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Graves’ disease: Causes, symptoms and treatment
10 July 2019 | Category: Ear Nose Throat Print Share Tweet Share 25SHARES Graves’ disease is an autoimmune disease causing excessive thyroid hormone release from thyroid gland – hyperthyroidism. As thyroid hormones affect many different body regions, there is a broad range of symptoms of Graves’ disease, and these significantly affect your daily life. It is frequently seen in young adult women. It may cause symptoms such as palpitation, chest pain, shortness of breath, sweating, diarrhea, concentration problems and irritability. If left untreated, it may result in death due to development of certain disorders. The main goal of treatment is to prevent the excessive thyroid hormone production and reduce the severity of symptoms. It can be controlled using anti-thyroid medications. Moreover, it can be cured using radioactive iodine treatment and surgical methods. Table of Contents What is Graves’ disease? Causes of Graves’ disease Symptoms of Graves’ disease Diagnosis of Graves’ disease Treatment of Graves’ disease Herbal treatment of Graves’ disease Nutrition in Graves’ disease Health problems from graves disease Recommendations for Graves’ patients What is Graves’ disease? Graves’ disease (toxic diffuse goiter) is a disease characterized by excessive hormone release from thyroid gland due to immune system cells attacking the body’s own cells. It causes thyroid gland enlargement, i.e. Goiter. It is seen 4- to 5-fold more in women than men. Hyperthyroidism is the most frequent cause. It can be seen at all ages; however, it is most commonly seen between the ages of 20 and 40. Thyroid gland is a hormone-secreting endocrine gland placed on the anterior-middle part of the neck. It resembles a butterfly. It is a vital organ which ensures a balanced and regular functioning of many important organs and systems such as the heart and the brain. Over- or under-functioning of the thyroid gland leads to many problems in the body. Excessive hormone production by an over-functioning thyroid gland is called ‘hyperthyroidis m’. Causes of Graves’ disease Our immune system protects us against possibly detrimental organisms such as bacteria and viruses. In genetically predisposed individuals, immune system cells attack and damage certain organs as if they are detrimental organisms, and the reason for this is not exactly known. Diseases occurring via this mechanism are called autoimmune diseases. Graves’ disease is also an autoimmune disease seen due to immune cells attacking the thyroid gland. In this disease, your immune system produces some antibodies called thyroid stimulating immunoglobulins (TSIs). These antibodies lead to excessive thyroid hormone production that is more than the body’s need. This results in hyperthyroidism. Risk factors for Graves’ disease Genetic: It is more frequent in individuals with familial history of Graves’ disease. Sex: It is more common in women than men. Age: It is frequently seen at younger and middle ages. Presence of another autoimmune disease: It is more common in individuals with autoimmune diseases such as type 1 diabetes or rheumatoid arthritis. Emotional and physical stress: Stressful events or illnesses may trigger the development of Graves’ disease in genetically predisposed individuals. Tobacco: Smoking increases the risk by affecting the immune system. Furthermore, in Graves’ patients who are smokers, the possibility of disease-induced eye involvement is higher. Medications: It may occur due to the use of medications such as amiodarone and alemtuzumab. Symptoms of Graves’ disease Ophthalmopathy (eye involvement) Chest pain, palpitation Weight loss despite increased appetite Anxiety, restlessness, irritability Sleeplessness, concentration problems Intolerance to heat, excessive sweating Shortness of breath, labored breathing Diarrhea Menstrual irregularity Muscle weakness Hair loss Shaky hands Sexual function disorder In case of Graves’ disease-induced eye involvement, the eyeball appears like it is placed outwards. Eye dryness, pain, photosensitivity and double vision may be seen. Eye movements become difficulty. Blindness may be seen due to the involvement of optic nerve Diagnosis of Graves’ disease The diagnosis is made by medical history, physical examination, laboratory analyses and imaging methods. Medical history: presence of any co-existing condition, medication use, smoking status, and familial history of the disease is questioned. Physical examination: The size of the thyroid gland, the presence of pain and temperature increase is checked by palpation. Additionally, presence of nodule (lump) may be checked. The heart and the abdomen are checked by auscultation using stethoscope. The hands are examined for the presence of shaking. Eyes are also examined in detail. Laboratory tests: Hormone levels indicating thyroid dysfunction including thyroid stimulating hormone (TSH), free T4 and T3 are checked. Moreover, levels of thyroid autoantibodies which may increase in Graves’ disease are also checked. Imaging methods: The structure of the thyroid gland is assessed using thyroid ultrasound, mainly for the presence of nodule. US-guided sampling may be performed when necessary. Radioactive iodine uptake test: It is the radioactive form of the iodine taken with food. It is taken orally in liquid or capsule form. As iodine is used by thyroid gland in the body, it is transferred to thyroid gland via blood. After the iodine is taken, body images are taken using special cameras at certain intervals. Thereby, the amount of iodine uptake by the thyroid gland or the presence of non-thyroid iodine accumulation is checked. The use of certain medications which may affect the test result is interrupted before the procedure. Some foods including seafood should not be consumed. It is used for diagnosis and treatment. Treatment of Graves’ disease Graves’ disease can be controlled by a successful treatment using proper methods. The goal is to reduce the excessive thyroid hormone levels and protect the body from the effects. Therapeutic options may vary based on the co-existing conditions and being pregnant. Medical treatment, radioactive iodine treatment and surgical treatment can be used. Medical treatment of Graves’ disease Beta-blocker medications: They are used for the symptoms including palpitation, high blood pressure, shaky hands and irritability caused by excessive thyroid hormones. The beta-blocker medications in use include propranolol and atenolol. They provide symptom relief until the hormone levels return to normal. Anti-thyroid medications: They show their effect by reducing the thyroid hormone production. Methimazole and propylthiouracil are used for this purpose. They do not provide cure and their effects are not permanent. Due to the presence of previously synthesized hormones, their effects start late. Propylthiouracil is the one with the fastest onset of action and with the least amount crossing placenta. As methimazole is detrimental to the fetus especially in the first trimester, propylthiouracil is used in pregnant and breastfeeding women. The most common side effects include skin rashes and itching. They may cause infection by decreasing the levels of immune cells of the body, and bleeding by decreasing the level of platelets. Therefore, regular blood analysis is required. They may rarely cause liver failure and jaundice. Radioactive iodine treatment The thyroid gland gets damaged by radioactive iodine via oral route, thereby, excessive hormone release can be reduced. The amount of the iodine used is more than the amount used for diagnosis. It can be used in inoperable patients who are not adequately responding to treatment. It must definitely not be used in pregnant and breastfeeding women. Thyroid gland shrinkage is usually seen a few weeks to a few months after the treatment, and the complaints gradually decrease. The most important side effect is the under-functioning of the thyroid gland due to excessive damage. Treatment of ophthalmopathy The first step is to treat Graves’ disease. In addition, cortisone treatment may be initiated. Eye drops can be used and eyes can be closed using dressing to prevent dryness. Sunglasses can be used to reduce photosensitivity. Sleeping with head elevated helps reduce both dryness and swelling. Surgical procedures can be used when necessary. Surgical treatment for Graves’ disease Pregnant women, women who are planning to get pregnant early after treatment, younger individuals, patients with moderate-to-severe ophthalmopathy (especially who are smokers), and patients who cannot tolerate antithyroid medications are treated surgically. In addition, surgical treatment is considered if the thyroid gland enlargement is severe to the extent of damaging the surrounding structures. T hyroid hormone levels are returned to normal using medical treatment before the operation. Based on the hormone levels and the patient’s complaints, total or near-total thyroidectomy may be performed. Hormone levels are checked at frequent intervals after treatment, and in case of deficiency, external thyroid hormone supplement might be initiated. Bleeding may occur early after the operation. The most important possible side effect is hoarseness. How long does the treatment of Graves’ disease take? The risk of recurrence of Graves’ disease is high with treatments shorter than 6 months using antithyroid medications. In this respect, the average treatment duration is 13 months (1- to 2-year). The rate of disease recurrence 1 to 2 years after the medication is discontinued is around 40-80%. The medication is used temporarily (4 to 8 weeks) to prepare the patient for operation. Thyroid hormone levels should be checked at frequent intervals after the medications are discontinued. Thyroid hormone levels return to normal within 2 months with radioactive iodine treatment. They stay within normal levels for 6 months in 50% of the patients. Over- or under-functioning of thyroid gland may be seen in other patients. The risk of an under-functioning thyroid increases every year. Beta blocker medications are used until symptom relief. Herbal treatment of Graves’ disease As herbal treatment methods may lead to side effects especially in individuals using medications and who have co-existing conditions, you should consult with your doctor before using herbal treatment methods. Medicinal herbs good for Graves’ disease In animal studies, certain herbs including Melissa plant (lemon balm), St. John’s wort, throw-wort, club moss have been demonstrated to be effective in hyperthyroidism by reducing the levels of thyroid hormones via various mechanisms. However, human studies on these herbs are lacking, thus, the evidence is insufficient. Moreover, as they affect the thyroid hormone levels, they may cause changes in other hormones related with the thyroid gland. Therefore, they should only be used within a doctor’s knowledge or if recommended by a doctor. Nutrition in Graves’ disease Graves’ disease cannot be treated by only dietary changes nor the disease development can be prevented. However, dietary changes may help with the conditions induced by Graves’ disease including weight loss and bone thinning. It should be remembered that effect of each food is not same for every person. Vitamin D: Individuals with Graves’ disease should consume foods containing vitamin D, and if necessary, use vitamin D supplements. Foods including eggs, mushroom, salmon may help prevent bone thinning which may be caused by Graves’ disease. Calcium: Dairy products including milk, cheese and yogurt should be consumed for calcium supplementation. They contribute bone strengthening. Magnesium: It is possible to increase calcium absorption by magnesium by consuming foods rich in magnesium such as avocado, dark chocolate, almond and legumes. Selenium: A study performed in regions with mild selenium deficiency has detected that selenium treatment at a dose of 100 microgram given twice a day for six months improves eye manifestations and the quality of life. Therefore, especially patients with eye involvement may prefer foods rich in selenium such as seafood, egg, cereal and dairy products. High-energy foods: As muscle weakness and thinning may be seen due to this disease, foods rich in protein and energy such as chicken, turkey, beans and hazelnut should be consumed. Caffeine restriction: Consumption of foods and beverages containing caffeine such as coffee, tea, coke and chocolate should be restricted. Because caffeine may exacerbate the symptoms of anxiety, irritability, palpitation and weight loss caused by Graves’ disease. Iodine: Iodine is a necessary substance for thyroid hormone synthesis. Adequate dietary iodine intake is necessary. Iodine deficiency may result in thyroid gland enlargement and iodine excess may result in hyperthyroidism. Therefore, you should consult with your doctor about the amount of iodine to be consumed. Health problems from graves disease Graves’ disease and hyperthyroidism Hyperthyroidism develops due to excessive thyroid hormone release in Graves’ disease. One of the most common reasons of hyperthyroidism is Graves’ disease. One goal of the treatment of Graves’ disease is to return the hyperthyroid state to euthyroid state. Graves’ ophthalmopathy It is the involvement of the eyes in Graves’ disease. It is mostly seen in Graves’ patient who are also smokers. Patients with Graves’ ophthalmopathy must definitely quit smoking. Symptoms including burning eyes, watering of eyes, photosensitivity, blurred vision, eyelid retraction, swelling and redness, eye inflammation, abnormal eyeball protrusion, being unable to completely close eyelids during sleep, headache and double vision may be seen. Eye movements become difficulty. Blindness may be seen due to the involvement of optic nerve. Graves’ dermopathy (pretibial myxedema) It is seen in approx. 5-15% of the patients. It is characterized with non-pitting swellings on both sides of the extremities and red-orange flaky skin. It may cause itching and pain. Sometimes, it is also possible that there is no sign or symptom. It is mainly seen on tibial area, but also on the dorsum of the foot, back, neck and ankles. Thyroid storm It is a rare, however, a life-threatening condition if left untreated. It’s frequently seen in Graves’ disease. It is an emergency seen due to previously-stored thyroid hormones being release into blood. Symptoms include fever, nausea, vomiting, diarrhea, palpitation, heart failure, and mental fog. Beta-blocker medications and anti-thyroid medications are used for symptom alleviation. Cortisone treatment might be necessary in severe cases. Heart diseases If left untreated, Graves’ disease may result in cardiac rhythm problems, cardiac muscle functioning and structure problems, and heart failure. Bone thinning Excessive thyroid hormone blocks calcium entry into the bones and impairs bone structure. If left untreated, Graves’ disease results in bone fragility and weakness. Graves’ disease and pregnancy Graves’ disease is detected in less than 1% of all pregnant women. If a woman with Graves’ disease gets pregnant, it may affect both the pregnancy and the mother’s health. Pregnancy may trigger Graves’ disease in some women. During pregnancy, Graves’ disease increases the risk of abortion, premature delivery, toxemia of pregnancy, heart failure in mother; and the risk of thyroid disease and low birth-weight in baby. If you are genetically predisposed or if you have Graves’ disease, you should consult with your doctor when planning pregnancy. You should be sure that hyperthyroidism is under control. For medical treatment during pregnancy, propylthiouracil should be used instead of methimazole. Graves’ disease usually tends to improve spontaneously in the 2nd or 3rd trimester. Medications might even be stopped in many patients. Radioactive iodine treatment cannot be used in pregnant or breast-feeding women. Pregnancy must be planned at least 6 months after radioactive iodine treatment. Recommendations for Graves’ patients Follow your doctor’s treatment recommendations. Do not miss your follow-up visits as your thyroid hormone levels may change very frequently. As the medications may have significant side effects, return for regular blood tests. As stress may trigger Graves’ disease, try methods to overcome stress. You can get support from your family and friends. As smoking may exacerbate ocular signs, you must absolutely quit smoking. In case of eye involvement, wear sunglasses to protect your eyes from the sun. You can use synthetic tear drops to prevent eye dryness. Sleep with head elevated to decrease the edema around the eyes. Hormone levels may increase greatly and thyroid storm may occur. In case of sudden-onset mental fog, fever, palpitation and shortness of breath related with this entity, seek emergency medical help. For more: >>> Graves’ disease Resources and References: |
Oncology dietitians rarely ask cancer patients about food insecurity, study finds
14 1 Share Home Oncology & Cancer Home Health FEBRUARY 11, 2022 Oncology dietitians rarely ask cancer patients about food insecurity, study finds by Sharita Forrest, University of Illinois at Urbana-Champaign Credit: CC0 Public Domain Although studies suggest that many cancer patients experience food insecurity, few oncology dietitians routinely ask them if they are having problems affording or obtaining food, new research has found. Despite awareness that many cancer patients are food insecure, most of the 41 registered dietitian nutritionists interviewed by researchers at the University of Illinois Urbana-Champaign said they did not use a validated tool to screen patients for it. The dietitians' estimates of the prevalence of the problem varied widely, from less than 20% to more than 50% of their patients. The participants worked in various types of clinical settings, including outpatient cancer treatment centers and inpatient units at hospitals in urban, suburban and rural locales across the U.S. Just two of the dietitians in the study reported using a validated screener, while four additional dietitians reported using other tools, such as screening questions developed by the local food bank or questions recommended by a professional organization for oncology nutritionists. "This study highlights the need for developing education and training opportunities for oncology registered dietitians that will enhance their knowledge of food insecurity as well as their ability to screen for and address it with their patients," said Anna Arthur, the senior and corresponding author of the study who was then a professor of food science and human nutrition at the U. of I. She is currently a professor of dietetics and nutrition at the University of Kansas Medical Center. "Oncology patients face a number of barriers and burdens that increase their risks of food insecurity and malnutrition," said Amirah A. Burton-Obanla, a graduate student in nutritional sciences at Illinois and the first author of the study, published in the Journal of the Academy of Nutrition and Dietetics. "They may be sick from the disease and treatment side effects. Many patients experience debilitating fatigue that prevents them from working and hinders their ability to follow dietary recommendations, prepare food and eat." Some of the dietitians reported that food insecurity was more prevalent among certain populations, such as elderly patients and those diagnosed with cancers of the head and neck or gastrointestinal tract. The burdensome costs of cancer treatment and nutritional products can be obstacles for patients as well. "Patients with lower incomes may be unable to afford the recommended nutritional supplements that could help them get optimal nutrition during treatment," Burton-Obanla said. One of patients' greatest barriers to obtaining needed food was a lack of transportation, study participants said. Patients living in rural areas and those who lacked family members or friends who could provide rides or assistance with shopping or preparing meals were likely to be at greater risk of food insecurity. The few dietitians who did ask their patients if they were food insecure said they used various strategies to assist patients with obtaining food or transportation, such as connecting them with Meals on Wheels and other meal services, food pantries, government benefits and grants that provide gas cards and bus tokens. Despite these efforts, most of the dietitians felt they had little control over their patients' food security. "The quality of cancer survivors' diet is essential to their overall health, quality of life and survival," said Brenda Koester, the associate director of the Family Resiliency Center at the university and one of the co-authors of the study. "The inability to obtain adequate or nutritious food may lead to malnutrition and impact patients' tolerance and response to oncology treatment, increasing their risks of cancer recurrence and mortality." With the number of cancer survivors expected to increase to more than 20 million by 2026, there is an urgent need to address food insecurity in this population, the authors wrote. "Currently, there are no guidelines or recommendations on assessing oncology patients' food security status, but the findings suggest there's a need to do so using a validated screening tool," Koester said. "Implementing routine screenings as standard care in oncology settings would enable dietitians, potentially in collaboration with social workers and other health care providers, to identify food-insecure cancer survivors and develop early intervention strategies." U. of I. scholars who co-wrote the study are Barbara H. Fiese, the co-director of the STRONG Kids 2 program and a professor emerita of human development and family studies; research specialist Stephanie Sloane; and Craig Gundersen, then the Soybean Industry Endowed Professor of Agricultural Strategy. |
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Share Home Neuroscience FEBRUARY 11, 2022 Researchers find new clues in the brain linking pain and food by Kelsie Smith Hayduk, University of Rochester Medical Center Credit: Pixabay/CC0 Public Domain It has long been known that there is an association between food and pain, as people with chronic pain often struggle with their weight. Researchers at the Del Monte Institute for Neuroscience may have found an explanation in a new study that suggests that circuitry in the brain responsible for motivation and pleasure is impacted when someone experiences pain. "These findings may reveal new physiological mechanisms linking chronic pain to a change in someone's eating behavior," said Paul Geha, M.D., lead author on the study published in PLOS ONE. "And this change can lead to the development of obesity." Finding pleasure in food comes from how our brain responds to what we are eating. In this study researchers were looking at the brain's response to sugar and fat. Using a gelatin dessert and pudding, researchers altered the sugar, fat, and texture of the foods. They found that none of the patients experienced eating behavior changes with sugar, but they did with fat. Those with acute lower back pain who later recovered were most likely to lose pleasure in eating the pudding and show disrupted satiety signals—the communication from the digestive system to the brain—while those with acute lower back pain whose pain persisted at one year did not initially have the same change in their eating behavior. But chronic lower back pain patients did report that eventually foods high in fat and carbohydrates, like ice cream and cookies, became problematic for them over time and brain scans showed disrupted satiety signals. "It is important to note, this change in food liking did not change their caloric intake," said Geha, who first authored a previous study published in PAIN that recent research is building on. "These findings suggest obesity in patients with chronic pain may not be caused by lack of movement but maybe they change how they eat." Brain scans of the study participants revealed that the nucleus accumbens—a small area of the brain mostly known for its role in decision-making—may offer clues to who is at risk to experience a long-term change in eating behavior. Researchers found the structure of this area of the brain was normal in of patients who initially experienced changes in their eating behavior but whose pain did not become chronic. However, patients whose eating behavior was normal, but whose pain became chronic had smaller nucleus accumbens. Interestingly, the nucleus accumbens predicted pleasure ratings only in chronic back pain patients and in patients who became chronic after an acute bout of back pain suggesting that this region becomes critical in motivated behavior of chronic pain patients. Previous research by Geha, found a smaller nucleus accumbens can indicate if someone is at a greater risk of developing chronic pain. Additional authors include Yezhe Lin, Ph.D., and Gelsina Stanley of the University of Rochester, Ivan de Araujo, Ph.D., of Icahn School of Medicine at Mount Sinai, and Dana Small, Ph.D., of Yale University. |
Researchers restore brain immune system function after prenatal exposure to environmental toxin
by University of Rochester Medical Center Credit: Pixabay/CC0 Public Domain New research shows that exposure to the industrial byproduct TCDD in utero could cause the brain's immune system to go array later in life, damaging important brain circuits, and potentially giving rise to neurodevelopmental disorders, such as autism and ADHD. TCDD is primarily released into the environment by vehicle exhaust and burning wood and low levels of the toxin are found in air, soil, and food. The most common way people are exposed is through meat, dairy, and fish. In the same study, recently published in the journal Brain, Behavior, and Immunity, researchers also found that pharmacological manipulation could restore the function of microglia, important cells in the brain's immune system. "This suggests that defects in microglia function resulting from prenatal exposures can be reversed later in life, indicating a possible additional therapeutic avenue for neurodevelopmental disorders," said Rebecca Lowery, Ph.D., assistant research professor in the Del Monte Institute for Neuroscience at the University of Rochester, and co-first author of the study. The research, which was conducted in mice, showed that when the brains of males were exposed to TCDD in utero, it caused inflammation which cause microglia to go array when responding to injury. While the microglia themselves appeared healthy, the cells became over activated while responding to injury in a way that could damage important brain circuits. But investigators found that by using the drug Pexidartinib (PLX3397) they could 'shut-off' the hyper-responsive microglia and those were replaced by new microglia that functioned normally. This work offers new clues to when exposure to TCDD is most dangerous. Past research has found that adults exposed to TCDD did not have inflammation in the brain and there was no impact on microglia function. "Microglia are outside of the brain during pregnancy," said Ania Majewska, Ph.D., lead author on this study. "But after birth they are protected, possibly by the blood brain barrier, this barrier may be what prevents the harmful effects of TCDD from entering the brain." Researchers now want to understand if other environmental exposures impact microglia similarly, and whether these changes lead to long-term alterations in brain circuitry and function. |
Exercise post-vaccine bumps up antibodies, new study finds
by Iowa State University A student walks across ISU's central campus in Ames, IA, Oct. 2015. Credit: Christopher Gannon/Iowa State University Researchers at Iowa State University found 90 minutes of mild- to moderate-intensity exercise directly after a flu or COVID-19 vaccine may provide an extra immune boost. In the newly published study, participants who cycled on a stationary bike or took a brisk walk for an hour-and-a-half after getting a jab produced more antibodies in the following four weeks compared to participants who sat or continued with their daily routine post-immunization. The researchers found similar results when they ran an experiment with mice and treadmills. Antibodies are essentially the body's "search and destroy" line of defense against viruses, bacteria, fungi and parasites. Vaccines help the immune system learn how to identify something foreign and respond by bolstering the body's defenses, including an increase in antibodies. "Our preliminary results are the first to demonstrate a specific amount of time can enhance the body's antibody response to the Pfizer-BioNtech COVID-19 vaccine and two vaccines for influenza," said Kinesiology Professor Marian Kohut, lead author of the paper published in the journal Brain, Behavior, and Immunity. The researchers said the study's findings could directly benefit people with a range of fitness levels. Nearly half of the participants in the experiment had a BMI in the overweight or obese category. During 90 minutes of exercise, they focused on maintaining a pace that kept their heart rate around 120–140 beats per minute rather than distance. In the study, the researchers also tested whether participants could get the same bump in antibodies with just 45-minutes of exercising. They found the shorter workout did not increase the participants' antibody levels. Kohut said the research team may test whether 60 minutes is enough to generate a response in a follow-up study. Why the boost? As to why prolonged, mild- to moderate-intensity exercise could improve the body's immune response, Kohut said there may be multiple reasons. Working out increases blood and lymph flow, which helps circulate immune cells. As these cells move around the body, they're more likely to detect something that's foreign. Data from the mouse experiment also suggested a type of protein (i.e., interferon alpha) produced during exercise helps generate virus-specific antibodies and T-cells. "But a lot more research is needed to answer the why and how. There are so many changes that take place when we exercise—metabolic, biochemical, neuroendocrine, circulatory. So, there's probably a combination of factors that contribute to the antibody response we found in our study," said Kohut. The researchers are continuing to track the antibody response in the participants six months post-immunization and have launched another study that focuses on exercise's effects on people who receive booster shots. Postdoctoral Researcher Tyanez Jones, Graduate Assistant Jessica Alley and Justus Hallam, a graduate student at the time of the study, co-authored the recently published paper with Marian Kohut. Kohut said the research team also received a lot of help from undergraduate students, including students from the ISU Science Bound Scholars Program. |
Pfizer booster more than 50% protective against omicron
by Nature Publishing Group Credit: Unsplash/CC0 Public Domain A booster dose of the Pfizer–BioNTech vaccine (BNT162b2) against SARS-CoV-2 after an initial two doses of either the CoronaVac inactivated virus vaccine or Pfizer–BioNTech mRNA vaccine is shown to provide protection against the omicron variant, in a pair of papers published in Nature Medicine. David Hui, Malik Peiris and colleagues investigate differences in antibody responses to infection with wild-type or the omicron variant of SARS-CoV-2 in people who had either recovered from COVID-19 (30 participants; mean age, 48.9 years) or received vaccinations. This included uninfected people one month after their second of two doses of either the Pfizer–BioNTech mRNA vaccine (31 participants; mean age, 51.7 years) or the CoronaVac vaccine (30 participants; mean age, 52.1 years), those who received two doses of CoronaVac and an additional booster dose of CoronaVac (30 participants; mean age, 50.5 years) or three doses of Pfizer–BioNTech (25 participants; mean age, 50.6 years). The authors found that two doses of either the Pfizer–BioNTech or CoronaVac vaccine provided little neutralizing antibody immunity against omicron infection, even at one month after vaccination. Supplementing two doses of either vaccine with a Pfizer–BioNTech booster vaccination, however, provided acceptable immunity—defined as antibody levels sufficient to elicit greater than 50% protection against SARS-CoV-2—at one month after booster-dose administration. Three doses of the Pfizer–BioNTech vaccine resulted in mean neutralizing antibody titers against omicron a third higher than those elicited by two doses of CoronaVac plus a Pfizer–BioNTech booster. However, three doses of CoronaVac did not elicit sufficient neutralizing antibody responses against omicron. In a second paper, Akiko Iwasaki and colleagues examine the effectiveness of a three-part vaccine regime, consisting of two doses of CoronaVac followed at least four weeks later by booster vaccination with Pfizer–BioNTech, against the delta and omicron variants of SARS-CoV-2 in 101 participants (70% female; mean age, 40.4 years) in the Dominican Republic. Participants who received this combination of vaccines had elevated levels of virus-specific antibodies and strong antibody neutralization responses against both the original, ancestral form of SARS-CoV-2 and the delta variant compared to levels prior to the mRNA booster. Although neutralization of omicron was undetectable in those who had received just two doses of CoronaVac, additional booster vaccination with Pfizer–BioNTech resulted in a 1.4-fold increase in antibody neutralization activity against omicron, relative to those who received two doses of Pfizer-BioNTech or Moderna vaccines. Despite this increase, however, levels of neutralizing antibodies against omicron were still reduced overall by 7.1-fold and 3.6-fold, relative to levels of antibodies against the ancestral virus or delta variant of the virus, respectively. Notably, previous infection with SARS-CoV-2 did not significantly elevate the levels of antibodies against omicron in participants who had received the mixed-vaccine regime. The authors conclude that these findings further highlight the ability of the omicron variant to evade vaccine- or infection-induced immunity, emphasizing the global importance of booster vaccinations in efforts to combat emerging variants of SARS-CoV-2. |
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Share Home Vaccination DECEMBER 14, 2021 Two doses of BNT162b2 (BioNTech) or Coronavac (Sinovac) vaccines are inadequate against Omicron virus variants by The University of Hong Kong Cells are NOT protected from killing by Omicron virus despite addition of serum from individuals vaccinated by Coronavac. Credit: The University of Hong Kong Researchers at the Department of Microbiology of the University of Hong Kong (HKU) have found that most individuals after given two doses of the vaccine (either BioNtech or Coronavac) do not produce sufficient levels of serum antibodies against the new Omicron virus variant. The public is advised to get a third dose of the vaccine as soon as possible while awaiting for the next generation of more matched vaccine. The results of the study have been accepted for publication in the medical journal Clinical Infectious Diseases. It is available online as a preprint. Background The SARS-CoV-2 Omicron variant, first identified in November 2021, is spreading worldwide. This variant is particularly worrisome due to the large number of mutations in the virus that could affect infectivity or vaccine efficacy. To assess the effectiveness of existing COVID-19 vaccines in Hong Kong against this novel variant, researchers at the Department of Microbiology tested the ability of serum samples from fully vaccinated recipients to neutralize this variant. Serum neutralizing antibody titers are currently the only easily reproducible surrogate marker of protection against COVID-19. Research findings To test the ability of vaccine recipients' serum antibodies to neutralize the Omicron variant, the team used sera from two groups of vaccine recipients who have received two doses of BNT162b2 (BioNtech) or Coronavac. Each group consists of 25 people. The study aims to more fully evaluate the health risk of the Omicron variant to the Hong Kong population and the need for a universal third dose. Cells are protected from killing by Ancestral SARS-CoV-2 after addition of serum from individuals vaccinated by Coronavac. Credit: The University of Hong Kong Two Omicron variants present in Hong Kong were tested, one from South Africa and the other from Nigeria (with the additional R346K mutation). The ability of serum antibodies to neutralize the Alpha, Beta, and Delta strains was also tested as a control. Only five out of 25 Biontech vaccine recipients had neutralizing ability against the Omicron variant virus, and the vaccine efficiency was significantly reduced to 20—24%. Compared to the original SARS-CoV-2 strain, the titer of neutralizing antibodies against the Omicron variant has decreased by 36—40 fold. None of the serum of the 25 Coronavac vaccine recipients contain sufficient antibody to neutralize the Omicron variant at the limit of 1 in 10 dilution. Implications of the study 1. The Omicron variant virus was able to reduce the effectiveness of two doses of COVID-19 vaccine, particularly against Coronavac. Therefore, COVID-19 vaccine recipients or even those recovered COVID-19 patients may be at a higher risk of breakthrough or reinfection. Our findings suggest that the design of the next generation of COVID-19 vaccine should consider sufficient coverage against this novel viral variant. 2. A third dose of COVID-19 vaccine is needed to enhance the antibody response against the Omicron variant. 3. Whether a third dose of the present Coronavac vaccine will enhance the neutralizing antibody response against the Omicron variant remains to be determined. |
Study: COVID-19 variant Omicron significantly reduces virus neutralization ability of BioNTech vaccine
by The University of Hong Kong Cells infected were infected with each virus alone or virus mixed with blood serum from vaccinated persons. The cells stain blue but when the cells are killed by virus you see a hole (white) in the cell sheet. In the figure you see that the original 2020 SARS-CoV-2 is completely killed by the blood of vaccinated people but the Omicron virus killing is much reduced. Credit: The University of Hong Kong A recent study jointly conducted by the LKS Faculty of Medicine, The University of Hong Kong (HKUMed) and the Faculty of Medicine, The Chinese University of Hong Kong (CU Medicine) has revealed that Omicron, the latest COVID-19 variant, can significantly reduce the virus neutralization ability of Pfizer BioNTech (BNT162b2) vaccine by 32 folds or more. A similar test of another vaccine used in Hong Kong, CoronaVac, is being conducted and the results will soon be available. However, vaccines are still likely to be effective in protecting against death and severe disease. The research team thus renewed calls on high-risk groups, such as the elderly and those with immunocompromised conditions or other chronic diseases to get booster doses as soon as possible. Background COVID-19 continues to pose major threats to global public health. The emergence of the Omicron virus variant is of great concern because it has more than 35 mutations in its spike protein, which suggests that the newly emerged variant has capacity to escape immunity from past infection or from vaccines. But direct data on escape from vaccine immunity is still awaited. Testing the blood of people vaccinated with COVID-19 vaccines for ability to kill virus in the test tube (called the virus neutralization test) is one way to establish how well these vaccines protect against symptomatic infection. Previous studies carried out by Professor David Hui Shu-cheong, Stanley Ho Professor of Respiratory Medicine and Chairman of Department Medicine and Therapeutics, CU Medicine have followed up people vaccinated with the two vaccines used in Hong Kong, Pfizer BioNTech (BNT162b2) and CoronaVac. Results of these studies have been published recently in the journal Respirology. Research methods and findings Professor Malik Peiris, Tam Wah-Ching Professor in Medical Science and Professor of Virology at the School of Public Health, HKUMed and Managing Director, Centre for Infection and Immunity (C2i), Hong Kong Science and Technology Park and his team isolated the Omicron variant and carried out the virus neutralization tests to measure virus killing antibody in the serum to the Omicron variant compared with the original SARS-CoV-2 virus. In the recent initial experiments on Omicron variant, the blood of 10 people vaccinated with two doses of the Pfizer BioNTech (BNT162b2) vaccine was tested against the original SARS-CoV-2 virus from 2020 and the Omicron variant that the School of Public Health, HKUMed isolated from the first Hong Kong case. The blood tested was collected one month after the second dose of the vaccine, the time when the highest level of virus-killing antibodies in the blood was expected. "We can see that most individuals had high levels of virus killing (neutralization) activity against the original SARS-CoV-2 but this ability was markedly reduced by 32 folds or more against the Omicron variant," said Professor Peiris. He added that these findings suggest that vaccine-protection against breakthrough infection with Omicron will be much reduced. The data from CoronaVac vaccinated individuals will also soon be available but because previous studies suggested that virus-killing antibody levels in CoronaVac vaccines were lower than with the BioNTech vaccines, it is very likely that the loss of activity against CoronaVac will also be very large. Professor Hui has pointed out that antibodies are one (though important) arm of the immune response. The second arm of the immune response is cell mediated immunity and this is less likely to be affected by the Omicron variant. "We may expect that vaccines may still have protective effect against severe disease and death. It is therefore important that all those who are eligible for vaccination get fully vaccinated," he said. The joint research team will be testing the blood of those who have received a booster-dose of vaccines in the coming week and it is expected that the booster dose will provide increased levels of protection. "It will be important for those who are at higher risk, including older age and those with immunocompromised conditions or other chronic diseases such as diabetes and high blood pressure to take booster doses of vaccine as soon as possible," added Professor Peiris. |
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Share Home Vaccination DECEMBER 9, 2021 Vaccine booster increases protection against COVID, including omicron by Cyra Patel, Jean Li-Kim-Moy, Robert Booy, The Conversation Credit: The Conversation If it's been six months since you got the second COVID vaccine dose, it's time to book in for your booster shot. This will provide additional protection against COVID, including the new Omicron variant. While the evidence is still emerging, preliminary data suggests a Pfizer booster might give the same protection against Omicron as double-dose vaccination did for the original strain. Why get a booster? When you get your first dose of COVID vaccine, your body produces an immune response against a part of the virus called the spike protein. If you're exposed to the SARS-CoV-2 virus, your immune system can recognize and fight the virus quickly. The immune response to a single dose of COVID vaccine is generally short-lived. So a second dose is needed to have a stronger and longer-lasting response. Over time, the amount of antibodies in your body decreases—this is referred to as waning immunity. If the immune response wanes below the level needed for protection against COVID—the "protective threshold"—your immune system may not be able to prevent infection when exposed to the virus. Vaccine doses given some time after the initial course help boost the level of antibodies above the protective threshold. How much does immunity wane after 2 doses? Antibodies decrease over a period of six months or more after the second dose of COVID vaccine. Vaccine effectiveness against COVID infection decreases, on average, by 18.5 percentage points, six months after completing vaccination. On a positive note, protection against serious COVID illness, including hospitalization or death, does not seem to be reduced to the same extent, only by about 8 percentage points. This is likely because other components of the immune response (T cells and immune memory cells) stay in the body for longer than antibodies and prevent serious illness. Waning protection is more of a concern among elderly and immunocompromised people because they tend to have weaker immune responses to vaccines compared with young, healthy people. How effective are booster doses? Antibody levels after a booster dose are higher than those after the initial vaccination course. Although protection against COVID infection from two doses was slightly lower against Delta than the original strain, a booster dose restores protection to the same level. In Israel, people who received a booster dose (five or more months after completing vaccination) had infection rates ten times lower than in people who had only received the initial two-dose course. From a safety perspective, the types and frequency of side effects after the booster dose have been similar to first and second doses. Credit: The Conversation Which vaccine should I get as my booster dose? The two mRNA COVID vaccines available in Australia—Pfizer and Moderna—are so far approved for use as a booster dose. A recent clinical trial showed several COVID vaccines, including all three currently available in Australia (Pfizer, Moderna and AstraZeneca), and the Novavax and Janssen vaccines, produce strong immune responses after a course of either Pfizer or AstraZeneca vaccines. Based on what we know so far about immune responses to COVID vaccines, any of these vaccines given as a booster should be effective in reducing your risk of infection, regardless of which vaccine you initially received. The highest immune responses were seen with mRNA vaccines, but it's too early to tell whether these provide better protection against COVID infections when used as a booster, or how quickly immune responses will wane compared with the other vaccines. When is the best time to get my booster dose? Booster doses are timed to boost your antibody levels before they get below the protective threshold. The difficulty with COVID is we don't yet know what the protective immune threshold is. So the timing also involves other factors such as how much disease is in the community and vaccine availability. Some countries, such as the United Kingdom, have recommended getting a booster dose as soon as three months after the initial course. The UK has much higher daily cases of COVID, and face the potential for increased Omicron cases in winter, when hospitals are often at capacity due to other common respiratory viruses including influenza. In that context, early boosters are like an insurance policy to prevent an overwhelming winter peak. However, a shorter interval may mean the boost to the immune response is not as high or long lasting. A longer interval between the first and second dose of COVID vaccine is more effective. Given the COVID virus is circulating at much lower rates in Australia than other countries and vaccine coverage is generally high, a booster dose six months after the initial course seems reasonable. With this vaccination schedule, most adults in Australia will be eligible for their booster before winter 2022. Will the booster protect me against Omicron? We're still learning how the new Omicron variant, with so many mutations, may change our existing immunity (from past infection or vaccination) to be less effective. Early laboratory studies show two doses of the Pfizer vaccine provide some immunity against Omicron, but not as much as against previous strains. This means we're likely to see more infections in fully vaccinated people. However a booster dose appears to improve the immune response to a level similar to that observed against previous strains in fully vaccinated people, and is expected to provide good protection against serious illness. As more data on the effectiveness of boosters emerges, and if Omicron cases increase rapidly, the recommended timing of booster doses may also change. While we wait for more data to confirm the vaccines provide good protection against hospitalization and death, we can take some comfort knowing early data indicate this variant may even be less severe than previous ones. In the future, booster doses may be adapted for emerging variants, much like influenza vaccines are modified each year depending on what new strains are circulating. The benefits of new vaccine technologies like mRNA is the time required to manufacture new variant vaccines is only about 100 days. So if a vaccine-resistant variant does arise, we might not need to wait too long for an updated vaccine. |
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Share Home Vaccination OCTOBER 8, 2021 What's the difference between a COVID-19 booster shot and a third dose? by Ileana Varela, Florida International University Dr. Eneida Roldan administers a COVID-19 vaccine at FIU vaccination site. January 27, 2021. Credit: Florida International University COVID-19 vaccine choices are getting more complicated. So don't feel bad if you are confused about the different COVID-19 vaccines and who's eligible for what. In addition to the three original vaccines approved by the Food and Drug Administration—Pfize r, Moderna, and Johnson & Johnson—booster shots and third doses are now available. But they are not for everyone. And they are not the same thing. Dr. Eneida Roldan, FIU Health CEO and clinical director of FIU's vaccine initiative, explained the difference between the new shots. "A booster shot is for people whose immune response may have weakened over time," Roldan said. "A third dose is for people who may not have had a strong enough immune response from the first two doses." Consult your health care provider about which might be right for you. Here are some guidelines on eligibility from the Centers for Disease Control and Prevention (CDC). Booster shot: Pfizer only The Federal Drug Administration (FDA) has only approved booster shots for the Pfizer vaccine. Who is eligible for a booster? Only people initially vaccinated with Pfizer can get the booster. And they must have completed their initial vaccination series at least 6 months ago. 65 years and older 18+ years living in a long-term setting 18+ years with underlying medical conditions including cancer, chronic liver, and kidney disease, weakened immune system. The CDC has a complete list of eligible conditions. 18+ years who live or work in high-risk settings including health care, schools, correctional facilities, homeless shelters. Third dose- Pfizer and Moderna Third doses have been approved only for the Pfizer and Moderna vaccines. "You need to get the same vaccine for all three doses. And you need to wait at least 28 days after your second dose," Roldan said. Who is eligible for a third dose? People with moderately to severely compromised immune systems. This includes people undergoing cancer treatment, organ or stem cell transplant recipients who take medicine to suppress the immune system, and people with immunodeficiency diseases. Why get these additional shots? The CDC says, "an additional dose may prevent serious and possibly life-threatening COVID-19 in people who may not have responded to their initial vaccine series." There is no approved booster shot or third dose for the Johnson & Johnson vaccine. However, on Oct. 5, the company asked the FDA to authorize boosters for people who received its one-shot vaccine. Who is eligible for the initial COVID-19 vaccines? The CDC currently recommends COVID-19 vaccination for all people 12 years and older. Only the Pfizer vaccine is currently approved for children younger than 16, but the pharmaceutical company is hoping to expand to younger children. Pfizer just applied for approval for use in children ages 5 to 11. |
Diabetes, metabolic syndrome in mice treated with novel class of compounds
by Julia Evangelou Strait, Washington University School of Medicine Researchers at Washington University School of Medicine in St. Louis have shown, in mice, that a new class of compounds they developed can improve several aspects of metabolic syndrome. Such conditions often lead to cardiovascular disease, the leading cause of death worldwide. Pictured are two of the compounds (yellow) in the new class—SN-401 (left) and SN-406 (right). Credit: Susheel K. Gunasekar (Sah Lab), Pratik R. Chheda (Kerns Lab) A study in mice—led by researchers at Washington University School of Medicine in St. Louis—shows that a new class of compounds the scientists developed can improve multiple aspects of metabolic syndrome. An increasingly common group of conditions that often occur together, metabolic syndrome includes type 2 diabetes, high cholesterol, fat buildup in the liver, and excess body fat, especially around the waist. This syndrome often leads to cardiovascular disease, the leading cause of death worldwide. The study is published in the journal Nature Communications. Testing one of the compounds referred to as SN-401, the researchers found it treats diabetes by improving the ability of the pancreas to secrete insulin and boosting the ability of other tissues to utilize that insulin to more effectively remove sugar from the bloodstream. In an effort to optimize the treatment, the researchers fine-tuned the compound—creating a class of related compounds—based on their studies of a key protein called SWELL1 (also LRRC8a). The gradual decline of this protein may have a central role in the development of diabetes and other aspects of metabolic syndrome. "Our goal is to develop better therapies for cardiovascular disease, including diabetes and metabolic syndrome, which are major risk factors for worsening heart and vascular problems," said senior author Rajan Sah, MD, Ph.D., an associate professor of medicine. "We have many treatments for diabetes, but even with those therapies, cardiovascular disease remains a leading cause of death among patients with type 2 diabetes. There is a need for new treatments that work differently from the current standard-of-care therapies." The protein Sah and his colleagues studied is called SWELL1 because of its role in sensing the size or volume of cells. Their new research reveals that the protein also helps to control insulin secretion from the pancreas and improve insulin sensitivity, including in skeletal muscle and adipose tissue, the body's fat stores. Surprisingly, the researchers showed that SWELL1 does both of these seemingly independent tasks because the protein has a previously unknown double life. It acts as a signaling molecule, turning on cellular tasks that govern how well cells use insulin and also facilitates the pancreas' secretion of insulin into the bloodstream. "This protein, SWELL1, has a sort of dual personality," Sah said. "The compound binds to SWELL1 in a manner that stabilizes the protein complex so as to enhance expression and signaling across multiple tissues, including adipose, skeletal muscle, liver, the inner lining of blood vessels, and pancreatic islet cells. This restores both insulin sensitivity across tissue types and insulin secretion in the pancreas." Sah and his colleagues showed that the SN-401 compound improved multiple aspects of metabolic syndrome in two groups of mice that each developed diabetes from different causes, one because of a genetic predisposition and the other due to a high-fat diet. In addition to improving insulin sensitivity and secretion, treatment with the compound also improved blood sugar levels and reduced fat buildup in the liver. Most of these studies were conducted with an injected form of the compound, but the researchers showed evidence that it also could be effective if taken by mouth. The researchers further showed that the compound does not have a big impact on blood sugar in healthy mice, which is important for its potential as a future possible therapy. Current medications for diabetes can result in blood sugar levels that are too low. The evidence suggests that this compound does not lower blood sugar in situations when it doesn't need to. |
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Home Diseases, Conditions, Syndromes Home Vaccination FEBRUARY 11, 2022 Study: COVID booster effectiveness wanes but remains strong by Mike Stobbe Credit: Unsplash/CC0 Public Domain An early look at the performance of COVID-19 booster shots during the recent omicron wave in the U.S. hinted at a decline in effectiveness, though the shots still offered strong protection against severe illness. The report, published by the Centers for Disease Control and Prevention on Friday, is considered an early and limited look at the durability of booster protection during the omicron surge that exploded in December and January but has been fading in recent weeks. "COVID-19 vaccine boosters remain safe and continue to be highly effective against severe disease over time," said Kristen Nordlund, a CDC spokesperson. The researchers looked at patient visits to hospitals and urgent care centers in 10 states. They estimated how well Pfizer or Moderna booster shots prevented COVID-related visits to emergency departments and urgent care centers, and how well the vaccines prevented hospitalizations. About 10% of people in the study were boosted. Vaccine effectiveness was higher in people who had received boosters than in people who had received only the original series of shots. But researchers also found that during the time that the omicron variant has been predominant, vaccine effectiveness against outpatient visits was 87% in people who had gotten a booster two months earlier, but to 66% at four months after. Vaccine effectiveness against hospitalization fell from 91% at two months to 78% by the fourth month. Those results, however, were based on only a small number of patients—fewer than 200—who had been boosted four months earlier at the time of the omicron wave. And it's unclear if those people had gotten boosters early for medical reasons that may have made them more vulnerable to severe illness. Effectiveness after a booster was higher last year, when the delta variant was causing most U.S. cases, the study noted. Health experts expect protection from the vaccines to wane. The U.S. booster campaign was based on evidence that emerged last year that vaccine protection was fading six months after people got their initial vaccinations. And from the beginning, vaccines have offered less protection against the omicron mutant than earlier versions of the virus. The study couldn't address how protection will hold up against the next variant to come along. Still, the new study's finding was notable, said Dr. William Schaffner, a Vanderbilt University vaccines expert. "I'm a little surprised, according to the data, that it's starting to wane already," he said, adding that he would have anticipated higher estimates of vaccine effectiveness at the four-month post-booster mark. But Schaffner also said he'd like to see more research about the durability of booster protection, adding "let's take this with a grain of salt." Dr. Michael Saag, an infectious diseases physician at the University of Alabama at Birmingham, said 78% effectiveness against hospitalization "is still pretty effective." "Anecdotally, I'm seeing very few people die who got boosted," he said, even among those with weakened immune systems. "The vaccines are still working." |
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Share Home Vaccination JANUARY 10, 2022 Expert clears up confusion about COVID-19 boosters by Jason Howland Credit: Pixabay/CC0 Public Domain The Centers for Disease Control and Prevention (CDC) has updated its recommendations for the Pfizer COVID-19 vaccine to expand the use of a single booster dose to 12- to 15-year-olds. "Everyone at age 12 and up is approved for a booster after they've completed their initial series," says Dr. Melanie Swift, co-chair of Mayo Clinic's COVID-19 Vaccine Allocation and Distribution Work Group. What constitutes an initial series depends on the COVID-19 vaccine you were given. If it was Johnson & Johnson, it's one shot. If it was an mRNA vaccine, which is Moderna or Pfizer, an initial series is two shots. And if you are immunocompromised and were vaccinated with Moderna or Pfizer, it's three shots. "To keep it clear, just remember that it's your initial series, however many doses that is, and one booster for now," says Dr. Swift. "At least that is in the United States right now. And that's, with everything COVID, always subject to change." "The timing of the booster depends upon the brand of your initial series. If you got Johnson & Johnson, it's two months. If you got Pfizer initially, it's five months. If you got Moderna initially, it's six months. Now that might change in the future. But that's the current guidance based upon the available data," she says. This comes at a time when the omicron variant is spreading rapidly across the nation. The U.S. recently hit a new pandemic high of over 300,000 average new daily cases of COVID-19. And COVID-19 hospitalizations are on the rise, as well. "We know that one of the things about omicron is that it makes your vaccines less effective. The vaccination protection with two doses of an mRNA vaccine against omicron is down in the 40-something percent range—so not great. But with a booster, that protection goes up over 75%," says Dr. Swift. "We know that in addition to the fact that your immunity just wanes over time, omicron, in particular, is more susceptible to your immune response after the third or booster dose. So we are really encouraging people to get that booster dose." |
Preclinical study shows ketogenic diet could enhance pancreatic cancer therapy
by Ludwig Institute for Cancer Research Credit: Pixabay/CC0 Public Domain A Ludwig Cancer Research preclinical study has demonstrated that a common weight-loss diet could enhance the efficacy of chemotherapy for pancreatic cancer. Published in the journal Med, the study shows that a ketogenic diet—or high fat, modest protein and very low carbohydrate intake—synergizes with chemotherapy to triple survival time compared to chemotherapy alone in rigorous mouse models of pancreatic ductal adenocarcinoma (PDAC). The researchers, led by Ludwig Princeton Branch Director Joshua Rabinowitz, also describe findings from an intricate examination of how ketogenic diets affect the metabolism of PDAC tumors, and identify mechanisms that might account for the therapeutic effect. Their findings are now being evaluated in a clinical trial (NCT04631445) testing the benefits of a ketogenic diet in PDAC patients receiving chemotherapy. "There's been real progress against pancreatic cancer over the past two decades," said Rabinowitz, who is also a Professor in the Department of Chemistry and the Lewis-Sigler Institute for Integrative Genomics at Princeton University. "The problem is that, while a number of patients now see their tumors stabilize or shrink, the benefits of chemotherapy are very short lived. It often extends patients' lives six months to a year, but way too rarely do we see the three-plus years of extension in survival that people would, at a minimum, hope for." Substantial preclinical evidence suggests that fasting, or diets that resemble fasting in their metabolic effects, could enhance therapy for a variety of cancers. The ketogenic diet mimics fasting by reducing circulating glucose and depressing levels of insulin, a hormone that drives tissues and tumors to consume the sugar. Insulin is an important promoter of cancer growth—especially in pancreatic tumors—while glucose is a critically important fuel for cancer cell proliferation. Rabinowitz's own studies previously revealed that PDAC tumors, despite their aggressive growth, are starved of glucose, which suggested they could be especially vulnerable to additional glucose deprivation. In the current study, Rabinowitz and his colleagues conducted multiple experiments over many years—with early and ongoing support from Stand Up to Cancer—using mice that were engineered to develop PDAC or implanted with tumors that resembled those seen in patients. The mice were fed either a normal, carbohydrate rich diet or a ketogenic diet and treated with a standard-of-care combination of chemotherapies—nab-paclitaxel (Abraxane), gemcitabine and cisplatin. They found that the ketogenic diet alone did not affect tumor growth. But it did triple median survival time when combined with chemotherapy. Notably, while the therapeutic benefit did not depend on the immune system, only mice with intact immune systems were among the long-term survivors. Rabinowitz and his team also conducted studies to explore the effects of the combination therapy on tumor metabolism. "We know that glucose is a major cancer fuel, and insulin is a cancer promoting hormone, and that the ketogenic diet in one stroke decreases both," said Rabinowitz. "We found in this study that the diet decreases levels of glucose more profoundly in the tumor than in healthy tissues and that it dramatically suppresses levels of insulin." By depriving the body of sugar, the ketogenic diet forces the body to break down fats to generate molecules known as ketone bodies that can be burned by cells to generate energy. Chief among these is 3-hydroxybutyrate. "One thing we noticed is that 3-hydroxybutyrate acts like a supercharged fuel that dumps electrons into cells, and tumor cells are wired for other reasons to be extra-good at taking up this fuel," said Rabinowitz. "Fortuitously, too much of this super-charged fuel may be toxic to cancer." This excess of electrons causes the generation of reactive oxygen species (ROS), extremely unstable molecules that are also generated by chemotherapy. ROS kill cancer cells by damaging DNA, membranes and other components of cells. This, the researchers hypothesize, may enhance the antitumor effects of the chemotherapy. "I think that the most exciting thing here is that we can take chemotherapy regimens that we know to be active, that offer patients the best chance in the clinic right now and, at least in mice, make them work substantially better by pairing them with a ketogenic diet," said Rabinowitz. "We hope that we'll see the same types of benefits in patients." |
Could ketogenic diet be helpful with brain cancer?
by American Academy of Neurology Credit: Unsplash/CC0 Public Domain A modified ketogenic diet may be worth exploring for people with brain tumors, according to a new study published in the July 7, 2021, online issue of Neurology. The diet is high in fat and low in carbohydrates. The small study found that the diet was safe and feasible for people with brain tumors called astrocytomas. All of the people had completed radiation treatment and chemotherapy. The diet led to changes in the metabolism in the body and the brain. The study was not designed to determine whether the diet could slow down tumor growth or improve survival. "There are not a lot of effective treatments for these types of brain tumors, and survival rates are low, so any new advances are very welcome," said study author Roy E. Strowd, MD, MS, MEd, of Wake Forest School of Medicine in Winston-Salem, N.C., and a Fellow of the American Academy of Neurology. "These cancer cells rely on glucose, or sugar, to divide and grow. Since the ketogenic diet is low in sugar, the body changes what it uses for energy—instead of carbohydrates, it uses what are called ketones. Normal brain cells can survive on ketones, but the theory is that cancer cells cannot use ketones for energy." The study involved 25 people with astrocytomas. They followed a type of ketogenic diet, the modified Atkins diet with intermittent fasting, for eight weeks. The diet includes foods such as bacon, eggs, heavy cream, butter, leafy green vegetables and fish. Participants met with a dietician at the start of the study and then every two weeks. Five days a week they followed the modified Atkins diet, which combined carbohydrate restriction with high amounts of fats. Two days a week they fasted, eating up to 20% of their recommended daily calorie amount. The main goal of the study was to see if people were able to follow the diet with no serious side effects. A total of 21 people completed the study, and 48% followed the diet completely, according to their food records. But urine tests showed that 80% of the people reached the level where their body was primarily using fats and protein for fuel, rather than carbohydrates. The diet was well-tolerated. Two people had serious side effects during the study—one was not related to the diet and one was possibly related. By the end of the study, changes in the metabolism in the body and the brain were seen. Hemoglobin A1c levels, insulin levels, and fat body mass all decreased. Lean body mass increased. Specialized brain scans that detect changes in brain metabolites showed an increase in concentrations of ketones and metabolic changes in the tumor. "Of course more studies are needed to determine whether this diet can prevent the growth of brain tumors and help people live longer, but these results show that the diet can be safe for people with brain tumors and successfully produce changes in the metabolism of the body and the brain," Strowd said. A limitation of the study is that study team members provided a high amount of contact with participants, which may not be feasible in a larger study or in routine clinical care. |
New research reveals that a low-calorie ketogenic diet can help testosterone levels in overweight men
by European Society of Endocrinology Credit: Pixabay/CC0 Public Domain A very low-calorie ketogenic diet can help testosterone and sex hormone (SHBG) levels in overweight men, according to a study being presented at the 23rd European Congress of Endocrinology (e-ECE 2021), on Monday 24 May 2021. The study found that after following a recommended low-calorie ketogenic diet for four weeks, body weight, fat mass and body mass index (BMI) significantly decreased and a substantial increase of total testosterone and SHBG levels were also found. Testosterone is responsible for sexual and reproductive functions. However, it plays a significant role in calorie utilisation and metabolism as well. This study was the first of its kind to examine the effect of a very low-calorie ketogenic diet on testosterone and SHBG levels and therefore highlighted the tight relation between insulin action, energy balance, and testicular function. As men who are overweight or obese can also suffer from low levels of testosterone and SHBG levels, the data suggests that further research into a low-calorie ketogenic diet and its effect on male testosterone and SHBG levels may be a promising area for additional research. The worldwide prevalence of obesity nearly doubled between 1980 and 2008. According to country estimates for 2008, over 50% of men in the WHO European Region were overweight, and roughly 20% were obese. Obesity can lead to diabetes and heart disease, as well as psychological problems. To tackle this, various lifestyle changes, activities and treatments are widely recommended, and a ketogenic diet is becoming increasingly recognised as one of them. The diet consists of little protein and very little carbohydrates, and when done as very-low calorie a daily intake of less than 800 calories is advised. A very low-calorie ketogenic diet has previously been found to reduce body weight, glycaemia and insulinemia, but its effects on total testosterone and SHBG levels were less clear, until now. Dr. Angelo Cignarelli and a team of colleagues from the University of Bari in Italy investigated whether this controlled diet would have the same, positive effect that it does on overall bodyweight on total testosterone and SHBG levels. The 17 male subjects in the study underwent a low-calorie ketogenic diet for four weeks, and various tests were carried out before and after one (1) and four (4) weeks. "We aimed to evaluate the response of total testosterone and sex hormone levels to a very low-calorie ketogenic diet in a cohort of overweight or obese non-diabetic male subjects and what we found was that there is a noticeable relation between a specific, controlled diet and insulin action, energy balance, and testicular function," says Dr. Cignarelli. This is the first study that has evaluated the early response of androgen levels to the institution of a very low-calorie ketogenic diet, and highlights the relation between insulin action, energy balance, and testicular function. Results from this study now prove that a very low-calorie ketogenic diet can positively effect on total testosterone and SHBG levels. Further analysis will provide information about the effect of this nutritional intervention on additional clinical outcomes related to testosterone such as sexual function, muscle strength and quality of life. |
Inflammatory diet linked to testosterone deficiency in men
by Wolters Kluwer Health Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills/Wikipedia Consuming a diet high in pro-inflammatory foods—including foods that contain refined carbohydrates and sugar as well as polyunsaturated fats—may be associated with increased odds of developing testosterone deficiency among men, suggests a study in The Journal of Urology, Official Journal of the American Urological Association (AUA). The risk of testosterone deficiency is greatest in men who are obese and consume a refined diet that scores high on the dietary inflammatory index (DII), according to the new research by Qiu Shi, MD, Zhang Chichen, MD, and colleagues of West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. "While these findings do not prove causation, they do support previous research suggesting a pro-inflammatory diet can contribute to testosterone deficiency, among other potentially debilitating health issues," Drs. Qiu and Zhang comment. Does diet influence testosterone levels? New study discovers link Testosterone is a male sex hormone that plays important roles in reproduction and sexual function. However, 20 to 50 percent of US men have testosterone deficiency—defined as a testosterone level less than 300 ng/dL (nanograms per deciliter). Symptoms of testosterone deficiency may include low libido, decreased energy, poor concentration and depression. Testosterone deficiency is also associated with chronic diseases, including cardiovascular disease and obesity. Human and animal studies have linked testosterone deficiency with increased levels of inflammation in the body. Men with low testosterone have higher levels of pro-inflammatory cytokines: small proteins released by cells during injury, infection or in response to inflammatory factors in the environment. The DII has emerged as a tool for assessing the inflammatory potential of a person's diet, particularly in relation to other markers of health. The researchers studied the association between the DII and testosterone deficiency in 4,151 men from the National Health and Nutrition Examination Survey, all of whom completed a 24-hour dietary interview and underwent sex hormone testing. Each participant's DII was calculated based on the dietary history interview. Calculated DII scores ranged from -5.05 (most anti-inflammatory) to +5.48 (most pro-inflammatory). Average total testosterone level was 410.42 ng/dL in men with the most pro-inflammatory diet versus 422.71 ng/dL in those with the most anti-inflammatory diet. Overall, about 26 percent of the men had testosterone deficiency. For men with the most pro-inflammatory diet, the odds of testosterone deficiency were about 30 percent higher compared to men with the most anti-inflammatory diet. The associations remained significant after adjustment for other characteristics, including body mass index and smoking. In a fully adjusted analysis, the risk of testosterone deficiency was greatest in men who were obese and had a higher DII. For this group, the odds of testosterone deficiency were nearly 60 percent higher compared to men with obesity who had a lower DII. Drs. Qiu, Zhang, and coauthors note some important limitations of their study, including the fact that the DII was calculated based on a limited number of anti-inflammatory and pro-inflammatory food parameters. "Our results suggest men who eat a pro-inflammatory diet, particularly those who are obese, are more likely to have testosterone deficiency," Drs. Qiu and Zhang comment. "Since men with obesity likely already experience chronic inflammation, physicians should be aware of contributing factors, like diet, that could likely worsen this inflammation and contribute to the risk of other health conditions, such as diabetes and heart disease." Drs. Qiu and Zhang and colleagues call for further studies to verify the causal relationship between DII and testosterone deficiency. They also suggest that consuming a more anti-inflammatory diet "could be a feasible method to reduce the accumulated inflammatory burden, [potentially] leading to an increased testosterone level." |
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Share Home Health JANUARY 10, 2020 Low-fat diet linked to lower testosterone levels in men by Wolters Kluwer Health Credit: CC0 Public Domain For the many men diagnosed with testosterone deficiency, losing weight can help increase testosterone levels. But certain diets—specifically a low-fat diet—may be associated with a small but significant reduction in testosterone, suggests a study in The Journal of Urology, Official Journal of the American Urological Association (AUA). "We found that men who adhered to a fat restrictive diet had lower serum testosterone than men on a nonrestrictive diet," according to the report by Jake Fantus, MD, of the Section of Urology, Department of Surgery, University of Chicago Medicine and colleagues from the Department of Urology, Northwestern University Feinberg School of Medicine, and the Department of Surgery, NorthShore University Health System. "However," the researchers add, "the clinical significance of small differences in serum T across diets is unclear." Best Diet for Low Testosterone? No Single Right Answer Yet Dr. Fantus and colleagues analyzed data on more than 3,100 men from a nationwide health study (the National Health and Nutrition Examination Survey, or NHANES). All participants had available data on diet and serum testosterone level. Based on two-day diet history, 14.6 percent of men met criteria for a low-fat diet, as defined by the American Heart Association (AHA). Another 24.4 percent of men followed a Mediterranean diet high in fruits, vegetables, and whole grains but low in animal protein and dairy products. Only a few men met criteria for the AHA low-carbohydrate diet, so this group was excluded from the analysis. The average serum testosterone level was 435.5 ng/dL (nanograms per deciliter). Serum testosterone was lower in men on the two restrictive diets: average 411 ng/dL for those on a low-fat diet and 413 ng/dL for those on the Mediterranean diet. The associations were adjusted for other factors that can affect testosterone, including age, body mass index, physical activity, and medical conditions. After adjustment, the low-fat diet was significantly associated with reduced serum testosterone, although the Mediterranean diet was not. Overall, 26.8 percent of men had testosterone levels less than 300 ng/dL. Despite the difference in average testosterone levels, the proportion of men with low testosterone was similar across all diet groups. Low testosterone is highly prevalent in the United States, as approximately 500,000 men are diagnosed with testosterone deficiency each year. Testosterone deficiency can lead to problems, including decreased energy and libido, along with physiological alterations, including increased body fat and reduced bone mineral density. In addition to medications, treatment for low testosterone often includes lifestyle modifications, such as exercise and weight loss. But the effects of diet on testosterone levels have been unclear. Because testosterone is a steroid hormone derived from cholesterol, changes in fat intake could alter testosterone levels. This new analysis of how diet affects serum testosterone provides evidence that a low-fat diet is associated with lower testosterone levels, compared to an unrestricted diet. So what diet is best for men with testosterone deficiency? The answer remains unknown, according to the authors. In overweight or obese men, the health benefits of a low-fat diet likely far exceed the small reduction in serum testosterone. In contrast, for men who are not overweight, avoiding a low-fat diet "may be a reasonable component" of a multifaceted approach to increasing serum testosterone. Dr. Fantus and coauthors note that further studies will be needed to corroborate their findings, and to clarify the mechanism by which restrictive diets reduce testosterone. But due to the difficulties of large-scale dietary studies, definitive trials are unlikely to be performed. "Therefore, our data represent a valuable approach towards answering this important question," the authors conclude. |
Fewer fats over the festive season may be the perfect formula for men's fertility
by University of South Australia Credit: Shutterstock A diet low in fat and high in egg whites could be the key to boosting male fertility according to a new pilot study. The research, by Dr. Karma Pearce from the University of South Australia in collaboration with fertility specialist Prof Kelton Tremellen, Repromed, and Flinders University, presents a direct link between diet and testosterone—showing that what men eat could affect their fundamental male sex hormone. The study is the first to identify that a diet high in any type of fat—including healthy mono-saturated fats such as olive oil—negatively impacts testosterone production over as little as five hours, yet one supplemented with egg whites, and to a lesser extent whey protein, can positively affect serum testosterone. Globally, infertility affects 15 percent of couples, with the World Health Organization estimating that up to 25 percent of couples in developing countries are affected. While the causes are many and varied, 20-30 percent of the problems are attributed to male factors alone. Lead researcher, Dr. Karma Pearce, says the preliminary findings present controversial insights over the shorter five-hour term about the link between testosterone and "healthy" monounsaturated fat, which is popularly considered to be a component of a healthy diet, including the Mediterranean dietary pattern. "There's an assumption that 'good' fats and 'bad' fats perform as they're described—but what's surprising, is that it wasn't the type of fat that mattered at all, as an equal amount of the good and bad fats significantly supressed testosterone production," Dr. Pearce says. While the researchers acknowledge they have tested individual nutrients and the effects may be different in the context of whole food dietary patterns, their earlier work has shown that "Western diets' typified by fast food dietary pattern produced a 25 percent decrease in serum testosterone within an hour of eating, with levels remaining suppressed below fasting baseline for up to four hours. "In this study we also found that consuming albumen—the protein in egg whites—increased testosterone levels, and did so by four-fold relative to fasting, while albumin, combined with the bad saturated fat somewhat ameliorated the effect of the bad fats on testosterone levels, providing another diet-based influencer of testosterone levels." The study tested eight diet protocols (meals comprising polyunsaturated fat; monounsaturated fat; refined carbohydrate (orange juice); whey; egg white; and mixed meals of polyunsaturated fat and refined carbohydrate; polyunsaturated fat and egg white; refined carbohydrate (orange juice) and egg white) with four blood tests/hormone analyses taken before eating and at every hour afterwards for five hours. Dr. Pearce says the study is one step in a series of work needed to support and enhance fertility. While the study only analyses the impact of various dietary macronutrients on testosterone production, not sperm quality, the researchers believe the study results suggest at least the potential for diet to negatively impact on sperm production and fertility. The findings are extremely promising for couples trying to start a family. "It's important to note that it's still early days and more research needs to be done, particularly at looking at the effect of these nutrients in the context of whole food dietary patterns over the longer-term," Dr. Pearce says. "Over the Christmas period, for infertile men, and men with lower than normal testosterone levels, lowering the overall fat content and possibly increasing whey or adding egg whites may lead to improvements in testosterone levels over the shorter term." The next step in their research is to evaluate the longer-term effect of these nutrients on testosterone levels in the context of whole food dietary patterns. "The Effect of Macronutrients on Reproductive Hormones in Overweight and Obese Men: A Pilot Study" is published in the journal Nutrients. |
Fast food leads to slow testosterone
by Flinders University Credit: CC0 Public Domain Obese men hoping to sire children—beware. Obesity is known to be associated with impaired testicular function, potentially resulting in androgen deficiency and sub-fertility. Now it is clear that fast food meals consumed by obese or overweight men have an immediate negative impact on testicular performance and testosterone production. While many facts are involved in the underlying cause of obesity-related male hypogonadism, Flinders University and UniSA researchers have found that a high fat intake from fast food meals has a decisive negative effect on a man's serum testosterone levels. Their investigation into the impact of dietary fat on testicular endocrine function showed some alarming results. They found that the ingestion of a high-fat Fast Food mixed meal, which is a common practice for obese men, produced a 25% fall in serum testosterone within an hour of eating, with levels remaining suppressed below fasting baseline for up to 4 hours. These results—which only investigated the impact on overweight and obese men, and therefore may not apply to lean men—suggest that the passage of fat through the intestinal tract elicits a response that indirectly elicits a post-prandial fall in testosterone. "The observed falls in serum testosterone (25% decline from baseline, 2–3 nmol in absolute terms) are likely to be clinically significant for the obese or older man with low baseline levels of testosterone," says Flinders University's Professor Kelton Tremellen, Gynaecologist and Strategic Professor of Reproductive Medicine, who undertook the research with Dr. Karma Pearce from UniSA. "These men are likely to be placed into a continuous hypogonadal state during waking hours if they frequently consume meals and snacks high in fat. This will clearly have an adverse impact on both their mental and physical wellbeing, plus possibly their fertility potential. "Our results suggest that these men should minimize their fat intake and avoid inter‐meal snacking in order to optimize testicular function." The paper—"Mechanistic insights into the aetiology of post-prandial decline in testosterone in reproductive-aged men," by Kelton Tremellen, Amy Hill and Karma Pearce, has been published in Andrologia journal, September 2019 |
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Share Home Health NOVEMBER 7, 2016 Testosterone levels improve in overweight, obese men after 12-week exercise program by American Physiological Society Ball-and-stick model of the testosterone molecule, C19H28O2, as found in the crystal structure of testosterone monohydrate. Credit: Ben Mills/Wikipedia Twelve weeks of aerobic exercise significantly boosted testosterone levels in overweight and obese men, with the greatest increases seen among vigorous exercisers, according to research presented today at the Integrative Biology of Exercise 7 meeting in Phoenix. Researchers from Tsukuba University and Ryutsu Keizai University in Japan previously found that a combination of diet and exercise was effective in increasing the testosterone in this population. For this study, however, they looked specifically at the effect of regular aerobic exercise on testosterone levels. "Testosterone is a male sex hormone, and low circulating testosterone levels lead to various health disorders in men. Obesity, one of the biggest problems in the world, results in reduction in circulating testosterone levels in men," the research team wrote. Fatigue, decreased sex drive and decreases in muscle and bone mass are some of the common symptoms of low testosterone in men. The research team compared 16 normal weight men to 28 overweight/obese men. None of the men were regular exercisers. At baseline, the overweight/obese men had significantly lower total, free and bioavailable testosterone level than normal weight men. All of the study volunteers completed a 12-week aerobic exercise plan that entailed 40–60 minutes of walking or jogging on one to three days per week. Testosterone levels were also recorded at the end of the study. While their testosterone was still at lower levels than the normal weight men at baseline, overweight and obese men saw a significant increase in all measured testosterone levels. This effect was particularly evident among the men who exercised vigorously. However, the exercise intervention had no significant effect on testosterone levels in the normal weight men. Body weight also significantly decreased following the exercise intervention in the overweight/obese cohort. "I think decrease in body mass is one of the factors for increasing serum testosterone levels," said Hiroshi Kumagai, lead researcher on the study. "However, the degree of weight loss is small, and we found that the increase in vigorous physical activity was independently associated with the increase in serum testosterone levels. So, it seems the increase in physical activity, especially vigorous physical activity, is the main factor for increasing serum testosterone levels." |
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Share Home Diabetes AUGUST 25, 2016 Low testosterone thresholds established for type 2 diabetes by Elliott Richardson, University of Western Sydney Credit: University of Western Sydney Research into type 2 diabetes conducted by Western Sydney University has for the first time established a range of clinical thresholds for testosterone levels in men associated with developing diabetes. The link between low testosterone levels and risk of type 2 diabetes is well documented, and the new research pinpoints the level of risk to men according to their blood testosterone levels. Research leader Dr Evan Atlantis says the findings indicate that men with decreasing testosterone levels have corresponding increasing risk of developing diabetes. "For example, if you have a testosterone level of less than 16 nanomoles per litre, which is really common, you have a 13% chance of developing diabetes within 5 years. "But if you have a level less than 10, which is found in about 8% of men in this age group, the chance of developing diabetes jumps to 20%," says Dr Atlantis. Developed in collaboration with the University of Adelaide, the research gives general practitioners and diabetes specialists a better understanding about low testosterone levels in men to improve current type 2 diabetes screening programs.. "Low testosterone levels in men are associated with a range of medical conditions, including obesity, sexual dysfunction, depression and heart disease, as well as diabetes," he says. However Dr Atlantis says all hope is not lost for men with low testosterone levels. "Men with low testosterone levels can start by making small changes to their everyday lives, such as improving diet and exercise habits," he says. "Lifestyle interventions that focus on achieving a healthy body weight are proven strategies for preventing diabetes". And there is exciting new drug research underway to improve the benefits of lifestyle intervention. "Currently, we are undertaking research to determine whether testosterone therapy with lifestyle intervention will reduce the rate of type 2 diabetes in men with both low testosterone and pre-diabetes or newly diagnosed type 2 diabetes more than lifestyle intervention alone over two years." |
Low testosterone linked to adverse outcomes in T2DM
(HealthDay)—For men with type 2 diabetes, low serum testosterone seems to be implicated in adverse clinical outcomes, according to a review published online Nov. 3 in the Journal of Diabetes Investigation. Kitty Kit Ting Cheung, from The Chinese University of Hong Kong, and colleagues conducted a systematic review of the literature to examine the evidence on low serum testosterone levels in patients with type 2 diabetes. The authors examined the implications of these levels on cardiovascular risk factors, metabolic syndrome, and adverse clinical outcomes. The researchers note that there is accumulating evidence that low serum testosterone is associated with type 2 diabetes. Multiple lines of evidence indicate a possible causal role of low serum testosterone level in type 2 diabetes and obesity. Data from epidemiological studies, mainly in Caucasian populations, have confirmed inverse correlations between serum testosterone level and aging, metabolic syndrome, cardiovascular disease, and cardiovascular-disease-related and all-cause mortality. "In conclusion, review of the literature has identified multiple mechanisms supportive of the effects of low serum testosterone level on causing insulin resistance, obesity, vascular dysfunction, and inflammation," the authors write. "At this moment, the results from these studies could not support checking testosterone level in asymptomatic men with type 2 diabetes, as an independent predictor effect of low testosterone on adverse clinical outcomes has not been clearly established." |
Diabetic men with low testosterone run higher risk of developing atherosclerosis
Men who have low testosterone and Type 2 diabetes face a greater risk of developing atherosclerosis – a condition where plaque builds up in the arteries – than men who have diabetes and normal testosterone levels, according to a new study published in the Endocrine Society's Journal of Clinical Endocrinology & Metabolism (JCEM). Atherosclerosis occurs when fats, cholesterol and other substances build up in and on the walls of the body's arteries. This can restrict blood flow through the body's blood vessels. The plaques also can burst and cause blood clots. "Our study indicates a strong association between low testosterone concentration and the severity of atherosclerotic plaques as well as other key atherosclerotic markers in middle-aged men with Type 2 diabetes," said one of the study's authors, Javier Mauricio Farias, MD, of the Hospital Universitario Sanatorio Guemes in Buenos Aires, Argentina. "The results of our study advance our understanding of the interplay between low testosterone and cardiovascular disease in patients with diabetes." Several studies have raised concerns about the safety of testosterone therapy and the risk of cardiovascular complications. This has public health implications because the number of older men receiving testosterone replacement therapy has jumped sharply during the past decade. The Endocrine Society recommends that testosterone treatment should be reserved for men with clinical symptoms of hypogonadism and consistently low levels of testosterone. The Society also has called for large-scale, well-controlled trials to assess the long-term cardiovascular risks associated with testosterone therapy. The cross-sectional prospective study published in JCEM examined testosterone levels and key atherosclerotic markers, including intimal media thickening of the layers in the carotid artery, the presence of atherosclerotic plaques, function of the endothelial cells that line the heart and blood vessels, and inflammatory markers in 115 men with Type 2 diabetes. The participants were younger than age 70 and had no history of cardiovascular disease. Researchers measured the levels of testosterone in each participant's blood. Among the participants, more than half of patients with diabetes were found to have low testosterone levels. The study found men who had low testosterone and Type 2 diabetes were six times more likely to have increased thickness of the carotid artery and endothelium dysfunction compared to men with normal serum testosterone levels. A total of 54 percent of the men with low testosterone and 10 percent of the men with normal testosterone were found to be at higher risk for vascular disease. "We still need to determine whether testosterone is directly involved in the development of atherosclerosis or if it is merely an indicator of advanced disease," Farias said. "This study is a stepping stone to better understanding the risks of cardiovascular events in men who have both low testosterone and Type 2 diabetes." |
Testosterone promotes prostate cancer in rats
by The Endocrine Society A researcher who found that testosterone raised the risk of prostate tumors and exacerbated the effects of carcinogenic chemical exposure in rats is urging caution in prescribing testosterone therapy to men who have not been diagnosed with hypogonadism, according to a new study published in the Endocrine Society's journal Endocrinology. Testosterone use has soared in the last decade among older men seeking to boost energy and feel younger. One study published in The Journal of Clinical Endocrinology & Metabolism found that the number of American men who started testosterone therapy has nearly quadrupled since 2000, despite concerns about potential cardiovascular risks. The Endocrine Society's Clinical Practice Guidelines on testosterone therapy in adult men recommend prescribing testosterone only to men who have unequivocally low levels of the hormone and decreased libido, erectile dysfunction or other symptoms of hypogonadism, a condition that results from low testosterone. "This research demonstrates that testosterone on its own is a weak carcinogen in male rats," said the study's author, Maarten C. Bosland, DVSc, PhD, of the University of Illinois at Chicago. "When it is combined with cancer-causing chemicals, testosterone creates a hospitable environment for tumors to develop. If these same findings hold true in humans, there is serious cause for public health concern." Two dose-response studies examined the incidence of prostate cancer in rats. The rats were given testosterone through slow-release implant devices. Before the rats were dosed with testosterone, some of the animals were given injections of the carcinogenic chemical N-nitroso-N-methylurea (MNU). These rats were compared to a control group that received MNU but had empty slow-release devices implanted. Among the rats that received testosterone without the carcinogenic chemical, 10 to 18 percent developed prostate carcinomas. Testosterone treatment alone did not induce specific tumors at other sites, but compared with control rats, it caused a significant increase in the number of rats with malignant tumors at any site. When rats were exposed to testosterone and the carcinogen, the treatment caused prostate cancer in 50 to 71 percent of the rats. Even when the hormone dose was too low to elevate testosterone levels in the bloodstream, half of the rats developed prostate tumors. Animals that were exposed to the carcinogenic chemical but not testosterone did not develop prostate cancer. "Since the growth of testosterone therapy is relatively recent and prostate cancer is a slow-moving disease, there are at present no data to determine if testosterone could heighten the risk of prostate cancer in humans," Bosland said. "While human studies are conducted, it would be prudent to limit testosterone prescriptions to men with symptomatic clinical hypogonadism and avoid testosterone use by men for non-medical purposes, including addressing normal signs of aging." The study, "Testosterone Treatment is a Potent Tumor Promoter for the Rat Prostate," was published online, ahead of print. |
Low testosterone levels may indicate worsening of disease for men with prostate cancer
by Wiley Micrograph showing prostatic acinar adenocarcinoma (the most common form of prostate cancer) Credit: Wikipedia For men with low-risk prostate cancer, low levels of testosterone may indicate a worsening of their disease. That's the conclusion of a new study published in BJU International. The findings may help physicians identify patients with low-risk prostate cancer who should receive aggressive anticancer treatment. Men with prostate cancer that is not life threatening and is only slowly progressing, can often forego treatment and instead undergo active surveillance. This involves close monitoring to ensure that their disease does not become serious and jeopardize their health. Unfortunately, doctors currently have no reliable way of predicting which men will develop evidence of worsening or more aggressive disease during active surveillance. Ignacio San Francisco, MD, of the Pontificia Universidad Católica de Chile, and his colleagues looked to see if testosterone levels might provide any indication. After following 154 men with low-risk prostate cancer for 38 months, the investigators found that low levels of free testosterone were significantly linked with an increased risk of developing more aggressive disease. They found no significant association with total testosterone concentrations, although there was a general trend towards increased risk with lower levels. Free testosterone comprises one to two percent of total testosterone and is considered a useful surrogate for the biologically active portion of circulating testosterone. "These results suggest low levels of testosterone are associated with more aggressive prostate cancer. This contradicts long-held beliefs that high testosterone is risky for prostate cancer, and low testosterone is protective," said Dr. San Francisco. The results of this study provide valuable information to clinicians and their patients concerning risk factors for prostate cancer progression in men undergoing active surveillance. "In borderline cases, the presence of low values of free testosterone may help determine whether it is more prudent to initiate treatment rather than continue observation," said Dr. San Francisco. |
Researchers restore brain immune system function after prenatal exposure to environmental toxin
by University of Rochester Medical Center Credit: Pixabay/CC0 Public Domain New research shows that exposure to the industrial byproduct TCDD in utero could cause the brain's immune system to go array later in life, damaging important brain circuits, and potentially giving rise to neurodevelopmental disorders, such as autism and ADHD. TCDD is primarily released into the environment by vehicle exhaust and burning wood and low levels of the toxin are found in air, soil, and food. The most common way people are exposed is through meat, dairy, and fish. In the same study, recently published in the journal Brain, Behavior, and Immunity, researchers also found that pharmacological manipulation could restore the function of microglia, important cells in the brain's immune system. "This suggests that defects in microglia function resulting from prenatal exposures can be reversed later in life, indicating a possible additional therapeutic avenue for neurodevelopmental disorders," said Rebecca Lowery, Ph.D., assistant research professor in the Del Monte Institute for Neuroscience at the University of Rochester, and co-first author of the study. The research, which was conducted in mice, showed that when the brains of males were exposed to TCDD in utero, it caused inflammation which cause microglia to go array when responding to injury. While the microglia themselves appeared healthy, the cells became over activated while responding to injury in a way that could damage important brain circuits. But investigators found that by using the drug Pexidartinib (PLX3397) they could 'shut-off' the hyper-responsive microglia and those were replaced by new microglia that functioned normally. This work offers new clues to when exposure to TCDD is most dangerous. Past research has found that adults exposed to TCDD did not have inflammation in the brain and there was no impact on microglia function. "Microglia are outside of the brain during pregnancy," said Ania Majewska, Ph.D., lead author on this study. "But after birth they are protected, possibly by the blood brain barrier, this barrier may be what prevents the harmful effects of TCDD from entering the brain." Researchers now want to understand if other environmental exposures impact microglia similarly, and whether these changes lead to long-term alterations in brain circuitry and function. |
Ally and enemy? Scientists explore immune cell suspect in Alzheimer's disease
by Bill Hathaway, Yale University Fig. 1: Characterization of microglia-like cells in mhCOs. a Schematic for generating mhCOs. 10% of PU.1-infected hESCs were mixed with 90% parental HES3 hESCs, and PU.1 priming and full induction were performed on day 2 and 18, respectively. b Expression of microglia-related genes from control hCOs and mhCOs (30-day and 70-day old). Gene expression was measured relative to control organoids on day 30 and normalized to β-Actin. Data represent the mean ± SEM (n = 5, three independent batches). c Left, immunostaining for IBA1 reveals the production of microglia-like cells in sectioned-mhCOs at days 30 and 70. IBA1+ cells were not found in control hCOs. Right, Sholl analysis of IBA1 + microglia-like cells from mhCOs at different time points. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESCs lines). d and e Immunostaining of mhCOs at day 70 and isolated microglia co-cultured with neurons (2D) for IBA1 and CSF1R (d) TMEM119 and P2RY12 (e). Representative images were shown (n = 5, from two independent batches). f Top, co-expression of PU.1 and IBA1 in hCOs and mhCOs at day 30 and 70. Bottom, quantification of Pu.1-derived IBA1 microglia-like cells. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESCs lines). Bottom, Pearson’s correlation coefficient of IBA1 with PU.1 in mhCOs at days 30 and 70. g Top, co-immunostaining for Ki67 and IBA1 in mhCOs at day 70. Bottom, quantification of proliferating IBA1 microglia-like cells. Data represent the mean ± SEM (n = 5 organoids from three independent differentiation replicates of two hESC lines). h Left, high-resolution imaging showed microglia isolated from mhCOs at day 90 and co-cultured D90 cortical neurons for 3 days contained inclusions of PSD95. Right, quantification of PSD95 particles in IBA1+ microglia-like cells. Data represent the mean ± SEM (n = 8, from three independent differentiation replicates of hESCs lines). The scale bar represents 50 μm in c–g and 20 μm in h. Credit: DOI: 10.1038/s41467-022-28043-y As scientists search for the roots of Alzheimer's disease, they have had a hard time determining whether microglia, an immune system cell crucial to brain development and maintenance of the adult brain, is a friend or foe. Evidence shows that a lack of microglia contributes to accumulation of amyloid plaques, a hallmark of Alzheimer's. Alternately, an excess of microglia has been implicated in the destruction of neurons and brain synapses which also characterizes neurodegeneration in the disease. Now, Yale researchers have developed a way to tease out factors that may determine which of those roles microglia might play, they report in the journal Nature Communications. "All microglia we possess as adults are created before we are born," said In-Hyun Park, associate professor of genetics at the Yale Stem Cell Center. "Microglia are crucial in neurogenesis because they do the synaptic pruning that allows neurons to communicate properly." In adult brains, they act as a kind of cellular trash collector, identifying and disposing of debris from dead neurons. But microglia have been a challenge to study because they form soon after conception and migrate quickly to the developing nervous system. Once they find a home in the developing brain, microglia are cut off from most interaction with other parts of the body by the blood-brain barrier, which protects the brain from pathogens. Dysfunction of microglia has been associated with neurodevelopmental and neurodegenerative diseases, but studying the link has been difficult due to the limited models of the human brain. For the new study, Bilal Cakir and Yoshiaki Tanaka from Park's lab developed a method to generate functional microglia in human cortical organoids, which are small, three-dimensional replicas of the developing brain formed from early-stage stem cells. In laboratory tests, they identified an active gene created very early in development that is crucial to the birth of microglia. They were then able to activate the gene to coax the creation of microglia in the brain organoid. In preliminary experiments, they found organoids lacking microglia were susceptible to accumulation amyloid, a protein that forms plaques linked with Alzheimer's disease. But organoids with functioning microglia were not. The findings suggest that in this case microglia play a protective role. The organoids can be used to study effects of other genes linked to the development of Alzheimer's, the researchers said. |
Microglial methylation "landscape" in human brain
by Elsevier Credit: Unsplash/CC0 Public Domain In the central nervous system, microglial cells play critical roles in development, aging, brain homeostasis, and pathology. Recent studies have shown variation in the gene-expression profile and phenotype of microglia across brain regions and between different age and disease states. But the molecular mechanisms that contribute to these transcriptomic changes in the human brain are not well understood. Now, a new study targets the methylation profile of microglia from human brain. The study appears in Biological Psychiatry. Microglia, the brain's own immune cells, were once thought of as a homogenous population that was either "activated" or "inactivated," with either pro-inflammatory or neuroprotective effects. But the cells are now recognized to have a vast array of phenotypes depending on environmental conditions with myriad functional consequences. Microglia are increasingly appreciated as critical players in neurologic and psychiatric disorders. Fatemeh Haghighi, Ph.D., senior author of the new work, said that "to address this gap in knowledge, we set out to characterize the DNA methylation landscape of human primary microglia cells and factors that contribute to variations in the microglia methylome." DNA methylation is the main form of epigenetic regulation, which determines the pattern of which genes are being turned "on" or "off" in various circumstances over time. The researchers studied isolated microglia cells from post-mortem human brain tissue from 22 donors of various age, including 1 patient with schizophrenia, 13 with mood disorder, and 8 controls with no psychiatric disorder, taken from 4 brain regions. They analyzed the microglia using genome-scale methylation microarrays. Unsurprisingly, microglia showed DNA methylation profiles that were distinct from other cells in the central nervous system. But less expected, said Haghighi, "we found that interindividual differences rather than brain region differences had a much larger effect on the DNA methylation variability." In addition, an exploratory analysis showed differences in the methylation profile of microglia from brains of subjects with psychiatric disorders compared to controls. John Krystal, MD, Editor of Biological Psychiatry, said of the work, "These promising data point to pathology of the microglia, key immune cells of the brain, in the biology of depression." |
Physical activity may improve Alzheimer's disease outcomes by lowering brain inflammation
by Society for Neuroscience Conceptual diagram of moderated mediation models. Models examine the mediating effect of inferior temporal microglial activation (PAM IT) on the relationship between physical activity and global cognitive outcomes or synaptic integrity markers in the inferior temporal gyrus. Credit: Casaletto et al., JNeurosci 2021 No one will disagree that an active lifestyle is good for you, but it remains unclear how physical activity improves brain health, particularly in Alzheimer's disease. The benefits may come about through decreased immune cell activation, according to new research published in JNeurosci. Microglia, the brain's resident immune cells, activate to clear debris and foreign invaders from the brain. But too much activation can trigger inflammation, damage neurons, and disrupt brain signaling. Exercise helps reduce aberrant activation in animals, but that link hadn't been established in humans. Casaletto et al. examined the relationship between physical activity and microglia activation in 167 older adults across the spectrum of cognitive aging (majority nondemented) as part of the Rush Memory and Aging Project. The participants wore activity monitors 24 hours a day for up to ten days straight before annual cognitive exams. The researchers measured microglia activation and Alzheimer's disease (AD) pathology in postmortem brain tissue analyses. Greater physical activity was linked to lower microglial activation, particularly in the inferior temporal gyrus, a brain region hit the hardest by AD. Physical activity had a more pronounced effect on inflammation in people with more severe AD pathology. Future research will examine if physical activity interventions can alter microglia activation in AD patients. |
Do microglia hold the key to stop Alzheimer's disease?
by VIB (the Flanders Institute for Biotechnology) Credit: CC0 Public Domain A Leuven research team led by Prof. Bart De Strooper (VIB-KU Leuven, UK DRI) studied how specialized brain cells called microglia respond to the accumulation of toxic proteins in the brain, a feature typical of Alzheimer's. The three major disease risk factors for Alzheimer's—age, sex and genetics—all affect microglia response, raising the possibility that drugs that modulate this response could be useful for treatment. One of the hallmarks of Alzheimer's disease is the presence of so-called amyloid plaques in the brain. Research suggests that these plaques trigger a series of processes in which microglia play a central role. Microglia are specialized brain cells that act as the first and main form of immune defense in the brain. "The response of these important support cells to the accumulation of toxic amyloid beta may have a big effect on the disease process," says Alzheimer expert Bart De Strooper (VIB-KU Leuven, UK DRI). "That's why we wanted to understand better the microglial response to amyloid beta and how it may differ across individuals." The activation state of 10,000 cells "We know microglia get involved in Alzheimer's disease by switching into an activated mode," explains Dr. Carlo Sala Frigerio. "We were interested to know if aging in the presence or absence of amyloid beta deposition would affect this activation." Sala Frigerio worked in De Strooper's lab in Leuven and recently started his own group at the UK Dementia Research Institute in London. The researchers used a genetic mouse model in which amyloid beta progressively accumulates, mimicking the disease process in human patients. The team analyzed the gene expression profiles of more than 10,000 individual microglia cells isolated from different brain regions of both male and female mice at different disease stages. "We found that the microglial responses to amyloid beta were complex but could essentially be catalogued into two major activation states. The same two activation states that are found during normal ageing, but then activation was slower and less pronounced." In female mice, the microglia reacted earlier to amyloid beta, especially if the mice were older. Similar findings resulted from analyzing the microglia in a different Alzheimer mouse model and in human brain tissue. Targeting microglia activation "Our data indicate that major Alzheimer risk factors, such as age, sex and genetic risk, affect the complex microglia response to amyloid plaques in the brain," says De Strooper. "In other words, different Alzheimer's risk factors converge on the activation response of microglia." Both De Strooper and Sala Frigerio believe that the response of individual microglia will largely depend on their direct environment within the brain. "A particular challenge will be to dissect the distribution of microglia in different activation states across the brain. Such a detailed dissection could lead to a whole set of new drug targets that could be useful to tune the microglia response in a beneficial way." |
New PET imaging biomarker could better predict progression of Alzheimer's disease
by Society of Nuclear Medicine and Molecular Imaging Multimodal correlation analysis of cognitive testing with terminal PET and immunohistochemical results in PS2APP mice at study termination. Representative PET images (z score on MRI template), immunohistochemistry (fused methoxy-X04 [blue] and Iba1 [red]), and WM findings of individual mice, showing either low (orange) or high (magenta) markers of microglial activation at study termination. Credit: Focke C, Blume T, Zott B, Shi Y, et al. Researchers have discovered a way to better predict progression of Alzheimer's disease. By imaging microglial activation levels with positron emission tomography (PET), researchers were able to better predict progression of the disease than with beta-amyloid PET imaging, according to a study published in the April issue of the Journal of Nuclear Medicine. According to the Alzheimer's Association, an estimated 5.3 million Americans are currently living with Alzheimer's disease. By 2025, that number is expected to increase to more than seven million. The hallmark brain changes for those with Alzheimer's disease include the accumulation of beta-amyloid plaques. When microglial cells from the central nervous system recognize the presence of beta-amyloid plaques, they produce an inflammatory reaction in the brain. "The 18-kD translocator protein (TSPO) is highly expressed in activated microglia, which makes it a valuable biomarker to assess inflammation in the brain," said Matthias Brendel, MD, MHBA, at Ludwig-Maximilians-University of Munich in Germany. "In our study, we utilized TSPO-PET imaging to determine whether microglial activation had any influence on cognitive outcomes in an amyloid mouse model." In the study, researchers compiled a series of PET images for 10 transgenic mice with beta-amyloid proteins and seven wild-type mice. TSPO PET imaging of activated microglia was conducted at eight, 9.5, 11.5 and 13 months, and beta-amyloid PET imaging was performed at eight and 13 months. Upon completion of the imaging, researchers then subjected the mice to a water maze in which the mice were to distinguish between a floating platform that would hold their weight and one that would sink. The tasks were performed several times a day during a 1.5-week period. Memory performance in the water maze was assessed by measuring the average travel time from the start point to a platform each day of training and by calculating the traveled distance at the last day of training. After completing the water maze task, immunohistochemistry analyses were performed for microglia, amyloid and synaptic density. Transgenic mice with the highest TSPO PET signal in the forebrain or other areas associated with spatial learning tended to have better cognitive performance in the water maze, while beta-amyloid signals in the same areas of the brain showed no correlation to cognitive outcomes in the maze. Researchers found that an earlier microglial response to amyloid pathology in transgenic mice also protected synaptic density at follow-up. Specifically, transgenic mice with higher TSPO expression at eight months had much better cognitive outcomes in the water maze and higher synaptic density as confirmed by immunochemistry analyses. "This study provides the first evidence that the level of microglial activation could be a far better predictor of current and future cognitive performance than beta-amyloid levels," noted Brendel. "Keeping the limitations of mouse models in mind, it could be crucial to modify an individual's microglial activation state to ameliorate future cognitive decline. We believe that a balanced microglia activation is crucial for prevention of cognitive impairment." |
The brain's immune system may be key to new Alzheimer's treatments
by Sanford-Burnham Prebys Medical Discovery Institute Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative. Credit: Sanford Burnham Prebys Medical Discovery Institute Sanford Burnham Prebys Medical Research Institute (SBP) researchers have published two new studies in Neuron that describe how TREM2, a receptor found on immune cells in the brain, interacts with toxic amyloid beta proteins to restore neurological function. The research, performed on mouse models of Alzheimer's disease, suggests boosting TREM2 levels in the brain may prevent or reduce the severity of neurodegenerative disorders including Alzheimer's disease. "Our first paper identifies how amyloid beta binds to TREM2, which activates neural immune cells called microglia to degrade amyloid beta, possibly slowing Alzheimer's disease pathogenesis," says Huaxi Xu, Ph.D., professor and director of SBP's Neuroscience Initiative, Jeanne and Gary Herberger Leadership Chair in Neuroscience Research and senior author of the study. "The second study shows that increasing TREM2 levels renders microglia more responsive and reduces Alzheimer's disease symptoms." Alzheimer's disease affects more than 47 million people worldwide, a number expected to grow as the population ages. One of the hallmarks of the disease is the accumulation of amyloid plaques that form between neurons and interfere with brain function. Many drug companies have been working for years to reduce amyloid beta production to thwart Alzheimer's—but with minimal success. "TREM2 offers a potential new strategy," says Xu."Researchers have known that mutations in TREM2 significantly increase Alzheimer's risk, indicating a fundamental role for this particular receptor in protecting the brain. This new research reveals specific details about how TREM2 works, and supports future therapeutic strategies to strengthen the link between amyloid beta and TREM2, as well as increasing TREM2 levels in the brain to protect against pathological features of the disease. Xu led the first study (TREM2 is a receptor for β-amyloid which mediates microglial function), showing that TREM2 binds quite specifically to amyloid beta. In particular, it connects with amyloid beta oligomers (proteins that bind together to form a polymer), which are the protein's most toxic configuration. Without TREM2, microglia were much less successful at binding to, and clearing out, amyloid beta. Further investigation showed that removing TREM2 downregulated microglial potassium ion channels, impairing the electrical currents associated with the activation of these immune cells. In addition, TREM2 turned on a number of mechanisms associated with the amyloid beta response in microglia. The second study (TREM2 Gene Dosage Increase Reprograms Microglia Responsivity and Ameliorates Pathological Phenotypes in Alzheimer's Disease Models), a collaboration led by with X. William Yang, M.D., Ph.D., professor in Jane and Terry Semel Institute for Neuroscience and Human Behavior, and Department of Psychiatry & Biobehavioral Sciences at David Geffen School of Medicine at UCLA, added TREM2 to a mouse model with aggressive Alzheimer's disease. They found that the added TREM2 signaling stopped disease progression and even restored cognitive function. "These studies are important because they show that in addition to rescuing the pathology associated with Alzheimer's disease, we are able to reduce the behavioral deficits with TREM2," says Xu. "To our knowledge this provides convincing evidence that minimizing amyloid beta levels alleviates Alzheimer's disease symptoms." As they learn more about how TREM2 modulates the amyloid signals that put microglia to work, the Xu lab and other researchers have their work cut out for them. "It could be beneficial in early stages to activate microglia to eat up amyloid beta," says Xu, "but if you over-activate them, they may release an overabundance of cytokines (causing extensive inflammation) damaging healthy synaptic junctions as a side-effect from overactivation." Still, the ability to use the brain's existing immune mechanisms to clear amyloid offers intriguing possibilities. "Going after microglia, rather than amyloid beta generation, may be a new research avenue for Alzheimer's disease," says Xu. "We could use brain immune cells to solve what's becoming a public health crisis." |
One step closer to defeating Alzheimer's disease
by Rockefeller University Press In mice with Alzheimer's-like disease, removal of TREM2 (right) decreased the formation of toxic plaques (arrows) that characterize the disease. Credit: Jay et al., 2015 Tackling brain inflammation ameliorates Alzheimer's disease (AD), according to a study published in The Journal of Experimental Medicine. AD is characterized by the toxic build-up of a brain protein called beta-amyloid, and clearance of these protein "plaques" reduces disease. Immune cells called macrophages infiltrate the brain during AD and are thought to help clear away these toxic proteins, with the help of resident brain cells called microglia. Macrophages and microglia express a surface receptor called TREM2, and although debilitating mutations in TREM2 have been associated with AD, the function of the receptor is uncertain. To decipher TREM2's role in AD, Bruce Lamb and colleagues from the Cleveland Clinic's Lerner Research Institute deleted the receptor in mice that develop an AD-like disease. Removal of TREM2 decreased plaque formation, reduced brain inflammation, and improved the survival of neurons. This protection was associated with fewer infiltrating macrophages. Macrophages lacking TREM2 were apparently better at engulfing beta-amyloid aggregates, suggesting that they might assist in the brain clean-up effort. Although additional studies are needed to clarify the exact mechanism of TREM2's action in AD, these results suggest that toning down the receptor's activity may help put a stop to neurodegeneration in AD patients. |
Targeting inflammatory pathway reduces Alzheimer's disease in mice
by Journal of Clinical Investigation Alzheimer's disease (AD) is the most common form of dementia and is characterized by the formation of β-amyloid plaques throughout the brain. Proteins known as chemokines regulate inflammation and the immune response. In both patients with AD and mouse AD models, the chemokine CXCL10 is found in high concentrations in the brain and may contribute to AD. A new study in the Journal of Clinical Investigation indicates that activation of the CXCL10 receptor, CXCR3, contributes to AD pathology. Using a murine model of AD, Michael Heneka and colleagues at the University of Bonn found that mice lacking CXCR3 had reduced β-amyloid plaque formation. Importantly, loss of CXCR3 signaling in AD mice attenuated behavioral deficits. The results of this study suggest that CXCR3 should be explored as a potential therapeutic target for AD. |
Drugs targeting blood vessels may be candidates for treating Alzheimer's
by University of British Columbia (Medical Xpress)—University of British Columbia researchers have successfully normalized the production of blood vessels in the brain of mice with Alzheimer's disease (AD) by immunizing them with amyloid beta, a protein widely associated with the disease. While AD is typically characterized by a build-up of plaques in the brain, recent research by the UBC team showed a near doubling of blood vessels in the brain of mice and humans with AD. The new study, published online last week in Scientific Reports, a Nature journal, shows a reduction of brain capillaries in mice immunized with amyloid beta – a phenomenon subsequently corroborated by human clinical data – as well as a reduction of plaque build-up. "The discovery provides further evidence of the role that an overabundance of brain blood vessels plays in AD, as well as the potential efficacy of amyloid beta as basis for an AD vaccine," says lead investigator Wilfred Jefferies, a professor in UBC's Michael Smith Laboratories. "Now that we know blood vessel growth is a factor in AD, if follows that drugs targeting blood vessels may be good candidates as an AD treatment." AD accounts for two-thirds of all cases of dementia. The number of Canadians living with dementia is expected to reach 1.4 million by 2013, according to the Alzheimer's Society of Canada. |
Common epilepsy drug could prevent and treat Alzheimer's disease
The team led by UBC Psychiatry Prof. Weihong Song, who is also the Jack Brown and Family Professor and Chair in Alzheimer's Disease at UBC, found that if Valproic Acid (VPA) is used as a treatment in early stages of AD memory deficit is reversed. The study, published in the Journal of Experimental Medicine, reveals that VPA works by inhibiting the activity of an enzyme that produces a neurotoxic protein called beta Amyloid. In doing so, plaque formation is discontinued. Amyloid beta-proteins are the central component of neurotoxic plaques in AD. "We found that if we used VPA in the early stage of Alzheimer's disease, in model mice, it reduced plaque formation and further prevented brain cell death and axon damage," says Song, who is a Canada Research Chair in Alzheimer's disease and Director of the Townsend Family Laboratories in UBC's Faculty of Medicine. "The drug also improved performance in memory tests." The results will help inform the design of human clinical trials because researchers now understand the mechanisms and pathology of VPA in AD animal models. "We are very excited about these results because we now know when VPA should be administered to be most effective and we now know how VPA is working to prevent AD," says Song, who is also a member of the Brain Research Centre at UBC and VCHRI. "A small human clinical trial is currently underway and we expect results to be available in the next year." AD is a neurodegenerative disorder characterized by progressive cognitive deterioration and is the most common form of dementia. The Alzheimer Society of Canada estimates that AD affects close to 300,000 Canadians and accounts for two-thirds of all cases of dementia. By 2031, about 750,000 Canadians will suffer from AD and related dementias. Source: University of British Columbia |
Researchers generate new neurons in brains, spinal cords of living adult mammals
by UT Southwestern Medical Center UT Southwestern Medical Center researchers created new nerve cells in the brains and spinal cords of living mammals without the need for stem cell transplants to replenish lost cells. Although the research indicates it may someday be possible to regenerate neurons from the body's own cells to repair traumatic brain injury or spinal cord damage or to treat conditions such as Alzheimer's disease, the researchers stressed that it is too soon to know whether the neurons created in these initial studies resulted in any functional improvements, a goal for future research. Spinal cord injuries can lead to an irreversible loss of neurons, and along with scarring, can ultimately lead to impaired motor and sensory functions. Scientists are hopeful that regenerating cells can be an avenue to repair damage, but adult spinal cords have limited ability to produce new neurons. Biomedical scientists have transplanted stem cells to replace neurons, but have faced other hurdles, underscoring the need for new methods of replenishing lost cells. Scientists in UT Southwestern's Department of Molecular Biology first successfully turned astrocytes – the most common non-neuronal brain cells – into neurons that formed networks in mice. They now successfully turned scar-forming astrocytes in the spinal cords of adult mice into neurons. The latest findings are published today in Nature Communications and follow previous findings published in Nature Cell Biology. "Our earlier work was the first to clearly show in vivo (in a living animal) that mature astrocytes can be reprogrammed to become functional neurons without the need of cell transplantation. The current study did something similar in the spine, turning scar-forming astrocytes into progenitor cells called neuroblasts that regenerated into neurons," said Dr. Chun-Li Zhang, assistant professor of molecular biology at UT Southwestern and senior author of both studies. "Astrocytes are abundant and widely distributed both in the brain and in the spinal cord. In response to injury, these cells proliferate and contribute to scar formation. Once a scar has formed, it seals the injured area and creates a mechanical and biochemical barrier to neural regeneration," Dr. Zhang explained. "Our results indicate that the astrocytes may be ideal targets for in vivo reprogramming." The scientists' two-step approach first introduces a biological substance that regulates the expression of genes, called a transcription factor, into areas of the brain or spinal cord where that factor is not highly expressed in adult mice. Of 12 transcription factors tested, only SOX2 switched fully differentiated, adult astrocytes to an earlier neuronal precursor, or neuroblast, stage of development, Dr. Zhang said. In the second step, the researchers gave the mice a drug called valproic acid (VPA) that encouraged the survival of the neuroblasts and their maturation (differentiation) into neurons. VPA has been used to treat epilepsy for more than half a century and also is prescribed to treat bipolar disorder and to prevent migraine headaches, he said. The current study reports neurogenesis (neuron creation) occurred in the spinal cords of both adult and aged (over one-year old) mice of both sexes, although the response was much weaker in the aged mice, Dr. Zhang said. Researchers now are searching for ways to boost the number and speed of neuron creation. Neuroblasts took four weeks to form and eight weeks to mature into neurons, slower than neurogenesis reported in lab dish experiments, so researchers plan to conduct experiments to determine if the slower pace helps the newly generated neurons properly integrate into their environment. In the spinal cord study, SOX2-induced mature neurons created from reprogramming of astrocytes persisted for 210 days after the start of the experiment, the longest time the researchers examined, he added. Because tumor growth is a concern when cells are reprogrammed to an earlier stage of development, the researchers followed the mice in the Nature Cell Biology study for nearly a year to look for signs of tumor formation and reported finding none |
Natural mineral may help reverse memory loss
by University of Queensland Credit: Pixabay/CC0 Public Domain Selenium—a mineral found in many foods—could reverse the cognitive impact of stroke and boost learning and memory in aging brains, according to University of Queensland research. Queensland Brain Institute (QBI) lead researcher Dr. Tara Walker said studies on the impact of exercise on the aging brain found levels of a protein key to transporting selenium in the blood were elevated by physical activity. "We've known for the last 20 years that exercise can create new neurons in the brain, but we didn't really understand how," Dr. Walker said. The research team investigated whether dietary selenium supplements could replicate the effects of exercise. "Our models showed that selenium supplementation could increase neuron generation and improve cognition in elderly mice," Dr. Walker said. "The levels of new neuron generation decrease rapidly in aged mice, as they do in humans. "When selenium supplements were given to the mice, the production of neurons increased, reversing the cognitive deficits observed in aging." Selenium is an essential trace mineral absorbed from soil and water and is found in foods such as grains, meat and nuts, with the highest levels found in Brazil nuts. The scientists also tested whether selenium would have an impact on the cognitive decline sometimes experienced following stroke, which can affect people's memory and ability to learn. "Young mice are really good at the learning and memory tasks, but after a stroke, they could no longer perform these tasks," Dr. Walker said. "We found that learning and memory deficits of stroke affected mice returned to normal when they were given selenium supplements." Dr. Walker said the results opened a new therapeutic avenue to boost cognitive function in people who were unable to exercise due to poor health or old age. "However, selenium supplements shouldn't be seen as a complete substitute for exercise, and too much can be bad for you," she said. "A person who is getting a balanced diet of fruits, nuts, veggies and meat usually has good selenium levels. "But in older people, particularly those with neurological conditions, selenium supplements could be beneficial." |
Selenium status influence cancer risk
by Charité - Universitätsmedizin Berlin As a nutritional trace element, selenium forms an essential part of our diet. In collaboration with the International Agency for Research on Cancer, researchers from Charité - Universitätsmedizin Berlin have been able to show that high blood selenium levels are associated with a decreased risk of developing liver cancer. In addition to other risk factors, the study also examines in how far selenium levels may influence the development of other types of cancer. Results from this study have been published in the American Journal of Clinical Nutrition. Selenium (Se) is found in foods like fish, shellfish, meat, milk and eggs; certain South American nuts, such as Brazil nuts, are also good sources of selenium. It is a trace element that occurs naturally in soil and plants, and enters the bodies of humans and animals via the food they ingest. European soil has a rather low selenium concentration, in comparison with other areas of the world, especially in comparison to North America. Deficiencies of varying degrees of severity are common among the general population, and are the reason why German livestock receive selenium supplements in their feed. While in Europe, neither a selenium-rich diet nor adequate selenium supplementation is associated with adverse effects, selenium deficiency is identified as a risk factor for a range of diseases. "We have been able to show that selenium deficiency is a major risk factor for liver cancer," says Prof. Dr. Lutz Schomburg of the Institute of Experimental Endocrinology, adding: "According to our data, the third of the population with lowest selenium status have a five- to ten-fold increased risk of developing hepatocellular carcinoma - also known as liver cancer." In this case-control study, the team of European researchers investigated a cohort of 477,000 participants, and selected individuals who had developed hepatocellular carcinoma during a 10-year follow up. Blood samples were also chosen from healthy participants and subsequently analyzed to determine their selenium status. "Our study does not show that selenium supplementation has a direct protective effect against liver cancer. However, it does confirm the importance of a balanced diet, of which selenium forms an integral part," explains Prof. Schomburg. Previous studies had suggested a similar relationship between a person's selenium status and their risk of developing colon cancer, as well as their risk of developing autoimmune thyroid disease. |
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