Benefits of Drinking Coffee
Benefits
All-cause mortality:
In women, coffee consumption significantly decreases all-cause mortality, apparently decreasing somewhat linearly to a relative risk of approximately 0.85 for those drinking 3 cups per day compared to those who consume no coffee, but the relative risk then remains almost the same for up to 6 cups per day, according to a large prospective cohort study in 1993. In men, these beneficial effects were not as great, in fact with an increased risk for those drinking approximately one cup every other day compared to those drinking none, but yet having a significant trend towards less mortality for those who drink more than 2 cups per day compared to those who drink none. Results were similar for decaffeinated coffee. An inverse association between coffee consumption and total and cause-specific mortality was also found in a 2012 analysis of data from the National Institutes of Health–AARP Diet and Health Study.
Reduced risk of Alzheimer's disease and Dementia:
Several studies comparing moderate coffee drinkers (defined as 3–5 cups per day) with light coffee drinkers (defined as 0–2 cups per day) found that those who drank more coffee were significantly less likely to develop Alzheimer's disease later in life.
A longitudinal study in 2009 found that moderate coffee drinkers had reduced risk of developing dementia in addition to Alzheimer's disease.
Reduced risk of gallstone disease:
Drinking caffeinated coffee has been correlated with a lower incidence of gallstones and gallbladder disease in both men and women in two studies performed by the Harvard School of Public Health. A lessened risk was not seen in those who drank decaffeinated coffee.
Reduced risk of Parkinson's disease:
A study comparing heavy coffee drinkers (3.5 cups a day) with non-drinkers found that the coffee drinkers were significantly less likely to develop Parkinson's disease later in life. Likewise, a second study found an inverse relationship between the amount of coffee regularly drunk and the likelihood of developing Parkinson's disease.
Cognitive performance:
Many people drink coffee for its ability to increase short term recall.
Likewise, in tests of simple reaction time, choice reaction time, incidental verbal memory, and visuospatial reasoning, participants who regularly drank coffee were found to perform better on all tests, with a positive relationship between test scores and the amount of coffee regularly drunk. Elderly participants were found to have the largest effect associated with regular coffee drinking. Another study found that women over the age of 80 performed significantly better on cognitive tests if they had regularly drunk coffee over their lifetimes. A recent study showed that roast coffee protected primary neuronal cells against hydrogen peroxide-induced cell death.
Caffeine and analgesics:
Coffee contains caffeine, which may increase the effectiveness of gastrointestinal uptake of some pain killers, especially in patients with migraine and headache medications. For this reason, many over-the-counter headache drugs include caffeine in their formula. Caffeine itself does not have analgesic properties. In some patients with migraine, caffeine can alleviate pain by acting on the cerebral blood vessels. A 2012 study suggested caffeinated coffee reduced pain in an office environment.
Antidiabetic:
Coffee intake may reduce one's risk of diabetes mellitus type 2 by up to half. While this was originally noticed in patients who consumed high amounts (7 cups a day), the relationship was later shown to be linear. This effect has been attributed to the compounds caffeic acid and chlorogenic acid, which are thought to suppress the formation of human islet amyloid polypeptide (hlAPP).
Liver protection:
Coffee can also reduce the incidence of cirrhosis of the liver and has been linked to a reduced risk of hepatocellular carcinoma, a primary liver cancer that usually arises in patients with preexisting cirrhosis. The exact mechanism and the amount of coffee needed to achieve a beneficial effect have long been unclear. The cytokine transforming growth factor (TGF) beta has long been recognized for promoting fibrosis ability acting through the Smad family of transcription factors. In a report published in the Journal of Hepatology, Gressner and colleagues provide the first mechanistic context for the epidemiological studies on coffee drinkers by showing that caffeine may have potent anti-fibrotic capabilities through its ability to antagonize the Smad pathway.
Cancer:
Coffee consumption is also correlated in Africa to a reduced risk of oral, esophageal, and pharyngeal cancer. In ovarian cancer, no benefit was found. In the Nurses' Health Study and a 2011 Swedish study, a modest reduction in breast cancer was observed in postmenopausal women only, which was not confirmed in decaffeinated coffee, and a reduction in endometrial cancer was observed in people who drank either caffeinated or decaffeinated coffee. The Harvard Medical School reported in 2006 that researchers found that coffee drinkers were 50% less likely to get liver cancer than nondrinkers. Another study found a correlation between coffee consumption (both regular and decaffinated) and a lower risk of aggressive prostate cancer.
Instant coffee contains a much higher level of acrylamide than brewed coffee.
Cardioprotective:
Coffee moderately reduces the incidence of dying from cardiovascular disease, according to a large prospective cohort study published in 2008.
A 2009 prospective study in Japan following nearly 77,000 individuals aged 40 to 79 found that coffee consumption, along with caffeine intake, was associated with a reduced risk of dying from cardiovascular disease.
A 2012 meta-analysis concluded that people who drank moderate amounts of coffee had a lower rate of heart failure, with the biggest effect found for those who drank more than four cups a day.
Laxative / diuretic:
Coffee is also a powerful stimulant for peristalsis and is sometimes considered to prevent constipation. However, coffee can also cause excessively loose bowel movements. The stimulative effect of coffee consumption on the colon is found in both caffeinated and decaffeinated coffee.
Contrary to popular belief, caffeine does not act as a diuretic when consumed in moderation (less than five cups a day or 500 to 600 milligrams), and does not lead to dehydration or to a water-electrolyte imbalance; current evidence suggests that caffeinated beverages contribute to the body's daily fluid requirements no differently from pure water.
Antioxidant:
Coffee contains polyphenols such as flavan-3-ols (monomers and procyanidins), hydroxycinnamic acids, flavonols and anthocyanidins. These compounds have antioxidative effect and potentially reduce oxidative cell damage. One particular substance with putative anticarcinogenic effect is methylpyridinium. This compound is not present in significant amounts in other foods. Methylpyridinium is not present in raw coffee beans but is formed during the roasting process from trigonelline, which is common in raw coffee beans. It is present in both caffeinated and decaffeinated coffee, and even in instant coffee. Research funded by Kraft Foods shows that roast coffee contains more lipophilic antioxidants and chlorogenic acid lactones and is more protective against hydrogen peroxide-induced cell death in primary neuronal cells than green coffee. The espresso method of extraction yields higher antioxidant activity than other brewing methods.
Prevention of dental cavities:
The tannins in coffee may reduce the cariogenic potential of foods. In vitro experiments have shown that these polyphenolic compounds may interfere with glucosyltransferase activity of mutans streptococci, which may reduce plaque formation.
Gout:
Coffee consumption contributes to a decreased risk of gout in men over age 40. In a large study of over 45,000 men over a 12-year period, the risk for developing gout in men over 40 was inversely proportional with the amount of coffee consumed.
Blood pressure:
A 2011 study showed that moderate (≤4 cups per day) coffee consumption was inversely associated with high blood pressure and high triglyceride level in Japanese men. However, the study showed no significant association between coffee consumption and prevalence of metabolic syndrome for Japanese women.
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
-----
Bring A Smile To Someone's Day
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Wednesday, May 29, 2013
Saturday, May 18, 2013
Indoor Air Pollution
Indoor Air Pollution
Is Your Home A Healthy Home? http://ow.ly/1z7GnH
Air pollution is the introduction into the atmosphere of chemicals, particulate matter, or biological materials that cause discomfort, disease, or death to humans, damage other living organisms or damage the natural environment or built environment.
In this context, we often think of our outside environment, but air pollution takes place inside our homes as well.
Indoor air pollution and urban air quality are listed as two of the World’s Worst Toxic Pollution Problems in the 2008 Blacksmith Institute World's Worst Polluted Places report.[1]
A lack of ventilation indoors concentrates air pollution where people often spend the majority of their time. Radon (Rn) gas, a carcinogen, is exuded from the Earth in certain locations and trapped inside houses. Building materials including carpeting and plywood emit formaldehyde (H2CO) gas. Paint and solvents give off volatile organic compounds (VOCs) as they dry. Lead paint can degenerate into dust and be inhaled. Intentional air pollution is introduced with the use of air fresheners, incense, and other scented items. Controlled wood fires in stoves and fireplaces can add significant amounts of smoke particulates into the air, inside and out.[2] Indoor pollution fatalities may be caused by using pesticides and other chemical sprays indoors without proper ventilation.
Carbon monoxide (CO) poisoning and fatalities are often caused by faulty vents and chimneys, or by the burning of charcoal indoors. Chronic carbon monoxide poisoning can result even from poorly adjusted pilot lights. Traps are built into all domestic plumbing to keep sewer gas, hydrogen sulfide, out of interiors. Clothing emits tetrachloroethylene, or other dry cleaning fluids, for days after dry cleaning.
Though its use has now been banned in many countries, the extensive use of asbestos in industrial and domestic environments in the past has left a potentially very dangerous material in many localities. Asbestosis is a chronic inflammatory medical condition affecting the tissue of the lungs. It occurs after long-term, heavy exposure to asbestos from asbestos-containing materials in structures. Sufferers have severe dyspnea (shortness of breath) and are at an increased risk regarding several different types of lung cancer. As clear explanations are not always stressed in non-technical literature, care should be taken to distinguish between several forms of relevant diseases. According to the World Health Organisation (WHO), these may defined as; asbestosis, lung cancer, and Peritoneal Mesothelioma (generally a very rare form of cancer, when more widespread it is almost always associated with prolonged exposure to asbestos).
Biological sources of air pollution are also found indoors, as gases and airborne particulates. Pets produce dander, people produce dust from minute skin flakes and decomposed hair, dust mites in bedding, carpeting and furniture produce enzymes and micrometre-sized fecal droppings, inhabitants emit methane, mold forms in walls and generates mycotoxins and spores, air conditioning systems can incubate Legionnaires' disease and mold, and houseplants, soil and surrounding gardens can produce pollen, dust, and mold. Indoors, the lack of air circulation allows these airborne pollutants to accumulate more than they would otherwise occur in nature.
-----
[1] "Reports". WorstPolluted.org. Archived from the original on 11 August 2010. Retrieved 2010-08-29.
close
[2] "Duflo, E., Greenstone, M., and Hanna, R. (2008) "Indoor air pollution, health and economic well-being". ''S.A.P.I.EN.S.'' '''1''' (1)". Sapiens.revues.org. Retrieved 2010-08-29.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not, and is not intended to replace actual medical advice from a qualified doctor.
To receive your free 'Manna Goods Health Bulletin' via email, send an email to: the.manna.goods@gmail.com (Put 'Subscribe' in the subject line.)
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Is Your Home A Healthy Home? http://ow.ly/1z7GnH
Air pollution is the introduction into the atmosphere of chemicals, particulate matter, or biological materials that cause discomfort, disease, or death to humans, damage other living organisms or damage the natural environment or built environment.
In this context, we often think of our outside environment, but air pollution takes place inside our homes as well.
Indoor air pollution and urban air quality are listed as two of the World’s Worst Toxic Pollution Problems in the 2008 Blacksmith Institute World's Worst Polluted Places report.[1]
A lack of ventilation indoors concentrates air pollution where people often spend the majority of their time. Radon (Rn) gas, a carcinogen, is exuded from the Earth in certain locations and trapped inside houses. Building materials including carpeting and plywood emit formaldehyde (H2CO) gas. Paint and solvents give off volatile organic compounds (VOCs) as they dry. Lead paint can degenerate into dust and be inhaled. Intentional air pollution is introduced with the use of air fresheners, incense, and other scented items. Controlled wood fires in stoves and fireplaces can add significant amounts of smoke particulates into the air, inside and out.[2] Indoor pollution fatalities may be caused by using pesticides and other chemical sprays indoors without proper ventilation.
Carbon monoxide (CO) poisoning and fatalities are often caused by faulty vents and chimneys, or by the burning of charcoal indoors. Chronic carbon monoxide poisoning can result even from poorly adjusted pilot lights. Traps are built into all domestic plumbing to keep sewer gas, hydrogen sulfide, out of interiors. Clothing emits tetrachloroethylene, or other dry cleaning fluids, for days after dry cleaning.
Though its use has now been banned in many countries, the extensive use of asbestos in industrial and domestic environments in the past has left a potentially very dangerous material in many localities. Asbestosis is a chronic inflammatory medical condition affecting the tissue of the lungs. It occurs after long-term, heavy exposure to asbestos from asbestos-containing materials in structures. Sufferers have severe dyspnea (shortness of breath) and are at an increased risk regarding several different types of lung cancer. As clear explanations are not always stressed in non-technical literature, care should be taken to distinguish between several forms of relevant diseases. According to the World Health Organisation (WHO), these may defined as; asbestosis, lung cancer, and Peritoneal Mesothelioma (generally a very rare form of cancer, when more widespread it is almost always associated with prolonged exposure to asbestos).
Biological sources of air pollution are also found indoors, as gases and airborne particulates. Pets produce dander, people produce dust from minute skin flakes and decomposed hair, dust mites in bedding, carpeting and furniture produce enzymes and micrometre-sized fecal droppings, inhabitants emit methane, mold forms in walls and generates mycotoxins and spores, air conditioning systems can incubate Legionnaires' disease and mold, and houseplants, soil and surrounding gardens can produce pollen, dust, and mold. Indoors, the lack of air circulation allows these airborne pollutants to accumulate more than they would otherwise occur in nature.
-----
[1] "Reports". WorstPolluted.org. Archived from the original on 11 August 2010. Retrieved 2010-08-29.
close
[2] "Duflo, E., Greenstone, M., and Hanna, R. (2008) "Indoor air pollution, health and economic well-being". ''S.A.P.I.EN.S.'' '''1''' (1)". Sapiens.revues.org. Retrieved 2010-08-29.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not, and is not intended to replace actual medical advice from a qualified doctor.
To receive your free 'Manna Goods Health Bulletin' via email, send an email to: the.manna.goods@gmail.com (Put 'Subscribe' in the subject line.)
-----
Bring A Smile To Someone's Day
http://ow.ly/1z4j1b
Friday, May 17, 2013
Re-occlusion
In-Stent Restenosis
(Also Called 'Re-occlusion')
Dr. Ellis, head of Invasive and Interventional Cardiology and Director of the Cleveland Clinic’s Sones Cardiac Catheterization Laboratories, responds to this question that his patients often ask him:
"What are the treatment options for restenosis that occurs at the site of a previously implanted stent?”
There are many treatment options for blockages that occur at the site where a stent was placed. The first step is to meet with an experienced cardiac interventionalist who can tailor a treatment approach based on the location of the blocked stent, extent of the blockage, the patient’s age, type of cardiovascular disease and coexisting medical conditions. A number of things need to be considered.
Is the artery totally blocked?
First, the interventionalist should determine whether or not angioplasty equipment can even be placed across the blockage, depending on the location and severity of the blockage. If the stent is not totally blocked, the interventionalist is often able to access the blockage using traditional percutaneous techniques.
What are options for totally blocked arteries (total coronary occlusion)?
If the stent is totally blocked, alternate percutaneous techniques may be used by experienced interventionalists to access the blockage and considerably improve the success rate of this treatment approach. Special guide wires and catheters can be gently steered across the total blockages. The fine movement of new guide wire tips is much easier to control than previous guide wire tips. Success rates approach 80%. In addition, Cleveland Clinic interventionalists can use the "retrograde" approach, in which total coronary blockages are accessed from collateral blood vessels. Collateral blood vessels are new blood vessels that form to reroute blood flow around a blockage, and develop when the blockage becomes severely narrowed.
In some cases when the blockage cannot be accessed surgery may be recommended.
Has the blockage occurred where a bare metal stent was placed?
To treat a blockage that has occurred at the site of an uncoated, bare metal stent, placement of a drug-eluting stent (for eligible patients) often provides a very satisfactory long-term outcome.
If the blockage is short, sometimes balloon angioplasty or cutting balloon angioplasty are enough to effectively treat the blockage.
Balloon angioplasty is a procedure in which a small balloon at the tip of the catheter is inserted near the blocked or narrowed area of the coronary artery. When the balloon is inflated, the scar tissue of the blockage is compressed against the artery walls and the diameter of the blood vessel is widened (dilated) to increase blood flow to the heart.
The cutting balloon catheter has a balloon tip with small blades. When the balloon is inflated, the blades are activated. The small blades score the plaque, and the balloon expands the previously placed stent .
Has the blockage occurred where a drug-eluting stent was placed?
Determine proper placement. First, it is important to know if the stent was actually placed and expanded properly. An intravascular ultrasound examination can help determine if the stent was properly deployed. If the stent wasn't properly placed, sometimes simply re-expanding it is all that is needed. If the stent was well-expanded and tissue regrowth has occurred within the stent, using a different type of drug-eluting stent is generally the best option.
Review the type of drug eluting stent used. If a Sirolimus – type (Cypher, Xience, Endeavor) drug eluting stent was used, the physician will consider a Taxus stent (delivers paclitaxel). If a Taxus stent was used, the physician will consider a Sirolimus analog delivering stent.
Long-term anticoagulation therapy.
Almost all coronary interventional procedures involve the use of stents. Until the artery around the stent has healed there is a risk of blood clots forming on the metal. With bare metal stents, clopidigrel needs to be taken for at least 4 weeks and with DES, at least a year. Randomized trials are ongoing to better clarify the optimal duration of clopidigrel and related medications. In addition, in some patients prasugrel may be a better choice than clopidogrel. Talk to your doctor about the latest information about this choice. Aspirin is known to reduce the risk of heart attack in anybody with coronary artery disease bad enough to require a stent and should be taken indefinitely.
Consider bypass surgery as treatment options.
Coronary artery bypass graft surgery is a treatment in which one or more blocked coronary arteries are bypassed by a blood vessel graft to restore normal blood flow to the heart. These grafts usually come from the patient’s own arteries and veins located in the chest, leg or arm. The graft goes around the blocked artery (or arteries) to create new pathways for oxygen-rich blood to flow to the heart.
An experienced team of cardiologists and surgeons can evaluate your cardiac catheterization and medical history to determine the best option to treat restenosis.
In Summary
While restenosis that occurs at the site of a previously implanted stent can be a challenging condition to treat, experienced interventionalists who are familiar with multiple treatment options can often provide you with a treatment option that has a high likelihood of success.
For more information:
-Total Coronary Occlusions: Treatment for a totally blocked coronary artery
-Cardiac Catheterization and Coronary Interventional Procedures (angioplasty and stent)
-Bifurcation Blockage
-Live Web Chat Transcripts - see Coronary Artery Disease and Interventional Procedures
References:
-Holmes, DR, et al. Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents. JAMA. 2006;295:1264-1273.
-Smith, SC, Jr, et al. “Management Strategies for Restenosis After PTCA,” from ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions. Circulation. 2006;113:156-75. http://circ.ahajournals.org/cgi/content/full/113/1/156
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. A prospective, multicenter, randomized trial evaluating the TAXUS paclitaxel-eluting coronary stent versus vascular brachytherapy for the treatment of bare metal stent in-stent restenosis: the TAXUS-V ISR trial. Program and abstracts from the Innovation in Intervention i2 Summit 2006; March 11-14, 2006; Atlanta, Georgia. Abstract 2402-9.
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295:1253-1263
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
(Also Called 'Re-occlusion')
Dr. Ellis, head of Invasive and Interventional Cardiology and Director of the Cleveland Clinic’s Sones Cardiac Catheterization Laboratories, responds to this question that his patients often ask him:
"What are the treatment options for restenosis that occurs at the site of a previously implanted stent?”
There are many treatment options for blockages that occur at the site where a stent was placed. The first step is to meet with an experienced cardiac interventionalist who can tailor a treatment approach based on the location of the blocked stent, extent of the blockage, the patient’s age, type of cardiovascular disease and coexisting medical conditions. A number of things need to be considered.
Is the artery totally blocked?
First, the interventionalist should determine whether or not angioplasty equipment can even be placed across the blockage, depending on the location and severity of the blockage. If the stent is not totally blocked, the interventionalist is often able to access the blockage using traditional percutaneous techniques.
What are options for totally blocked arteries (total coronary occlusion)?
If the stent is totally blocked, alternate percutaneous techniques may be used by experienced interventionalists to access the blockage and considerably improve the success rate of this treatment approach. Special guide wires and catheters can be gently steered across the total blockages. The fine movement of new guide wire tips is much easier to control than previous guide wire tips. Success rates approach 80%. In addition, Cleveland Clinic interventionalists can use the "retrograde" approach, in which total coronary blockages are accessed from collateral blood vessels. Collateral blood vessels are new blood vessels that form to reroute blood flow around a blockage, and develop when the blockage becomes severely narrowed.
In some cases when the blockage cannot be accessed surgery may be recommended.
Has the blockage occurred where a bare metal stent was placed?
To treat a blockage that has occurred at the site of an uncoated, bare metal stent, placement of a drug-eluting stent (for eligible patients) often provides a very satisfactory long-term outcome.
If the blockage is short, sometimes balloon angioplasty or cutting balloon angioplasty are enough to effectively treat the blockage.
Balloon angioplasty is a procedure in which a small balloon at the tip of the catheter is inserted near the blocked or narrowed area of the coronary artery. When the balloon is inflated, the scar tissue of the blockage is compressed against the artery walls and the diameter of the blood vessel is widened (dilated) to increase blood flow to the heart.
The cutting balloon catheter has a balloon tip with small blades. When the balloon is inflated, the blades are activated. The small blades score the plaque, and the balloon expands the previously placed stent .
Has the blockage occurred where a drug-eluting stent was placed?
Determine proper placement. First, it is important to know if the stent was actually placed and expanded properly. An intravascular ultrasound examination can help determine if the stent was properly deployed. If the stent wasn't properly placed, sometimes simply re-expanding it is all that is needed. If the stent was well-expanded and tissue regrowth has occurred within the stent, using a different type of drug-eluting stent is generally the best option.
Review the type of drug eluting stent used. If a Sirolimus – type (Cypher, Xience, Endeavor) drug eluting stent was used, the physician will consider a Taxus stent (delivers paclitaxel). If a Taxus stent was used, the physician will consider a Sirolimus analog delivering stent.
Long-term anticoagulation therapy.
Almost all coronary interventional procedures involve the use of stents. Until the artery around the stent has healed there is a risk of blood clots forming on the metal. With bare metal stents, clopidigrel needs to be taken for at least 4 weeks and with DES, at least a year. Randomized trials are ongoing to better clarify the optimal duration of clopidigrel and related medications. In addition, in some patients prasugrel may be a better choice than clopidogrel. Talk to your doctor about the latest information about this choice. Aspirin is known to reduce the risk of heart attack in anybody with coronary artery disease bad enough to require a stent and should be taken indefinitely.
Consider bypass surgery as treatment options.
Coronary artery bypass graft surgery is a treatment in which one or more blocked coronary arteries are bypassed by a blood vessel graft to restore normal blood flow to the heart. These grafts usually come from the patient’s own arteries and veins located in the chest, leg or arm. The graft goes around the blocked artery (or arteries) to create new pathways for oxygen-rich blood to flow to the heart.
An experienced team of cardiologists and surgeons can evaluate your cardiac catheterization and medical history to determine the best option to treat restenosis.
In Summary
While restenosis that occurs at the site of a previously implanted stent can be a challenging condition to treat, experienced interventionalists who are familiar with multiple treatment options can often provide you with a treatment option that has a high likelihood of success.
For more information:
-Total Coronary Occlusions: Treatment for a totally blocked coronary artery
-Cardiac Catheterization and Coronary Interventional Procedures (angioplasty and stent)
-Bifurcation Blockage
-Live Web Chat Transcripts - see Coronary Artery Disease and Interventional Procedures
References:
-Holmes, DR, et al. Sirolimus-Eluting Stents vs Vascular Brachytherapy for In-Stent Restenosis Within Bare-Metal Stents. JAMA. 2006;295:1264-1273.
-Smith, SC, Jr, et al. “Management Strategies for Restenosis After PTCA,” from ACC/AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention. American College of Cardiology, American Heart Association, Society for Cardiovascular Angiography and Interventions. Circulation. 2006;113:156-75. http://circ.ahajournals.org/cgi/content/full/113/1/156
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. A prospective, multicenter, randomized trial evaluating the TAXUS paclitaxel-eluting coronary stent versus vascular brachytherapy for the treatment of bare metal stent in-stent restenosis: the TAXUS-V ISR trial. Program and abstracts from the Innovation in Intervention i2 Summit 2006; March 11-14, 2006; Atlanta, Georgia. Abstract 2402-9.
-Stone GW, Ellis SG, O'Shaughnessy CD, et al. Paclitaxel-eluting stents vs vascular brachytherapy for in-stent restenosis within bare-metal stents: the TAXUS V ISR randomized trial. JAMA. 2006;295:1253-1263
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
Thursday, May 9, 2013
Stress, Serotonin Receptors, and the Neurobiology of Depression
Stress, Serotonin Receptors, and the Neurobiology of Depression
http://www.cyberounds.com
Juan F. López, M.D.
Department of Psychiatry and Mental Health Research Institute
University of Michigan, Ann Arbor
Introduction
Major Depressive Disorder (MDD), also known as Major Depression, is a psychiatric syndrome characterized by pervasive disturbances in mood, sleep, appetite, energy, motivation, hedonic capacity, and thinking. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a depressive episode must be diagnosed if a patient has had depressed mood, or has lost interest or pleasure in most activities, for a duration of at least two weeks. However, depressive episodes often last months, sometimes years, and they carry a significant impairment in social and occupational functioning. Depressive episodes also tend to be recurrent, and if left untreated, most patients will have multiple episodes during their lifetime. The episodes tend to become more frequent, and/or more severe as the disease progresses (Post 1992). This is known as the "kindling" or "sensitization" hypothesis of mood disorders.
MDD is a common medical disorder, with a lifetime prevalence of 17.1%, and a 12 month prevalence of 10.3%, in the general population (Kessler et al., 1994). However, the prevalence of MDD in medical populations is even higher, with rates ranging from 30% to 50%, depending on the specific medical condition. This psychiatric disorder also carries a significant morbidity and mortality, with a negative impact not only for the patient itself, but also for the family, and for society in general. About two thirds of severely depressed patients exhibit suicidal ideation, and 10% to 15% commit suicide (Kaplan and Sadock, 1991).
The specific pathogenetic cause of depression is unknown, but it is widely accepted that its etiology, course, and long-term prognosis are influenced by genetic, environmental and neurobiological factors. A greater understanding of the neurobiology of this disorder is leading us to better treatment strategies that can prevent or decrease the impact of this disease. Although many neurotransmitters and neurohormones have been linked to the pathophysiolgy of depression, (e.g. norepinephrine, dopamine, thyroid hormones), research studies have implicated disturbances in the serotonin (5-HT) system and the Hypothalamic-Pituitary-Adrenal (HPA) axis as two of the neurobiological alterations most consistently associated with affective illness (Gold et al., 1988; Meltzer, 1988; Kathol et al., 1989; Nemeroff, 1998). Therefore, this presentation will focus on the regulation of these two systems, as they relate to depression.
Historically, the role of each of these two biological systems in mood disorders have been studied independently, but more recently, their interaction in the brain, as it relates to the pathophysiology of depression, has received increased attention. In this presentation, we will review recent animal and human findings, from the perspective of the 5-HT and HPA axis, which shed new light into the neurobiology of MDD. We will discuss some of the ways in which adrenal glucocorticoids and 5-HT receptors interact during conditions of chronic stress, or severe "allostatic load". We will also discuss what is the potential significance of these findings for the pathophysiology and treatment of mood disorders.
That disturbances in the Hypothalamic-Pituitary-Adrenal axis and in serotonin may share a common pathophysiological mechanism is not surprising, since we know from animal studies that they interact extensively and that they are related in a variety of ways (McEwen, 1987; Chalmers et al., 1993; López et al., 1999). The hippocampus, and the paraventricular nucleus of the hypothalamus (PVN), in particular, are anatomical regions in which components of the Hypothalamic-Pituitary-Adrenal axis and the 5-HT systems have a rich representation (see Figure 1 for an illustration of how serotonin neurons from the raphe nucleus project to the PVN and hippocampus). These regions are also part of the limbic system, an area implicated in the regulation of several vegetative functions (arousal, sleep, appetite and hedonic capacity) as well as in the control of mood. The hippocampus has also been implicated in memory and cognitive function. The recognition that the hippocampus is an integral component of the Hypothalamic-Pituitary-Adrenal axis has led some investigators (including our laboratory) to refer to this neuroendocrine system as the "Limbic"-Hypothalamic-Pituitary-Adrenal (LHPA) axis. We will therefore, for the purpose of this presentation, use the term "LHPA", instead of the more commonly used term "HPA", when referring to this system.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis and Stress
The LHPA is the classic neuroendocrine system that responds to stress. Perception of stress by an organism results in a series of events, the final result of which is the secretion of glucocorticoids (cortisol in humans, corticosterone in rats) from the adrenal cortex (Dallman et al., 1987). Activation and termination of the adrenocortical stress response is critical for adaptation and survival. Inhibition of stress responsiveness is partly achieved by the binding of circulating glucocorticoids to specific cytoplasmic receptors in hypothalamus, where they inhibit corticotropin releasing hormone (CRH) and consequently pituitary adrenocorticotropin (ACTH) secretion. Additional modulation of the system is apparently achieved in limbic structures, especially the hippocampus, a structure that is linked to the hypothalamus through neuronal connections that converge on the paraventricular nucleus of the hypothalamus (PVN), where the stress responsive CRH and vasopressin (AVP) neurons reside (López et al., 1991).
There are several lines of evidence that highlight the importance of the hippocampus for LHPA feedback mechanisms (McEwen, 1991). Pioneer work by McEwen demonstrated that the hippocampus contains a high abundance of two types of glucocorticoid receptors which are thought to control negative feedback: Type I (also known as Mineralocorticoid Receptor, or "MR") and Type II (also known as Glucocorticoid receptors or "GR"). Type I (or MR) resembles the kidney mineralocorticoid receptor and has stringent specificity, binding selectively corticosterone, the main glucocorticoid of the rat. In the rodent brain, MR is most densely localized in hippocampal and septal neurons. Type II or GR receptors are widely distributed in rat brain, including hippocampus, hypothalamus, and prefrontal cortex. However, they bind corticosterone with a lower affinity compared to the Type I (or MR) receptor. Their highest affinity is for potent synthetic glucocorticoids, such as dexamethasone (McEwen, 1991). These receptor characteristics complement each other and put the MR and GR in a position to modulate LHPA responses (see DeKloet et al., 1998, for a recent excellent review on the neurobiology of GR and MR). The MR receptors appear to be operative at low corticosterone concentrations and may offer tonic inhibition to the axis during the nadir of the circadian rhythm (De Kloet et al., 1988; McEwen 1991). When high concentrations are present, MR receptors saturate, and the GR receptors ensure the return of homeostasis. As stated above, it is also well established that the hippocampus is a central component of limbic circuitry and is fundamental in controlling aspects of cognitive and behavioral functions, putting these receptors in a position to modulate simultaneously the neuroendocrine and cognitive response of the organism to stress.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis in Depression
Hyperactivity of the LHPA axis is a well documented phenomena in MDD. This dysregulation is manifested, among other things, by cortisol hypersecretion, failure to suppress cortisol secretion after dexamethasone administration, exaggerated adrenal responses to endocrine challenges, and blunted ACTH response to CRH administration (Carroll et al., 1976; Kalin et al., 1987; López et al., 1987; Gold et al., 1988; Kathol et al., 1989b). This last observation has been interpreted as evidence of pituitary downregulation of CRH receptors secondary to an increase in secretion of CRH. There is indeed good evidence of increased central drive, based on increased activity at the nadir of the circadian rhythm (Young et al., 1995) as well as more direct findings of elevated CRH in the CSF of depressed patients (Nemeroff et al., 1984), and increased CRH immunoreactivity and mRNA levels in the PVN (Raadsheer et al., 1994, 1995). Interestingly, post-mortem studies have also found evidence of chronic LHPA activation in suicide victims, such as adrenal hyperplasia (Dorovini-Zis and Zis, 1987), downregulation of CRH receptors (Nemeroff et al., 1988), and increases in proopiomelanocortin mRNA, the precursor for ACTH, in the pituitary (López et al., 1992). It is not known whether these LHPA changes in suicide are due to the fact that a significant subset of suicide victims are patients with depressive disorders, to the stress surrounding the suicide itself, or to a neurobiological "abnormality" common to all suicides irrespective of diagnosis.
We have found, in a group of suicide victims with a history of depression, decreases in hippocampal MR mRNA levels (López et al., 1998), and more recently, a decrease in GR mRNA levels in prefrontal cortex (unpublished observation) an area of the brain which is associated with higher cognitive, and executive function. We don't know whether these changes represent a genetic, or developmental, vulnerability "marker" for suicide, or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress and/or to high peripheral glucocorticoid levels (Herman and Watson, 1994; Herman et al., 1995).
Historically, the presence of LHPA overactivity in patients with depression was believed by many to be a "secondary" phenomena of the illness, reflecting either a central monoaminergic disturbance, the stress of the illness, or both. However, over the past few years, it has become clearer that the LHPA abnormalities in MDD are intimately linked to the pathohysiology of the disease. This change in perspective was stimulated in part by the increased awareness that glucocorticoids, the final products of the LHPA axis have been shown to have profound effects on mood and behavior (McEwen 1987). For example, a high incidence of depression is linked to pathologies involving elevated corticosteroid levels, such as Cushing's syndrome. This corticosteroid-induced depression usually disappears when corticosteroid levels return to normal (Kathol 1985; Murphy 1991). In fact, it has become increasingly clear, from both animal and clinical studies, that circulating glucocorticoid levels provide important hormonal control of affect, which may be mediated by steroid-induced modulation of central limbic circuitry (McEwen 1987). The precise mechanism by which corticosteroids exert this influence on affect is not well understood. However, this mechanism is likely to involve interactions with brain neurotransmitters, since we know that central control of affect is intimately associated with the actions of the monoamines serotonin, norepinephrine and dopamine.
Serotonin Receptors and Depression
The serotonin system has been widely investigated as a key element in the pathophysiology of Depression (Meltzer, 1989), and of suicide (Mann et al., 1989), and as a mediator of the therapeutic action of antidepressants (Berendsen, 1995). Although the 5-HT system has many components, the three 5-HT molecules believed to be most closely associated with the neurobiology of mood are the serotonin transporter (5-HTt), the serotonin 1a receptor (5-HT1a), and the serotonin 2a receptor (5-HT2a, formerly 5-HT2). Most new (as well as older) antidepressants inhibit the re-uptake of serotonin from the synapse, and alter 5-HTt protein and mRNA levels (López et al., 1994; Owens and Nemeroff, 1998). Animal studies have also demonstrated that chronic antidepressant administration affects the function and number of the 5-HT1a and 2a receptors. Many electrophysiological studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a function in the hippocampus, while at the same time they "down-regulate" or "desensitize" 5-HT1a function in the raphe, where it acts as an inhibitory somatodendritic receptor (Blier and de Montigny, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in hippocampus following antidepressant administration to rodents (Welner et al., 1989; Klimek et al., 1994). We have found that suicide victims with a history of depression have decreases in 5-HT1a gene expression in hippocampus (López et al., 1998). These changes are in the opposite direction of what is observed with antidepressant treatment in rat hippocampus.
The 5-HT2a receptor has also been shown to be affected by chronic antidepressant treatment. Most, but not all, studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic antidepressant administration (Peroutka and Snyder, 1980; Bourin and Baker, 1996). The opposite changes (5-HT2a upregulation) are found in the prefrontal cortex of suicide victims (Mann et al., 1986; Arango et al., 1990; Hrdina et al., 1993), although these findings are not universal (Stockmeier, 1997). In addition, subjects with a history of MDD dying of natural causes have increases in 5-HT2a binding in the prefrontal cortex (Yates et al., 1990).
These findings have led several investigators to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects (Schreiber and De Vry, 1993), that a disturbed balance of these receptors may be contributing to the pathophysiology of Depression (Berendsen, 1995), and that restoring this balance is necessary for antidepressant action (Borsini, 1994).
Interaction Between the LHPA axis and Serotonin
Another level of complexity is added by the fact that 5-HT and the LHPA axis interact at multiple levels. For example, it is known that some of the 5-HT neurons arising from the nucleus raphe dorsalis and nucleus raphe magnus project to the PVN and synapse onto CRH neurons (Fuller, 1992). 5-HT neurons also project to other brain areas, such as the amygdala and the suprachiasmatic nucleus, which are thought to modulate the function of the PVN (Törk, 1990). Pharmacological stimulation with 5-HT agents can activate ACTH and cortisol release (Fuller, 1992). Many brain areas that express 5-HT receptors also have abundant concentrations of corticosteroid receptors. In the limbic system in particular, the hippocampus has high concentrations of 5-HT1a in the same neurons that contain abundant GR and MR receptor levels, and the prefrontal cortex is rich in 5-HT2a receptors (Pazos and Palacios, 1987), as well as GR receptors.
Interestingly, unlike rodents, human prefrontal cortex also has significant amounts of MR mRNA. This constitutes anatomical evidence suggesting that MR may have a more expanded role in modulating brain function in humans than in rodents. Furthermore, the co-localization of MR and GR in prefrontal cortex suggest that both of these receptors are capable of modulating higher brain functions, such as mood, social behavior, and cognitive processing, perhaps by interacting with 5-HT receptors.
Serotonin and corticosteroid receptors not only interact anatomically, but also functionally. It has been reported that administration of serotonin can up-regulate GR in the hippocampus, and that conversely, pharmacological destruction of serotonergic projections decreases GR and MR mRNA levels in the hippocampus (Betitto et al., 1990; Seckl et al., 1990). Regulation in the other direction, i.e. glucocorticoid regulation of 5-HT receptors, has also been reported. Animal studies have demonstrated that adrenalectomy and corticosteroid administration powerfully regulate 5-HT1a receptor number and mRNA in the hippocampus (Chalmers et al., 1992, 1994; Kuroda et al., 1994). This effect of glucocorticoids seems to be specific for the postsynaptic 5-HT1a receptor, since the somatodendritic 5-HT1a is not affected by these manipulations (Chalmers et al., 1992).
The 5-HT2a receptor is also sensitive to changes in peripheral glucocorticoid levels. Upregulation of 5-HT2a in rat neocortex cortex has been reported following ten days of exogenous administration of ACTH (Kuroda et al., 1992). This effect is abolished by adrenalectomy and mimicked by corticosterone administration for ten days. Dexamethasone treatment for the same amount of time also causes a dose dependent increase in 5-HT2a binding in cortex (Kuroda et al., 1993), suggesting that this effect is mediated by GR, since dexamethasone is a potent GR agonist. Interestingly, the effect of corticosteroids on 5-HT2a receptor number seems to be specific for the cortex. Dexamethasone did not alter 5-HT2a binding in rat hippocampus. Given the relatively equal abundance of MR and GR in the hippocampus, and the preponderance of GR in rat frontal cortex, it is plausible that 5-HT receptor regulation in the cortex is mediated through different mechanisms than in the hippocampus.
Stress, Serotonin and the LHPA axis
In reviewing the clinical, psychological and biological literature on depressive illness, one factor that emerges as being closely associated with depression is stress. Stress and depression have been linked in a variety of ways: For example, both physical and psychological stressors have been shown to be temporally (and perhaps causally) related to the onset of depressive episodes (Post 1992). Some studies have suggested that, at least for recurrent depression, stressful life events are more common in "non-endogenous depression" (Frank et al., 1994). Other studies have found that stressful life events are significantly correlated even with the first episode of psychotic/endogenous depression (Brown et al., 1994). This is not to say that stress "causes" depression in people. Rather, stress is very likely interacting with an endogenous genetic predisposition, such that in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e. vulnerability + stress = depression). In fact, studies in twins by Kendler et al have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode: the more the genetic "loading" for depression, the more likely than a stressful event will trigger an episode. There are of course cases in which the genetic "loading" or predisposition is so high, that an episode of depression can occur in the absence of any apparent precipitating factors.
Another important link between depression and stress is the fact that both the LHPA and 5-HT systems, in addition to been involved in the pathophysiology of depression, are also, as we have discussed above, critical contributors to the neurobiology of stress (McEwen 1987) . Therefore, studying the neurobiology of stress by focusing on these two systems has given us important clues into the pathophysiology of affective illness, shed light on the actions of antidepressants, and begin to reveal how stress and mood disorders are related.
We have used chronic unpredictable stress, a postulated animal model of depression (Katz and Sibell, 1982; Armario et al., 1988) to investigate the parallel changes in 5-HT and LHPA related molecules, and to study how chronic stress and circulating glucocorticoids influence the 5-HT receptor system (López et al., 1997, 1998,1999b). In this paradigm, rats are exposed to different mild to moderate stressors everyday, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity, and increases in peripheral glucocorticoids, very similar to those found in MDD (Chapel et al., 1996; Armario et al., 1988). We found that rats subjected to this paradigm show a significant decrease in 5-HT1a mRNA and binding in the hippocampus, as well as decreases in MR mRNA levels in this same region (López et al., 1998). Chronic unpredictable stress also causes a significant increase in 5-HT2a receptor and mRNA levels in the prefrontal cortex (López et al, submitted). As stated above, these "opposite" effects (hippocampal 5-HT1a downregulation, cortical 5-HT2a upregulation) are also found in suicide victims with a history of depression (Mann et al., 1989; López et al., 1997). It is not clear if these 5-HT receptor changes are due to a direct effect of corticosteroids on the receptor themselves, or if they are secondary to corticosteroid induced changes in serotonin synthesis and turnover. However, the effects of chronic stress on these 5-HT receptors are prevented if the stress-related glucocorticoid increase is abolished. No changes are found in the presynaptic 5-HT transporter sites after chronic stress, suggesting that the effects are mainly in the postsynaptic receptors (López et al., 1997, 1998).
Antidepressant Medications, the LHPA Axis and 5-HT Receptors
The LHPA overactivity observed with chronic unpredictable stress can also be prevented by the chronic administration of either imipramine or desipramine, two tricyclic antidepressants (López et al., 1998). Both desipramine and imipramine also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in cortex. On the other hand, zimelidine and fluoxetine, two specific serotonin reuptake inhibitors, are unable to prevent the stress-induced elevation in corticosterone levels. This failure to prevent the LHPA overactivity is associated with a failure to restore the 5-HT receptor changes to baseline levels. This suggests that failure of an antidepressant to reverse the LHPA hypersecretion is associated with a failure to prevent the 5-HT receptor "dysregulation" secondary to chronic stress. We have proposed that this may be one of the neurobiological mechanisms underlying "treatment resistance" in patients with severe depression (López et al., 1997).
There is some clinical evidence that these mechanisms may be operating in depressive disorders. Persistence of hypercortisolemia after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome (Greden et al., 1983; Ribeiro et al., 1995). In addition, some clinical studies have found that tricyclics are more effective than SSRIs in the treatment of melancholia (Danish University Antidepressant Group, 1986, 1990; Roose et al., 1994), Venlafaxine, an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported to be more effective than fluoxetine in treating melancholic depression (Clerc et al., 1994), and in comorbid depression and anxiety (Silverstone et al., 1999). Since melancholia and severity of depression are associated with a higher incidence of hypercortisolemia (Kathol et al., 1989; Meador-Woodruff et al., 1990), it is possible that the presence of a severely disturbed LHPA axis in this population may be contributing to the relative resistance to SSRI treatment. Interestingly, many augmentation strategies in treatment resistant patients are in effect attempts to broaden the biochemical profile of the pharmacological treatment, which may be more effective in reversing LHPA overactivity than a treatment whose main impact is in a single neurotransmitter system.
Interplay Between Stress, the LHPA Axis, Serotonin, and Antidepressants
Based on the animal and human studies reviewed here, we can generate a working model of the interplay between stress, the LHPA axis, 5-HT receptors, and their potential interactions in suicide and depression. Figure 2 illustrates this model (solid arrows represent known effects, dashed arrows represent possible effects).
While it is possible that some monoamine receptor changes are due to antecedent changes in their endogenous ligands, we propose that many of the receptor changes observed may be a result of the LHPA overactivity present in at least some suicide victims, in particular those with a history of affective disorders. The rationale for this hypothesis derives from the above evidence, which can be summarized as follows:
1) Depressed patients, as well as suicide victims, show evidence of overactivity of the LHPA axis.
2) Chronic stress and/or high steroid levels in rats result in an alteration of specific 5-HT receptors (e.g. increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a).
3) Many human studies show the same receptor changes in the brain of suicide victims (increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a) as found in hypercorticoid states.
4) Chronic antidepressant administration causes opposite 5-HT receptor changes to those seen with chronic stress
5) Antidepressant administration reverses the overactivity of the LHPA axis.
If indeed the 5-HT1a and 5-HT2a receptors have at least a partial role in controlling affective states (either directly or secondarily through other systems), then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. This of course does not exclude the possibility that stress can be simultaneously acting through other systems, such as the CRH receptors, thereby synergistically affecting mood and behavior. Antidepressants can counteract this phenomenon by affecting 5-HT receptor function directly and by simultaneously regulating stress induced corticosteroid secretion.
Conclusion
Corticosteroid modulation of 5-HT receptors has important implications for the pathophysiology and treatment of mood disorders, and perhaps suicide. This may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and or precipitate suicidal behavior. Another implication is that altered 5-HT levels or metabolism do not necessarily have to be present for 5-HT receptor abnormalities to occur. Based on the animal data, it is apparent that specific 5-HT receptors may be directly regulated in response to alterations of corticosteroid levels. Thus, in depressed patients normal levels of serotonin and its metabolites may not necessarily reflect normal central 5-HT activity.
An important therapeutic implication of this model is the prediction that agents that can reduce the stress response, and/or decrease LHPA activation, will be useful in the pharmacological treatment of anxiety, depression and perhaps suicidal behavior. In fact, patients with MDD who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole (Murphy et al 1991; Wolkowitz et al 1993). However, these agents have many side effects, and are often difficult for patients to tolerate. In this respect, CRH receptor antagonists, which are currently under development, may provide us with a new therapeutic weapon to treat these patients (De Souza 1995, Chalmers et al., 1996). These compounds could be used in conjunction with antidepressants, as adjuvants or augmenting agents, and may decrease treatment resistance. This agents may also be useful in monotherapy, since preventing hypercortisolemia may be translated into an improvement of monoaminergic receptor function. The use of modern biochemical and pharmacological tools, coupled with our increased understanding of the neurobiology of depression, should allow us to test these hypotheses, first in animal models and then directly in patients with affective illness.
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Researched by:
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Juan F. López, M.D.
Department of Psychiatry and Mental Health Research Institute
University of Michigan, Ann Arbor
Introduction
Major Depressive Disorder (MDD), also known as Major Depression, is a psychiatric syndrome characterized by pervasive disturbances in mood, sleep, appetite, energy, motivation, hedonic capacity, and thinking. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), a depressive episode must be diagnosed if a patient has had depressed mood, or has lost interest or pleasure in most activities, for a duration of at least two weeks. However, depressive episodes often last months, sometimes years, and they carry a significant impairment in social and occupational functioning. Depressive episodes also tend to be recurrent, and if left untreated, most patients will have multiple episodes during their lifetime. The episodes tend to become more frequent, and/or more severe as the disease progresses (Post 1992). This is known as the "kindling" or "sensitization" hypothesis of mood disorders.
MDD is a common medical disorder, with a lifetime prevalence of 17.1%, and a 12 month prevalence of 10.3%, in the general population (Kessler et al., 1994). However, the prevalence of MDD in medical populations is even higher, with rates ranging from 30% to 50%, depending on the specific medical condition. This psychiatric disorder also carries a significant morbidity and mortality, with a negative impact not only for the patient itself, but also for the family, and for society in general. About two thirds of severely depressed patients exhibit suicidal ideation, and 10% to 15% commit suicide (Kaplan and Sadock, 1991).
The specific pathogenetic cause of depression is unknown, but it is widely accepted that its etiology, course, and long-term prognosis are influenced by genetic, environmental and neurobiological factors. A greater understanding of the neurobiology of this disorder is leading us to better treatment strategies that can prevent or decrease the impact of this disease. Although many neurotransmitters and neurohormones have been linked to the pathophysiolgy of depression, (e.g. norepinephrine, dopamine, thyroid hormones), research studies have implicated disturbances in the serotonin (5-HT) system and the Hypothalamic-Pituitary-Adrenal (HPA) axis as two of the neurobiological alterations most consistently associated with affective illness (Gold et al., 1988; Meltzer, 1988; Kathol et al., 1989; Nemeroff, 1998). Therefore, this presentation will focus on the regulation of these two systems, as they relate to depression.
Historically, the role of each of these two biological systems in mood disorders have been studied independently, but more recently, their interaction in the brain, as it relates to the pathophysiology of depression, has received increased attention. In this presentation, we will review recent animal and human findings, from the perspective of the 5-HT and HPA axis, which shed new light into the neurobiology of MDD. We will discuss some of the ways in which adrenal glucocorticoids and 5-HT receptors interact during conditions of chronic stress, or severe "allostatic load". We will also discuss what is the potential significance of these findings for the pathophysiology and treatment of mood disorders.
That disturbances in the Hypothalamic-Pituitary-Adrenal axis and in serotonin may share a common pathophysiological mechanism is not surprising, since we know from animal studies that they interact extensively and that they are related in a variety of ways (McEwen, 1987; Chalmers et al., 1993; López et al., 1999). The hippocampus, and the paraventricular nucleus of the hypothalamus (PVN), in particular, are anatomical regions in which components of the Hypothalamic-Pituitary-Adrenal axis and the 5-HT systems have a rich representation (see Figure 1 for an illustration of how serotonin neurons from the raphe nucleus project to the PVN and hippocampus). These regions are also part of the limbic system, an area implicated in the regulation of several vegetative functions (arousal, sleep, appetite and hedonic capacity) as well as in the control of mood. The hippocampus has also been implicated in memory and cognitive function. The recognition that the hippocampus is an integral component of the Hypothalamic-Pituitary-Adrenal axis has led some investigators (including our laboratory) to refer to this neuroendocrine system as the "Limbic"-Hypothalamic-Pituitary-Adrenal (LHPA) axis. We will therefore, for the purpose of this presentation, use the term "LHPA", instead of the more commonly used term "HPA", when referring to this system.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis and Stress
The LHPA is the classic neuroendocrine system that responds to stress. Perception of stress by an organism results in a series of events, the final result of which is the secretion of glucocorticoids (cortisol in humans, corticosterone in rats) from the adrenal cortex (Dallman et al., 1987). Activation and termination of the adrenocortical stress response is critical for adaptation and survival. Inhibition of stress responsiveness is partly achieved by the binding of circulating glucocorticoids to specific cytoplasmic receptors in hypothalamus, where they inhibit corticotropin releasing hormone (CRH) and consequently pituitary adrenocorticotropin (ACTH) secretion. Additional modulation of the system is apparently achieved in limbic structures, especially the hippocampus, a structure that is linked to the hypothalamus through neuronal connections that converge on the paraventricular nucleus of the hypothalamus (PVN), where the stress responsive CRH and vasopressin (AVP) neurons reside (López et al., 1991).
There are several lines of evidence that highlight the importance of the hippocampus for LHPA feedback mechanisms (McEwen, 1991). Pioneer work by McEwen demonstrated that the hippocampus contains a high abundance of two types of glucocorticoid receptors which are thought to control negative feedback: Type I (also known as Mineralocorticoid Receptor, or "MR") and Type II (also known as Glucocorticoid receptors or "GR"). Type I (or MR) resembles the kidney mineralocorticoid receptor and has stringent specificity, binding selectively corticosterone, the main glucocorticoid of the rat. In the rodent brain, MR is most densely localized in hippocampal and septal neurons. Type II or GR receptors are widely distributed in rat brain, including hippocampus, hypothalamus, and prefrontal cortex. However, they bind corticosterone with a lower affinity compared to the Type I (or MR) receptor. Their highest affinity is for potent synthetic glucocorticoids, such as dexamethasone (McEwen, 1991). These receptor characteristics complement each other and put the MR and GR in a position to modulate LHPA responses (see DeKloet et al., 1998, for a recent excellent review on the neurobiology of GR and MR). The MR receptors appear to be operative at low corticosterone concentrations and may offer tonic inhibition to the axis during the nadir of the circadian rhythm (De Kloet et al., 1988; McEwen 1991). When high concentrations are present, MR receptors saturate, and the GR receptors ensure the return of homeostasis. As stated above, it is also well established that the hippocampus is a central component of limbic circuitry and is fundamental in controlling aspects of cognitive and behavioral functions, putting these receptors in a position to modulate simultaneously the neuroendocrine and cognitive response of the organism to stress.
The Limbic-Hypothalamic-Pituitary-Adrenal Axis in Depression
Hyperactivity of the LHPA axis is a well documented phenomena in MDD. This dysregulation is manifested, among other things, by cortisol hypersecretion, failure to suppress cortisol secretion after dexamethasone administration, exaggerated adrenal responses to endocrine challenges, and blunted ACTH response to CRH administration (Carroll et al., 1976; Kalin et al., 1987; López et al., 1987; Gold et al., 1988; Kathol et al., 1989b). This last observation has been interpreted as evidence of pituitary downregulation of CRH receptors secondary to an increase in secretion of CRH. There is indeed good evidence of increased central drive, based on increased activity at the nadir of the circadian rhythm (Young et al., 1995) as well as more direct findings of elevated CRH in the CSF of depressed patients (Nemeroff et al., 1984), and increased CRH immunoreactivity and mRNA levels in the PVN (Raadsheer et al., 1994, 1995). Interestingly, post-mortem studies have also found evidence of chronic LHPA activation in suicide victims, such as adrenal hyperplasia (Dorovini-Zis and Zis, 1987), downregulation of CRH receptors (Nemeroff et al., 1988), and increases in proopiomelanocortin mRNA, the precursor for ACTH, in the pituitary (López et al., 1992). It is not known whether these LHPA changes in suicide are due to the fact that a significant subset of suicide victims are patients with depressive disorders, to the stress surrounding the suicide itself, or to a neurobiological "abnormality" common to all suicides irrespective of diagnosis.
We have found, in a group of suicide victims with a history of depression, decreases in hippocampal MR mRNA levels (López et al., 1998), and more recently, a decrease in GR mRNA levels in prefrontal cortex (unpublished observation) an area of the brain which is associated with higher cognitive, and executive function. We don't know whether these changes represent a genetic, or developmental, vulnerability "marker" for suicide, or for depression. Nevertheless, these findings are consistent with a history of exposure to chronic stress and/or to high peripheral glucocorticoid levels (Herman and Watson, 1994; Herman et al., 1995).
Historically, the presence of LHPA overactivity in patients with depression was believed by many to be a "secondary" phenomena of the illness, reflecting either a central monoaminergic disturbance, the stress of the illness, or both. However, over the past few years, it has become clearer that the LHPA abnormalities in MDD are intimately linked to the pathohysiology of the disease. This change in perspective was stimulated in part by the increased awareness that glucocorticoids, the final products of the LHPA axis have been shown to have profound effects on mood and behavior (McEwen 1987). For example, a high incidence of depression is linked to pathologies involving elevated corticosteroid levels, such as Cushing's syndrome. This corticosteroid-induced depression usually disappears when corticosteroid levels return to normal (Kathol 1985; Murphy 1991). In fact, it has become increasingly clear, from both animal and clinical studies, that circulating glucocorticoid levels provide important hormonal control of affect, which may be mediated by steroid-induced modulation of central limbic circuitry (McEwen 1987). The precise mechanism by which corticosteroids exert this influence on affect is not well understood. However, this mechanism is likely to involve interactions with brain neurotransmitters, since we know that central control of affect is intimately associated with the actions of the monoamines serotonin, norepinephrine and dopamine.
Serotonin Receptors and Depression
The serotonin system has been widely investigated as a key element in the pathophysiology of Depression (Meltzer, 1989), and of suicide (Mann et al., 1989), and as a mediator of the therapeutic action of antidepressants (Berendsen, 1995). Although the 5-HT system has many components, the three 5-HT molecules believed to be most closely associated with the neurobiology of mood are the serotonin transporter (5-HTt), the serotonin 1a receptor (5-HT1a), and the serotonin 2a receptor (5-HT2a, formerly 5-HT2). Most new (as well as older) antidepressants inhibit the re-uptake of serotonin from the synapse, and alter 5-HTt protein and mRNA levels (López et al., 1994; Owens and Nemeroff, 1998). Animal studies have also demonstrated that chronic antidepressant administration affects the function and number of the 5-HT1a and 2a receptors. Many electrophysiological studies have shown that antidepressants "upregulate" or "sensitize" 5-HT1a function in the hippocampus, while at the same time they "down-regulate" or "desensitize" 5-HT1a function in the raphe, where it acts as an inhibitory somatodendritic receptor (Blier and de Montigny, 1994). Some studies have also reported a modest increase in 5-HT1a receptor number in hippocampus following antidepressant administration to rodents (Welner et al., 1989; Klimek et al., 1994). We have found that suicide victims with a history of depression have decreases in 5-HT1a gene expression in hippocampus (López et al., 1998). These changes are in the opposite direction of what is observed with antidepressant treatment in rat hippocampus.
The 5-HT2a receptor has also been shown to be affected by chronic antidepressant treatment. Most, but not all, studies have reported decreases in 5-HT2a binding in the prefrontal cortex after chronic antidepressant administration (Peroutka and Snyder, 1980; Bourin and Baker, 1996). The opposite changes (5-HT2a upregulation) are found in the prefrontal cortex of suicide victims (Mann et al., 1986; Arango et al., 1990; Hrdina et al., 1993), although these findings are not universal (Stockmeier, 1997). In addition, subjects with a history of MDD dying of natural causes have increases in 5-HT2a binding in the prefrontal cortex (Yates et al., 1990).
These findings have led several investigators to propose that postsynaptic 5-HT1a and 5-HT2a receptors have functionally opposing effects (Schreiber and De Vry, 1993), that a disturbed balance of these receptors may be contributing to the pathophysiology of Depression (Berendsen, 1995), and that restoring this balance is necessary for antidepressant action (Borsini, 1994).
Interaction Between the LHPA axis and Serotonin
Another level of complexity is added by the fact that 5-HT and the LHPA axis interact at multiple levels. For example, it is known that some of the 5-HT neurons arising from the nucleus raphe dorsalis and nucleus raphe magnus project to the PVN and synapse onto CRH neurons (Fuller, 1992). 5-HT neurons also project to other brain areas, such as the amygdala and the suprachiasmatic nucleus, which are thought to modulate the function of the PVN (Törk, 1990). Pharmacological stimulation with 5-HT agents can activate ACTH and cortisol release (Fuller, 1992). Many brain areas that express 5-HT receptors also have abundant concentrations of corticosteroid receptors. In the limbic system in particular, the hippocampus has high concentrations of 5-HT1a in the same neurons that contain abundant GR and MR receptor levels, and the prefrontal cortex is rich in 5-HT2a receptors (Pazos and Palacios, 1987), as well as GR receptors.
Interestingly, unlike rodents, human prefrontal cortex also has significant amounts of MR mRNA. This constitutes anatomical evidence suggesting that MR may have a more expanded role in modulating brain function in humans than in rodents. Furthermore, the co-localization of MR and GR in prefrontal cortex suggest that both of these receptors are capable of modulating higher brain functions, such as mood, social behavior, and cognitive processing, perhaps by interacting with 5-HT receptors.
Serotonin and corticosteroid receptors not only interact anatomically, but also functionally. It has been reported that administration of serotonin can up-regulate GR in the hippocampus, and that conversely, pharmacological destruction of serotonergic projections decreases GR and MR mRNA levels in the hippocampus (Betitto et al., 1990; Seckl et al., 1990). Regulation in the other direction, i.e. glucocorticoid regulation of 5-HT receptors, has also been reported. Animal studies have demonstrated that adrenalectomy and corticosteroid administration powerfully regulate 5-HT1a receptor number and mRNA in the hippocampus (Chalmers et al., 1992, 1994; Kuroda et al., 1994). This effect of glucocorticoids seems to be specific for the postsynaptic 5-HT1a receptor, since the somatodendritic 5-HT1a is not affected by these manipulations (Chalmers et al., 1992).
The 5-HT2a receptor is also sensitive to changes in peripheral glucocorticoid levels. Upregulation of 5-HT2a in rat neocortex cortex has been reported following ten days of exogenous administration of ACTH (Kuroda et al., 1992). This effect is abolished by adrenalectomy and mimicked by corticosterone administration for ten days. Dexamethasone treatment for the same amount of time also causes a dose dependent increase in 5-HT2a binding in cortex (Kuroda et al., 1993), suggesting that this effect is mediated by GR, since dexamethasone is a potent GR agonist. Interestingly, the effect of corticosteroids on 5-HT2a receptor number seems to be specific for the cortex. Dexamethasone did not alter 5-HT2a binding in rat hippocampus. Given the relatively equal abundance of MR and GR in the hippocampus, and the preponderance of GR in rat frontal cortex, it is plausible that 5-HT receptor regulation in the cortex is mediated through different mechanisms than in the hippocampus.
Stress, Serotonin and the LHPA axis
In reviewing the clinical, psychological and biological literature on depressive illness, one factor that emerges as being closely associated with depression is stress. Stress and depression have been linked in a variety of ways: For example, both physical and psychological stressors have been shown to be temporally (and perhaps causally) related to the onset of depressive episodes (Post 1992). Some studies have suggested that, at least for recurrent depression, stressful life events are more common in "non-endogenous depression" (Frank et al., 1994). Other studies have found that stressful life events are significantly correlated even with the first episode of psychotic/endogenous depression (Brown et al., 1994). This is not to say that stress "causes" depression in people. Rather, stress is very likely interacting with an endogenous genetic predisposition, such that in some vulnerable individuals, a stressor can precipitate a mood disorder (i.e. vulnerability + stress = depression). In fact, studies in twins by Kendler et al have demonstrated a clear interaction between genetic substrate and a recent stressful life event in the precipitation of a depressive episode: the more the genetic "loading" for depression, the more likely than a stressful event will trigger an episode. There are of course cases in which the genetic "loading" or predisposition is so high, that an episode of depression can occur in the absence of any apparent precipitating factors.
Another important link between depression and stress is the fact that both the LHPA and 5-HT systems, in addition to been involved in the pathophysiology of depression, are also, as we have discussed above, critical contributors to the neurobiology of stress (McEwen 1987) . Therefore, studying the neurobiology of stress by focusing on these two systems has given us important clues into the pathophysiology of affective illness, shed light on the actions of antidepressants, and begin to reveal how stress and mood disorders are related.
We have used chronic unpredictable stress, a postulated animal model of depression (Katz and Sibell, 1982; Armario et al., 1988) to investigate the parallel changes in 5-HT and LHPA related molecules, and to study how chronic stress and circulating glucocorticoids influence the 5-HT receptor system (López et al., 1997, 1998,1999b). In this paradigm, rats are exposed to different mild to moderate stressors everyday, therefore making the stress "unpredictable" from day to day. Rats that undergo this treatment show LHPA overactivity, and increases in peripheral glucocorticoids, very similar to those found in MDD (Chapel et al., 1996; Armario et al., 1988). We found that rats subjected to this paradigm show a significant decrease in 5-HT1a mRNA and binding in the hippocampus, as well as decreases in MR mRNA levels in this same region (López et al., 1998). Chronic unpredictable stress also causes a significant increase in 5-HT2a receptor and mRNA levels in the prefrontal cortex (López et al, submitted). As stated above, these "opposite" effects (hippocampal 5-HT1a downregulation, cortical 5-HT2a upregulation) are also found in suicide victims with a history of depression (Mann et al., 1989; López et al., 1997). It is not clear if these 5-HT receptor changes are due to a direct effect of corticosteroids on the receptor themselves, or if they are secondary to corticosteroid induced changes in serotonin synthesis and turnover. However, the effects of chronic stress on these 5-HT receptors are prevented if the stress-related glucocorticoid increase is abolished. No changes are found in the presynaptic 5-HT transporter sites after chronic stress, suggesting that the effects are mainly in the postsynaptic receptors (López et al., 1997, 1998).
Antidepressant Medications, the LHPA Axis and 5-HT Receptors
The LHPA overactivity observed with chronic unpredictable stress can also be prevented by the chronic administration of either imipramine or desipramine, two tricyclic antidepressants (López et al., 1998). Both desipramine and imipramine also reverse the stress induced downregulation of 5-HT1a in hippocampus, and the 5-HT2a upregulation in cortex. On the other hand, zimelidine and fluoxetine, two specific serotonin reuptake inhibitors, are unable to prevent the stress-induced elevation in corticosterone levels. This failure to prevent the LHPA overactivity is associated with a failure to restore the 5-HT receptor changes to baseline levels. This suggests that failure of an antidepressant to reverse the LHPA hypersecretion is associated with a failure to prevent the 5-HT receptor "dysregulation" secondary to chronic stress. We have proposed that this may be one of the neurobiological mechanisms underlying "treatment resistance" in patients with severe depression (López et al., 1997).
There is some clinical evidence that these mechanisms may be operating in depressive disorders. Persistence of hypercortisolemia after antidepressant administration in depressed patients has been associated with relapse and poorer treatment outcome (Greden et al., 1983; Ribeiro et al., 1995). In addition, some clinical studies have found that tricyclics are more effective than SSRIs in the treatment of melancholia (Danish University Antidepressant Group, 1986, 1990; Roose et al., 1994), Venlafaxine, an antidepressant with both norepinephrine and 5-HT reuptake activity, was reported to be more effective than fluoxetine in treating melancholic depression (Clerc et al., 1994), and in comorbid depression and anxiety (Silverstone et al., 1999). Since melancholia and severity of depression are associated with a higher incidence of hypercortisolemia (Kathol et al., 1989; Meador-Woodruff et al., 1990), it is possible that the presence of a severely disturbed LHPA axis in this population may be contributing to the relative resistance to SSRI treatment. Interestingly, many augmentation strategies in treatment resistant patients are in effect attempts to broaden the biochemical profile of the pharmacological treatment, which may be more effective in reversing LHPA overactivity than a treatment whose main impact is in a single neurotransmitter system.
Interplay Between Stress, the LHPA Axis, Serotonin, and Antidepressants
Based on the animal and human studies reviewed here, we can generate a working model of the interplay between stress, the LHPA axis, 5-HT receptors, and their potential interactions in suicide and depression. Figure 2 illustrates this model (solid arrows represent known effects, dashed arrows represent possible effects).
While it is possible that some monoamine receptor changes are due to antecedent changes in their endogenous ligands, we propose that many of the receptor changes observed may be a result of the LHPA overactivity present in at least some suicide victims, in particular those with a history of affective disorders. The rationale for this hypothesis derives from the above evidence, which can be summarized as follows:
1) Depressed patients, as well as suicide victims, show evidence of overactivity of the LHPA axis.
2) Chronic stress and/or high steroid levels in rats result in an alteration of specific 5-HT receptors (e.g. increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a).
3) Many human studies show the same receptor changes in the brain of suicide victims (increases in cortical 5-HT2a, decreases in hippocampal 5-HT1a) as found in hypercorticoid states.
4) Chronic antidepressant administration causes opposite 5-HT receptor changes to those seen with chronic stress
5) Antidepressant administration reverses the overactivity of the LHPA axis.
If indeed the 5-HT1a and 5-HT2a receptors have at least a partial role in controlling affective states (either directly or secondarily through other systems), then their modulation by corticosteroids provides a potential mechanism by which these hormones may regulate mood. This of course does not exclude the possibility that stress can be simultaneously acting through other systems, such as the CRH receptors, thereby synergistically affecting mood and behavior. Antidepressants can counteract this phenomenon by affecting 5-HT receptor function directly and by simultaneously regulating stress induced corticosteroid secretion.
Conclusion
Corticosteroid modulation of 5-HT receptors has important implications for the pathophysiology and treatment of mood disorders, and perhaps suicide. This may be one of the mechanisms by which stressful events can precipitate depressive episodes in some (genetically) vulnerable individuals and or precipitate suicidal behavior. Another implication is that altered 5-HT levels or metabolism do not necessarily have to be present for 5-HT receptor abnormalities to occur. Based on the animal data, it is apparent that specific 5-HT receptors may be directly regulated in response to alterations of corticosteroid levels. Thus, in depressed patients normal levels of serotonin and its metabolites may not necessarily reflect normal central 5-HT activity.
An important therapeutic implication of this model is the prediction that agents that can reduce the stress response, and/or decrease LHPA activation, will be useful in the pharmacological treatment of anxiety, depression and perhaps suicidal behavior. In fact, patients with MDD who are resistant to antidepressant treatment, have been reported to improve after receiving steroid suppression agents, like ketoconazole (Murphy et al 1991; Wolkowitz et al 1993). However, these agents have many side effects, and are often difficult for patients to tolerate. In this respect, CRH receptor antagonists, which are currently under development, may provide us with a new therapeutic weapon to treat these patients (De Souza 1995, Chalmers et al., 1996). These compounds could be used in conjunction with antidepressants, as adjuvants or augmenting agents, and may decrease treatment resistance. This agents may also be useful in monotherapy, since preventing hypercortisolemia may be translated into an improvement of monoaminergic receptor function. The use of modern biochemical and pharmacological tools, coupled with our increased understanding of the neurobiology of depression, should allow us to test these hypotheses, first in animal models and then directly in patients with affective illness.
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Fuller, R. W., 1992. The involvement of serotonin in regulation of pituitary-adrenocortical function. Front Neuroendocrinol 13: 250-270.
Gold PW, Goodwin FK, Chrousos GP, 1988. Clinical and biochemical manifestations of depression. Relation to the neurobiology of stress (second of two parts). N. Eng. J. Med. 319:413-420.
Greden, J. F., Gardner, R., King, D., Grunhaus, L., Carroll, B. J.,Kronfol, Z., 1983. Dexamethasone suppression tets in antidepressant treatment of melancholia. Arch Gen Psychiatry 40: 493-500.
Herman, J. P.,Watson, S. J., 1994. Glucocorticoid regulation of stress-induced mineralocorticoid receptor gene transcription in vivo. Ann NY Acad Sci 746: 485-488.
Herman, J. P.,Watson, S. J., 1995. Stress regulation of mineralocorticoid receptor heteronuclear RNA in rat hippocampus. Brain Res 677: 243-249.
Hrdina, P. D., Demeter, E., Vu, T. B., Sotonyi, P.,Palkovits, M., 1993. 5-HT uptake sites and 5-HT2 receptors in brain of antidepressant-free suicide victims/depressives: Increase in 5-HT2 sites in cortex and amygdala. Brain Res. 614: 37-44.
Kalin, N. H., Dawson, G., Tariot, P., Shelton, S., Barksdale, C., Weiler, S.,Thienemann, M., 1987. Function of the adrenal cortex in patients with major depression. Psy Res 22: 117-125.
Kaplan HC, Sadock BJ, 1991. Comprehensive Textbook of Psychiatry, Fifth Edition. Baltimore, Md: Williams & Wilkins.
Kathol RG, 1985. Etiologic implications of corticosteroid changes in affective disorder. Psychiatr Med 3:135-155.
Kathol RG, Jaeckel RS, Lopez JF, Meller WH, 1989. Pathophysiology of HPA axis abnormalities in patients with major depression: an update. Am J Psychiatry 146:311-317.
Katz, R. J.,Sibel, M., 1982. Further analysis of the specificity of a novel animal model of depression-- effects of an antihistaminic, antipsychotic and anxiolytic compound. Pharmacology of Biochemical Behavior 16: 979-982.
Kendler KS, Kessler RC, Neale MC, Heath AC, Eaves LJ, 1993. The prediction of major depression in women: toward an integrated etiological model. Am J. Psychiatry 150:1139-1148.
Kessler RC. McGonagle KA. Zhao S. Nelson CB. Hughes M. Eshleman S. Wittchen HU. Kendler KS., 1994. Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey. Arch Gene Psychiatry. 51:8-19.
Klimek, V., Zak-Knapik, J.,Mackowiak, M., 1994. Effects of repeated treatment with fluoxetine and citalopram, 5-HT uptake inhibitors, on 5-HT1A and 5-HT2 receptors in the rat brain. J Psy Neuroscience 19: 63-70.
Kuroda, Y., Mikuni, M., Ogawa, T.,Takahashi, K., 1992. Effect of ACTH, adrenalectomy and the combination treatment on the density of 5-HT2 receptor binding sites in neocortex of rat forebrain and 5-HT2 receptor-mediated wet-dog shake behaviors. n: Psychopharmacology (Berl) (1992) 108(1-2):27-32 108: 27-32.
Kuroda, Y., Mikuni, M., Nomura, N.,Takahashi, K., 1993. Differential effect of subchronic dexamethasone treatment on serotonin-2 and beta-adrenergic receptors in the rat cerebral cortex and hippocampus. Neurosci Lett 155: 195-198.
Kuroda, Y., Watanabe, Y., Albeck, D. S., Hastings, N. B.,McEwen, B. S., 1994. Effects of adrenalectomy and type I or type II glucocorticoid receptor activation on 5-HT1A and 5-HT2 receptor binding and 5-HT transporter mRNA expression in rat brain. Brain Res 648: 157-161.
López, J. F., Kathol, R. G., Jaeckle, R. S.,Meller, W. M., 1987. The HPA response to insulin hypoglycemia in depression. Biol Psychiatry 22: 153-166.
López, J. F., Young, E. A., Herman, J. P., Akil, H.,Watson, S. J., 1991. The Regulatory Biology of the HPA axis: An Integrative Approach. In : Central Nervous System peptide mechanisms in stress and depression. S. Risch. Washington D.C., American Psychiatric Press, Inc. 30: 1-52.
López, J. F., Palkovits, M., Arato, M., Mansour, A., AKil, H.,Watson, S. J., 1992. Localization and quantification of pro-opiomelanocortin mRNA and glucocorticoid receptor mRNA in pitutiaries of suicide victims. Neuroendocrinology 56: 491-501.
López, J. F., Chalmers, D. T., Vázquez, D. M., Watson, S. J.,Akil, H., 1994. Serotonin transporter mRNA in rat brain is regulated by classical antidepressants. Biol. Psychiatry 35: 287-290.
López, J. F., Chalmers, D., Little, K. Y.,Watson, S. J., 1998. Regulation of 5HT1a receptor, glucocorticoid and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression. Biol Psychiatry 43: 547-573.
López, J. F., Liberzon, I., Vázquez, D. M., Young, E. A.,Watson, S. J., 1999a. Serotonin 1a receptor mRNA regulation in the hippocampus after acute stress. Biological Psychiatry 45: 943-947.
López, J. F., Akil, H.,Watson, S. J., 1999b. Neural circuits mediating stress and anxiety. Biological Psychiatry (In press).
Mann JJ, Arango V, Marzuk PM, Theccanat S, Reis DJ, 1989. Evidence for the 5-HT hypothesis of suicide: A review of post-mortem studies. Br J Psychiatry 155:7-14.
McEwen BS, 1987. Glucocorticoid-biogenic amine interactions in relation to mood and behavior. Biochemical Pharmacology 36:1755-1763.
McEwen BS, 1991. Stress and hippocampus. An update on current knowledge. Presse Med. 20:1801-1806.
Meador-Woodruff, J., Greden, J. F., Grunhaus, L.,Haskett, R. F., 1990. Severity of depression and hypothalamic-pituitary-adrenal axis dysregulation: identification of contributing factors. Acta Psychiatrica Scandinavica 81: 364-371.
Melzter H, 1989. Serotonergic dysfunction in depression. Br J Psychiatry 155:25-31.
Murphy BEP, Dhar V, Ghadirian AM, Chouinard G, Keller R, 1991. Response to steroid suppression in major depression resistant to antidepressant therapy. J Clinl Psychopharmacol 11:121-126.
Murphy BEP, 1991. Steroids and Depression. J Steroid Biochem 38:537-559.
Nemeroff, C. B., Widerlov, E., Bisette, G., Walleus, H., Karlsson, I., Eklund, K., Kilts, C., Loosen, P. T.,Vale, W., 1984. Elevated concentrations of CSF corticoptropin-releasing-factor-like immunoreactivity in depressed patients. Science 226: 1342-1344.
Nemeroff, C. B., Owens, M. J., Bissette, G., Andorn, A. C.,Stanley, M., 1988. Reduced corticotropin releasing factor binding sites in the frontal cortex of suicide victims. Arch Gen Psychiatry 45: 577-579.
Nemeroff, C. B., 1998. The neurobiology of depression. Sci Am 278: 42-49.
Owens, M. J.,Nemeroff, C. B., 1998. The serotonin transporter and depression. Depression & Anxiety 8 Suppl 1: 5-12.
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Post RM. 1992. Transduction of psychosocial stress into the neurobiology of recurrent affective disorder. Am J Psychiatry 149:999-1010.
Raadsheer, F. C., Hoogendijk, W. J., Stam, F. C., Tilders, F. J.,Swaab, D. F., 1994. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60: 436-444.
Raadsheer, F. C., van Heerikhuize, J. J., Lucassen, P. J., Hoogendijk, W. J., Tilders, F. J.,Swaab, D. F., 1995. Corticotropin-releasing hormone mRNA levels in the paraventricular nucleus of patients with Alzheimer's disease and depression. Am J Psychiatry 152: 1372-1376.
Ribeiro, S. C., Tandon, R., Grunhaus, L.,Greden, J. F., 1995. The DST as a predictor of outcome in depression: a meta-analysis. Am J Psychiatry 152: 1618-1629.
Roose, S. P., Glassman, A. H., Attia, E.,Woodring, S., 1994. Comparative efficacy of selective serotonin reuptake inhibitors and tricyclics in the treatment of melancholia. Am J Psychiatry 151: 1735-1739.
Seckl, J. R., Dickson, K. L.,Fink, G., 1990. Central 5,7-dihydroxytryptamine lesions decrease hippocampal glucorticoid and mineralocorticoid receptor messenger ribonucleic acid expression. Journal of Neuroendocrinology 2: 911-916.
Silverstone, P. H.,Ravindran, A., 1999. Once-daily venlafaxine extended release compared with fluoxetine in outpatients with depression and anxiety. J Clin Psychiatry 60: 22-28.
Stockmeier, C., 1997. Neurobiology of Serotonin in Depression and Suicide. Ann. N.Y. Acad. Sci. 836: 220-232.
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Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine L, Weingartner H, 1993. Ketoconazole administration in hypercortisolemic depression. Am J Psychiatry 150:810-812.
Yates, M., Leake, A., Candy, J. M., Fairbairn, A. F., McKeith, I. G.,Ferrier, I. N., 1990. 5HT2 receptor changes in major depression. Biol. Psychiatry 27: 489-496.
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Researched by:
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---------
http://www.melaleuca.info
Call 1-866-451-8715
Tuesday, May 7, 2013
Hoxsey Cancer Treatment
Hoxsey Cancer Treatment
Hoxsey Cancer Clinic
Founded by Harry Hoxsey
http://m.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/HerbsVitaminsandMinerals/hoxsey-herbal-treatment
Treatment:
Hoxsey herbal treatments include a topical paste of antimony, zinc and bloodroot, arsenic, sulfur, and talc for external treatments, and a liquid tonic of licorice, red clover, burdock root, Stillingia root, barberry, Cascara, prickly ash bark, buckthorn bark, and potassium iodide for internal consumption.
In addition to the herbs, the Hoxsey treatment now also includes antiseptic douches and washes, laxative tablets, and nutritional supplements. A mixture of procaine hydrochloride and vitamins, along with liver and cactus, is prescribed. During treatment, patients are asked to avoid consumption of tomatoes, vinegar, pork, alcohol, salt, sugar, and white flour products.
In 2005, the cost of initial evaluation and treatment with Hoxsey Therapy at the Bio-Medical Center in Tijuana, Mexico was reported to be between $3,900 and $5,100, though this price did not include the recommended purchase of an unspecified number of dietary supplements and 3 years of return visits.
Nine herbs:
Red Clover Blossom
Burdock Root
Poke Root (Potent)
Barberry Bark
Prickly Ash Bark
Barbarine
Super Ways That Super Foods Can Bring Super Health
http://iwitness5.html21.hop.clickbank.net/ #SuperFoods
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not meant to replace medical advice from a doctor.
Hoxsey Cancer Clinic
Founded by Harry Hoxsey
http://m.cancer.org/Treatment/TreatmentsandSideEffects/ComplementaryandAlternativeMedicine/HerbsVitaminsandMinerals/hoxsey-herbal-treatment
Treatment:
Hoxsey herbal treatments include a topical paste of antimony, zinc and bloodroot, arsenic, sulfur, and talc for external treatments, and a liquid tonic of licorice, red clover, burdock root, Stillingia root, barberry, Cascara, prickly ash bark, buckthorn bark, and potassium iodide for internal consumption.
In addition to the herbs, the Hoxsey treatment now also includes antiseptic douches and washes, laxative tablets, and nutritional supplements. A mixture of procaine hydrochloride and vitamins, along with liver and cactus, is prescribed. During treatment, patients are asked to avoid consumption of tomatoes, vinegar, pork, alcohol, salt, sugar, and white flour products.
In 2005, the cost of initial evaluation and treatment with Hoxsey Therapy at the Bio-Medical Center in Tijuana, Mexico was reported to be between $3,900 and $5,100, though this price did not include the recommended purchase of an unspecified number of dietary supplements and 3 years of return visits.
Nine herbs:
Red Clover Blossom
Burdock Root
Poke Root (Potent)
Barberry Bark
Prickly Ash Bark
Barbarine
Super Ways That Super Foods Can Bring Super Health
http://iwitness5.html21.hop.clickbank.net/ #SuperFoods
Researched by
@mannaglide
http://MannaGoods.blogspot.com
-----
This information is not meant to replace medical advice from a doctor.
Saturday, May 4, 2013
Heart Bypass Complications
Heart Bypass Complications
Coronary artery bypass surgery is usually reserved for patients with multiple sites of disease in their coronary arteries. Patients with diabetes and poor heart function may do better with bypass surgery than with angioplasty, according to MayoClinic.com. Heart bypass surgery requires the surgeon to use pieces of vein from the legs or other extremities and place them on the heart to bypass the blocked vessels. Sometimes the surgeon uses the internal mammary artery for bypass as well. This major surgery does have potential complications.
According to the Mayo Clinic, complications are rare following heart bypass surgery. The most common problems are stroke, bleeding, irregular heart rhythm (arrhythmias), kidney failure, memory loss that can persist for six months to a year, and infections of the chest wound.
Fact is, bypassed arteries may be blocked again but not for another ten to fifteen years and depending on the patient’s lifestyle after the surgery.
Here are the reported serious as well as mild complications of the surgery, either triple bypass surgery or quadruple bypass surgery. The injection of general anaesthesia on the patient could lead to serious problems like state of shock and heart collapse. It would take time to revive the heart and may be fatal to the patient. The mild allergic reactions of the patient are nausea and vomiting.
Another risky complication during the surgery is the bleeding of the organs near the heart or the heart itself. It would imply great loss of blood from the patient and would require bags of blood to transfuse and replace the loss. The patient must be prepared with bags of blood with the same blood type ahead of time. Blood clotting may also take place during the surgery. There is a machine called heart- lung bypass that assists the surgeon to keep the blood from the heart to divert the flow through the machine.
Memory loss is another mild complication after the surgery. The lack of sleep and narcotics injected cause confusion and memory loss. Often times, this will only last for a few days and soon after the patient will regain his memory again.
Lastly, the worst surgery complication is infection. The infection may start from the incised area of the chest and getting vast penetration inside. It may reach the immediate organ involved in the surgery which is the heart. Infection may affect other organs like the lungs and the bladder. If it affects the lungs it may lead to pneumonia and the bladder infection may lead to cystitis. Infection could also travel through the bloodstream that may lead to sepsis.
It must be countered with strong and costly antibiotics given to the patient through intravenous fluids. The vial is injected directly to the intravenous fluid that penetrates the veins of the patient. The patient who has acquired sepsis stays at the hospital for few weeks to have the infection fully reversed. Sepsis is a fatal infection if left untreated.
The presence of other illness lengthens the recovery period of the patient. The span of recovery varies from case to case. Some may undergo cardiac rehabilitation for few weeks after the surgery while others may be physically well after few weeks of suffering from pain after the surgery. Some may still be sensitive in the coldness of the weather for few months, which will constantly cause chest pain. A recovery period varies from two months until a year. It is when their hearts have fully recovered that they can go back to their daily routine without any hassles for the heart. But there are some who may not recover from the surgery and adds to the fatality rate.
STERNAL INFECTION:
In order to access the heart, traditionally an incision is made from the top of the chest bone--the sternum--to the bottom.Then it is necessary to saw the sternum open. If the internal mammary artery will be used for a bypass, it is dissected away from the chest wall to use as a new vessel for the heart. Disrupting this blood flow to the chest wall, and the trauma that occurs during opening of the chest, can result in an infection of the chest bone and surrounding tissues. This complication can be devastating and result in the removal of the sternum if long-term antibiotics fail. Sternal infection is a rare complication but potentially life-threatening.
BLEEDING:
The cardiopulmonary bypass machine,also known as the CPM or the heart-lung machine, is used to maintain circulation to the body while the heart is stopped during the procedure. This machine takes the patient's blood through a system of tubes placed in the aorta and right atrium and cleans the toxins and oxygenates the blood. The blood is subsequently returned to the patient. Use of this machine can create bleeding because as the blood passes through the machine, it is diluted with extra fluids, thereby diluting the necessary clotting factors. In addition, the platelets, which are also necessary for clotting, can become damaged as they pass through the CPM. Finally, heparin, a blood thinner, is used to prevent the blood from clotting while passing through the tubing, but this can also lead to undesired bleeding later.
ARRHYTHMIAS:
The significant handling of the heart during surgery can affect the conduction system of the heart. About 15 to 40 percent of patients will have atrial fibrillation about two to three days after surgery, states the Merck Manual. Nonsustained ventricular tachycardia, a fast, chaotic, heart rhythm, is seen in about 50 percent of patients. This rhythm can quickly switch to a sustained ventricluar tachycardia and become life-threatening. About 1 percent of patients will have a heart attack after the operation.
ORGAN FAILURE:
The blood reacts to the tubing of the CPM by releasing special proteins called cytokines into the blood. These cytokines are responsible for creating a system-wide inflammatory response. Cytokines travel in the bloodstream and when they pass through the organs, they can cause organ damage or failure. Cytokines can cause the lungs to react with acute respiratory distress syndrome or cause kidney failure.
REFERENCES:
MayoClinic.com: Coronary Artery Disease: Angioplasty or Bypass Surgery?
BMC: Superficial and Deep Sternal Wound Infection after more than 9000 coronary artery bypass grafts, incidence, risk factors and mortality. Abbas Salehi Omran, MD and et.al. BMC Infectious Disease. 2007
The Merck Manual Online Medical Library.com: Coronary Artery Bypass Grafting (CABG)
Sage Journals Online: Understanding Cytokines Part I: Physiology and Mechanism of Action.
MedlinePlus: Acute Respiratory Distress Syndrome
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
Coronary artery bypass surgery is usually reserved for patients with multiple sites of disease in their coronary arteries. Patients with diabetes and poor heart function may do better with bypass surgery than with angioplasty, according to MayoClinic.com. Heart bypass surgery requires the surgeon to use pieces of vein from the legs or other extremities and place them on the heart to bypass the blocked vessels. Sometimes the surgeon uses the internal mammary artery for bypass as well. This major surgery does have potential complications.
According to the Mayo Clinic, complications are rare following heart bypass surgery. The most common problems are stroke, bleeding, irregular heart rhythm (arrhythmias), kidney failure, memory loss that can persist for six months to a year, and infections of the chest wound.
Fact is, bypassed arteries may be blocked again but not for another ten to fifteen years and depending on the patient’s lifestyle after the surgery.
Here are the reported serious as well as mild complications of the surgery, either triple bypass surgery or quadruple bypass surgery. The injection of general anaesthesia on the patient could lead to serious problems like state of shock and heart collapse. It would take time to revive the heart and may be fatal to the patient. The mild allergic reactions of the patient are nausea and vomiting.
Another risky complication during the surgery is the bleeding of the organs near the heart or the heart itself. It would imply great loss of blood from the patient and would require bags of blood to transfuse and replace the loss. The patient must be prepared with bags of blood with the same blood type ahead of time. Blood clotting may also take place during the surgery. There is a machine called heart- lung bypass that assists the surgeon to keep the blood from the heart to divert the flow through the machine.
Memory loss is another mild complication after the surgery. The lack of sleep and narcotics injected cause confusion and memory loss. Often times, this will only last for a few days and soon after the patient will regain his memory again.
Lastly, the worst surgery complication is infection. The infection may start from the incised area of the chest and getting vast penetration inside. It may reach the immediate organ involved in the surgery which is the heart. Infection may affect other organs like the lungs and the bladder. If it affects the lungs it may lead to pneumonia and the bladder infection may lead to cystitis. Infection could also travel through the bloodstream that may lead to sepsis.
It must be countered with strong and costly antibiotics given to the patient through intravenous fluids. The vial is injected directly to the intravenous fluid that penetrates the veins of the patient. The patient who has acquired sepsis stays at the hospital for few weeks to have the infection fully reversed. Sepsis is a fatal infection if left untreated.
The presence of other illness lengthens the recovery period of the patient. The span of recovery varies from case to case. Some may undergo cardiac rehabilitation for few weeks after the surgery while others may be physically well after few weeks of suffering from pain after the surgery. Some may still be sensitive in the coldness of the weather for few months, which will constantly cause chest pain. A recovery period varies from two months until a year. It is when their hearts have fully recovered that they can go back to their daily routine without any hassles for the heart. But there are some who may not recover from the surgery and adds to the fatality rate.
STERNAL INFECTION:
In order to access the heart, traditionally an incision is made from the top of the chest bone--the sternum--to the bottom.Then it is necessary to saw the sternum open. If the internal mammary artery will be used for a bypass, it is dissected away from the chest wall to use as a new vessel for the heart. Disrupting this blood flow to the chest wall, and the trauma that occurs during opening of the chest, can result in an infection of the chest bone and surrounding tissues. This complication can be devastating and result in the removal of the sternum if long-term antibiotics fail. Sternal infection is a rare complication but potentially life-threatening.
BLEEDING:
The cardiopulmonary bypass machine,also known as the CPM or the heart-lung machine, is used to maintain circulation to the body while the heart is stopped during the procedure. This machine takes the patient's blood through a system of tubes placed in the aorta and right atrium and cleans the toxins and oxygenates the blood. The blood is subsequently returned to the patient. Use of this machine can create bleeding because as the blood passes through the machine, it is diluted with extra fluids, thereby diluting the necessary clotting factors. In addition, the platelets, which are also necessary for clotting, can become damaged as they pass through the CPM. Finally, heparin, a blood thinner, is used to prevent the blood from clotting while passing through the tubing, but this can also lead to undesired bleeding later.
ARRHYTHMIAS:
The significant handling of the heart during surgery can affect the conduction system of the heart. About 15 to 40 percent of patients will have atrial fibrillation about two to three days after surgery, states the Merck Manual. Nonsustained ventricular tachycardia, a fast, chaotic, heart rhythm, is seen in about 50 percent of patients. This rhythm can quickly switch to a sustained ventricluar tachycardia and become life-threatening. About 1 percent of patients will have a heart attack after the operation.
ORGAN FAILURE:
The blood reacts to the tubing of the CPM by releasing special proteins called cytokines into the blood. These cytokines are responsible for creating a system-wide inflammatory response. Cytokines travel in the bloodstream and when they pass through the organs, they can cause organ damage or failure. Cytokines can cause the lungs to react with acute respiratory distress syndrome or cause kidney failure.
REFERENCES:
MayoClinic.com: Coronary Artery Disease: Angioplasty or Bypass Surgery?
BMC: Superficial and Deep Sternal Wound Infection after more than 9000 coronary artery bypass grafts, incidence, risk factors and mortality. Abbas Salehi Omran, MD and et.al. BMC Infectious Disease. 2007
The Merck Manual Online Medical Library.com: Coronary Artery Bypass Grafting (CABG)
Sage Journals Online: Understanding Cytokines Part I: Physiology and Mechanism of Action.
MedlinePlus: Acute Respiratory Distress Syndrome
Researched by:
@mannaglide
http://MannaGoods.blogspot.com
---------
Arginine
Arginine
Arginine (or L-Arginine) is an amino acid involved in numerous areas of human biochemistry, including ammonia detoxification, hormone secretion, and the immune system. Arginine is also well known as a precursor to nitric oxide, a key component of endothelial-derived relaxing factor. The endothelium is the lining inside blood vessels and arginine supplements help make more nitric oxide. Therefore, arginine, by making more nitric oxide helps to relax and dilate blood vessels.
Nitric oxide is a messenger molecule involved in a variety of endothelium-dependent effects in the cardiovascular system. Because of arginine's nitric oxide-stimulating effects, it may potentially be useful in angina pectoris, congestive heart failure, hypertension, coronary heart disease, preeclampsia, intermittent claudication, and erectile dysfunction. In addition, arginine has been studied for its role in HIV/AIDS, athletic performance, burns and trauma, diabetes and syndrome X, male and female infertility, and interstitial cystitis. Source: Appleton J., Altern Med Rev. 2002 Dec;7(6):512-22.
Dr. Sahelian says: Even though arginine has been claimed to be useful for some of the conditions listed above, it would be premature to be overly excited. Much research needs to be done before we can be more confident about arginine's potential. However, so far, arginine appears to have a role to play in conditions involving blood vessel dilation. Whether the dilation is short lived or continues for an adequate period is still being evaluated.
Arginine and Erectile Dysfunction
One of the more popular supplements for sexual dysfunction is L-arginine, also referred to as arginine. Arginine is a versatile amino acids in animal cells, serving as a precursor for the making not only of proteins but also of nitric oxide, urea, glutamate, and creatine. What makes l-arginine interesting is that it can be metabolized to nitric oxide (NO). NO is the most powerful chemical known to dilate and engorge blood vessels in the penis and clitoris. What does the research say about the role of arginine in erectile dysfunction?
A Low dose of l-arginine, at 500 mg three times a day, has not been found to be effective for erectile dysfunction.
A double-blind, placebo-controlled study of 50 men with erectile dysfunction tested arginine at a dose of 5 grams per day for six weeks. About a third of the participants who received arginine showed improvement, and that improvement was greater than the 10% improvement seen in the placebo group.
Arginine has been studied in combination with other nutrients as a treatment for sexual dysfunction in women. A small trial found some improvement with a combination treatment providing a daily dose of 2,500 mg of arginine, as well as ginseng, ginkgo, and damiana. In a four-week, double-blind study, 77 women with decreased libido were given either the combination product or a placebo. Those taking the arginine-blend showed statistically greater improvement, reporting increased sexual desire in 71% of participants given the treatment. In the placebo group, 42% reported an increased libido. Other improvements included relative satisfaction with sex life and heightened clitoral sensation. No significant side effects were seen in either group. However, we don't know if the arginine had anything to do with the results.
A study done at the University of Texas at Austin examined the effects of arginine, combined with yohimbine, on sexual arousal in postmenopausal women. Twenty-four women participated in three sessions in which sexual responses to erotic stimuli were measured following treatment with either arginine glutamate (6 g) plus yohimbine (6 mg), yohimbine alone (6 mg), or a placebo, using a randomized, double-blind design. Sexual responses were measured at one hour after taking the supplements. Compared to placebo, the combined oral administration of arginine and yohimbine substantially increased vaginal pulse amplitude responses to the erotic film. It is well known that yohimbine, alone, has a significant effect on sexuality and whether arginine was a factor is not known.
Mechanism of Action of Arginine
The most likely explanation for the mild effectiveness of arginine is its conversion into nitric oxide. As discussed in Chapter 2 of Natural Sex Boosters book, nitric oxide is converted into cGMP, which becomes the secondary messenger that causes smooth muscle relaxation, resulting in more blood going into the genital organs, which leads to erections. However, nitric oxide is quickly metabolized and any potential effectiveness of arginine could be very short lived.
Potential Arginine Benefits
There is some supporting evidence that arginine may be helpful in reducing angina and lowering blood pressure (see studies bottom of page). Research indicates supplemental arginine reduces pulmonary resistance and blood pressure. Arginine supplementation improves renal function in patients with chronic heart failure. Polish researchers have found that arginine supplementation increases exercise tolerance in stable coronary artery disease patients. Oral L-arginine improves endothelial function in older healthy individuals. However, I am not convinced yet that arginine is a worthwhile supplement for erectile function or sexual enhancement, at least in low dosages.
L Arginine Dosage
L Arginine is available most often as 1,000 mg capsules and in powder form. Dosage of l arginine depends on the condition being treated.
History of Arginine
L arginine was first isolated in 1886. In 1932, L arginine was found to be required for the generation of urea, which is necessary for the removal of toxic ammonia from the body. In 1939, L arginine was also shown to be required for the synthesis of creatine.
Arginine Deficiency
Symptoms of arginine deficiency include poor wound healing, hair loss, skin rash, constipation, and fatty liver. Arginine is considered a semi-essential amino acid, because although it is normally synthesized in sufficient amounts by the body, arginine supplementation is sometimes required (for example, due to inborn errors of urea synthesis, protein malnutrition, excessive lysine intake, burns, peritoneal dialysis, rapid growth).
Arginine and Nitric Oxide
Arginine is a precursor of nitric oxide, which causes blood vessel relaxation. Although there is some evidence that suggests that arginine may be useful in the treatment of medical conditions that are improved by vasodilation, such as angina, atherosclerosis, coronary artery disease, erectile dysfunction, heart failure, intermittent claudication/peripheral vascular disease, and vascular headache, more proof is needed. The appropriate dosage and long term safety is not clear at this time. Arginine also stimulates protein synthesis and has been studied for wound healing, bodybuilding, enhancement of sperm production (spermatogenesis), and prevention of wasting in people with critical illness.
Arginine Research Update
L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor.
Altern Med Rev. 2005 Mar;10(1):14-23.
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction
Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency?
American Journal of Clinical Nutrition, Vol. 81, No. 5, 1142-1146, May 2005
The disturbances leading to cancer cachexia remain to be unraveled. Preliminary evidence suggests that arginine availability in cancer is reduced. However, no valid data are available on plasma arginine concentrations in cancer patients. Objective: We aimed to determine whether there is evidence for disturbed arginine metabolism in cancer. Design: We measured plasma arginine concentrations postabsorptively in patients with various types of tumors, hypothesizing that arginine concentrations would be lower than those in age- and sex-matched control subjects. Patients with localized tumors with a range of metabolic implications were studied: breast cancer (no weight loss), colonic cancer (sometimes weight loss), and pancreatic cancer (usually weight loss). Plasma amino acid concentrations were measured by HPLC. Results: Plasma arginine concentrations were lower in patients with cancer (breast cancer: 80 ± 3 compared with 103 ± 9 µmol/L; colonic cancer: 80 ± 3 compared with 96 ± 7 µmol/L; pancreatic cancer: 76 ± 5 compared with 99 ± 7 µmol/L; P < 0.05 versus respective age- and sex-matched control subjects), irrespective of tumor type, weight loss, tumor stage, or body mass index (correlations with P > 0.05). Conclusions: Malignant tumors associated with various degrees of metabolic derangements are all associated with decreased plasma arginine concentrations, even without weight loss. This suggests that decreased arginine availability is a specific feature of the presence of cancer. These disturbances in arginine metabolism could contribute to the cascade of metabolic events leading to cancer cachexia.
Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic men.
J Nutr. 2005 Feb;135(2):212-7.
When administered intravenously, l-arginine substantially reduces blood pressure (BP) and peripheral vascular resistance in healthy adults and in patients with vascular disease. Oral l-arginine has been shown to improve endothelial function; however, it is not clear whether oral administration has significant effects on systemic hemodynamics. In a randomized, placebo-controlled, crossover study we tested whether oral l-arginine (12 g/d for 3 wk) affected hemodynamics, glucose, insulin, or C-reactive protein in 16 middle-age men with hypercholesterolemia. After each treatment, hemodynamic variables were measured at rest and during 2 standardized stressor tasks (a simulated public-speaking task and the cold pressor).
Regardless of treatment, the stressor tasks increased BP and heart rate (P Effect of oral L-arginine on oxidant stress, endothelial dysfunction, and systemic arterial pressure in young cardiac transplant recipients.
Am J Cardiol. 2004 Sep 15;94(6):828-31. Department of Pediatrics, University of Virginia, Charlottesville, VA
Oral L-arginine therapy reverses endothelial dysfunction and attenuates high blood pressure in hypertensive cardiac transplant recipients. L-arginine corrects derangements in the vascular endothelial nitric oxide (NO)-dependent signaling pathway. Our data support the concept that cardiac transplant recipients use excess endogenous NO from L-arginine supplementation to buffer increased vascular oxidant stress.
Effect of L-arginine on age-related changes in macrophage phagocytic activity.
Immunol Invest. 2004 Aug;33(3):287-93.
Aging is associated with decline in the functioning of immune cells and reductions in serum L-arginine and excretion of nitric oxide metabolites. Studies have shown that L-arginine plays an important role in many physiological, biological and immunological processes. The present study was performed to determine if treatment with L-arginine could prevent age-related changes in phagocytic function of peritoneal macrophages. The effects of L-arginine on phagocytic activity of peritoneal macrophages were compared between young and middle-aged rats. Studies were performed in four groups of rats for 8 weeks: group 1 (3 month-old) received physiological saline; group 2 (3 month-old) received L-arginine; group 3 (12 month-old) received physiological saline; group 4 (12 month-old) received L-arginine.
There were no significant differences in percentage of cells which were phagocytized. However, the phagocytosis of activated charcoal by peritoneal macrophages reduced with age. Thus, the phagocytic index was lower in macrophages of middle-aged rats. L-arginine treatment increased phagocytosis by peritoneal macrophages of both young and middle-aged rats. L-arginine-induced augmentation in phagocytosis by macrophages were much higher in the middle-aged rats compared with young rats. In summary, we found that L-arginine prevented the age-related reduction in phagocytic capability of peritoneal macrophages. l arginine side effects.
Effect of oral L-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol. 2004 Apr 1;93(7):933-5.
Thirteen hypertensive patients with microvascular angina were studied before and after receiving oral L-arginine (4 weeks, 2 g, 3 times daily). L-arginine significantly improved angina class, systolic blood pressure at rest, and quality of life. Maximal forearm blood flow, plasma L-arginine, L-arginine : asymmetric dimethyl arginine ratio, and cyclic guanylate monophosphate increased significantly after treatment. In medically treated hypertensive patients with micro-vascular angina, oral L-arginine may represent a useful therapeutic option.
Acute pancreatitis possibly due to arginine use: A case report.
Turk J Gastroenterol. 2004 Mar;15(1):56-8.
Arginine has been used by millions of athletes over the past 20 years to enhance production of human growth hormone. The effects of arginine supplementation include increased fat burning and muscle building, enhanced immunity, and improvement in erectile function in men. Excessive doses of basic amino acids such as ethionine, methionine and lysine are known to damage the rat pancreas. Recent studies have demonstrated that excessive doses of arginine induce necrotizing pancreatitis in rats. In this article, we report a 16-year-old male patient hospitalized in our clinic because of severe pain in upper abdomen, nausea and vomiting who was suspected to have arginine-induced acute pancreatitis.
The influence of two different doses of L arginine oral supplementation on nitric oxide (NO) concentration and total antioxidant status (TAS) in atherosclerotic patients.
Med Sci Monit. 2004 Jan;10(1):CR29-32.
The purpose of this study was to assess the effect of two different doses in 28-day L arginine oral supplementation on nitric oxide (NO) concentration and total antioxidant status (TAS) in patients with atherosclerotic peripheral arterial disease. 32 patients were divided into 2 groups receiving L-arginine at 3i2 g/day (group A) or 3i4 g/day (group B). RESULTS: Group A showed substantially higher NO levels after 14 and 28 days of therapy. In group B, the NO level increase was substantial after 28 days. Noticeably higher total antioxidant statuses were noted in both groups: group A showed this only after 28 days of treatment, while group B exhibited substantial increase in TAS after 7, 14 and 28 days of L-arginine supplementation.
CONCLUSIONS: Oral supplementation of L arginine for 28 days leads to substantial increases in NO and TAS levels (comparable in both groups of patients) in the blood of patients with atherosclerotic peripheral arterial disease at Fontaine's stages II and III. The TAS concentration rise points to an antioxidative effect of L arginine oral supplementation.
Treatment of erectile dysfunction with pycnogenol and L-arginine.
J Sex Marital Ther. 2003 May-Jun;29(3):207-13.
Penile erection requires the relaxation of the cavernous smooth muscle, which is triggered by nitric oxide (NO). We investigated the possibility of overcoming erectile dysfunction by increasing the amounts of endogenous NO. For this purpose, we orally administered Pycnogenol, because it is known to increase production of NO by nitric oxide syntase together with L-arginine as substrate for this enzyme. The study included 40 men, aged 25-45 years, without confirmed organic erectile dysfunction. Throughout the 3-month trial period, patients received 3 ampoules Sargenor a day, a drinkable solution of the dipeptide arginyl aspartate (equivalent to 1.7 g L arginine per day). During the second month, patients were additionally supplemented with 40 mg Pycnogenol two times per day; during the third month, the daily dosage was increased to three 40-mg Pycnogenol tablets. After 1 month of treatment with L-arginine, a statistically nonsignificant number of 2 patients experienced a normal erection. Treatment with a combination of L-arginine and Pycnogenol for the following month increased the number of men with restored sexual ability to 80%. Finally, after the third month of treatment, 92% of the men experienced a normal erection. We conclude that oral administration of L-arginine in combination with Pycnogenol causes a significant improvement in sexual function in men with erectile dysfunction without any side effects. l arginine benefit.
Dietary supplementation with L-arginine or placebo in women with pre-eclampsia.
Staff AC.. Departments of Obstetrics and Gynecology, Ulleval University Hospital, Kirkeveien 166, Oslo, Norway.
To investigate the effect of dietary intake of the NO-donor L-arginine on the diastolic blood pressure in women with pre-eclampsia. A randomized double-blind study was designed to compare the effect of L-arginine and placebo in pre-eclamptic women with gestational length ranging from 28+0 to 36+0 weeks. The women received orally 12 g of L-arginine or placebo daily for up to 5 days. The primary end-point was to identify a difference in diastolic blood pressure alteration between the two groups after 2 days of intervention. There was no statistically significant alteration in diastolic blood pressure in the L-arginine group compared with the placebo group after 2 days of treatment.
CONCLUSIONS: Oral L-arginine supplementation did not reduce mean diastolic blood pressure after 2 days of treatment compared with placebo in pre-eclamptic patients with gestational length varying from 28 to 36 weeks. Whether L-arginine treatment could be clinically beneficial for the mother or the fetus if started earlier in the disease process than for the women in our study remains to be seen.
Adjuvant L-arginine treatment for in-vitro fertilization in poor responder patients.
Hum Reprod. 1999 Jul;14(7):1690-7.
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). The plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate. l arginine hcl.
Oral L-arginine improves endothelial function in healthy individuals older than 70 years.
Bode-Boger SM. University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
Ageing is associated with progressive endothelial dysfunction in normal humans. Flow-mediated dilation (FMD) of the brachial artery is impaired in elderly individuals with cardiovascular disease and vascular nitric oxide (NO) bioavailability is reduced. We investigated whether oral L-arginine, the substrate for NO synthesis, can improve impaired FMD in healthy very old people. In a prospective, double-blind, randomized crossover trial, 12 healthy old subjects took L-arginine (8 g p.o. two times daily) or placebo for 14 days each, separated by a wash-out period of 14 days. L-Arginine significantly improved FMD, whereas placebo had no effect. After L-arginine, plasma levels of L-arginine increased significantly, but placebo had no effect. As NO synthesis can be antagonized by its endogenous inhibitor asymmetric dimethyl L-arginine (ADMA), we determined ADMA plasma concentrations, which were elevated at baseline in comparison to healthy middle-aged individuals. ADMA remained unchanged during treatment, but L-arginine supplementation normalized the L-arginine/ADMA ratio. We conclude that in healthy very old age endothelial function is impaired and may be improved by oral L-arginine supplementation, probably due to normalization of the L-arginine/ADMA ratio. arginine pyroglutamate/
Practical recommendations for immune-enhancing diets.
J Nutr. 2004 Oct;134(10 Suppl):2868S-2872S; discussion 2895S.
Immune-enhancing diets contain nutrients that have putative benefits, including arginine, (n-3) fats, glutamine, nucleotides, and structured lipids. Although under most circumstances the systemic inflammatory response is beneficial to the host, improving the eventual outcome of injury, infection, or inflammation, excessive proinflammation (leading to cardiac, hepatic, and mitochondrial dysfunction) or excessive counterinflammation (leading to immune depression) can worsen outcome. In critically ill septic patients, the synthesis of arginine can be exceeded by its catabolism to nitric oxide (NO) and urea, rendering arginine conditionally essential. In patients with sepsis, increased production of NO increases serum nitrite and nitrate levels, whereas levels in patients with trauma and trauma with sepsis are lower than in controls. In septic patients, supplemental arginine might further increase NO levels and be potentially harmful through excessive proinflammation. However, administration of increased amounts of arginine might improve immune function in surgical and trauma patients by increasing NO production in macrophages. Thus, the effects of arginine and (n-3)-fat supplementation might be expected to be complementary- arginine might improve cytokine and NO production in patients with immunodepression, whereas (n-3) fats might be beneficial when there is excessive proinflammation, particularly when supplemental arginine is supplied, by reducing cytokine-induced eicosanoid production.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
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Arginine (or L-Arginine) is an amino acid involved in numerous areas of human biochemistry, including ammonia detoxification, hormone secretion, and the immune system. Arginine is also well known as a precursor to nitric oxide, a key component of endothelial-derived relaxing factor. The endothelium is the lining inside blood vessels and arginine supplements help make more nitric oxide. Therefore, arginine, by making more nitric oxide helps to relax and dilate blood vessels.
Nitric oxide is a messenger molecule involved in a variety of endothelium-dependent effects in the cardiovascular system. Because of arginine's nitric oxide-stimulating effects, it may potentially be useful in angina pectoris, congestive heart failure, hypertension, coronary heart disease, preeclampsia, intermittent claudication, and erectile dysfunction. In addition, arginine has been studied for its role in HIV/AIDS, athletic performance, burns and trauma, diabetes and syndrome X, male and female infertility, and interstitial cystitis. Source: Appleton J., Altern Med Rev. 2002 Dec;7(6):512-22.
Dr. Sahelian says: Even though arginine has been claimed to be useful for some of the conditions listed above, it would be premature to be overly excited. Much research needs to be done before we can be more confident about arginine's potential. However, so far, arginine appears to have a role to play in conditions involving blood vessel dilation. Whether the dilation is short lived or continues for an adequate period is still being evaluated.
Arginine and Erectile Dysfunction
One of the more popular supplements for sexual dysfunction is L-arginine, also referred to as arginine. Arginine is a versatile amino acids in animal cells, serving as a precursor for the making not only of proteins but also of nitric oxide, urea, glutamate, and creatine. What makes l-arginine interesting is that it can be metabolized to nitric oxide (NO). NO is the most powerful chemical known to dilate and engorge blood vessels in the penis and clitoris. What does the research say about the role of arginine in erectile dysfunction?
A Low dose of l-arginine, at 500 mg three times a day, has not been found to be effective for erectile dysfunction.
A double-blind, placebo-controlled study of 50 men with erectile dysfunction tested arginine at a dose of 5 grams per day for six weeks. About a third of the participants who received arginine showed improvement, and that improvement was greater than the 10% improvement seen in the placebo group.
Arginine has been studied in combination with other nutrients as a treatment for sexual dysfunction in women. A small trial found some improvement with a combination treatment providing a daily dose of 2,500 mg of arginine, as well as ginseng, ginkgo, and damiana. In a four-week, double-blind study, 77 women with decreased libido were given either the combination product or a placebo. Those taking the arginine-blend showed statistically greater improvement, reporting increased sexual desire in 71% of participants given the treatment. In the placebo group, 42% reported an increased libido. Other improvements included relative satisfaction with sex life and heightened clitoral sensation. No significant side effects were seen in either group. However, we don't know if the arginine had anything to do with the results.
A study done at the University of Texas at Austin examined the effects of arginine, combined with yohimbine, on sexual arousal in postmenopausal women. Twenty-four women participated in three sessions in which sexual responses to erotic stimuli were measured following treatment with either arginine glutamate (6 g) plus yohimbine (6 mg), yohimbine alone (6 mg), or a placebo, using a randomized, double-blind design. Sexual responses were measured at one hour after taking the supplements. Compared to placebo, the combined oral administration of arginine and yohimbine substantially increased vaginal pulse amplitude responses to the erotic film. It is well known that yohimbine, alone, has a significant effect on sexuality and whether arginine was a factor is not known.
Mechanism of Action of Arginine
The most likely explanation for the mild effectiveness of arginine is its conversion into nitric oxide. As discussed in Chapter 2 of Natural Sex Boosters book, nitric oxide is converted into cGMP, which becomes the secondary messenger that causes smooth muscle relaxation, resulting in more blood going into the genital organs, which leads to erections. However, nitric oxide is quickly metabolized and any potential effectiveness of arginine could be very short lived.
Potential Arginine Benefits
There is some supporting evidence that arginine may be helpful in reducing angina and lowering blood pressure (see studies bottom of page). Research indicates supplemental arginine reduces pulmonary resistance and blood pressure. Arginine supplementation improves renal function in patients with chronic heart failure. Polish researchers have found that arginine supplementation increases exercise tolerance in stable coronary artery disease patients. Oral L-arginine improves endothelial function in older healthy individuals. However, I am not convinced yet that arginine is a worthwhile supplement for erectile function or sexual enhancement, at least in low dosages.
L Arginine Dosage
L Arginine is available most often as 1,000 mg capsules and in powder form. Dosage of l arginine depends on the condition being treated.
History of Arginine
L arginine was first isolated in 1886. In 1932, L arginine was found to be required for the generation of urea, which is necessary for the removal of toxic ammonia from the body. In 1939, L arginine was also shown to be required for the synthesis of creatine.
Arginine Deficiency
Symptoms of arginine deficiency include poor wound healing, hair loss, skin rash, constipation, and fatty liver. Arginine is considered a semi-essential amino acid, because although it is normally synthesized in sufficient amounts by the body, arginine supplementation is sometimes required (for example, due to inborn errors of urea synthesis, protein malnutrition, excessive lysine intake, burns, peritoneal dialysis, rapid growth).
Arginine and Nitric Oxide
Arginine is a precursor of nitric oxide, which causes blood vessel relaxation. Although there is some evidence that suggests that arginine may be useful in the treatment of medical conditions that are improved by vasodilation, such as angina, atherosclerosis, coronary artery disease, erectile dysfunction, heart failure, intermittent claudication/peripheral vascular disease, and vascular headache, more proof is needed. The appropriate dosage and long term safety is not clear at this time. Arginine also stimulates protein synthesis and has been studied for wound healing, bodybuilding, enhancement of sperm production (spermatogenesis), and prevention of wasting in people with critical illness.
Arginine Research Update
L-Arginine improves vascular function by overcoming deleterious effects of ADMA, a novel cardiovascular risk factor.
Altern Med Rev. 2005 Mar;10(1):14-23.
There is abundant evidence that the endothelium plays a crucial role in the maintenance of vascular tone and structure. One of the major endothelium-derived vasoactive mediators is nitric oxide (NO), an endogenous messenger molecule formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA)--an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Supplementation with L-arginine has been shown to restore vascular function and to improve the clinical symptoms of various diseases associated with vascular dysfunction
Plasma arginine concentrations are reduced in cancer patients: evidence for arginine deficiency?
American Journal of Clinical Nutrition, Vol. 81, No. 5, 1142-1146, May 2005
The disturbances leading to cancer cachexia remain to be unraveled. Preliminary evidence suggests that arginine availability in cancer is reduced. However, no valid data are available on plasma arginine concentrations in cancer patients. Objective: We aimed to determine whether there is evidence for disturbed arginine metabolism in cancer. Design: We measured plasma arginine concentrations postabsorptively in patients with various types of tumors, hypothesizing that arginine concentrations would be lower than those in age- and sex-matched control subjects. Patients with localized tumors with a range of metabolic implications were studied: breast cancer (no weight loss), colonic cancer (sometimes weight loss), and pancreatic cancer (usually weight loss). Plasma amino acid concentrations were measured by HPLC. Results: Plasma arginine concentrations were lower in patients with cancer (breast cancer: 80 ± 3 compared with 103 ± 9 µmol/L; colonic cancer: 80 ± 3 compared with 96 ± 7 µmol/L; pancreatic cancer: 76 ± 5 compared with 99 ± 7 µmol/L; P < 0.05 versus respective age- and sex-matched control subjects), irrespective of tumor type, weight loss, tumor stage, or body mass index (correlations with P > 0.05). Conclusions: Malignant tumors associated with various degrees of metabolic derangements are all associated with decreased plasma arginine concentrations, even without weight loss. This suggests that decreased arginine availability is a specific feature of the presence of cancer. These disturbances in arginine metabolism could contribute to the cascade of metabolic events leading to cancer cachexia.
Oral L-arginine improves hemodynamic responses to stress and reduces plasma homocysteine in hypercholesterolemic men.
J Nutr. 2005 Feb;135(2):212-7.
When administered intravenously, l-arginine substantially reduces blood pressure (BP) and peripheral vascular resistance in healthy adults and in patients with vascular disease. Oral l-arginine has been shown to improve endothelial function; however, it is not clear whether oral administration has significant effects on systemic hemodynamics. In a randomized, placebo-controlled, crossover study we tested whether oral l-arginine (12 g/d for 3 wk) affected hemodynamics, glucose, insulin, or C-reactive protein in 16 middle-age men with hypercholesterolemia. After each treatment, hemodynamic variables were measured at rest and during 2 standardized stressor tasks (a simulated public-speaking task and the cold pressor).
Regardless of treatment, the stressor tasks increased BP and heart rate (P Effect of oral L-arginine on oxidant stress, endothelial dysfunction, and systemic arterial pressure in young cardiac transplant recipients.
Am J Cardiol. 2004 Sep 15;94(6):828-31. Department of Pediatrics, University of Virginia, Charlottesville, VA
Oral L-arginine therapy reverses endothelial dysfunction and attenuates high blood pressure in hypertensive cardiac transplant recipients. L-arginine corrects derangements in the vascular endothelial nitric oxide (NO)-dependent signaling pathway. Our data support the concept that cardiac transplant recipients use excess endogenous NO from L-arginine supplementation to buffer increased vascular oxidant stress.
Effect of L-arginine on age-related changes in macrophage phagocytic activity.
Immunol Invest. 2004 Aug;33(3):287-93.
Aging is associated with decline in the functioning of immune cells and reductions in serum L-arginine and excretion of nitric oxide metabolites. Studies have shown that L-arginine plays an important role in many physiological, biological and immunological processes. The present study was performed to determine if treatment with L-arginine could prevent age-related changes in phagocytic function of peritoneal macrophages. The effects of L-arginine on phagocytic activity of peritoneal macrophages were compared between young and middle-aged rats. Studies were performed in four groups of rats for 8 weeks: group 1 (3 month-old) received physiological saline; group 2 (3 month-old) received L-arginine; group 3 (12 month-old) received physiological saline; group 4 (12 month-old) received L-arginine.
There were no significant differences in percentage of cells which were phagocytized. However, the phagocytosis of activated charcoal by peritoneal macrophages reduced with age. Thus, the phagocytic index was lower in macrophages of middle-aged rats. L-arginine treatment increased phagocytosis by peritoneal macrophages of both young and middle-aged rats. L-arginine-induced augmentation in phagocytosis by macrophages were much higher in the middle-aged rats compared with young rats. In summary, we found that L-arginine prevented the age-related reduction in phagocytic capability of peritoneal macrophages. l arginine side effects.
Effect of oral L-arginine on blood pressure and symptoms and endothelial function in patients with systemic hypertension, positive exercise tests, and normal coronary arteries. Am J Cardiol. 2004 Apr 1;93(7):933-5.
Thirteen hypertensive patients with microvascular angina were studied before and after receiving oral L-arginine (4 weeks, 2 g, 3 times daily). L-arginine significantly improved angina class, systolic blood pressure at rest, and quality of life. Maximal forearm blood flow, plasma L-arginine, L-arginine : asymmetric dimethyl arginine ratio, and cyclic guanylate monophosphate increased significantly after treatment. In medically treated hypertensive patients with micro-vascular angina, oral L-arginine may represent a useful therapeutic option.
Acute pancreatitis possibly due to arginine use: A case report.
Turk J Gastroenterol. 2004 Mar;15(1):56-8.
Arginine has been used by millions of athletes over the past 20 years to enhance production of human growth hormone. The effects of arginine supplementation include increased fat burning and muscle building, enhanced immunity, and improvement in erectile function in men. Excessive doses of basic amino acids such as ethionine, methionine and lysine are known to damage the rat pancreas. Recent studies have demonstrated that excessive doses of arginine induce necrotizing pancreatitis in rats. In this article, we report a 16-year-old male patient hospitalized in our clinic because of severe pain in upper abdomen, nausea and vomiting who was suspected to have arginine-induced acute pancreatitis.
The influence of two different doses of L arginine oral supplementation on nitric oxide (NO) concentration and total antioxidant status (TAS) in atherosclerotic patients.
Med Sci Monit. 2004 Jan;10(1):CR29-32.
The purpose of this study was to assess the effect of two different doses in 28-day L arginine oral supplementation on nitric oxide (NO) concentration and total antioxidant status (TAS) in patients with atherosclerotic peripheral arterial disease. 32 patients were divided into 2 groups receiving L-arginine at 3i2 g/day (group A) or 3i4 g/day (group B). RESULTS: Group A showed substantially higher NO levels after 14 and 28 days of therapy. In group B, the NO level increase was substantial after 28 days. Noticeably higher total antioxidant statuses were noted in both groups: group A showed this only after 28 days of treatment, while group B exhibited substantial increase in TAS after 7, 14 and 28 days of L-arginine supplementation.
CONCLUSIONS: Oral supplementation of L arginine for 28 days leads to substantial increases in NO and TAS levels (comparable in both groups of patients) in the blood of patients with atherosclerotic peripheral arterial disease at Fontaine's stages II and III. The TAS concentration rise points to an antioxidative effect of L arginine oral supplementation.
Treatment of erectile dysfunction with pycnogenol and L-arginine.
J Sex Marital Ther. 2003 May-Jun;29(3):207-13.
Penile erection requires the relaxation of the cavernous smooth muscle, which is triggered by nitric oxide (NO). We investigated the possibility of overcoming erectile dysfunction by increasing the amounts of endogenous NO. For this purpose, we orally administered Pycnogenol, because it is known to increase production of NO by nitric oxide syntase together with L-arginine as substrate for this enzyme. The study included 40 men, aged 25-45 years, without confirmed organic erectile dysfunction. Throughout the 3-month trial period, patients received 3 ampoules Sargenor a day, a drinkable solution of the dipeptide arginyl aspartate (equivalent to 1.7 g L arginine per day). During the second month, patients were additionally supplemented with 40 mg Pycnogenol two times per day; during the third month, the daily dosage was increased to three 40-mg Pycnogenol tablets. After 1 month of treatment with L-arginine, a statistically nonsignificant number of 2 patients experienced a normal erection. Treatment with a combination of L-arginine and Pycnogenol for the following month increased the number of men with restored sexual ability to 80%. Finally, after the third month of treatment, 92% of the men experienced a normal erection. We conclude that oral administration of L-arginine in combination with Pycnogenol causes a significant improvement in sexual function in men with erectile dysfunction without any side effects. l arginine benefit.
Dietary supplementation with L-arginine or placebo in women with pre-eclampsia.
Staff AC.. Departments of Obstetrics and Gynecology, Ulleval University Hospital, Kirkeveien 166, Oslo, Norway.
To investigate the effect of dietary intake of the NO-donor L-arginine on the diastolic blood pressure in women with pre-eclampsia. A randomized double-blind study was designed to compare the effect of L-arginine and placebo in pre-eclamptic women with gestational length ranging from 28+0 to 36+0 weeks. The women received orally 12 g of L-arginine or placebo daily for up to 5 days. The primary end-point was to identify a difference in diastolic blood pressure alteration between the two groups after 2 days of intervention. There was no statistically significant alteration in diastolic blood pressure in the L-arginine group compared with the placebo group after 2 days of treatment.
CONCLUSIONS: Oral L-arginine supplementation did not reduce mean diastolic blood pressure after 2 days of treatment compared with placebo in pre-eclamptic patients with gestational length varying from 28 to 36 weeks. Whether L-arginine treatment could be clinically beneficial for the mother or the fetus if started earlier in the disease process than for the women in our study remains to be seen.
Adjuvant L-arginine treatment for in-vitro fertilization in poor responder patients.
Hum Reprod. 1999 Jul;14(7):1690-7.
The objective of the present study was prospectively and randomly to evaluate the role of L-arginine in improving uterine and follicular Doppler flow and in improving ovarian response to gonadotrophin in poor responder women. A total of 34 patients undergoing assisted reproduction was divided in two groups according to different ovarian stimulation protocols: (i) flare-up gonadotrophin-releasing hormone analogue (GnRHa) plus elevated pure follicle stimulating hormone (pFSH) (n = 17); and (ii) flare-up GnRHa plus elevated pFSH plus oral L-arginine (n = 17). The plasma and follicular fluid concentrations of arginine, citrulline, nitrite/nitrate (NO2-/NO3-), and insulin-like growth factor-1 (IGF-1) were assayed. In the L-arginine treated group a lower cancellation rate, an increased number of oocytes collected, and embryos transferred were observed. In the same group, increased plasma and follicular fluid concentrations of arginine, citrulline, NO2-/NO3-, and IGF-1 was observed. Significant Doppler flow improvement was obtained in the L-arginine supplemented group. Three pregnancies were registered in these patients. No pregnancies were observed in the other group. It was concluded that oral L-arginine supplementation in poor responder patients may improve ovarian response, endometrial receptivity and pregnancy rate. l arginine hcl.
Oral L-arginine improves endothelial function in healthy individuals older than 70 years.
Bode-Boger SM. University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
Ageing is associated with progressive endothelial dysfunction in normal humans. Flow-mediated dilation (FMD) of the brachial artery is impaired in elderly individuals with cardiovascular disease and vascular nitric oxide (NO) bioavailability is reduced. We investigated whether oral L-arginine, the substrate for NO synthesis, can improve impaired FMD in healthy very old people. In a prospective, double-blind, randomized crossover trial, 12 healthy old subjects took L-arginine (8 g p.o. two times daily) or placebo for 14 days each, separated by a wash-out period of 14 days. L-Arginine significantly improved FMD, whereas placebo had no effect. After L-arginine, plasma levels of L-arginine increased significantly, but placebo had no effect. As NO synthesis can be antagonized by its endogenous inhibitor asymmetric dimethyl L-arginine (ADMA), we determined ADMA plasma concentrations, which were elevated at baseline in comparison to healthy middle-aged individuals. ADMA remained unchanged during treatment, but L-arginine supplementation normalized the L-arginine/ADMA ratio. We conclude that in healthy very old age endothelial function is impaired and may be improved by oral L-arginine supplementation, probably due to normalization of the L-arginine/ADMA ratio. arginine pyroglutamate/
Practical recommendations for immune-enhancing diets.
J Nutr. 2004 Oct;134(10 Suppl):2868S-2872S; discussion 2895S.
Immune-enhancing diets contain nutrients that have putative benefits, including arginine, (n-3) fats, glutamine, nucleotides, and structured lipids. Although under most circumstances the systemic inflammatory response is beneficial to the host, improving the eventual outcome of injury, infection, or inflammation, excessive proinflammation (leading to cardiac, hepatic, and mitochondrial dysfunction) or excessive counterinflammation (leading to immune depression) can worsen outcome. In critically ill septic patients, the synthesis of arginine can be exceeded by its catabolism to nitric oxide (NO) and urea, rendering arginine conditionally essential. In patients with sepsis, increased production of NO increases serum nitrite and nitrate levels, whereas levels in patients with trauma and trauma with sepsis are lower than in controls. In septic patients, supplemental arginine might further increase NO levels and be potentially harmful through excessive proinflammation. However, administration of increased amounts of arginine might improve immune function in surgical and trauma patients by increasing NO production in macrophages. Thus, the effects of arginine and (n-3)-fat supplementation might be expected to be complementary- arginine might improve cytokine and NO production in patients with immunodepression, whereas (n-3) fats might be beneficial when there is excessive proinflammation, particularly when supplemental arginine is supplied, by reducing cytokine-induced eicosanoid production.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
---------
Five Stages Of Grief
Five Stages Of Grief
The stages, popularly known by the acronym DABDA, include:
Denial — "I feel fine."; "This can't be happening, not to me."
Denial is usually only a temporary defense for the individual. This feeling is generally replaced with heightened awareness of possessions and individuals that will be left behind after death. Denial can be conscious or unconscious refusal to accept facts, information, or the reality of the situation. Denial is a defense mechanism and some people can become locked in this stage.
Anger — "Why me? It's not fair!"; "How can this happen to me?"; '"Who is to blame?"
Once in the second stage, the individual recognizes that denial cannot continue. Because of anger, the person is very difficult to care for due to misplaced feelings of rage and envy. Anger can manifest itself in different ways. People can be angry with themselves, or with others, and especially those who are close to them. It is important to remain detached and nonjudgmental when dealing with a person experiencing anger from grief.
Bargaining — "I'll do anything for a few more years."; "I will give my life savings if..."
The third stage involves the hope that the individual can somehow postpone or delay death. Usually, the negotiation for an extended life is made with a higher power in exchange for a reformed lifestyle.
Psychologically, the individual is saying, "I understand I will die, but if I could just do something to buy more time..." People facing less serious trauma can bargain or seek to negotiate a compromise. For example "Can we still be friends?.." when facing a break-up. Bargaining rarely provides a sustainable solution, especially if it's a matter of life or death.
Depression — "I'm so sad, why bother with anything?"; "I'm going to die soon so what's the point?"; "I miss my loved one, why go on?"
During the fourth stage, the dying person begins to understand the certainty of death. Because of this, the individual may become silent, refuse visitors and spend much of the time crying and grieving. This process allows the dying person to disconnect from things of love and affection. It is not recommended to attempt to cheer up an individual who is in this stage. It is an important time for grieving that must be processed. Depression could be referred to as the dress rehearsal for the 'aftermath'. It is a kind of acceptance with emotional attachment. It's natural to feel sadness, regret, fear, and uncertainty when going through this stage. Feeling those emotions shows that the person has begun to accept the situation.
Acceptance — "It's going to be okay."; "I can't fight it, I may as well prepare for it."
In this last stage, individuals begin to come to terms with their mortality, or that of a loved one, or other tragic event. This stage varies according to the person's situation. People dying can enter this stage a long time before the people they leave behind, who must pass through their own individual stages of dealing with the grief.
Kübler-Ross originally applied these stages to people suffering from terminal illness. She later expanded this theoretical model to apply to any form of catastrophic personal loss (job, income, freedom). Such losses may also include significant life events such as the death of a loved one, major rejection, end of a relationship or divorce, drug addiction, incarceration, the onset of a disease or chronic illness, an infertility diagnosis, as well many tragedies and disasters.
As stated before, the Kübler-Ross Model can be used for multiple situations where people are experiencing a significant loss. We explain how the model is applied differently in a few specific situations below. These are just some of the many examples that Kübler-Ross wanted her model to be used for.
Children grieving in divorce:
Denial – Children feel the need to believe that their parents will get back together or they will change their mind about the divorce. Example: “Mom or Dad will change their mind”
Anger – Children feel the need to blame someone for their sadness and loss. Example: “I hate dad for leaving us”
Bargaining - In this stage, children feel as if they have some say in the situation if they bring a bargain to the table. This helps them keep focused on the positive that the situation might change and less focused on the negative, the sadness they’ll experience after the divorce. Example: “If I do all of my chores maybe Mom won’t leave Dad”
Depression - This involves the child experiencing sadness when they know there is nothing else to be done and they realize they cannot stop the divorce. The parents need to let the child experience this process of grieving because if they do not it will only show their inability to cope with the situation. Example: “I’m sorry that I cannot fix this situation for you.”
Acceptance – This does not necessarily mean that the child is completely happy again. The acceptance is just moving past the depression and starting to accept the divorce. The sooner the parents start to move on from the situation the sooner the kids can begin to accept the reality of it.
Grieving a break-up
Denial – The person getting broken up with is unable to admit that the relationship is really over. They may try to continue to call the person when that person wants to be left alone.
Anger – When the reality sets in that the relationship is over, it is common to demand to know why they are being broken up with. This phase can make them feel like they are being treated unfairly and it may cause them to become angry at people close to them who want to help aid the situation.
Bargaining – After the anger stage, one will try to plead with their former partner by promising that whatever caused the breakup will never happen again. Example: “I can change. Please give me a chance”.
Depression – Next the person might feel discouraged that their bargaining plea did not convince their former partner to change their mind. This will send the person into the depression stage and can cause a lack of sleep, eating and even disrupt daily life tasks such as bowel movements.
Acceptance – Moving on from the situation and person is the last stage. The person accepts that the relationship is over and begins to move forward with their life. The person might not be completely over the situation but they are done going back and forth to the point where they can accept the reality of the situation.
Grieving in substance abuse
Denial – People feel that they do not have a problem concerning alcohol or substances. Even if they do feel as if they might have a small problem they believe that they have complete control over the situation and can stop drinking or doing drugs whenever they want. Example: “I don’t have to drink all of the time. I can stop whenever I want”
Bargaining – This is the stage that drug and alcohol abusers go through when they are trying to convince themselves or someone else that they are going to stop abusing in order to get something out of it or get themselves out of trouble. Example: “God, I promise I’ll never use again if you just get me out of trouble.”
Anger – The anger stage of abusers relates to how they get upset because they have this disease of addiction or are angry that they can no longer use drugs. Some of these examples include “I don’t want to have this addiction anymore.” “This isn’t fair I’m too young to have this problem.”
Depression – Sadness and hopelessness are important parts of the depression stage when dealing with a drug abuser. Most abusers experience this when they are going through the withdrawal stage quitting their addiction. It is important to communicate these feelings as a process of the healing.
Acceptance – With substance abusers admitting you have a problem is different than accepting you have a problem. When you admit you have a problem this is more likely to occur in the bargaining stage. Accepting that you have a problem is when you own that you have a problem and start the process to resolve the issue.
As stated above, according to her hypothesis, Kübler-Ross claimed these stages do not necessarily come in order, nor are all stages experienced by all patients. She stated, however, that a person will always experience at least two of the stages. Often, people will experience several stages in a "roller coaster" effect—switching between two or more stages, returning to one or more several times before working through it. Women are more likely than men to experience all five stages.
However, the Kübler-Ross hypothesis holds that there are individuals who struggle with death until the end. Some psychologists believe that the harder a person fights death, the more likely they will be to stay in the denial stage. If this is the case, it is possible the ill person will have more difficulty dying in a dignified way. Other psychologists state that not confronting death until the end is adaptive for some people.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
---------
The stages, popularly known by the acronym DABDA, include:
Denial — "I feel fine."; "This can't be happening, not to me."
Denial is usually only a temporary defense for the individual. This feeling is generally replaced with heightened awareness of possessions and individuals that will be left behind after death. Denial can be conscious or unconscious refusal to accept facts, information, or the reality of the situation. Denial is a defense mechanism and some people can become locked in this stage.
Anger — "Why me? It's not fair!"; "How can this happen to me?"; '"Who is to blame?"
Once in the second stage, the individual recognizes that denial cannot continue. Because of anger, the person is very difficult to care for due to misplaced feelings of rage and envy. Anger can manifest itself in different ways. People can be angry with themselves, or with others, and especially those who are close to them. It is important to remain detached and nonjudgmental when dealing with a person experiencing anger from grief.
Bargaining — "I'll do anything for a few more years."; "I will give my life savings if..."
The third stage involves the hope that the individual can somehow postpone or delay death. Usually, the negotiation for an extended life is made with a higher power in exchange for a reformed lifestyle.
Psychologically, the individual is saying, "I understand I will die, but if I could just do something to buy more time..." People facing less serious trauma can bargain or seek to negotiate a compromise. For example "Can we still be friends?.." when facing a break-up. Bargaining rarely provides a sustainable solution, especially if it's a matter of life or death.
Depression — "I'm so sad, why bother with anything?"; "I'm going to die soon so what's the point?"; "I miss my loved one, why go on?"
During the fourth stage, the dying person begins to understand the certainty of death. Because of this, the individual may become silent, refuse visitors and spend much of the time crying and grieving. This process allows the dying person to disconnect from things of love and affection. It is not recommended to attempt to cheer up an individual who is in this stage. It is an important time for grieving that must be processed. Depression could be referred to as the dress rehearsal for the 'aftermath'. It is a kind of acceptance with emotional attachment. It's natural to feel sadness, regret, fear, and uncertainty when going through this stage. Feeling those emotions shows that the person has begun to accept the situation.
Acceptance — "It's going to be okay."; "I can't fight it, I may as well prepare for it."
In this last stage, individuals begin to come to terms with their mortality, or that of a loved one, or other tragic event. This stage varies according to the person's situation. People dying can enter this stage a long time before the people they leave behind, who must pass through their own individual stages of dealing with the grief.
Kübler-Ross originally applied these stages to people suffering from terminal illness. She later expanded this theoretical model to apply to any form of catastrophic personal loss (job, income, freedom). Such losses may also include significant life events such as the death of a loved one, major rejection, end of a relationship or divorce, drug addiction, incarceration, the onset of a disease or chronic illness, an infertility diagnosis, as well many tragedies and disasters.
As stated before, the Kübler-Ross Model can be used for multiple situations where people are experiencing a significant loss. We explain how the model is applied differently in a few specific situations below. These are just some of the many examples that Kübler-Ross wanted her model to be used for.
Children grieving in divorce:
Denial – Children feel the need to believe that their parents will get back together or they will change their mind about the divorce. Example: “Mom or Dad will change their mind”
Anger – Children feel the need to blame someone for their sadness and loss. Example: “I hate dad for leaving us”
Bargaining - In this stage, children feel as if they have some say in the situation if they bring a bargain to the table. This helps them keep focused on the positive that the situation might change and less focused on the negative, the sadness they’ll experience after the divorce. Example: “If I do all of my chores maybe Mom won’t leave Dad”
Depression - This involves the child experiencing sadness when they know there is nothing else to be done and they realize they cannot stop the divorce. The parents need to let the child experience this process of grieving because if they do not it will only show their inability to cope with the situation. Example: “I’m sorry that I cannot fix this situation for you.”
Acceptance – This does not necessarily mean that the child is completely happy again. The acceptance is just moving past the depression and starting to accept the divorce. The sooner the parents start to move on from the situation the sooner the kids can begin to accept the reality of it.
Grieving a break-up
Denial – The person getting broken up with is unable to admit that the relationship is really over. They may try to continue to call the person when that person wants to be left alone.
Anger – When the reality sets in that the relationship is over, it is common to demand to know why they are being broken up with. This phase can make them feel like they are being treated unfairly and it may cause them to become angry at people close to them who want to help aid the situation.
Bargaining – After the anger stage, one will try to plead with their former partner by promising that whatever caused the breakup will never happen again. Example: “I can change. Please give me a chance”.
Depression – Next the person might feel discouraged that their bargaining plea did not convince their former partner to change their mind. This will send the person into the depression stage and can cause a lack of sleep, eating and even disrupt daily life tasks such as bowel movements.
Acceptance – Moving on from the situation and person is the last stage. The person accepts that the relationship is over and begins to move forward with their life. The person might not be completely over the situation but they are done going back and forth to the point where they can accept the reality of the situation.
Grieving in substance abuse
Denial – People feel that they do not have a problem concerning alcohol or substances. Even if they do feel as if they might have a small problem they believe that they have complete control over the situation and can stop drinking or doing drugs whenever they want. Example: “I don’t have to drink all of the time. I can stop whenever I want”
Bargaining – This is the stage that drug and alcohol abusers go through when they are trying to convince themselves or someone else that they are going to stop abusing in order to get something out of it or get themselves out of trouble. Example: “God, I promise I’ll never use again if you just get me out of trouble.”
Anger – The anger stage of abusers relates to how they get upset because they have this disease of addiction or are angry that they can no longer use drugs. Some of these examples include “I don’t want to have this addiction anymore.” “This isn’t fair I’m too young to have this problem.”
Depression – Sadness and hopelessness are important parts of the depression stage when dealing with a drug abuser. Most abusers experience this when they are going through the withdrawal stage quitting their addiction. It is important to communicate these feelings as a process of the healing.
Acceptance – With substance abusers admitting you have a problem is different than accepting you have a problem. When you admit you have a problem this is more likely to occur in the bargaining stage. Accepting that you have a problem is when you own that you have a problem and start the process to resolve the issue.
As stated above, according to her hypothesis, Kübler-Ross claimed these stages do not necessarily come in order, nor are all stages experienced by all patients. She stated, however, that a person will always experience at least two of the stages. Often, people will experience several stages in a "roller coaster" effect—switching between two or more stages, returning to one or more several times before working through it. Women are more likely than men to experience all five stages.
However, the Kübler-Ross hypothesis holds that there are individuals who struggle with death until the end. Some psychologists believe that the harder a person fights death, the more likely they will be to stay in the denial stage. If this is the case, it is possible the ill person will have more difficulty dying in a dignified way. Other psychologists state that not confronting death until the end is adaptive for some people.
Researched by
@mannaglide
http://MannaGoods.blogspot.com
---------
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