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Nathan Goodyear

Dietary glycine and blood pressure: the International Study on Macro/Micronutrients and... - 0 views

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    This study links glycine to increased blood pressure.  However, meat is the primary source of glycine. So, if the meat is loaded with omega-6, hormones...these will be the source of the inflammation and resultant increase in blood pressure, not the glycine.  One must read these studies closely.  No conclusion can be made from this study.
Nathan Goodyear

Testosterone for secondary prevention in men with ischaemic heart disease? - 0 views

  • Androgens and in particular testosterone have an inverse relationship with fibrinogen such that low endogenous testosterone is associated with elevated fibrinogen
  • testosterone administration causes a significant fall in fibrinogen
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    this article looks at the use of normalization of testosterone levels in men with CAD.  This study presents the data that low T is associated with increased CAD, yet says more studies needed.  This study should have used salivary testing and been more definitive in their conclusion
Nathan Goodyear

PLOS ONE: Increased Risk of Non-Fatal Myocardial Infarction Following Testosterone Ther... - 0 views

  • For all TT prescription subjects combined, the post/pre prescription rate ratio for MI (RR)was 1.36
  • In men aged 65 years and older the RR was 2.19 (1.27, 3.77), while in men under age 65 years the RR was 1.17
  • increasing RR with increasing age.
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  • The RRs were 0.95 (0.54, 1.67) under 55 years
  • 1.35 (0.77, 2.38) at 55–59
  • 1.29 (0.71, 2.35) at 60–64,
  • 1.35 (0.44, 4.18) at 65–69, 1.62
  • 3.43 (1.54, 7.66) at 75 years and older
  • The adjusted post/pre RR for PDE5I across all ages was 1.08
  • For TT prescription, in men under age 65 years, the RR was 2.90 (1.49, 5.62) for those with a history of heart disease and 0.90 (0.61, 1.34) for those without
  • In men aged 65 year and older, the RR was 2.16 (0.92, 5.10) for those with a history of heart disease and 2.21 (1.09, 4.45) for those without.
  • Among men aged 65 years and older, we observed a two-fold increase in the risk of MI in the 90 days after filling an initial TT prescription
  • Among younger men with a history of heart disease, we observed a two to three-fold increased risk of MI in the 90 days following an initial TT prescription and no excess risk in younger men without such a history
  • Among older men, the two-fold increased risk was associated with TT prescription regardless of cardiovascular disease history
  • our own findings appear consistent with a higher frequency of thrombotic events following TT prescription among men with more extensive coronary vascular disease.
  • Our findings are consistent with a recent meta-analysis of placebo-controlled randomized trials of testosterone therapy lasting 12 or more weeks among mainly older men, which reported that testosterone therapy increased the risk of adverse cardiovascular-related events (OR = 1.54, 95%CI:1.09, 2.18), as well as serious adverse cardiovascular-related events (OR = 1.61, 95%CI:1.01, 2.56) which included myocardial infarction along with other conditions
  • This association appeared unrelated to average baseline testosterone level (p = 0.70) but varied by source of funding (p = 0.03), with a stronger summary effect in a meta-analysis of studies not funded by the pharmaceutical industry (OR = 2.06, 95%CI:1.34, 3.17) compared with studies funded by the pharmaceutical industry
    • Nathan Goodyear
       
      This supports prior analysis that studies done by pharmaceutical corps will be more favorable to their product(s) than those independently funded.  This is called bias.
  • the evidence supports an association between testosterone therapy and risk of serious, adverse cardiovascular-related events–including non-fatal myocardial infarction–in men
  • there is some evidence that low endogenous testosterone levels may also be positively associated with cardiovascular events
  • effects of endogenous and exogenous testosterone may differ. Exogenous testosterone (TT) is associated with physiologic changes that predispose to clotting and thrombotic disorders including increased blood pressure [18], polycythemia [19], reductions in HDL cholesterol [18], [20], and hyperviscosity of the blood and platelet aggregation. [20]–[23]; TT also increases circulating estrogens [24], [25] which may play a role in the observed excess of adverse cardiovascular-related events, given that estrogen therapy has been associated with this excess in both men and women
  • did not include information on the serologic or diagnostic indications for treatment.
  • no association between PDE5I prescriptions and the risk of MI
  • Recently TT has been increasing extraordinarily rapidly, including among younger men and among those without hormone measurement
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    New cohort study finds increased risk of Testosterone in men > 65 and those : these are based in marketing-based medicine not evidence based medicine.
Nathan Goodyear

Reduced breast cancer incidence in women treated with subcutaneous testosterone, or tes... - 0 views

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    Study finds that Testosterone with or with the aromatase inhibitor anastrazole as a pellet reduced breast cancer risk.  This conclusion should be taken with caution.  It is well know that abnormal breast tissue, breast cancer, highly expresses aromatase activity which would increase Testosterone to estradiol production.  This would feed any growing tumor.  But, this study finds protection.  The failure of this study is the measurement of hormone levels.
Nathan Goodyear

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

  • 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.
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  • 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
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    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

Reevaluation of the protein requirement in young men with the indicator amino acid oxid... - 0 views

  • the mean and population-safe protein requirements were estimated to be 0.93 and 1.2 g · kg−1 · d
  • diet containing 0.90 g · kg−1 · d−1 was at or above physiologic protein requirements for sedentary men
  • The current EAR recommendation and RDA for protein are 0.66 and 0.80 g · kg−1 · d−1, respectively. We believe that these recommendations are tentative because no long-term studies have suggested that these values would maintain nitrogen balance along with lean body mass, muscle mass, serum protein concentrations, immunity, functional capacity etc
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  • a series of long-term balance studies (67-69) showed that intake of the proposed safe allowance of 0.57 g (70) egg protein resulted in negative nitrogen balance, loss of lean body mass, and deteriorating serum protein and transferase values unless additional energy or nonessential nitrogen was supplied
  • The results of the present study suggest that the current EAR recommendations (0.66 g · kg−1 · d−1) and RDA (0.80 g · kg−1 · d−1) for protein are underestimated at 29% and 33%, respectively
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    study looked at protein requirements in 8 "healthy" men.  This study pointed to 1.2 g/kg/day as an appropriate daily dietary protein intake for healthy men.  This far exceeds levels per RDA.
Nathan Goodyear

Estrogen metabolite ratio: Is the 2-hydroxyestrone to 16α-hydroxyestrone rati... - 0 views

  • A recent study of nine patients concluded that the urinary EMR is a good approximation for breast tissue EMR
  • A single study in young women not using oral contraceptives found fair correlation coefficients between urinary and plasma EMR
  • All of nine properly designed epidemiological studies (six prospective case-control studies and three retrospective studies) failed to show a significant relationship between urinary or circulating EMR (2OHE1/16αOHE1) and breast cancer risk
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  • premenopausal studies on urinary EMR have suggested a potentially weak inverse relationship, associations were not significantly different compared with postmenopausal or overall combined studies
  • at present, there is no evidence that the EMR can predict breast cancer risk
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    The 2:16 OH estrone pathway is shown to not be predictive biomarker for breast cancer.
Nathan Goodyear

European Journal of Clinical Nutrition - Effect of maternal n-3 long-chain polyunsatura... - 0 views

  • It is estimated that approximately 30% of children and adolescents in the United States and about 15–30% of those in Europe can be classified as overweight or obese
  • An increasing body of evidence now suggests that the nutritional environment encountered in utero and the early postnatal life may elicit permanent alterations in adipose tissue structure or function and, thereby, programme the individual’s propensity to later obesity
  • The composition of fatty acids in the Western diets has shifted toward an increasing dominance of n-6 relative to n-3 LCPUFAs over the past decades.9,10 This shift is also reflected in the fatty acid composition of breast milk
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  • Evidence from animal studies suggests that the n-6 LCPUFA arachidonic acid promotes adipose tissue deposition, whereas the n-3 LCPUFAs eicosapentaenoic acid and docosahexaenoic acid seem to exert an opposite effect
  • Overall, no effect of supplementation was found on BMI in preschool (<5 years) and school-aged (6–12 years) children
  • increased adiposity, once established in childhood, tends to track into adulthood
  • Many studies have shown that even children <2 years with a high BMI are at increased risk of developing obesity later in life
  • The acquisition of fat cells early in life appears to be an irreversible process
  • Evidence from cell culture and animal studies suggests that early exposure to n-3 LCPUFAs has the potential to limit adipose tissue deposition mainly by attenuating the production of the arachidonic acid metabolite prostacyclin, which has been shown to enhance adipogenesis
  • In conclusion, there is currently no evidence to support that maternal n-3 LCPUFA supplementation during pregnancy and/or lactation exerts a favourable programming effect on adiposity status in childhood
  • our systematic review highlights that most of the trials reviewed were prone to methodological limitations
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    Literature review finds limited data (9 studies, only 6 RCTs) of omega-3 during pregnancy.  No data was found that supported reduced obesity in children by mothers taking n-3 during pregnancy.  No harm was found either.  Data was sparse.   Take home: not enough data, no harm to pregnancy, children, thus if indications are present for mother, then recommend n-3.  At this point not studies have pointed to reduced obesity in children.
Nathan Goodyear

Physical activity and all-cause mortality across levels of overall and abdominal adipos... - 0 views

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    New study finds that inactive lifestyle leads to more early deaths than obesity.  Of course, the 2 are interrelated.  The study found a 16-30% reduction in early death due to 20 minutes of walking daily.  This came from analysis of the EPIC study
Nathan Goodyear

Relationship between Low Free Testosterone Levels and Loss of Muscle Mass : Scientific ... - 0 views

  • Our data confirm that a low FT level is a significant predictor of a risk for loss of appendicular muscle
  • Total lean mass is associated with bioavailable T in postmenopausal women
  • Further studies are needed to determine the role of androgens in preserving muscle mass in women
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  • Approximately 1% to 2% of T in the blood exists as FT
  • appendicular muscle loss was significantly associated with low levels of FT
  • These results suggest that a threshold level of FT exists for muscle loss, rather than a dose-response relationship
  • In the previous cross-sectional and longitudinal studies of French and American men, no dose-response relationships were reported between T and muscle mass
  • A minimal serum level of FT may be needed to preserve muscle mass in men, regardless of race/ethnicity.
  • Our result is in line with previous studies that reported a relationship between low FT and low muscle mass in men
  • T stimulates protein synthesis and inhibits protein degradation in muscle cells
  • T also increases satellite cell replication and activation in older men
  • In this study, no significant association between TT levels and muscle loss were observed
  • Although a progressive decrease in TT levels with ageing is observed in middle-aged and elderly American men16, 17, the TT levels do not change during ageing in Japanese men
  • FT levels may be a good marker for the loss of muscle mas
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    study of Japanese men finds that low free Testosterone was a predictor of decrease in muscle mass.
Nathan Goodyear

Estrogenic regulation of skeletal muscle proteome: a study of premenopausal women and p... - 0 views

  • Female aging is characterized by menopausal change in sex steroid hormones concomitant to increase in aging-related decrements in skeletal muscle performance that can be attenuated by HRT use
  • The major canonical pathways found to be differentially regulated included mitochondrial dysfunction, oxidative phosphorylation, glycolysis, and TCA-cycle, strong indicators for affected energy metabolism
  • E2 to exert anti-apoptotic effects in muscle progenitor cells by improving mitochondrial function
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  • E2 is a major regulator of human skeletal muscle signaling in women
  • After menopause, when ovarian E2 production is ceased, the prevalence of cardio-metabolic diseases increases. Our result that different trajectories of the energy pathways in the skeletal muscle may be regulated by E2 provides candidate molecules as key targets for future interventions to prevent or treat postmenopausal metabolic dysregulation
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    Study finds Estradiol regulates human skeletal muscle cell signaling (mitochondrial function, oxidative phosphorylation, glycolysis, and TCA cycle) in study of pre/post menopause women through proteome analysis. This study would have been complete if they had carried to search beyond that of protein to epigenetics.
Nathan Goodyear

Vitamin C preferentially kills cancer stem cells in hepatocellular carcinoma via SVCT-2... - 0 views

  • Chen et al. have revealed that ascorbate at pharmacologic concentrations (0.3–20 mM) achieved only by intravenously (i.v.) administration selectively kills a variety of cancer cell lines in vitro, but has little cytotoxic effect on normal cells.
  • Ascorbic acid (the reduced form of vitamin C) is specifically transported into cells by sodium-dependent vitamin C transporters (SVCTs)
  • SVCT-1 is predominantly expressed in epithelial tissues
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  • whereas the expression of SVCT-2 is ubiquitous
  • differential sensitivity to VC may result from variations in VC flow into cells, which is dependent on SVCT-2 expression.
  • high-dose VC significantly impaired both the tumorspheres initiation (Fig. 4d, e) and the growth of established tumorspheres derived from HCC cells (Fig. 4f, g) in a time-dependent and dose-dependent manner.
  • Hepatocellular carcinoma (HCC)
  • The antioxidant, N-acetyl-L-cysteine (NAC), preventing VC-induced ROS production (a ROS scavenger), completely restored the viability and colony formation among VC-treated cells
  • DNA double-strand damage was found following VC treatment
  • DNA damage was prevented by NAC
  • Interestingly, the combination of VC and cisplatin was even more effective in reducing tumor growth and weight
  • Consistent with the in vitro results, stemness-related genes expressions in tumor xenograft were remarkably reduced after VC or VC+cisplatin treatment, whereas conventional cisplatin therapy alone led to the increase of CSCs
  • VC is one of the numerous common hepatoprotectants.
  • Interestingly, at extracellular concentrations greater than 1 mM, VC induces strong cytotoxicity to cancer cells including liver cancer cells
  • we hypothesized that intravenous VC might reduce the risk of recurrence in HCC patients after curative liver resection.
  • Intriguingly, the 5-year disease-free survival (DFS) for patients who received intravenous VC was 24%, as opposed to 15% for no intravenous VC-treated patients
  • Median DFS time for VC users was 25.2 vs. 18 months for VC non-users
  • intravenous VC use is linked to improved DFS in HCC patients.
  • In this study, based on the elevated expression of SVCT-2, which is responsible for VC uptake, in liver CSCs, we revealed that clinically achievable concentrations of VC preferentially eradicated liver CSCs in vitro and in vivo
    • Nathan Goodyear
       
      the authors here made similar mistakes to the Mayo authors i.e. under doses here in this study.  They dosed at only 2 grams IVC.  A woefully low dose of IVC.
  • Additionally, we found that intravenous VC reduced the risk of post-surgical HCC progression in a retrospective cohort study.
    • Nathan Goodyear
       
      positive results despite a low dose used.
    • Nathan Goodyear
       
      Their comfort zone was 1mM.  They should have targeted 20-40 mM.
  • Three hundred thirty-nine participants (55.3%) received 2 g intravenous VC for 4 or more days after initial hepatectomy
  • As the key protein responsible for VC uptake in the liver, SVCT-2 played crucial roles in regulating the sensitivity to ascorbate-induced cytotoxicity
  • we also observed that SVCT-2 was highly expressed in human HCC samples and preferentially elevated in liver CSCs
  • SVCT-2 might serve as a potential CSC marker and therapeutic target in HCC
  • CSCs play critical roles in regulating tumor initiation, relapse, and chemoresistance
  • we revealed that VC treatment dramatically reduced the self-renewal ability, expression levels of CSC-associated genes, and percentages of CSCs in HCC, indicating that CSCs were more susceptible to VC-induced cell death
  • as a drug for eradicating CSCs, VC may represent a promising strategy for treatment of HCC, alone or particularly in combination with chemotherapeutic drugs
  • In HCC, we found that VC-generated ROS caused genotoxic stress (DNA damage) and metabolic stress (ATP depletion), which further activated the cyclin-dependent kinase inhibitor p21, leading to G2/M phase cell cycle arrest and caspase-dependent apoptosis in HCC cells
  • we demonstrated a synergistic effect of VC and chemotherapeutic drug cisplatin on killing HCC both in vitro and in vivo
  • Intravenous VC has also been reported to reduce chemotherapy-associated toxicity of carboplatin and paclitaxel in patients,38 but the specific mechanism needs further investigation
    • Nathan Goodyear
       
      so, exclude the benefit to patients until the exact mechanism of action, which will never be fully elicited?!?!?
  • Our retrospective cohort study also showed that intravenous VC use (2 g) was related to the improved DFS in HCC patients after initial hepatectomy
    • Nathan Goodyear
       
      Terribly inadequate dose.  Target is 20-40 mM which other studies have found occur with 50-75 grams of IVC.
  • several clinical trials of high-dose intravenous VC have been conducted in patients with advanced cancer and have revealed improved quality of life and prolonged OS
  • high-dose VC was not toxic to immune cells and major immune cell subpopulations in vivo
  • high recurrence rate and heterogeneity
  • tumor progression, metastasis, and chemotherapy-resistance
  • SVCT-2 was highly expressed in HCC samples in comparison to peri-tumor tissues
  • high expression (grade 2+/3+) of SVCT-2 was in agreement with poorer overall survival (OS) of HCC patients (Fig. 1c) and more aggressive tumor behavior
  • SVCT-2 is enriched in liver CSCs
  • these data suggest that SVCT-2 is preferentially expressed in liver CSCs and is required for the maintenance of liver CSCs.
  • pharmacologic concentrations of plasma VC higher than 0.3 mM are achievable only from i.v. administration
  • The viabilities of HCC cells were dramatically decreased after exposure to VC in dose-dependent manner
  • VC and cisplatin combination further caused cell apoptosis in tumor xenograft
  • These results verify that VC inhibits tumor growth in HCC PDX models and SVCT-2 expression level is associated with VC response
  • qPCR and IHC analysis demonstrated that expression levels of CSC-associated genes and percentages of CSCs in PDXs dramatically declined after VC treatment, confirming the inhibitory role of VC in liver CSCs
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    IV vitamin C in vitro and in vivo found to "preferentially" eradicate cancer stem cells.  In addition, IV vitamin C was found to be adjunctive to chemotherapy, found to be hepatoprotectant.  This study also looked at SVCT-2, which is the transport protein important in liver C uptake.
Nathan Goodyear

Phase I study of high-dose ascorbic acid with mFOLFOX6 or FOLFIRI in patients with meta... - 0 views

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    Phase I study of vitamin C and FOLFOX or FOLFIRI. Numerous studies have shown the extremely high safety profile of IV vitamin C in cancer. The need to show the same thing time and time again borders on the insanity. The potential adverse events listed in this study is from the FOLFOX or FOLFIRI, not the vitamin C.
Nathan Goodyear

Testosterone supplementation in aging men and women: possible impact on cardiovascular-... - 0 views

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    This study proposes that testosterone therapy aids in renal dysfunction in men.  However, they document that IL-6 and TNF-alpha and oxidative stress are a part of this process. What they fail to mention is that aromatase activity and conversion of T to E in men increases IL-6 and TNF-alpha.  Studies have also shown that T decreases TNF-alpha. Very likely, it is high aromatase activity causing the effects documented by this study.
Nathan Goodyear

inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induce... - 0 views

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    Study finds that inhibition of aromatase activity in diabetic male rats provided renal protection. There has been debate about the effects of testosterone therapy on the renal system. However, I propose that aromatase activity and conversion to estrogen is the negative effects of Testosterone. Other than over dosing men. Though this is a rat study, this study does support the theory.
Nathan Goodyear

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

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    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

Study Finds High-dose Intravenous Vitamin C Reduces Pain and Inflammation in Those... -... - 0 views

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    High dose IV vitamin C shown to reduce both pain and inflammation in patients with RA.  This study looked at doses only up to 50 grams.  The specific inflammatory marker that this study looked at was CRP and it was reduced on average by 44%.
Nathan Goodyear

AACI | Full text | The role of Probiotics in allergic diseases - 0 views

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    studies of probiotics in the treatment of asthma and allergic rhinitis are mixed.  Studies do strongly suggest benefit in therapy for allergic rhinitis, but this study found no benefit with regards to asthma in its review of the literature.
Nathan Goodyear

Maternal Immune Activation Alters Fetal Brain Development through Interleukin-6 - 0 views

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    this study, though in mice, should strike fear in all parents.  This study found that the inflammatory biomarker IL-6 was critical in the development of autism and schizophrenia in the mice offspring.  Neuro development was altered by inflammation exposure during preganancy.  This was from a single injection of IL-6!  This in light of recent studies that show that the flu vaccine and other vaccines increase IL-6 production in pregnant mothers.  So, why did ACOG promote flu vaccines in pregnancy again?
Nathan Goodyear

Blood type diets lack supporting evidence: a systematic review - 0 views

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    This study, a review of 16 articles, found little scientific support for the "blood type" diet.  This is why I have not made this recommendation to our clients--no real data to support this diet.   One question, is what was the eligibility criteria for inclusion of the studies.  Only one out of the 16 was selected.  Inclusion/exclusion criteria in these studies can brian bias.
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