This document discusses omega-3 fatty acids EPA and DHA. It begins with definitions of triglycerides, fatty acid absorption in the intestines, and saturated versus unsaturated fatty acids. It then focuses on omega-3s, explaining their anti-inflammatory, anti-arrhythmic, and triglyceride-lowering effects. Large clinical trials on omega-3 supplementation and cardiovascular outcomes are also reviewed.
Food, medicine, B-complex vitamins, diseases due to lack of B vitamins, B vitamins as coenzymes, B vitamins in energy metabolism and electron transport chain; ATP production, intracellular and extracellular functions; Importance of B complex vitamins; dietary recommended intakes; toxicity of vitamin B complex; clinical studies of vitamin B complex; dietary guidelines for Americans 2015-2010
Plasma proteins, the components of plasma proteins, the protein fractions and condition causing the alteration in the each protein fraction. Clinical implications of the each fraction, the electrophorotic pattern of plasma protein. Acute phase proteins which include the positive and negative phase proteins.
Cofactor of Enzymes
Mohammed Haddad
PHD Student
Prof . Dr. Emine Karaku
A cofactor is a non-protein chemical compound that is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations.
Food, medicine, B-complex vitamins, diseases due to lack of B vitamins, B vitamins as coenzymes, B vitamins in energy metabolism and electron transport chain; ATP production, intracellular and extracellular functions; Importance of B complex vitamins; dietary recommended intakes; toxicity of vitamin B complex; clinical studies of vitamin B complex; dietary guidelines for Americans 2015-2010
Plasma proteins, the components of plasma proteins, the protein fractions and condition causing the alteration in the each protein fraction. Clinical implications of the each fraction, the electrophorotic pattern of plasma protein. Acute phase proteins which include the positive and negative phase proteins.
Cofactor of Enzymes
Mohammed Haddad
PHD Student
Prof . Dr. Emine Karaku
A cofactor is a non-protein chemical compound that is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations.
After the advent of "lipid hypothesis", which linked the consumption of dietary fat with increased risk of heart disease and other health problems, fats were so highly defamed by the medical establishment that many people started thinking that the best answer to the "fat problem" is to stay away from it as far as possible. Food processing companies quickly took advantage of this era of “fat phobia”, and soon flooded the market with "low fat" and "no free" products, promising to put an end to heart disease and obesity, but the incidence of these diseases is still skyrocketing.
The truth is that not all fats are equal. While the consumption of some ugly fats (trans-fats) are, really, a risk factor for many health problems, some other fats, including alpha-linolenic acid ALA (head of the omega-3 family) and linoleic acid LA (head of the omega-6 family), are so important for health that they have been termed "essential fatty acids" (EFAs). Our body need them to perform vitally important functions, but is unable to produce them. Therefore, we must get them from our food. That's why any attempt to indiscriminately reduce or eliminate all fats from our diet inevitably leads to an EFA deficiency, which may be very dangerous to health.
For all the good it does, fat is often blamed to cause obesity, because it contains 9 calories per gram, while carbohydrate and protein contain only 4 calories. Yet, it's a mistake to relate dietary fat with body fat. You can get fat eating carbs and protein, even if you eat little dietary fat.
In 1956, Hugh Sinclair, one of the world's greatest researchers in the field of nutrition, suggested that an upsurge in the so-called "diseases of civilization" e.g. coronary heart disease, strokes, type-2 diabetes, arthritis and cancer - was caused by modern diets being extremely poor in essential fatty acids (EFA) and full of processed foods rich in trans-fatty acids. Although Sinclair's opinions were not supported by his pears, and he was even criticized by some of them for his bold hypothesis, later research convincingly shown that he was, indeed, correct. In fact, he is now praised for insights that were far ahead of his time.
Omega 3 fatty acid Best Source is Flaxseed Om Verma
Fatty acid is a carboxylic acid with a long unbranched aliphatic carbon chain, which is either saturated or unsaturated.
Most naturally occurring fatty acids have a chain of 4 to 28 carbons.
There are always even number of carbons.
First Carbon from carboxyl end is called α, second β, third γ, fourth δ ….. and last carbon is called ω or omega and the last end is called omega end.
Nutritional immunology is a fascinating but highly complex and conflicted subject area. With almost every nutrient we consume having the ability to affect our immune response in one way or another and the activation of the immune system dramatically increasing nutrient requirements, understanding the genetic, cellular and metabolic mechanisms that interact, control and conflict with the immune system and how to manipulate them to our advantage, is fundamental to optimal health.
We are thrilled to announce that we have linked up with Professor Phillip Calder, a world renowned and highly cited expert in nutritional immunology, with over 500 publications to his name. Professor Calder will be joining us as our guest speaker for our January Webinar to help us kick off what promises to be our most exciting year of clinical nutrition education yet.
In this detailed Q&A session Professor Calder will shed light on a whole host of fascinating topics from the latest research into nutrition immunology, his projects involving nutrigenomics, probiotics and omega-3s, the real science behind effective clinical omega-3 interventions, his thoughts on the best forms of lipid supplementation, and doing some serious nutrition science myth busting.
Hosted by with Sophie Tully BSc MSc, 10th October
This presentation addresses the role of cholesterol in CVD and the latest evidence into nutritional strategies to manage and treat high cholesterol and support healthy CVD function. Sophie covers the aetiology of CVD and why cholesterol has long been considered an important marker of CVD health and the emergence of newly identified CVD risk factors which may offer a more effective diagnostic tool. Finally she discusses new opinions on nutritional approaches to keep cholesterol levels healthy and prevent CVD events.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Acute scrotum is a general term referring to an emergency condition affecting the contents or the wall of the scrotum.
There are a number of conditions that present acutely, predominantly with pain and/or swelling
A careful and detailed history and examination, and in some cases, investigations allow differentiation between these diagnoses. A prompt diagnosis is essential as the patient may require urgent surgical intervention
Testicular torsion refers to twisting of the spermatic cord, causing ischaemia of the testicle.
Testicular torsion results from inadequate fixation of the testis to the tunica vaginalis producing ischemia from reduced arterial inflow and venous outflow obstruction.
The prevalence of testicular torsion in adult patients hospitalized with acute scrotal pain is approximately 25 to 50 percent
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Seth Baum, MD - Wading through the Sea of Fish Oil Choices; How do we Sort Science from Marketing
1. Wading through the Sea
of Fish Oil Choices:
Separating Science from
Marketing
What comprises the fats we speak so
much about?
And, do they truly help our Hearts?
Seth J. Baum, MD, FACC, FAHA, FACPM, FNLA
Director, Women’s Preventive Cardiology, BRRH
4. Today’s Goals
• Critical Definitions
• Properly read a Fish Oil Label
• Understand EPA, DHA, and their
derivatives
• Review the largest Omega-3 CVD
Intervention Trials
6. Triglycerides
• More properly known as Triacylglycerol
• Glycerol (an alcohol) is esterified with
three Fatty Acids (which can all be
different)
• The main constituent of vegetable oil and
animal fat
9. Intestinal Absorption of TG
• Bile Acids act as soaps to emulsify fats
• Small fat globules result allowing water soluble
•
•
•
•
Lipase to interact more effectively with fat
Triglycerides are broken into Monoglycerides
and Free Fatty Acids by Lipases
Micelles transport these breakdown products
into the enterocytes
FFAs are absorbed directly
Chylomicrons formed in enterocytes enter body
through lymphatics
12. Phospholipids
• Class of lipids ESSENTIAL for membrane
•
•
•
•
function
Contain phosphate group and built upon
nitrogen-containing alcohol
Amphiphilic (Amphipathic) – head is hydrophilic
while tail is lipophilic
Integral part of Lipid Bilayer
Phospholipids move laterally in membranes –
essential for lipid polymorphism (how lipids
aggregate)
14. Saturation/Unsaturation of
Fatty Acids
• Saturated Fats contain the MAXIMUM # of
•
•
•
Hydrogen atoms and NO Double Bonds – They
are Saturated with Hydrogen Atoms
Unsaturated Fats Lack two or more Hydrogen
Atoms and thus have one or more Double Bond
Mono-unsaturated Fats (MUFAs) have one DB
Polyunsaturated Fats (PUFAs) have >1 DB
20. Polyunsaturated Fatty Acids:
PUFAs
• PUFA’s (Omega 3,6,9) defined by the location of
•
•
•
the first DB, counting from the terminal carbon
Omega-3 FA have their first DB in 3rd carbon
position from the chain’s end
Omega-6 FA have their first DB in 6th carbon
position from the end
Essential Fatty Acids LA and ALA were originally
defined as Vitamin F in 1923
21. Linoleic Acid (LA): The 18 carbon
Omega-6 Essential Fatty Acid
LA 18:2 n-6
Number of
carbon atoms
Number of
double
bonds
Position of
the first
double bond
22. Alpha Linolenic Acid (ALA):
The 18 carbon Omega-3
Essential Fatty Acid
ALA 18:3 n-3
Number of carbon
atoms
Number of
double
bonds
Position of the
first double
bond
23. Relationships Among the
PUFAs
• In general, the longer the chain (more carbon atoms)
and the less saturated (more DB) the more
metabolically active the FA
27. EPA, DHA, AND THEIR
DERIVATIVES:
WHY THESE FATS ARE SO
ESSENTIAL
28. Different Aspects of the Omega3s DHA and EPA
• DHA is preferentially taken up by cell
•
•
•
•
membranes to increase membrane fluidity,
regulate gene expression, modulate ion
channels, and enhance pinocytosis. DHA is the
precursor for Docosanoids.
EPA is used mostly as precursor for
Eicosanoids.
Conversion of ALA to EPA is approximately
10%, while conversion to DHA is only 1-2%.
Retroconversion of DHA to EPA may be more
prevalent than forward conversion.
Trans fats further reduce conversion to DHA.
30. Biologic Effects of EPA and
DHA
•
•
•
•
•
Triglyceride Lowering
Anti-arrhythmic
Anti-oxidant
Anti-inflammatory
Anti-thrombotic
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
31. Triglyceride - Lowering
• Both lower TG (8%/1000 mg)
• 4 Nuclear receptors influenced to decrease TG
•
•
•
•
production and increase degradation (LXR,
HNF4 alpha, FXR, PPARs)
SREBP 1c is impacted by all 4
LPL is increased
Apo C3 is decreased
VLDL production is decreased and Chylomicron
clearance is increased
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
32. Anti-arrhythmic effects
• Structural plasticity and free caboxyl group
•
•
•
•
are essential
Direct effects on several channels
Improved cell signaling from DHA
incorporation in cell membrane
Stabilize cardiac myocytes - lower resting
membrane potential & prolong refractory
period
“Fuel” function
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
33. Anti-oxidant effects
• Decrease production of F2 Isoprostanes
• No increase in F3 and F4 Isoprostanes
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
34. Anti-inflammatory effects
• Multi-factorial
• Decrease intra-plaque IL6, T cells, MMPs,
ICAM-1
• N.B. IL6 is the only cytokine known to
influence ALL inflammatory acute phase
reactants
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
35. Anti-thrombotic effects
• Doses < 5 gm/day do not increase
•
•
•
•
bleeding times
DHA&EPA incorporation into Platelet
phospholipids leads to these effects:
Decrease platelet activating factor (PAF)
Down-regulate platelet-derived growth
factors, A&B
Indirectly reduce monocyte-derived
thromboplastin and thromboxane B2
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
36. Eicosanoids
• 20 carbon FA derivatives of AA and EPA
• Essential for homeostasis with respect to inflammation,
•
thrombosis, endothelial function, vascular resistance
Two groups: Classical (Prostanoids and Leukotrienes)
and Non-classical (Lipoxins, Resolvins, EETs)
– Prostaglandins (PG)
– Prostacyclin (PG)
– Thromboxanes (TX)
– Leukotrienes (LT)
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
37. Classical Eicosanoids:
• Leukotrienes: Created by action of
lipoxygenases (LOX)
• Prostanoids: Created by action of
cyclooxygenases (COX)
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
38. The Danger of Misguided
Manipulation of Eicosanoids:
The NSAIDS
• Basal state COX-1 predominates, protecting GI
•
•
tract (protective PGs) and producing low levels
of PGI2
Upregulation of COX-2 increases PGE2 but also
makes PGI2 dominant
Non-specific NSAIDS decrease pain, but
increase GI bleeds by inhibiting COX-1
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
39. The Danger of Misguided
Manipulation of Eicosanoids,
Con’t
• Hypothesis: Selective COX-2 inhibition would
•
“kill 2 birds with one stone”: by decreasing
PGE2, decrease both pain and CVD. Also, no
COX-1 inhibition so no GI SE
Unfortunately, COX-2 inhibition also dramatically
decreases PGI2. CV events increased as TXA2
became ”unopposed” by PGI2
• PG balance is delicate
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
40. ASA, the Only NSAID to
Decrease CVD Events
• Only NSAID to Irreversibly block COX-1
• Results in nearly complete inhibition of
platelets’ ability to produce TXA2
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
41. Non-Classical Eicosanoids
EETs
• Derived from CYP 2C and 2J
• 4 EETs formed from AA and ALL are
vasculoprotective
• Short-lived as consequence of sEH
(soluble Epoxide Hydrolase)
• Potential for future drug development
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
42. Non-Classical Eicosanoids
Lipoxins
• Formed from action of 12- and 15- LOX on
AA or EPA
• LXA4 is prototypical Lipoxin
–
–
–
–
Anti-inflammatory
Decrease Neutrophil chemotaxis
Attenuate TNF�
Antithesis of LTB4 (but made from same
precursor!)
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
43. Non-Classical Eicosanoids
Resolvins
• As opposed to previous Lipoxins,
Resolvins are derived from ONLY
EPA&DHA
• EPA-Derived are Resolvin Es
• DHA-Derived are Resolvin Ds
• Sequential actions of 3 enzymes –
CYP450, COX-2, LOXs
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
44. Non-Classical Eicosanoids
Resolvins Con’t
• Anti-inflammatory
• Inflammation-Resolving
• Suppress cytokine secretion and
Neutrophil infiltration
• Block pro-inflammatory effects of TXs
• Utilize receptors distinct from those for
Lipoxins and “Resolve” Inflammation
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
45. Docosanoids
• DHA most abundant of LCPUFA omega-
3s
• DHA is particularly concentrated in neural
tissue
• Docosanoids are derived from ONLY DHA
– Maresins
– Neuroprostanes
– Neuroprotectin D1 (NPD1)
Baum, Curr Cardiovasc Risk Rep
DOI 10.1007/s12170-012-0224-6
47. Clinical Trials
• Observational Trials consistently showed
association of high fish intake with low
CVD and low fish intake with high CVD
• Next came the Intervention trials
48. Eight Large CVD Intervention
Trials
• Comparisons are difficult secondary to
design differences –
–
–
–
–
Time of intervention relative to CVD Event
Dose of Intervention
Duration of Intervention
Baseline PUFA intake
49. 1. DART: Diet And Reinfarction
Trial
• Randomized 2,000 men s/p MI.
• Three dietary advice interventions:
•
a.low-fat, increased fiber diet
b. increased n-3 fatty acids, either in the form of
fatty fish (200 - 400 gm per week, providing 500800 mg n-3 fatty acids per day) or c. fish oil
capsules (900 mg EPA+DHA per day)
N-3 group had a 29% decreased mortality at 2
years secondary to decreased CHD
Burr ML, Fehily AM, Gilbert JF, et al. Effects of changes in fat, fish, and fibre intakes on death
and myocardial reinfarction: Diet and Reinfarction Trial (DART). Lancet 1989;2:757-761
50. 2. DART 2
• 3,000 male patients with angina and 4
dietary advice arms:
a.No advice
b.Increased fruits, vegetables, and oats
c. Increased fish oil in one of two ways: two fatty
fish meals per week or 3 fish oil pills daily
• Study was negative but rife with flaws –
intergroup differences in meds, diseases and
compliance.
Burr ML, Ashfield-Watt PA, Dunstan FD, et al. Lack of benefit of dietary advice to men with
angina: results of a controlled trial. Eur J Clin Nutr 2003;57:193-200
51. 3. GISSI-Prevenzione: The Gruppo Italiano
per lo Studio della Sopravvivenza
nell’Infarto Miocardico
• 11,000 patients within 3 months of MI
• 4 groups: n-3 fatty acids 840 mg daily; Vitamin E
300 mg QD; Both; Neither
• At 3.5 years 15% reduction in composite endpoint of death, non-fatal MI, non-fatal CVA
• At 3.5 years 21% reduction in total mortality
• At 3.5 years 30% reduction in CVD mortality
• Results primarily driven by 45% reduction in
SCD seen by month 4
GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto
miocardico) Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after
myocardial infarction: results of the GISSI-Prevenzione trial. Lancet 1999;354:447–455
52. 4. OMEGA: Germany
• OMEGA, a randomized, placebo-
controlled trial to test the effect of highly
purified omega-3 fatty acids on top of
modern guideline-adjusted therapy after
myocardial infarction
• Patients were aggressively managed with
combination drug therapy and intervention: 95%
were catheterized and 80% had PCI. Also, about
half of patients in both groups ate fatty fish
several times a week
Rauch B, Schiele R, Schneider S, et al. OMEGA, a randomized, placebo-controlled trail to test
the effect of highly purified omega-3 fatty acids on top of modern guideline-adjusted therapy
after myocardial infarction. Circulation 2010;122:2152-2159
53. OMEGA continued
•
•
•
•
•
a. 3,800 patients 3-14 days post-MI
B. 840 mg omega-3 vs. placebo (olive oil)
c. Primary endpoint: SCD within 1 year of MI
d. Secondary endpoint: Total mortality and nonfatal clinical events
SCD Rate was 1.5% in both arms –
unexpectedly low: thereby under powering trial.
This, with high baseline fish intake and only one
year f/u contributed to null results
54. 5. Alpha Omega Trial:
Netherlands
• a. 5,000 patients with h/o MI within 10 years
•
•
•
•
•
(median 3.7 years)
b. 4 Trial Margarines: 400 mg EPA+DHA; 2 gm
ALA; Both; Neither
c. Primary endpoint: Major CV events
d. Patients treated with aggressive medical
management
e. 3.5 year f/u – Major CV events in about 14%
f. No difference among groups
Kromhout D, Giltay EJ, Geleijnse JM, et al. N-3 fatty acids and cardiovascular events
after myocardial infarction. N Eng J Med 2010;363:2015-2026
55. Alpha Omega Trial: Continued
• g. Design flaws: Low dose omega-3s
EPA+DHA; high dose of ALA; long period
post-MI prior to enrollment.
• h. Post-hoc: DM patients taking EPA+DHA
had a statistically significant 50%
reduction in death from coronary disease
56. 6. SU.FOL.OM3 Study: Supplement with
Folic Acid and/or Omega-3 fatty Acids:
France
• a. 2,500 patients with coronary or cerebral events in the
•
•
•
prior year
b. Primary outcome to prevent major cardiovascular
events
c. 4 Groups: B vitamins (5-methyltetrahydrofolate
(560mcg), vitamin B-6 (3 mg) and B-12 (20mcg);
EPA+DHA – 400 and 200 mg respectively; Both; Neither
d. Null results: flaws: low dose, long time interval s/p
initial event; lower than expected overall event rate,,
underpowered
Galan P, Kesse-Guyot E, Czernichow S, et al. Effects of B vitamins and omega-3
fatty acids on cardiovascular diseases: a randomized placebo controlled trial. BMJ
2010;341:c6273
57. 7. ORIGIN: The Outcome Reduction
with Initial Glargine Intervention
• a. 12,500 patients with IGT or DM
• b. 2X2 Factorial Design
• c. 840 mg EPA+DHA or Placebo; and
Insulin Glargine or Standard care
• d. Primary outcome CV Death
• e. 6 year follow up no benefit from n-3 FA
The ORIGIN Trial Investigators. N-3 fatty acids and cardiovascular outcomes in
patients with dysglycemia. N Engl J Med 2012;367:309-318
58. 8. JELIS: Japan EPA Lipid
Intervention Study
• a. 18,500 patients: 15,000 Primary and
3,500 Secondary Prevention
• b. Open-label design: 1,800 mg EPA plus
statin vs. Statin alone
• c. Major Cardiovascular event was primary
endpoint
• d. At 4.5 years 19% reduction in primary
endpoint driven by reduction in non-fatal
events
Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on
major coronary events in hypercholesterolaemic patients (JELIS): a randomised
open-label, blinded endpoint analysis. Lancet 2007;369:1090-1098
59. JAMA Meta-analysis, Rizos et al
• September 2012: Association between omega-3
•
•
fatty acid supplementation and risk of major
cardiovascular disease events: a systematic
review and meta-analysis
a. “There is no evidence for routine use of
omega-3 fatty acids” – direct expert
quote/conclusion
b. Dr. Arnett (president, AHA) comment to
Reuters, “this closes the issue of omega-3's role
in heart disease "
60. JAMA (Con’t)
• c. Authors required a p value < 0.0063. If
conventional < 0.05 p value, results would
have been significant: fish oil did reduce
cardiovascular death (p value of 0.01)
• d. Authors excluded GISSI and JELIS
• e. Patients were optimally treated, had
CVD, got omega-3s for about 4 years,
averaged 63 y.o. Very specific subset of
patients.
61. SCD vs. Non-fatal CVD Events
• Non-linear relationship of fish oil to SCD
• Approximately 250 mg/day is threshold to
decrease SCD
• Japanese consume 10x EPA/DHA
compared with USA; therefore fully
protected against SCD.
• Non-fatal CVD protection requires higher
doses – NOT achieved in western trials
62. Prostate Cancer - SELECT:
Brasky’s Blemishes
1. Don’t Ignore earlier positive trials: PHS, Harvard Trial,
2.
3.
4.
5.
6.
Terry’s study
Insignificant difference in plasma EPA+DHA PL
between cancer and controls: 3.62% and 3.75%
Association ≠ Cause: Reverse Causation more likely
here
Source of EPA and DHA not revealed (? Fish
contaminants)
Japanese consume 10x fish we do yet have 1/8 risk of
prostate cancer
Findings contradict biology of these PUFAs
Brasky jnci.oxfordjournals.org
63. Guidelines
• AHA: 1,000 mg combined EPA+DHA in
•
•
•
•
CVD
AHA: Fatty fish > 2x/wk or 500 mg QD
EuroPRevent: “Regular consumption of
fatty fish”
ISSFAL: Minimum of 500 mg/day
EPA+DHA
ISSFAL: Pregnant/Lactating women > 200
mg DHA
64. Final Thoughts
• In view of our Current Diet, EPA and DHA are
•
•
•
“Essential” Fats
EPA and DHA have myriad physiologic effects
Outcome data are limited and will likely remain
so
We must rely upon our understanding of
physiology, molecular and cell biology, and
nutrition to guide us. RCTs will not “save us”
here.