1 votes
Posted 03 August 2013 - 08:06 AM
Posted 11 December 2013 - 08:12 PM
Posted 12 December 2013 - 12:16 AM
Still trying to wrap my head around this study discussed earlier of resveratrol blood levels with/without fats as well as with/without quercetin:
http://www.ncbi.nlm....pubmed/20528005
The fats part sounds a little off to me. That fats decreased both near-term and 12-hour blood levels of resveratrol. I would have expected the 12-hour levels to remain unchanged or go up a little, given that resveratrol is somewhat fat soluble. Maybe the alcohol creates a preference for blood stream to liver uptake which the added fats inhibit. And/or substantially more of the 12-hour detected resveratrol was 2nd pass material rather than lymphatic system left-overs.
I've found that grinding in a little dry lecithin (50 mg lecithin to 450 mg resv) makes capping easier by reducing static electricity... wonder if adding an emulsifier like that, and leaving the alcohol out, would change the results by boosting lymphatic system uptake. I would definitely expect that with ptero in the mix since its more fat soluble to start with.
Howard
Posted 12 December 2013 - 03:39 PM
Posted 13 December 2013 - 03:08 PM
Been mulling it over and I have a theory. That we are misinterpreting the 12-hour blood reading level. It doesn't really represent longer term absorption or even a secondary bloodstream peaking level. It's just a bloodstream level at an arbitrary fixed point in time.
Posted 13 December 2013 - 05:03 PM
Been mulling it over and I have a theory. That we are misinterpreting the 12-hour blood reading level. It doesn't really represent longer term absorption or even a secondary bloodstream peaking level. It's just a bloodstream level at an arbitrary fixed point in time.
The 12 hour number they give is called the "Area Under the Curve", or AUC. The x-axis of the curve is time and the y-axis is concentration of the compound in the blood. Thus, the AUC is kind of a "total exposure" number.
Posted 13 December 2013 - 05:44 PM
Single-centre, open-label, randomized, 2-way crossover study on 24 healthy subjects. The study consisted of two consecutive treatment periods separated by a washout of 7 days or more. On each of the study periods subjects were administered a single-dose of 400 mg of trans-resveratrol following either a standard high fat content meal or 8 hs of fasting.
...
The rate of absorption of trans-resveratrol following an oral 400 mg single-dose was significantly delayed by the presence of food, as reflected by Cmax and tmax. However, the extent of absorption, as reflected by AUC- yen, was not affected in a relevant way.
Posted 13 December 2013 - 06:45 PM
Posted 15 December 2013 - 04:51 PM
Posted 16 December 2013 - 10:42 AM
This sounds somewhat positive. In any case I have a one-year supply of resveratrol with quercetin from LEF, so I hope this formulation is doing me at least some good.."Quercetin was also synergistic with Resveratrol in protection of blood vessels[242] and inhibition of adipogenesis and slightly more potent than Genistein in the overall percent synergism.[243]
Combining all three bioflavonoids showed further synergism[244] and low-dosing the three can provide cumulatively similar benefits at cheaper costs.[245]" (examine)
Kleinedler JJ, et al. Synergistic effect of resveratrol and quercetin released from drug-eluting polymer coatings for endovascular devices. J Biomed Mater Res B Appl Biomater. (2011)
Yang JY, et al. Enhanced inhibition of adipogenesis and induction of apoptosis in 3T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci. (2008)
Park HJ, et al. Combined effects of genistein, quercetin, and resveratrol in human and 3T3-L1 adipocytes. J Med Food. (2008)
Rayalam S, Della-Fera MA, Baile CA. Synergism between resveratrol and other phytochemicals: implications for obesity and osteoporosis. Mol Nutr Food Res. (2011)
Posted 27 December 2013 - 12:56 AM
J Clin Exp Cardiolog. 2013 Mar 2;4(3). pii: 238.
Nutritional Supplement-5 with a Combination of Proteasome Inhibitors (Resveratrol, Quercetin, δ-Tocotrienol) Modulate Age-Associated Biomarkers and Cardiovascular Lipid Parameters in Human Subjects.
Qureshi AA, Khan DA, Mahjabeen W, Papasian CJ, Qureshi N.
Author information
- Department of Basic Medical Science, University of Missouri-Kansas City, 2411 Holmes Street, Kansas City, MO 64108, USA.
Abstract
BACKGROUND:
Age-associated altered redox imbalances and dysregulated immune function, contribute to the development of a variety of age associated diseases. Inflammatory markers and lipid profiles are useful prognostic indicators of a variety of age-associated and cardiovascular diseases. We have previously studied the impact of several proteasome inhibitors on several markers of inflammation and lipid profiles in vitro, in vivo, in cell lines, animal models, and in human subjects. The current study represents an extension of this work. Our main hypothesis is that a combination of various naturally-occurring proteasome inhibitors, which inhibits nitric oxide (NO), and C-reactive protein (CRP) mediated inflammation, will have better efficacy in the prevention and treatment of age-associated disorders including cardiovascular disease.
METHODS:
Two double blind, randomized, placebo-controlled cross-over trials were conducted to determine the impact of a mixture of NS-5 (resveratrol, pterostilbene, quercetin, δ-tocotrienol, nicotinic acid) on serum NO, CRP, γ-glutamyl-transferase (γ-GT) activity, total antioxidant status (TAS), total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides levels. Healthy seniors (Group-1; n = 32) free-living (A, B; 16/group), and hypercholesterolemic (Group-2; n = 64) subjects on AHA-Step-1-diet were divided into two groups (C, D; 32/group). Baseline levels were established for parameters as mentioned above. Groups A, C were administered 4-capsules/d of NS-5 and groups B, D, placebo (starch) for 6-weeks. Groups were crossed-over, followed by a 2-week wash-out period. Groups A, C were given 4-capsules/d of placebo and groups B, D, 4-capsules/d of NS-5 for 6-weeks. Groups C, D were continued on AHA-Step-1-diet.
RESULTS:
All the subjects completed each phase in both studies without any complaints. There were significant ( P < 0.01 - 0.05) decreases in the serum levels of NO (30%, 26%), CRP (29%, 21%), γ-GT activity (14%, 17%), and blood pressure (systolic/diastolic, 3/6%, 3/3%) of Groups A and B, respectively, of free-living healthy seniors without affecting the total, HDL-, LDL-cholesterol or triglycerides compared to their respective baseline values. However, serum levels of NO (36%, 43%), CRP (31%, 48%), γ-GT (17%, 20%), total cholesterol (19%, 15%), LDL-cholesterol (28%, 20%), triglycerides (11%, 18%) of Groups C and D were significantly ( P < 0.01-0.05) decreased with NS-5 treatment of hypercholesterolemic subjects compared to baseline values, without affecting the serum HDL-cholesterol levels. The serum levels of total antioxidant status (TAS) were increased (10%, 14%; P < 0.05) in Groups A and B, increased (19%, 24%; P < 0.02), and blood pressure (systolic/diastolic, 5/6%, 3/5%) in Groups C and D with NS-5 treatment, compared to respective baseline values.
CONCLUSIONS:
The consumption of NS-5 mixture decreased significantly serum NO, CRP and γ-GT levels, improved TAS and lipid profiles at risk cardiovascular and hold promise for delaying onset of age-associated diseases.
Posted 27 December 2013 - 01:04 AM
Nutrients. 2013 Jun 4;5(6):1989-2005. doi: 10.3390/nu5061989.
Observation of human retinal remodeling in octogenarians with a resveratrol based nutritional supplement.
Richer S, Stiles W, Ulanski L, Carroll D, Podella C.
Author information
Eye Clinic 112e, Captain James Lovell Federal Health Care Center, 3001 Green Bay Rd, North Chicago, IL 60064, USA. stuart.richer1@VA.Gov
Abstract
PURPOSE:
Rare spontaneous remissions from age-related macular degeneration (AMD) suggest the human retina has large regenerative capacity, even in advanced age. We present examples of robust improvement of retinal structure and function using an OTC oral resveratrol (RV) based nutritional supplement called Longevinex® or L/RV (circa 2004, Resveratrol Partners, LLC, Las Vegas, NV, USA). RV, a polyphenolic phytoalexin caloric-restriction mimic, induces hormesis at low doses with widespread beneficial effects on systemic health. RV alone inhibits neovascularization in the murine retina. Thus far, published evidence includes L/RV mitigation of experimentally induced murine cardiovascular reperfusion injury, amelioration of human atherosclerosis serum biomarkers in a human Japanese randomized placebo controlled trial, modulation of micro RNA 20b and 539 that control hypoxia-inducing-factor (HIF-1) and vascular endothelial growth factor (VEGF) genes in the murine heart (RV inhibited micro RNA20b 189-fold, L/RV 1366-fold). Little is known about the effects of L/RV on human ocular pathology.
METHODS:
Absent FDA IRB approval, but with permission from our Chief of Staff and medical center IRB, L/RV is reserved for AMD patients, on a case-by-case compassionate care basis. Patients include those who progress on AREDS II type supplements, refuse intra-vitreal anti-VEGF injections or fail to respond to Lucentis®, Avastin® or Eylea®. Patients are clinically followed traditionally as well as with multi-spectral retinal imaging, visual acuity, contrast sensitivity, cone glare recovery and macular visual fields. Three cases are presented.
RESULTS:
Observed dramatic short-term anti-VEGF type effect including anatomic restoration of retinal structure with a suggestion of improvement in choroidal blood flow by near IR multispectral imaging. The visual function improvement mirrors the effect seen anatomically. The effect is bilateral with the added benefit of better RPE function. Effects have lasted for one year or longer when taken daily, at which point one patient required initiation of anti-VEGF agents. Unanticipated systemic benefits were observed.
CONCLUSIONS:
Preliminary observations support previous publications in animals and humans. Restoration of structure and visual function in octogenarians with daily oral consumption of L/RV is documented. Applications include failure on AREDS II supplements, refusing or failing conventional anti-VEGF therapy, adjunct therapy to improve RPE function, and compassionate use in medically underserved or economically depressed third-world countries.
Edited by cudBwrong, 27 December 2013 - 01:21 AM.
Posted 27 December 2013 - 02:30 AM
A mixture of 5 substances ("NS-5") including resveratrol and quercetin improved age associated and
cardiovascular biomarkers, here:CONCLUSIONS:
The consumption of NS-5 mixture decreased significantly serum NO, CRP and γ-GT levels, improved TAS and lipid profiles at risk cardiovascular and hold promise for delaying onset of age-associated diseases.
Posted 27 December 2013 - 03:50 AM
Why would significantly decreasing serum NO be considered a good thing...especially in regard to delaying onset of age-associated diseases? The pharmaceutical industry makes billions selling little blue pills to precisely counter this effect of aging (decreased NO). Along with selling other pharmaceuticals to boost NO in heart patients with angina. NO is also a very important biological messenger and I can think of no reason why you would want to suppress it (especially further than natural aging already seems to do)....quite to the contrary. Athletes like to supplement NO boosting supplements to improve performance...and not just in the bedroom. This conclusion seem counter intuitive and makes no sense.
Edited by cudBwrong, 27 December 2013 - 03:55 AM.
Posted 28 December 2013 - 03:47 AM
Posted 28 December 2013 - 04:06 AM
I thought where Nitric Oxide was good was in blood vessel endothelial cell walls. Making them more elastic, relaxing them, and lowering blood pressure. If it stays floating around in your blood, its close but not exactly where you want it.
Howard
Biological functions[edit]
Main article: Biological functions of nitric oxide
NO is one of the few gaseous signalling molecules known and is additionally exceptional due to the fact that it is a radical gas. It is a key vertebrate biological messenger, playing a role in a variety of biological processes.[14] It is a known bioproduct in almost all types of organisms, ranging from bacteria to plants, fungi, and animal cells.[15]
Nitric oxide, known as the 'endothelium-derived relaxing factor', or 'EDRF', is biosynthesized endogenously from L-arginine, oxygen, and NADPH by various nitric oxide synthase (NOS) enzymes. Reduction of inorganic nitrate may also serve to make nitric oxide. The endothelium (inner lining) of blood vessels uses nitric oxide to signal the surrounding smooth muscle to relax, thus resulting in vasodilation and increasing blood flow. Nitric oxide is highly reactive (having a lifetime of a few seconds), yet diffuses freely across membranes. These attributes make nitric oxide ideal for a transient paracrine (between adjacent cells) and autocrine (within a single cell) signaling molecule.[16]
Independent of nitric oxide synthase, an alternative pathway, coined the nitrate-nitrite-nitric oxide pathway, elevates nitric oxide through the sequential reduction of dietary nitrate derived from plant-based foods.[17] Nitrate-rich vegetables, in particular leafy greens, such as spinach, arugula, and beetroot, have been shown to increase cardioprotective levels of nitric oxide with a corresponding reduction in blood pressure in pre-hypertensive persons.[18][19] For the body to generate nitric oxide through the nitrate-nitrite-nitric oxide pathway, the reduction of nitrate to nitrite occurs in the mouth, by commensal bacteria, an obligatory and necessary step.[20] Monitoring nitric oxide status by saliva testing detects the bioconversion of plant-derived nitrate into nitric oxide. A rise in salivary levels is indicative of diets rich in leafy vegetables which are often abundant in anti-hypertensive diets such as the DASH diet.[21]
The production of nitric oxide is elevated in populations living at high altitudes, which helps these people avoid hypoxia by aiding in pulmonary vasculature vasodilation. Effects include vasodilatation, neurotransmission (see gasotransmitters), modulation of the hair cycle,[22] production of reactive nitrogen intermediates and penile erections (through its ability to vasodilate). Nitroglycerin and amyl nitrite serve as vasodilators because they are converted to nitric oxide in the body. The vasodilating antihypertensive drug minoxidil contains an NO moiety and may act as an NO agonist. Likewise, Sildenafil citrate, popularly known by the trade name Viagra, stimulates erections primarily by enhancing signaling through the nitric oxide pathway in the penis.
Nitric oxide (NO) contributes to vessel homeostasis by inhibiting vascular smooth muscle contraction and growth, platelet aggregation, and leukocyte adhesion to the endothelium. Humans with atherosclerosis, diabetes, or hypertension often show impaired NO pathways.[23] A high salt intake was demonstrated to attenuate NO production in patients with essential hypertension, although bioavailability remains unregulated.[24]
Nitric oxide is also generated by phagocytes (monocytes, macrophages, and neutrophils) as part of the human immune response.[25] Phagocytes are armed with inducible nitric oxide synthase (iNOS), which is activated by interferon-gamma (IFN-γ) as a single signal or by tumor necrosis factor (TNF) along with a second signal.[26][27][28] On the other hand, transforming growth factor-beta (TGF-β) provides a strong inhibitory signal to iNOS, whereas interleukin-4 (IL-4) and IL-10 provide weak inhibitory signals. In this way, the immune system may regulate the armamentarium of phagocytes that play a role in inflammation and immune responses.[29] Nitric oxide is secreted as free radicals in an immune response and is toxic to bacteria and intracellular parasites, including Leishmania[30] and malaria;[31][32][33] the mechanism for this includes DNA damage[34][35][36] and degradation of iron sulfur centers into iron ions and iron-nitrosyl compounds.[37]
In response, many bacterial pathogens have evolved mechanisms for nitric oxide resistance.[38] Because nitric oxide might serve as an inflammetur in conditions like asthma, there has been increasing interest in the use of exhaled nitric oxide as a breath test in diseases with airway inflammation. Reduced levels of exhaled NO have been associated with exposure to air pollution in cyclists and smokers, but, in general, increased levels of exhaled NO are associated with exposure to air pollution.[39]
Nitric oxide can contribute to reperfusion injury when an excessive amount produced during reperfusion (following a period of ischemia) reacts with superoxide to produce the damaging oxidant peroxynitrite. In contrast, inhaled nitric oxide has been shown to help survival and recovery from paraquat poisoning, which produces lung tissue-damaging superoxide and hinders NOS metabolism.
In plants, nitric oxide can be produced by any of four routes: (i) L-arginine-dependent nitric oxide synthase,[40][41][42] (although the existence of animal NOS homologs in plants is debated),[43] (ii) plasma membrane-bound nitrate reductase, (iii) mitochondrial electron transport chain, or (iv) non-enzymatic reactions. It is a signaling molecule, acts mainly against oxidative stress and also plays a role in plant pathogen interactions. Treating cut flowers and other plants with nitric oxide has been shown to lengthen the time before wilting.[44]
Two important biological reaction mechanisms of nitric oxide are S-nitrosation of thiols, and nitrosylation of transition metal ions. S-nitrosation involves the (reversible) conversion of thiol groups, including cysteine residues in proteins, to form S-nitrosothiols (RSNOs). S-Nitrosation is a mechanism for dynamic, post-translational regulation of most or all major classes of protein.[45] The second mechanism, nitrosylation, involves the binding of NO to a transition metal ion like iron or copper. In this function, NO is referred to as a nitrosyl ligand. Typical cases involve the nitrosylation of heme proteins like cytochromes, thereby disabling the normal enzymatic activity of the enzyme. Nitrosylated ferrous iron is particularly stable, as the binding of the nitrosyl ligand to ferrous iron (Fe(II)) is very strong. Hemoglobin is a prominent example of a heme protein that may be modified by NO by both pathways: NO may attach directly to the heme in the nitrosylation reaction, and independently form S-nitrosothiols by S-nitrosation of the thiol moieties.[46]
Mechanism of action[edit]
There are several mechanisms by which NO has been demonstrated to affect the biology of living cells. These include oxidation of iron-containing proteins such as ribonucleotide reductase and aconitase, activation of the soluble guanylate cyclase, ADP ribosylation of proteins, protein sulfhydryl group nitrosylation, and iron regulatory factor activation.[47] NO has been demonstrated to activate NF-κB in peripheral blood mononuclear cells, an important transcription factor in iNOS gene expression in response to inflammation.[48]
It was found that NO acts through the stimulation of the soluble guanylate cyclase, which is a heterodimeric enzyme with subsequent formation of cyclic-GMP. Cyclic-GMP activates protein kinase G, which causes reuptake of Ca2+ and the opening of calcium-activated potassium channels. The fall in concentration of Ca2+ ensures that the myosin light-chain kinase (MLCK) can no longer phosphorylate the myosin molecule, thereby stopping the crossbridge cycle and leading to relaxation of the smooth muscle cell.[49]
Posted 29 December 2013 - 04:01 PM
I suspect that NO, as a "free radical messenger", is being suppressed by the anti-oxidant properties of the "NS-5" stack and in this case, I'm still not convinced that is a good thing. Perhaps a case where anti-oxidants, like with most things, more isn't better.
Posted 08 January 2014 - 01:01 AM
Posted 22 March 2014 - 08:43 PM
Been mulling it over and I have a theory. That we are misinterpreting the 12-hour blood reading level. It doesn't really represent longer term absorption or even a secondary bloodstream peaking level. It's just a bloodstream level at an arbitrary fixed point in time.
The 12 hour number they give is called the "Area Under the Curve", or AUC. The x-axis of the curve is time and the y-axis is concentration of the compound in the blood. Thus, the AUC is kind of a "total exposure" number.
Thanks, niner. I think I get it a little better now. So they must have taken multiple measurements over the 12-hour period to generate a curve. Makes me wonder if the full-text shows the curve with more detail on the peaks and dips... I'll see if I can round it up somewhere, perhaps in the members area.
Howard
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Posted 23 March 2014 - 12:47 AM
For the reader's convenience, here is a link to the full text of the paper cited above.Hi,Sorry to be so late in answering. Health problems. Re- quercetin, it is a pro-oxidant and not an anti-oxidant, as it stimulates AhR induction of Cyp1A1. Hence producing ROS.It also opposes AhR down-regulation by resveratrol.In a nutshell, it's like shooting your own foot. See more thru my first publication: Casper et al, Mol. Phamacol, 1999.Regards,JF Savouret
Posted 10 April 2014 - 02:32 PM
Apples have quercetin in them, and red grapes have resveratrol. So if someone ate a fruit salad with both of these fruits, you guys are saying something bad would happen to them?
The dose makes the poison. The amounts present are so low as to be irrelevant in relation to the amounts in the studies.
Posted 11 April 2014 - 02:50 AM
Quercetin and resveratrol in combination have anti-cancer activity in colon cancer cells. In vitro.
http://www.ncbi.nlm....pubmed/23530649
Now how do we make the RQ mixture work on Humans?
How about we design a monoclonal antibody with a ligand attached to an RQ molecule?
Design it species specific toward HT-29 colon cancer cell line.
RQ decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold
Posted 11 April 2014 - 03:52 AM
Quercetin and resveratrol in combination have anti-cancer activity in colon cancer cells. In vitro.
http://www.ncbi.nlm....pubmed/23530649
Now how do we make the RQ mixture work on Humans?
How about we design a monoclonal antibody with a ligand attached to an RQ molecule?
Design it species specific toward HT-29 colon cancer cell line.
RQ decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold
Edited by cudBwrong, 11 April 2014 - 03:56 AM.
Posted 11 April 2014 - 09:49 PM
Quercetin and resveratrol in combination have anti-cancer activity in colon cancer cells. In vitro.
http://www.ncbi.nlm....pubmed/23530649
Now how do we make the RQ mixture work on Humans?
How about we design a monoclonal antibody with a ligand attached to an RQ molecule?
Design it species specific toward HT-29 colon cancer cell line.
RQ decreased the generation of reactive oxygen species (ROS) by up to 2.25-fold
There are several methods being tested to improve delivery of things like resveratrol and quercetin to target tissues. Encapsulation in tiny liposomes seems to help. Search pubmed.org for "resveratrol liposome" to see examples such as this:
http://www.ncbi.nlm....pubmed/21851312
However, especially with the addition of a bioavailability enhancer such as piperine, you can achieve blood concentrations that are in the same ballpark as some of the values used in various in vitro studies. So an oral dose may be all you need, depending on what you are trying to accomplish.
See this study for blood concentrations of oral quercetin (without piperine):
http://www.ncbi.nlm....pubmed/23094941
That sounds like fun using liposomes as a RES delivery system.
But I wanted to test if Resveratrol is indeed a medication to treat cancer directly.
Now if I could deliver the Resveratrol molecule ported directly in IV to the cancer cells.
Supposingly we have p53/AKT (Actin) cycle cited in efficacy studies for the anticancer benefits of Resveratrol.
In order to prove this to be valid.
Additionally, I see further studies claiming that a ligand was attached to
the Resveratrol with anticancer benefits.
Take it one step further and attach the other end of the studied Ligand-Res to a monoclonal antibody.
Test this on animals and see if this feeds the cancer or apothesis results.
I am not a scientist but I have studied cancer drugs for over a decade.
Get to the end and annouce if Res is a marketable pharmaceutical.
Posted 16 April 2014 - 01:47 PM
Could the mixed studies on Quercetin be due to the fact that it inhibits CD38 ?
Certainly the inhibition of cd38 is responsible for some of the effects of quercetin.
CD38 is not necessarily a bad thing. You can live without it -- some organisms, including people, cannot produce it, due to a mutation -- but that causes a lot of health problems.
However, the downregulation of cd38 might be a good thing, especially in conjunction with resveratrol, as I suggested in the very active thread on the important recent study on mitochondria in the aging cell. See the many references in:
http://www.longecity...-strikes-again/
This is the Gomes, et. al. paper in Cell:
http://www.cell.com/...8674(13)01521-3
Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging
At issue is the NAD+ / NADH ratio. In old cells, NADH begins to predominate, resulting in mitochondrial malfunction. Resveratrol promotes an NAD+ synthesis pathway, while CD38, as an "NAD-ase" catalyses the reduction of NAD+ . So resveratrol and quercetin in combination, by affecting both the "supply side" and the "demand side," may shift the balance back towards NAD+.
The larger question is, why does this ratio shift with age? I sure don't know, but consider that cd38 is active in the immune response, and that many diseases of aging are now thought to result from chronic inflammation. So perhaps NADH is up because cd38 is up because there is inflammation from -- something. Many phytophenols like resveratrol and quercetin are regarded as anti-inflammatories. So what you are doing here, maybe, is suppressing the immune response to avoid autoimmune damage to healthy tissue.
If this is even remotely correct, then the even larger issue is, "What's causing the inflammation in the first place?" We like to think, oh, it's just "old age," but that's about as informative as blaming it on demons or sea monsters. My suspicion, and this goes way off topic, is that refined carbohydrate consumption, especially, added sugars, is an important root cause here, but that is a topic for some other thread.
Edited by cudBwrong, 16 April 2014 - 01:51 PM.
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