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A preliminary study in JAMA Internal Medicine reported that older women in Spain who ate a traditional Mediterranean diet enhanced with extra-virgin olive oil were less likely to be diagnosed with breast cancer.

The breast cancer study was bootstrapped onto a landmark clinical trial in Spain called Prevención con Dieta Mediterránea (PREDIMED). In 2013, the first results from this study established that people who ate a Mediterranean diet — rich in extra-virgin olive oil, fruits and vegetables, nuts and legumes,— were 30% less likely to have heart attacks or strokes or to die from heart-related causes, compared with people who were just told to eat less fat.

But the PREDIMED researchers were not done. They also kept track of how many women were diagnosed with breast cancer during the study period so they could see if the rates were different across three different groups—women who followed the diet plus extra servings of olive oil, women who followed the diet plus extra servings of nuts, and women who were simply advised to reduce fat intake. They followed about 4,300 women ages 60 to 80.

Out of a total of 35 breast cancers diagnosed during the study period, there were 62% fewer cancers in the women who ate the olive-oil–enhanced diet, compared with women just told to cut their fat intake. The rate of breast cancer in women who ate the Mediterranean diet plus extra servings of nuts was not statistically different from that in the women told to reduce fat intake. Based on the study’s numbers, in a group of 1,000 women who eat a Mediterranean-style diet with extra olive oil for 10 years, 14 women would be diagnosed with breast cancer. A similar group of women who only cut fat from their diet without eating in the Mediterranean style would see 29 cases, meaning 15 additional breast cancers over a decade in every 1,000 women.

That’s great news — but it isn’t definite proof that eating Mediterranean prevents breast cancer. The study’s conclusions are based on just 35 cases of breast cancer. The small numbers leave the study more vulnerable to factors besides diet that could have skewed the math.

A healthy diet is only one influence of lifestyle on the risk of breast cancer. The study says a healthy diet may be very important — plus you need to exercise, plus you need to lose weight. Fortunately, we know that the Mediterranean diet prevents heart disease and reduce the risk of dementia. The evidence for whether it fights breast cancer may be preliminary, but what’s the downside of trying it?

Thanks for reading.

Dr. Connie Wan

Journal Reference: Anita Slomski, Mediterranean Diet With Olive Oil May Reduce Breast Cancer Risk JAMA. 2015; 314(20) : 2122. doi:10.1001/jama.2015.15119

There is mounting evidence that a diet containing omega-3 fatty acids not only helps prevent cardiovascular disease but may also help prevent depression. New research has shown that increasing omega-3 consumption reduces incidence of neurological and immune disorders. The relation of omega-3 fatty acids — mainly DHA (docosahexaenoic acid and EPA (eicosapentaenoic acid) — and depression has been revealed in several studies worldwide.

In a large Finnish study of fish consumption and depressive symptoms, published in Psychiatric Services in April 2001, Tanskanen, et al. demonstrated that the likelihood of having depressive symptoms was significantly higher among infrequent fish consumers than among frequent fish consumers.¹ The researchers theorized that the human brain is adapted to Paleolithic diets of our ancient ancestors, whose diet comprised equal proportions of omega-3 fatty acids and omega-6 fats (found in corn and soy seed oils). In the past 100 years, Western diets have lowered the ratio of omega-3 to omega-6 to about 1:25; simultaneously, the prevalence of major depression has increased.

In the 2003 Rotterdam Study, published in the American Journal of Clinical Nutrition, Tiemeir, et al. found that elderly persons with depression had a fatty acid composition different from that of non-depressed persons.² Percentages of omega-3 fatty acids were significantly lower, and the ratios of omega-6 to omega-3 were significantly higher in subjects with depressive disorders than in control subjects.

Dr. Joseph R. Hibbeln from the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health (NIH), discovered that omega-3 fatty acids may influence serotonin functionality in the brain. In a letter published in The Lancet in April 1998, he reported that among healthy volunteers, low plasma concentrations of DHA predict low concentrations of a marker of brain serotonin turnover. Low concentrations of serotonin are strongly associated with depression and suicide.³

DHA is a primary building block in the gray matter of the human brain and in the retina of the eye, and is present in every cell in the body. The fatty acid is essential at every stage of human life, beginning in utero. DHA together with its precursor EPA must be derived from foods because human body cannot produce its own supply. Fish and nutritional supplements (using either fish oil or plant oil as the omega-3 source) tend to provide an ideal ratio of omega-3s to omega-6s (10:1). Supplementing your diet with Omega-3 fatty acids sources and therefore bring the ratio of Omega-3 to Omega-6 to an ideal balance is essential for maintaining a healthy brain.

Thanks for reading.

Dr. Connie Wan

Journal References:

Tanskanen A. et al. Fish Consumption and Depressive Symptoms in the General Population in Finland, Psychiatric Services 2001; 52 (4): 529-531.
Tiemeier, H. et al. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study, The American Journal of Clinical Nutrition 2003; 78 (1): 40-46.
HibbeIn, J. Fish consumption and major depression, The Lancet 1998; 351:1213.

Blood levels omega-3 fatty acids from either fish or plants are moderately associated with a lower risk of dying from heart attacks, according to a new epidemiological study, published in JAMA Internal Medicine, by researchers from Stanford and Tufts.¹

Omega-3 fatty acids are polyunsaturated fatty acids with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Omega-3 fatty acids are important for normal metabolism.² Human body cannot synthesize omega-3 fatty acids, but can obtain the shorter-chain omega-3 fatty acid alpha-linolenic acid (ALA, C18:3(n-6)) through diet and use it to form the more important long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA, C20:5(n-3)) and then from EPA, the most crucial, docosahexaenoic acid (DHA, C22:6(n-3)).² The ability to make the longer-chain omega-3 fatty acids from ALA may be impaired in aging.^3,4

Animal based omega-3 fatty acids including eicosapentaenoic acid (EPA, C20:5(n-3)) and docosahexaenoic acid (DHA, C22:6(n-3)) were usually obtained exclusively from fish, especially fatty fish such as salmon, trout, anchovies, sardines, and herring. Plant-based omega-3 fatty acids including alpha-linolenic acid (ALA, C18:3(n-6)) may be found various plant sources including in walnuts, flaxseed oil, algea oil, canola oil and some other seed and nuts oils. An extensive list of omega-3 rich foods can be found here.

By pooling findings from diverse large studies that had measured blood or tissue levels of omega-3 fatty acids, Stanford and Tufts scientists evaluated relationships between omega-3 fatty acids in blood with heart disease events over time. A total of 19 studies were involved from 16 countries including 45,637 participants. Of these, 7,973 people developed a first heart attack over time, including 2,781 deaths and 7,157 nonfatal heart attacks. The meta-analysis of these 19 studies showed that both fish-sourced and plant sourced omega-3s were associated with about a 10 percent lower risk of fatal heart attacks.

The study is one of a large body of recent studies, either experimental or statistical, showing the beneficial effect of omega-3 fatty acids on cardiovascular health.

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Del Gobbo, L.C.; and Mozaffarian, D., et al. ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease: Pooling project of 19 cohort studies.. JAMA Internal Medicine, June 2016 DOI: 1001/jamainternmed.2016.2925
“Omega-3 Fatty Acids and Health: Fact Sheet for Health Professionals”. US National Institutes of Health, Office of Dietary Supplements. 2005. Retrieved 12 April 2014.
Freemantle E, Vandal M, Tremblay-Mercier J, Tremblay S, Blachère JC, Bégin ME, Brenna JT, Windust A, Cunnane SC (2006). “Omega-3 fatty acids, energy substrates, and brain function during aging”. Prostaglandins, Leukotrienes and Essential Fatty Acids. 75 (3): 213–20.
Gao F, Taha AY, Ma K, Chang L, Kiesewetter D, Rapoport SI (2012). “Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver”. AGE. 35 (3): 597–608.

A diet lacking in omega-3 fatty acids, specifically docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), nutrients commonly found in fish, may cause your brain to age faster and lose some of its memory and thinking abilities, according to a study published in Neurology, the medical journal of the American Academy of Neurology.¹

In the study conducted by the researchers from UCLA and supported by the Framingham Heart Study’s National Heart, Lung, and Blood Institute and the National Institute on Aging, 1,575 people with an average age of 67 and free of dementia underwent MRI brain scans. They were also given tests that measured mental function, body mass and the omega-3 fatty acid levels in their red blood cells.

The researchers found that people whose DHA levels were among the bottom 25 percent of the participants had lower brain volume compared to people who had higher DHA levels. Similarly, participants with levels of all omega-3 fatty acids in the bottom 25 percent also scored lower on tests of visual memory and executive function, such as problem solving and multi-tasking and abstract thinking. The researchers concluded that people with lower blood levels of omega-3 fatty acids had lower brain volumes that were equivalent to about two years of structural brain aging.

Essential fatty acids (EFAs), mainly DHA and EPA, are required for maintenance of optimal health but they cannot be synthesized by the body and must be obtained from dietary sources. The human brain is nearly 60 percent fat. Approximately 8% of the brain’s weight is comprised of omega-3 fatty acids²—the building block for an estimated 100 billion neurons.³ DHA and EPA play a host of vital roles in neuronal structure and function, protecting them from oxidative damage, inflammation, and the cumulative destruction inflicted by other chronic insults.^4,5 Therefore, getting enough DHA and EPA through diet or supplements are crucial for your brain’s integrity and ability to perform.

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Z. S. Tan, W. S. Harris, A. S. Beiser, R. Au, J. J. Himali, S. Debette, A. Pikula, C. DeCarli, P. A. Wolf, R. S. Vasan, S. J. Robins, S. Seshadri. Red blood cell omega-3 fatty acid levels and markers of accelerated brain aging. Neurology, 2012; 78 (9): 658 DOI: 10.1212/WNL.0b013e318249f6a9
O’Brien JS, Sampson EL. Lipid composition of the normal human brain: gray matter, white matter, and myelin. J Lipid Res. 1965 Oct;6(4):537-44.
Chang CY, Ke DS, Chen JY. Essential fatty acids and human brain. Acta Neurol Taiwan. 2009 Dec; 18(4):231-41.
Robinson JG, Ijioma N, Harris W. Omega-3 fatty acids and cognitive function in women. Womens Health (Lond Engl). 2010 Jan;6(1):119-34.
Eckert GP, Franke C, Noldner M, et al. Plant derived omega-3-fatty acids protect mitochondrial function in the brain. Pharmacol Res. 2010 Mar; 61(3):234-41.

Source: Informed Nutrition

Individuals who have higher levels of a fatty acid known as docosahexaenoic acid (DHA) in their blood may have a significantly lower risk of developing dementia and Alzheimer’s disease, according to a report in the Archives of Neurology, one of the Journal of the American Medical Association (JAMA) Archives journals.

Age, family history and genetic factors have all been found to increase the risk of dementia and Alzheimer’s disease, a neurodegenerative disorder that causes 70 percent of cases of dementia in the elderly, according to background information in the article. A study by researchers from the Tufts University has found that DHA, an omega-3 polyunsaturated fatty acid found in fish, appears to affect dementia risk and to be important for the proper functioning of the central nervous system.

Ernst J. Schaefer, M.D., Jean Mayer U.S. Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, and colleagues studied the association between DHA levels and dementia in the blood of 899 men and women who were part of the population-based Framingham Heart Study. The participants of an average age of 76 years provided blood samples and underwent neuropsychological testing, and were followed for an average of nine years. A subgroup of 488 also filled out a questionnaire assessing their diet, including information about fish consumption. None of the participants had dementia at the beginning of the study; and they were given a mental examination every two years to screen for its development.

Through the nine-year study period, 99 out of 899 participants developed dementia, including 71 with Alzheimer’s disease. After controlling for other known risk factors for dementia, including age, and dividing the study population into fourths (quartiles) based on levels of DHA, the researchers found that men and women in the quartile with the highest DHA levels had a 47 percent lower risk of developing dementia and 39 percent lower risk of developing Alzheimer’s disease than the other three quartiles with lower DHA levels. Among the participants who completed the dietary questionnaire, those in the top quartile of blood DHA levels reported that they ate an average of .18 grams of DHA a day and an average of three fish servings a week. Participants in the other quartiles ate substantially less fish.

DHA levels in the blood could be contributed to two dietary sources: from consumption of fish (or DHA supplement), or from the liver conversion of alpha-linolenic acid, an omega-3 fatty acid rich in flaxseeds and nuts, to DHA. In this Tufts’ study, the correlation between blood DHA content and development of dimension is significant, indicating that DHA intake is an important in lowering the risk of dimension later in life.

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Ernst J. Schaefer et al. Plasma Phosphatidylcholine Docosahexaenoic Acid Content and Risk of Dementia and Alzheimer Disease: The Framingham Heart Study, Arch Neurol. 2006; 63(11):1545-1550. doi: 10.1001/archneur.63.11.1545

A range of diseases — from diabetes to cardiovascular disease, and from Alzheimer’s disease to attention deficit hyperactivity disorder — are linked to changes to genes in the brain. A study by UCLA scientists has found that hundreds of those brain genes can be damaged by fructose, a sugar that’s common in the Western diet. This means that, by altering genes in the brain, fructose could affect the occurrence of these diseases. However, the researchers discovered good news as well: the omega-3 fatty acid, docosahexaenoic acid (DHA), seems to reverse the harmful changes produced by fructose.

DHA occurs naturally in the membranes of our brain cells, but not in a large enough quantity to help fight diseases. Human brain and the body are deficient in the machinery to make DHA; it has to come through our diet. DHA strengthens synapses in the brain and enhances learning and memory. It is abundant in wild salmon and, to a lesser extent, in other fish and fish oil, as well as walnuts, flaxseed, and fruits and vegetables.

To test the effects of fructose and DHA, the researchers trained rats to escape from a maze, and then randomly divided the animals into three groups. Then, for six weeks, one group of rats drank water with an amount of fructose that would be roughly equivalent to a person drinking a liter of soda per day. The second group was given fructose water and a diet rich in DHA. The third received water without fructose and no DHA.

After the six weeks, the rats were put through the maze again. The animals that had been given only the fructose navigated the maze about half as fast than the rats that drank only water — indicating that the fructose diet had impaired their memory. The rats that had been given fructose and DHA, however, showed very similar results to those that only drank water — which strongly suggests that the DHA eliminated fructose’s harmful effects.

Other tests on the rats revealed more major differences: The rats receiving a high-fructose diet had much higher blood glucose, triglycerides and insulin levels than the other two groups. Those results are significant because in humans, elevated glucose, triglycerides and insulin are linked to obesity, diabetes and many other diseases.

The research team sequenced more than 20,000 genes in the rats’ brains, and identified more than 700 genes in the hypothalamus (the brain’s major metabolic control center) and more than 200 genes in the hippocampus (which helps regulate learning and memory) that were altered by the fructose. The altered genes they identified, the vast majority of which are comparable to genes in humans, are among those that interact to regulate metabolism, cell communication and inflammation. Among the conditions that can be caused by alterations to those genes are Parkinson’s disease, depression, bipolar disorder, and other brain diseases.

The research also uncovered new details about the mechanism fructose uses to disrupt genes. The scientists found that fructose removes or adds a biochemical group to cytosine, one of the four nucleotides that make up DNA. This type of modification plays a critical role in turning genes “on” or “off.”

Americans get most of their fructose in foods that are sweetened with high-fructose corn syrup such as soda drinks. Next time, when top off your cup at the soda fountain, remember to take your omega-3 supplement with the drink.

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Meng, QY et al. Systems Nutrigenomics Reveals Brain Gene Networks Linking Metabolic and Brain Disorders. EBioMedicine, 2016; DOI: 10.1016/j.ebiom.2016.04.008

Depression is known to cause coronary heart disease in healthy patients. In patients with existing coronary heart disease, depression could cause adverse cardiovascular outcomes. A study carried out jointly by the scientists from NIH, Stanford, UCSF and Emery University showed that lower levels of omega–3 fatty acids in diet not only increase coronary heart disease risk, but may also be involved in the pathophysiology of depression.

The investigators measured red blood cell levels of two omega–3 fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and assessed depressive symptoms in a cross-sectional study of 987 adults with coronary heart disease. Omega –3 fatty acids were blindly measured in fasting venous blood samples. Specifically, the fatty acid composition of red blood cell membranes was measured. Red blood cell levels of EPA and DHA are presented as a percentage composition of total fatty acids.

The investigators assessed current depression using the 9-item Patient Health Questionnaire. They evaluated the association between omega –3 fatty acid levels and depressive symptoms. The investigators also examined the association of omega–3 fatty acids with depression.

The prevalence of depression ranged from 23% in participants with less than 3.1% EPA + DHA in total blood fatty acids to 13% in participants with more than 4.3% EPA + DHA in total blood fatty acids. Each unit decrease in EPA + DHA was inversely associated with depressive symptoms, and these associations persisted after adjustment for age, sex and race. Similarly, each unit decrease in EPA + DHA was associated with significantly greater odds of depression.

This study extends the existing literature by finding a strong association between low omega–3 fatty acids and depression in outpatients with stable coronary hear disease. Therefore, supplementing DHA+EPA in a low omega-3 diet may help with managing both the progression and the physiological complications of coronary heart disease.

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Ali et al. Association between Omega-3 Fatty Acids and Depressive Symptoms among Patients with Established Coronary Artery Disease: Data from the Heart and Soul Study. Psychotherapy and Psychosomatics, 2009; 78 (2): 125 DOI: 10.1159/000203118

High doses of docosahexaenoic acid (DHA) supplements may help prevent progression to dementia in people who carry the apolipoprotein ε4 allele (APOE4), a new review published online January 17, 2017 in JAMA Neurology.

DHA (docosahexaenoic acid), found almost exclusively in marine organisms living in cold water, is an essential long-chain omega-3 polyunsaturated fatty acid. As one of the primary components of cell membranes, DHA is a key building block in every cell in a human body. Notably, DHA is a major structural fatty acid in the brain and eyes, representing approximately 97% of all omega-3 fats in the brain and 93% of all omega-3 fats in the retina. It plays a role in the formation of synapses and indirectly limits the production of amyloid deposition and helps cells clear toxic amyloid peptides.

Having the APOE4 allele is one of the strongest risk factors for developing Alzheimer’s disease. This allele is present in 20% of the general population but in about 50% of patients with Alzheimer’s disease.

Animal studies have shown that mice or rats given enough DHA over at least 10% of their lifespan don’t develop Alzheimer’s disease pathology (amyloid) in the brain. Observational studies in humans further suggested the link between DHA consumption and lower risk for Alzheimer’s disease. A meta-analysis published in the American Journal of Clinical Nutrition summarized 21 studies of 181,580 participants with 4,438 dementia cases identified during a follow-up ranging from 2.1 to 21 years.² The analysis found that compared with not eating fish, consuming 1 serving of fish per week was associated with a significantly lower risk for Alzheimer’s disease dementia. Additional epidemiologic studies and clinical trials further suggested a trend of cognitively healthy APOE4 carriers benefiting from taking fish oil supplements over an extended period of time. In the Rush Memory and Aging Project, participants free of dementia underwent annual clinical neurologic evaluations and brain autopsy at death. After a mean follow-up of 8 years, the study showed APOE4 carriers who consumed at least one meal of seafood per week had fewer Alzheimer’s disease neuropathologic changes compared with those who consumed less fish.³

Scientists hypothesized several possible mechanisms that might link APOE4 with DHA metabolism. These include accelerated liver catabolism of DHA; defective DHA transfer across the blood-brain barrier; and hypolipidated or decreased APOE4 particle numbers, resulting in less efficient brain DHA metabolism. The conclusion from these scientific studies suggests that supplementing DHA may reduce Alzheimer’s disease risk.

Thanks for reading!

Dr. Connie Wan

[email protected]

Scientific references:

Yassine, HN et al.; Association of Docosahexaenoic Acid Supplementation With Alzheimer Disease Stage in Apolipoprotein E ε4 Carriers, JAMA Neurol. Published online January 17, 2017. doi:10.1001/jamaneurol.2016.4899
Zhang, Y et al.; Intakes of fish and polyunsaturated fatty acids and mild-to-severe cognitive impairment risks: a dose-response meta-analysis of 21 cohort studies, American Journal of Clinical Nutrition 2016; 103(2): 330-340

Bennett, DA et al.; Overview and Findings from the Rush Memory and Aging Project, Curr Alzheimer Res. 2012 Jul 1; 9(6): 646-663

In a large Finnish study of fish consumption and depressive symptoms, published in Psychiatric Services in April 2001, Tanskanen, et al. demonstrated that the likelihood of having depressive symptoms was significantly higher among infrequent fish consumers than among frequent fish consumers.¹ The researchers theorized that the human brain is adapted to Paleolithic diets of our ancient ancestors, whose diet comprised equal proportions of omega-3 fatty acids and omega-6 fats (found in corn and soy seed oils). In the past 100 years, Western diets have lowered the ratio of omega-3 to omega-6 to about 1:25; simultaneously, the prevalence of major depression has increased.

In the 2003 Rotterdam Study, published in the American Journal of Clinical Nutrition, Tiemeir, et al. found that elderly persons with depression had a fatty acid composition different from that of non-depressed persons.² Percentages of omega-3 fatty acids were significantly lower, and the ratios of omega-6 to omega-3 were significantly higher in subjects with depressive disorders than in control subjects.

Dr. Joseph R. Hibbeln from the National Institute on Alcohol Abuse and Alcoholism, part of the National Institutes of Health (NIH), discovered that omega-3 fatty acids may influence serotonin functionality in the brain. In a letter published in The Lancet in April 1998, he reported that among healthy volunteers, low plasma concentrations of DHA predict low concentrations of a marker of brain serotonin turnover. Low concentrations of serotonin are strongly associated with depression and suicide.³

Thanks for reading.

Dr. Connie Wan

Journal References:

Tanskanen A. et al. Fish Consumption and Depressive Symptoms in the General Population in Finland, Psychiatric Services 2001; 52 (4): 529-531.
Tiemeier, H. et al. Plasma fatty acid composition and depression are associated in the elderly: the Rotterdam Study, The American Journal of Clinical Nutrition 2003; 78 (1): 40-46.
HibbeIn, J. Fish consumption and major depression, The Lancet 1998; 351:1213.

Omega-3 fatty acids are polyunsaturated fatty acids with a double bond (C=C) at the third carbon atom from the end of the carbon chain. Omega-3 fatty acids are important for normal metabolism.²Human body cannot synthesize omega-3 fatty acids, but can obtain the shorter-chain omega-3 fatty acid alpha-linolenic acid (ALA, C18:3(n-6)) through diet and use it to form the more important long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA, C20:5(n-3)) and then from EPA, the most crucial, docosahexaenoic acid (DHA, C22:6(n-3)).²The ability to make the longer-chain omega-3 fatty acids from ALA may be impaired in aging.^3,4

Thanks for reading.

Dr. Connie Wan

Journal Reference:

Del Gobbo, L.C.; and Mozaffarian, D., et al. ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease: Pooling project of 19 cohort studies.. JAMA Internal Medicine, June 2016 DOI: 1001/jamainternmed.2016.2925
“Omega-3 Fatty Acids and Health: Fact Sheet for Health Professionals”. US National Institutes of Health, Office of Dietary Supplements. 2005. Retrieved 12 April 2014.
Freemantle E, Vandal M, Tremblay-Mercier J, Tremblay S, Blachère JC, Bégin ME, Brenna JT, Windust A, Cunnane SC (2006). “Omega-3 fatty acids, energy substrates, and brain function during aging”. Prostaglandins, Leukotrienes and Essential Fatty Acids. 75 (3): 213–20.
Gao F, Taha AY, Ma K, Chang L, Kiesewetter D, Rapoport SI (2012). “Aging decreases rate of docosahexaenoic acid synthesis-secretion from circulating unesterified α-linolenic acid by rat liver”. AGE. 35 (3): 597–608.