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The Good HDL Cholesterol Isn’t So Good

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Most of us have had cholesterol levels drawn where the different types of lipoproteins are explained as the bad LDL cholesterol, and the more protective good HDL. This idea came out of the Framingham Heart Study, a primary research project begun in 1948, that identified many risks for cardiovascular disease. But what if the good HDL cholesterol isn’t so good? High levels of low density lipoprotein (LDL) builds up in arterial walls and can cause atherosclerosis increasing ones risk of heart attacks and stroke. High density lipoprotein (HDL) on the other hand can lower overall cholesterol levels by binding with LDL and moving it to the liver, where it is excreted as waste. You can think of HDL as garbage trucks taking cholesterol away from the tissues, whereas LDL and other particles are delivery trucks of cholesterol. The more garbage trucks would mean less build up of cholesterol and fewer cardiovascular events. So a higher level of HDL is better…right?

Recent research reveals that very high HDL levels actually increase the risk of atherosclerotic cardiovascular disease (ASCVD). The authors defined high HDL as >80 mg/dL in men and >100 mg/dL in women. In a study of more than 400,000 people from the general population in the UK., men with HDL levels below 40 or above 80 and women with levels above 100 were at greater risk of both mortality from all causes and cardiovascular death in particular. Two smaller groups surprisingly with coronary disease and HDL levels over 80 had a 96% higher risk of dying overall than those with lower HDL levels.

There are some that are anti-inflammatory and others that can become pro-inflammatory if in an oxidative environment. So the HDL story is not so simple.

Data on HDL can vary on many levels. For example, there are ethnic variations, women have higher HDL levels than men and quitting smoking and moderate alcohol intake can increase HDL levels. Metabolic syndrome or pre-diabetes can lower HDL levels. Further, not all HDL particles are the same. There are some that are anti-inflammatory and others that can become pro-inflammatory if in an oxidative environment. So the HDL story is not so simple. Niacin, commonly used to treat elevated Lp(a) levels can significantly increase HDL levels but has been found to have no reductions in ASCVD. This suggests that there is a U-shaped curve for HDL cholesterol where very low levels are bad and very high levels are also bad. The best solution is the more Goldilocks than the Jekyll and Hyde result which is getting just the right amount of HDL lying between 40-80 mg/dL. But how do we identify how well the HDL family is working? In other words…we want more garbage trucks moving out the garbage (LDL) but we don’t want the garbage trucks stuck in traffic.

One solution would be to measure cholesterol efflux. This was done in the Dallas Heart Study, which was a better predictor of cardiovascular (CV) risk. If you have low cholesterol efflux, then you are at risk. A high efflux means you are good. This marker takes the guess work out of whether high HDL particles are effective and you don’t have to deal with all the different sub-particles in the HDL family.

Unfortunately, we cannot measure cholesterol efflux easily, so the next best thing is to treat what we can control which is high LDL and low HDL. You may have more efficient trucks but not enough of them. People need to know that high HDL is not a universal protective factor for atherosclerosis and puts them actually at higher risk. So lowering LDL through healthy lifestyle changes such as exercise, and a high fiber, low sugar diet is very effective.  Estrogen has been shown to be protective for women starting in early menopause. And especially avoid smoking which can raise LDL and lower HDL.

References: Denworth, L. When “Good” Cholesterol Turns Bad. ScientificAmerican.com. The Science of Health.  June 2023.

Lin, P. Are higher HDL-C levels really better? Obesity, Metabolic Syndrome, and Prediabetes. Protective Effect of HDL-C Against Cardiovascular Disease. August 01, 2023.

Long-haul COVID and Chronic Fatigue Syndrome

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Long haul COVID, otherwise known as SARS-CoV-2 is still with us and growing. Its defined as prolonged recovery lasting more than 3 months after first contracting the virus. It now effects 65 million people around the world, about 1 in 13 adults in the U.S. We didn’t know what to make of this virus when it first appeared.  Then it became clear that following recovery from COVID-19, some patients were left with persistent  symptoms similar to other conditions such as Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Long-haul COVID and Chronic Fatigue Syndrome have a lot in common.

The research behind ME/CFS did not emerge until the 1980’s. The underlying biological abnormalities were uncertain and standard clinical laboratory tests were normal. Skeptics felt patients were suffering from depression or fabricating their symptoms to achieve some secondary gain. It wasn’t until 2020 that thousands of published scientific papers had identified multiple abnormalities and research on the illness was underway at laboratories around the world. Sound familiar??

Not only do ME/CFS and long-haul COVID share symptoms, but they have similar underlying biological abnormalities.

Many people including physicians still don’t believe that long-haul COVID exists. Ignoring this condition that has disrupted so many people’s lives only delays further research desperately needed for  treatment.  Long-haul COVID and Chronic Fatigue Syndrome have a lot in common such as brain fog, executive function loss, inability to drive, post-exertion malaise, disrupted sleep, orthostatic intolerance, joint and muscle pain, racing heart rate and gastrointestinal symptoms. Not only do ME/CFS and long-haul COVID share symptoms, but they have similar underlying biological abnormalities. Here are some of the most recent findings that are noted in both illnesses:

Neurological: Cognitive deficits, especially in reaction and attention time. Reduced cerebral blood flow, white matter abnormalities on MRI, reduced sleep efficiency, down-regulation of the hypothalamic-pituitary-adrenal axis and autonomic dysfunction (POTS).

Immunological and Infectious: Both illnesses involve elevated levels of cytokines, particularly pro-inflammatory cytokines, high levels of autoantibodies, including antibodies that target the nervous system. Reactivation of latent herpes viruses, particularly Epstein Barr virus (EBV) commonly know as “Mono”, human herpes virus-6 and cytomegalovirus, and a pro-inflammatory gut microbiome.

Metabolic: Reduced ability to generate ATP energy from glucose, fatty acids and amino acids. Increased oxidative stress. Increased rates of insulin resistance and type 2 diabetes, early onset dementia and autoimmune diseases. Both conditions increase oxidative stress.

Cardiovascular/Cardiopulmonary: exercise capacity is diminished, ventilatory efficiency is reduced and endothelial dysfunction occurs. Platelets are hyperactivated forming micro-clots.

Research is finding that after recovery from acute infections of ME/CFS and Long-haul COVID, some patients will have persistent symptoms of a variety of viral, bacterial, and protozoan agents, including EBV, West Nile virus, Borrelia burgdorferi (Lyme disease co-infection) and Giardia lamblia. A similar syndrome of persisting symptoms has been reported following “recover” from major physical trauma, sometimes called “SICU” syndrome.

So why would multiple different infectious agents and major physical trauma produce a similar syndrome? One hypothesis is that this syndrome is driven by an evolutionary protective response in which it changes an animals behavior. The symptoms of fatigue and brain fog discourage activities that consume energy (ATP) like movement, thinking and digesting. This frees up available supplies of energy for the fight against infections or injury. In some people, perhaps this protective response is not turned off when the infections are resolved and the injury is healed, or some on-going inflammation in the body continually signals the brain that the battle is still not over.

The National Institute of Health (NIH) has invested more than $1 billion to understand the biology of long-haul COVID. This investment will hopefully also provide answers for people suffering from ME/CFS as well as other similar chronic conditions. For now the best treatment has been integrative medicine. This type of medicine has addressed post viral conditions for decades. The use of herbal medicine, acupuncture, nutritional infusions and individualized assessment and treatments have been very successful in recovery and long-term resilience. Go to Coloradocovidcare.com for more information CCC

Komaroff, A., Lipkin, W. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front medicine 2023; 10:1187163

Davis, H, McCorkell, L, Vogel, J, Topol, E. Long COVID: major findings, mechanisms  and recommendations. Nat Rev Microbiol 2023.

 

 

 

Things to know about Late Life Weight Gain

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When it comes to weight, it seems to be more of an issue in our later years…especially after our 60’s. Having a negative body image occurs for over half of women in their 60’s. Men are no exception. In a small Canadian study, half of men ages 60-83 said they felt unattractive because of their weight. Body dissatisfaction is associated with a higher risk of depression, poorer sleep and sub-optimal self care. Many people struggle with controlling those extra pounds that tend to deposit themselves around the middle while losing important muscle mass. Visceral fat is the fat that surrounds internal organs and is hidden in your abdominal cavity. What we have learned since the mid-1990’s, is that the fat cell is an endocrine organ, secreting hormones and other molecules that have far-reaching effects on other tissues. There are a host of chemicals that link visceral fat to a wide variety of diseases. This combination can lead to health problems such as high blood pressure and cholesterol, type 2 diabetes, sleep apnea and a decline in physical function. Your weight is one indicator of your health, but it matters where you carry those extra pounds. Here are some things to know about late life weight gain.

Visceral fat makes more of the proteins called cytokines, which triggers low lying inflammation and is a risk factor for heart disease and other chronic conditions.

Aging is an inflammatory process. The uncomfortable fact is that the fat you gained in your 50’s may continue in your 60’s. There is a natural increase in body fat until your 80’s!! While subcutaneous fat produces a higher proportion of beneficial chemicals, visceral fat produces chemicals that are far more harmful. Visceral fat makes more of the proteins called cytokines, which triggers low lying inflammation and is a risk factor for heart disease and other chronic conditions.

There is also a hormonal mechanism that perpetuates middle age weight gain (obesity) through eating high glycemic foods. Foods that have a high glycemic index pack alot of sugar into a small package. High glycemic foods cause a fast rise in blood sugar resulting in insulin release. Highly processed refined carbohydrates are absorbed quickly, increasing insulin levels that can result in rebound hypoglycemia and insulin resistance. These mechanisms increase insulin sensitivity in adipose tissue but create insulin resistance in muscle and brain. Your body continues to make more and more insulin which leads to metabolic dysfunction, inflammation, weight gain, fatty liver and plaque development. Weight gain has been said to be nothing more than your body’s chemical reaction to foods. It comes down to 2 things: hormones and inflammation.

A 2022 meta analysis described the metabolic consequences of partial sleep restriction. Out of 26 randomized clinical trials, 400 adults were studied under controlled laboratory conditions. It concluded that insufficient sleep results in a clinically significant decrease in whole body insulin sensitivity. This condition can lead to obesity and diabetes. This present study was the first to assess the impact of sleep restriction in post-menopausal women. The proportion of adults with chronic insufficient sleep (< 6 hours/night) is around 30%. And 41.5% of adults ages 60 and older are obese according to the Centers of Disease Control and Prevention. So getting enough sleep is important. At least 7 hours is ideal because sleeping less has been shown to elevate the hormone Ghrelin that signals us to eat. So less sleep= more hunger and calories.

We may want to eat as we did in our 20’s and 30’s but our metabolism slows down significantly as we age. Your body requires fewer calories to keep it working (calories needed for our lungs to breath and our heart to pump). Less muscle mass also contributes to this slower metabolism. We lose lean muscle as we age. So just walking those 10,000 steps is not enough. We need to fit in some weight resistance (weight lifting, push-ups, planks, etc) at least twice per week while consuming abut 25 percent of our calories from protein. Aerobic exercise like walking, biking, jogging or swimming are still important, but our muscles need protection and strength. You lose as much as 3% of overall muscle strength every year in your 60’s. Men hold on to more of their muscle power than women.

Menopause and it’s decline in estrogen also contributes to weight gain. By the time a woman is postmenopausal, 15-20% of her body fat is visceral fat, compared to 5-8% when she was premenopausal. Estrogen has direct actions in pancreatic islet beta-cells in regulating insulin secretion, nutrient homeostasis and in promoting fat burning. When estrogen falls during menopause, it is thought to reduce a women’s ability to use fat as an energy source leading to weight gain, high blood pressure and cholesterol, type 2 diabetes and inflammation. Estrogen replacement therapy may increase a woman’s resting metabolic rate.

Another common killer that becomes more common as we age is our risk for cancer. One reason according to the NIH is the decline in the immune system’s ability to detect and correct cell defects. Obesity is linked to at least 13 types of cancer. Some are hormone related. Obesity creates inflammation which disrupts the immune system and causes dysregulation of the endocrine system. Fat cells increase estrogen and other hormone levels that lead to an increase in cancer: breast, endometrial, thyroid and pancreas to name a few. Losing weight can reduce this risk.

Obesity is also a risk factor for autoimmune disease, a problem more common in women and as we age. This is when the immune system starts to attack the body’s own healthy tissues. People with rheumatoid arthritis in particular have premature aging. Researchers have found that their immune age is about 25 years older than their actual age.

Obesity, especially when there’s lots of visceral fat is a risk factor for faster brain aging and Alzheimer’s disease according to Howard Fillit, M.D. cofounder and chief science officer at the Alzheimer’s Drug Discovery Foundation. Belly fat can: reduce blood flow to the brain, shrink brain volume (up to 4%- 8%) and reduce cognitive function.

Think about monitoring your weight, BMI (body mass index- an estimate of your body fat based on your height and weight, aarp.org/bmi) and waist measurement as important as monitoring your cholesterol, blood pressure and blood sugar levels. A healthy BMI is 18.5-24.9 and 25-29.9 is considered overweight. A waist measurement (place a tape measure above your hip bones) above 35 inches for women or above 40 inches for men means you are at higher risk for heart disease or type 2 diabetes according to the National Institutes of health (NIH). Also if your waist size is more than half your height, you might be at greater risk.

Our immune systems can be re-set and inflammation significantly reduced with weight loss. Here are some tips:

  1. Increase your protein intake..especially in the morning. Eating 25-30 grams of protein with each meal helps maintain muscle mass and reduces fat gain.
  2. Choose fresh farm food over processed food. Consider following the MIND diet (a combination of the Mediterranean and DASH -low sodium diet).
  3. Move at least 30 minutes/day for cardiovascular fitness and add weight resistance at least twice per week for muscle strength. Exercise is the best thing you can do to prevent Alzheimer’s disease!
  4. Cut down on simple carbs, especially sugar. This includes alcohol too which is a toxin to the brain and destroys sleep. Simple carbs also retain fluid.
  5. Get some sleep…at least 7 hours. Avoid late night food and alcohol. Stop eating at 7 PM as it stores more body fat since you are not burning it off.
  6. Sunlight, especially in the morning even if it is overcast. It helps elevate Cortisol in the morning which you need for energy and resets your circadian rhythm for better sleep at night by increasing melatonin in the evening.
  7. Social connection is important. Remember that hormones are involved in weight gain and the more we can reduce high levels of cortisol throughout the day, the less insulin gets produced to allow fat to be stored. When you are connecting and having fun, it lowers cortisol and raises serotonin and oxytocin which help us relax, digest better and utilize glucose for energy more efficiently.  Meditation, deep breathing and prayer are also important.
  8. Consider getting a food allergy test. Learn to avoid “trigger foods” (foods you are reacting to) so that inflammation and insulin subside and weight loss can begin. Reactive calories will put on weight.
  9. Get your thyroid level checked. It’s a major player when it comes to hormone health since it stimulates metabolism.
  10. Drink water. It is essential to drink approximately half your body weight in ounces. For every 16 ounces less than your body needs, it will hold onto half a pound! When you are dehydrated, your body has to extract water from your food and holds on to it in your tissues. When you drink enough, the body can let go of the extra water it’s been holding on to, and the numbers on the scale go down.

 

References: Mauvais-Jarvis, F, et al. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis. NIH: Nation Library of Medicine. Endocrine Review, 2013 June; 34 (3): 309-338.

Cauter, E. and Spiegel, K. Effect of sleep restriction on insulin sensitivity and energy metabolism in postmenopausal women. Obesity, Metabolic Syndrome and Prediabetes. May 9, 2023. Practiceupdate.com.

Stuart, A. Menopause, Weight Gain, and Exercise Tips. WebMD. March 17, 2023.

Migala, J. The Weight Issue. AARP, the magazine. April/May 2023. pp 52-57.

Genet-Recitas, L. “The Plan”. Grand Central Publishing, 2013.

Healthline.com/nutrition/mind-diet. The MIND diet: A detailed guide for beginners.

 

 

 

Ketamine or Electroconvulsive Therapy for Resistant Depression

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An estimated 30% of major depressive disorders are resistant to treatment in the United States. This means a person has tried at least 2 antidepressants for at last 6 weeks each and has not experienced remission or at least a 50% improvement in mood. Two common treatments for this condition are Ketamine or Electroconvulsive therapy for resistant depression. Ketamine has drawn a lot of attention recently. This drug has been studied and administered in controlled, clinical settings to help with treatment-resistant depression and other conditions. Ketamine is an anesthetic and a sedative and has been used to treat suicidal thoughts. . It causes a dissociative experience that makes the brain more malleable and receptive to therapy or alternative ways of thinking. Ketamine influences the neurotransmitter, Glutamate while its causes a cascade of biologic, structural and functional changes in the brain.

Electroconvulsive therapy (ECT) is a medical treatment also used for drug-resistant depression and bipolar disorder. It involves a brief electrical stimulation of the brain to create a generalized cerebral seizure while the person is under anesthesia. Dopamine function is thought to be impaired in people with depression causing impairment in concentration, motivation and pleasure. ECT improves this system while lowering stress hormones and helps feedback regulation.

While both of these treatments have rapid responses (hours to days), is there one better than the other? A meta-analysis was done in which researchers examined 6 studies looking at Ketamine infusions (3 times per week for 2 weeks) and ECT (3 times/week for 4 weeks). Results showed that at 1 month, ECT was significantly more effective than ketamine, with remission rates of 63% versus 43% in the largest study. Both Ketamine and ECT were effective in reducing suicidal ideation. ECT had more cognitive side effects and ketamine was associated with more depersonalization, vertigo and visual disturbance. The effects of both treatments waned over time with comparable outcomes at 3 and 12 months.

There is evidence of long-term maintenance with ECT. Unfortunately, intravenous Ketamine is not reimbursed by insurance companies which is the most bioavailable, precise treatment. Ketamine comes in different forms such as oral, topical, intramuscular, sublingual and intranasal. In the U.S the only FDA-approved form is nasal esketamine (Spravato) but it is only 25-50% bioavailable. Bioavailability means the amount of medication that actually goes to the bodies tissues and the brain. Intravenous treatments are 100% bioavailable. When you take other forms of the drug, parts of the active ingredients don’t go to the bloodstream, but get digested and altered into an unusable form, metabolized and excreted into your body. Although ECT appears to be superior, ketamine might be preferred by those looking for more rapid effects and wanting to avoid ECT’s short-term cognitive effects.

Youth depression rates have risen from 12.9% to 25.2% from pre-pandemic to 2021.

Mental health illness has risen in the United States, with about 20% of people in the country experiencing some form of it. There are many reasons for this sharp increase. The increase can be due to social media, the COVID-19 pandemic, and societal trends resulting in smaller family units, increased financial pressure, social isolation and political and economic stressors. Youth depression rates have risen from 12.9% to 25.2% from pre-pandemic to 2021. More than 50 million Americans struggle with mental illness and most lack access to adequate mental health treatment.

Other brain stimulation treatments include Transcranial magnetic stimulation (TMS) and Vagus nerve stimulation (VNS). Unlike ECT, TMS does not cause a seizure and the patient stays awake through the entire non-invasive process. Rapidly alternating magnetic fields stimulate specific areas of the brain. It is usually administered 4 or 5 times per week for 4-6 weeks. Side effects are usually mild including headaches, twitching and pain at the stimulation site.

Vagus nerve stimulation was originally used to treat seizures but can be effective in treating depression that has not responded to other therapies. It involves implanting an electrical pulse generator under the skin in the patient’s chest that provides intermittent electrical stimulation to the vagus nerve in the neck. Response may take months, so it is not used as a treatment for acute severe depression.

Mental health is so important for our overall health because of its relationship with our physical health. For example, depression raises the risk of diabetes, heart disease and stroke. Similarly, the presence of chronic illnesses can increase the risk of mental illness. Solutions consist of spending time in nature, healthy eating and exercise, connecting with others, reducing stress and getting enough sleep. Other effective treatments include psychotherapy, and many of the above medications or procedures.

Reference: dosomething.org. “11 Facts About Mental Health”. 2023.

Zimmerman, R. Ketamine for depression: What it feels like and who it can help. The Washington Post. 9/12/2022.

The American Psychiatric Association. What is Electroconvulsive therapy? Psychiatry.org

Principium Psychiatry. IV vs Oral Intramuscular vs Intranasal Ketamine: Why route matters. principiumpsychiatry.com

Rhee TG et al. Efficacy and safety of ketamine vs electroconvulsive therapy among patients with major depressive episode: A systemic review and meta-analysis. JAMA Psychiatry 2022. Oct 19; [e-pub]. (https://doi.org/10.1001/jamapsychiatr. 2022.3352)

Brain Therapy TMS: Transcranial magnetic Stimulation. Top 5 treatment-resistant depression statistics you need to know. May 28, 2021.

So If It’s Not Alzheimer’s, Then What Is It?

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Many older Americans expect to lose brain function but most don’t ask their doctors about preventing dementia. Walking into a room and then forgetting why you are there. Or unable to recall names of old TV shows or long-lost friends or classmates. Even though these instances can be a normal sign of aging, if they become more frequent or escalate, then it’s time to evaluate other causes. In reality, research suggests that less than 20% of people who have reached age 65 will go on to lose cognitive ability from Alzheimer’s disease, vascular dementia or other conditions. So if it’s not Alzheimer’s, then what is it? It could be something known as mild cognitive impairment. Mild cognitive impairment (MCI) is an early stage of memory loss in people who are still independent.

For people diagnosed with MCI, there are some screening tests worth doing. Screening includes: Checking thyroid and other hormone levels and B12 as well as other markers of inflammation. Ruling out sleep apnea and ADHD are important screening tests but are commonly forgotten. ADHD is a conditon which a person may have had all their lives but is more pronounced since entering menopause. Also, screening for depression and looking for side effects of certain medications are essential in looking for answers.

If symptoms are more related to feeling overwhelmed, forgetful, lack of concentration and difficulty prioritizing, then consider getting screened for ADHD (attention deficit hyperactivity disorder). It is a neuropsychiatric disorder that starts in childhood and and continues throughout life. Three quarters of adults 18 to 44 who are diagnosed with ADHD were never diagnosed as children. For adults 60 and older, that’s 100% according to Dr. David Goodman, assistant professor of psychiatry and behavior sciences at the Johns Hopkins University School of Medicine. The reason is that half a century ago, practitioners simply didn’t know how to screen for it in children.

When a woman reaches menopause or the stretch of time before her last menstrual period (peri-menopause), the symptoms of ADHD can be significantly worse. The drop in estrogen (which is very protective for the brain) can make hyperactivity, distractibility, executive function challenges, including time management and impulse control more difficult.  This means coping methods that you may have relied on no longer work. Lowered estrogen levels affect short-term memory and the ability to focus. Many women complain of “brain fog”. These lowered estrogen levels in women may also not allow ADHD stimulants to work effectively. This is more of a problem for women than men since testosterone seems to have no effect on either the impairments of ADHD or the effects of ADHD medications in men.

Only 1 in 5 memory disorder clinics actively screen for ADHD. People can have ADHD all their lives and now they are developing dementia. Now you have 2 processes contributing to cognitive difficulty.

Menopausal women experiencing cognitive decline should be screened for ADHD.  If ADHD is positive, then behavior strategies, counseling and medication should be considered. Stimulants such as Ritalin, Adderall, and Vyvanse are typically used to treat ADHD in young people. Many doctors have been trained to avoid these meds due to their risk of high blood pressure and other cardiovascular problems. The studies are mixed and a 2020 review in the Journal of the American College of Cardiology found a link between stimulant use and modest elevation of heart rate and blood pressure. But according to Dr. Bill Dodson, a Denver psychiatrist who specializes in adults with ADHD, “the effects observed were minuscule and of no clinical significance”.

Clinical trials from the 2002 Women’s Health initiative have cast a shadow on the safety of hormone replacement therapy. Subsequent evaluations have found the dangers of HRT to be overstated, while the health risks of low estrogen are well established. For more, check out What you need to know about hormone replacement therapy

There are ways to manage your symptoms. See a practitioner and express your concerns so biological markers can be ruled out and screening tests can be performed. Not all slowing cognition at middle age is due to a medical reason. Stress management and good support can make a significant difference in our lives. People with ADHD have a tendency to overcommit. When you feel overwhelmed, that is a sign you need to simplify. There are ADHD coaches and support groups that can help. CHADD.org is an educational and advocacy nonprofit that offers a network of regional support groups.

References: Macmillan, C. Mild Cognitive Impairment: It’s Not “Normal” Aging. Yalemedicine.org. Doctors & Advice, Family Medicine. June 6,2022.

Barger, T. Attention, Please! If memory and focus problems are placing you at midlife, it could be undiagnosed ADHD. Here’s how to tell. AARP Bulletin Dec 2022. pp. 20-21