Interesting observations to share on Lactoferrin
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Protein heals wounds, boosts immunity and protects from cancer – Lactoferrin
Posted in Nutrition, tagged lactoferrin, Nutrition on July 17, 2014| Leave a Comment »
Malnutrition in India, High Newborn Death Rate and Stunting of Children Age Under Five Years
Posted in Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Bone Disease and Musculoskeletal Disease, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Curation, Discovery process, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Liver & Digestive Diseases Research, Metabolomics, Nutrigenomics, Nutrition, Origins of Cardiovascular Disease, Population Health Management, Nutrition and Phytochemistry, Proteomics, tagged Childhood malnutrition, Ganges River, Himalayan Plateau, hyperhomocysteinemia, Population sanitation, Protein-energy malnutrition, S deficiency, stunting of growth, Transthyretin on July 15, 2014| Leave a Comment »
Malnutrition in India, High Newborn Death Rate and Stunting of Children Age Under Five Years
Curator: Larry H Bernstein, MD, FCAP
A lead report in the New York Times focuses on a major public health problem in India today, with the irony of high growth rate and malnutrition and stunting of children under age 5 years that occurs in the majority and wealthy Hindu population, but not to any comparable degree in the Muslim population or in Bangladesh. This is prevalent along the Ganges River, which crosses India below the Himalaya Mountains. The inference is that the problem is perhaps solely related to poor sanitation, which is to a large degree indisputable, and the disease is related to the gut microbiome (not so stated), that leaves an intestinal mucosa with flattened epithelia, and no observation is made of the submucosal thymic-derived T-cell lymphocyte population, the largest in the human body.
Moreover, I might point out that the turnover of the intestinal epithelium with its large surface area is very high under normal metabolic circumstances. The result is that the children are malnourished, and they have visceral protein losses as well as somatic protein loss (stunted growth, probably affecting both skeletal muscle and the metaphyseal growth plates of long bones). This is not quite stated this way.
The irony is that they have sufficient food supply, except that if there is a diarrhea or intestinal malabsorption at an early age, the children just might not eat, except for perhaps soft foods. So it is not explicitly cleat that their is sufficient animal protein in the diet, which has a S:N ratio that is roughly twice that of an exclusively plant diet. The distinction is made between marasmus and kwashiorkor in that in kwashiorkor the protein deficiency is in the visceral compartment. Consequently, there is a reprioriotization of the liver to synthesize acute phase proteins with a decline in albumin, transthyretin, and retinol-binding protein. This is not insignificant, even though there may also be an inflammatory state, as from repeated infections.
I certainly would be interested in seeing data from the ongoing study that measures the serum protein analytes, and also a measurement of serum red cell Hb, serum cysteine, homocysteine, and glutathione, and perhaps a muscle biopsy.
I go directly to the article at this point.
Poor Sanitation in India May Afflict Well-Fed Children With Malnutrition
By GARDINER HARRIS JULY 13, 2014
http://www.nytimes.com/2014/07/15/world/asia/poor-sanitation-in-india-may-afflict-well-fed-children-with-malnutrition.html
SHEOHAR DISTRICT, India — He wore thick black eyeliner to ward off the evil eye, but Vivek, a tiny 1-year-old living in a village of mud huts and diminutive people, had nonetheless fallen victim to India’s great scourge of malnutrition.
His parents seemed to be doing all the right things. His mother still breast-fed him. His family had six goats, access to fresh buffalo milk and a hut filled with hundreds of pounds of wheat and potatoes. The economy of the state where he lives has for years grown faster than almost any other. His mother said she fed him as much as he would eat and took him four times to doctors, who diagnosed malnutrition. Just before Vivek was born in this green landscape of small plots and grazing water buffalo near the Nepali border, the family even got electricity.
So why was Vivek malnourished?
‘Bihar grew at 12% last 7 years’
Abhay Singh, TNN | Feb 15, 2014, 02.15AM IST
Bihar’s average annual growth rate has been 12% in the last seven fiscal years
The report has taken 1999-2006 as the cut-off period to highlight spectacular Bihar turnaround story achieved under CM Nitish Kumar.
PATNA: Bihar’s average annual growth rate has been 12% in the last seven fiscal years, one of the highest among all Indian states, on the back of high growth rate achieved in the agriculture and allied sectors. Besides, advancement has also been made in healthcare and education.
The state’s Economic Survey Report for 2013-14, which was tabled in the assembly on Friday, has concluded this. The summary of the report said, “During 1990-91 to 2005-06, the state’s income at constant prices grew at an annual rate of 5.7%.” It said after that the economy witnessed a turnaround and grew at an annual rate of 12%. “The rate of growth achieved by the economy during 2006-13 is not only much higher, but also one of the highest among all Indian states.”
The report has taken 1999-2006 as the cut-off period to highlight spectacular Bihar turnaround story achieved under CM Nitish Kumar.
Poor Sanitation Linked to Malnutrition in India
New research on malnutrition, which leads to childhood stunting, suggests that a root cause may be an abundance of human waste polluting soil and water, rather than a scarcity of food.
SANITATION – bathing in Ganges River contaminated by human waste
Like almost everyone else in their village, Vivek and his family have no toilet, and the district where they live has the highest concentration of people who defecate outdoors. As a result, children are exposed to a bacterial brew that often sickens them, leaving them unable to attain a healthy body weight no matter how much food they eat.
“These children’s bodies divert energy and nutrients away from growth and brain development to prioritize infection-fighting survival,” said Jean Humphrey, a professor of human nutrition at Johns Hopkins Bloomberg School of Public Health. “When this happens during the first two years of life, children become stunted. What’s particularly disturbing is that the lost height and intelligence are permanent.”
Two years ago, Unicef, the World Health Organization and the World Bank released a major report on child malnutrition that focused entirely on a lack of food. Sanitation was not mentioned. Now, Unicef officials and those from other major charitable organizations said in interviews that they believe that poor sanitation may cause more than half of the world’s stunting problems.
“Our realization about the connection between stunting and sanitation is just emerging,” said Sue Coates, chief of water, sanitation and hygiene at Unicef India. “At this point, it is still just an hypothesis, but it is an incredibly exciting and important one because of its potential impact.”
This research has quietly swept through many of the world’s nutrition and donor organizations in part because it resolves a great mystery: Why are Indian children so much more malnourished than their poorer counterparts in sub-Saharan Africa?
A child raised in India is far more likely to be malnourished than one from the Democratic Republic of Congo, Zimbabwe or Somalia, the planet’s poorest countries. Stunting affects 65 million Indian children under the age of 5, including a third of children from the country’s richest families.
This disconnect between wealth and malnutrition is so striking that economists have concluded that economic growth does almost nothing to reduce malnutrition.
Half of India’s population, or at least 620 million people, defecate outdoors. And while this share has declined slightly in the past decade, an analysis of census data shows that rapid population growth has meant that most Indians are being exposed to more human waste than ever before.
In Sheohar, for instance, a toilet-building program between 2001 and 2011 decreased the share of households without toilets to 80 percent from 87 percent, but population growth meant that exposure to human waste rose by half.
“The difference in average height between Indian and African children can be explained entirely by differing concentrations of open defecation,” said Dean Spears, an economist at the Delhi School of Economics. “There are far more people defecating outside in India more closely to one another’s children and homes than there are in Africa or anywhere else in the world.”
SANITATION-children defecate outside – 162 million malnourished and stunted
Not only does stunting contribute to the deaths of a million children under the age of 5 each year, but those who survive suffer cognitive deficits and are poorer and sicker than children not affected by stunting. They also may face increased risks for adult illnesses like diabetes, heart attacks and strokes.
“India’s stunting problem represents the largest loss of human potential in any country in history, and it affects 20 times more people in India alone than H.I.V./AIDS does around the world,” said Ramanan Laxminarayan, vice president for research and policy at the Public Health Foundation of India.
India is an increasingly risky place to raise children. The country’s sanitation and air quality are among the worst in the world. Parasitic diseases and infections like tuberculosis, often linked with poor sanitation, are most common in India. More than one in four newborn deaths occur in India.
Open defecation has long been an issue in India. Some ancient Hindu texts advised people to relieve themselves far from home, a practice that Gandhi sought to curb.
“The cause of many of our diseases is the condition of our lavatories and our bad habit of disposing of excreta anywhere and everywhere,” Gandhi wrote in 1925.
SANITATION-disposing of excreta anywhere and everywhere
Other developing countries have made huge strides in improving sanitation. Just 1 percent of Chinese and 3 percent of Bangladeshis relieve themselves outside compared with half of Indians. Attitudes may be just as important as access to toilets. Constructing and maintaining tens of millions of toilets in India would cost untold billions, a price many voters see no need to pay — a recent survey found that many people prefer going to the bathroom outside.
Few rural households build the sort of inexpensive latrines that have all but eliminated outdoor waste in neighboring Bangladesh.
“We need a cultural revolution in this country to completely change people’s attitudes toward sanitation and hygiene,” said Jairam Ramesh, an economist and former sanitation minister.
India’s government has for decades tried to resolve the country’s stubborn malnutrition problems by distributing vast stores of subsidized food. But more and better food has largely failed to reverse early stunting, studies have repeatedly shown.
India now spends about $26 billion annually on food and jobs programs, and less than $400 million on improving sanitation — a ratio of more than 60 to 1.
Lack of food is still an important contributor to malnutrition for some children, and some researchers say the field’s sudden embrace of sanitation has been overdone. “In South Asia, a more important factor driving stunting is diet quality,” said Zulfiqar A. Bhutta, a director of the Center for Global Child Health at the Hospital for Sick Children in Toronto.
Studies are underway in Bangladesh, Kenya and Zimbabwe to assess the share of stunting attributable to poor sanitation. “Is it 50 percent? Ninety percent? That’s a question worth answering,” said Dr. Stephen Luby, a professor of medicine at Stanford University who is overseeing a trial in Bangladesh that is expected to report its results in 2016. “In the meantime, I think we can all agree that it’s not a good idea to raise children surrounded by poop.”
Better sanitation in the West during the 19th and early 20th centuries led to huge improvements in health long before the advent of vaccines and antibiotics, and researchers have long known that childhood environments play a crucial role in child death and adult height.
The present research on gut diseases in children has focused on a condition resulting from repeated bacterial infections that flatten intestinal linings, reducing by a third the ability to absorb nutrients. A recent study of starving children found that they lacked the crucial gut bacteria needed to digest food.
In a little-discussed but surprising finding, Muslim children in India are 17 percent more likely to survive infancy than Hindus, even though Muslims are generally poorer and less educated. This enormous difference in infant mortality is explained by the fact that Muslims are far more likely to use latrines and live next to others also using latrines, a recent analysis found.
So widespread housing discrimination that confines many Muslims to separate slums may protect their children from increased exposure to the higher levels of waste in Hindu communities and, as a result, save thousands of Indian Muslim babies from death each year.
SANITATION-one in 4 newborn deaths related to sanitation
Discussion:
The coexistence of poor sanitation, where has a very large cultural barrier, with serious protein-energy malnutrition, is a toxic mix. There is the comparison with the Muslim population at the adjoining border of the Ganges River outflow in Bangladesh. One might also look at the catholic Portuguese population in Goa, the Jewish population in Mumbai and Kochi, and the nearby Catholic population. There is no malnutrition in those populations, or in the Siiks. This is undoubtedly a cultural phenomenon of ancient origin. (The migration of the jews and of the catholics to Kochi occurred around the Indian Ocean at the time of Christ. The catholic population in Goa was from Portugal.
I don’t think we have enough of the story here. The Ganges river flows centrally across India, and is not far from the Himalayas. This has some significance in the sufficiency of animal protein availability, and most importantly, of what I might expect of the tissue S:N ratio, which is critical for availability of methionine, S-adenosyl methionine, and mitochondrial energy reactions. These are also mediated by transsulfuration reactions and by cystathionine beta-synthase. Detailed discussions are available elsewhere. It has been pointed out by Vernon Young and Yve Ingenbleek that sulfur is insufficient in the soil where there is not a lava flow of volcanic ash, which could be the case here. So it is at best not a good geographic situation, even before compounding the issue.
The relationship to heart attack and stroke is established for elevated homocysteine.
Homocysteine and Vascular Disease
STEVEN E . S. MINER , M.D. , DAVID E .C. COLE *, M.D. , PHD. AND DUNCAN J . STEWART, M.D.
Cardiology Rounds A U G U S T 1 9 9 6 ; I(5)
Homocysteine is a naturally occurring, sulfur-containing amino acid. Continuously formed and catabolized in vivo, its metabolism is dependent on a complex interaction of genetics and physiology (Fig. 1). Its relevance is based on the increasing recognition of the correlation between elevated levels of homocysteine and human disease.
Table 1
Selected Determinants of Plasma Homocysteine*
1. Genetic
• Cystathionine-beta-synthase:
heterozygote mutations 0.5-1.5% {451}
• Methionine synthase: rare
• MTHFR: heterozygote mutations
approximately 50% {403}
2. Physiologic
• age: Hcy increases with increasing age {336}
• sex: pre-and post-menopausal women
have lower levels than men {247}
• diet: related to methionine and vitamin cofactor
(folate, vitamins B6 and B12) intake {437}
• alcohol: relationship unclear {375}
3. Pathologic
• vitamin deficiency: increased homocysteine
concentrations {10}
• renal disease: increase correlated
with increasing serum creatinine {81}
• transplantation: increased levels {149, 435}
• post stroke: transiently decreased levels {341}
• severe psoriasis: elevated levels {438}
4. Medications
• oral contraceptives/hormone replacement:
decreased levels {269}
• corticosteriods: increased {159}
• cyclosporine: increased {393}
• smoking: increased {336}
Abstracts of Interest
Serum total homocysteine and coronary heart disease in middleaged
British men.
IJ PERRY, H REFSUM, RW MORRIS, SB EBRAHIM, PM UELAND, AG SHAPER.
D E PA RTMENT OF PRIMARY CARE & POPULATION SCIENCES, ROYAL FREE
H O S P I TAL SCHOOL OF MEDICINE, LONDON, AND DEPA RTMENT OF CLINICAL
B I O L O G Y, UNIVERSITY OF BERGEN, NORWAY.
Serum total homocysteine (tHcy) levels are inversely associated with dietary intake of folic acid and B vitamins. Raised tHcy levels have been linked with coronary heart disease (CHD). We have examined the association between tHcy concentration and the subsequent risk of CHD, using a nested case control study design, within a prospective study of cardiovascular disease in British men. tHcy concentration was measured in serum samples, stored at entry to the study, from 110 incident cases of myocardial infarction and 118 controls. Cases were randomly sampled from events which occured after the first five years of follow-up. Cases and controls were frequency matched by town and age group. Levels of homocysteine [geometric mean (95% CI)] were significantly higher in cases than controls: homocysteine 13.5 (12.6 – 14.3) μmol/L vs 11.9 (11.3 – 12.6) μmol/L; p=0.005. There was a graded increase in the relative risk (odds ratio; OR) of CHD in the 2nd, 3rd and 4th quartile of tHcy (OR 1.4, 1.9, 2.2; trend p=0.006) relative to the first quartile. Adjustment for age, town, social class, body mass index, smoking, physical activity, alcohol intake, hypertensive status, serum cholesterol, and serum creatinine did not attenuate this association, (OR 2.1, 2.3, 2.7; trend p=0.04). tHcy levels were higher at baseline in men with evidence of pre-existing CHD and (as expected) adjustment for this factor attenuated the linear association between tHcy and subsequent events, trend p=0.07. The findings suggest that homocysteine is an independent risk factor for CHD
with no threshold level.
Reprinted from Heart, Volume 75 /Number 5 (Supplement 1), May 1996.
Homocysteine and Coronary Atherosclerosis
ELLEN L. MAYER, MD, DONALD W. JACOBSEN, PHD, KILLIAN ROBINSON, MD,
FACC, CLEVELAND, OHIO
The conventional risk factors for premature coronary artery disease include smoking, hyperlipidemia, hypertension, diabetes and a positive family history. However, many patients have precocious atherosclerosis without having any of these standard risk factors. Identification of other markers that increase the risk of coronary disease may improve our understanding of the pathophysiologic mechanisms of this disorder and allow the development of new preventive or therapeutic measures. An elevated plasma homocysteine level has recently received greater attention as an important risk factor for vascular disease, including coronary atherosclerosis. This review discusses the biochemistry of homocysteine and the related metabolic importance of folate, vitamin B6 (pyridoxine) and B12 (cobalamin) as well as a number of essential enzymes. The major factors that influence homocysteine concentration are genetic, nutritional and pathologic.
There is a large body of experimental and clinical evidence for high plasma homocysteine to be a risk factor for vascular disease, including coronary atherosclerosis.
Excerpted from Journal of the American College of Cardiology 1996;27:517-27
An important meta-analysis by Boushey et al in 1995 further quantified the magnitude of risk. In their analysis of all major studies available at that time, they found a linear, independent risk for increments in homocysteine. There were no levels above or below which an incremental rise in homocysteine did not affect cardiovascular risk. Specifically, every 5 μmol/L increment in homocysteine was found to be associated with odds ratios of 1.6 for m e n ; (95% Cl 1.4-1.7) and 1.8 for women; (95% CI 1.3-1.9) for coronary artery disease.
Cystathionine beta synthase (CBS) catalyzes the reaction taking homocysteine to cystathionine. This enzyme requires pyridoxine as a co-factor and is an integral part of the transsulfuration or
pyridoxine – dependent pathway. 33 distinct mutations have been identified with heterozygosity occurring at a prevalence of 0.5-1.5%. The majority of heterozygotes will have normal fasting homocysteine levels, but can be detected with a methionine load test.
Hyperhomocysteinemia is a Biomarker of Sulfur-Deficiency in Human Morbidities
Yves Ingenbleek
Laboratory of Nutrition, University Louis Pasteur Strasbourg, France
The Open Clinical Chemistry Journal, 2009, 2, 49-60
Abstract: Methionine (Met) is crucially involved in the synthesis of S-compounds endowed with molecular, structural and functional properties of survival value. Dietary Met may undergo transmethylation processes to release homocysteine (Hcy) which may either be regenerated to Met following remethylation (RM) pathways or catabolized along the transsulfuration
(TS) cascade. The activity of enzymes governing RM and TS pathways is depending on pyridoxine, folate and cobalamin bioavailability. Dietary restriction in any of these watersoluble B-vitamins may lead to hyperhomocysteinemia (HHcy) causing a panoply of cardiovascular disorders. Taken together, the vitamin triad only affords partial account of Hcy variance, prompting the search for additional causal factor(s). Body composition studies demonstrate that nitrogen (N) and sulfur (S) maintain tightly correlated concentrations in tissues of both healthy subjects and diseased patients. Any morbid condition characterized by insufficient N intake or assimilation, as seen in protein malnutrition or intestinal malabsorption, reduces body S accretion rates. Excessive urinary N-losses, as reported in acute or chronic inflammatory disorders, entail proportionate obligatory S-losses. As a result, lean body mass (LBM) undergoes downsizing and concomitant depletion of N and S body stores which depresses the activity of cystathionine--synthase, thereby promoting upstream accumulation of Hcy and overstimulation of RM processes. HHcy thus appears as the dark side of efforts developed by S-deprived patients to safeguard Met homeostasis. Irrespective of vitamin-B status, Hcy values are negatively correlated with LBM shrinkage well identified by the serial measurement of plasma transthyretin (TTR). The S deprivation theory fulfills the gap and allows full causal coverage of the metabolic anomaly, hence providing together with vitamin-deficiencies an unifying overview of the main nutritional determinants implicated in HHcy epidemiology.
The Oxidative Stress of Hyperhomocysteinemia Results from Reduced Bioavailability of Sulfur-Containing Reductants
Yves Ingenbleek
Laboratory of Nutrition, Faculty of Pharmacy, University Louis Pasteur Strasbourg, France
The Open Clinical Chemistry Journal, 2011, 4, 34-44
Abstract: Vegetarian subjects consuming subnormal amounts of methionine (Met) are characterized by subclinical protein malnutrition causing reduction in size of their lean body mass (LBM) best identified by the serial measurement of plasma transthyretin (TTR). As a result, the transsulfuration pathway is depressed at cystathionine-beta-synthase (C-b-S) level triggering the upstream sequestration of homocysteine (Hcy) in biological fluids and promoting its conversion to Met. Maintenance of beneficial Met homeostasis is counterpoised by the drop of cysteine (Cys) and glutathione (GSH) values downstream to CbS causing in turn declining generation of hydrogen sulfide (H2S) from enzymatic sources. The biogenesis of H2S via non-enzymatic reduction is further inhibited in areas where earth’s crust is depleted in elemental sulfur (S8) and sulfate oxyanions. Combination of subclinical malnutrition and S8-deficiency thus maximizes the defective production of Cys, GSH and H2S reductants, explaining persistence of unabated oxidative burden. The clinical entity increases the risk of developing cardiovascular diseases (CVD) and stroke in underprivileged plant-eating populations regardless of Framingham criteria and vitamin-B status. Although unrecognized up to now, the nutritional disorder is one of the commonest worldwide, reaching top prevalence in populated regions of Southeastern Asia. Increased risk of hyperhomocysteinemia and oxidative stress may also affect individuals suffering from intestinal malabsorption or westernized communities
having adopted vegan dietary lifestyles.
The Experience of a Patient with Thyroid Cancer
Posted in Best evidence, Clinical Diagnostics, Curation, Developmental biology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Electrophysiology, Endocrine Diseases, Experimental validation, Explanatory, Historical relevance, Immunodiagnostics, Inferential analysis, Innovation in Immunology Diagnostics, Interventional Oncology: Radiofrequency Ablation, Transarterial Chemoembolization, Microwave Ablation and Irreversible Electroporation (IRE), Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Nutrition, Patient Experience: Personal Memories of Invasive Medical Intervantion, Personalized and Precision Medicine & Genomic Research, Proteomics, Sensors & Analytics, Signaling, Technology Advance Assessment of, Translational Effectiveness, Translational Science, tagged Graves' disease, thyroid cancer, thyroid eye disease, TSH on July 14, 2014| Leave a Comment »
The Experience of a Patient with Thyroid Cancer
Interviewer and Curator: Larry H Bernstein, MD, FCAP
Thyroid cancer is usually a fairly innocuous disease, but it can present in different ways. There are are perhaps two main types – medullary, and follicular. But an anaplastic type is also a third uncommon type. It is speculative for me to suggest that the anaplastic type is a progression of either of the two main types. A RAS genotype coexists with the aggressive anaplastic carcinoma. Thyroid cancers are BRAF positive in genotype. The histological feature that is used to identify this neoplasm is the presence of “sammoma bodies”. It is more common in women, and less common in the elderly, and the incidence appears to have increased regionally in recent years. A recent paper suggests a common specific feature with breast cancer, which is unconfirmed.
When we consider thyroid disease, we start with euthyroid status, hypothyroid and hyperthyroid, all of which are related to the synthetic activity of the gland, that has a right and left lobe joined by a isthmus. In the midwestern US there is a deficiency of iodine, which leads to nodular thyroid goiter. The Mayo brothers pioneered in thyroid surgery at their clinic in Rochester, MN. This led to the insertion of iodine in table salt (Morton’s salt- “when it rains, it pours). Hyperthyroid status is over production of the hormone by an overactive gland. It is usually primary disease, called Grave’s Disease, after the physician who described it. I am not aware of the occurrence secondary to hyperactivity of the pituitary gland, which would result in both an increased thyroid stimulating hormone (TSH), thyrotropin, and elevated thyroid hormone, except by a primary neoplasm of thyrotropin secreting cells. The two hormones are under feedback control. This feedback is a valuable diagnostic indicator because the TSH is suppressed with Grave’s disease. The TSH assay is very accurate, and as the TSH falls, the TH increases, but the TH assay has never been as accurate as the TSH. The TH is transported in serum by three proteins: thyroxin-binding globulin (TBG), albumin, and trans-thy-retin (TTR), a quadruplex peptide with one subunit binding to retinol-binding protein (RPB), which transports retinol, vitamin A). The importance of TTR is not a subject for discussion here, but it has extremely important ties to metabolic disease that includes hyperhomocysteinemia and Alzheimer’s disease, as this protein is produced by both the liver and the choroid plexus, but the CP production declines in the elderly. The TTR metabolism is closely linked to total body sulfur, measured by K+ isotope measurement of lean body mass (fat free mass), and is a more accurate measure than use of urinary creatinine loss, which only measure the structural body mass, but not the visceral component.
There is another twist to the story in that thyroid hormone may be depressed over time secondary to an autoantibody to thyroid “peroxidase”, leading to destruction of the gland. The thyroid antibody that occurs has been recently reported to be a “peroxidase” antibody in common with the mammary gland. The disorder is denominated – Hashimoto’s thyroiditis. The presence of thyroid antibody may occur with Grave’s disease, with an occular protrusion with inflammation of the adductor muscles of eye movement. This is termed “exophthalmus”. However, thyroid eye disease is known to occur with hypo-, hyper-, and euthyroid status.
I here describe the long and difficult search to identify a confusing case.
Family history: Mother had thyroid cancer, surgically cured at Mayo Clinic. Sister had Hashimoto’s thyroiditis. Father had severe rheumatoid arthritis.
History of Illness. The patient is a male over 65 years age who attended a discussion group for several years and participated in supervised fitness exercises and did daily walks for 2-3 years prior to the discovery of the problem when he recalls, his voice was weak in making presentations to the discussion group (age 86 and over).
At the end of summer, 2013, he experienced shortness of breath and dizziness on walking. His physician had been concerned about the change of voice prior to this. He had a history of sleep apnea, and he was actively trying to lose weight. Cardiac and vascular examination of carotid and of peripheral circulation were unexpectedly excellent. Pulmonary studies were good.
A visit to an ENT physician did not explain the voice impairment. An unexpected low TSH result came back < 0.01, compared to a normal result 9 months earlier. This was the first indication of an active cyst or Grave’s disease. The patient was referred for ultrasound exam, and a thyroid panel was ordered. The result of the ultrasound was an enlarged right lobe with two large degenerate cysts, and a central small calcified cyst. The cyst was biopsied and it was malignant. It was BRAF pos and RAS negative.
He was referred to the nearest world-class academic center for further endocrine evaluation. The endocrinologist palpated a thyroid enlargement, and a biopsy was performed of the lymph nodes under a full scan of the neck. Surgery was scheduled and a surgeon skilled in endocrine surgery and cancer removed the thyroid, and noted that the right lobe compressed the recurrent laryngeal nerve. This was consistent with en ENT examination of the larynx that showed paralysis of the right larynx. The good news was that the prediction was that the nerve innovation was good, and would return.
There were a few involved lymph nodes in the removed specimen. The patient was put on synthroid. The next step was to schedule I131 radioiodine treatment by oral tablets. This required a preparatory diet of no salt or iodine intake prior to treatment. There was also a 5 day isolation for beta ray emission (which kills residual thyroid cells). The neck was scanned with a gamma scanned prior to induction of treatment, which required a dose of synthetic TSH and a low dose of I131. The patiemt is recovered for 14 days post treatment and has regained much energy.
There is a residual burden of the thyroid eye disease that requires special optical care because of loss of distance perception with diplopia. This is stable, but any surgical repair would have to wait for a year.
Notes from PathologyOutlines.com, Nathan Pernick, Editor-in-Chief
Thyroid gland
Reviewer: Zubair W. Baloch, M.D., Shahidul Islam, M.D., Ph.D., Ricardo R. Lastra, M.D., Michelle R. Pramick, M.D., Phillip A. Williams, M.D., MSC (see Reviewers page)
Revised: 11 July 2014, last major update IN PROGRESS
Copyright: (c) 2001-2014, PathologyOutlines.com, Inc.
Endocrine abnormalities and thyroid gland
Hyperthyroidism
Reviewer: Shahidul Islam, M.D., Ph.D.
General
=======================================================
- Accelerated thyroid hormone biosynthesis and secretion by thyroid gland
- Early symptoms: anxiety, palpitations, rapid pulse, fatigue, muscle weakness, tremor, weight loss, diarrhea, heat intolerance, warm skin, excessive perspiration, menstrual changes, hand tremor
- Ocular changes: wide staring gaze and lid lag due to sympathetic overstimulation of levator palpebrae superioris
Thyrotoxicosis: hypermetabolic clinical syndrome due to elevated serum T3 or T4
Types
=======================================================
- Primary hyperthyroidism: intrinsic thyroid abnormality
- Low TSH, high free T4, normal TRH stimulation test
- Secondary hyperthyroidism: high TSH, abnormal TRH stimulation test
- Subclinical hyperthyroidism: low TSH (< 0.1 µIU/ml), normal T3 and T4 (Eur J Endocrinol 2005;152:1), no clinical hyperthyroidism
- May be due to exogenous thyroid hormone (Hormones (Athens) 2006;5:119)
- Patients have increased risk of coronary heart disease (Int J Cardiol 2008;125:41)
- T3 hyperthyroidism: 1-4%ofhyperthyroid patients
- Low TSH, high free T3, normal free T4
- Associated with early treatment of hyperthyroidism with antithyroid drugs
- T4 hyperthyroidism:highT4, normal T3
- Due to primary hyperthyroidism causes, also iodine, amiodarone (Arch Pathol Lab Med 2003;127:e275), pregnancy (2%)
Graves’ disease (85%)
Micro images
=======================================================
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Additional references
=======================================================
Hashimoto’s thyroiditis
General
=======================================================
- Autoimmune disease with goiter, elevated circulating anti-thyroid peroxidase and anti-thyroglobulin antibodies
- First described by Hakaru Hashimoto in 1912 (World J Surg 2008;32:688)
Epidemiology
=======================================================
- 90-95% in women, usually 45-65 years old; clusters in families
- More common in Whites than Blacks or Japanese (Am J Clin Pathol 1994;101:698)
- Most common cause of sporadic goiter in children in iodine sufficient areas (J Pediatr Endocrinol Metab 2007;20:1199)
Clinical features
Clinical features
=======================================================
- Adults present with painless, gradual thyroid failure due to autoimmune destruction, may initially have transient hyperthyroidism
- Children have variable hypothyroidism and reversion to euthyroidism so must monitor thyroid function (Clin Endocrinol (Oxf) 2009;71:451)
- Associated with HLA-DR5 (goitrous form), HLA-DR3 (atrophic form)
- May coexist with SLE, rheumatoid arthritis, Sjögren’s syndrome, pernicious anemia, type 2 diabetes, Graves’ disease, chronic active hepatitis, adrenal insufficiency, MALT lymphoma of gastrointestinal tract (80:1 relative risk), other B cell lymphomas
- Associated with well differentiated thyroid cancer (J Am Coll Surg 2007;204:764)
- May evolve into thyroid lymphoma (J Clin Pathol 2008;61:438)
Laboratory
=======================================================
- Autoantibodies include:
- Anti-TSH (specific for Hashimoto’s and Graves’ disease)
- Anti-thyroglobulin (less sensitive but similar specificity as anti-thyroid peroxidase, Clin Chem Lab Med 2006;44:837)
- Anti-thyroid peroxidase (previously called antimicrosomal antibody, sensitive but not specific as 20% of adult women without disease have these antibodies); anti-iodine transporter (rare)
- Note: anti-TSH antibodies block the TSH receptor in Hashimoto’s disease but stimulate the TSH receptor in Graves’ disease
Papillary carcinoma
- 75-80% of thyroid carcinomas
- Occult tumors in 6% at autopsy (1 to 10 mm), 46% multicentric, 14% with nodal metastases (Am J Clin Pathol 1988;90:72)
- Occult tumors in up to 24% with other thyroid disease, but with male predominance (Mod Pathol 1996;9:816)
Epidemiology
=======================================================
- Usually women (70%) of reproductive age
Clinical features
=======================================================
- Usually presents as painless nodule or mass in neck or cervical node; usually cold on scan
- Usually diagnosed by FNA
- At presentation, 67% in thyroid only, 13% in thyroid and cervical nodes, 20% in nodes only
- Parathyroid gland invasion often occurs early (Arch Pathol Lab Med 2002;126:1511)
- Nodal involvement is often not clinically apparent due to small size and similar consistency; nodal metastases may undergo cystic change and resemble branchial cleft cysts (The Internet Journal of Nuclear Medicine 2007;4:2)
- Proteomic analysis of serum may be useful in future for screening or followup (Arch Otolaryngol Head Neck Surg 2008;134:198)
- Lymph nodes:
- Measurement of thyroglobulin in FNA from lymph nodes in patients with history of papillary thyroid carcinoma is useful in detecting recurrent disease, especially if specimen is or likely will be inadequate for evaluation (Cytojournal 2008;5:1)
- Risk factors:
- Ionizing radiation before age 20 (for acne – Surgery 1991;110:691, tonsillitis, tinea capitis, enlarged thymus)
- Post-Chernobyl (particularly children, Endocr Pathol 2006;17:307) or after exposure to nuclear explosions at Marshall Islands (J Epidemiol 2003;13:99)
- Hashimoto’s thyroiditis (possibly, Cancer 1995;76:2312)
- Familial adenomatous polyposis (World J Surg 1998;22:738)
- Is familial in 4.5%, similar prognosis as sporadic disease (Surgery 2009;145:100)
Prognostic factors
=======================================================
- 10 year survival is 98%, similar to general population (versus 92% for follicular carcinoma); 100% if under age 20, even with nodal metastases
- Cervical nodal involvement does NOT affect prognosis
- 5-20% have local recurrences, 10-15% have distant metastases (lung, bones, CNS)
- Poorer prognosis:
- Age 40+ or elderly, male (possibly), local invasion (associated with higher incidence of nodal metastases, Arch Pathol Lab Med 1998;122:166), distant metastases (other sites worse than lung, Surgery 2008;143:35), large tumor size, multicentricity, tall cell, columnar or diffuse sclerosing variants
- Poorly differentiated, anaplastic or squamous foci
added July 14, 2014
Summary – Intraoperative laryngeal nerve monitoring
Objectives: The aim of this study was to stimulate the recurrent laryngeal nerve during thyroidectomy or parathyroidectomy and to record the muscle responses in an attempt to predict postoperative vocal fold mobility.
Patients and methods: Intraoperative recurrent laryngeal nerve monitoring during general anaesthesia was performed by using an electrode-bearing endotracheal tube (nerve integrity monitor EMG endotracheal tube [Medtronic Xomed, Jacksonville, Flo, USA]). Two hundred and fifteen recurrent laryngeal nerves from 141 patients undergoing total thyroidectomy (n = 74),
hemithyroidectomy (n = 63), or parathyroidectomy (n = 4) were prospectively monitored. In each case, the muscle potential was recorded after stimulation of the recurrent laryngeal nerve by a monopolar probe.
Results: The nerve stimulation threshold before and after dissection that induced a muscle response of at least 100 V ranged from 0.1 to 0.85 mA (mean 0.4 mA). The supramaximal stimulation intensity was defined as 1 mA. The amplitude of muscle response varied considerably from one patient to another, but the similarity of the muscle response at supramaximal intensity between pre- and postdissection and between postdissection at the proximal and distal exposed
portions of the nerve was correlated with normal postoperative vocal fold function. Inversely, alteration of the muscle response indicated a considerable risk of recurrent laryngeal nerve palsy, but was not predictive of whether or not this lesion would be permanent. http://dx.doi.org:/10.1016/j.anorl.2011.09.003
Summary – Prognostic impact of tumour multifocality in thyroid papillary microcarcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 175—178
Objective: The objective of this study was to evaluate the prognostic impact of tumour multifocality in papillary thyroid microcarcinoma (PTMC).
Methods: All patients who underwent total thyroidectomy and central neck dissection for PTMC in our institution between 1990 and 2007 were included in this retrospective study. Statistical correlations between tumour multifocality and various clinical or pathological prognostic parameters were assessed by univariate and multivariate analyses.
Results: A total of 160 patients (133 women and 27 men; mean age: 47.8 ± 13.7 years) were included in this study. Tumour multifocality was demonstrated in 59 (37%) patients. Central neck metastatic lymph node involvement was identified in 46 (28%) patients. No statistical correlation was demonstrated between tumour multifocality and the following factors: age, gender, tumour size, extension beyond the thyroid, metastatic central neck lymph node involvement and risk of recurrence. A tumour diameter greater than 5 mm was associated with a higher risk of recurrence (P = 0.008).
Conclusion: Tumour multifocality does not appear to have a prognostic impact in PTMC. http://dx.doi.org:/10.1016/j.anorl.2011.11.003
Positron emission tomography thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 251—256
Objectives: Recurrence is observed in 15—20% of patients under surveillance following treatment of differentiated thyroid cancer (DTC). However, due to cell dedifferentiation, the recurrence may be iodine-negative, thereby compromising detection. For this reason, new methods of exploration are indispensable to enable localization of such recurrences. The purpose of this work is to review the contribution of positron emission tomography—computed tomography (PET-CT) in the exploration of iodine-negative recurrent DTC.
Method: A comprehensive review and discussion of the medical literature was carried out.
Results: Depending on the report, the sensitivity of PET-CT ranged from 70% to 85%, with up to 90% specificity. However, the large number of false negatives, which can reach 40%, is the
disadvantage of this examination. PET-CT results lead to change in the therapeutic strategy in approximately 50% of patients with isolated raised serum thyroglobulin levels, and surgical exploration of a precise anatomical area in the neck.
Conclusion: As post-treatment recurrence of a DTC can affect patient survival, a thorough diagnostic work-up is required in these cases. Where thyroglobulin levels are elevated with no uptake on 131-iodine scans, PET-CT can be a useful complementary exploration, especially for localizing the site of recurrence.
http://dx.doi.org:/10.1016/j.anorl.2012.01.003
French ENT Society (SFORL) practice guidelines for lymph-node management in adult differentiated thyroid carcinoma
European Annals of Otorhinolaryngology, Head and Neck diseases (2012) 129, 197—206
Cervical and mediastinal lymph-node management differentiated thyroid carcinoma of the follicular epithelium (DTC) remains controversial. Depending on the situation, pre-operative staging and indications for and extent of lymph-node dissection are still matters of debate, even in case of palpable nodes found on primary surgery. Procedural indications for adenectomy, selective neck dissection, and anatomic regional extension of dissection are not clearly defined.
Questions raised:
• what is lymph-node involvement in DTC?
• what is the prognostic value of lymph-node invasion: for
recurrence, and for survival?
• what baseline assessment is required ahead of treatment
of papillary thyroid carcinoma to assess possible lymphnode
involvement?
• what are the principles of lymph-node surgery?
Central and lateral dissection, and dissection extended to the mediastinum;
• what is the iatrogenesis in cN0 and cN+ neck?
• what is the impact of central and lateral neck dissection on recurrence, survival, secondary treatment and surveillance in cN0 and cN+ ?
• in cN0 patients, when neck dissection is considered, what lymph-node regions should be indicated?
http://www.orlfrance.org/ download.php?id=159.
Molecular Diagnosis for Indeterminate Thyroid Nodules on Fine Needle Aspiration
Expert Rev Mol Diagn. 2013;13(6):613-62
Somatic mutation testing, mRNA gene expression platforms, protein immunocytochemistry and miRNA panels have improved the diagnostic accuracy of indeterminate thyroid nodules, and although no test is perfectly accurate, in the authors’ opinion, these methods will most certainly become an important part of the diagnostic tools for clinicians and cytopathologists in the future.
Several point mutations and gene rearrangements have been identified in thyroid cancer. The most common somatic mutation in differentiated thyroid cancer has been studied as a potential tool to enhance the diagnostic accuracy of indeterminate FNA lesions – BRAF. This mutation occurs in papillary, poorly differentiated and anaplastic thyroid cancer and causes a V600E substitution in the BRAF protein, which results in neoplastic progression by aberrant activation of the MAPK pathway. The BRAF V600E mutation, along with RET/PTC rearrangements, are a hallmark of thyroid cancer and a vast majority of indeterminate thyroid nodules harboring either one of these two mutations are malignant on final pathology.
The RAS proto-oncogene encodes three different membrane associated GTP proteins: HRAS, KRAS and NRAS. Mutation of these domains causes increased signal transduction through both the MAPK and the PI3K/AKT pathways. These mutations are highly prevalent in FTC and in the follicular variant of papillary thyroid cancer (40–50%) and seldom detected in the classic variant papillary thyroid cancer (10%). RAS mutations have also been identified in benign FA; however, it is unclear whether RAS-positive FA have a higher chance of progression to cancer.
Recurrence detection in differentiated thyroid cancer patients..
Clinical endocrinology, Vol. 72, No. 4. (10 September 2009), pp. 558-563, doi:10.1111/j.1365-2265.2009.03693.x
There was a correlation between TgAb level and recurrence (p = 0.032).
). Recurrence was found in 37.5% of 24 TgAb+/Tg- patients who showed a gradually increasing tendency in serial measurements of TgAb. Sixteen cervical foci (21.1%) missed on neck USG and 17 lesions (22.4%) located outside the neck were additionally detected with PET/CT in TgAb+ patients.
Solving the mystery of iodine uptake
Science 20 June 2014: Vol. 344 no. 6190 p. 1355 http://dx.doi.org:/10.1126/science.344.6190.1355-a
The cell membrane protein NIS (sodium/iodine symporter) transports iodine into thyroid cells, but because iodine concentrations outside of the cell are so low, how it does so is a mystery. The key? Moving two sodium ions along with the iodine ion, Nicola et al found. NIS also does not bind sodium very tightly, but the high concentrations of sodium outside the cell allow one sodium ion to bind. This binding increases the affinity of NIS for a second sodium ion and also for iodine. With the three ions bound, NIS changes its conformation so that it opens to the inside of the cell, where the sodium concentration is low enough for NIS to release its sodium ions. When the sodium goes away, so does NIS’s affinity for iodine, leading NIS to release it.
Study suggests consuming whey protein before meals could help improve blood glucose control in people with diabetes
Posted in Diabetes Mellitus, Nutrition, Nutrition and Phytochemistry, Nutritional Supplements: Atherogenesis, Plant extract, tagged Type2DM, whey protein on July 12, 2014| Leave a Comment »
Good focus on glucose control before breakfast
Omega-3 fatty acids, depleting the source, and protein insufficiency in renal disease
Posted in Affordable Care Act, Cerebrovascular and Neurodegenerative Diseases, Chemical Biology and its relations to Metabolic Disease, Curation, Discovery process, Evolutionary cognition, Explanatory, Health Economics and Outcomes Research, Health Law & Patient Safety, Indigent Nutrition, Innovations in Neurophysiology & Neuropsychology, Liver & Digestive Diseases Research, Medicare and Medicaid, Metabolomics, Nephrology, Neurodegenerative Diseases, Nutrigenomics, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Population Health Management, Nutrition and Phytochemistry, Proteomics, Skilled Nursing Facilities, Uninsured and Underinsured, tagged fish, memory loss, muscle wasting, omega-3 PUFA, sarcopenia, stage 3 & 4 renal disease on July 6, 2014| Leave a Comment »
Larry H. Bernstein, MD, FCAP, Curator
This article is concerned only with updating the importance of key nutrients for maintenance of health. Nutritional losses are associated with memory loss, impaired immunity, and loss of lean body mass.
Low levels of omega-3 fatty acids may cause memory problems
Disease and Conditions, General Diet • Tags: Alzheimer’s disease, American Academy of Neurology, Docosahexaenoic acid, Magnetic resonance imaging, Neurology, Omega-3 fatty acid, United States Environmental Protection Agency, University of California Los Angeles
09 Mar 2012
ST. PAUL, Minn. – A diet lacking in omega-3 fatty acids, nutrients commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking abilities, according to a study published in the February 28, 2012, print issue of Neurology®, the medical journal of the American Academy of Neurology. Omega-3 fatty acids include the nutrients called docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
salmon dinner
“People with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging,” said study author Zaldy S. Tan, MD, MPH, of the Easton Center for Alzheimer’s Disease Research and the Division of Geriatrics, University of California at Los Angeles.
For the study, 1,575 people with an average age of 67 and free of dementia underwent MRI brain scans. They were also given tests that measured mental function, body mass and the omega-3 fatty acid levels in their red blood cells.
The researchers found that people whose DHA levels were among the bottom 25 percent of the participants had lower brain volume compared to people who had higher DHA levels. Similarly, participants with levels of all omega-3 fatty acids in the bottom 25 percent also scored lower on tests of visual memory and executive function, such as problem solving and multi-tasking and abstract thinking.
Related articles
- Potentially Helpful Omega-3 Fatty Acids Can Cross to Brain: Study(news.health.com)
- Omega 3 FA (wedishnutrition.wordpress.com)
- Omega Fatty Acids: The Science Behind Fish Oil- Guest post from Beauty by the Geeks (antisensescienceblog.wordpress.com)
- Omega 3 Fatty Acids Slow Brain Aging? (futurepundit.com)
- Why is Omega-3 Essential to the Human Body?(horningchiropracticcenter.wordpress.com)
- Proof that omega-3 supplements can reach the brain(nyrnaturalnews.com)
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Mechanisms of muscle wasting in chronic kidney disease.
Xiaonan H Wang, William E Mitch
Nature Reviews Nephrology (Impact Factor: 7.94). 07/2014; DOI: 10.1038/nrneph.2014.112
Source: PubMed
ABSTRACT In patients with chronic kidney disease (CKD), loss of cellular proteins increases the risks of morbidity and mortality. Persistence of muscle protein catabolism in CKD results in striking losses of muscle proteins as whole-body protein turnover is great; even small but persistent imbalances between protein synthesis and degradation cause substantial protein loss. No reliable methods to prevent CKD-induced muscle wasting currently exist, but mechanisms that control cellular protein turnover have been identified, suggesting that therapeutic strategies will be developed to suppress or block protein loss. Catabolic pathways that cause protein wasting include activation of the ubiquitin-proteasome system (UPS), caspase-3, lysosomes and myostatin (a negative regulator of skeletal muscle growth). These pathways can be initiated by complications associated with CKD, such as metabolic acidosis, defective insulin signalling, inflammation, increased angiotensin II levels, abnormal appetite regulation and impaired microRNA responses. Inflammation stimulates cellular signalling pathways that activate myostatin, which accelerates UPS-mediated catabolism. Blocking this pathway can prevent loss of muscle proteins. Myostatin inhibition could yield new therapeutic directions for blocking muscle protein wasting in CKD or disorders associated with its complications.
We’re Fishing the Oceans Dry. It’s Time to Reconsider Fish Farms.
Food and Agriculture Organization of the United Nations -State of World Fisheries and Aquaculture 2014
Aquaculture has gotten much greener, with American innovators leading the way.
— Text by Maddie Oatman; video by Brett Brownell
| Wed Jul. 2, 2014 6:00 AM EDT MotherJones.com
When I meet Kenny Belov mid-morning at San Francisco’s Fisherman’s Wharf, the boats that would normally be out at sea chasing salmon sit tethered to their docks. The steady breeze coursing through the bay belies choppier conditions farther out—so rough that the local fishermen threw in the towel for the fifth morning in a row. Belov scans the horizon as he explains this, feet away from the warehouse of his sustainable seafood company, TwoXSea. Because his business hinges on what local fishermen can bring in, he’s used to coping with wild fish shortages.
If we continue to fish at the current pace, some scientists predict we’ll be facing oceans devoid of edible marine creatures by 2050.
But unlike these fishermen, Belov has a stash of treasure in his warehouse, as he soon shows me: a golf-cart-size container of plump trout, their glossy bodies still taut from rigor mortis. The night before, Belov drove north to Humboldt to help “chill kill” the fish by submerging them live into barrels of slushy ice water. Belov can count on shipments of these McFarland Springs trout every week—because he helped grow them himself on a farm.
For many consumers, aquaculture lost its appeal after unappetizing news spread about commercial fish farms—like fish feed’s pressure on wild resources, overflowing waste, toxic buildup in the water, and displacement of natural species. But consider this: Our appetite for seafood continues to rise. Globally, we’ve hungered for 3.2 percent more seafood every year for the last five decades, double the rate of our population. Yet more than four-fifths of the world’s wild fisheries are overexploited or fully exploited (yielding the most fish possible with no expected room for growth). Only 3 percent of stocks are considered underexploited—meaning they have any significant room for expansion. If we continue to fish at the current pace, some scientists predict we’ll be facing oceans devoid of edible marine creatures by 2050.
Aquaculture could come to the rescue. The Food and Agriculture Organization of the United Nations predicts that farmed fish will soon surpass wild-caught; by 2030, aquaculture may produce more than 60 percent of fish we consume as food.
Food and Agriculture Organization of the United Nations “State of World Fisheries and Aquaculture” 2014 report
One of the most pressing concerns about aquaculture, though, is that many farmed fish are raised on a diet of 15 million tons a year of smaller bait fish—species like anchovies and menhaden. These bait—also known as forage fish—are ground up and converted into a substance called fishmeal. It takes roughly five pounds of them to produce one pound of farmed salmon. Bait fish are also used for nonfood products like pet food, makeup, farm animal feed, and fish oil supplements.
Forage fish are a “finite resource that’s been fully utilized.”
It may appear as though the ocean enjoys endless schools of these tiny fish, but they too have been mismanaged, and their populations are prone to collapse. They’re a “finite resource that’s been fully utilized,” says Mike Rust of NOAA’s fisheries arm. Which is disturbing, considering that researchers like those at Oceana argue that forage fish may play an outsize role in maintaining the ocean’s ecological balance, including by contributing to the abundance of bigger predatory fish.
And that’s where Belov’s trout come in: Though he swears no one can taste the difference, his fish are vegetarians. That means those five pounds of forage fish can rest easy at sea. It also means that the trout don’t consume some of the other rendered animal proteins in normal fishmeal pellets: bone meal, feather meal, blood meal, and chicken byproducts.
Belov and McFarland Springs’ owner David McFarland were inspired to switch to vegetarian feed in part by Rick Barrows, a USDA researcher. About six years ago, recounts Barrows, several USDA studies confirmed that fish rely on nutrients—vitamins, minerals, fatty acids, and protein—rather than fishmeal or fish oil, to thrive. If those nutrients could be found in other products, including purely plant-based substances, then aquaculture might not be so dependent on feeding fish other smaller fish.
Barrows and team began to test about 50 potential materials a year, and now have a database of 140 that anyone can browse through online. Belov was one of their first commercial partners. The plant-based food fed to McFarland Springs’ trout consists of a hearty blend of marine algae, freshwater micro algae, vitamins, minerals, flax, flax oil, corn, and nut waste. The resulting complete protein means the trout’s omega 3s are high and their omega 6s are low—a ratio that’s said to enhance anti-inflammatory properties. And “they don’t have the concentration of heavy metals that come from the bait fish,” Belov says. I took one of his rosy fillets home and turned it into trout lox; find the recipe here.
McFarland Springs manages the trout’s waste by funneling it out into a natural sagebrush pasture where it composts the soil.
Belov’s fish feed includes California nuts that are too broken or disfigured to be sold.
Barrows thinks region-specific material for this type of feed offers the most potential. For instance, his team learned that around 5 percent of California nuts can’t be sold because they’re broken or disfigured. They realized they could repurpose excess nut parts for the trout feed; the nut bits helped round out the complete protein. Lately, Barrows has become especially excited about turning barley surplus from the beer industry—which comes at a cheap price in Montana, where he’s based—into a feed-grade concentrate for trout feed.
“You can get just as much growth rate out of fishmeal-free feeds as fishmeal,” says Barrows. And his lab has proven as much with eight different fish species: cobia, Florida pompano, coho salmon, Atlantic salmon, walleye, yellowtail, and White seabass.
But the price difference still stands in the way for many fish farmers. Belov pays slightly more than $1/pound for his plant-based feed, whereas fishmeal pellets average around $0.71/pound. He sells his trout for $6.95/pound, about a dollar more than conventional. But he’s well positioned in the affluent Bay Area, and he usually sells out of his McFarland Springs trout well before the end of each week. As innovation continues in the realm of plant-based feeds, he’s hopeful, along with Barrows, that the price of the pellets will continue to drop.
Here in the United States, we consume plenty of farmed fish already, but only 5 percent of it is sourced domestically. “If we didn’t import so much farmed seafood,” implored Four Fish author Paul Greenberg in a recent New York Times op-ed, “we might develop a viable, sustainable aquaculture sector of our own.” It doesn’t just boil down to economics: The locations we generally export from, like China and South Asia, don’t have near the stringent environmental and health regulations as the US. “Growing more seafood at home would help with trade deficit, but also we could control the safety more,” says Barrows.
Though our current aquaculture sector is relatively tiny, US farmers are in a better position to innovate, because we have a sophisticated animal nutrition research center and feed sector, says NOAA’s Rust. “We’re the leading technical country in the world on feed.”
Belov wasn’t always open to aquaculture, and he still feels that fish—such as some salmon—with healthy wild fisheries attached to them should never be farmed. That way, environmentally responsible fishermen can stay in business. His long-term strategy for sustainable seafood? Draw from the “amazing [wild] fisheries that exist, and then you backfill with intelligent aquaculture, and yes, you can feed the planet with sustainable marine products.” Which may take more work, but as he puts it, “We depleted the ocean. It wasn’t anybody else’s fault. So it’s our job to fix it.”
The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor
Posted in Anaerobic Glycolysis, Biomedical Measurement Science, Ca2+ triggered activation, CANCER BIOLOGY & Innovations in Cancer Therapy, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Toxicity, Experimental validation, FDA, CE Mark & Global Regulatory Affairs: process management and strategic planning - GCP, GLP, ISO 14155, Historical relevance, Intellectual Property, Innovations, Commercialization, Investment in technological breakthrough, International Global Work in Pharmaceutical, Interviews with Scientific Leaders, ISO 10993 for Product Registration: FDA & CE Mark for Development of Medical Devices and Diagnostics, Metabolomics, Nutrition, Oxidative phosphorylation, Phosphorylation, Population Health Management, Nutrition and Phytochemistry, Proteomics, Scientific & Biotech Conferences: Press Coverage, Signaling, Translational Science, Ubiquitinylation, tagged alternative medicine, Avemar, Chemotherapy, complementary medicine, Dietary supplement, experimental cancer research, fermented wheat germ extract, functional foods, gene expression, glucose consumption, pancreatic carcinoma, regulation of metabolism, RNA, tyrosine phosphorylation on June 7, 2014| Leave a Comment »
Larry H Bernstein, MD, FCAP, Contributor
Article ID #143: The Discovery and Properties of Avemar – Fermented Wheat Germ Extract: Carcinogenesis Suppressor. Published on 6/7/2014
WordCloud Image Produced by Adam Tubman
The following discussion will be a review of the current interest in Avemar, a nontoxic, fermentation product of wheat germ extract, garnering interest with respect to alternative and complementary medicinal use.
Extracts from an interview by Sandra Cascio with Mate Hidvegi
Mate’s Transylvania Professor Lajos David was the organizer of the Department of Pharmacy of the University of Szeged in the 1920’s. He was elected as the Dean of the Faculty of Medicine, the first and only pharmacist who reached this high position at the University since. Dr. Hidvegy’s grandfather was a devout Roman catholic, who publicly opposed Nazi persecution of Jews during the Holocaust. One of his colleagues and, perhaps his best friend, was Albert SzentGyorgyi, the Nobel laureate who discovered vitaminC. SzentGyorgyi moved to the United States after World War II, where he turned to studies of muscle biochemistry. In his later years he turned to cancer research. He theorized that a revolutionary anticancer drug could be based upon vitamin C combined with methoxysubstituted benzoquinones, the precursors of which can be found in wheat germ. After completion of the PhD, Dr. Hidvegi spent two years with the Wheat Grain Trust in Winnipeg, Canada, before returning to Hungary in 1990. He decided to followthepathwaythat SzentGyorgyi was now engaged intocompletehisgoals.He contacted anoldfriend,GaborFodor, a brilliantchemist, also a collaborator withSzentGyorgyiincancerresearch.
He wasinvited by Hermann Esterbauer, the head of the Institute of Biochemistry at the University of Graz, to work in his laboratory. Thanks to the generosity of Professor Esterbauer, he accomplished much at Graz together with his student, Dr. Rita Farkas. It was soon after Szent-Gyorgyi’s death when, with the help of Dr. Fodor, they prepared the chemicals to make the drug Szent-Gyorgyi had intended to make, with encouragement from the great quantum biochemist, Janos Ladik. They made wheat germ extracts with the highest free benzoquinone content.This required a fermentation process to liberate the benzoquinone moieties from the chemical bonds which keep them in natural forms: in glycosides. He recalls the purple colored active molecules in the fermentation liquid. Living cells with their exo and endoenzymes are used to split bonds and make new molecules. This is also true for the manufacturing process of Avemar. This extract contains new molecules which cannot be found elsewhere.
“WhenAvemar was voted by the majority of the more than 50,000 professionals for NutrAward, it became obvious that this product is of biological efficacy plus safety, and it is based on good science.” It received the financial support needed. From this, he was able to complete the experiments and get the approval for the registration. The time arrived when he really had to give a name to the product which had only had a code name. One late night it just came: Avemar, from the Latin prayer: Ave Maria.
Avemar with widely used chemotherapeutic drugs completely inhibited the development of metastases. Exploring its whole activity profile might even take a lifetime of research. So far he has supervised Avemar research done in Hungary, Israel, the United States, Austria, Italy, Spain, Slovakia, the Czech Republic, Germany,the United Kingdom, Russia, Australia, Korea, Vietnam. It has been a good experience to see the scientific interest it has generated worldwide. In 2009, Dr. Hidvegy received an invitation from the Nobel laureate, James Watson, codiscoverer of DNA’s double helix. It was a great honor. Avemar, he hopes,will be a significant cancer drug.
Mate Hidvegi was born in Budapest, Hungary, in 1955. He studied, then taught at what is now Budapest University of Technology and Economics. After finishing university, he worked in the cereal industry and was codeveloper of patented feed advisory system based on near infrared ingredient data. In Hungary, Hidvegi was one of the pioneers in the development of technologies for large scale production of instantized extracts for therapeutic use.
Carcinogenesis vol.22 no.10 pp.1649–1652, 2001
Wheat germ extract inhibits experimental colon carcino-genesis in F-344 rats
Attila Zalatnai, Karoly Lapis, Bela Szende, Erzsebet Raso, Andros Telekes, Akos Resetar, and Mate Hidvegi
| It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis was induced by azoxy-methane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three weekly subcutaneous injections at 15 mg/kg body weight (b/w). In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 only the basal diet and MSC were administered. At the end of the experiment all the rats were exsanguinated under a light ether anesthesia and necropsied. Percentage of animals developing colon tumors and number of tumors per animals: group 1 – 0 and 0; group 2– 83.0 and 2.3; group 3 – 44.8 (P ≤ 0.001) and 1.3 (P ≤ 0.004); group 4 – 0 and 0. All the tumors were histologically neoplastic. The numbers of the aberrant crypt foci (ACF) per area (cm2) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P ≤ 0.0001). | |||||||||||||||||||||||||||
|
| Fig. 1. Experimental schedule. Colon carcinogenesis was induced by three consecutive s.c. doses of AOM 1 week apart in F-344 rats. Oral administration of MSC was started 2 weeks before the carcinogen treatments. All the animals were killed at the end of the experiment, e.g. on the 32nd week. (not shown) |
Summing up, although the chemoprevention of colon cancers (and their pre-neoplastic lesions) has well and long been established and could be achieved by totally different compounds, the mechanisms have still remained to be clarified. This is also true for MSC.
The exact mechanism by which the fermented wheat germ concentration can prevent colon cancer is still partly unknown. MSC did inhibit the AOM-induced ACF and colon neoplasm formation, the multiplicity of the tumors, apparently acting in the initiation phase. Regarding this, we can hypothesize that MSC acts as an immunomodulator.
Wheat Germ Extract Decreases Glucose Uptake and RNARibose Formation but Increases Fatty Acid Synthesis in MIAPancreatic Adenocarcinoma Cell
LG Boros, K Lapis, B Szende, R Tömösközi-Farkas, Ádám Balogh, …., and M Hidvégi
UCLA School of Medicine, Harbor-UCLA Research and Education Institute, Torrance, Ca.; First Institute of Pathology and Experimental Cancer Research, Semmelweis Medical University, Budapest, Hungary; Central Food Research Institute, Budapest, Hungary; Department of Surgery, Albert Szent-Gyorgyi Medical and Pharmaceutical Center, School of General Medicine, University of Szeged, Szeged, Hungary; Department of Biochemistry and Molecular Biology, Institut d’Investigacions Biomediques August Pi i Sunyer, University of Barcelona, Barcelona, Spain; andDepartment of Biochemistryand Food Technology, Technical University of Budapest and Biromedicina Company, Budapest, Hungary
Pancreas 2001; 23 (2), pp. 141–147
Summary: The fermented wheat germ extract with standardized composition has potent tumor inhibitory properties. The fermented wheat germ extract controls tumor propagation. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2- 13C2] glucose isotope is used as the single tracer with biologic gas chromatography–mass spectrometry.
MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption, consumption, uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 8.0%), and release of 13CO2 . Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also increased with all doses of wheat germ extract.
The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation–related and cell differentiation–related macromolecules. Wheat germ extract treatment is likely associated with the phosphor-ylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell the direct oxidative degradation of glucose,proliferation–related structural and functional macromolecules(RNA, DNA) and the direct oxidative degradation and survival of pancreatic adenocarcinoma cells in culture.
Key Words: Pentose cycle—Ribose synthesis—Fermented wheat germ extract—Nonoxidative glucose metabolism—Cell proliferation—Avemar.
Fig 1 glu consumption of MIA pancreatic carcinoma cells in response to WGE
Figure 1. Glucose consumption of MIA pancreatic adenocarcinoma cells in response to increasing doses of fermented wheat germ extract (Avemar) treatment after 72 hours of culture. Glucose consumption (measured in milligrams) was estimated by the difference in media glucose content between Avemar-treated and control cultures. MIA cell glucose consumption was significantly inhibited in the presence of either 1 mg/mL (*p < 0.05) or 10 mg/mL (**p < 0.01) Avemar (x + SD; n = 6).
fig-3-rna-syn-of-mia-pancreatic-carcinoma-cells-in-response-to-wge.jpg
Figure 3. Ribosomal RNA synthesis of MIA pancreatic adenocarcinoma cells in response to increasing doses of fermented wheat germ extract (Avemar) treatment after 72 hours of culture. Glucose carbon incorporation into ribose isolated from ribosomal RNA is expressed as molar enrichment. The dose-dependent decrease in of rRNA after Avemar treatment indicates that ribosomal RNA synthesis is the primary site significantly affected by all doses of Avemar treatment with a maximum decrease of 29% after 10 mg/mL treatment (x + SD; n = 9; *p < 0.05, **p < 0.01).
changes in metabolic activity indicate that Avemar treatment affects cell metabolism primarily by decreasing glucose uptake and nucleic acid ribose synthesis while increasing glucose oxidation through the oxidative reactions of the pentose cycle and fatty acid synthesis from glucose carbon. The effect of Avemar treatment on lactate production and TCA cycle anapleurotic flux compared with glucose oxidation is less prominent
Fermented wheat germ extract induces apoptosis and downregulation of major histocompatibility complex class I proteins in tumor T and B cell lines
R FAJKA-BOJA, M HIDVÉGI, Y SHOENFELD, G ION, D DEMYDENKO, R TÖMÖSKÖZI-FARKAS, et al.
INTL J ONCOLOGY 2002; 20: 563-570.
Lymphocyte Signal Transduction Laboratory, Institute of Genetics, and Cytokine Group, Institute of Biochemistry, Biological Research Center of the Hungarian Academy of Sciences, Szeged; Department of Biochemistry and Food Technology, Budapest University of Technology and Economics, Budapest, Hungary; Department of Medicine ‘B’, Center for Autoimmune Diseases, Sheba Medical Center, Tel-Hashomer, Israel; Central Food Research Institute; National Institute of Oncology; Biromedicina Co., Budapest, Hungary
Abstract. The fermented wheat germ extract (code name: on cyto-fluorimeter using a monoclonal antibody to the MSC, trade name: Avemar), with standardized benzoquinone non-polymorphic region of the human MHC class I. MSC content has been shown to inhibit tumor propagation and stimulated tyrosine phosphorylation of intracellular proteins metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. As a result of the MSC treatment, cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control.
Prominent apoptosis of and the influx of extracellular Ca2+ resulted in elevation of the amount of the intracellular Ca2+ concentration. 20-40% was detected upon 24 h of MSC treatment of the cell lines. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the ‘sub-G ’ cell population.
Tyrosine phosphorylation of intra-cellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells.
Inhibition of the cellular tyrosine phosphatase activity or Ca2+ influx resulted in the opposite effect – increasing or diminishing the Avemar induced apoptosis as well as the MHC class I downregulation. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence. The benzoquinone component (2,6-dimethoxi-p-benzoquinone) in MSC induced similar apoptosis and downregulation of the MHC class I molecules in the tumor T and B cell lines to that of MSC. These results suggest that MSC acts on lymphoid tumor cells by reducing MHC class I expression and selectively promoting apoptosis of tumor cells on a tyrosine phosphorylation and Ca2+ influx dependent way. One of the components in MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor in MSC mediated cell response.
| Abbreviations:MHC, major histocompatibility complex;NK, natural killer;DMBQ, 2,6-dimethoxi-p-benzoquinone; FCS, fetal calf serum;PBMC, peripheral bloodmononuclear cells; TCR, T cell receptor;BCR, B cell receptor; mAb, monoclonal antibody;PMSF,phenylmethyl-sulfonylfluoride;pNPP, para-nitrophenyl-phosphate; PHA,phytohemagglutinineKey words: fermented wheat germ extract, Avemar, MSC, 2+ benzoquinone, tyrosine phosphorylation, intracellular Ca , CD45, tyrosine phosphatase, MHC class I downregulation, apoptosis | |
fig-4-apoptosis-of-t-cell-lines-induced-by-avamer.jpg
Figure 4. Apoptosis of tumor T cell lines and healthy lymphocytes upon MSC treatment. Jurkat cells were treated with 1 mg/ml MSC or .3 µg/ml DMBQ and PBMC were treated with 1 mg/ml
MSC for 24 h (A) or Jurkat cells were treated for 12 h (thick line in panel B). Control cells were left unstimulated (black bars in panel A or thin line on panel B). Apoptotic cells were enumerated
with the DNA analysis of the ‘sub-G ’ population (A) or with staining the cells with FITC1 labeled Annexin V
(B). Representative experiments are shown. The difference between the % of apoptosis in the case of treated and non-treated Jurkat cells was significant (MSC, p<0.001, n=14; DMBQ, p<0.05, n=3,
using paired, two-tailed t-test). No difference was found for PBMC (n=2).
MSC treatment causes prominent apoptosis in lymphoid tumor cells but it does not induce apoptosis of healthy resting mononuclear cells. Moreover, although MSC blocks the proliferation of PBM cells stimulated with PHA, it does not induce apoptosis in PHA stimulated cells (data not shown).
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