Tag Archives: inflammation

Can an aspirin a day keep the psychiatrist away?

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Floating across my Facebook feed this morning was an article on the possible link between depression and inflammation.  Its premise was that depression, the joyless soul-sucking disease affecting millions of people around the world, is related to inflammation.  If that were true, might mean that we could cure depression with medications that stop inflammation.  Maybe we should be consuming an aspirin a day to keep the doctor away, and not the proverbial apple?

Inflammation is a hot topic right now.  Inflammation in the medical sense refers to a normal body process to promote healing and recovery from sickness or injury.  It’s a complex dance of chemical signals which is triggered by damage to tissue.  Inflammation is essential to life. Without it, we would be unable to repair our tissues if they were damaged.

When tissues are damaged, a number of local cells in the damaged area release pro-inflammatory cytokines which then trigger a cascade of responses; increase in the size of the local blood vessels to allow greater blood flow to the area, attracting pus-cells (neutrophils) to the area, and increasing the ‘leakiness’ of the blood vessels to allow the pus cells into the area. This response is governed by a number of chemical mediators throughout the body, including histamine, serotonin, complement system, kinins, substance P, prostaglandins and leukotrienes, cytokines and nitric oxide. Anti-inflammatory cytokines balance out the process, keeping the pro-inflammatory cytokines in check so that the process doesn’t spiral out of control.

Despite the literal plethora of chemical reactions going on simultaneously, most of the time the reaction eventually runs out of noxious agents, the anti-inflammatory cytokines dampen down the reaction, and the tissue returns to either normal, or at least functional.  Though inflammation isn’t just limited to repairing damage but also preparing for damage –psychological stress prepares the inflammation system for potential damage.  Physical stress triggers the inflammation system to repair any damage.

Chronic inflammation occurs when the acute illness or injury does not fully resolve and continues to smoulder, the natural healing pathway is obstructed, or the body remains in a psychological state in which it is always expecting a fight.  In chronic inflammation, the processes of active inflammation, tissue destruction and attempts at healing occur simultaneously. In terms of cytokines, the anti-inflammatory cytokines can’t balance out the excess pro-inflammatory cytokines.

There’s a theory about depression which is gaining momentum within the scientific community, that depression and a number of other psychiatric and neurodegenerative conditions are the result of chronic inflammation which occurs because of chronic stress.

Remember when I said before that psychological stress readies the inflammatory system for potential damage?  Well, what if that damage never comes?  If there’s chronic psychological stress, the system is constantly being worn down, and never getting a chance to recover.  This seems to make sense – chronic stress reduces new nerve cell production and growth, and may interfere with the action of nerve growth factors like BDNF and neurotransmitters like serotonin.  Hence why this article by Feelguide seems to ring true.

But is it true?  Is depression fundamentally an inflammatory disease, and if so, can we treat it with medications that decrease inflammation, like aspirin?

Let’s go through the various statements made in the Feelguide article and see what the medical evidence says.

First, a necessary correction to avoid confusion.  The Feelguide article says that, “New research is revealing that many cases of depression are caused by an allergic reaction to inflammation.”  Depression is not an allergic reaction.  A true allergy is an antibody response which releases a chemical called histamine from cells called mast cells.  If the current theory about depression and inflammation is true, then depression is related to cytokines, chemicals that are entirely different to histamine.  It may be really annoying to sneeze like you’re demon possessed if a cat’s been in the same room a week ago, but it’s not going to make you depressed.

Is inflammation caused by obesity, high sugar diets, high quantities of trans fats, unhealthy diets in general?  There’s limited evidence that the foods you eat result in inflammation.  Most of the positive data comes from observational studies which are relatively weak.  Better, stronger studies generally give conflicting information [1].  For example, if high fat, sugary foods were really the cause of low grade inflammation, then diets like the Palaeolithic diet, which replace sugary, fatty processed foods with a bucket load of vegetables should improve inflammation.  Yet there have been no statistically significant changes in inflammatory markers recorded in subjects following the Palaeolithic diet [2].

The Feelguide article claims that, “By treating the inflammatory symptoms of depression – rather than the neurological ones – researchers and doctors are opening up an exciting new dimension in the fight against what has become a global epidemic”, but let’s not get too excited.  Again, there’s precious little evidence that medications or supplements reported to reduce inflammation make any difference to depression.  For example, the article mentions omega-3 and curcumin as having some benefit in the treatment of depression, which is half-right.  There’s some evidentiary support that EPA-predominant omega-3 supplements may have some effect on depression, but none at all for DHA omega-3’s [3] or curcumin [4].

When it comes to other medications with an anti-inflammatory effect, the results are similarly mixed.  The issue seems to be the specific cellular action of the medication on a particular immune cell in the brain called the microglial cell.  For example, normal anti-inflammatory medications like aspirin and other Non-Steroidal Anti-Inflammatory Drugs (NSAID’s) increased the activity of these special microglial cells which resulted in an increase in depressive symptoms in otherwise healthy individuals, whereas a medication called minocycline has been noted to decrease the activity of these microglia, and reduced the risk of depressive symptoms (in animal studies at least) [5].

So we really can’t say whether medications believed to have an anti-inflammatory effect really have any significant benefit.  As neuroscientists, Dr Dora Brites and Dr Adelaide Fernandes wrote,

“Nevertheless, we should be cautious in believing that depression can be treated by therapies targeting inflammation. Further studies are required to evaluate whether a combined therapy with anti-inflammatory compounds and antidepressants will result in additional clinical benefits.” [5]

That’s really because we don’t know whether inflammation causes depression, or if depression causes inflammation.  The article by Feelguide seem pretty confident, but the science is still a long way from being settled.

The final word is this:
1. Depression is complicated and still poorly understood.
2. It may be related to inflammation, but please don’t rely on herbs or medications that claim to have anti-inflammatory or “immune boosting” properties.
3. If you really want to try and treat your depression without pharmaceutical medications, take some EPA Omega 3 supplements by all means, although I’d encourage you to exercise and engage with a good psychologist too, both of which have more evidence of benefit overall.

References

[1]        Minihane AM, Vinoy S, Russell WR, et al. Low-grade inflammation, diet composition and health: current research evidence and its translation. The British journal of nutrition 2015 Oct 14;114(7):999-1012.
[2]        Pitt CE. Cutting through the Paleo hype: The evidence for the Palaeolithic diet. Aust Fam Physician 2016 Jan-Feb;45(1):35-8.
[3]        Hallahan B, Ryan T, Hibbeln JR, et al. Efficacy of omega-3 highly unsaturated fatty acids in the treatment of depression. The British journal of psychiatry : the journal of mental science 2016 Apr 21.
[4]        Andrade C. A critical examination of studies on curcumin for depression. J Clin Psychiatry 2014 Oct;75(10):e1110-2.
[5]        Brites D, Fernandes A. Neuroinflammation and Depression: Microglia Activation, Extracellular Microvesicles and microRNA Dysregulation. Front Cell Neurosci 2015;9:476.

Olive Leaf Extract – A potential treatment, but not for what you think

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Here in Australia, it’s winter. It’s currently warmer in the fridge than it is outside. We’ve just been blasted by a wall of frigid air straight from Antarctica, and much of the south-eastern corner of our continent has snow drifts over parts that not so long ago were baking under the hot Autumn sun. It’s not something we’re used to in Australia.

Of course, now that winter is firmly entrenched, more people are coming to see me with their viral upper respiratory tract infections, better known as ‘colds’. Yes, ’tis the season to be sneezin’!  Over my years of practice, I’ve seen enough people with a cold to last me a thousand winters.

What always fascinates me are the things that people try to use to cure their cold. I think I’ve heard everything over the last decade: garlic, ginger, peppermint, chicken soup, honey, tea, honey mixed with lemon mixed with tea, or honey mixed with lemon mixed cayenne pepper mixed with tea.   Some people rub Vicks on their feet. Other people douse their pillows in eucalyptus oil.

Another common recommendation that gets around the grape vine and social media is olive leaf extract, used in traditional ‘medicine’ for thousands of years, and those witch-doctors and shamans can’t all be wrong.

One published review described the ‘science’ of olive leaf extract: “Constituents of the olive tree, Olea europaea, have been studied and utilized in folk medicine for centuries. Olive leaf extract, derived from the leaves of the olive tree, contains phenolic compounds, specifically oleuropein, that have demonstrated potent antimicrobial, antioxidant, and anti-inflammatory activity. Oleuropein and derivatives such as elenolic acid have been shown to be effective in in vitro and animal studies against numerous microorganisms, including retroviruses, coxsackie viruses, influenza, and parainfluenza as well as some bacteria. Research suggests that olive leaf constituents interact with the protein of virus particles and reduce the infectivity and inhibit replication of viruses known to cause colds, influenza, and lower respiratory infection. Olive leaf extract has also been shown to stimulate phagocytosis, thereby enhancing the immune response to viral infection. Anecdotal reports indicate olive leaf extract taken at the onset of cold or flu symptoms prevents or shortens the duration of the disease. For viral sore throats, gargling with olive leaf tea may alleviate symptoms, possibly by decreasing inflammation and viral infectivity.” [1]

It’s always a concern when a supposedly peer reviewed journal allows an article to get through which seriously discusses anecdotal evidence as something worthy of attention. Anecdotal evidence is the weakest level of evidence possible. Anecdotal evidence is essentially just stories and opinion [2]. There’s anecdotal evidence for the Tooth Fairy. The other ‘evidence’ that this review describes is from in vitro studies, which are trials in test tubes not in people. In vitro evidence is only helpful in a general sense. Just because a reaction happens in a test tube or petri dish doesn’t mean that it will happen in a real life human being.

So then, do the claims for olive leaf extract stand up to the rigors of modern scientific enquiry or is it like every other cold and flu ‘remedy’ – just another individualised mythology?

Being sceptical, I wanted to find out. So I searched through the published medical literature for quality clinical trials that studied olive leaf extract in humans, and I found only six trials. Interestingly, all of the trials studying olive leaf extract weren’t looking at its effect on immune function but on cholesterol and blood sugar control, blood pressure, and oxidative stress.

In 2009, Kendall et al published a single-centre, randomized, single-blinded, prospective pilot comparison of the effect of dietary supplementation with olive leaf extract on the markers of oxidative stress in 45 healthy young adult volunteers. They found that olive leaf extract had no effect on oxidative stress compared to the control group [3].

Susalit et al (2011) published a double-blind, randomized, parallel and active-controlled clinical study looking at the tolerability, cholesterol-lowering and anti-hypertensive effect of Olive leaf extract in comparison with Captopril (a common blood pressure medication) in patients with early hypertension. After 8 weeks of treatment, there were similar reductions in blood pressure in both the olive leaf extract and the blood pressure pill groups. There was a significant drop in triglyceride levels in the olive leaf extract group, but not in Captopril group [4].

Wainstein et al (2012) performed a randomized controlled trial on 79 adults with non-insulin dependent diabetes, comparing a single 500mg dose of olive leaf extract with placebo over 14 weeks. They measured the HbA1c (a surrogate measurement of the average blood sugar over a three month period) and plasma insulin levels. They also did studies in rats to study the mechanism of action of the olive leaf extract. In the human trials, the subjects treated with olive leaf extract exhibited significantly lower HbA1c and fasting plasma insulin levels. This effect was thought to be reflected in the rat study which suggested that olive leaf extract reduced the digestion and absorption of starch from the intestines [5].

de Bock et al (2013) did a randomized, double-blinded, placebo-controlled, crossover trial on 46 patients in New Zealand, over a 30 week period. The participants were middle aged and overweight. The researchers were primarily studying insulin sensitivity but they also looked at glucose and insulin profiles, cytokines, lipid profile, body composition, 24-hour ambulatory blood pressure, and carotid intima-media thickness. The olive leaf extract group had a statistically significant improvement in insulin sensitivity and responsiveness of the pancreatic β-cell. Interestingly, the olive leaf extract supplementation improved some inflammatory markers, but not others, and made no difference to the patients lipid profile, blood pressure, body composition (their body fatness), carotid intima-media thickness (a risk predictor of cardiovascular disease), or liver function [6].

For completeness, de Bock lead another trial, also published in 2013, although this trial was more a study of the absorption of the compounds in olive leaf extract than a study of their effects [7]. There was a 1996 Belgian study which was written in French. I’m not very good with French, but according to the English abstract, there was no difference between the olive leaf extract and placebo in terms of blood pressure and blood sugar levels [8].

Reconciling the research on olive leaf extract makes for an interesting narrative. There are a couple of really strong, methodologically robust trials on olive leaf extract, and with positive results in favour of it. However, I can count them on one hand, and while the results are encouraging for proponents of olive leaf extract, there needs to be a lot more research before those claims can be made with certainty. And in contrast to its usual selling points, those positive effects for olive leaf extract were for blood sugar control, not the prevention or treatment of viral illnesses.

The bottom line – olive leaf extract may one day prove to be a useful herbal supplement, but there’s not enough clinical evidence to support it at the present moment. And there’s certainly no evidence that olive leaf extract will do anything for your viral upper respiratory tract infections.

So next time you get a cold, don’t bother spending money on olive leaf extract. Have a couple of paracetamol, a long hot shower and a good rest.

And if symptoms persist, don’t forget to see your GP.

References

[1]        Roxas M, Jurenka J. Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Alternative medicine review : a journal of clinical therapeutic 2007 Mar;12(1):25-48.
[2]        Fowler G. Evidence-based practice: Tools and techniques. Systems, settings, people: Workforce development challenges for the alcohol and other drugs field 2001:93-107.
[3]        Kendall M, Batterham M, Obied H, Prenzler PD, Ryan D, Robards K. Zero effect of multiple dosage of olive leaf supplements on urinary biomarkers of oxidative stress in healthy humans. Nutrition 2009 Mar;25(3):270-80.
[4]        Susalit E, Agus N, Effendi I, et al. Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril. Phytomedicine : international journal of phytotherapy and phytopharmacology 2011 Feb 15;18(4):251-8.
[5]        Wainstein J, Ganz T, Boaz M, et al. Olive leaf extract as a hypoglycemic agent in both human diabetic subjects and in rats. Journal of medicinal food 2012 Jul;15(7):605-10.
[6]        de Bock M, Derraik JG, Brennan CM, et al. Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial. PloS one 2013;8(3):e57622.
[7]        de Bock M, Thorstensen EB, Derraik JG, Henderson HV, Hofman PL, Cutfield WS. Human absorption and metabolism of oleuropein and hydroxytyrosol ingested as olive (Olea europaea L.) leaf extract. Molecular nutrition & food research 2013 Nov;57(11):2079-85.
[8]        Cherif S, Rahal N, Haouala M, et al. [A clinical trial of a titrated Olea extract in the treatment of essential arterial hypertension]. Journal de pharmacie de Belgique 1996 Mar-Apr;51(2):69-71.

Seven Elements of Good Mental Health: 7. Create social networks – The Prospering Soul

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Life shouldn’t just be about avoiding poor health, but also enjoying good health. Our psychological health is no different.

Before we take a look at poor mental health, let’s look at some of the ways that people can enjoy good mental health and wellbeing. This next series of posts will discuss seven elements that are Biblically and scientifically recognised as important to people living richer and more fulfilling lives.

These aren’t the only ways that a person can find fulfilment, nor are they sure-fire ways of preventing all mental health problems either. They’re not seven steps to enlightenment or happiness either.   But applying these principles can improve psychosocial wellbeing, and encourage good mental health.

7. Create social networks

Before 2004, everyone knew what social networks were. Now when you talk about ‘social networks’, people assume you’re referring to Facebook. It seems like virtual social networking has been around forever, whereas in contrast, real social networking actually has.

We know this, because we’re wired for social interaction, with specific areas of the brain devoted to social behaviour, such as the orbitofrontal cortex, and there are neurotransmitters and hormones that are strongly associated with bonding and maintenance of social relationships, like oxytocin and β-endorphins. Research has also shown that both humans and other primates find social stimuli intrinsically rewarding – babies look longer at faces than at non-face stimuli, for example [1].

People who engage in social relationships are more likely to live longer, some estimate by an extra 50% [2]. Certainly it appears that the opposite is true. Loneliness predicts depressive symptoms, impaired sleep and daytime dysfunction, reductions in physical activity, and impaired mental health and cognition. At the biological level, loneliness is associated with altered blood pressure, increased stress hormone secretion, a shift in the balance of cytokines towards inflammation and altered immunity. Loneliness may predict mortality [3].

So what is loneliness, and conversely, what defines good social relationships? Fundamentally, good or bad social relationships are related to the quality of the social interaction. This rule applies equally to real social networks [3] and their on-line equivalents [4]. So quality is fundamentally more important than quantity in terms of friendships, with that quality strongly determined by the connection within those social relationships. For example, loneliness “can be thought of as perceived isolation and is more accurately defined as the distressing feeling that accompanies discrepancies between one’s desired and actual social relationships” [3].

The corollary is that friendship can be thought of as perceived connection within social relationships, or the comforting feeling that accompanies the match between one’s desired and actual social relationships.

So healthy social relationships aren’t defined by the size of your network, but by the strength of the connections that your network contains, relative to what’s important to you. Just because you’re not a vivacious extrovert who’s friends with everyone doesn’t mean that your social network is lacking. It also means that you can have meaningful connections to friends through social media, just as much as you can have meaningful connections through face to face interactions. It’s not the way you interact, but the quality of the connection that counts.

What is it about other people that makes us more likely to be their friends? Connection between friends is often the result of attraction to individuals of similar personalities or skills, although recent research suggests that friendship may be related to a much deeper level. Brent et al notes that “Humans are especially predisposed toward homophily, with recent evidence suggesting this even extends to the genetic level; people are more likely to be friends if they have similar genotypes. Taken together, these findings advocate the need to consider not only an individual’s genome, but also their metagenome, when asking questions about the causes of friendship biases … Unrelated friends are more likely to be genetically similar, equivalent to the level of fourth cousins, compared to unrelated strangers.” [1]

As Christians, we’re encouraged to engage with other Christians on a regular basis, which in our modern world, is through regular church attendance. As the Bible says in Hebrews 10:23-25, “Let us hold unswervingly to the hope we profess, for he who promised is faithful. And let us consider how we may spur one another on towards love and good deeds, not giving up meeting together, as some are in the habit of doing, but encouraging one another – and all the more as you see the Day approaching.” But as the research has shown, it’s not just being part of the crowd, but connecting with those in the church in a meaningful way. It’s very easy to be lonely in a crowded church.

Always remember: “Befriend, and be a friend” – that’s how you’ll find benefit to your spirit, soul and body.

References

[1]        Brent LJ, Chang SW, Gariepy JF, Platt ML. The neuroethology of friendship. Annals of the New York Academy of Sciences 2014 May;1316:1-17.
[2]        Holt-Lunstad J, Smith TB, Layton JB. Social relationships and mortality risk: a meta-analytic review. PLoS medicine 2010 Jul;7(7):e1000316.
[3]        Luo Y, Hawkley LC, Waite LJ, Cacioppo JT. Loneliness, health, and mortality in old age: a national longitudinal study. Social science & medicine 2012 Mar;74(6):907-14.
[4]        Oh HJ, Ozkaya E, LaRose R. How does online social networking enhance life satisfaction? The relationships among online supportive interaction, affect, perceived social support, sense of community, and life satisfaction. Computers in Human Behavior 2014;30:69-78.

Scars

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I’ve spent a lot of time in trees.

When I grew up, there was no such thing as video games. In those days, we were lucky to have a colour TV and four channels, but watching it was a privilege. Instead, I would usually be outside, bare foot and naive, exploring the creek behind my house and the thin ribbon of bushland that guarded it, or climbing the tree in my backyard, or picking up sticks from the ground and using them as weapons so I could fight off pretend villains like the superheroes I aspired to.

Eventually I discovered cricket and learnt to ride my bike, which changed my outdoor pass times. If I wasn’t practising my cricket skills, I would ride for hours on the footpaths and bikeways that criss-crossed my neighbourhood. There were no bike helmets in those days, and still no shoes. It was an innocent time.

My adventurous spirit and lack of protective equipment invariably resulted in injuries. Once when playing with a stick in the front yard, I somehow managed to dig the sharp end into my right leg, gouging a chunk out of my lower thigh. A few years later when riding my bike, the handlebars of my BMX came loose and trapped my legs so I was unable to peddle. It also stopped me from using the footbrake and steering properly, and there was nowhere else for me to go except into a pole next to a low concrete bridge over the creek, and then over the handlebars and onto a causeway which was covered in large rocks and debris. Amongst the injuries sustained was a large graze to my elbow, which my teenage sister helped tend and dress for me. Unfortunately no one had taught her that the dressing needed to go cotton side up, not onto the wound. A few days later, the scab had to be torn off to remove the dressing.

Several decades later, I would also find myself being thrown off a bike, but this time after a man driving a 4-Wheel Drive didn’t notice that I was riding on the footpath and kept coming out of the driveway he was in. Thankfully this time I was wearing shoes and a helmet, though it still didn’t help much when face smacked into the bitumen after bouncing of his windscreen and sprawling five metres through the air. I wasn’t that beautiful to start with, so my bitumen face didn’t matter too much and the scars eventually healed. But three weeks later when I couldn’t move my arm properly, I suspected that there was something wrong and the MRI showed a fracture of the head of my left radius (bone near my elbow).

The common link in each of my war stories was the eventual outcome – scars. I’ve now got a collection of scars ranging from small to obvious, internal and external. Scars are an interesting though rarely considered part of our normal function. Our body faces assault in various forms all the time. Usually we’re able to stop infections before they take hold. Sometimes, an infection or injury will still get the better of us, but our body will be able to heal our tissues completely, fully restoring our function and appearance as if nothing ever happened. Sometimes, there’s just too much damage, and our body has to do the best it can. It has to fill in the gap left by the irreparable tissue to maximise the structure and function of that tissue. To do that, it uses a scar.

Microscopically, scar tissue is made up of collagen, a dense fibrous tissue that’s also found in tendons. When a breach in the tissue occurs, there are three distinct phases that are followed to create a scar: the inflammatory phase, the fibroplastic phase, and the remodelling phase. The boring, intricate scientific details don’t matter for this essay, but essentially the phases are needed for cleaning up the debris, laying the scaffolding, and reinforcing the scar.

What’s more interesting are some other characteristics of scars that we don’t often appreciate. Firstly, scars hurt. Ok, so that sounds obvious … it always hurts when the injury first happens. The inflammatory phase is the time that a wound hurts the most, but in physiological terms, this phase only lasts about 48 hours. As time goes on, the scar hurts less and less, and in most scars, the pain eventually goes away completely. However, there are a few scars that are still sensitive when touched, sometimes for years.

Some people have a tendency to form bigger scars than others. This is called keloid scarring, and is a process of excessive inflammation of the forming scar tissue which causes too much collagen to be laid down. Keloid scars can be large, itchy and painful. Keloid scarring is thought to have a genetic component to it.

Even if you’re lucky to avoid keloid scarring, scars are usually considered ugly and unwanted. Maybe it’s because they’re associated with pain, or they ruin our otherwise perfect skin. Either way, many people don’t like their scars.

Scars are also weaker than normal tissue, though not by much. By the time a wound has completely healed, the scar strength is about 98% of that of the normal tissue.

Sometimes we’re afraid of getting scars, probably for the same reasons I’ve described. Doing things that are risky might lead to getting hurt, and those scars are a permanent reminder of how we not only failed but also how we hurt ourselves in the process.

Although, I think we have the wrong ideas about scarring. Sure, sometimes scars can be ugly, or painful, or weak. But scars can also tell us a lot about ourselves if we’re willing to look past the superficial and see what they really represent.

Scars can show our bravery to others, remind us of our courage, help us learn from our mistakes, and remember our successes. They can enable empathy, and remind us of our vulnerability and our humanity. They prove that we’ve overcome adversity. Altogether, they tell us our history.

When I see my scars, I remember how I should be careful with sharp objects, or to dress wounds carefully, or to watch out for 4-Wheel Drives. The caesarean scar on my wife’s abdomen reminds me of the mix of fear and joy at the birth of my two children. My scars help me to remember what others are going through in their journey. They remind me that I’m not invincible. When I ask my patients about their scars, they often tell me of how they overcame desperate illness and survived.

At Easter time, we often focus on the power of the resurrection, and so we should. Through the resurrection, we have the opportunity to embrace eternal life with a loving God, who sacrificed his own son to give us that chance.

But one thing that always intrigued me about the Easter story was that after Jesus was resurrected, in his glorious new body, he still bore the scars of the crucifixion. John gives a clear account in the gospel of John 20:24-27, “Now Thomas (also known as Didymus), one of the Twelve, was not with the disciples when Jesus came. So the other disciples told him, ‘We have seen the Lord!’ But he said to them, ‘Unless I see the nail marks in his hands and put my finger where the nails were, and put my hand into his side, I will not believe.’ A week later his disciples were in the house again, and Thomas was with them. Though the doors were locked, Jesus came and stood among them and said, ‘Peace be with you!’ Then he said to Thomas, ‘Put your finger here; see my hands. Reach out your hand and put it into my side. Stop doubting and believe.’”

Before I fully understood the significance of this verse, I had assumed that Jesus’s resurrected body was supernaturally perfect. He had just experienced the power of the resurrection after all. It sort of threw me when I realised that Jesus’s supernatural body was still scarred. And if scars are considered ugly, painful and weak, then it doesn’t seem to make sense.

I’ve come to realise that God knew exactly what he was doing. Those scars on Jesus’s hands, feet and side demonstrate that he gave up his deity to embrace humanity. They show his amazing sacrifice by taking our place on the cross. They prove that that he overcame the power of sin and death. They will remind us of his amazing love for us for the rest of eternity.

Yes, our scars seem ugly, painful and weak on the outside, but they are signs of our struggles, our strength, our victories – things that we have learnt from, and things that we can be proud of.

Scars aren’t a sign of weakness, but of our humanity. Scars are evidence that we’ve overcome adversity, that we are strong. Scars are a permanent reminder of the gift of God to man. Scars are nothing to be ashamed of.

Don’t look at your scars as a sign of weakness and shame, but instead, see your strengths through the story of your scars.

Bibliography

Gauglitz, G. G., Korting, H. C., Pavicic, T., Ruzicka, T., & Jeschke, M. G. (2011). Hypertrophic scarring and keloids: pathomechanisms and current and emerging treatment strategies. Mol Med, 17(1-2), 113-125. doi: 10.2119/molmed.2009.00153

Hardy, M. A. (1989). The biology of scar formation. Phys Ther, 69(12), 1014-1024.

Gluten mad!

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Tonight as I was browsing Facebook again, I came across an article a person had posted on gluten. The article claimed that gluten is connected to depression, and indeed, nearly every other neurological disorder for good measure.

Gluten is a protein found in certain grains like wheat, barley and rye. Gluten also makes foods taste better and improves their texture, so it’s often added to everything else.

The “gluten is toxic” meme is a very catchy one that’s doing the rounds again. I first heard of the idea that gluten is the cause of nearly every disease when I was in medical school, when every person I knew who’d seen a naturopath was told they had gluten intolerance and were conned into an unappetising and restrictive diet which didn’t make any of them better.

The same meme is now making it’s way back around again now that the low-fat, sugar-free, zucchini broth-type diet fads are waning.

The proposed link between depression, anxiety and gluten is a new twist to the old story. But with depression becoming a preeminent disease in the 21st century, the link doesn’t surprise me.

So what does the evidence say? Is gluten the culprit behind the modern scourge of mental illness?

I certainly don’t think so, at least according to my interpretation of the medical literature. As far back as 2001, researchers studying the mental health of patients with coeliac disease noted that coeliac disease patients had much higher levels of anxiety and depression than healthy matched controls (up to about three to six times greater in one study), and after a year on a gluten free diet, there were no changes to the rates of anxiety and depression (Addolorato et al., 2001).

In more recent times, larger studies have been performed. Hauser, Janke, Klump, Gregor, and Hinz (2010) confirmed higher levels of anxiety in German female coeliac patients who were on a gluten free diet, compared to the normal controlled population. Mazzone et al. (2011) showed that children with coeliac disease on gluten-free diets for about 7 years on average still showed an increased rate of anxiety and depression symptoms and showed higher scores in “harm avoidance” and “somatic complaints” as compared to healthy control subjects.

A larger cross sectional survey was performed in the Netherlands in 2013, on 2265 adults with coeliac disease (van Hees, Van der Does, & Giltay, 2013). That survey showed that a significantly higher proportion of those with coeliac disease, despite being on a strict gluten free diet, reporting a higher rate of anxiety and depression compared to the general population. It also showed (albeit in a smaller subgroup of respondents) that poor adherence with a gluten free diet did not affect the likelihood of depressive symptoms.

To be fair, cross sectional surveys and longitudinal cohorts aren’t necessarily the strongest form of evidence, but it is the best we’ve currently got. There was a recent randomised controlled trial, a stronger form of evidence, looking at the effect the introduction of gluten had on depressive symptoms in people who did not have coeliac disease but reported gluten sensitivity and were controlled on a gluten free diet (Peters, Biesiekierski, Yelland, Muir, & Gibson, 2014). While this showed some worsening of depressive symptoms in those subjects given gluten, the exposure was short, the effect was moderate, and the results should be considered cautiously given the small number of subjects reduced the power of the study.

Given the weight of evidence, I can’t help but be sceptical of books touting the ‘gluten = depression’ theory, books like “Grain Brain”. It’s author, American neurologist Dr David Perlmutter, attests that more than 38 different diseases are caused by gluten, including autism and depression. If you believe the celebrity chiropractor who reviewed Perlmutter’s work (http://www.glutenfreesociety.org/gluten-free-society-blog/gluten-leaky-brain-the-connection-to-depression/), increased intestinal permeability and intestinal dysbiosis (“leaky gut” and bad gut bacteria) combine to increase inflammation in the blood and in the brain, causing depression.

But correlation does not equal causation. Just because brain diseases, inflammation and gut problems tend to occur together does not prove that gut problems cause inflammation and brain problems. Rather, the evidence suggests that it’s the other way around, with all of the processes linked to genetics.

For example, autism is related to a number of genes that both reduce the proteins that help nerve cells grow branches (Won, Mah, & Kim, 2013), and at the same time, switch on a low grade form of inflammation (Onore, Careaga, & Ashwood, 2012). I believe it’s the pre-existing inflammation that adds to the cellular dysfunction of the brain and at the same time, promoting low grade inflammation of a number of organs, including the gut. It’s the pre-existing inflammation that causes the gut to become “leaky”, not the “leaky” gut causing the inflammation.

Because if gluten was the primary cause, then why do people with coeliac disease who do not eat gluten report more depressive and anxious symptoms than control groups who do eat gluten? Why would those with coeliac disease who are eating sporadic gluten be just as depressed as those patients who do not?

If you don’t have coeliac disease, then gluten free diets are just like Amway products. You really don’t need them, and you could probably do much better without them. All you’re really doing is just making someone else obscenely rich.

Not only are you wasting your money, but you might also be harming your health by eating gluten free foods, since most foods that are stripped of gluten are also stripped of most of their other nutrients.

As Nash and Slutzky (2014) summarise, “Every major change in our diet carries with it the possibility of unforeseen risks. Many readers — the general public, as well as medical professionals — accept what they read at first glance. Myths have been part of our medical lore for millennia. Those jumping on the gluten-free/high-fat bandwagon may be disappointed when their symptoms are not mitigated; more critically, they may be at increased risk for other, more dangerous ailments.”

If you really think you feel better off gluten, then talk to your doctor or registered dietician to make sure you remain healthy off it.

References

Addolorato, G., Capristo, E., Ghittoni, G., Valeri, C., Masciana, R., Ancona, C., & Gasbarrini, G. (2001). Anxiety but not depression decreases in coeliac patients after one-year gluten-free diet: a longitudinal study. Scand J Gastroenterol, 36(5), 502-506.

Hauser, W., Janke, K. H., Klump, B., Gregor, M., & Hinz, A. (2010). Anxiety and depression in adult patients with celiac disease on a gluten-free diet. World J Gastroenterol, 16(22), 2780-2787.

Mazzone, L., Reale, L., Spina, M., Guarnera, M., Lionetti, E., Martorana, S., & Mazzone, D. (2011). Compliant gluten-free children with celiac disease: an evaluation of psychological distress. BMC Pediatr, 11, 46. doi: 10.1186/1471-2431-11-46

Nash, D. T., & Slutzky, A. R. (2014). Gluten sensitivity: new epidemic or new myth? Every major change in our diet carries with it the possibility of unforeseen risks. Am J Cardiol, 114(10), 1621-1622. doi: 10.1016/j.amjcard.2014.08.024

Onore, C., Careaga, M., & Ashwood, P. (2012). The role of immune dysfunction in the pathophysiology of autism. Brain Behav Immun, 26(3), 383-392. doi: 10.1016/j.bbi.2011.08.007

Peters, S. L., Biesiekierski, J. R., Yelland, G. W., Muir, J. G., & Gibson, P. R. (2014). Randomised clinical trial: gluten may cause depression in subjects with non-coeliac gluten sensitivity – an exploratory clinical study. Aliment Pharmacol Ther, 39(10), 1104-1112. doi: 10.1111/apt.12730

van Hees, N. J., Van der Does, W., & Giltay, E. J. (2013). Coeliac disease, diet adherence and depressive symptoms. J Psychosom Res, 74(2), 155-160. doi: 10.1016/j.jpsychores.2012.11.007

Won, H., Mah, W., & Kim, E. (2013). Autism spectrum disorder causes, mechanisms, and treatments: focus on neuronal synapses. Front Mol Neurosci, 6, 19. doi: 10.3389/fnmol.2013.00019

Fats and Figures: Re-examining saturated fat and what’s really good for your heart

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A Facebook friend forwarded me an article a few weeks back and asked for my humble medical opinion.

The article was entitled, “World Renowned Heart Surgeon Speaks Out On What Really Causes Heart Disease”. It was written by a man who said he was a heart surgeon, and who claimed to be coming clean on the real reason why our world has an epidemic of obesity and heart disease despite the low fat advice of the medical profession.

It’s a highly controversial topic right now. For decades, the western world was under the impression that fat was tobaccos right hand man in a war on good health. Standard medical dogma was that high cholesterol was bad, and that saturated fat was its main source. Evil butter was replaced with angelic margarine. Fatty red meat was always served with a generous side portion of guilt. Low fat became high fashion.

Today, the pendulum of public opinion has swung back with such amazing ferocity, it’s become more like a wrecking ball. Fat has returned to the fold as friend instead of foe. The once mighty cholesterol lowering medications called statins have become seen as another example of pharmaceutical company profits-before-patients. Sugar has become the new villain, and along with it, the nebulous concept of “inflammation” as the key mechanism of heart disease and strokes, and nearly every other medical ailment.

What started off as a three-paragraph reply on Facebook has evolved into a short eBook, which you can download for free from Smashwords (https://www.smashwords.com/books/view/514719)

In today’s post, I want to look at six things that, over the years, have been touted as contributing to or preventing heart disease, and see what the evidence says. The results may be surprising!

1. Is saturated fat bad? Is polyunsaturated fat good?

According to a meta-analysis of observational studies on dietary fats by Chowdhury et al. (2014), relative risks for coronary disease were 1.02 (95% CI, 0.97 to 1.07) for saturated fats, 0.99 (CI, 0.89 to 1.09) for monounsaturated, 0.93 (CI, 0.84 to 1.02) for long-chain n-3 polyunsaturated, 1.01 (CI, 0.96 to 1.07) for n-6 polyunsaturated, and 1.16 (CI, 1.06 to 1.27) for trans fatty acids. The total number of patients in all of the trials was more than half a million. This is pretty convincing evidence that saturated fats aren’t as bad as first believed.

What does all this mean? In statistical terms, a relative risk is the incidence of disease in one group compared to the incidence of disease in another. The risk of the disease in the two groups is the same if the relative risk = 1. A relative risk of 7.0 means that the experiment group has seven times the risk of a control group. A relative risk of 0.5 would mean the experiment group has half the risk of the control group. The confidence interval is a range of numbers in which there is a 95% chance that the true relative risk is in the interval. A result is “statistically significant” when the confidence interval (CI) does not cross the number 1.

So going back to the study by Chowdhury et al. (2014), only 2% more patients in the group with the highest saturated fat consumption had heart disease compared to the lowest saturated fat consumption. The confidence interval crossed 1, so that result may have been due to chance alone. For trans fatty acid consumption, 16% more people had heart disease in the higher consumption group compared to the lower consumption group, which was probably a real effect and not due to chance (the confidence interval did not cross 1). Simply put, trans-fats are bad. Saturated fats probably aren’t.

The same meta-analysis by Chowdhury et al. (2014) also reviewed supplementation with PUFA’s on the overall risk of heart disease. They found that in 27 randomised controlled trials with more than 100,000 people, relative risks for coronary disease were 0.97 (CI, 0.69 to 1.36) for alpha-linolenic acid supplements, 0.94 (CI, 0.86 to 1.03) for long-chain n-3 polyunsaturated acid supplements, and 0.89 (CI, 0.71 to 1.12) for n-6 polyunsaturated fatty acid supplements. In this case, there was a trend in favour of supplementation with omega-3 and omega-6 supplements, but it was small, and may have been due to chance. This is confirmed by other reviews (Rizos, Ntzani, Bika, Kostapanos, & Elisaf, 2012; Schwingshackl & Hoffmann, 2014)

So it appears that it doesn’t matter what fat you consume, saturated or polyunsaturated, or whether you supplement with fish oils or eat lots of fish, your cardiovascular risk is much the same. The only thing that’s definitely clear is that you should avoid trans-fats.

2. Is sugar bad for you?

That depends.

When we think of sugar, we think of sucrose, a carbohydrate made up of one glucose and one fructose molecule. There are many carbohydrates, which are just various combinations of different numbers of glucose/fructose molecules, sucrose being one type.

Sugar consumption is thought to be the modern scourge, it’s consumption linked to everything from cancer to gallstones. It’s been recently become the villain of cardiovascular disease as well. It’s thought to cause insulin resistance, inflammation and an increase in the fats circulating in the blood stream. So, is it as bad as they say? The evidence is surprising.

First of all, sugar doesn’t make you fat. Rather, it’s the calories you consume that make you fat. Te Morenga, Mallard, and Mann (2013) conclude their meta-analysis of dietary sugar and body weight, “Among free living people involving ad libitum diets, intake of free sugars or sugar sweetened beverages is a determinant of body weight. The change in body fatness that occurs with modifying intakes seems to be mediated via changes in energy intakes, since isoenergetic exchange of sugars with other carbohydrates was not associated with weight change.”

The intake of sugar and glucose don’t cause an increase in inflammation or cholesterol in healthy people. In a study on effects of sugar consumption on the biomarkers of healthy people, Jameel, Phang, Wood, and Garg (2014) found that consumption of sucrose and glucose actually decreased cholesterol. Fructose increased cholesterol, though interestingly, the Total:HDL ratio (which is prognostic for heart disease) did not change significantly with the consumption of any form of sugar. They also found that fructose was associated with an increase in inflammation, but glucose and sucrose reduced inflammation.

On the other hand, a study by Isordia-Salas et al. (2014) showed a small but significant association between those with high blood glucose level and inflammation, though they also found an association between inflammation and BMI (the body-mass index), so it’s not clear what the causal factor is.

There seems to be a clearer association between blood glucose after meals in those who have abnormal glucose metabolism. In patients with pre-diabetes, higher levels of blood glucose two hours after eating were associated with increased risk of death from cardiovascular disease and all causes (Coutinho, Gerstein, Wang, & Yusuf, 1999; Decode Study Group, 2003; Lind et al., 2014).

To melt your brain a little more, just because high glucose levels are associated with higher mortality doesn’t mean the lower the glucose, the better. In the study by the Decode Study Group (2003), low blood glucose had a higher mortality than normal glucose levels, and a meta-analysis by Noto, Goto, Tsujimoto, and Noda (2013) showed that low carbohydrate diets have a 30% increase in all-cause mortality.

How do you pull all of these seemingly contradictory studies together? The bottom line appears to be, according to the evidence so far, that consumption of sugar does not cause inflammation or significantly increase the risk of heart disease in healthy people who are able to metabolise it properly.

In those people who have abnormal glucose metabolism, the higher the glucose is after a meal (a measure of how well the body processes glucose), then the higher the risk is of inflammation, heart disease, and all-cause mortality.

The distinction between who has normal glucose metabolism and who has dysfunctional glucose metabolism is probably related to genetics. A study by Sousa, Lopes, Hueb, Krieger, and Pereira (2011) showed that genetic information was able to predict 5-year incidence of major cardiovascular events and overall mortality in non-diabetic individuals, even after adjustment for the persons blood sugar. Those without diabetes but who had a high genetic risk had a similar incidence of cardiovascular events compared to diabetics. So if you have the genes, your body doesn’t process the glucose properly and your risk is increased, even if you aren’t bad enough to have a diagnosis of diabetes.

Thus it appears that sugar is not the bad guy that everyone makes it out to be. Excess sugar will make you fat, but so will excess everything-else. It probably won’t kill you unless you’re genetically pre-disposed to handle it poorly. And there’s the rub, because we don’t have the capacity to test for that clinically yet.

So the last word on sugar is that it’s a sometimes food. You may be lucky enough to handle large amounts of sugar, but the best advice at this time is don’t tempt fate by eating large quantities of it.

3. Is obesity bad for you?

Again, that depends.

It used to be thought that obesity posed a linear risk, that is, the fatter you were the higher your risk of heart attacks, cancer, diabetes, everything. Then in 2013, a meta-analysis by Flegal, Kit, Orpana, and Graubard (2013) showed that people who were overweight (but not obese) had better survival than those who were normal weight.

Later in 2013, Kramer, Zinman, and Retnakaran (2013) published a meta-analysis which showed that metabolically unhealthy people of normal BMI were at greater risk of cardiovascular disease than metabolically healthy obese people.

Last year a paper by Barry et al. (2014) showed that those who were unfit were twice as likely to die compared to people who were fit, irrespective of their BMI.

So obesity doesn’t seem to be the problem after all, rather it’s a persons ability to handle blood sugar, cholesterol and blood pressure that’s the problem. It seems that more people with obesity have these metabolic problems, but correlation does not equal causation. There’s probably a undetermined factor that links obesity and metabolic dysfunction.

I’m not suggesting that we should all get fatter. Obesity has problems of its own, unrelated to metabolic issues, that make it problematic. We should still be careful about our weight. The take-home message is that skinny does not necessarily mean healthy and that focusing on what the scales are saying may be distracting us from the real problem.

4. Is meat bad for you? Should we be vegetarians?

In a word, no.

In the two available meta-analyses of the studies on red meat consumption (Larsson & Orsini, 2014), and red meat vs white meat vs all meat (Abete, Romaguera, Vieira, Lopez de Munain, & Norat, 2014), there was a statistical but moderate increase in death and heart disease from processed meats.

There was a trend towards a higher death rate in those who ate the most red meat, but the trend wasn’t statistically significant (i.e.: may have been related to chance). There was no trend associated with white meat consumption. So it appears that as long as it’s not processed meat, red meat isn’t as bad as people first thought.

Meat might not be particularly bad, but are vegetarian diets better? Again, probably not. The meta-analysis by Huang et al. (2012) shows that there’s a positive trend for vegetarian diets, though again, that might be attributable to chance as the results are not statistically significant.

The take-away message? Even though the trends may be related to chance, the trend is favourable for vegetables and not as favourable for red meat. So eat more veggies, eat less red meat, but don’t let some sanctimonious vegan convince you that meat is noxious and vile.

5. Is alcohol good for you?

A different meme recently came around my Facebook feed, entitled, “Is Drinking Wine Better Than Going To The Gym? According To Scientists, Yes!” For a while there, I had fantasies about giving my membership card back to the gym and heading down to the local bottle shop for my daily workout instead.

Disappointingly, it turns out that red wine isn’t better than exercise according to the research that I uncovered. However, my research did suggest that the daily exercise of wine drinking is still beneficial, and not just red wine, but alcohol of any form. Ronksley, Brien, Turner, Mukamal, and Ghali (2011) showed about two standard drinks of alcohol daily conferred a 25% reduction in deaths from heart disease (relative risk 0.75 (0.68 to 0.81)), and a small but statistically strong reduction in death from all causes of 13% (relative risk 0.87 (0.83 to 0.92)). The risk reduction of coronary heart disease from alcohol was also confirmed in a more recent study by Roerecke and Rehm (2014), who showed that death from heart disease was reduced by 36% for those who consistently consumed less than three standard drinks a day (relative risk 0.64 (0.53 to 0.71)).

The effect applies to consistent daily consumption, not to drinking in a cluster pattern (binging or weekend-drinking only, for example). And there’s a gender difference, women having the maximum beneficial effect at about one drink a day, and two drinks a day in men.

6. Is exercise good for you?

In a word, yes!

I’ve never seen a study that showed exercise was harmful. Exercise improves overall metabolism, decreases cardiovascular disease, improves mood and memory and increases your lifespan, amongst many other things. If exercise came in pill form, it would be labelled a wonder-drug.

As discussed earlier, fit people have a better rate of survival compared to unfit people, whether they’re obese or not (Barry et al., 2014). And the key to fitness is exercise. In a large meta-analysis by Samitz, Egger, and Zwahlen (2011), 80 studies involving more than 1.3 million subjects in total were analysed, showing that the highest levels of exercise had an all cause mortality reduction of 35% (relative risk 0.65 (0.6 to 0.71)).

There’s always debate about what form of exercise is best. Are you better to do weights, do interval training, or run for hours? Honestly, it probably doesn’t matter that much in the end. What is important is that you work hard enough to elevate your heart rate and break a sweat. If you aren’t very fit, it won’t take much exercise to do that. If you are very fit, it probably will. But for the average person, you don’t have to jump straight into a boot camp style program and work so hard that you’re puking everywhere, and so sore afterwards that you can’t move for a week. Common sense prevails!

References

Abete, I., Romaguera, D., Vieira, A. R., Lopez de Munain, A., & Norat, T. (2014). Association between total, processed, red and white meat consumption and all-cause, CVD and IHD mortality: a meta-analysis of cohort studies. Br J Nutr, 112(5), 762-775. doi: 10.1017/S000711451400124X

Barry, V. W., Baruth, M., Beets, M. W., Durstine, J. L., Liu, J., & Blair, S. N. (2014). Fitness vs. fatness on all-cause mortality: a meta-analysis. Prog Cardiovasc Dis, 56(4), 382-390. doi: 10.1016/j.pcad.2013.09.002

Chowdhury, R., Warnakula, S., Kunutsor, S., Crowe, F., Ward, H. A., Johnson, L., . . . Di Angelantonio, E. (2014). Association of dietary, circulating, and supplement fatty acids with coronary risk: a systematic review and meta-analysis. Ann Intern Med, 160(6), 398-406. doi: 10.7326/M13-1788

Coutinho, M., Gerstein, H. C., Wang, Y., & Yusuf, S. (1999). The relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care, 22(2), 233-240.

Decode Study Group, E. D. E. G. (2003). Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care, 26(3), 688-696.

Flegal, K. M., Kit, B. K., Orpana, H., & Graubard, B. I. (2013). Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis. JAMA, 309(1), 71-82. doi: 10.1001/jama.2012.113905

Huang, T., Yang, B., Zheng, J., Li, G., Wahlqvist, M. L., & Li, D. (2012). Cardiovascular disease mortality and cancer incidence in vegetarians: a meta-analysis and systematic review. Ann Nutr Metab, 60(4), 233-240. doi: 10.1159/000337301

Isordia-Salas, I., Galvan-Plata, M. E., Leanos-Miranda, A., Aguilar-Sosa, E., Anaya-Gomez, F., Majluf-Cruz, A., & Santiago-German, D. (2014). Proinflammatory and prothrombotic state in subjects with different glucose tolerance status before cardiovascular disease. J Diabetes Res, 2014, 631902. doi: 10.1155/2014/631902

Jameel, F., Phang, M., Wood, L. G., & Garg, M. L. (2014). Acute effects of feeding fructose, glucose and sucrose on blood lipid levels and systemic inflammation. Lipids Health Dis, 13(1), 195. doi: 10.1186/1476-511X-13-195

Kramer, C. K., Zinman, B., & Retnakaran, R. (2013). Are metabolically healthy overweight and obesity benign conditions?: A systematic review and meta-analysis. Ann Intern Med, 159(11), 758-769. doi: 10.7326/0003-4819-159-11-201312030-00008

Larsson, S. C., & Orsini, N. (2014). Red meat and processed meat consumption and all-cause mortality: a meta-analysis. Am J Epidemiol, 179(3), 282-289. doi: 10.1093/aje/kwt261

Lind, M., Tuomilehto, J., Uusitupa, M., Nerman, O., Eriksson, J., Ilanne-Parikka, P., . . . Lindstrom, J. (2014). The association between HbA1c, fasting glucose, 1-hour glucose and 2-hour glucose during an oral glucose tolerance test and cardiovascular disease in individuals with elevated risk for diabetes. PLoS One, 9(10), e109506. doi: 10.1371/journal.pone.0109506

Noto, H., Goto, A., Tsujimoto, T., & Noda, M. (2013). Low-carbohydrate diets and all-cause mortality: a systematic review and meta-analysis of observational studies. PLoS One, 8(1), e55030. doi: 10.1371/journal.pone.0055030

Rizos, E. C., Ntzani, E. E., Bika, E., Kostapanos, M. S., & Elisaf, M. S. (2012). Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA, 308(10), 1024-1033. doi: 10.1001/2012.jama.11374

Roerecke, M., & Rehm, J. (2014). Alcohol consumption, drinking patterns, and ischemic heart disease: a narrative review of meta-analyses and a systematic review and meta-analysis of the impact of heavy drinking occasions on risk for moderate drinkers. BMC Med, 12(1), 182. doi: 10.1186/s12916-014-0182-6

Ronksley, P. E., Brien, S. E., Turner, B. J., Mukamal, K. J., & Ghali, W. A. (2011). Association of alcohol consumption with selected cardiovascular disease outcomes: a systematic review and meta-analysis. BMJ, 342, d671. doi: 10.1136/bmj.d671

Samitz, G., Egger, M., & Zwahlen, M. (2011). Domains of physical activity and all-cause mortality: systematic review and dose-response meta-analysis of cohort studies. Int J Epidemiol, 40(5), 1382-1400. doi: 10.1093/ije/dyr112

Schwingshackl, L., & Hoffmann, G. (2014). Dietary fatty acids in the secondary prevention of coronary heart disease: a systematic review, meta-analysis and meta-regression. BMJ Open, 4(4), e004487. doi: 10.1136/bmjopen-2013-004487

Sousa, A. G., Lopes, N. H., Hueb, W. A., Krieger, J. E., & Pereira, A. C. (2011). Genetic variants of diabetes risk and incident cardiovascular events in chronic coronary artery disease. PLoS One, 6(1), e16341. doi: 10.1371/journal.pone.0016341

Te Morenga, L., Mallard, S., & Mann, J. (2013). Dietary sugars and body weight: systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ, 346, e7492. doi: 10.1136/bmj.e7492