Niacin Supplementation Against Congenital Malformations

At left, adult consequences of niacin deficiency. By Dr James W Babcock (1856-1922) - http://history.nih.gov/exhibits/goldberger/docs/intro_2.htm reproduced with permission of the Waring Historical Library of the Medical University of South Carolina, Charleston, SC., Public Domain, https://commons.wikimedia.org/w/index.php?curid=3741262

Niacin supplementation during gestation prevents congenital malformation is mice, and there is reason to believe the same may apply to humans, due to associations with NAD synthesis.  Abstract:

BACKGROUND:Congenital malformations can be manifested as combinations of phenotypes that co-occur more often than expected by chance. In many such cases, it has proved difficult to identify a genetic cause. We sought the genetic cause of cardiac, vertebral, and renal defects, among others, in unrelated patients.METHODS:We used genomic sequencing to identify potentially pathogenic gene variants in families in which a person had multiple congenital malformations. We tested the function of the variant by using assays of in vitro enzyme activity and by quantifying metabolites in patient plasma. We engineered mouse models with similar variants using the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 system.RESULTS:Variants were identified in two genes that encode enzymes of the kynurenine pathway, 3-hydroxyanthranilic acid 3,4-dioxygenase (HAAO) and kynureninase (KYNU). Three patients carried homozygous variants predicting loss-of-function changes in the HAAO or KYNU proteins (HAAO p.D162*, HAAO p.W186*, or KYNU p.V57Efs*21). Another patient carried heterozygous KYNU variants (p.Y156* and p.F349Kfs*4). The mutant enzymes had greatly reduced activity in vitro. Nicotinamide adenine dinucleotide (NAD) is synthesized de novo from tryptophan through the kynurenine pathway. The patients had reduced levels of circulating NAD. Defects similar to those in the patients developed in the embryos of Haao-null or Kynu-null mice owing to NAD deficiency. In null mice, the prevention of NAD deficiency during gestation averted defects.CONCLUSIONS:Disruption of NAD synthesis caused a deficiency of NAD and congenital malformations in humans and mice. Niacin supplementation during gestation prevented the malformations in mice. (Funded by the National Health and Medical Research Council of Australia and others.).

The best prediction of our future

 
“The best way to predict your future is to create it”
Abraham Lincoln

A couple of years ago, I was listening to the “America’s cheapest family”, the Economides family, and realized that I have already made mistakes with my daughter. The father asked whether we all wanted to raise responsible adults or perpetual children. The two Economides parents advised that even if the parents were financially comfortable, they should not allow the children to buy and live at the parents’ spending level, because by doing so the children would be “locked” into a likely unsustainable lifestyle. It is quite possible that the children would not have the income that the parents make. Of course, this does not mean that the children would be less happy than the “richer” parents. After all, the millionaires and billionaires are not much happier than the average American. However, if the children have lower income and yet, spend at the level of the rich parents, happiness is unlikely.

This trajectory of thoughts brought more questions about the future. Would our children have any job stability? It has been predicted that in the future, there might be only temporary job contracts; people would rarely stop to live in one place, since they will be in pursuit of their next job/contract. Would the informational technology and automation continue to evolve and what would the consequences be… As we exhaust the world’s resources and take unwise decisions to address the world’s problems, would our society recess and shrink back to the mechanical and handmade devices? With all these uncertainties, am I making a mistake by pushing my child into the time-devouring, super-expensive, goal-disorienting, haphazard educational system? By conforming to the prefabricated mold of our educational system and its regulations and artificially-imposed standards, do I suffocate the imagination and creativity of my child?

As I asked myself these questions, and felt more and more upset. I thought that the answers to these questions depended on whether I wanted to see my child become a happy adult or a successful adult. Strangely enough, in our society the most popular definition of success rarely overlaps with the understanding of individual happiness. Success in our world is frequently measured in dollar signs. The schools prepare our children to be successful (i.e., earn money); the schools do not explain to our children how to seek happiness. And we, as dutiful parents, reinforce the lessons from the schools. Have you recently looked at how happiness changes with age? It seems that at age of 15, our children become increasingly unhappy with their lives – the school seems worse than a prison, and all their activities in and out of school are rationed and predetermined.

Peter Gray, a psychology professor wrote, “Children are forced to attend school, where they are stripped of most of their rights,”… “The debate shouldn’t be about whether school is prison, because unless you want to change the definition of prison, it is.” … My daughter cannot go to the school’s bathroom unless she has a permission slip, she can attend school only dressed by THE code. There is also a system of increasing in intensity punishments, if she does not observe the rules.

Masters of imagination such as Hans Christian Andersen and Beatrix Potter shared their true feelings about school. Andersen reminisced that "his years in school were the darkest and most bitter of his life. At one school, he lived at his schoolmaster's home. There he was abused in order to improve his character... He later said the faculty had discouraged him from writing in general, causing him to enter a state of depression”. Beatrix Potter, the author of the whimsical fairy tales about Peter Rabbit, admitted “Thank goodness I was never sent to school; it would have rubbed off some of the originality.”

Children in the U.S. may spend 17 years in school if they attend college for four years and forgo graduate education. This is overschooling. Learning useful skill should not take this long. Worse, the 17 years do not guarantee any useful job skills – frequently, the young people are catapulted out of college into a spotty work world without any applicable skills. The lucky ones, who do find a job, frequently feel like apprentices and start learning meaningful skills at the job.

As every extreme gives rise to another extreme, the overschooling has given rise to the unschooling - read Hewitt B. We Don't Need No Education, Magazine, September 2014.

“The best way to predict your future is to create it”, said Abraham Lincoln. We should create the future of America by educating and preparing our children for the real world. However, the future is glum, if we rely on the current educational system. The present overschooling prunes the children’s imagination into a shriveled trunk without brunches and flowers, diminishes the future children’s productivity, and tempers with their health. As a result, we squander our greatest potential, our children, and jeopardize their future.

Compare the current overschooling, the lack of responsibility among our children, the scarcity of job opportunities to the responsibilities given to young people a century or more ago. We delay and postpone adulthood as long as possible. And yet, it is worth remembering that at 17 years of age, George Washington left home to become a surveyor; and a few years later, he was appointed as a district adjutant, with the rank of major in the Virginia militia.

At age of 21, Emil Herman Grubbe, assembled the first X-ray machine in Chicago and used it to treat a woman with recurrent breast carcinoma.

At age of 26, William Bradley Coley joined as a medical doctor the staff of the New York Hospital and at age of 29, he injected his first patient with streptococcal microorganisms to treat a malignant tumor. Today, Coley is considered "the father of immunotherapy".

Is there any good reason to keep the young in school for a long time? Since I am a biologist, I have read that the biomedical knowledge doubles about every 19 years (Smith, R., What clinical information do doctors need? BMJ, 1996. 313(7064): p. 1062-8). It is true that technology and science are dynamic; however, is this is a good excuse to keep the young people longer in school? If yes, the same logic would imply that we should stay in school forever, as new discoveries and knowledge are reported every day. It is obvious that only basic, foundational knowledge and critical reasoning skills should be acquired in school. In addition, there should be novel educational models that support ongoing knowledge upgrades for professionals without taking them away from their families and jobs.

My random lessons/concepts for today are: shorten the schooling period, give our children job responsibilities earlier in life, and prevent the children from inflating their lifestyle.

Wnt Signaling In Arthritis

http://www.mayoclinic.org/diseases-conditions/arthritis/home/ovc-20168903

A review on the role of Wnt signaling - often deregulated  in cancer particularly colon cancer - in arthritis can be found here. This is an example of the benefits of basic science research: first, by understanding Wnt signaling in general we better understand the diseases that exhibit aberrant forms of this signaling; second, by dissecting the finer details of how this signaling is controlled and what the downstream effects are, therapeutic interventions can be developed that targets this signaling to treat disease. Perhaps even preventive approaches can be devised as well. Arthritis may be another example of this pathway from lab bench to clinic. Abstract:

PURPOSE OF REVIEW:Arthritis defines a large group of diseases primarily affecting the joint. It is the leading cause of pain and disability in adults. Osteoarthritis (OA) affecting the knee or hip is the most common form among over 100 types of arthritis. Other types of arthritis include erosive hand OA, temporomandibular joint (TMJ) OA, facet joint OA, diffuse idiopathic skeletal hyperostosis (DISH), and spondyloarthritis (SpA). However, the specific molecular signals involved in the development and progression of OA and related forms of arthritis remain largely unknown. The canonical wingless/integrated (Wnt)/β-catenin signaling pathway could play a unique role in the pathogenesis of arthritis. In this review article, we will focus on the molecular mechanisms of Wnt/β-catenin signaling in the pathogenesis of OA and other types of arthritis.RECENT FINDINGS:Emerging evidence demonstrates that Wnts and Wnt-related molecules are involved in arthritis development and progression in human genetic studies and in vitro studies. Also, mouse models have been generated to determine the role of Wnt/β-catenin signaling in the pathogenesis of arthritis. Wnt/β-catenin signaling represents a unique signaling pathway regulating arthritis development and progression, and the molecules in this particular pathway may serve as targets for the therapeutic intervention of arthritis. Mediators and downstream effectors of Wnt/β-catenin signaling are increased in OA as well other forms of arthritis, including DISH and SpA. Through extensive investigations, including pre-clinical studies in transgenic mice and translational and human studies, the Wnt/β-catenin signaling pathway has been proven to play roles in bone and joint pathology by directly affecting bone, cartilage, and synovial tissue; further, these pathologies can be reduced through targeting this pathway. Continued investigation into the distinct molecular signaling of the Wnt/β-catenin pathway will provide additional insights toward the therapeutic intervention in arthritis.

Dangers Of American Football

By Paul Keleher - Flickr, CC BY 2.0, https://commons.wikimedia.org/w/index.php?curid=1555657

American football can cause brain damage to those who play it. Abstract:

IMPORTANCE:Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE).OBJECTIVE:To determine the neuropathological and clinical features of deceased football players with CTE.DESIGN, SETTING, AND PARTICIPANTS:Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history.EXPOSURES:Participation in American football at any level of play.MAIN OUTCOMES AND MEASURES:Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia.RESULTS:Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre-high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia.CONCLUSIONS AND RELEVANCE:In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

Gene Editing In Human Embryos

By The original uploader was GoldenBear at German Wikipedia - Life Issues Institute, 1721W Galbraith Road, Cincinnati, OH 45239, 513.729.3600, www.lifeissues.org, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=22862400

Here is a breakthrough paper detailing genome editing of mutations in a gene associated with cardiac myopathy, using the CRISPR gene editing methodology. This is an important step in using gene therapy to eliminate genetic disorders.  Abstract:

Genome editing has potential for the targeted correction of germline mutations. Here we describe the correction of the heterozygous MYBPC3 mutation in human preimplantation embryos with precise CRISPR-Cas9-based targeting accuracy and high homology-directed repair efficiency by activating an endogenous, germline-specific DNA repair response. Induced double-strand breaks (DSBs) at the mutant paternal allele were predominantly repaired using the homologous wild-type maternal gene instead of a synthetic DNA template. By modulating the cell cycle stage at which the DSB was induced, we were able to avoid mosaicism in cleaving embryos and achieve a high yield of homozygous embryos carrying the wild-type MYBPC3 gene without evidence of off-target mutations. The efficiency, accuracy and safety of the approach presented suggest that it has potential to be used for the correction of heritable mutations in human embryos by complementing preimplantation genetic diagnosis. However, much remains to be considered before clinical applications, including the reproducibility of the technique with other heterozygous mutations.

More: Fat Not Fit

By Victovoi - Own work, Public Domain, https://commons.wikimedia.org/w/index.php?curid=9857499

All the past "feel good" stories over the past few years stating it is possible to be "fat but still fit" (physically healthy) are, unsurprisingly, being proven wrong.

Thus, we read:

A new study published in the European Heart Journal Monday finds that being overweight increases your risk of coronary heart disease, even if you are otherwise considered healthy, destabilizing the common conception that someone can be "fat but fit"...

...Researchers analyzed thousands of incidences of coronary heart disease over a more than 12-year period in 10 countries in Europe. They found that being overweight or obese was associated with a more than 25 percent higher risk of developing coronary heart disease, even in people who did not have any other markers that reflected an increased risk of heart disease.

Dr. Jennifer Ashton, ABC News' chief medical correspondent, said the research shows that even if people appear healthy based on blood tests today, the risk of health complications can increase over time if they are obese.

And we read this, showing even more types of cancer are associated with obesity:

While obesity is often associated with a host of other health issues including high blood pressure, stroke and heart attack, a new study is examining how the condition is also related to cancer risk.

A review of several studies published today in the New England Journal of Medicine found new associations between obesity the development of eight additional cancers, in addition to others previously known.

Researchers from the World Health Organization’s International Agency for Research on Cancer (IARC) looked at more than 1,000 epidemiological studies and found that "excess body fatness" is also linked to the risk of developing gastric, liver, gallbladder, pancreatic, ovarian, thyroid, blood (multiple myeloma) and brain (meningioma) cancers.

"I think the main takeaway point is that your health and specifically your body fatness is an important factor for many types of cancer," Dr. Richard Lee, Medical Director of the Integrative and Supportive Oncology Program at the University Hospitals Seidman Cancer Center, told ABC News.

"Patients should understand that they can decrease the risk for developing cancer and improving overall survivorship," by keeping their weight below obesity thresholds, he said. This information can help doctors advising patients on cancer risk, he added.

Researchers in this study also attempted to quantify the risk for obese people to develop this variety of cancers. They found obese people had 1.8 times the risk for developing liver cancer, 4.8 times as high for esophageal adenocarcinoma, and 7.1 times as high for uterine cancer. They also confirmed that for some of these cancers, as your weight goes up, so does the risk.

We read a lot online about "fat shaming" - in reality, what goes on in society today is "fat norming." But it is a serious health problem, both for the affected individual and for society as a whole.  We need more realism and less "feel good" stories that mislead people about real lifestyle risks.

Nut Intake Equals Reduced Weight Gain

By Sage Ross - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=30392736

Nut intake is associated with “reduced weight gain and a lower risk of becoming overweight or obese.”  So, in moderation, eating a healthy “energy-dense food” like nuts can be beneficial for weight control.  Don’t over-indulge of course, but it would seem like a handful of nuts is better than a handful of doughnuts.  Abstract:

PURPOSE:There is inconsistent evidence regarding the relationship between higher intake of nuts, being an energy-dense food, and weight gain. We investigated the relationship between nut intake and changes in weight over 5 years.METHODS:This study includes 373,293 men and women, 25-70 years old, recruited between 1992 and 2000 from 10 European countries in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Habitual intake of nuts including peanuts, together defined as nut intake, was estimated from country-specific validated dietary questionnaires. Body weight was measured at recruitment and self-reported 5 years later. The association between nut intake and body weight change was estimated using multilevel mixed linear regression models with center/country as random effect and nut intake and relevant confounders as fixed effects. The relative risk (RR) of becoming overweight or obese after 5 years was investigated using multivariate Poisson regressions stratified according to baseline body mass index (BMI).RESULTS:On average, study participants gained 2.1 kg (SD 5.0 kg) over 5 years. Compared to non-consumers, subjects in the highest quartile of nut intake had less weight gain over 5 years (-0.07 kg; 95% CI -0.12 to -0.02) (P trend = 0.025) and had 5% lower risk of becoming overweight (RR 0.95; 95% CI 0.92-0.98) or obese (RR 0.95; 95% CI 0.90-0.99) (both P trend <0.008).CONCLUSIONS:Higher intake of nuts is associated with reduced weight gain and a lower risk of becoming overweight or obese.

Do you like saxophone? Listen to this old song again:
Men At Work - Who Can It Be Now?

Miscellaneous

Here are a few random, or not so random, thoughts from the past few weeks:

A jolt into thinking
Have you been jolted into thinking recently? Listen to Joshua Sheats in his podcast # 473 – What’s Wrong With Radical Personal Finance? This podcast is a heart-wrenching and honest confession; it is also an exploration of our reasoning to exist. In this podcast, Joshua also refers to a book called “Out of the Ashes: Rebuilding American Culture” by Anthony Esolen. At least the introduction of the book sounds provocative, thought-inducing and nostalgic, when read by Joshua. I found a few highly negative comments about the book on Amazon, but as any provocative work, there would be a wide range of emotions evoked. I have no opinion yet, I have not read the book!

Let bygones be bygones
Recently I watched a documentary on poverty in India. The days of the poorest were revolving around the trash – the mountains of garbage that were piled daily. The condemned people were going through the remnants and the discarded of other people’s lives. Digging into the dirt of yesterday … trying to find a single thing worth anything. As I watched, this picture of people sifting through the past turned into a symbol – the symbol of us sometimes looking back at the past, at the darkest, lowest moments of life, trying to find anything of value, anything redeeming. But sometimes all of the search is in vain. I do not claim that we should forget where we came from and what we went through, but a daily dive into the past keeps us poor. A daily dive into the past leads to poverty of the spirit and morale, it limits initiative. What do you think?

Freedom

Here is a great though that I shared with my daughter recently: "What's money? A man is a success if he gets up in the morning and goes to bed at night and in between does what he wants to do." -Bob Dylan
My girl will be soon deciding on what to do with herself after high school. I hope that she takes the right decision. I try not to meddle. Sometimes I think that by being passive, I am insuring myself against giving the wrong advice, but then I know my child – she would not change her mind no matter what I say. So, I am just sitting on the sidelines and waiting for her decision.

What happens to our children after high school
I recently found these stats on education:

"But for too many graduates, no matter the level of education they’re just completing, the transition to their next destination will be fraught with potential hurdles. Nearly 70 percent of this year’s high school graduates will go right on to college this fall, but if history is any guide only about half of them will graduate in four years. For those who do graduate, more than 40 percent of them might be underemployed, working in jobs that don’t require a bachelor’s degree, according to data from the Federal Reserve Bank of New York."
This is frightening, and discouraging. The education system needs to change. We need apprenticeships similar to these in Switzerland . After the apprentices learn about the real work world, then they can access more education, if they are inclined to do so. Watch what the future student may look like.

Quo vadis, Domine
Where are we going? Where is America headed?
These questions come to mind when watching the interview with Linh Dinh: America Is The Poorest First World Country. It is a scary, but honest view on America.