Tired of being tired?

The Doctor Says I am Not Sick but I Know I am not Well

SymptomsSymptoms
 Excessive Fatigue
 Nervousness/Irritability
 Mental Depression
 Inability to Concentrate
 Apprehensions
 Weakness
 Feelings of frustration
 Cravings
 Vertigo
 Light headedness
 Insomnia
 PMS
 Headaches
 Muscle pains and
spasms
 Epigastric Pain
 Food and other
allergies
 Dyspepsia-indigestion
 Diarrhea-Constipation

OptionsOptions
 Order tests- FSH, Serum Thyroid, CBC,
SMA-7, cholesterol……..
 Ultrasounds, CT scans, UGI, endoscopes,
laparoscopes
 Visitus Interuptus-Prescription

Popular Non-Diagnosis
 Chronic Fatigue
 Fibromyalgia
 Depression
 Attention Deficit Hyperactivity Disorder
 Irritable bowel
 Bipolar

Top 10 DrugsTop 10 Drugs
 Lipitor
 Premarin
 Synthroid
 Hydrocodone
 Prilosec
 Norvasc
 Glucophage
 Albuterol
 Claratin
 Zoloft

Popular ThinkingPopular Thinking
 The problem with popular thinking is that
it doesn’t require you to think at all. Kevin
Myers
 It is easier to do what other people do
and hope that theythey thought it out.
 John Maxwell “Thinking for a Change”

Definition Of Stress
 Any Disruption of Homeostasis
(Balance)
Whether internal or external in origin

The Impact of StressThe Impact of Stress
 43% of all adults suffer stress related adverse health effects.
 75-90% of all visits to primary care physicians are for
stress-related complaints or disorders.
 Stress has been linked to all the leading causes of death:
 CVD, cancer, lung ailments, accidents, cirrhosis and suicide.
 An estimated 1 million workers are absent each day with stress
related complaints.
 Stress is responsible for more than 25 billion workdays lost
annually because of absenteeism.

Fight
What a Zebra Needs
Run fast
Fight Hard
Energy
Lightweight
Think quickly
Block Pain

What You Don’t Need If You are aWhat You Don’t Need If You are a
ZebraZebra
 Reproduction
 Energy storage
 Metabolism
 Growth
 Water wasting
 Sleep
 Immunity
 Hormone disruption
 Insulin resistance
 Thyroid dysfunction
 Decreased GI absortion
 Decreased kidney
function, water retention
 Insomnia
 Altered Immunity

What a Human Doesn’tNeeds
Run fast
Fight Hard
Energy
Lightweight
Think quickly
Block Pain

Wilson J. Adrenal Fatigue, The 21
st
Century Stress Syndrome

 Ann Clin Biochem. 1983 Nov;20 (Pt 6):329-35.
 Salivary cortisol: a better measure of adrenal cortical function than serum
cortisol.
Vining RF, McGinley RA, Maksvytis JJ, Ho KY.
Salivary cortisol concentration was found to be directly proportional to the serum
unbound cortisol concentration both in normal men and women and in women
with elevated cortisol-binding globulin (CBG). The correlation was excellent in
dynamic tests of adrenal function (dexamethasone suppression, ACTH
stimulation), in normals and patients with adrenal insufficiency, in tests of
circadian variation and randomly collected samples. Women in the third trimester
of normal pregnancy exhibited elevated salivary cortisol throughout the day. The
relationship between salivary and serum total cortisol concentration was
markedly non-linear with a more rapid increase in salivary concentration once
the serum CBG was saturated. The rate of equilibrium of cortisol between blood
and saliva was very fast, being much less than 5 minutes. These data, combined
with a simple, stress-free, non-invasive collection procedure, lead us to suggest
that salivary cortisol is a more appropriate measure for the clinical assessment
of adrenocortical function than is serum cortisol.
PMID: 6316831 [PubMed - indexed for MEDLINE]

 Clin Endocrinol (Oxf). 1982 Dec;17(6):583-92. Salivary cortisol
assays for assessing pituitary-adrenal reserve. Peters JR,
Walker RF, Riad-Fahmy D, Hall R.
 Cortisol concentrations were determined in matched samples of plasma and
saliva from patients and healthy volunteers throughout the course of standard
tests of pituitary and adrenal reserve. During insulin tolerance tests the
percentage incremental changes in cortisol concentrations in saliva were strictly
comparable with those in plasma and showed less inter-subject variance. The
clinical decision taken with regard to the integrity of the pituitary-adrenal axis
was the same whether plasma or salivary cortisol was measured. In the short
tetracosactrin test changes in salivary cortisol reflected those in plasma and
patients with loss of adrenal responsiveness would have been diagnosed as
such using either measurement. In normal subjects, the circadian rhythm in
salivary cortisol concentrations exactly paralleled that in plasma. Absence of
the circadian rhythm in cases of hypercortisolism was seen as well in saliva as
in plasma. Assays for salivary cortisol therefore provide information which is as
clinically useful as that of plasma determinations. Since salivary cortisol
concentrations were shown to reflect the free, biologically active fraction in
plasma, salivary assay may, in selected cases, provide results of greater
diagnostic significance than plasma total concentrations. PMID: 6762264
[PubMed - indexed for MEDLINE]

Anxiety And DepressionAnxiety And Depression
 An imbalance of adrenalin and serotonin
not a Zoloft deficiency
Adrenalin
Serotonin

Stress and
Cardiovascular Disease
 Hypertension
 Atherosclerosis
 Decreased blood flow to heart
 Heart Attack
 Heart Failure

Things You Do Need if you are aThings You Do Need if you are a
HumanHuman
 Reproduction
 Energy Utilization
 Metabolism
 Growth
 Fluid Balance
 Sleep
 Immunity
Hormone disruption
Insulin resistance
Thyroid dysfunction
Decreased GI absorption
Decreased kidney function
Insomnia
Decreased immune
function

Central fat accumulation
Decrease in muscle and bone mass
Cardiovascular disease

Stress and the HPT axisHPT axis::
• CRH inhibits TSH directly, and TRH secondarily.
• Glucocorticoids inhibit TSH, and T4 to T3
conversion.

Stress and Thyroid Function
 Activation of the HPA axis is associated with
decreased production of thyroid stimulating hormone
(TSH) and inhibition of conversion of the relatively
inactive thyroxine to the more biologically active
triiodothyronine in peripheral tissues (the "euthyroid
sick" syndrome) (81, 82). Although the exact
mechanism(s) for these phenomena is not known,
both phenomena maybe caused by the increased
levels of glucocorticoids and theoretically serve a
desired energy conservation during stress. Inhibition
of TSH secretion by CRH-induced increases in
somatostatin might also participate in the central
component of thyroid axis suppression during stress.
81. Benker G, Raida M, Olbricht T, et al (1990) TSH secretion in Cushing's syndrome: Relation to
glucocorticoid excess, diabetes, goiter, and the "the sick euthyroid syndrome." Clin Endocrin 133:779-
86
82. Duick DS, Wahner HW (1979) Thyroid axis in patients with Cushing's syndrome. Arch Intern Med
139:767-72

The Digestion Process
 Eating
 Digestion
 Absorption
 Assimilation
 Elimination of waste
 Water

Digestive Process Where in the Body Function
Eating/food choices Mouth/mind Portal for all nutrients/
materials to enter the
body
Digestion Stomach/small intestine;
to a lesser degree, saliva
in the mouth
Breaks down food into
basic components for
use by the bloodstream
Absorption Small intestine/ large
intestine, bloodstream
liver
Food comes through the
intestinal wall into the
bloodstream
Assimilation Cellular Nutrients enter cells and
are used for energy,
storage, and structure
Elimination Colon, kidneys, skin,
lymph system, cells and
bloodstream
Wastes are excreted

Brain and Digestion
 Food choices
Herbivores
Cravings
○ Low serotonin-carbs
○ Low adrenal function- salt
Prepare for consumption
of food
( enzymes, hormones)
Relaxation

The GI Experiment
 Industrial Revolution
Refined sugar and flour became affordable
Frozen, packaged, microwavable, globally
shipped
Additives: preservatives, dyes, artificial
flavors and sweeteners
Stress, poor air and water quality

What You Are Eating
 638 cans of carbonated drinks (age 12-29)
 134 pounds of refined sugar
 90 pounds of fats and oils
 63 dozen donuts
 60 pounds of cakes and cookies
 23 gallons of ice cream
 22 pounds of candy
 8 pounds of corn chips, popcorn and
pretzels
 7 pounds of potatochips

Why Are We Surprised That:
 Americans are fatter than ever
 More violent than ever
 Infertility rates are higher than ever
 New conditions are recognized i.e.
ADD
ADHD
Chronic fatigue
Children committing suicide
 Diabetes and Metabolic Syndrome in
young children

The Liver and GI System
 Protects us from the environment and what we
eat
 The liver has a finite functioning capacity
 When the GI system is abused, our protection
from the environment is compromised
 This allows the GI system to be an ideal point
of entry for disease causing antigens

Brain
 Digestive juices
 Saliva
 Enzymes
 Digestive hormones
 Receives satiety
signals

Stomach
 Begins protein digestion
(pepsin and HCL)
 HCL
Break down proteins to amino acids
Kills microbes
 Lining protected by mucous
produced by prostaglandins
 Low acid = low B 12

Pancreas
 Digestive Enzymes
Lipase
Amylase
Protease
 Insulin
 Bicarbonate

Small Intestines
 Microvilli
Produces digestive enzymes
Absorbs nutrients
Block the absorption of non-
nutrients

Gut Associated Lymphatic Tissue
(GALT)
 Seventy percent of the immune system

Liver
 Manufactures and
Metabolizes
Cholesterol
Hormones
 Regulates blood
sugar
 Processes all food,
nutrients, alcohol,
drugs etc

Liver
 Environmental toxins are an increasing
problem
300,000 new chemicals are listed each year
We consume 14 lbs of food additives each year
70,000 are used in foods, drugs and pesticides
 If the liver cannot detoxify the chemicals the
chemicals are stored in tissues throughout
the body

Large Intestine
 Function:
 absorb water and remaining
nutrients
 Form stool
○ Two thirds water
○ Fiber and undigested food
○ Living and dead bacteria
 Intestinal bacteria
 Lower pH
 Produce vitamins A, B and K
 Produce short chain FA
(butyric acid) deficiency
associated with colon cancer
and IBD

Large Intestine
 Western diet produces 5 oz. of stool a day
 Africans eating traditional diet produce 16 oz.
of stool
 Normal bowel movements should be 2-3/day
 The longer stool is in the bowel the more
reabsorption

Probiotic Benefits
Nutritional Digestive Immune Metabolism
Manufacture
vitamins in our
foods and bodies
Digest Lactose Produce antibiotics
and antifungals,
breakdown bile
acids
Breakdown and
rebuild hormones
B3,B5,B6, B12, A
and K
Regulate
peristalsis
Manufacture EFA
Decrease pH
Promote healthy
metabolism
Digest protein to
release amino
acids
Increase number
of immune system
cells
Convert
flavonoids into
useful forms
Establish good
digestion in
infants
Breakdown
bacterial toxins
reducing colitis
Normalizes serum
cholesterol and
triglycerides
Protect against
xenobiotics and
pollutants

Dysbiosis
 Caused by
Constant high levels of stress
Exposure to manufactured chemicals
Poor food choices
Oral contraceptives
Surgery
Use of antibiotics- Most common

Dysbiosis
 NSAIDS
Block prostaglandin induced repair of the
intestinal lining
 Poor diet-not enough nutrients to
provide the building blocks for GI repair
 Low stomach acid

Leaky Gut Syndrome
 Increased Intestinal
Permeability
Not a disease,
however it can be
manifested by an
enormous variety of
symptoms depending
upon genes and
ecology
This is a dysfunction
of the “barrier
function” the brush
border

Leaky Gut
 Undigested food is
exposed to the
immune system, IgG
antibody production
is stimulated
 This leads to food
sensitivities that
have a delayed
reaction

Symptoms Associated with Leaky Gut
 Abdominal pain
 Asthma
 Chronic joint pain
 Muscle pain
 Fuzzy thinking
 Gas
 Indigestion
 Mood swings
 Poor immunity
 Recurrent vaginal
infections
 Skin rashes
 Diarrhea
 Recurrent bladder
infections
 Fevers of unknown origin
 Poor memory
 Shortness of breath
 Constipation
 Bloating
 Aggressive behavior
 Anxiety
 Primary biliary cirrhosis
 Fatigue and malaise
 Toxic feelings

 Psychoneuroendocrinology. 2005 Jul;30(6):568-76.Related Articles, Links

Decreased cortisol awakening response after early
loss experience.
Meinlschmidt G, Heim C.
Division of Clinical and Theoretical Psychobiology, Department of Psychobiology, University of
Trier, 54286 Trier, Germany.
Early loss experience (ELE) due to death or separation is a major risk factor for the
development of several psychiatric and physical disorders in adulthood. Few studies have
focused on the effects of ELE on neuroendocrine systems, which might mediate this risk in
part. The goal of this study was to evaluate salivary cortisol responses to awakening in
individuals with and without ELE. A total of 95 healthy college students (29 men, 66 women)
completed a questionnaire on ELE and were instructed to collect saliva immediately after
awakening and 30 min later. Fifty-five of the 95 subjects reported having experienced the
separation or divorce of their parents and/or the death of a close relative before the age of 14
years. Subjects with such ELE exhibited decreased salivary cortisol responses to awakening
compared to subjects without ELE (net increase: 4.78 nmol/l versus 9.83 nmol/l; t93 = 2.88, p
= 0.005). The effect was most pronounced in individuals who experienced multiple types of
ELE, while there were no sex differences. In conclusion, ELE appears to be associated with
decreased salivary cortisol responses to awakening. Low cortisol awakening responses are
believed to reflect altered dynamics of the hypothalamic-pituitary-adrenal (HPA) axis, possibly
conferring risk for certain stress-related disorders.

Sleep Duration and Breast Cancer:
A Prospective Cohort Study
Cancer Research 65, 9595-9600, October 15, 2005]
© 2005 American Association for Cancer Research
Epidemiology and Prevention
Pia K. Verkasalo1, Kirsi Lillberg2, Richard G. Stevens7, Christer Hublin3, Markku Partinen6, Markku
Koskenvuo4 and Jaakko Kaprio4,5
. Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence
of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We
hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to
greater overall melatonin production in longer sleepers. This population-based study includes information from
women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were
assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to
1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were
obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast
cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these
women, the HRs for breast cancer in the short ( 6 hours), average (7-8 hours), and long sleep ( 9 hours) duration
groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the
7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable
sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This
study provides some support for a decreased risk of breast cancer in long sleepers.


 J Natl Cancer Inst. 2000 Jun 21;92(12):994-1000.Related Articles, Links

Comment in:
 J Natl Cancer Inst. 2002 Apr 3;94(7):530; author reply 532-3.

Diurnal cortisol rhythm as a predictor of breast cancer survival.
Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D.
Department of Psychiatry and Behavioral Sciences, University of Louisville School of Medicine, KY 40292-
0001, USA. sephton@louisville.edu
BACKGROUND:: Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic
value of such alterations has not been confirmed. We examined the association between diurnal variation of
salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships
between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical
treatment, and psychosocial variables. METHODS: Salivary cortisol levels of 104 patients with metastatic
breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive
days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol
concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell
activity was measured by the chromium release assay. The survival analysis was conducted by the Cox
proportional hazards regression model with two-sided statistical testing. RESULTS: Cortisol slope predicted
subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms,
indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest
metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles.
Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of
these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival
time. NK cell count emerged as a secondary predictor of survival. CONCLUSIONS: Patients with metastatic
breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of
NK cell count and NK function may be a mediator or a marker of more rapid disease progression.
PMID: 10861311 [PubMed - indexed for MEDLINE]
CONCLUSIONS: Patients with metastatic breast cancer
whose diurnal cortisol rhythms were flattened or abnormal
had earlier mortality. Suppression of NK cell count and NK
function may be a mediator or a marker of more rapid
disease progression.

Chronic Fatigue
ADHD
Depression
Insulin Resistance
Fibromyalgia

3 Ways To Cope With
Stress
1. Eliminate the Stress
2. Change Your Response to the Stress
3. Prepare Your Body for the Stress

 J Clin Endocrinol Metab. 2001 Aug;86(8):3545-54.Related Articles, Links

Hypothalamo-pituitary-adrenal axis dysfunction in chronic fatigue syndrome,
and the effects of low-dose hydrocortisone therapy.
Cleare AJ, Miell J, Heap E, Sookdeo S, Young L, Malhi GS, O'Keane V.
Department of Psychological Medicine, Institute of Psychiatry and Guy's, King's and St Thomas' School of Medicine,
London SE5 8AZ, United Kingdom. a.cleare@iop.kcl.ac.uk
These neuroendocrine studies were part of a series of studies testing the hypotheses that 1) there may be reduced activity
of the hypothalamic-pituitary-adrenal axis in chronic fatigue syndrome and 2) low-dose augmentation with hydrocortisone
therapy would improve the core symptoms. We measured ACTH and cortisol responses to human CRH, the insulin stress
test, and D-fenfluramine in 37 medication-free patients with CDC-defined chronic fatigue syndrome but no comorbid
psychiatric disorders and 28 healthy controls. We also measured 24-h urinary free cortisol in both groups. All patients (n =
37) had a pituitary challenge test (human CRH) and a hypothalamic challenge test [either the insulin stress test (n = 16) or
D-fenfluramine (n = 21)]. Baseline cortisol concentrations were significantly raised in the chronic fatigue syndrome group
for the human CRH test only. Baseline ACTH concentrations did not differ between groups for any test. ACTH responses
to human CRH, the insulin stress test, and D- fenfluramine were similar for patient and control groups. Cortisol responses
to the insulin stress test did not differ between groups, but there was a trend for cortisol responses both to human CRH
and D-fenfluramine to be lower in the chronic fatigue syndrome group. These differences were significant when ACTH
responses were controlled. Urinary free cortisol levels were lower in the chronic fatigue syndrome group compared with the
healthy group. These results indicate that ACTH responses to pituitary and hypothalamic challenges are intact in chronic
fatigue syndrome and do not support previous findings of reduced central responses in hypothalamic-pituitary-adrenal axis
function or the hypothesis of abnormal CRH secretion in chronic fatigue syndrome. These data further suggest that the
hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output. Thirty-two patients
were treated with a low-dose hydrocortisone regime in a double-blind, placebo-controlled cross-over design, with 28 days
on each treatment. They underwent repeated 24-h urinary free cortisol collections, a human CRH test, and an insulin
stress test after both active and placebo arms of treatment. Looking at all subjects, 24-h urinary free cortisol was higher
after active compared with placebo treatments, but 0900-h cortisol levels and the ACTH and cortisol responses to human
CRH and the insulin stress test did not differ. However, a differential effect was seen in those patients who responded to
active treatment (defined as a reduction in fatigue score to the median population level or less). In this group, there was a
significant increase in the cortisol response to human CRH, which reversed the previously observed blunted responses
seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome
during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.
We conclude that the improvement in fatigue seen in some
patients with chronic fatigue syndrome during
hydrocortisone treatment is accompanied by a reversal of the
blunted cortisol responses to human CRH.

 J Psychosom Res. 2000 Nov;49(5):335-42. Salivary cortisol
patterns in vital exhaustion. Nicolson NA, van Diest R.
Department of Psychiatry and Neuropsychology -
 PAR 45, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The
Netherlands. n.nicolson@sp.unimaas.nl OBJECTIVE: The syndrome of vital
exhaustion (VE), a risk indicator for myocardial infarction, is characterized by
excessive fatigue, irritability, and demoralization. Dysregulation of the
hypothalamic-pituitary-adrenocortical (HPA) axis is a potential pathogenic
mechanism in fatigue syndromes, but little is known about HPA function in
syndromal VE. METHOD: We assessed basal free cortisol levels and
responses to a speech task and to morning awakening by collecting multiple
saliva samples over 2 days from 29 VE men and 30 controls. RESULTS: VE
subjects reported higher perceived stress, poorer sleep, and greater fatigue
than controls. Basal cortisol levels were lower in VE subjects, especially in the
evening, and were negatively associated with fatigue. Overall cortisol
responses to the speech task were similar in VE and control groups, although
VE subjects were less likely to show large (> or =2.76 nmol/l) responses. The
cortisol response to awakening was associated with concurrent fatigue and
poor sleep quality. CONCLUSION: These findings suggest a subtle HPA
hypoactivity in VE, which may arise through chronic stress and associated
sleep disturbances.
The cortisol response to awakening
was associated with concurrent
fatigue and poor sleep quality.
CONCLUSION: These findings
suggest a subtle HPA hypoactivity
in VE, which may arise through
chronic stress and associated sleep
disturbances.

 Psychoneuroendocrinology. 2004 Oct;29(9):1184-91.Related Articles, Links

Sleep disturbances are correlated with decreased morning
awakening salivary cortisol.
Backhaus J, Junghanns K, Hohagen F.
Department of Psychiatry and Psychotherapy, University of Luebeck, Ratzeburger
Allee 160, D-23538 Luebeck, Germany. backhaus.j@gmx.de
Morning and evening salivary cortisol levels were correlated with sleep parameters in
14 patients with primary insomnia and 15 healthy controls. Salivary cortisol was
sampled immediately after awakening (T1), 15 min later (T2), and immediately before
going to bed (T3) for 1 week at home. In parallel with this, subjects estimated
parameters of sleep in a daily sleep log. Patients and controls were all non-smokers
who did not differ regarding morning awakening time or bedtime. Cortisol after
awakening was significantly decreased in primary insomnia. Salivary cortisol at the
time of awakening correlated negatively with the subjective estimation of sleep quality,
i.e. a low salivary cortisol level directly after awakening correlated with a higher
frequency of nightly awakenings (r = -0.50), a diminished sleep quality (r = -0.34) and a
decreased feeling of recovery after awakening (r = -0.35; all p < 0.05). Furthermore,
awakening cortisol was negatively correlated with the Pittsburgh Sleep Quality Index (r
= -0.43) and with a questionnaire on sleep-related cognitions with the subscales
rumination in bed (r = -0.56 ) and focusing on sleep-related thoughts (r = -0.46; all p <
0.05).
Cortisol after awakening was significantly decreased in
primary insomnia. Salivary cortisol at the time of awakening
correlated negatively with the subjective estimation of sleep
quality, i.e. a low salivary cortisol level directly after
awakening correlated with a higher frequency of nightly
awakenings (r = -0.50),

Ginseng improved fatigue in 25% of cancer patients
Compared to 10% on placebo

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