisation, crossover from experimental to control group, and blinding of investigators and participants), experimental and control groups, enrolment, primary and secondary endpoints, magnitude of benefit on survival and quality of life, and narrative interpretation of the findings
  • Only 18 of the 68 (26%) were supported by a pivotal study powered to evaluate overall survival as the primary outcome
  • From 2009 to 2013, the EMA approved use of 48 oncology drugs
  • Seventeen drugs were approved for treatment of haematological malignancies and 51 for treatment of solid tumours
  • Overall, 72 clinical trials supported the approval of 68 novel drug uses
  • Our scoring was limited to drugs for solid tumours
  • Among 68 cancer drug indications approved by the EMA in the period 2009-13, and with a median of 5.4 years’ follow-up, only 35 (51%) were associated with a significant improvement in survival (26/35) or quality of life (9/35) over existing treatment options, placebo, or as add on treatment
  • Only two of the 26 drugs shown to extend life also showed benefits on quality of life
  • 33 (49%) had not shown any improvement on survival or quality of life
  • This systematic evaluation of oncology drug approvals by the EMA in 2009-13 shows that most of the drugs (39/68, 57%) entered the market without evidence of improved survival or quality of life
  • At a minimum 3.3 years after market entry, there was still no conclusive evidence that 33 of these 39 cancer drugs either extended or improved life
  • What are potential reasons for the paucity of drug approvals with demonstrable survival advantages over existing treatments?
  • Firstly, only 18 (26%) indications for use in our cohort were supported by trials in which extension of life was the primary outcome
  • None of the pivotal studies supporting oncology drug approvals from 2009 to 2013 included quality of life as a primary outcome measure
  • Most new oncology drugs authorised by the EMA in 2009-13 came onto the market without clear evidence that they improved the quality or quantity of patients’ lives
  • Nathan Goodyear on 20 Dec 17
     
    New study from European Medicines Agency questions alot of the new cancer drugs brought to the market 2009-2013.  57% of the new drugs (39/68) were brought to the market without evidence of improved survival or quality of life.
Nathan Goodyear

Late Disseminated Lyme Disease: Associated Pathology and Spirochete Persistence Post-Tr... - 0 views

ajp.amjpathol.org/...fulltext

Lyme Lyme disease borrelia burgdorferi

shared by Nathan Goodyear on 14 Dec 17 - No Cached
  • In this study, we have demonstrated microscopic pathology ranging from minimal to moderate in multiple different tissues previously reported to be involved with LD, including the nervous system (central and peripheral), heart, skeletal muscle, joint-associated tissues, and urinary bladder 12 to 13 months following tick-inoculation of rhesus macaques by Bb strain B31
  • Based on histomorphology, inflammation consisted predominantly of lymphocytes and plasma cells, with rare scattered histiocytes
  • in rare instances, morphologically intact spirochetes were observed in inflamed brain and heart tissue sections from doxycycline-treated animals
  • ...41 more annotations...
  • colocalization of the Bb 23S rRNA probe was not observed in any of the sections of experimental inoculated animals shown to harbor rare persistent spirochetes (Supplemental Figure S1). Previous in vitro work has shown large decreases in Bb rRNA levels when in a stationary phase of growth despite the majority of spirochetes remaining viable
  • The possibility that the spirochetes were intact but dead also exists, though this may be unlikely given the precedence for viable but non-cultivable B. burgdorferi post-treatment
  • The doxycycline dose utilized in this study (5mg/kg) was based on a previous pharmacokinetic analysis of oral doxycycline in rhesus macaques proven to be comparable to levels achieved in humans and was meant to mimic treatment of disseminated LD
  • In addition to the brain of two treated animals, rare morphologically intact spirochetes immunoreactive to OspA were observed in the heart of one treated animal
  • Although we did not measure the doxycycline levels in the cerebrospinal fluid, they have been found to be 12% to 15% of the amount measured in serum
  • We and others have demonstrated the development of a drug-tolerant persister population when B. burgdorferi are treated with antibiotics in vitro
  • The adoption of a dormant or slow-growing phenotype likely allows the spirochetes to survive and re-grow following removal of antibiotic
  • The basic premise that antibiotic tolerance may be an adaptation of the sophisticated stringent response required for the enzootic cycle by the spirochetes is described in a recent review as well
  • Although current IDSA guidelines recommend intravenous ceftriaxone (2g daily for 30 days) over oral doxycycline for treatment of neuroborreliosis, a randomized clinical trial failed to show any enhanced efficacy of I.V. penicillin G to oral doxycycline for treatment of Lyme neuroborreliosis (no treatment failures were reported in this study of 54 patients).
  • we can speculate that the minimal to moderate inflammation that was observed, especially within the CNS and PNS can, in part, explain the breadth of symptoms experienced by late stage Lyme disease patients, such as cognitive impairment and neuralgia.
  • Erythema migrans, the clinical hallmark of early localized Lyme disease, was observed in one of the rhesus macaques from this study.
  • In 2014, a trailblazing study in mice demonstrated a dramatic decline in B. burgdorferi DNA in the tissues for up to eight months after antibiotic treatment followed by the resurgence of B. burgdorferi growth 12 months after treatment
  • This study provides evidence that the slow-growing spirochetes which persist after treatment, but are not cultivable in standard growth media may remain viable.
  • The first well-documented indication of Lyme disease (LD) in the United States occurred in the early 1970s
  • Lyme, Connecticut.
  • Lyme disease is now known to be caused by multiple closely related genospecies classified within the Bb sensu lato complex, representing the most common tick-borne human disease in the Northern Hemisphere
  • approximately 30,000 physician-reported cases occur annually in the United States, the annual incidence has been estimated to be 10-fold higher by the Centers for Disease Control and Prevention.6
  • Current antibiotic therapy guidelines outlined by the Infectious Disease Society of America (IDSA) are successful in the treatment of LD for the majority of LD patients, especially when administered early in disease immediately following identification of erythema migrans (EM)
  • ‘post-treatment Lyme disease syndrome’ (PTLDS)
  • host-adapted spirochetes that persist in the tissues, probably in small numbers, inaccessible or impervious to antibiotic
  • inflammatory responses to residual antigens from dead organisms
  • residual tissue damage following pathogen clearance;
  • autoimmune responses, possibly elicited by antigenic mimicry
  • Experimental studies on immunocompetent mice, dogs, and rhesus macaques have provided evidence for the persistence of Bb spirochetes subsequent to antibiotic treatment in the form of residual spirochetes detected within tissue by IFA and PCR, and recovered by xenodiagnoses
  • Ten male rhesus macaques
  • half (five) of the NHP received antibiotic treatment, consisting of 5 mg/kg oral doxycycline twice per day.
  • Minimal and focal lymphoplasmacytic inflammation
  • inflammation was observed in the leptomeninges overlying a section of temporal cerebral cortex
  • Minimal localized lymphoplasmacytic choroiditis
  • Peripheral nerves contained minimal to moderate lymphoplasmacytic inflammation with a predilection for collagen-rich epineurium and perivascular spaces
  • Inflammation was observed in 56% (5/9) of the NHPs irrespective of treatment group
  • For all animals, inflammation was reserved to perineural tissue
  • The treatment lasted 28 days
  • Minimal to mild lymphoplasmacytic inflammation of either the myocardial interstitium (Figure 2Figure 2A), pericardium (Figure 2Figure 2B), or combination therein was observed in 60% of NHPs
  • A single morphologically intact spirochete, as indicated by positive red immunofluorescence (Figure 2Figure 2C), was observed in the myocardium of one treated animal
  • mild, multifocal lymphoplasmacytic inflammation was observed in one doxycycline-treated animal
  • three animals exhibited minimal to mild lymphoplasmacytic inflammation affecting joint-associated structures
  • 10% to -20% of human patients treated
  • Multiple randomized placebo-controlled studies which evaluated sustained antimicrobial therapy concluded that there is no benefit in alleviating patients’ symptoms and indicated that long-term antibiotic therapy may even be detrimental to patients due to potential associated complications (ie, catheter infection and/or clostridial colitis)
  • and the rapid clearance of dead spirochetes in a murine model
  • higher doses may be needed to combat neuroborreliosis
  • Nathan Goodyear on 14 Dec 17
     
    persistent borrelia burgdorferia were found in the brain (2) and the heart (1) up to 13 months post standard antibiotic treatment suggesting borrelia burdorferia, the cause of Lyme, can persist in a chronic, persistant state poste acute treatment.
Nathan Goodyear

Ibuprofen alters human testicular physiology to produce a state of compensated hypogona... - 0 views

www.pnas.org/...1715035115.full

ibuprofen Testosterone epigenetics hormones low Testosterone low T

shared by Nathan Goodyear on 09 Jan 18 - No Cached
  • The levels of LH in the ibuprofen group had increased by 23% after 14 d of administration
  • This increase was even more pronounced at 44 d, at 33%
  • We found an 18% decrease (P = 0.056) in the ibuprofen group compared with the placebo group after 14 d (Fig. 1A) and a 23% decrease (P = 0.02) after 44 d (Fig. 1C). Taken together, these in vivo data suggest that ibuprofen induced a state of compensated hypogonadism during the trial, which occurred as early as 14 d and was maintained until the end of the trial at 44 d
  • ...27 more annotations...
  • We first investigated testosterone production after 24 and 48 h of ibuprofen exposure to assess its effects on Leydig cell steroidogenesis. Inhibition of testosterone levels was significant and dose-dependent (β = −0.405, P = 0.01 at 24 h and β = −0.664, P < 0.0001 at 48 h) (Fig. 2A) and was augmented over time
  • The AMH data show that the hypogonadism affected not only Leydig cells but also Sertoli cells and also occurred as early as 14 d of administration
  • Sertoli cell activity showed that AMH levels decreased significantly with ibuprofen administration, by 9% (P = 0.02) after 14 d (Fig. 1B) and by 7% (P = 0.05) after 44 d compared with the placebo group
  • Examination of the effect of ibuprofen exposure on both the ∆4 and ∆5 steroid pathways (Fig. 2B) showed that it generally inhibited all steroids from pregnenolone down to testosterone and 17β-estradiol; the production of each steroid measured decreased at doses of 10−5–10−4 M. Under control conditions, production of androstenediol and dehydroepiandrosterone (DHEA) was below the limit of detection except in one experiment with DHEA
  • Measuring the mRNA expression of genes involved in steroidogenesis in vitro showed that ibuprofen had a profound inhibitory effect on the expression of these genes (Fig. 3 B–D), consistent with that seen above in our ex vivo organ model. Taken together, these data examining effects on the endocrine cells confirm that ibuprofen-induced changes in the transcriptional machinery were the likely reason for the inhibition of steroidogenesis.
  • Suppression of gene expression concerned the initial conversion of cholesterol to the final testosterone synthesis. Hence, expression of genes involved in cholesterol transport to the Leydig cell mitochondria was impaired
  • A previous study reported androsterone levels decreased by 63% among men receiving 400 mg of ibuprofen every 6 h for 4 wk
  • We next examined the gene expression involved in testicular steroidogenesis ex vivo and found that levels of expression of every gene that we studied except CYP19A1 decreased after exposure for 48 h compared with controls
  • the changes in gene expression indicate that the transcriptional machinery behind the endocrine action of Leydig cells was most likely impaired by ibuprofen exposure.
  • Together, these data show that ibuprofen also directly impairs Sertoli cell function ex vivo by inhibiting transcription
  • ibuprofen use in men led to (i) elevation of LH; (ii) a decreased testosterone/LH ratio and, to a lesser degree, a decreased inhibin B/FSH ratio; and (iii) a reduction in the levels of the Sertoli cell hormone AMH
  • The decrease in the free testosterone/LH ratio resulted primarily from the increased LH levels, revealing that testicular responsiveness to gonadotropins likely declined during the ibuprofen exposure. Our data from the ex vivo experiments support this notion, indicating that the observed elevation in LH resulted from ibuprofen’s direct antiandrogenic action
  • AMH levels were consistently suppressed by ibuprofen both in vivo and ex vivo, indicating that this hormone is uncoupled from gonadotropins in adult men. The ibuprofen suppression of AMH further demonstrated that the analgesic targeted not only the Leydig cells but also the Sertoli cells, a feature encountered not only in the human adult testis but also in the fetal testis
  • ibuprofen displayed broad transcription-repression abilities involving steroidogenesis, peptide hormones, and prostaglandin synthesis
  • a chemical compound, through its effects on the signaling compounds, can result in changes in the testis at gene level, resulting in perturbations at higher physiological levels in the adult human
  • The analgesics acetaminophen/paracetamol and ibuprofen have previously been shown to inhibit the postexercise response in muscles by repressing transcription
  • Previous ex vivo studies on adult testis have indeed pointed to an antiandrogenicity, only on Leydig cells, of phthalates (41), aspirin, indomethacin (42), and bisphenol A (BPA) and its analogs
  • ibuprofen’s effects were not restricted to Leydig and Sertoli cells, as data showed that the expression of genes in peritubular cells was also affected
  • short-term exposure
  • In the clinical setting, compromised Leydig cell function resulting in increased insensitivity to LH is defined as compensated hypogonadism (4), an entity associated with all-cause mortality
  • compensated hypogonadic men present with an increased likelihood of reproductive, cognitive, and physical symptoms
  • an inverse relationship was recently reported between endurance exercise training and male sexual libido
  • AMH concentrations are lower in seminal plasma from patients with azoospermia than from men with normal sperm levels
  • inhibin B is a key clinical marker of reproductive health (32). The function of AMH, also secreted by Sertoli cells, and its regulation through FSH remain unclear in men
  • the striking dual effect of ibuprofen observed here on both Leydig and Sertoli cells makes this NSAID the chemical compound, of all the chemical classes considered, with the broadest endocrine-disturbing properties identified so far in men.
  • after administration of 600 mg of ibuprofen to healthy volunteers
  • 14 d or at the last day of administration at 44 d
  • Nathan Goodyear on 09 Jan 18
     
    ibuprofen alters genetic expression that results in decreased Testosterone production.
Nathan Goodyear

TSH and free triiodothyronine concentrations are associated with weight loss in a lifes... - 0 views

www.eje-online.org/...323.abstract

free T3 T3 overweight obesity weight loss children

shared by Nathan Goodyear on 05 Mar 13 - No Cached
  • Nathan Goodyear on 05 Mar 13
     
    weight loss in obese children with low TSH and free T3 indicates high risk or regain of weight.  The important value here is the free T3.
Nathan Goodyear

Testosterone Induces Dilation of Canine Coronary Conductance and Resistance Arteries In... - 0 views

circ.ahajournals.org/...2614.abstract

testosterone vasodilation androgen receptor AR androgen receptor antagonist blockade antagonist male men

shared by Nathan Goodyear on 14 May 13 - No Cached
  • Nathan Goodyear on 14 May 13
     
    another animal study, but blockade of androgen receptor, in this study, was not found to diminish the vasodilatory effect of testosterone.  This indicates that some of the vasoactive responses to testosterone are independent of AR and this has been shown in other studies ie. AR knockout mice.
Nathan Goodyear

Metabolic management of brain cancer - 0 views

www.sciencedirect.com/...S0005272810006857

brain cancer

shared by Nathan Goodyear on 17 Jun 13 - No Cached
  • Glutamine is a major metabolic fuel for both brain tumor cells and tumor-associated macrophages (TAMs)
  • the malignant phenotype of brain tumor cells that survive radiotherapy is often greater than that of the cells from the original tumor.
  • Conventional chemotherapy has faired little better than radiation therapy for the long-term management of malignant brain cancer
  • ...37 more annotations...
  • most conventional radiation and brain cancer chemotherapies can enhance glioma energy metabolism and invasive properties, which would contribute to tumor recurrence and reduced patient survival [34].
  • We contend that all cancer regardless of tissue or cellular origin is a disease of abnormal energy metabolism
  • complex disease phenotypes can be managed through self-organizing networks that display system wide dynamics involving oxidative and non-oxidative (substrate level) phosphorylation
  • As long as brain tumors are provided a physiological environment conducive for their energy needs they will survive; when this environment is restricted or abruptly changed they will either grow slower, growth arrest, or perish [8] and [19]
  • New information also suggests that ketones are toxic to some human tumor cells and that ketones and ketogenic diets might restrict availability of glutamine to tumor cells [68], [69] and [70].
  • The success in dealing with environmental stress and disease is therefore dependent on the integrated action of all cells in the organism
  • Tumor cells survive in hypoxic environments not because they have inherited genes making them more fit or adaptable than normal cells, but because they have damaged mitochondria and have thus acquired the ability to derive energy largely through substrate level phosphorylation
  • Cancer cells survive and multiply only in physiological environments that provide fuels (mostly glucose and glutamine) subserving their requirement for substrate level phosphorylation
  • Integrity of the inner mitochondrial membrane is necessary for ketone body metabolism since β-hydroxybutyrate dehydrogenase, which catalyzes the first step in the metabolism of β-OHB to acetoacetate, interacts with cardiolipin and other phospholipids in the inner membrane
  • the mitochondria of many gliomas and most tumors for that matter are dysfunctional
  • Cardiolipin is essential for efficient oxidative energy production and mitochondrial function
  • Any genetic or environmental alteration in the content or composition of cardiolipin will compromise energy production through oxidative phosphorylation
  • The Crabtree effect involves the inhibition of respiration by high levels of glucose
  • the Warburg effect involves elevated glycolysis from impaired oxidative phosphorylation
  • the Crabtree effect can be reversible, the Warburg effect is largely irreversible because its origin is with permanently damaged mitochondria
  • The continued production of lactic acid in the presence of oxygen is the metabolic hallmark of most cancers and is referred to as aerobic glycolysis or the Warburg effect
  • We recently described how the retrograde signaling system could induce changes in oncogenes and tumor suppressor genes to facilitate tumor cell survival following mitochondrial damage [48].
  • In addition to glycolysis, glutamine can also increase ATP production under hypoxic conditions through substrate level phosphorylation in the TCA cycle after its metabolism to α-ketoglutarate
  • mitochondrial lipid abnormalities, which alter electron transport activities, can account in large part for the Warburg effect
  • targeting both glucose and glutamine metabolism could be effective for managing most cancers including brain cancer
  • The bulk of experimental evidence indicates that mitochondria are dysfunctional in tumors and incapable of generating sufficient ATP through oxidative phosphorylation
  • Cardiolipin defects in tumor cells are also associated with reduced activities of several enzymes of the mitochondrial electron transport chain making it unlikely that tumor cells with cardiolipin abnormalities can generate adequate energy through oxidative phosphorylation
  • The Crabtree effect involves the inhibition of respiration by high levels of glucose
  • Warburg effect involves elevated glycolysis from impaired oxidative phosphorylation
  • TCA cycle substrate level phosphorylation could therefore become another source of ATP production in tumor cells with impairments in oxidative phosphorylation
  • Caloric restriction, which lowers glucose and elevates ketone bodies [63] and [64], improves mitochondrial respiratory function and glutathione redox state in normal cells
  • DR naturally inhibits glycolysis and tumor growth by lowering circulating glucose levels, while at the same time, enhancing the health and vitality of normal cells and tissues through ketone body metabolism
  • DR is anti-angiogenic
  • DR also reduces angiogenesis in prostate and breast cancer
  • We suggest that apoptosis resistance arises largely from enhanced substrate level phosphorylation of tumor cells and to the genes associated with elevated glycolysis and glutaminolysis, e.g., c-Myc, Hif-1a, etc, which inhibit apoptosis
  • Modern medicine has not looked favorably on diet therapies for managing complex diseases especially when well-established procedures for acceptable clinical practice are available, regardless of how ineffective these procedures might be in managing the disease
  • More than 60 years of clinical research indicates that such approaches are largely ineffective in extending survival or improving quality of life
  • The process is rooted in the well-established scientific principle that tumor cells are largely dependent on substrate level phosphorylation for their survival and growth
  • Glucose and glutamine drive substrate level phosphorylation
  • targeting the glycolytically active tumor cells that produce pro-cachexia molecules, restricted diet therapies can potentially reduce tumor cachexia
  • It is important to recognize, however, that “more is not better” with respect to the ketogenic diet
  • Blood glucose ranges between 3.0 and 3.5 mM (55–65 mg/dl) and β-OHB ranges between 4 and 7 mM should be effective for tumor management
  • Nathan Goodyear on 17 Jun 13
     
    Dr Seyfriend presents his metabolic approach to the treatment of brain cancer.
Nathan Goodyear

Thyrotropin Suppression by Metformin - 0 views

jcem.endojournals.org/...225.long

TSH thyroid metformin

shared by Nathan Goodyear on 31 Jan 13 - No Cached
  • Nathan Goodyear on 31 Jan 13
     
    Metformin shown to suppress TSH secretion without change in free t4 or free t3 levels.  This again, shows the lack of reliability of the test TSH.  With the suppression of TSH indicated in this study, the free t4 and t3 should have been elevated, but were obviously not.
Nathan Goodyear

[Serum and salivary testosterone levels in erectil... [Orv Hetil. 1998] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...9745307

testosterone saliva salivary hormone hormones ED men male

shared by Nathan Goodyear on 30 Oct 12 - No Cached
  • Nathan Goodyear on 30 Oct 12
     
    Small study looking at testosterone in men with ED.  They found "serum total testosterone level is not a sensitivity indicator for detection of hypogonadism".  Salivary free testosterone levels is the best way to evaluate androgen levels.
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