243CNO20APR2017
CNO Report # 242
Release Date 05 MAY 2017
Draft Report Compiled by
Ralph Turchiano
1. Cow’s milk interferes with absorption of thyroid supplement levothyroxine
2. No more ‘superbugs’? Maple syrup extract enhances antibiotic action
3. Omega-3 fatty acid supplementation may treat autoimmunity in type 1 diabetes
4. Vitamin B diminishes effects of air pollution-induced cardiovascular disease
5. Proof that magnesium could prevent fractures
6. Seemingly innocuous virus can trigger celiac disease
7. Intestinal bacteria may protect against diabetes
8. KU Leuven researchers unravel how stevia controls blood sugar levels
9. Orange essential oil may help alleviate post-traumatic stress disorder
10. Italian-style coffee reduces the risk of prostate cancer
11. Chronic fatigue syndrome linked to imbalanced microbiome
12. Widespread vitamin D deficiency likely due to sunscreen use, increase of chronic diseases
13. Common cold duration is shortened similarly by zinc acetate and zinc gluconate lozenges
14. Psychological benefits for kids when mums keep taking folic acid
15. Study suggests omega-3 in mothers’ diets may lower children’s risk of type 1 diabetes
16. Can the antioxidant resveratrol reduce artery stiffness in diabetics?
17. Vitamin A deficiency is detrimental to blood stem cells
Public Release: 1-Apr-2017
Cow’s milk interferes with absorption of thyroid supplement levothyroxine
The Endocrine Society
ORLANDO–Taking the common oral thyroid hormone medication levothyroxine with a glass of cow’s milk significantly decreases the body’s ability to absorb the drug, a preliminary study finds. Results will be presented Sunday at ENDO 2017, the Endocrine Society’s 99th annual meeting in Orlando, Fla.
“These findings support previous research showing that calcium supplements can interfere with levothyroxine absorption,” said principal investigator Deborah Chon, M.D., an endocrinology fellow at the UCLA David Geffen School of Medicine and the VA (Veterans Affairs) Greater Los Angeles Healthcare System, Los Angeles, Calif. “Decreased absorption means that patients may not get the full dose of thyroid hormone that they are prescribed.”
Although it makes sense that milk, which contains calcium, might interfere with levothyroxine absorption, no study has proved that it does until now, according to Chon.
Levothyroxine is prescribed for patients with an underactive thyroid, called hypothyroidism, to replace the natural thyroid hormone thyroxine (T4) that is too low, or for patients with thyroid cancer, to suppress their thyroid stimulating hormone levels. In 2014, levothyroxine was the most commonly prescribed medication in the U.S., a survey from the IMS Institute for Healthcare Informatics (now QuintilesIMS) found.
Chon and fellow investigators studied 10 adults (six men and four women), with an average age of 33.7 years, who had no known thyroid disease and had normal thyroid hormone function at the start of the study. No one was allergic to cow’s milk or levothyroxine, and none of the women were pregnant or using birth control pills.
Participants fasted overnight before each of two study visits, spaced a month apart. At one visit, participants took 1,000 micrograms of oral levothyroxine alone and at the other visit, they took the same dose concurrently with 12 ounces of 2 percent milk. Before dosing and one, two, four and six hours after ingestion of levothyroxine, participants gave blood samples for measurement of their total T4 levels. Chon said they tested with generic levothyroxine, which most of their patients are taking.
The investigators measured the levothyroxine absorption as the concentration of total T4 in the blood plotted on a graphic curve against time after drug administration, called area under the curve. Over the six hours after the participants took levothyroxine, those who consumed milk at the same time as the medicine had significantly lower total T4 absorption than when they took the drug alone: average area under the curve of 67.3 versus 73.5.
The manufacturer of a brand of levothyroxine recommends that the medication be taken preferably on an empty stomach, 30 to 60 minutes before eating food or taking other medications or vitamins.
“The main message of this study is that patients managed with thyroid hormone replacement therapy should be advised to avoid taking levothyroxine simultaneously with cow’s milk, given its interference,” Chon said.
Public Release: 2-Apr-2017
No more ‘superbugs’? Maple syrup extract enhances antibiotic action
American Chemical Society
SAN FRANCISCO, April 2, 2017 — Antibiotics save lives every day, but there is a downside to their ubiquity. High doses can kill healthy cells along with infection-causing bacteria, while also spurring the creation of “superbugs” that no longer respond to known antibiotics. Now, researchers may have found a natural way to cut down on antibiotic use without sacrificing health: a maple syrup extract that dramatically increases the potency of these medicines.
The researchers will present their work today at the 253rd National Meeting & Exposition of the American Chemical Society (ACS). ACS, the world’s largest scientific society, is holding the meeting here through Thursday. It features more than 14,000 presentations on a wide range of science topics.
“Native populations in Canada have long used maple syrup to fight infections,” says Nathalie Tufenkji, Ph.D. “I’ve always been interested in the science behind these folk medicines.”
The idea for the project really gelled when Tufenkji, who had been studying the antimicrobial effects of cranberry extracts, learned of the anti-cancer properties of a phenolic maple syrup extract. “That gave me the idea to check its antimicrobial activity,” Tufenkji says. “So, I sent my postdoc to the store to buy some syrup.”
Using the same extraction approach as other researchers have in the past, Tufenkji’s team at McGill University separated the sugar and water from the syrup’s phenolic compounds, which contribute to maple syrup’s signature golden hue.
In an initial test, the team exposed several disease-causing bacterial strains to the extract, but they didn’t see much of an effect. Rather than give up on maple syrup altogether, Tufenkji decided to check whether the extract could enhance the antimicrobial potency of the commonly used antibiotics ciprofloxacin and carbenicillin. When her team mixed the phenolic extract with either of these medicines, they indeed found a synergistic effect, allowing them to get the same antimicrobial effect with upwards of 90 percent less antibiotic. The approach worked on a variety of bacterial strains, including E. coli, which can cause gastrointestinal problems; Proteus mirabilis, responsible for many urinary tract infections; and Pseudomonas aeruginosa, which can cause infections often acquired by patients in hospitals.
Building on this work, Tufenkji’s team next tested the extract in fruit flies and moth larvae. The researchers dosed fly food with pathogenic bacteria and antibiotic, with and without the phenolic extract. Flies with meals doused in maple syrup extract lived for days longer than those denied the syrupy topper. The researchers observed a similar outcome with the moth larvae.
To figure out how the extract makes antibiotics work better, the researchers investigated whether the extract changed the permeability of bacterial cells. The extract increased the permeability of the bacteria, suggesting that it helps antibiotics gain access to the interior of bacterial cells. Another experiment suggested that the extract may work by a second mechanism as well, disabling the bacterial pump that normally removes antibiotics from these cells.
Currently, the researchers are testing the maple syrup extract in mice. While it is likely to be years before it would be available to patients as a prescribed medical protocol, and a pharmaceutical company would likely need to purify the extract further to avoid any potential allergic reactions, Tufenkji says, she’s hopeful that it may have an edge over other would-be medications thanks to its source. “There are other products out there that boost antibiotic strength, but this may be the only one that comes from nature,” she says.
Public Release: 4-Apr-2017
Omega-3 fatty acid supplementation may treat autoimmunity in type 1 diabetes
JCI Journals
Type I diabetes (T1D) is an autoimmune condition that develops after the immune system attacks and destroys pancreatic β cells, leading to impaired insulin production. Currently, no therapies can successfully reverse the damage or progression of autoimmune attacks in T1D, but recent findings have suggested that people with autoimmune conditions may benefit from supplementation with omega-3 fatty acid (FA), a type of polyunsaturated FA found in fish oil.
In this issue of the JCI, researchers in Allan Zhao’s lab at Guangdong University of Technology determined that dietary supplementation with omega-3 FAs can diminish the inflammatory processes that contribute to development of T1D. In a mouse model of T1D, they observed that increasing omega-3 FA consumption improved glucose metabolism and reduced the occurrence of diabetes. These improvements were associated with reductions in pro-inflammatory signaling molecules as well as reductions in immune cell infiltration into pancreatic islets. Both dietary supplementation and gene therapy-mediated increases in omega-3 FAs led to long-term improvements in glucose and insulin levels. Moreover, the researchers observed signs of β-cell regeneration in the omega-3-treated T1D mice.
These findings suggest that increasing intake of omega-3 FAs could have beneficial effects by reducing the autoimmune responses that lead to T1D.
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TITLE: ω-3 polyunsaturated fatty acids ameliorate type 1 diabetes and autoimmunity
Public Release: 12-Apr-2017
Vitamin B diminishes effects of air pollution-induced cardiovascular disease
Columbia University’s Mailman School of Public Health
April 12, 2017 — B vitamins can mitigate the impact of fine particle pollution on cardiovascular disease, according to new research conducted at Columbia University’s Mailman School of Public Health. Healthy non-smokers who took vitamin B supplements nearly reversed any negative effects on their cardiovascular and immune systems, weakening the effects of air pollution on heart rate by 150 percent, total white blood count by 139 percent, and lymphocyte count by 106 percent.
This is the first clinical trial to evaluate whether B vitamin supplements change the biologic and physiologic responses to ambient air pollution exposure. The study initiates a course of research for developing preventive pharmacological interventions using B vitamins to contain the health effects of air pollution. The findings are published online in the Nature Publishing Group journal, Scientific Reports.
Ambient fine particulate pollution contributes to 3.7 million premature deaths annually worldwide, predominantly through acute effects on the cardiovascular system. Particulate matter pollution is the most frequent trigger for myocardial infarction at the population level.
“Ambient PM2.5 pollution is one of the most common air pollutants and has a negative effect on cardiac function and the immune system,” said Jia Zhong, PhD, principal investigator, and postdoctoral research officer in the Department of Environmental Health Sciences at Columbia’s Mailman School. “For the first time, our trial provides evidence that B-vitamin supplementation might attenuate the acute effects of PM2.5 on cardiac dysfunction and inflammatory markers.”
The paper builds on research published in March that found B vitamins reduce the negative effects of air pollution as measured by epigenetic markers.
In the new study, researchers recruited ten healthy, 18 to 60-year-old, non-smoking volunteers who were not on any form of B vitamin supplements or other medication. All volunteers received a placebo for four weeks preceding a two-hour exposure experiment to concentrated ambient PM2.5 (250 μ g/m3), after which they were administered B vitamin supplements for four weeks before the next two-hour exposure experiment to PM2.5. A particle-free two-hour exposure was included to provide baseline data. The controlled exposure experiments were conducted from July 2013 to February 2014 at the same time of day and adjusted for season, temperature, and humidity.
“Our results showed that a two-hour exposure to concentrated ambient PM2.5 had substantial physiologic impacts on heart rate, heart rate variability, and white blood counts. Further, we demonstrated that these effects are nearly reversed with four-week B-vitamin supplementation,” noted Andrea Baccarelli, MD, PhD, chair and Leon Hess Professor of Environmental Health Sciences at the Mailman School.
Because the researchers studied healthy adults from lightly polluted urban environment, they caution that their findings might not be generalizable to populations that are at higher risk for pollution-induced cardiovascular effects, including children, older adults, individuals with pre-existing cardiovascular disease, and individuals residing in heavily polluted areas.
“With ambient PM2.5 levels far exceeding air quality standards in many large urban areas worldwide, pollution regulation remains the backbone of public health protection against its cardiovascular health effects. Studies like ours cannot diminish–nor be used to underemphasize–the urgent need to lower air pollution levels to–at a minimum–meet the air quality standards set forth in the United States and other countries. However, residual risk remains for those who are sensitive, and high exposures are, unfortunately, the rule still in many megacities throughout the world,” said Dr. Baccarelli.
Public Release: 12-Apr-2017
Proof that magnesium could prevent fractures
University of Bristol
Magnesium could hold the key to preventing one of the most preventable causes of disability in middle-aged to elderly people, according to new research led by academics at the Universities of Bristol and Eastern Finland.
Bone fractures are one of the leading causes of disability and ill health especially among the ageing population and this increases the burden on the health care system. It is well-known that calcium and vitamin D play an important role in bone health. Magnesium is an essential nutrient and is an important component of the bone. Though there have been suggestions that magnesium may have a beneficial effect on bone health, no study has been able to show its effect on bone fractures.
Researchers at the Universities of Bristol and Eastern Finland followed 2,245 middle-aged men over a 20-year period. They found that men with lower blood levels of magnesium had an increased risk of fractures, particularly fractures of the hip. The risk of having a fracture was reduced by 44 per cent in men with higher blood levels of magnesium. None of the 22 men who had very high magnesium levels (> 2.3 mg/dl) in the study population experienced a fracture during the follow-up period. In the same study, dietary magnesium intake was not found to be linked with fractures. A finding that has been consistently demonstrated in several previous studies.
Dr Setor Kunutsor, Research Fellow from the University of Bristol’s Musculoskeletal Research Unit and lead researcher, said: “The findings do suggest that avoiding low serum concentrations of magnesium may be a promising though unproven strategy for risk prevention of fractures.”
Although blood levels of magnesium depend on magnesium intake from food and water, this may not be the case for the elderly, people with certain bowel disorders, and those on certain medications. For such people, increasing the intake of foods rich in magnesium may not necessarily increase blood magnesium levels. Treating the underlying conditions and magnesium supplementation may be another way of avoiding low blood levels of magnesium.
These new findings may have public health implications as low blood levels of magnesium are very common in the population. This is especially among middle-aged to elderly individuals who are also prone to fractures. Majority of these individuals do not experience any symptoms. Since blood magnesium is not measured routinely in the hospital, individuals with low levels of magnesium are very difficult to identify. These findings could help trigger initiatives to include blood magnesium screening in routine blood panels, especially for the elderly.
Professor Jari Laukkanen from the University of Eastern Finland and principal investigator, said: “The overall evidence suggests that increasing serum magnesium concentrations may protect against the future risk of fractures; however, well-designed magnesium supplementation trials are needed to investigate these potential therapeutic implications.”
Public Release: 6-Apr-2017
Seemingly innocuous virus can trigger celiac disease
Infection with common reoviruses can trigger the immune system response to gluten, further implicating viruses in the development of autoimmune disorder
University of Chicago Medical Center
Infection with reovirus, a common but otherwise harmless virus, can trigger the immune system response to gluten that leads to celiac disease, according to new research from the University of Chicago and the University of Pittsburgh School of Medicine.
The study, published April 7, 2017 in Science, further implicates viruses in the development of autoimmune disorders such as celiac disease and type 1 diabetes, and raises the possibility that vaccines could one day be used to prevent these diseases.
“This study clearly shows that a virus that is not clinically symptomatic can still do bad things to the immune system and set the stage for an autoimmune disorder, and for celiac disease in particular,” said study senior author Bana Jabri, MD, PhD, professor in the Department of Medicine and Pediatrics, vice chair for research in the Department of Medicine, and director of research at the University of Chicago Celiac Disease Center. “However, the specific virus and its genes, the interaction between the microbe and the host, and the health status of the host are all going to matter as well.”
Celiac disease is an autoimmune disorder that affects one in 133 people in the United States, although it is believed that only 17 percent of those have been diagnosed. It is caused by an improper immune response to the protein gluten, found in wheat, rye, and barely, that damages the lining of the small intestine. There is no cure for celiac, and the only effective treatment is a gluten-free diet.
Gluten is a dietary protein that is naturally poorly digested, and therefore more likely to engage the immune system than other proteins, even in people without celiac. However, the way inflammatory immune responses to gluten work remains poorly understood. In a 2011 study published in Nature, Jabri’s laboratory reported that IL-15, a cytokine upregulated in the intestinal lining of celiac disease patients, can break oral tolerance to gluten. However, not all celiac disease patients overexpress IL-15.
The current study, a collaboration with Terence Dermody, MD, chair of the Department of Pediatrics at the University of Pittsburgh School of Medicine and physician-in-chief and scientific director at Children’s Hospital of Pittsburgh of UPMC, shows that intestinal viruses can induce the immune system to overreact to gluten and trigger the development of celiac disease. Using two different reovirus strains, the researchers showed how genetic differences between viruses can change how they interact with the immune system. Both reovirus strains induced protective immunity and did not cause overt disease. However, when given to mice, one common human reovirus triggered an inflammatory immune response and the loss of oral tolerance to gluten, while another closely related but genetically different strain did not.
“We have been studying reovirus for some time, and we were surprised by the discovery of a potential link between reovirus and celiac disease,” said Dermody. “We are now in a position to precisely define the viral factors responsible for the induction of the autoimmune response.”
The study also found that celiac disease patients had much higher levels of antibodies against reoviruses than those without the disease. The celiac patients who had high levels of reovirus antibodies also had much higher levels of IRF1 gene expression, a transcriptional regulator that plays a key role in the loss of oral tolerance to gluten. This suggests that infection with a reovirus can leave a permanent mark on the immune system that sets the stage for a later autoimmune response to gluten.
The study suggests that infection with a reovirus could be a key initiating event for developing celiac. For example, in the United States, babies are usually given their first solid foods–often containing gluten–and weaned from breastfeeding around six months of age. Children with immature immune systems are more susceptible to viral infections at this stage, and for those genetically predisposed to celiac disease, the combination of an intestinal reovirus infection with the first exposure to gluten could create the right conditions for developing celiac.
“During the first year of life, the immune system is still maturing, so for a child with a particular genetic background, getting a particular virus at that time can leave a kind of scar that then has long term consequences,” Jabri said. “That’s why we believe that once we have more studies, we may want to think about whether children at high risk of developing celiac disease should be vaccinated.”
Jabri and her team, including postdoctoral researchers Romain Bouziat, PhD, and Reinhard Hinterleitner, PhD, are collaborating with graduate student Judy Brown and additional members of Dermody’s team at UPMC to study the common critical features of host-viral interactions driving loss of tolerance to dietary antigens. Furthermore, Jabri and Seungmin Hwang from the Department of Pathology at UChicago are investigating the possibility that other viruses can trigger the same series of events. All together, their work provides more evidence that viruses can trigger development of complex immune-mediated diseases, and raises the possibility that vaccines targeting viruses infecting the intestine could be used to protect children at risk for celiac and other autoimmune disorders.
The study was supported by the National Institutes of Health, the University of Chicago Celiac Disease Center and Digestive Disease Research Center Core, the Bettencourt Schueller Foundation, the Dutch Sophia Research Foundation, and the Austrian Science Fund.
Additional authors include Jennifer E. Stencel-Baerenwald, Mine Ikizler, Andrea J. Pruijssers, Jason A. Iskarpatyoti, Solomiia Khomandiak, Nicole McAllister, Pavithra Aravamudhan, and Karl W. Boehme from Vanderbilt University; Toufic Mayassi, Marlies Meisel, Sangman M. Kim, Jordan D. Ernest, Ian Lawrence, Matthew A. Zurenski, Fengling Hu, Sonia S. Kupfer, Stefano Guandalini, and Carol E. Semrad from the University of Chicago; Valentina Discepolo from the University of Chicago and the University of Naples Federico II and CeInGe-Biotecnologie Avanzate, Naples, Italy; Léa M.M. Costes from the University of Chicago and Erasmus University Medical Center Rotterdam, Netherlands; Janneke N. Samsom from Erasmus University Medical Center Rotterdam, Netherlands; Mukund Varma, Hans-Christian Reinecker, Aylwin Ng, and Ramnik J Xavier from Massachusetts General Hospital, Harvard Medical School, the Broad Institute at MIT, and Harvard University; Valérie Abadie from the University of Montreal and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Canada; Luis B. Barreiro from the CHU Sainte-Justine Research Center, Montreal, Canada; and Chaitan Khosla and Brad A. Palanski from Stanford University.
Public Release: 11-Apr-2017
Intestinal bacteria may protect against diabetes
University of Eastern Finland
A high concentration of indolepropionic acid in the serum protects against type 2 diabetes, shows a new study from the University of Eastern Finland. Indolepropionic acid is a metabolite produced by intestinal bacteria, and its production is boosted by a fibre-rich diet. According to the researchers, the discovery provides additional insight into the role of intestinal bacteria in the interplay between diet, metabolism and health.
The findings were published in Scientific Reports. The study was carried out in the LC-MS Metabolomics Centre of the University of Eastern Finland together with a large number of partners from Finnish and Swedish research institutes.
The study compared two groups participating in the Finnish Diabetes Prevention Study, DPS. At the onset of the study, all participants were overweight and had impaired glucose tolerance. The researchers investigated the serum metabolite profile of 200 participants with impaired glucose tolerance, who either developed type 2 diabetes within the first 5 years, or did not convert to type 2 diabetes within a 15-year follow-up. The differences between the groups were analysed by non-targeted metabolomics analysis. Instead of focusing on just a few pre-defined markers, metabolomics analysis allows for the determination of the study participants’ metabolic profile, i.e. the concentrations of several metabolites. The greatest differences in the metabolic profiles of those who developed type 2 diabetes and those who didn’t were observed in the concentrations of indolepropionic acid and certain lipid metabolites.
A high concentration of indolepropionic acid in the serum was discovered to protect against diabetes. Indolepropionic acid is a metabolite produced by intestinal bacteria. A diet rich in whole grain products and dietary fibre increased the indolepropionic acid concentration. A higher concentration of indolepropionic acid also seemed to promote insulin secretion by pancreatic beta cells, which may explain the protective effect.
In addition to the DPS data, the association of indolepropionic acid with the risk of diabetes was also studied in two other population-based datasets: in the Finnish Metabolic Syndrome In Men Study, METSIM, and in the Swedish Västerbotten Intervention Project, VIP. In these datasets too, indolepropionic acid was discovered to protect against diabetes.
The study also identified several new lipid metabolites whose high concentrations were associated with improved insulin resistance and reduced risk of diabetes. The concentrations of these metabolites were also associated with dietary fat: the lower the amount of saturated fat in the diet, the higher the concentrations of these metabolites. Similarly to indolepropionic acid, high concentrations of these lipid metabolites also seemed to protect against low-grade inflammation.
“Earlier studies, too, have linked intestinal bacteria with the risk of disease in overweight people. Our findings suggest that indolepropionic acid may be one factor that mediates the protective effect of diet and intestinal bacteria,” Academy Research Fellow Kati Hanhineva from the University of Eastern Finland says.
A direct identification of intestinal bacteria is a complex process, which is why identifying the metabolites produced by intestinal bacteria may be a more feasible method for analysing the role of intestinal bacteria in the pathogenesis of, for example, diabetes.
The Finnish Diabetes Prevention Study was the first randomised, controlled lifestyle intervention study to show that in persons with impaired glucose tolerance, type 2 diabetes can be prevented by lifestyle changes. The most important lifestyle changes included weight loss, more exercise and dietary adjustments to include more whole grain products, fruits and vegetables.
Public Release: 11-Apr-2017
KU Leuven researchers unravel how stevia controls blood sugar levels
KU Leuven
What makes stevia taste so extremely sweet? And how does the sweetener keep our blood sugar level under control? Researchers at KU Leuven (University of Leuven, Belgium) have discovered that stevia stimulates a protein that is essential for our perception of taste and is involved in the release of insulin after a meal. These results create new possibilities for the treatment of diabetes.
Stevia extract is very popular as a non-caloric substitute for sugar. The plant-based sweetener is also believed to have a positive effect on blood sugar levels, although nobody understood why. Koenraad Philippaert and Rudi Vennekens from the KU Leuven Department of Cellular and Molecular Medicine have now revealed the underlying mechanism. They collaborated with other KU Leuven scientists and with researchers from Université catholique de Louvain and University of Oxford.
“Our experiments have shown that the active components of stevia extract, stevioside and steviol, stimulate the ion channel TRPM5,” Dr Philippaert explains. “The proteins known as ion channels are a kind of microscopic pathway through which minuscule charged particles enter and leave the cell.” These channels are behind many processes in the body.”
“TRPM5 is first and foremost essential for the taste perception of sweet, bitter, and umami on the tongue,” Philippaert continues. “The taste sensation is made even stronger by the stevia component steviol, which stimulates TRPM5. This explains the extremely sweet flavour of stevia as well as its bitter aftertaste.”
TRPM5 also ensures that the pancreas releases enough insulin, for instance after a meal. Therefore, it helps prevent abnormally high blood sugar levels and the development of type 2 diabetes. This condition develops if the pancreas releases insufficient amounts of insulin, often as a result of an unhealthy lifestyle.
“If mice consume a high-fat diet for a long period of time they eventually develop diabetes,” Professor Vennekens explains. “But this is less the case for mice that also receive a daily dose of stevioside: they are protected against diabetes. Stevia did not have this protective effect on mice without TRPM5. This indicates that the protection against abnormally high blood sugar levels and diabetes is due to the stimulation of TRPM5 with stevia components.”
The study opens up perspectives for the development of new treatments to control or possibly prevent diabetes. “But we must not get ahead of ourselves,” warns Philippaert. “This is fundamental research, and there is still a long way to go before we can think of new treatments for diabetes. For one thing, the dosages that the mice received are much higher than the amount of stevioside found in beverages and other products for human consumption. Further research is necessary in order to show if our findings readily apply to humans. All this means that new treatments for diabetes will not be for the very near future.”
Public Release: 24-Apr-2017
Orange essential oil may help alleviate post-traumatic stress disorder
Researchers find evidence that essential oil reduces fear, diminishes immune system markers of stress in mice
Experimental Biology 2017
About 8 percent of people will develop post-traumatic stress disorder at some point in their lives, according to the U.S. Department of Veterans Affairs, yet treatments for this debilitating condition remain limited. In a new study, mice exposed to orange essential oil after a stressful situation showed improvements in markers of stress and fear, suggesting essential oil may offer a nonpharmaceutical option to help alleviate PTSD.
Cassandra Moshfegh, research assistant in Paul Marvar’s laboratory at the George Washington University, will present the work at the American Physiological Society’s annual meeting during the Experimental Biology 2017 meeting, to be held April 22-26 in Chicago.
“Relative to pharmaceuticals, essential oils are much more economical and do not have adverse side effects,” said Moshfegh. “The orange essential plant oil showed a significant effect on the behavioral response in our study mice. This is promising, because it shows that passively inhaling this essential oil could potentially assuage PTSD symptoms in humans.”
Essential oils are aromatic compounds produced naturally by plants. Orange essential oil is typically extracted from the peel of the orange fruit. People use essential oils for therapeutic purposes by diffusing them into the air, applying them to the skin or ingesting them in foods or beverages.
The researchers tested the effects of orange essential oil using Pavlovian Fear conditioning, a behavioral mouse model used to study the formation, storage and expression of fear memories as a model for PTSD. Mice were exposed to the orange essential oil by passive inhalation 40 minutes before and after fear conditioning. Typically mice freeze in fear when they hear a certain audial tone later, a response that diminishes gradually over time.
Twelve mice received the tone by itself, 12 mice received water and fear conditioning, and 12 mice received an orange essential oil and fear conditioning. Mice exposed to orange essential oil by passive inhalation showed a significant reduction in freezing behavior and stopped freezing earlier than the water-exposed, fear-conditioned mice. They also showed significant differences in the types of immune cells present after fear conditioning. The immune system contributes to the inflammation associated with chronic stress and fear, so immune cells are a marker of the biochemical pathways involved in PTSD.
Preliminary results point to differences in the gene expression in the brain between the mice that were exposed to essential oil and those that were not, hinting at a potential mechanism to explain the behavioral results. Moshfegh said further studies would be needed to understand the specific effects of orange essential oil in the brain and nervous system and shed light on how these effects might help to reduce fear and stress in people with PTSD.
Public Release: 26-Apr-2017
Italian-style coffee reduces the risk of prostate cancer
A research on 7,000 Italian men, combined with laboratory studies, confirms that drinking more than 3 Italian-style coffee cups a day reduces prostate cancer risk by more than 50 percent
Istituto Neurologico Mediterraneo Neuromed I.R.C.C.S.
Add another typical component of the Italian way of life to the long list of foods characterizing one of the most healthy populations in the world. This time it’s coffee, prepared the Italian way. A research by the Department of Epidemiology and Prevention – I.R.C.C.S. Neuromed, Italy, in collaboration with the Italian National Institute of Health and the I.R.C.C.S. Istituto Dermopatico dell’Immacolata of Rome, shows that three or more cups a day can lower prostate cancer risk. An antitumor action confirmed also by laboratory experiments.
The study, published in the International Journal of Cancer, sheds light in a field still hotly debated to this day: the role of coffee, and specifically caffeine, in relation to prostate cancer. A protective effect of the popular drink has already been suggested by some recent studies.
“In recent years we have seen a number of international studies on this issue – explains George Pounis, greek researcher at Neuromed and first author of the paper – But scientific evidence has been considered insufficient to draw conclusions. Moreover, in some cases results were contradictory. Our goal, therefore, was to increase knowledge in this field and to provide a clearer view”.
About seven thousand men, resident in Molise region and participating in the epidemiological study Moli-sani, were observed for four years on average. “By analyzing their coffee consumption habits – explains Pounis – and comparing them with prostate cancer cases occurred over time, we saw a net reduction of risk, 53%, in those who drank more than three cups a day”.
Then researchers sought confirmation by testing the action of coffee extracts on prostate cancer cells in laboratory studies. They tested, in particular, extracts containing caffeine or decaffeinated. Only the first ones significantly reduced cancer cells proliferation, as well as their ability to metastasize. An effect that largely disappeared with decaf.
“The observations on cancer cells – says Maria Benedetta Donati, Head of Laboratory of Translational Medicine – allow us to say that the beneficial effect observed among the seven thousand participants is most likely due to caffeine, rather than to the many other substances contained in coffee”.
“We should keep in mind – says Licia Iacoviello, head of the Molecular and Nutritional Epidemiology Laboratory – that the study is conducted on a central Italy population. They prepare coffee rigorously Italian way: high pressure, very high water temperature and with no filters. This method, different from those followed in other areas of the world, could lead to a higher concentration of bioactive substances. It will be very interesting, now, to explore this aspect. Coffee is an integral part of Italian lifestyle, which, we must remember, is not made just by individual foods, but also by the specific way they are prepared”.
Public Release: 26-Apr-2017
Chronic fatigue syndrome linked to imbalanced microbiome
Scientists identify abnormal levels of specific gut bacteria in individuals with chronic fatigue syndrome, including those with and without co-morbid IBS
Columbia University’s Mailman School of Public Health
Scientists at the Center for Infection and Immunity (CII) at Columbia University’s Mailman School of Public Health have discovered abnormal levels of specific gut bacteria related to chronic fatigue syndrome/myalgic encephalomyelitis, or ME/CFS, in patients with and without concurrent irritable bowel syndrome, or IBS. Findings are published in the journal Microbiome.
The study is among the first to disentangle imbalances in the gut bacteria in individuals with ME/CFS and IBS. ME/CFS is a complex, debilitating disorder characterized by extreme fatigue after exertion and other symptoms including muscle and joint pain, cognitive dysfunction, sleep disturbance, and orthostatic intolerance. Up to 90 percent of ME/CFS patients also have IBS.
The researchers followed 50 patients and 50 matched healthy controls recruited at four ME/CFS clinical sites. They tested for bacterial species in fecal samples, and for immune molecules in blood samples.
They report:
· Levels of distinct intestinal bacterial species–Faecalibacterium, Roseburia, Dorea, Coprococcus, Clostridium, Ruminococcus, Coprobacillus–were strongly associated with ME/CFS; their combined relative abundance appeared to be predictive of diagnosis
· Increased abundance of unclassified Alistipes and decreased Faecalibacterium were the top biomarkers of ME/CFS with IBS; while increased unclassified Bacteroides abundance and decreased Bacteroides vulgatus were the top biomarkers of ME/CFS without IBS
· An analysis of bacterial metabolic pathways associated with disturbances in gut bacteria revealed distinct differences between ME/CFS and ME/CFS subgroups relative to healthy controls
· In ME/CFS subgroups, symptom severity measures, including pain and fatigue, correlated with the abundance of distinct bacterial types and metabolic pathways
· No changes were observed in immune markers–a finding that may reflect the dearth of participants who had been ill for a short time; earlier research suggests immune changes may only be evident when comparing short and long duration cases
“Individuals with ME/CFS have a distinct mix of gut bacteria and related metabolic disturbances that may influence the severity of their disease,” says co-lead investigator Dorottya Nagy-Szakal, postdoctoral research scientist at CII.
“Our analysis suggests that we may be able to subtype patients with ME/CFS by analyzing their fecal microbiome,” says co-lead investigator Brent L. Williams, assistant professor of Pathology and Cell Biology at CII. “Subtyping may provide clues to understanding differences in manifestations of disease.”
“Much like IBS, ME/CFS may involve a breakdown in the bidirectional communication between the brain and the gut mediated by bacteria, their metabolites, and the molecules they influence,” says senior author W. Ian Lipkin, director of CII and John Snow Professor of Epidemiology at Columbia’s Mailman School. “By identifying the specific bacteria involved, we are one step closer to more accurate diagnosis and targeted therapies.”
Public Release: 1-May-2017
Widespread vitamin D deficiency likely due to sunscreen use, increase of chronic diseases
Study in The Journal of the American Osteopathic Association highlights risk factors, treatment protocols
American Osteopathic Association
CHICAGO — May 1, 2017 — Results from a clinical review published in The Journal of the American Osteopathic Association find nearly 1 billion people worldwide may have deficient or insufficient levels of vitamin D due to chronic disease and inadequate sun exposure related to sunscreen use.
The study also found that 95 percent of African American adults may have vitamin D deficiency or insufficiency. Vitamin D variations among races are attributed to differences in skin pigmentation.
“People are spending less time outside and, when they do go out, they’re typically wearing sunscreen, which essentially nullifies the body’s ability to produce vitamin D,” said Kim Pfotenhauer, DO, assistant professor at Touro University and a researcher on this study. “While we want people to protect themselves against skin cancer, there are healthy, moderate levels of unprotected sun exposure that can be very helpful in boosting vitamin D.”
Dr. Pfotenhauer also said chronic diseases like Type 2 Diabetes and those related to malabsorption, including kidney disease, Crohn’s and celiac disease greatly inhibit the body’s ability to metabolize vitamin D from food sources.
Considered a hormone rather than a vitamin, vitamin D is produced when skin is exposed to sunlight. Vitamin D receptors are found in virtually every cell in the human body. As a result, it plays a wide role in the body’s functions, including cell growth modulation, neuromuscular and immune function and inflammation reduction.
Symptoms for insufficient or deficient vitamin D include muscle weakness and bone fractures. People exhibiting these symptoms or who have chronic diseases known to decrease vitamin D, should have their levels checked and, if found to be low, discuss treatment options. However, universal screening is likely neither necessary nor prudent absent significant symptoms or chronic disease.
Increasing and maintaining healthy vitamin D levels can be as easy as spending 5-30 minutes in midday sun twice per week. The appropriate time depends on a person’s geographic location and skin pigmentation — lighter skin synthesizes more vitamin D than darker skin. It is important to forgo sunscreen during these sessions because SPF 15 or greater decreases vitamin D3 production by 99 percent.
“You don’t need to go sunbathing at the beach to get the benefits,” said Dr. Pfotenhauer. “A simple walk with arms and legs exposed is enough for most people.”
Food sources such as milk, breakfast cereals, and Portobello mushrooms are also fortified with vitamin D. Dr. Pfotenhauer said supplements are a good option, as they are effective and pose few risks, provided they are taken as directed and a physician is consulted beforehand.
Research is ongoing to determine whether vitamin D deficiency has a role in multiple sclerosis, autoimmune disorders, infections, respiratory disease, cardiometabolic disease, cancer, and fracture risk.
“Science has been trying to find a one-to-one correspondence between vitamin D levels and specific diseases,” said Dr. Pfotenhauer. “Given vitamin D’s ubiquitous role in the body, I believe sufficient vitamin D is more about overall health. Our job as osteopathic physicians is to recognize those patients that need to be tested and treat them accordingly.”
Currently, insufficiency is defined as between 21 and 30 ng/ml and deficiency is considered below 20ng/ml by the Endocrine Society.
Public Release: 3-May-2017
Common cold duration is shortened similarly by zinc acetate and zinc gluconate lozenges
University of Helsinki
There is no significant difference between zinc acetate lozenges and zinc gluconate lozenges regarding their efficacy in shortening the duration of common colds according to a meta-analysis published in Journal of the Royal Society of Medicine Open. Seven randomized trials with zinc acetate and zinc gluconate lozenges found that the duration of colds was shortened on average by 33%.
Zinc lozenges appear to influence the common cold through the release of free zinc ions into the oro-pharyngeal region. However, zinc ions can bind tightly to various chemical complexes in such a way that little or no free zinc ions are released. Previously zinc lozenges containing citric acid were shown to be ineffective in treating colds because citric acid binds zinc ions very tightly and no free zinc is released.
Zinc acetate has been proposed as the most ideal salt for zinc lozenges since acetate binds to zinc ions very weakly. Zinc gluconate is another salt that has been frequently used in zinc lozenges. However, gluconate binds the zinc ion more tightly than acetate does. Because of the somewhat stronger binding, zinc gluconate has been proposed to be less suitable constituent for lozenges. Although the binding difference between zinc acetate and zinc gluconate is a fact, it is not evident whether that causes significant differences at the clinical level for treating the common cold.
In the meta-analysis, Dr. Harri Hemilä from the University of Helsinki, Finland, collected randomized trials on zinc acetate and zinc gluconate lozenges and compared their observed efficacies. Three trials had used zinc acetate lozenges and found that colds were shortened on average by 40%. Four trials had used zinc gluconate lozenges and colds were shortened on average by 28%. The 12% difference between the average effects of the two kinds of lozenges was explained purely by random variation. Furthermore, one of the zinc gluconate lozenge trials was an outlier inconsistent with all the other six zinc lozenge trials. If that outlier trial was excluded, the difference between the three zinc acetate and the three zinc gluconate trials shrinked to just 2%, i.e., a 40% vs. 38% reduction in common cold duration. Thus, properly composed zinc gluconate lozenges may be as effective as zinc acetate lozenges.
Dr. Hemilä also analyzed the dose response relationship between the elemental zinc dose and the observed efficacy in reducing common cold duration. There was no difference in the efficacy between five trials that used 80 to 92 mg of zinc per day and the two trials that used 192 and 207 mg of zinc per day. Thus, zinc doses of over 100 mg per day do not seem to provide any more benefit.
According to Dr. Hemilä, there is no justification for the popular phrase that “there is no cure for the common cold” because of the strong evidence that zinc lozenges can shorten common cold duration by over 30%. However, in future studies the optimal composition of zinc lozenges should be investigated. The optimum frequency of their administration also warrants further investigation. Nevertheless, he also considers that “the current evidence of efficacy for zinc lozenges is so strong that common cold patients should be encouraged to try them for treating their colds, but the patients should ascertain that the lozenges do not contain citric acid or its salt citrate.”
Public Release: 3-May-2017
Psychological benefits for kids when mums keep taking folic acid
Taking folic acid supplements throughout pregnancy may improve psychological development in children
British Psychological Society
Children’s emotional intelligence improved if mums take folic acid supplements throughout pregnancy.
Taking folic acid supplements throughout pregnancy may improve psychological development in children.
That is the finding of research by Professor Tony Cassidy and colleagues from Ulster University who will present their study today, Thursday 4 May, to the Annual Conference of the British Psychological Society in Brighton.
Professor Cassidy said: “There is evidence that folic acid supplements taken during the first three months of pregnancy can have beneficial effects on children’s brain development. We wanted to investigate whether continued supplementation throughout pregnancy had any additional effects.”
The researchers asked the parents of 39 children, now aged seven, to answer questions about their child’s personality, including levels of resilience, relationships with others and how they express their emotions. Within this group 22 mothers had taken the supplement throughout their pregnancy while the other 19 took it during the first three months only.
Analysis showed that children whose mothers took the supplement throughout pregnancy demonstrated higher levels of emotional intelligence and resilience. Additionally, the level of folic acid in mother’s blood towards the end of pregnancy was a good predictor of children’s resilience and emotional intelligence.
Professor Cassidy said: “Most expectant mothers know that taking folic acid supplements in the first three months of pregnancy is important for the baby’s spinal development. Our study shows that there are potential psychological benefits for the child if supplements are taken throughout the pregnancy.”
Public Release: 4-May-2017
Study suggests omega-3 in mothers’ diets may lower children’s risk of type 1 diabetes
Diabetologia
New research published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) suggests that omega 3 polyunsaturated fatty acids (PUFAs), derived primarily from fish in maternal diet during pregnancy or lactation, may help protect infants at high risk of type 1 diabetes (T1D) from developing the disease.
If confirmed, this could mean that increasing the intake of fish-derived fatty acids and the duration of breastfeeding may have beneficial effects by reducing the autoimmune responses that lead to T1D.
More than 20 million people worldwide are affected by T1D — an autoimmune disease in which the immune system turns on the body and destroys insulin-producing beta cells in the pancreas. The subclinical disease process can be detected in asymptomatic individuals by identifying autoantibodies that develop in infancy or early childhood. Fatty acids have been shown to alter the immune system and inflammatory reactions and may play a role in the development of type 1 diabetes-related autoimmunity. However, evidence to date has been inconclusive.
In this new study, Dr Sari Niinistö at the National Institute of Health and Welfare, Helsinki, Finland and colleagues investigated whether serum fatty acid levels during infancy are related to the development of autoimmunity among children at increased genetic risk of developing T1D from the Finnish ‘Type 1 Diabetes Prediction and Prevention Study’. In particular, they looked at whether especially high levels of omega 3 PUFAs reduce the risk of autoimmune responses that are associated with clinical disease.
Between 1997 and 2004, 7782 genetically predisposed newborns were monitored for islet cell autoantibodies, with blood samples drawn at regular intervals between 3 and 24 months of age, and then annually thereafter up to age 15, to determine islet autoimmunity. Questionnaires and food diaries were used to record breastfeeding and formula use–the main dietary sources of fatty acids in early infancy. 240 infants who developed islet autoimmunity (and 480 matched control infants) had their serum total fatty acid composition analysed from samples collected at the age of 3 and 6 months. The research team also assessed these positive cases for earlier signs of insulin and glutamic acid decarboxylase (GAD) autoantibodies — both closely related to the development of type 1 diabetes.
Results showed that high serum levels of fish-derived fatty acids (docosahexaenoic acid; DHA and docosapentaenoic acid; DPA) were associated with lower risk of early (insulin) autoimmunity. However, high serum levels of alpha-linolenic acid (ALA) and high ratios of arachidonic acid (AA):DHA and omega 6:omega 3 PUFA were linked to higher risk.
The researchers also found that fatty acid status in infants strongly reflected the type of milk feeding. Breastfed infants had higher serum levels of fatty acids (e.g., pentadecanoic, palmitic, DPA, and DHA) associated with lower risk of type 1 diabetes-related autoimmunity compared to non-breastfed infants. Quantity of breast milk consumed further reduced the risk, whereas the amount of cow’s milk-based formula was associated with higher risk of developing earlier (insulin) autoimmunity.
Despite the relatively small number of cases of insulin and GAD autoimmunity, the study revealed a number of clear links between fatty acid levels in infancy and type 1 diabetes-related autoimmunity. These were not affected when the researchers took into account other potential variables such as familial diabetes, maternal education, and amount of cow’s milk in diet.
The results point to new directions for tackling type 1 diabetes. But the authors caution that an association does not imply causality, and they say that more studies are needed to confirm whether fatty acids can protect children from autoimmune responses that can trigger type 1 diabetes. However, they add, “[Our] findings support the view that breastfeeding, or some components of breast milk, including fatty acids, are protective, particularly with early autoimmunity…[and] that long-chain omega-3 status during the early months, at a time when the immune system is maturing and being programmed, is critical.”
Public Release: 4-May-2017
Can the antioxidant resveratrol reduce artery stiffness in diabetics?
American Heart Association Meeting Report — Session 15 — Poster Presentation 164
American Heart Association
Minneapolis, May. 4, 2017 — Resveratrol, a natural compound found in red wine, peanuts, berries and the skin of red grapes, may reduce artery stiffness in some people with Type 2 diabetes, according to an abstract presented at the American Heart Association’s Arteriosclerosis, Thrombosis and Vascular Biology | Peripheral Vascular Disease 2017 Scientific Sessions.
“This adds to emerging evidence that there may be interventions that may reverse the blood vessel abnormalities that occur with aging and are more pronounced in people with Type 2 diabetes and obesity,” said Naomi M. Hamburg, M.D., M.S., senior author of the study and chief of the vascular biology section at the Boston University School of Medicine in Massachusetts.
As the body’s largest artery, the aorta, becomes stiffer, the risk of heart attacks and strokes increases. In the current study, researchers used a test called the carotid-femoral pulse wave velocity (CFPWV) to measure aortic stiffness in 57 patients with Type-2 diabetes (average age 56 years, 52 percent female, 67 percent African-American and on average rating as obese on standard height/weight charts). Tests were performed after patients consumed daily doses of 100 mg/day of resveratrol for two weeks followed by 300 mg/day of resveratrol for two weeks and after comparable placebo dosing for a total of four weeks. Participants were also tested on several other measures of their blood vessels’ ability to relax and expand as needed to accommodate changes in blood flow, an important indicator of healthy blood vessel function.
Researchers found:
· In the overall study group, there was a trend toward reduced aortic stiffness with resveratrol treatment; however, the change was not statistically significant.
· In a subset of 23 patients with high arterial stiffness at the start of the study, the 300 mg dose of resveratrol reduced aortic stiffness by 9.1 percent, the 100 mg lowered reduced aortic stiffness to a lesser extent, 4.8 percent, while stiffness increased with the placebo treatments.
“The effect of resveratrol may be more about improving structural changes in the aorta, and less about the relaxation of blood vessels, and people with more normal aortic stiffness may not get as much benefit,” Hamburg said.
In animal studies, resveratrol activates a gene (SIRT1) that delays aging and the development of several diseases. To look at that mechanism in humans, researchers in the current study took a sample of the inner lining of blood vessels from seven participants and examined the tissue for SIRT1 activity. Although they detected increased SIRT1 activity after resveratrol supplementation, the difference was not statistically significant.
“We found that resveratrol also activates the longevity gene SIRT1 in humans, and this may be a potential mechanism for the supplements to reduce aortic stiffness. However, the changes in this small and short-term study are not proof. Studies with longer treatment are needed to test the effects of a daily resveratrol supplement on vascular function,” said Ji-Yao Ella Zhang, Ph.D., lead study author and postdoctoral fellow at the Whitaker Cardiovascular Institute at Boston University.
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Other co-authors are Monika Holbrook, M.S.; Elika Inagaki, M.D.; Bihua Feng, Ph.D.; Dorae Ko, M.D.; Robert M. Weisbrod, M.A.; Reena Bastin; Margaret Stathos, B.A.; Rosa Breton-Romero, Ph.D.; and Jessica Fetterman, Ph.D. Author disclosures are on the abstract.
The National Heart, Lung, and Blood Institute and the National Center for Complementary and Integrative Health funded the study.
Note: Scientific presentation time is 6 p.m. CT/7 p.m. ET, Thursday, May 4, 2017.
Public Release: 5-May-2017
Vitamin A deficiency is detrimental to blood stem cells
German Cancer Research Center (Deutsches Krebsforschungszentrum, DKFZ)
Many specialized cells, such as in the skin, gut or blood, have a lifespan of only a few days. Therefore, steady replenishment of these cells is indispensable. They arise from so-called “adult” stem cells that divide continuously. In addition, there is a group of very special stem cells in the bone marrow that were first discovered in 2008 by a research team led by Andreas Trumpp, who is a division head at the DKFZ and director of HI-STEM. These cells remain in a kind of dormancy most of the time and only become active in an emergency such as bacterial or viral infections, heavy blood loss, or in the wake of chemotherapy. Once their work is done, the body sends its most potent stem cells back to sleep. The scientists assume that this protects them from dangerous mutations that may lead to leukemia.
The mechanisms that activate these special stem cells or make them go back to sleep after their work is done have remained elusive until now. The scientists have now identified retinoic acid, a vitamin A metabolite, as a crucial factor in this process. If this substance is absent, active stem cells are unable to return to a dormant state and mature into specialized blood cells instead. This means that they are lost as a reservoir. This was shown in studies with specially bred mice whose dormant stem cells are green fluorescent. “If we feed these mice on a vitamin A deficient diet for some time, this leads to a loss of the stem cells,” said Nina Cabezas-Wallscheid, who is the first author of the publication. “Thus, we can prove for the first time that vitamin A has a direct impact on blood stem cells.”
This finding not only enhances our understanding of the development of blood cells, it also sheds new light on prior studies that demonstrate that vitamin A deficiency impairs the immune system. “This shows how vitally important it is to have a sufficient intake of vitamin A from a balanced diet,” Cabezas-Wallscheid emphasized. The body cannot produce its own vitamin A.
The scientists also have hopes for new prospects in cancer treatment. There is evidence that cancer cells, like healthy stem cells, also rest in a state of dormancy. When dormant, their metabolism is almost completely shut down — and this makes them resistant to chemotherapy. “Once we understand in detail how vitamin A or retinoic acid, respectively, sends normal and malignant stem cells into dormancy, we can try to turn the tables,” explained Trumpp. “If we could make cancer cells temporarily enter an active state, we could thus make them vulnerable to modern therapies.”
In addition, in collaboration with colleagues from the European Bioinformatics Institute in Cambridge, the team performed genome-wide analyses of single cells and discovered that the transition from dormant to active stem cells and then on to progenitor cells is a continuous one and follows a different path for each individual cell. So far, scientists had assumed that specific cell types develop step by step in a defined pattern. This finding revolutionizes the previous concept of how cell differentiation in the body takes place.