Telomere extension after attenuation

This from the NEJM is an interesting application of Basic Science we sometimes have been taught

ORIGINAL ARTICLE

Danazol Treatment for Telomere Diseases

Danielle M. Townsley, M.D., Bogdan Dumitriu, M.D., Delong Liu, Ph.D., Angélique Biancotto, Ph.D., Barbara Weinstein, R.N., Christina Chen, B.S., Nathan Hardy, B.S., Andrew D. Mihalek, M.D., Shilpa Lingala, M.D., Yun Ju Kim, M.D., Jianhua Yao, Ph.D., Elizabeth Jones, M.D., Bernadette R. Gochuico, M.D., Theo Heller, M.D., Colin O. Wu, Ph.D., Rodrigo T. Calado, M.D., Ph.D., Phillip Scheinberg, M.D., and Neal S. Young, M.D.

N Engl J Med 2016; 374:1922-1931May 19, 2016DOI: 10.1056/NEJMoa1515319

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BACKGROUND

Genetic defects in telomere maintenance and repair cause bone marrow failure, liver cirrhosis, and pulmonary fibrosis, and they increase susceptibility to cancer. Historically, androgens have been useful as treatment for marrow failure syndromes. In tissue culture and animal models, sex hormones regulate expression of the telomerase gene.

Full Text of Background...

METHODS

In a phase 1–2 prospective study involving patients with telomere diseases, we administered the synthetic sex hormone danazol orally at a dose of 800 mg per day for a total of 24 months. The goal of treatment was the attenuation of accelerated telomere attrition, and the primary efficacy end point was a 20% reduction in the annual rate of telomere attrition measured at 24 months. The occurrence of toxic effects of treatment was the primary safety end point. Hematologic response to treatment at various time points was the secondary efficacy end point.

Full Text of Methods...

RESULTS

After 27 patients were enrolled, the study was halted early, because telomere attrition was reduced in all 12 patients who could be evaluated for the primary end point; in the intention-to-treat analysis, 12 of 27 patients (44%; 95% confidence interval [CI], 26 to 64) met the primary efficacy end point. Unexpectedly, almost all the patients (11 of 12, 92%) had a gain in telomere length at 24 months as compared with baseline (mean increase, 386 bp [95% CI, 178 to 593]); in exploratory analyses, similar increases were observed at 6 months (16 of 21 patients; mean increase, 175 bp [95% CI, 79 to 271]) and 12 months (16 of 18 patients; mean increase, 360 bp [95% CI, 209 to 512]). Hematologic responses occurred in 19 of 24 patients (79%) who could be evaluated at 3 months and in 10 of 12 patients (83%) who could be evaluated at 24 months. Known adverse effects of danazol — elevated liver-enzyme levels and muscle cramps — of grade 2 or less occurred in 41% and 33% of the patients, respectively.

Full Text of Results...

CONCLUSIONS

In our study, treatment with danazol led to telomere elongation in patients with telomere diseases. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01441037.)

The Late Bobby Bland

Condolence to the famiiles of Bobby Bland

who recently transitioned.  While we are at it, condolence to the late great Joe Medwick Veasy

writer of Bland's most requested tune "Further Up the Road." While there were incomplete to nonexistent journalistic efforts by the Houston Chronicle in quoting Don Robey's

alias, and Eric Clapton as a cover artist, they did not mention the other wrtiers of the tune Further Up the Road. The New York Times did in its obituary did. Thank God for good journalism + YouTube + Google for the truth in the details and technology. Thank God for BMI, the Library of Congress and Malaco Records.
   I was blessed with a long history of collaboration with Joe when he lived across the street from my 2916 Blodgett @ Ennis medical office. We had a studio upstairs called OTO (over the office) in the old John Chase office.  It was there that the old piano console was used to put the chords and arrangement to "If I Don't Get Involved" (I Won't Get Hurt). It was here that after years of playing behind him on Sax in the Prevost Center with Joe Nettles, and Kenny Andrews at Spillers place, that we settled down to get two of his songs down. (I have others still recorded soon to be released.)The flip side was "She Fooled Me This Time.", recorded at Gurlick sound and Believers Studios under Kimberly Records.

Fontenot did horn arrangements with overall arrangements by trombonist Jimmie Walker. Jimmie did these arrangements in 2 days for the whole band. Keith Anderson was lead trumpet with me on  saxes with Grady Gaines of Little Richard fame. IJ Gosey was the genius on guitar.  It was at OTO that Joe told me of the genius of Don Robey (as a 10 year predecessor to Motown's Berry Gordy)  who served as talent coordinator and CEO at Duke and Peacock Records, allowing the late Joe Scott to matriculate into such a good writer. It was at OTO that Joe told me of "This Business of Music". It was here that I learned of the love/knowledge given to Joe by Don Robey

 see video http://youtu.be/I9MUgbaDXog

For the Bobby Bland Midnight Run version of "If I Don't Get Involved". Thanks to Malaco Records and the late Dave Clark who as A and R man put our song into immortatlity.

http://youtu.be/ShgE7iI4nZ8

Check this out of " If I Don't Get Involved" for the Midnight Run arrangement. I personally liked Joe's Version on Kimberly Records better because of his emotion. After listening over, I personally think Joe wrote the lyric speaking of his addiction to alcohol.

May God's grace continue to be shed on us for allowing us to move forward even in our feeble efforts. I will always love my big brother Joe Medwick Veasey for the history, information,time  and knowlege that he gave me. I have been blessed with meeting his lovely daughter and look forward to redirecting the royalties of his music to her. He loved her dearly.

Thank you TEEBEEFERRIS!

See Sir Shamblin's take http://bit.ly/11FduDw. Thank you also for your abbreviated version of what you had before as documentation.

Alonzo Peters MD recently returned from forced sabbatical, fellow of American Academy of Family Practice, and CEO of Kimberly Records* . Member of musicians union since 1975 ,AMIE* (advanced medical and immunologic(cytokine)/ INFORMATIC EDUCATION. Writer of book/screenplay "What's REALLY Going On"* , a story of a forgotten hero. (Joe Medwick) all by God's grace.

*Subsidiary to Peters' Productions.

Injury to the Kidney

It appears that the molecular "shedding" of KIM-1 (Kidney injury Molecule-1) largely due to the actions of a metaloproteinase allows for reformation of the proximal tubule in areas of damage. The KIM goes thrrough a transmembrane potentiation of sorts and the simultaneous production of IL-18 allows the immunologic process to take part. Both molecules serve as early pre-creatinine,Glycosuria and proteinuria signs of kidney injury.

Inactivity and immunology

Thanks to Wikipedia and access to the net, I am going to earnestly attempt to post health from a biochemical and immunologic perspective. This is the first post in 5 years, due to my sabbatical responsibilities and internet inaccessibility.  Check out ALPINA GALANA. Check out the Thai spices as well as curries for cooking.

It was ironic that I visited a friend of mine's parents and found them to be overmedicated and under evaluated by their primary care. In general the mother was the worst with too much insulin being given in the evening dose causing hypoglycemia with symptoms including nightmares, syncope, and other bad things.

It appears that they had not been told of the metabolic syndrome, or Syndrome X, involving the TRIAD conundrum of Hyperglycemia,Hypercholesterolemia and Hypertension.

All three tend to exacerbate each other. They result from inactivity and DIET problems.Twitter is lit up today with mandates for the PEDIS to improve diet, and increase exercise. The bigger problem is children raising themselves as you know with no incentives for physical activity. Too much time on VIDEO GAMES. Thank you Queen Michelle Obama for your mandate taking fruit for the future generations of our country.

The end result of the metabolic syndrome is disordered metabolism in the face of localized hypovolemia and ischemia with subsequent TNF formation. Should one take medicine for this? I think not. but check out the natural herb above that diminishes IL6 and IL1 necessary for the  inflammatory cascade  of cytokines and bad chemistry, should it be occurring

Eat more fruit/vegetables. Eat less fried food, but if you eat it, eat it with Jalapenos and the herbs above.Go swimming. Get out, even if its hot. Ride your bike until it snows. Get a stationary bike/Treadmill .Put on a helmet. Do pushups, kneebends, jumping jacks. Lift weights. All my add muscle, and decrease your medication bill each month. This is a must NOW.The do as I do practiced by the kids will carry over to health for your progeny and YOU.

ALONZO PETERS MD