Published online December 9 in Nature Genetics, the findings describe the GNAL gene, the first primary torsion dystonia gene that directly points to signal transduction pathways in the dopamine system as the origin of pathophysiology. Genetic testing in volunteers from two dystonia families revealed mutations in GNAL. Further screening of 39 additional families identified another six mutations in this gene. This discovery will help development of genetic tests to confirm diagnosis, identify unaffected adult carriers, and provide greater reproductive health options for affected families. The research also unveils a new potential therapeutic target and thus an opportunity for developing new treatments.
“The technique used for the identification of the GNAL gene-called exome sequencing-is a powerful and efficient tool that will accelerate the pace of dystonia gene discovery and, consequently, our understanding of the pathways involved in primary torsion dystonia.” says Laurie Ozelius, PhD, of Mount Sinai School of Medicine, who led the research team. “Any new gene offers the potential to develop new therapeutics, but because GNAL belongs to a well-studied pathway, other components in this pathway may also be targets for drug development” adds Tania Fuchs, PhD, Instructor in the Department of Genetics and Genomic Sciences of Mount Sinai School of Medicine, who is first author of the paper.
Jan Teller, MA, PhD, Science Officer of the DMRF says, “Every time researchers identify a gene, another piece of the puzzle falls into place to clarify our understanding of dystonia. The protein associated with the GNAL gene may hold important clues about how dystonia originates in the brain and potential new strategies for treatment. ”
Primary torsion dystonia is a movement disorder characterized by repetitive twisting muscle contractions and postures that can affect the face, neck, arms, legs, or torso. Common symptoms include tremors, voice problems, or a dragging foot. Primary torsion dystonia may be adult onset or childhood onset. Symptoms can be focal, segmental or generalized. The disorder is dominantly inherited with reduced penetrance, making it difficult to predict which family members may at risk without genetic screening. Three additional genes associated with primary torsion dystonia have been identified: DYT1, THAP1, and CIZI.
Visit The Dystonia Foundation to learn more about their research efforts.
One review of four trials that comprised nearly 9000 participants looked at how well antihypertensive drugs prevent cardiovascular events and death in people with mild hypertension, defined as systolic blood pressure of 140–159 mm Hg or diastolic pressure 90–99 mm Hg (or both). All participants were free of cardiovascular disease at baseline.
No effects were seen over four to five years, compared with placebo, for overall mortality (relative risk 0.85, 95% CI 0.63 to 1.15), coronary heart disease (1.12, 0.80 to 1.57), stroke (0.51, 0.24 to 1.08), or total cardiovascular events (0.97, 0.72 to 1.32). One in 10 people stopped taking antihypertensives because of adverse effects, a fivefold increase over placebo. The review did not report effects of drugs on blood pressure, if any. Another review found two small trials that compared garlic powder with placebo in people with mild hypertension. Garlic might help reduce blood pressure—possibly by about 10 mm Hg for systolic blood pressure and a little less for diastolic blood pressure. However, the confidence intervals were wide, and no data were available on which to assess the potency of garlic to prevent cardiovascular events. Cocoa is rich in flavanols, which cause blood vessel dilatation and are thought to reduce blood pressure. Most of the 20 trials (about 850 participants) tested a daily dose of 500–750 mg of flavanols ingested through chocolate or cocoa products. Most participants were healthy and normotensive at baseline, and most trials lasted only about a month.
Small reductions in blood pressure were seen with cocoa, compared with placebo: −2.77 (−4.72 to −0.82) mm Hg for systolic pressure and −2.20 (−3.46 to −0.93) mm Hg for diastolic blood pressure. One in 20 people allocated cocoa had adverse effects, compared with one in 100 of those receiving placebo. Gastrointestinal effects and a dislike of the product’s taste were the most common problems.
Information sourced from BMJ:
ProteoTech, Inc., a privately held biotechnology company, has entered into a drug development agreement with GlaxoSmithKline R&D Company Limited to collaborate on ProteoTech’s small molecule technology platform against misfolded proteins to specifically advance work on its alpha-synuclein therapeutic program for the treatment of Parkinson’s disease and other synucleinopathies.
Steve Runnels, CEO of ProteoTech, stated “We are pleased to be working with GlaxoSmithKline on the identification and optimization of new therapeutic compounds for Parkinson’s and other synucleinopathies, such as Lewy Body Dementia and Multiple System Atrophy. We are excited to be working with this leading pharmaceutical company on this important project which further validates ProteoTech’s small molecule approach for developing therapies against diseases caused by misfolded proteins.”
Initial support for ProteoTech’s alpha-synuclein therapeutic research program was funded over a four- year period by the Michael J. Fox Foundation for Parkinson’s Research (MJFF). Todd Sherer, PhD, the Chief Executive Officer of the MJFF commented, “We have followed ProteoTech’s success on this therapeutic development program over the years and are extremely pleased to see this collaboration between them and GlaxoSmithKline to accelerate the development of a potential disease modifying treatment for this debilitating disease. This is what we all hoped to see when ProteoTech was initially granted the LEAPS award from our Foundation.”
About ProteoTech: ProteoTech is a private drug development company located in the Seattle, WA area (Kirkland, WA), and is focused on targeting amyloid diseases caused by protein misfolding. Besides the Company’s SynuclereTM program, in late pre-clinical development for the treatment of Parkinson’s disease, ProteoTech is developing Exebryl–1® for the treatment of diseases caused by beta-amyloid protein and tau protein aggregates and fibrils; and is in early human clinical studies with SystebrylTM for the treatment of Systemic AA Amyloidosis. The Company is also in late pre-clinical development for a novel small peptide (PepticlereTM) for the treatment of Alzheimer’s disease beta-amyloid protein aggregates. For more information please see the Company web site at Proteotech.com.
There has been a stream of new information on vitamin D and how it affects the body. New evidence suggests that minimum recommended intake is 2000 IU/day. The bigger you are the more you have to take. You can safely take no more than 10,000 IU/week. Your physician will prescribe 50,000 IU/Week which is a standard dose. Vitamin D in the body is not well understood and is known to be involved in the cell cycle and other cellular functions. Vitamin D deficiency increases the risk of Parkinson’s Disease and may be involved in many other diseases such as multiple sclerosis and cancer. The blood level on the lab form will say that the vitamin D low-normal level is 30 but newer scientific evidence suggests the number should be 40. Vitamin D levels should be monitored to ensure it does not increase past 100 but rather 40–75.
Overview of the latest vitamin D science
Vitamin D deficiency-related diseases and complications have been rising over the past decade. Physicians have been testing their patients' blood to monitor their vitamin levels and have been prescribing large doses of vitamins. Despite many physicians recommending their patients take vitamins, the effectiveness of popular dosages have been called into question with the latest scientific evidence. Many medical institutions and recommending children and adults triple their daily intake of Vitamin D, but a controversy lingers.
A quick glance and the medical literature shows that there are a wide range of opinions regarding how much Vitamin D one should take in order to stay healthy. Vitamin D has a pivotal role in maintaining the immune and skeletal system. Many of the scientific studies researching vitamin D have been conducted with rodents since human studies are difficult and expensive. Most of our knowledge of vitamin D was provided by epidemiological data.
Despite all the studying of vitamin D, we are still not sure what the optimal amount is for humans. Many factors determine which is the ideal amount for someone: body size, latitude, time spent outside, age, state of health, plasma levels, and more. Since there hasn’t been enough research on vitamin D levels in humans, most estimates are educated guesses or opinions. Generally, we can infer that city dwellers don’t get enough vitamin D levels since they aren’t outside much, nor do they consume enough dairy products, generally.
Some of the recent, popular, and well-researched scientific papers favor an increased vitamin D supplementation. The papers found that an intake of 40–60 ng/ml (100–150 nM) of vitamin D a day could reduce cancer risks. Taking this much vitamin D is only recommended for those with healthy diets and lifestyles, due to the possibility of vitamin D toxicity. A prominent proponent of increasing vitamin D intake is Dr. Michael Holick, an endocrinologist at Boston University Medical Center. Here is an excerpt of Dr. Michael Holick’s opinions:
“Vitamin D deficiency and insufficiency have been defined as a 25-hydroxyvitamin D 20 ng/ml and 21-29 ng/ml respectively. For every 100 IU of vitamin D ingested the blood level of 25-hydroxyvitamin D, the measure vitamin D status, increases by 1 ng/ml. It is estimated that children need at least 400-1000 IU of vitamin D a day while teenagers and adults need at least 2000 IU of vitamin D a day to satisfy their body's vitamin D requirement.“
Endocrinology Clinics of North America recently published many thorough articles by researchers who study specific the aspects of vitamin D metabolism in action. In general, these authors recommend “maintenance of plasma levels of 25-OH-D ≥ 30 ng/mL, requiring a daily intake of ≥1000 IU for most children and adults, and twice that for pregnant and lactating women.” These recommendations of the Institute of Medicine advise higher overall daily intake than previously indicated for both calcium and vitamin D.
Summary of IOM findings
This scientific research found compelling evidence in favor of the role for calcium and vitamin D in promoting skeletal health. A vitamin D overdose requires excess of 4,0000 UIs per day while a calcium overdose requires over 2,000 milligrams per day. Side effects of an overdose include hypercalcemia and hypercalciuria.
The studies found that vitamin D supplementation can help prevent bone fractures, but the IOM investigation failed to find evidence indicating a significant reduction in risk of falls that are directly related to vitamin D intake. Surprisingly, the role of supplemental calcium in supporting skeletal strength is still controversial.
Gender, age, diet, and overall health change the requirements for calcium and Vitamin D intake. Dairy products such as milk, yogurt, cheese, and juices fortified with calcium and vitamin D remain the best (food) sources of calcium and vitamin D. A cup serving of most dairy products contains 200–300 mg of calcium. Vitamin D can easily be acquired by being in the sun as well.
riedman, PA and Brunton LL. Updated Vitamin D and Calcium Recommendations. Goodman and Gilman’s Online, March 1, 2011. http://www.accessmedicine.comRelated to Chapter 61 Agents Affecting Mineral Ion Homeostasis and Bone Turnover, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th edition, Laurence L. Brunton, John S. Lazo, and Keith L. Parker, Eds. McGraw-Hill, New York, 2006.
An BS, Tavera-Mendoza LE, Dimitrov V, et al. Stimulation of Sirt1-regulated FoxO protein function by the ligand-bound vitamin D receptor. Mol Cell Biol 2010;30:4890–4900. [PubMed abstract]Bikle DD. Vitamin D: newly discovered actions require reconsideration of physiologic requirements. Trends Endocrinol Metab 2010;21:375–384. [PubMed abstract]Cauley JA, Lacroix AZ, Wu L, et al. Serum 25-hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008; 149:242–250. [PubMed abstract]Chung M, Balk EM, Brendel M, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep) 2009:1–420. [PubMed abstract]Cranney A, Horsley T, O’Donnell S, et al. Effectiveness and safety of vitamin D in relation to bone health. Evid Rep Technol Assess (Full Rep) 2007:1–235. [PubMed abstract]Cranney A, Weiler HA, O’Donnell S, et al. Summary of evidence-based review on vitamin D efficacy and safety in relation to bone health. Am J Clin Nutr 2008;88:513S–519S. [PubMed abstract]Egan, JB, Thompson PA, Vitanov MV, et al. Vitamin D receptor ligands, adenomatous polyposis coli, and the vitamin D receptor FokI polymorphism collectively modulate beta-catenin activity in colon cancer cells. Mol Carcinog 2010;49:337–352. [PubMed abstract]Garland CF, Gorham ED, Mohr SB, et al. Vitamin D for cancer prevention: global perspective. Ann Epidemiol 2009;19:468–483. [PubMed abstract]Higdon J, Drake VJ. Vitamin D. Linus Pauling Institute. 2010. http://lpi.oregonstate.edu/infocenter/vitamins/vitaminD/.
Holick MF. The vitamin D solution: a 3-step strategy to cure our most common health problem. New York: Hudson Street Press; 2010, p. 336.
Holick MF. Vitamin D: evolutionary, physiological and health perspectives. Curr Drug Targets 2011;12:4–18. [PubMed abstract]Hollis BW. Vitamin D requirement during pregnancy and lactation. J Bone Miner Res 2007;22 Suppl 2:V39–44. [PubMed abstract]Institute of Medicine. Dietary reference intakes for calcium and vitamin D. Washington, DC: The National Academies Press; 2011, p. 1015. Full Report: http://books.nap.edu/openbook.php?record_id=13050. Brief
Report: http://www.iom.edu/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D/Report-Brief.aspx. Lanham-New SA, Buttriss JL, Miles LM, et al. Proceedings of the Rank Forum on Vitamin D. Br J Nutr 2011;105(1):144–56. Epub 2010 Dec 7. [PubMed abstract]Multiple Authors. Vitamin D. Endocrinol Metab Clin North Am 2010;39:243–479.
Vieth R. Vitamin D and cancer mini-symposium: the risk of additional vitamin D. Ann Epidemiol 2009;19:441–445. [PubMed abstract]Copyright © The McGraw-Hill Companies. All rights reserved.
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