Tuesday, November 29, 2011

Advances in FSHD Research

New advances in FSHD research | The Leaders in FSHD research Today!

On November 7 and 8, eighty scientists met in Boston, Massachusetts, to share the latest results from their research on facioscapulohumeral muscular dystrophy (FSHD). This conference is hosted annually by the American FSH Society. Andreas Leidenroth, a Muscular Dystrophy Campaign-funded PhD student researching FSHD in Nottingham, attended the conference and here he reports on two important highlights presented at the meeting.

The highlights mentioned by this researcher are those achieved by researchers Friends of FSH Research has worked closely with since 2006!
Read this report - Dr. Tapscott and the Seattle FSH Research group has worked in collaboration with the researchers in Leiden for many years.
Friends of FSH Research has held an annual FSH workshop bringing these groups together & urging strong collaborative efforts in order to speed up the progress of FSH research.

Make a donation to Friends of FSH Research Today!
It DOES make a difference.

Friday, November 25, 2011

Meeting with Bill Moss

Video Discussion with Bill Moss

Here is a personal look at Bill Moss - in his own words.
Mr. Moss has become a leader for those with FSH Muscular Dystrophy - putting his influence to help move this research forward worldwide.

Thursday, November 17, 2011

Grants & Gala - Support FSH Research

Posted by PicasaThank You!!  (click here to see November news)

Your past support has been critical to the stimulation of new interest in Facioscapulohumeral (FSH) research.  You have helped to attract research scientists and to fund novel FSH projects that have expanded the world's understanding of the mechanisms at work in this form of Muscular Dystrophy.  

Our 8th annual charity gala is dedicated to YOU, our community.
The dinner and auction will be held at the Bellevue Hyatt on January 28th.  The theme of this year's gala, "With a Little Help from Our Friends," honors our community and its generous support.
We invite you to join with us as we celebrate our successes and your partnership.  

Progress has been made!   We will need your continued support to achieve our next goal, the development of an effective therapy for FSH Muscular Dystrophy.

Tuesday, November 8, 2011

FSHD Europe: The European voice of people with FSHD

FSHD Europe: The European voice of people with FSHD

The European FSHD advocacy groups have joined together - here is their newly developed website.
We are pleased that the video Friends of FSH Research produced is presented on their learning about FSHD page.

Working together we will find a treatment or cure for FSHD.

Saturday, November 5, 2011

PLOS Research Report - FSHD

Scientific Publications Explained

Title: The FSHD Atrophic Myotube Phenotype Is Caused by DUX4 Expression

Authors: Vanderplanck C, Ansseau E, Charron S, Stricwant N, Tassin A, Laoudj-Chenivesse D, Wilton SD, Coppée F, Belayew A.

Publication date and journal: 28 Oct 2011 in PLos One

This work was done by the group of Alexandra Belayew in Mons, Belgium, in collaboration with Dalila Laoudj-Chenivesse from Montpellier, France, and Professor Steve D. Wilton from Perth, Australia, who does much work with exon skipping in Duchenne. Muscle cells of healthy individuals cultured in the laboratory in which DUX4 was introduced were much thinner (atrophic) than muscle cells without active DUX4. (Such thin muscle cells are seen in FSHD.) A number of genes characteristic for the diseased muscle were also found to be activated (Atrogin1, MuRF1, CRYM and TP53). These genes may be used to measure the effect of drugs.

Next, the researcher developed siRNA molecules against DUX4 (these are molecules that cause degradation of the DUX4 messenger RNA so no more DUX4 protein is made). Muscle cells cultured in the laboratory with active DUX4 which were treated with this anti-DUX4 siRNA were less thin 8 days after treatment than untreated muscle cells. They made less DUX4 and TP53 proteins. Antisense Oligonucleotides (AOs) were then developed against DUX4. This is a different kind of anti-molecule which is used for exon skipping in Duchenne. Muscle cells from people with FSHD cultured in the laboratory and treated with a low concentration of anti-DUX4 AOs had less DUX4 and TP53, without much effect on DUX4c, a gene similar to DUX4 which probably has an important function in the human body.

The group of Alexandra Belayew and other research groups worldwide are now working on developing DUX4 mouse models to test whether these anti-DUX4 molecules can slow, stop or hopefully even improve the health of diseased animals.

Click on "PLOS ONE" to read complete study report

Friday, November 4, 2011

Thank You for Being a Friend

After tough voting in a facebook contest, our charity Friends of FSH Research won $5,000 from the Toyota of Kirkland dealership. Thanks to all the voters that took the time to “like” our charity, we were the top vote getters and the winners of this grant from Toyota.
Our charity auction’s theme this year is “With a Little Help from Our Friends.” Though it might be a song with some questionable references, for us it is a song that celebrates friends. It has taken the support of many friends to push our mission forward toward finding a treatment or cure for FSH Muscular Dystrophy. And now, our circle of friends just got bigger – thank you Toyota of Kirkland for being a friend!

Wednesday, October 19, 2011

Good Search for FSH Research

GoodSearch: You Search...We Give!

This is going to be the easiest thing we’ve ever asked you to do!
We just signed up with GoodSearch.com and now every time you shop online or search the internet, a donation will be made to Friends of FSH Research.
Here’s how:
GoodShop.com works with more than 2,500 stores (including Target, Apple, Petsmart etc..) and every time you purchase something, a percentage will be donated to us! And, even more exciting, GoodShop also offers over 100,000 of the most up-to-date coupons and free shipping offers so you can save money at the same time. It’s win win.
GoodSearch is a Yahoo powered search engine which makes a donation to us each time you do a search.

“Become a Supporter” button
Join the rest of our community in using these sites to help us easily raise money for our mission. Get started by clicking the  Good Search information 
on our website!

Monday, October 10, 2011

Whooping Cough - Risk to the Vulnerable

Whooping Cough (or Pertusis) is on the rise. As vaccines seem to lose effectiveness over time, adults need Pertusis booster every 10 years. Whooping Cough, also known as the 100 day cough, may not have serious consequences for healthy people but this condition can be life threatening for infants or vulnerable individuals. Get immunized!!
The Washington state Health Department says 431 cases have been reported so far this year, compared with 378 at this time last year.

Saturday, August 27, 2011

Collaborating Research Teams - Progress toward FSH Treatment

Two research teams make steps towards a treatment for FSH

Two research papers published in the past month by researchers in Italy and the US have shown that it is possible to reverse the symptoms of facioscapulohumeral muscular dystrophy (FSH) in a mouse model using a gene therapy approach. The techniques used may also be applicable to other dominantly inherited muscle conditions such as myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), Charcot-Marie-Tooth disease and some types of limb girdle muscular dystrophy, congenital muscular dystrophy and congenital myopathy.


Who are the Researchers?  
Joel Chamberlain PhD at the Division of Medical Genetics, University of Washington, Seattle, Washington and Davide Gabilini at the Division of Regenerative Medicine, Milan, Italy.

Original publication:  
AAV6-mediated Systemic shRNA Delivery Reverses Disease in a Mouse Model of Facioscapulohumeral Muscular Dystrophy

Background information

FSH is caused by changes to a region of DNA on chromosome 4 called D4Z4 that has the same piece of DNA code repeated many times. In healthy individuals the number of repeats varies between 11 and 100. People with FSH have less than 11 repeats.  Until recently scientists have struggled to understand how this caused the symptoms of the condition.
Recent research demonstrated that the repeated section of DNA contains a gene called DUX4 and the reduction in the number of repeats on D4Z4 changes the way this piece of DNA is folded. This results in the DUX4 gene being switched on and the DUX4 protein being produced which is toxic to the muscle. 
Although this is currently the most widely accepted theory about the underlying mechanism causing FSH, previous research has also shown that neighbouring genes such as one called FRG1 may also be involved. It has been proposed by some researchers that FRG1 is switched on in FSH which is toxic to the muscles. The importance of FRG1 in causing the symptoms of FSH in humans is still controversial though, because it hasn't been proven beyond doubt that it is involved.

What did the research show?

This research took advantage of natural processes in the body which regulate which genes are switched on and which are off.  When a gene is 'switched on', RNA 'photocopies' of the gene's code are made. The RNA moves outside the nucleus where they direct the manufacture of proteins. DNA can be thought of as a recipe book in the library that you can't take out. RNA is a photocopy of a recipe that you can take home to cook something in your kitchen (making the protein).
The new potential therapies involve switching off a gene so that the RNA copy is not made. This is called "RNA interference" or "gene silencing". It involves introducing into the cell tiny pieces of genetic material called "micro RNA" or "short hairpin RNA" that are designed to specifically switch off a particular gene. Although the strategy was similar in the two studies, the design of the microRNA was different.
Both research groups tested their new potential therapy in the only available mouse model for FSH - the FRG1 mouse. These mice have increased levels of FRG1 and develop muscle wasting and weakness.
Adeno-associated viruses (AAV) were used to deliver micro RNA that was designed to switch off the FRG1 gene into the cells of the mice. AAV is currently the most attractive candidate for gene therapy because it is not known to cause any severe disease in humans and is capable of infecting many different cell types including muscle cells.
Both studies reported that after the RNA interference treatment, the mouse muscles not only looked healthier under a microscope but their muscle size and strength was improved. For example in one study they measured how long the mice could run on a treadmill before they got tired. Untreated 12-week-old mice could only run for about 15 minutes whereas those that had been treated with the RNA interference were able to run for almost 25 minutes; on a par with healthy mice. One of the studies also included extensive toxicity monitoring and they concluded that the treatment appeared to be safe in mice.

What does this mean for FSH patients?

This research is exciting because it proves the principle that RNA interference is a promising therapeutic approach for FSH. One of the challenges of treating any muscle condition is to deliver the drug to all of the muscles of the body which make up a large proportion of our body mass. These studies were able to show that it is possible deliver the RNA efficiently to the muscles using a virus and this had a positive effect on muscle function.
Whether FRG1 is the correct target for a FSH therapy is still uncertain and more research is required to understand its role. However, the authors of these studies said that this technology could easily be applied to other target genes such as DUX4. Researchers are currently working to develop a DUX4 mouse model that would allow this to be tested.
RNA interference is very new technology and although there have been promising results from animal models, in particular for neurodegenerative conditions, no drugs have reached the clinic yet. Therefore, it may be several years before it is ready for testing in patients.
This strategy is similar to the exon skipping that is in clinical trial for Duchenne muscular dystrophy. Both strategies involve delivering small pieces of genetic material to change the way genes function. The difference is that for Duchenne muscular dystrophy a gene is repaired, whereas with for FSH a gene is switched off. The recent positive results in the Duchenne clinical trials will spur on researchers working on this strategy and inform them on ways to move this therapy forward to the clinic.

What about other conditions?

It is only in recent years that scientists have started to understand more about how genes are switched off  which has opened up the prospect of treating conditions that result in the production of harmful RNA or protein.
RNA interference could potentially be used to treat many other muscle conditions where the faulty gene has toxic effects on the muscle or interferes with the functioning of other healthy genes. These conditions are inherited in an "autosomal dominant" way, which means that only one faulty gene, inherited from either parent, is required to cause the condition.
Examples include myotonic dystrophy, oculopharyngeal muscular dystrophy (OPMD), Charcot-Marie-Tooth disease and some types of limb girdle muscular dystrophy, congenital muscular dystrophy and congenital myopathy. However, each affected gene will need to be looked at on a case by case basis, and researched in the laboratory before it can decided if it could possibly be amenable to RNA interference.
Considerable research has already been done in a mouse model of myotonic dystrophy using small pieces of DNA. Although closely related, that research was not the same as RNA interference. It involved blocking the interaction between RNA and proteins, rather than switching off the production of the RNA in the first place, which would be the case with RNA interference. So RNA interference adds another line of attack to the potential therapies currently being researched for myotonic dystrophy.
Article cited from: http://www.muscular-dystrophy.org/

Funding for Davide Gabelini's work provided by Muscular Dystrophy Campaign, UK

Monday, August 15, 2011

Big Stories - No Takers

It is perplexing how to get today's news organizations to pick up and share stories with their readers.....As a small, non-profit we have helped to fund research that is making major breakthroughs yet, the Seattle public has no idea that this work is being done in their own backyard.  Last year researchers here (at the Hutch & UW) in collaboration with scientists in the Netherlands & Rochester, NY made a huge breakthrough in Facioscapulohumeral (FSH) Muscular Dystrophy research - it made news in New York, being a featured story in the New York Times yet, Seattle readers were left in the dark.

It is amazing the progress we have made - functioning from our home on a "all volunteer" basis without getting the support from our local press.  Yet, our organization Friends of FSH Research (www.fshfriends.org) has been able to raise over a million dollars for FSH research and has helped launch pilot projects which generated new data, their findings which earned the respect and funding from the National Institutes of Health.

Facioscapulohumeral (FSH) Muscular Dystrophy, today believed to be the most common form of Muscular Dystrophy,  (who knew that there are more than one form?) has received little research support in the past from the existing funding sources.  This condition impacts the lives of those affected throughout their life span - causing a weakening then ultimately the death of the muscles of the upper back, upper arms and face. Eventually the muscle destruction extends into the muscles of the lower legs and trunk .... it is an unforgiving condition.  Not a sexy condition, not one which attracts media attention... one often overlooked, forgotten.

Friends of FSH Research proves the "Power of One" - one family, one love for their child.  We would not have been able to succeed without the internet, social media and the community.  This is one story that has not yet been helped by traditional media - though I am still hopeful that one day they will pick up our story for I think it is one worthy of telling.

Friday, August 5, 2011

FSHD and Standing Frame Exercise

FSHD and Standing Frame Exercise : Progressive Muscular Dystrophy

Standing Frame Exercises
People with FSHD may also benefit from exercises carried out using the support of the system known as a standing frame, which is designed to support a person with mobility restrictions stand and then remain in a standing position. potential advantages of using a standing frame include preserving some range of motion, enhancing bone strength, growing blood circulation and realigning the position within the inner organs. Other possible advantages include worry reduction and lowered risks for any form of abnormal muscle and tendon shortening known as contracture.

Monday, August 1, 2011

Generosity of Strangers and Old Friends - Amazing Grace

THANK YOU!! Spent the weekend sharing our story with artists at the Bellevue Art Festival. I am touched that so many individuals were willing to donate their artwork to us for our January auction. The generosity and kindness we have received has been amazing ... although the work of procurement is certainly not an easy one, I am forever grateful.
I will start posting pictures and website links of the artists over the coming weeks - Please check out their artwork!

Wednesday, July 20, 2011

Chris Carrino Foundation - The Power of One

Chris Carrino: Alumnus and Broadcaster's Personal Battle Becomes Public

Chris Carrino, GSB '92
Carrino has been battling Facioscapulohumeral Muscular Dystrophy (FSHD), a debilitating form of muscular dystrophy, for most of his adult life. (read complete story)

So glad to have a personality come forward and speak out for FSHD - increasing the public's awareness of this condition can only help in attracting new researchers to work on FSH and new donors to support their work.

Additionally, his leadership may help inspire others with FSH (and their loved ones and friends) to take action as well - seeing Chris's impact may show others what is possible.

I truly hope others will come forward.........

Sunday, July 17, 2011

FSHD Foundation - Netherlands

The great big work and life juggle - Business of Life - livemint.com

Defining Moments: By Kees van der Graaf, IMD International, 137 pages, $40  (around Rs 1,800).

Van der Graaf’s oldest son, Bart, was diagnosed with FSHD (facioscapulohumeral form of muscular dystrophy) in 1992, and that changed his life forever. He realized he had to establish a balance between his personal and professional life. Along with his wife, Renée, Van der Graaf founded the FSHD Foundation. In 2008, at the pinnacle of his career, he decided to take early retirement from Unilever and devote his time to the foundation.

Read more about Kees Van der Graaf, his work, his family's effort to fund FSHD research and their work toward finding a treatment or cure for their affected son.
Inspirational story of one family's dedication - the "power of one."

Thursday, June 30, 2011

Seeking Donations - Eager Recipient looking for Help!

Wondering if anyone out there that may read my blog might have ideas about how best to procure items for an auction.  I have done this now for over 7 years and every year it presents a huge obstacle.  I am dedicated and determined to raise money needed for FSH research yet, I find asking for help/donations continues to be hard.  I feel we do a great job of showing off the donor's items (such as artwork, jewelry, pottery, etc) and we put the donor's website's out there on our site and on all our written literature.... not sure if this is "giving back" enough to inspire spontaneous giving.
I wonder how other groups do this? in person contacts? emails? letters?
Feed back & ideas welcomed. (Donations greeted with great enthusiasm!!)

Friday, June 24, 2011

FSHD - Overview

Facioscapulohumeral Muscular Dystrophy - GeneReviews - NCBI Bookshelf

Facioscapulohumeral Muscular Dystrophy

FSH Muscular Dystrophy
RichardJLF Lemmers, PhD
Department of Human and Clinical Genetics
Leiden University Medical Center
SilvereM van der Maarel, MD
Department of Human and Clinical Genetics
Leiden University Medical Center

Excellent reference written by expert researchers in the field of FSH research.

Wednesday, June 22, 2011

GiveBig for FSHD research - June 23rd

                                    Dear Friends,Muscles for FSH

On June 23rd there is an exciting    opportunity to put more "muscle" in your donation to Friends of FSH Research. 
Give BIG is a community-wide giving challenge created by
The Seattle Foundation that will increase the size of your
donations to us. 

 This one-day, online charitable giving event will rally together our community on behalf of the amazing nonprofit organizations in King County - this includes Friends of FSH Research!

GiveBIG will grow your generosity in several ways:
·        Grow your gift! The Seattle Foundation and local businesses will match a share of every contribution made through The Seattle Foundation's online Giving Center between 7 a.m. and midnight on June 23.
·        Win a Golden Ticket! During the day, if your donation is selected at random, Friends of FSH Research will receive an additional $1,000 from GiveBIG's sponsors.

Your gift will help us support critical Facioscapulohumeral Muscular Dystrophy (FSH) research.  Help us make a treatment or cure to this debilitating condition a reality now!

Mark your calendar now! Make your donation to Friends of FSH Research between 7 a.m. and midnight on Thursday June 23 through our page in The Seattle Foundation's Giving Center. 

Help us make the most of GiveBIG!  Here are a few more things you can do in addition to making a generous gift:
1.      Mark your calendar today, so you don't forget to make a gift on June 23!
3.      Rally your friends to support Friends of FSH Research  on June 23!  Email, Facebook, Twitter & phone calls are great ways to spread the word and help us take advantage of GiveBIG. 
4. Be sure to share the link to our profile

Thank you in advance for Giving Big. With your help will truly be able to make a difference to those affected by FSH Muscular Dystrophy!! 

Terry Colella

PS: You can learn more about GiveBIG online atwww.seattlefoundation.org/GiveBIG.

Tuesday, June 14, 2011

Expression Profiling of FSHD-1 and FSHD-2 Cells during Myogenic Differentiation

Recent Report from Italy - FSHD research News

Global gene-expression profiles of myoblasts from FSHD-1 and FSHD-2 patients and healthy controls in the context of myogenic differentiation are discussed.

Monday, February 14, 2011

Kirkland mother fights to fund research, find cure for son’s degenerative muscle disease

Kirkland mother fights to fund research, find cure for son’s degenerative muscle disease

On a recent afternoon, the mother-of-four walks through the downstairs of her Kirkland home that is packed with dozens of acrylic and oil paintings, wine bottles, granite rock vases, French serving platters, gift baskets, books and more. Terry’s downstairs has become a storage for items up for bid at her annual auctions she hosts to fund research for Brian’s degenerative muscular disease, FSHD (Facioscapulohumeral Muscular Dystrophy). This year marks the 7th Annual “FiSHing for a Cure Gala” dinner and auction, which will be held on Saturday, Jan. 29 at the Bellevue Hyatt. To date, the auctions have raised more than $1.2 million that has funded groundbreaking research for the disease.

(read entire story at Kirkland Reporter)

Saturday, February 5, 2011

FSHD - 1st known human disease caused by unique circumstance

Trends Mol Med. 2011 Jan 31. [Epub ahead of print]

Facioscapulohumeral muscular dystrophy and DUX4: breaking the silence.

Department of Human Genetics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, Netherlands.


Autosomal dominant facioscapulohumeral muscular dystrophy (FSHD) has an unusual pathogenic mechanism. FSHD is caused by deletion of a subset of D4Z4 macrosatellite repeat units in the subtelomere of chromosome 4q. Recent studies provide compelling evidence that a retrotransposed gene in the D4Z4 repeat, DUX4, is expressed in the human germline and then epigenetically silenced in somatic tissues. In FSHD, the combination of inefficient chromatin silencing of the D4Z4 repeat and polymorphisms on the FSHD-permissive alleles that stabilize the DUX4 mRNAs emanating from the repeat result in inappropriate DUX4 protein expression in muscle cells. FSHD is thereby the first example of a human disease caused by the inefficient repression of a retrogene in a macrosatellite repeat array.
Copyright © 2011. Published by Elsevier Ltd.

Tuesday, February 1, 2011

NIH - Update FSH Research

Spotlight on Research 2011

January 2011

Genetic Discovery Improves Understanding of FSH Muscular Dystrophy Cause

A new study supported in part by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) has found that two separate genetic arrangements – both on chromosome 4 – are needed to start the disease process in facioscapulohumeral muscular dystrophy (FSHD), one of the most common forms of muscular dystrophy. The finding brings scientists a step closer to understanding the cause of FSHD, knowledge that would allow researchers to begin designing strategies that could eventually lead to treatments.
The study’s international team of investigators, including NIAMS-supported scientist Stephen Tapscott, M.D., Ph.D., of the Fred Hutchinson Cancer Research Center in Seattle, discovered that a repeating DNA unit containing a gene called DUX4 interacts with adjacent genetic variations to determine whether a person will have FSHD, which causes progressive muscle wasting in the upper body.
In the early 1990s, scientists found that FSHD is associated with a shortened DNA sequence at the end of chromosome 4, called a tandem repeat array. Normally, that region of the chromosome contains 10 to 100 repeating units of DNA. They found in most people with FSHD the array is smaller, with fewer than 10 repeats. Within each repeating unit is the DUX4 gene, which encodes a protein that harms muscle cells. Later research, however, showed that this genetic variation alone could not cause FSHD – something else was needed to trigger the disease’s muscle damage. The new research, reported in the journal Science, demonstrates that the smaller array only causes FSHD if there is an additional DNA mutation in the same region of chromosome 4 that allows DUX4’s RNA to stabilize and the protein to accumulate to disease-causing levels.
People with FSHD have chromosome variations that add a trailing segment called a poly(A) tail to the RNA. With the poly(A) tail, the RNA is more stable and accumulates to detectable levels. Previous studies have shown that expression of the DUX4 gene in muscle cells causes defects in cellular growth, development and the ability to maintain internal stability that are consistent. In a subsequent publication, Dr. Tapscott’s research group demonstrated a full-length DUX4 RNA with a poly(A) tail expressed in skeletal muscle from FSHD patients, but not in muscle from control subjects.
While further research is needed to confirm and better understand the implications of their findings, the scientists say that their results may make it easier for doctors to diagnose FSHD in people with muscular dystrophy symptoms. In addition, for those in affected families who have not yet experienced symptoms, the results will help predict who may develop the disease. The study also has important implications for treatment. Presently, treatment for FSHD is limited to physical therapy, orthopaedic procedures and drugs that may help with specific symptoms in some patients. Although there are no treatments for the progressive muscle weakness and wasting characteristic of FSHD, the new findings point to potential targets for treating the disease in novel ways that address the causes.
Support for the study was provided by a number of other organizations, including the National Institute of Neurological Disorders and Stroke (NINDS), the FSH Society, the Fields Center for FSHD and Neuromuscular Research, the Pacific Northwest Friends of FSH Research and the Muscular Dystrophy Association.
The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the U.S. Department of Health and Human Services’ National Institutes of Health (NIH), is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website athttp://www.niams.nih.gov.
Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camaño P, Dauwerse JG, Snider L, Straasheijm KR, van Ommen GJ, Padberg GW, Miller DG, Tapscott SJ, Tawil R, Frants RR, van der Maarel SM. A unifying genetic model for facioscapulohumeral muscular dystrophy. Science. 2010 Sep 24;329(5999):1650-3.