Chronic stress


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  • Brown Christmas
  • Development
  • “Origins and evolution of the Western diet: health implications for the 21st century”
  • Legumes are also suspect – anti-nutrients, can be reduced by soaking.Acellular flours, sugars and processed foods encourage inflammatory microbiota (may be key in leptin resistance and obesity):
  • Hypocaloric High Fat Low Carb vs. Low Fat High Carb – better control of triglycerides and CRP, better increases of HDLs and adinopectin: carb for weight loss and improvement of glycemic control in T2DM: glycemic control of low carb vs. low fat + orlistat: seen as more satiating by calorie by people with T2DM than a diabetic diet:
  • Thermic effect note: whole vs. processed foods – double the thermic effect! has by far the highest thermic effect – 25-35%
  • Sarah Robles is the strongest woman in the US – winning national championships three times. She competed in the +75kg weight class in the London Olympics, coming in 7th with a 265kg total.
  • For those who remember my talk last year, herbs don’t get the research dollars phamaceuticals get…I chose safe herbs where I could find at least one peer-reviewed study that backed up traditional use.
  • Chronic stress

    1. 1. Dealing with Chronic Stress: A Holistic Approach G. Maggio, RN, NREMT-B
    2. 2. AKA How to Avoid T2DM and other Chronic Non-Infectious Disease  The modern, western lifestyle is strongly correlated to the “diseases of civilization” – T2DM, CVD, and other chronic noninfectious diseases. We can easily show the causal mechanisms leading from specific parts of this lifestyle to chronic disease.  Chronic stress is characteristic of the modern, western lifestyle, and is a significant contributor to chronic disease.
    3. 3. Normally, Hormones have an Intricate Dance
    4. 4. But Chronic Stress Disrupts That Dance…
    5. 5. Topics Covered  Pathophysiology of Stress: Acute and Chronic  Dealing with Chronic Stress: The Foundation – Food, Sleep, Managing Psychosocial Stressors, and Exercise.  Dealing with Chronic Stress: Beyond the Foundation  Clinical Considerations and Discussion
    6. 6. Pathophysiology in 10 Minutes or Less    Acute stress is a response to a situation we perceive as threatening or requiring immediate action. “Fight or Flight” – the sympathetic nervous system is activated. The stressor stimulates the hypothalamus to release arginine-vasopressin (AVP) and corticotropin-releasing hormone (CRH). AVP reabsorption in the kidneys and induces vasoconstriction, BP.
    7. 7. The HPA Axis   Together, these two hormones activate the hypothalamic-pituitaryadrenal axis (HPA axis). CRH travels to the pituitary, which releases corticotropin, stimulating the adrenal cortex to release corticosteroids and catecholamines. Image Source:
    8. 8. Cortisol: A Busy Hormone      Cortisol blocks insulin by stimulating gluconeogenesis; it also stimulates glycogen production in the liver. It prevents cells from losing sodium, and increases potassium excretion, regulating ion balance. It reduces inflammation by blocking interleukin signals to T-Cells, and blocking histamines. It inhibits CRH. These functions – when things are running smoothly – help us recover from acute stress, and get going in the morning (when cortisol levels are highest).
    9. 9. Cortisol in Chronic Stress      In chronic stress, chronically elevated cortisol leads to chronically elevated blood sugar through increased gluconeogenesis and development of insulin resistance. The hippocampus has many corticosteroid receptors. Chronic stress affects memory formation and leads to premature aging of the hippocampus. The function of the immune system is impaired. Circadian rhythms are disrupted – cortisol should be low at night, and melatonin high. Chronic stress leads to failure of inhibition of CRH.
    10. 10. Hans Selye’s General Adaption Syndrome  The body tries to regain homeostasis, but, with the stressor still present, can’t.  First, the hyperarousal lessens.  Eventually, the body reaches a state of exhaustion as it can no longer cope (we will talk about adrenal fatigue in just a moment).
    11. 11. Other Effects of Chronic Stress    Chronic stress depresses HPA function (remember, it was working overtime!) – this disrupts thyroid function (symptoms of hypothyroid with no thyroid problem). It also causes thyroid hormone resistance. Release of IL-1, IL-6, and TNF causes systemic inflammation and disrupts conversion of T4 into T3. It encourages autoimmunity by weakening immune barriers in the GI tract, lungs, and the blood-brain barrier.
    12. 12. Adrenal Fatigue  As the adrenals are overworked, ability to release corticosteroids and catecholamines is reduced.  Symptoms of this adrenal insufficiency include dizziness, fatigue, low blood sugar and the attendant carb-cravings and weight gain, and depression.  Also associated with autoimmune disease.
    13. 13. The Road to T2DM    We can now easily see how chronic stress fits into this diagram. Research is showing that not only does T2DM cause inflammation, but that chronic systemic inflammation is a contributor to the disease process. Note: there is metabolically healthy obesity, and nonobese people who get T2DM tend to be hit harder (in fact, obesity may be the body’s way of trying to adapt!) Image source:
    14. 14. Food!      “Let food be thy medicine & thy medicine be food” - Hippocrates What we eat is the foundation of our health. Our guidelines as clinicians are outdated, and contradict the latest research. Food can be anti-inflammatory or inflammatory; it can lead to insulin resistance or it can help deal with it. The proper diet will help maintain blood glucose, reduce cravings, and reduce rather than exacerbate the symptoms of adrenal fatigue.
    15. 15. Problems with the Western Diet     The Western Diet is full of inflammatory foods – the worst of which are refined flours, high fructose corn syrup, and refined seed oils. It also has a dramatic imbalance of Omega-6 (pro-inflammatory) to Omega-3 fatty acids (antiinflammatory). Both are necessary, but our ratio is all wrong (15-16.7/1 as opposed to 2/1, which we evolved on). There are an excessive amount of carbohydrates, particularly high Glycemic Index carbohydrates. There is also an excess of energy dense, nutrient poor food.
    16. 16. Signs it Might not be Real Food…       There are exceptions, but… It has a lengthy list of ingredients, many of which you can’t pronounce, or last saw in a chemistry class. It doesn’t go bad, or takes months or years to go bad. It requires a “nutrition facts” label. You have trouble identifying what animal or plant it came from. It has “low fat” or “low calorie” on the label; the fat has most likely been replaced with refined sugars, and the calories with artificial sweeteners (which produce insulin spikes, among other things).
    17. 17. Fixing Your Diet    Increase consumption of whole fruits and vegetables, particularly vegetables. Fruits and vegetables are nutrient powerhouses, giving us vitamins, minerals, and phytochemicals that are antioxidants – we’re just scratching the surface of all the things they do for us. They are also far less calorie-dense than grains, give us more fiber, and way more micronutrients. Reduce or eliminate processed foods; reduce or eliminate grains (particularly refined flour, but whole grains are often not “whole”, and are still calorie dense and nutrient poor – and many, many people have gluten intolerances, found in several grains). Eliminate refined seed oils; replace with extra virgin olive oil for cold uses, and virgin coconut oil for high heat.
    18. 18.     Get protein from quality sources – unprocessed meats and eggs (not cured meats, slim jims, and “eggs” in a carton!). Cage-free eggs, pastured meats, and wild caught oily fish are great if you have access and can afford them. Leaner cuts are better choices for conventional meats. Low to moderate carbohydrates, and choose carbohydrates from low glycemic index sources. How many carbs you should eat is controversial, and depends on activity level, insulin sensitivity, and how you respond – in general, know your body – food should make you feel good in the short, moderate, AND long term. Don’t let the perfect be the enemy of the good – make the healthiest choices you can with what’s available to you and what you can afford. EAT YOUR VEGGIES!
    19. 19. How our Food has Changed     Wild or pastured animals have lower omega-6 to omega-3 ratios than grain-fed, confined animals. Cage-free eggs have much greater amounts of omega-3 fatty acids than conventional eggs! We treat animals horribly and make them terribly unhealthy – we shouldn’t be surprised when they aren’t as healthy for us. Monocrop, industrial agriculture depleting soil and leading to lower quality plant foods.
    20. 20. Don’t Fear Fat     Fat has been much maligned, but, finally, we’re coming around. Fat does not make you fat. Insulin resistance and caloric excess causes fat storage. Our bodies are not bomb calorimeters – the hormonal environment, macronutrient composition, and overall thermic effect of the food are all important variables. Fat doesn’t cause an insulin spike, and is very satiating. Of course, not all fats are created equal – avoid refined seed oils, due to free radicals produced by oxidation during heat processing and poor omega-6/omega-3 ratios; and trans fats should be completely eliminated from the diet (but you knew that). And avoid an excess of omega-6s.
    21. 21. Coconut Oil: MCTs     Coconut oil is an example of the changing view on fats (including saturated fats). Coconut oil is high in medium chain triglycerides (MCTs), a saturated fat easily used for fuel. It also leads to efficient energy use and can help restore thyroid function. It raises HDLs and lowers LDLs. It improves insulin sensitivity and glucose tolerance, and lowers abdominal adiposity. Get virgin coconut oil (the old “coconut oil is bad for you” was about hydrogenated coconut oil – don’t eat hydrogenated fats!)
    22. 22. To Repeat Myself… EAT YOUR VEGGIES!!! Image source: http://uhaweb.h UNEZ/ g
    23. 23. Some Tips on Eating Healthy When Stressed      Make the healthy option the easiest option – don’t keep unhealthy options around when you’re stressed and have more cravings. Take the time to cook most of your food for the week in one day – the goal is to have most of your meals for the week in the fridge, and ready in five minutes or less. Chop and steam veggies, so you can quick sauté them. It’s as easy to cook a few pounds of meat in the oven as it is to cook one serving. Stuff that simmers is your friend – get stuff done nearby while multiple meals simmer away! Frozen veggies are a good option – keep some on hand for those “I’m out of fresh veggies, but don’t have time to shop” days. Some kitchen gadgets can save you a lot of time and/or effort – e.g. crockpot, food processor.
    24. 24. Sleep  Chronic stress disrupts our sleep cycles.  Acute sleep deprivation causes drastic increases in cortisol, putting another stressor on the body.  Sleep loss reduces insulin sensitivity without beta cell compensation.  Sleep loss reduces leptin (hormone responsible for satiety) and increases ghrelin (increases appetite).
    25. 25.  Sleep durations shorter than 7-8 hours are associated with:  CVD and diabetes risk factors  Depression  Accidents  Learning and memory problems  Excess mortality  One study shows that 28.3% of US adults sleep 6 or fewer hours.  I would guess the percentage at YSN is higher!
    26. 26. Fixing Sleep      Practice good sleep hygiene – dark room, no electronics, maintain a regular bedtime, and so on. Exercise! Moderate caffeine consumption, and keep it earlier in the day. Acute sleep deprivation due to cramming does more harm than good. We’ll talk about supplements and herbs later.
    27. 27. Managing Psychosocial Stressors      Psychotherapy is beyond the scope of this presentation, but is a good option, especially focused on reframing life stress. Get reality-checked by friends, family, and/or loved ones – break out of those stress spirals! Reappraising our physiological response to stress improves performance, reduces cardiovascular and cognitive symptoms, and moderates the relationship with depression. Meditation and yoga – transcendental meditation found to be effective in secondary prevention of CVD. Find the things that center you that make you feel calm afterwards (for me, that’s putting heavy weights over my head, spending time in nature, making things, and Aikido – your mileage may vary).
    28. 28. Exercise!  In a study of medical residents, the two wellness behaviors most associated with higher well-being were restful sleep and exercise.  Physical activity is associated with decreased depression and anxiety.  Exercise improves insulin sensitivity in both normal and insulin resistant populations.
    29. 29. How to Exercise?     While you can overdo it, we mainly see overtraining (neuroendocrine derangement) in high-level athletes or the “more is always better” crowd. However, don’t get into the cycle of “I ate ___, now I’ll run off the calories”. It doesn’t work, and it turns exercise into a stressful punishment, rather than a challenging and rewarding activity. Exercise should be progressive – the body responds to exercise by adapting to it, and requires a greater stimulus to adapt further. High Intensity Interval Training (HIIT) has benefits over moderate intensity aerobic exercise, and is more time efficient.
    30. 30. We can’t all be Sarah Robles… But we all should do progressive resistance training as close to functional, whole body movements as our bodies allow. Resistance training improves insulin sensitivity over aerobic exercise alone, further decreases abdominal obesity, and muscle is highly metabolically active tissue. Plus, it reduces stress. And we’re all going to lose muscle and strength as we age – a higher starting point will keep us independent longer. Besides, it’s fun!!! Image source:
    31. 31. Beyond the Foundation: Vitamin D    We’re revising the minimum normal vitamin D level from 30 nmol/L to 50; at that level, a majority of the population is likely deficient. We live in northerly latitudes, don’t get much sunlight, and adipose tissue makes vitamin D unavailable. Very few foods are adequate sources of vitamin D – oily fish is the best natural source.
    32. 32.        Vitamin D is the new hot micronutrient (and is actually a hormone precursor). Its vital importance in calcium absorption is wellknown. Research is pointing toward a role in reducing metabolic and oxidative stress and reducing risk of cardiovascular disease. Vitamin D deficiency increases parathyroid hormone, worsening insulin resistance. In fact, vitamin D is inversely related to insulin resistance, independent of obesity, in a study of Korean adolescents. Correction of vitamin D insufficiency in obese children improved insulin sensitivity and glucose metabolism. Vitamin D may protect against stress-induced deterioration of the brain and heart. Vitamin D deficiency has also been associated with fatigue, depression, poor concentration, and muscle aches and pains.
    33. 33.  The RDA for vitamin D is rather low (and should be higher).  A conservative, safe UL is 4,000 IU a day.  1,000 and 2,000 IU vitamin D supplements are cheap and readily available.  Having your vitamin D level screened is probably a good idea; make sure you have a provider who is up to date on the latest recommendations (most aren’t, especially outside naturopathy and functional/integrative medicine).
    34. 34. Fish Oil        Fish oil is rich in omega-3 fatty acids, particularly Docosahexaenoic acid (DHA) and Eicosapentaenoic acid (EPA). Flax is a good plant source of omega-3 fatty acids, but the conversion of ALA to DHA and EPA is rate-limited, thus, it doesn’t do much for DHA and EPA blood levels. EPA reduced fasting blood glucose, HgA1C, and insulin resistance in overweight T2DM patients. There is a general association with improved insulin sensitivity. Studies have shown fish oil is effective in depression, and it is likely the EPA. Fish oil reduces basal cortisol levels. 2-4 grams a day, or 0.5-1.8g of EPA+DHA
    35. 35. Zinc, Magnesium, and Melatonin to Improve Sleep   In a study of residents of an Italian skilled nursing facility (SNF), 5 mg of melatonin, 225 mg magnesium, and 11.25 mg of zinc, administered an hour before bedtime, significantly improved ease of getting to sleep, quality of sleep, hangover on awakening from sleep, and alertness and behavioral integrity the following morning. Quality of life was also improved. The melatonin dose was very high; I suggest experimenting with lower doses. I also am wary of chronic melatonin supplementation and wonder if it could affect circadian rhythms.
    36. 36. Acupuncture     Found to improve memory and learning impairments due to chronic mild stress. Can improve sleep quality in patients with insomnia. Had beneficial effects on insulin, leptin, ghrelin, and cholecystokinin (CCK) levels in obese women. Can improve hyperglycemia, hyperlipidemia, altered sympathetic nervous system activity, and insulin signal defect, contributors to insulin resistance.
    37. 37. Herbs   German Chamomile (Matricaria recutita) has been shown to have mild to moderate anxiolytic activity, at least in patients with General Anxiety Disorder. It also has some antidepressant effects in anxious, depressed patients. Chamomile improved day time functioning in chronic primary insomnia, by improving sleep latency, night time awakenings, the fatigue severity scale.
    38. 38.     Lemon balm (Melissa officinalis), at a 1600mg dose of dried leaf, increased calmness and improved memory performance in healthy, young participants. Another study showed anxiolytic properties combined with Valerian (Valeriana officinialis). Skullcap (Scutellaria lateriflora) enhances mood without decreasing cognitive performance. Passionflower (Passiflora incarnata) improves subjective sleep quality in healthy adults. Passionflower is also used as an anxiolytic; two studies showed a lack of difference in efficacy as compared to benzodiazepines. One study showed statistically insignificant (but warranting further study) improvement in job performance (in comparison), and another a statistically insignificant lower incidence of drowsiness as compared to a benzodiazepine.
    39. 39.  Cinnamon (Cinnamomum sp.) – studies have shown improvement in glucose, insulin and insulin sensitivity, gastric emptying, blood pressure, lean body mass, lipids, and antioxidant status in patients with T2DM, metabolic syndrome, and PCOS. Cinnamon has been shown to moderate postprandial blood glucose levels in normal weight and obese adults, lowering them up until the two hour mark, with a higher level at two hours.
    40. 40. Adaptogens  Adaptogens are a class of herbs that help the body adapt to and better deal with stress.  They are some of the more powerful herbs in the herbal materia medica, and should be used by knowledgeable practitioners.  They don’t fit easily into the western allopathic model, however, research evidence is building.
    41. 41. Ginseng  Ginseng is a very important herb in Traditional Chinese Medicine (TCM); Panax ginseng and P. quinequefolius (American Ginseng) are the two most commonly used varieties; there are differences within TCM (American ginseng generates more yin), but they are similar.  Siberian Ginseng (Eleutherococcus senticocus) is in a different genus in the same family.
    42. 42.    P. ginseng has been shown to improve working memory performance and calmness in healthy young adults; decrease plasma cortisol levels and help with fatigue; and alleviate depression through peripheral antiinflammatory effects. It is thought to reduce fatigue through significant antioxidant properties. P. ginseng is protective against acute respiratory infection (ARI) and lessens the duration and severity of ARI. In patients with fibromyalgia, it reduced pain, improved fatigue, and improved sleep as well as amitriptyline; it improved anxiety, but not as well as amitriptyline. It also reduced the number of tender points and improved patients’ quality of life.
    43. 43.    P. quinequefolius decreased blood glucose and HgA1C in Type 1 and Type 2 diabetic mice. Interestingly, it increased plasma insulin and c-peptide in the Type 1 mice, while decreasing them in the Type 2 mice. There was an increase in islet area, possibly indicative of β-cell regeneration. It also prevented diabetic retinopathy and cardiomyopathy in diabetic mice. It has shown to be effective in glycemic control in T2DM patients. Studies have focused on patients with T2DM, but surmising, via mechanism of action and traditional use, that it would be helpful with insulin resistance in general is probably reasonable.
    44. 44. Ashawagandha and Tulsi      Ashawagandha (Withania somnifera) is an important herb in Ayurvedic medicine. It has been shown to safely and effectively promote resistance to stress and improve quality of life. It is used for memory, for neurodegenerative disease, as an anxiolytic, to improve energy and mitochondrial health, and as an anti-inflammatory and anti-arthritic. Studies are ongoing (mainly in India). Tulsi (Ocimum sanctum), also known as Holy Basil, has been demonstrated to have antioxidant properties in rats; it is used as an adaptogen in Ayurvedic medicine.
    45. 45. Rhodiola rosea   Rhodiola rosea has been shown in vitro to protect human cortical neurons against glutamate and hydrogen peroxide-mediated cell death through reduction of calcium accumulation, via improving calcium homeostasis. Rhodiola improves endurance exercise performance; it lowered heart rate during warm ups and significantly reduced six mile run times, likely due to decreasing the perception of effort.
    46. 46.  It has been most used in Eastern Europe, where, in addition to its use in training and exercise, it was also shown to improve cognitive function and reduce mental fatigue. Studies in Western Europe and North America have indicated substantial antioxidant properties.  It lowered the level of c-reactive protein and creatinine kinase after exhausting exercise, demonstrating anti-inflammatory and muscle protective properties.
    47. 47. Clinical Considerations    Don’t let the perfect be the enemy of the good for your patients, either. Conversely, don’t make assumptions about what patients are or are not capable of – going for a harder, but still achievable lifestyle change is probably worth it if they’re going to see better results. Work to improve access to quality, real foods – can we get community health centers having their own gardens and/or partnering with local farmers?
    48. 48.     Know the physiology of bodily responses to food – epidemiological studies are notorious for confounding variables and being able to be read any way you want to read them. Get skeptical if a dietary recommendation conflicts with human physiology or the anthropological record. And follow the money! Recognize that we have been giving conflicting and ineffective dietary recommendations for years – you’re going to have to win patients over, and they’re going to need to see serious results. Diet is one of those things where just jumping in is often easier than incremental changes. Food journals, even if they never show anyone else, are really effective at getting people to realize exactly what they’re eating – there’s a tendency to do a lot of snacking on unhealthy foods on autopilot. We really should be able to write a prescription for cooking classes, and to make sure there’s a kitchen that is in working order.
    49. 49.     Meditation is easy to do, requires no materials, and is easy to teach the basics. Teach it. Education on what stress responses mean in the body can help in reappraising them. Refer to psychotherapy when helpful – but try to get the “house in order” before you reach for the prescription pad for meds – why treat the symptoms when you can treat the cause? We can start slow and low volume in exercise and get a benefit, but don’t underestimate where patients can go – many of the studies cited for HIIT and resistance training were of patients with CVD or T2DM, generally older.
    50. 50.    Fit exercise recommendations with the patient’s access to resources. Good gyms are great, but if they can move, they can find a way to progress from cardiovascular exercise to HIIT; and there are a plethora of calisthenic/gymnastic exercises, with great variance in difficulty, to keep people busy with resistance training. Emphasize time management in regards to working harder, not longer. If you can refer a patient to physical therapy, do so. Physical therapists not only know rehab, they do exercise teaching. There are good coaches and trainers out there, but most personal trainers tend to be awful.
    51. 51.     Know when to test things like thyroid hormone levels, cortisol levels, and vitamin D, know why, and know how to get them covered by insurance! If not contraindicated, consider fish oil. Pretty much everyone should have some degree of vitamin D supplementation (we don’t get enough from food, and don’t get enough sunlight). Chris Kresser L.Ac has a great idea with glucometers – have patients test fasting, before lunch, and one, two, and three hours afterwards to map response. Postprandial responses will generally be abnormal before fasting and HgA1C (see earlier discussion of adrenal fatigue). Know your supplements and herbs. Try magnesium/zinc/melatonin and gentle herbs before going for the prescription pad for sleep issues if you can. Teach sleep hygiene first.
    52. 52.  If your further education doesn’t include a study of herbalism, know who you can refer patients to who is competent to advise on adaptogens when appropriate.  Know your local complementary and alternative medicine practitioners – be able to provide a variety of options, and be able to direct patients to good practitioners. For acupuncture in particular, there are often community acupuncture clinics that are very reasonable.
    53. 53.  Keep digging through the research, pay attention to related fields (like nutrition and exercise physiology), and look at the research the skeptics and outsiders are following – don’t fall for a consensus view that is really just the loudest voices with the most money.  Don’t be afraid to be an innovator or to buck the trends when you know the science supports you – but realize you’re going to need the research at your fingertips to back you up, and you’re going to need to draw attention to it.
    54. 54. Some Book Recommendations   Written for laypeople, It Starts With Food by Dallas and Melissa Hartwig (the folks behind the Whole30) is the absolute best book on nutrition, dietary change, and food’s effect on health for a general audience that I have ever read. Diane Sanfilippo’s Practical Paleo: A Customized Approach to Health and a Whole-Foods Lifestyle is also excellent, and has menus and food recommendations designed for a variety of health conditions.
    55. 55.  Melissa Joulwan’s Well Fed: Paleo Recipes for People Who Love to Eat and Well Fed 2: More Paleo Recipes for People Who Love to Eat are wonderful cookbooks full of delicious recipes that work exactly as described, and are made up of healthy, whole foods. Also, she has enormous amounts of advice in both books on prepping and cooking food to keep you in healthy food for the week when you have a busy life.
    56. 56. Discussion and Questions
    57. 57. References    s/1110/bookchapters/stressphysiologychapter .htm 411/Ch%202_Seaward_Managing%20Stress_5 e.pdf
    58. 58.  causes-hypothyroid-symptoms   D-HealthProfessional/ 
    59. 59. Peer-Reviewed Articles      13796/?tool=pubmed uppl_2/S108.full %2C+S.%2C+Wright%2C+J.+Postprandial+Energy+E xpenditure+in+Whole-Food+and+ProcessedFood+Meals%3A+Implications+for+Daily+Energy+E xpenditure
    60. 60.  826636  075505  015695  911112  890471
    61. 61.         17 36 89 MC2727237/ f aisal.pdf 43 5/6/750.full?sid=5bfb47bc-ce6d-4800-96932721f911c08c
    62. 62.        66 19 91 ll/icb200070a.html 20 12 18
    63. 63.              32898/ 898/
    64. 64.         37 09 68 32 41 79 36 46
    65. 65.        15 31 79 90 49 75 60
    66. 66.  878109  294203  253512  513336  102179  737519
    67. 67.        
    68. 68.  754076  922070  086763  443221  948486  514725