Feeds:
Posts
Comments

TAK 733 » All About Drugs

November 18, 2013 by larryhbern

 

via TAK 733 » All About Drugs.

Posted in Biological Networks, Gene Regulation and Evolution, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Genetics, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Genome Biology | Tagged , , | Leave a Comment »

Cocoa and Heart Health

November 17, 2013 by larryhbern

Cocoa and Heart Health

Reporter: Larry H. Bernstein, MD, FCAP

Nutrients 2013, 5(10), 3854-3870;   http://dx.doi.org/10.3390/nu5103854

Cocoa and Heart Health: A Historical Review of the Science

Deanna L. Pucciarelli

Department of Family and Consumer Sciences, Ball State University, Muncie, IN

Accepted: 11 September 2013 / Published: 26 September 2013

(This article belongs to the Special Issue Chocolate and Cocoa in Human Health)

Download PDF Full-Text[263 KB, uploaded 26 September 2013

Abstract: The medicinal use of cocoa has a long history dating back almost five hundred years when Hernán Cortés’s first experienced the drink
in Mesoamerica.  Doctors in Europe recommended the beverage to patients in the 1700s, and later American physicians followed suit  and prescribed the drink in early America—ca. 1800s.  This article delineates the historic trajectory of cocoa consumption, the linkage between cocoa’s bioactive-
mechanistic properties, paying special attention to

  • nitric oxides role in vasodilation of the arteries,
  • to the current indicators purporting the benefits of cocoa and cardiovascular health.

Keywords: cocoa; heart-health; nitric oxide; cardiovascular disease; medical history

Pucciarelli, D.L. Cocoa and Heart Health: A Historical Review of the Science. Nutrients 2013; 5(10): 3854-3870.

Comment

Aldujaili Emad

Senior Lecturer at Queen Margaret University

This review highlights the beneficial effect of dark chocolate intake on CVD risk factors. We have been doing trials
on dark chocolate since 2007 studying its effects on several risk factors influencing the heart function such as

  • blood pressure, 
  • BMI, 
  • insulin resistancce
  • and body fat. 

It is important here to emphasize the issue of what type of dark chocolate is the most beneficial? Not every dark
chocolate in the market is useful. It depends on the processing. some methods destroy the polyphenols and therefore
reduce the benefits. Below some of our publications using the Barry Callebaut chocolate produced by the Acticoa process:

S. Almoosawi, C. Tsang, L. M. Ostertag, L. Fyfe and E. A. S. Al-Dujaili (2012) Differential effect of polyphenol-rich
dark chocolate on biomarkers of glucose metabolism and cardiovascular risk factors in healthy, overweight and obese subjects: a randomized clinical trial.Food and Function.
Cite this: http://dx.doi.org/10.1039/c2fo30060e. This journal is of The Royal Society of Chemistry 2012

Almoosawi, Suzana and Fyfe, Lorna and Ho, Clement and Al-Dujaili, Emad A S (2010) The effect of polyphenol-rich dark
chocolate on fasting capillary whole blood glucose, total cholesterol, blood pressure and glucocorticoids in healthy overweight and obese subjects.
British Journal of Nutrition 2010;103(6):842-850. ISSN 0007-1145

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Frontiers in Cardiology and Cardiovascular Disorders, Liver & Digestive Diseases Research, Metabolomics, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry | Tagged | Leave a Comment »

NANOPUTIANS

November 17, 2013 by larryhbern

Here is a very interesting piece. and it has educational lessons/

Posted in Uncategorized | Leave a Comment »

Vegan Diet is Sulfur Deficient and Heart Unhealthy

November 17, 2013 by larryhbern

Vegan Diet is Sulfur Deficient and Heart Unhealthy

Larry H. Bernstein, MD, FCAP, Curator

 

The following is a reblog of “Heart of the Matter: Plant-Based Diets Lead to High Homocysteine, Low Sulfur and Marginal B12 Status”
Posted on September 26, 2011 by Dr Kaayla Daniel in WAPF Blog and tagged B12, Forks over Knives, Kaayla T. Daniel, Kilmer S. McCully, Yves Ingenbleek

It is a report of a scientific study carried out by Kilmer S. Cully and Yves Ingenbleek, Harvard Pathology and Univ Louis Pasteur.  I have previously written about the conundrum of transthyretin as an accurate marker of malnutrition, but also being lowered by the septic state.  This is accounted for by the catabolic state that sets off autocannabalization of skeletal muscle and lean body mass to provide gluconeogenic precursors to sustain life.  While serum albumin and transthyretin both decline, the former has a half-life of 20 days, while the latter is 48 hours.  Much work has been done to gain a better understand this rapid turnover protein that transports thyroxine, and the immediate result of the decline in concentration is a shift the the hormone protein binding equilibrium increasing the free thyroxine, a euthyroid hyperthyroid effect.  However, much work by Prof. Inglenbleek, some ion collaboration with Vernon Young, at MIT, showed that transthyretin reflects the sulfur stores of animals.  The sulfur to nitrogen ratio of plants is 1:20, but it is 1:12 in man, so the dietary intake would affect an omnivorous animal.  Recall that S is carried on amino acids that take part in disulfide linkage.  A deficiency in S containing amino acids would have a negative health effect.  The story is presented here.

The World Health Organization (WHO) reports that 16.7 million deaths occur worldwide each year due to cardiovascular disease, and more than half of those deaths occur in developing countries where plant-based diets high in legumes and starches are eaten by the vast majority of the people.

Yet “everyone knows” plant-based diets prevent heart disease.  Indeed this myth  is repeated so often that massive numbers of educated, health-conscious individuals in first world countries are consciously adopting third world style diets in the hope of preventing disease, optimizing health and maximizing longevity.   But if the WHO statistics are correct, plant-based diets might not be protective at all.   And today’s fashionable experiment in veganism could end very badly indeed.

A study out August 26 in the journal Nutrition makes a strong case against plant-based diets for prevention of heart disease.  The title alone  –  “Vegetarianism produces subclinical malnutrition, hyperhomocysteinemia and atherogenesis” — sounds a significant warning.   The article establishes  why subjects who eat mostly vegetarian diets develop morbidity and mortality from cardiovascular disease unrelated to vitamin B status and Framingham criteria.

Co-author Kilmer S. McCully, MD, “Father of the Homocysteine Theory of Heart Disease,” is familiar to WAPF members as winner of the Linus Pauling Award, WAPF’s Integrity in Science Award, and author of numerous articles published in peer-reviewed journals as well as the popular books The Homocysteine Revolution and The Heart Revolution.   In 2009 Dr. McCully was one of the signers of the Weston A. Price Foundation’s petition to the FDA in which we asked the agency to retract its unwarranted 1999 soy/heart disease health claim.  (http://www.westonaprice.org/soy-alert/soy-heart-health-claim)

Dr. McCully teamed up with Yves Ingenbleek, MD, of the University Louis Pasteur in Strasbourg, France, which funded the research.   Dr. Ingenbleek is well known for his work on malnutrition, the essential role of sulfur to nitrogen, and sulfur deficiency as a cause of  hyperhomocysteinemia.

The study took place in Chad, and involved 24 rural male subjects age 18 to 30, and 15 urban male controls, age 18-29.   (Women in this region of Chad could not be studied because of their animistic beliefs and proscriptions against collecting their urine.)

The rural men were apparently healthy, physically active farmers with good lipid profiles.  Their staple foods included cassava, sweet potatoes, beans, millet and ground nuts.   Cassava leaves, cabbages and carrots provided good levels of carotenes, folates and pyridoxine (B6).  The diet is plant-based there because of a shortage of grazing lands and livestock, but subjects occasionally consume  some B12-containing foods, mostly poultry and eggs, though very little dairy or meat.   Their diet could be described as high carb, high fiber,  low in both protein and fat, and low in the sulfur containing amino acids.    In brief, the very diet recommended by many of today’s nutritional “experts” for overall good health and heart disease prevention.

The urban controls were likewise healthy and ate a similar diet, but with beef, smoked fish and canned or powdered milk regularly on the menus.  Their diet was thus higher in protein, fat and the sulfur-containing amino acids though roughly equivalent in calories.

Dr. McCully’s research over the past 40 years on the pathogenesis of atherosclerosis has shown the role of homocysteine in free radical damage and the protective effect of  vitamins B6, B12 and folate.   Indeed, many doctors today recommend taking this trio of B vitamins as an inexpensive heart disease “insurance policy.”

In Chad, both groups showed adequate levels of B6 and folate.  The B12 levels of the vegetarian group were lower, but the difference was only of “borderline significance.”   However, as the researchers point out, ”A previous study undertaken in the same Chadian area in a larger group of 60 rural participants did demonstrate a weak inverse correlation between B12 and homocysteine concentrations in the 20 subjects most severely protein depleted .  .  .  It is therefore likely that the hyperhomocysteinemia status of some of our rural subjects in the present survey might have resulted from combined B12 and protein deficiencies.   The correlation of B12 deficiency with hyperhomocysteinemia could well reach statistical significance if a larger groups of subjects were studied.”

Clearly it’s wise for people on plant-based diets to supplement their diets with B12, but protein malnutrition must also be addressed.   And the issue is not just getting enough protein to eat, but the right kind.   Quality, not just quantity.   The bottom line is we must eat  protein rich in bioavailable, sulfur-containing amino acids — and that means animal products.   (Vegans at this point will surely claim the issue is insufficient protein and trot out soy as the solution.   Soy is indeed a  complete plant based protein, but notoriously low in methionine.  It does contain decent levels of cysteine, but the cysteine is bound up in protease inhibitors, making it largely  biounavailable. (For more information, read  my book The Whole Soy Story: The Dark Side of America’s Favorite Health Food, endorsed by Dr. McCully, as well as our petition to the FDA noted above.)

So what did  Drs. Ingenbleek and  McCully find among the study group of protein-deficient people?   Higher levels of homocysteine, of course.  Also significant alterations in body composition,  lean body mass, body mass index and plasma transthyretin levels.  In plain English, the near-vegetarian subjects were thinner, with poorer muscle tone and showed subclinical signs of protein malnutrition.   (So much for popular ideas of extreme thinness being healthy. )

The plant-based diet of the study group was low in all of the sulfur-containing amino acids.   As would be expected, labwork on these men showed lower plasma cysteine and glutathione levels compared to the controls.  Methionine levels, however,  tested comparably.   The explanation for this is  “adaptive response.”   In brief, mammals trying to function with insufficient sulfur-containing amino acids will do whatever’s necessary to survive.   Given the essential role of methionine in metabolic processes, that means deregulating the transsulfuration pathway, increasing homocysteine levels, and methylating homocysteine to make methionine.

Ultimately, it all boils down to our need for sulfur.   As Stephanie Seneff, PhD, and many others have written in Wise Traditions and on this website, sulfur is vital for disease prevention and maintenance of good health.   In terms of heart disease, Drs. Ingenbleek and McCully have shown sulfur deficiency not only leads to high homocysteine levels, but is the likeliest reason some clinical trials using B6, B12 and folate interventions have proved ineffective for the prevention of cardiovascular and cerebrovascular diseases.    Over the past few years, headlines from such studies have led to widespread dismissal of Dr. McCully’s  “Homocysteine Theory of Heart Disease” and renewed media focus on cholesterol, c-reactive protein and other possible culprits that can be treated by statins and other profitable drugs.   In contrast, Drs. McCully and Ingenbleek research suggests we can better prevent heart disease with three inexpensive B vitamins and traditional diets rich in the sulfur-containing amino acids found in animal foods.

In the blaze of publicity surrounding Forks Over Knives and other blasts of vegan propaganda, few people are likely to hear about this study.   That’s sad, for it provides an important missing piece in our knowledge of heart disease development, a strong argument against the plant-based fad, and a bright new chapter in what the New York Times has called “The Fall and Rise of Kilmer McCully.”

*  *  *  *  *

Thanks to Sylvia Onusic PhD who was able to access a full text copy of this article to share with  me.

This entry was posted in WAPF Blog and tagged B12, Forks over Knives, Kaayla T. Daniel, Kilmer S. McCully, Naughty Nutritionist, soy, sulfur, Yves Ingenbleek. Bookmark the permalink.

Sylvia says:

September 26, 2011 at 5:32 pm

Kaayla, I found the article but you brought it to life- what a great explanation backed by high levels of knowledge and analysis. We are grateful for your numerous contributions to the field of health!
Thanks so much.

Sylvia Onusic

 

 

Posted in Atherogenic Processes & Pathology, Cardiovascular Research, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Frontiers in Cardiology and Cardiovascular Disorders, Metabolomics, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nutrition, Origins of Cardiovascular Disease | Tagged , , , , , , , , | Leave a Comment »

CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

November 15, 2013 by 2012pharmaceutical

CT Angiography & TrueVision™ Metabolomics (Genomic Phenotyping) for new Therapeutic Targets to Atherosclerosis

Reporter: Aviva Lev-Ari, PhD, RN

Global Genomics Group (G3) and Metabolon today announced that they have entered into a collaboration agreement to investigate biological networks and pathways in order to discover novel biomarkers and pharmaceutical targets for cardiovascular diseases. Under the terms of the agreement, Metabolon will analyze the biochemicals for the GLOBAL (Genetic LOci and Burden of Atherosclerotic Lesions) study. GLOBAL is the largest pan-omic study combining genomics, epigenomics, transcriptomics,proteomics, metabolomics, lipidomics and lipoprotein proteomics with coronary computed tomographic (CT) angiography, an advanced imaging technology for phenotyping, which allows the precise disease classification in patients.

“Metabolon will employ its metabolomics platform and targeted assays to provide the most comprehensive assessment of the metabolism to complement the other ‘omic’ approaches used in this study,” said Szilard Voros, M.D., chief executive officer and co-founder of G3. “We expect to analyze 22 trillion data points from the CT phenotyping and the complete pan-omic analysis to decode the complex biology underlying atherosclerotic disease to identify new drug targets and biomarkers. The study will enroll 7,500 patients in Phase I, may be extended to 10,000 patients in Phase II and has already enrolled over 3,000 patients and is well ahead of schedule.”

Metabolon will utilize its TrueVision™ metabolomics offering, comprised of analytical chemistry (utilizing mass-spectroscopy), informatics and biological expertise, to measure and interpret the concentrations of relevant biochemicals and metabolites. Metabolomics can provide a complete picture of metabolism, including complex lipid metabolism, which is thought to play an important role in the development ofcardiovascular disease. Metabolon’s platform has lead to major advancements in disease research and biomarker discovery and is capable of surveying biological samples for over 4000 known metabolites contained in its chemical library.

John Ryals, president and CEO of Metabolon, Inc., added, “We are happy to participate in such an important study. We anticipate the results to be highly impactful.”

The ongoing GLOBAL study (ClincialTrials.gov Identifier NCT01738828) is an international, prospective, multi-center study recruiting up to 10,000 patients to characterize novel disease networks and biomarkers for coronary artery disease(CAD). The study is being funded by G3 and conducted together with strategic partner, Health Diagnostic Laboratory. Eligible patients undergo coronary CT angiographyproviding an accurate and detailed examination of the disease and disease status. This precision phenotyping is combined with a pan-omic analysis, and the data is then analyzed utilizing specifically-developed systems biology-based bioinformatics technology for identification of diagnostic biomarkers and potential therapeutic targets.

SOURCE Global Genomics Group (G3)

SOURCE

 

Posted in Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Metabolomics, Molecular Genetics & Pharmaceutical, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Population Health Management, Genetics & Pharmaceutical, Proteomics, Technology Transfer: Biotech and Pharmaceutical | Tagged , | Leave a Comment »

Protected: MRI Methods and Devices: Range of Potential Applications

November 15, 2013 by 2012pharmaceutical

This content is password-protected. To view it, please enter the password below.

Posted in Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound | Tagged , , , , |

A new take on efficient delivery in regenerative medicine

November 15, 2013 by larryhbern

Posted in Uncategorized | Leave a Comment »

Stem cell treatment may become option to treat nonhealing bone fractures

November 15, 2013 by larryhbern

Posted in Uncategorized | Leave a Comment »

Humacyte, Inc., presented the Results of Foundational U.S. Preclinical Studies of its Investigational Bioengineered blood vessel at the American Society of Nephrology’s ‘Kidney Week 2013’ Annual Meeting in Atlanta, GA.

November 13, 2013 by 2012pharmaceutical

Humacyte, Inc., a pioneer in regenerative medicine, presented the results of foundational U.S. preclinical studies of its investigational bioengineered blood vessel at the American Society of Nephrology’s ‘Kidney Week 2013’ Annual Meeting in Atlanta, GA.

Reporter: Aviva Lev-Ari, PhD, RN

HUMACYTE

Media Contacts:

Gail Thornton

West Mill Consulting

908-392-3420

Gail@westmillconsulting.com

Jim Modica

West Mill Consulting

908-872-4919

Jim@westmillconsulting.com

Humacyte Highlights Preclinical Data

Of Its Investigational Bioengineered Blood Vessel

 

  • Humacyte investigational bioengineered blood vessel technology represents a research and development milestone in the field of vascular tissue engineering.
  • Preclinical data on the investigational bioengineered blood vessel were presented at the American Society for Nephrology ‘Kidney Week’ meeting.
  • The pre-clinical data suggest that the Humacyte technology may have the potential to be associated with lowered vessel clotting and incorporation with animal model tissues.

RESEARCH TRIANGLE PARK, N.C., November 13, 2013 –Humacyte, Inc., a pioneer in regenerative medicine, presented the results of foundational U.S. preclinical studies of its investigational bioengineered blood vessel at the American Society of Nephrology’s ‘Kidney Week 2013’ Annual Meeting in Atlanta, GA.

The scientific presentation – by Shannon L. M. Dahl, Ph.D., co-founder and vice president, Technology and Pipeline Development, Humacyte – summarized U.S. preclinical data of the company’s investigational bioengineered vessel technology, which is being developed for use as the first off-the-shelf, human-derived, artificial blood vessel. The presentation’s title was ‘Preclinical Dataset Supports Initiation of Clinical Studies for Bioengineered Vascular Access Grafts.’ Co-authors were: Jeffrey H. Lawson, M.D., Ph.D.; Heather L. Prichard, Ph.D.; Roberto J. Manson, M.D.; William E.Tente, M.S.; Alan P. Kypson, M.D.; Juliana L. Blum, Ph.D.; and Laura E. Niklason, M.D., Ph.D.

Potential Of Investigational Bioengineered Vessels Explored In Pre-Clinical Studies

These U.S. preclinical data suggest that the investigational bioengineered vessel may be associated with lowered vessel clotting and incorporation with animal model tissues. This investigational technology is being developed with the goal of pursuing approval for use in patients with chronic kidney disease, a major global health problem affecting 26 million Americans[i] and around 40 million people in the European Union (EU).[ii] Individuals who progress to end-stage renal disease (ESRD) require renal replacement therapy (hemodialysis or kidney transplant); more than 380,000 patients currently require hemodialysis in the U.S.,[iii] and some 250,000 patients require hemodialysis or have had kidney transplants in the EU.[iv]

In ESRD patients, synthetic vascular grafts are prone to wall thickening, which results in graft clotting. Such clotting is the major cause of graft failures. As a result, ESRD patients experience frequent hospitalization and re-operation. The investigational bioengineered vessels, if successfully developed and approved by regulatory authorities, could offer the potential for significant cost savings to the healthcare system if approved for use in patients who require vascular access for ESRD. These investigational bioengineered vessels represent a research and development milestone in the field of vascular tissue engineering, as this technology could have the potential to help reduce or avoid surgical interventions and hospitalizations for patients with ESRD.

First Off-the-Shelf Investigational Bioengineered Vessel In Clinical Studies

“In the preclinical studies described, our investigational bioengineered vessels were repopulated with cells and remodeled like living tissue in the animal model,” said Dr. Dahl. “These investigational bioengineered vessels are produced using donated human vascular cells and then go through a process that is intended to decellularize the investigational vessels to remove the donor identity from the newly created vessels. This process is designed to produce investigational human grafts with the potential to be implanted into any patient at the time of medical need, enabling our investigational product to become the first truly off-the-shelf engineered graft to have moved into clinical evaluation. Demonstrating safety and performance in patients with end-stage renal disease could set the stage for follow-on development of our technology in other vascular procedures, such as replacement or bypass of diseased vessels, of vessels damaged by trauma, or for other vascular procedures.”

In 2012, Humacyte submitted an Investigational New Drug (IND) application to the U.S. Food and Drug Administration to conduct a multi-center U.S. clinical trial, involving up to 20 patients across three sites. In this trial, which will assess safety and performance of the investigational bioengineered vessels to provide vascular access for hemodialysis in ESRD patients, the first investigational bioengineered vessel was implanted in the arm of a kidney dialysis patient at Duke University Hospital in June, 2013.

European studies are already underway; as part of a multi-center study in Poland, the first patients were implanted with the investigational vessels in December 2012 and the vessels were first used for hemodialysis in February 2013. The primary endpoints of the study in Poland are safety, tolerability, and patency, to be examined at each visit within the first six months after graft implantation (see clinicaltrials.gov).

Studies Planned in Additional Patient Populations

Humacyte also will carry out a study in Poland to test safety and performance of the investigational bioengineered vessel as an above-knee bypass graft in patients with peripheral arterial disease (PAD). The study began in October of this year.

First-in-human interim study results for the investigational bioengineered vessel technology from Humacyte will be presented on Wednesday, November 20, 2013, at the American Heart Association Scientific Sessions (abstract) in Dallas, TX.

About Investigational Bioengineered Blood Vessels

The Humacyte investigational bioengineered blood vessels are manufactured in a novel bioreactor system. The investigational bioengineered vessels go through a process of decellularization, which is designed to render vessels potentially non-immunogenic and implantable into any patient. These investigational bioengineered vessels are designed to be stored for up to 12 months under standard refrigerated conditions, including, if successfully developed and approved, on-site in hospitals. Subject to receipt of regulatory approval, these properties could make the investigational bioengineered vessels readily available to surgeons and patients, and could eliminate the wait for vessel production or shipping. Data from studies of the investigational bioengineered vessels in large animal models reflect resistance to thickening for up to one year, and the early human studies that are now underway will provide safety and performance  data in patients to support a future application for regulatory approval.

About Humacyte

Humacyte, Inc., a privately held company founded in 2005, is a medical research, discovery and development company with clinical and pre-clinical stage investigational products. Humacyte is primarily focused on developing and commercializing a proprietary novel technology based on human tissue-based products for key applications in regenerative medicine and vascular surgery.  The company uses its innovative and proprietary platform technology to engineer human, extracellular matrix-based tissues that are designed be shaped into tubes, sheets, or particulate conformations, with properties similar to native tissues. These are being developed for potential use in many specific applications, with the goal to significantly improve treatment outcomes for a variety of patients, including those with vascular disease and those requiring hemodialysis. The company’s proprietary technologies are designed to result in off-the-shelf products that, once approved, can be utilized in any patient. The company web site is www.humacyte.com.

Forward-Looking Statement

Information in this news release contains “forward-looking statements” about Humacyte. These statements, including statements regarding management’s projections relating to future results and operations, are based on, among other things, management’s views, assumptions and estimates, developed in good faith, all of which are subject to known and unknown factors that may cause actual results, performance or achievements, or industry results, to differ materially from those expressed or implied by such forward-looking statements.

# # #

[iv]http://www.ekha.eu/usr_img/info/factsheet.pdf

SOURCE

From: Gail Thornton <gail@westmillconsulting.com>
Reply-To: Gail Thornton <gail@westmillconsulting.com>
Date: Wed, 13 Nov 2013 16:47:00 -0800 (PST)
To: Aviva Lev-Ari <AvivaLev-Ari@alum.berkeley.edu>
Subject: American Society of Nephrology Kidney Week – Humacyte Press Release

 

Posted in FDA Regulatory Affairs, Nephrology & Regenerative medicine | Tagged , , , , , | Leave a Comment »

Healing the Heart

November 13, 2013 by larryhbern

Posted in Uncategorized | Leave a Comment »

« Newer Posts - Older Posts »