Alcohol: Clinical Aspects





Acknowledgments


We thank Catharine Helms and Robert H. Cormier, Jr., for their assistance with manuscript preparation.




Introduction


Alcohol is one of the oldest and the most widely used psychoactive substances in the world, second only to caffeine. The use of alcohol is a part of most cultures worldwide, and it is recognized that there are both positive and negative aspects of alcohol consumption. Positive aspects might include the socialization, stimulation of appetite, more rapid onset of sleep, and reduction in the incidence of heart disease. The negative aspects include poor judgment, liver disease, hypertension, memory problems, and even death. Of course, as with all drugs, there is a risk of addiction to alcohol, which exacerbates the negative aspects of alcohol use and leads to its own sequelae of complications and disorders. The National Institute on Alcohol Abuse and Alcoholism notes that “men who drink 5 or more standard drinks in a day (or more than 14 per week) and women who drink 4 or more in a day (or more than 7 per week) are at increased risk for alcohol-related problems.”


The six levels of alcohol use are abstention, experimentation, social or recreational use, habituation, abuse, and, finally, addiction. Abstention is nonuse. Experimentation is the use of alcohol for curiosity and without any subsequent alcohol-seeking behavior. Social or recreational use of alcohol involves sporadic infrequent drinking without any real pattern. Habituation involves drinking with an established pattern, but without any major negative consequences. Abuse of alcohol is the continuation of drinking despite negative consequences. Finally, addiction involves a compulsion to drink, an inability to stop drinking, and the progression of major life dysfunction with continued use. . The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) has consolidated these last two levels of alcohol use to a diagnosis of alcohol use disorder (AUD), which is then rated by severity. .


In the United States, the per-capita consumption of alcohol from beer, wine, and spirits combined in 2013 was 2.34 gallons. This value was unchanged from 2012 but represents the highest per-capita consumption since before 1990. Essentially, after a steady decrease in the mid- to late 1990s, there has been a general increase in per-capita consumption of alcohol since 1999. .


Alcohol use is a significant cause of morbidity and mortality in the United States and worldwide. The World Health Organization reports that the deaths of 3.3 million men and women around the globe were attributable to alcohol consumption, making alcohol use the leading risk factor for premature death and disability among persons ages 15 to 49. In 2014, 16.3 million adults had a past year alcohol use disorder in the United States. Mortality rates follow drinking levels. A European study of 25 countries found that a rise of 1 L per capita in alcohol intake was associated with a 1% rise in all causes of morbidity. The global economic burden of alcohol was estimated to be in the range of $210–665 billion in 2002. The Centers for Disease Control and Prevention (CDC) estimated this figure at $232.5 billion in 2006 in the United States alone.


In the United States, more than 50% of adults have a close family member who is dependent on alcohol. More than 25% of youths younger than the age of 18 years are aware of a relative who is dependent on alcohol. Alcohol dependence runs in families.


The burden of the alcohol dependence disease is not equal across all regions. The disease impact of alcohol dependence is greatest in regions where the per-capita consumption is highest, such as Latin America, as compared with the Middle East. In addition, other factors, such as increasing economic growth, have raised the risk of alcohol dependence in Europe.


Alcohol consumption increases the risk of harm or death in the context of the operation of heavy machinery, fires, falls, and water activities. In the United States, approximately 40% of all traffic fatalities are alcohol related. Trauma and aggressive behavior are associated highly with alcohol consumption less than 6 hours before the event.




Alcohol-Related Disorders


Alcohol is associated with many physical and mental disorders. Perhaps the most well-documented physical disorder is alcohol-related liver disease. Alcohol-induced fatty liver disease and obesity are both associated with progression to cirrhosis. In the United States, more than 600,000 individuals have cirrhosis; about 20%–25% of these cases are attributed to excessive alcohol consumption. Typically, the development of cirrhosis requires the consumption of at least 30 grams of ethanol daily for women and 50 grams daily for men for at least 5 years. In addition, the presence of hepatitis C virus in the context of alcohol dependence is associated with increased rates of cirrhosis. Women have an increased incidence of liver cirrhosis compared to men with the same amount of alcohol consumption and their dose-dependent increase in risk is steeper. Globally, esophageal cancers, head and neck cancers, and liver cancers are of great concern, and are associated with alcohol use disorders.


Individuals with mental illness are susceptible to alcohol use disorders. This, in part, may be due to attempts to self-medicate underlying anxiety, depression, mania, or psychosis. However, drinking alcohol in excess tends to worsen underlying psychiatric illness. Excessive use of alcohol is associated with a poorer chance of recovery from anxiety and depressive disorders. Bipolar disorders and other impulse control disorders are associated with high rates of alcohol dependence. Dually diagnosed individuals have a poorer prognosis than those with just one of these disorders. Drinking more than 29 drinks per week can double the risk of a psychiatric disorder. Neurocognitive disorders such as Alzheimer’s dementia or multiinfarct dementia, can be worsened or be caused by alcohol, and the relationship between the two can be difficult to determine. Alcohol use disorders are common in individuals with schizophrenia and worsen symptoms of the disease. Unfortunately, individuals with mental illness tend to underreport their use of alcohol and remain untreated as a result.




Age at Onset of Drinking Behavior


The age at onset of drinking has a significant role in outcomes. An individual who starts drinking before the age of 15 years is approximately four times more likely to develop alcohol dependence, and this rate increases the earlier the onset of drinking. Data collected from the 2015 National Survey on Drug Use and Health found that 8.7 million 12 to 20 year olds were past-month drinkers, of which 5.3 million reported binge drinking and 1.3 million reported heavy use. Furthermore, according to the Monitoring the Future survey in 2015, 10% of 8th graders, 22% of 10th graders, and 35% of 12th graders reported past-month alcohol consumption. The risk of developing alcohol dependence and a more relapsing illness is greater in adolescents than in adults. Notably, between 20% and 30% of early alcohol drinkers progress to heavy drinking in adulthood. Children who drink often have behavioral problems, especially conduct disorders. Frequently, adolescents, much like adults, are self-medicating for anxiety and depression.


Alcohol dependence is a heterogeneous disorder and consists of subtypes, each with “varying degrees of biological and psychosocial antecedents.” The relationship between biological vulnerability, the environment, and their interactions in the development of alcohol dependence is the subject of active research. Current evidence suggests that alcoholism is 50%–60% determined genetically in both men and women. The term “psychiatric pharmacogenetics” has now entered the alcohol literature. Its purpose is to use genetic testing to predict, on an individual level, which treatment will be efficacious.


Contrary to conventional wisdom, there are a number of studies showing that alcohol dependence is not always a chronic and progressive disease. This assertion is based on longitudinal studies and national surveys. It appears that persons who develop alcohol dependence in middle age have the most stability in terms of the disease. In this population, alcoholism can be a chronic remitting disease. In contrast, individuals who develop alcoholism after the age of 50 years will often decrease their drinking as they age. Of interest, alcohol dependence in persons over 65 years of age continues to increase in the United States.


The 2001–2002 National Epidemiologic Survey on Alcohol and Related Conditions analyzed recovery rates of alcohol-dependent adults over a 1-year period. This population tended to be middle-aged, white males who were well educated (60% college educated); thus the generalizability is limited. More than half of the 4422 adults had experienced the onset of alcohol dependence between the ages of 18 and 24, and only 25% had ever received any treatment for alcohol problems. At 1 year, 35.9% were fully recovered (17.7% low-risk drinkers plus 18.2% abstainers), 25% were still dependent, 27.3% were in partial remission, and 11.8% were asymptomatic drinkers. Only 25% of the group had ever received any type of treatment.




Effects of Ethnicity, Gender, Place of Residence, and Religion on Alcohol Consumption


Ethnicity is a complex and multifaceted construct, and often the terms used by demographers do not reflect the different subgroups. For example, Korean Americans and Chinese Americans are both considered as Asian, but drinking patterns are quite distinct between these two groups. A study conducted in 2004 found a lower rate of alcohol dependence in Chinese-American college students (5%) as compared with Korean-American college students (13%). First-generation Mexicans and native-born Mexicans behave differently in their drinking patterns. Whites have the highest consumption levels, followed by Latinos and, then, Blacks. There is considerable ethnic disparity in the progression of drinking behavior. White men peak first (18–25 years), followed by Hispanic and Black men, with peak ages between 26 and 30 years. Although levels of drinking tend to be low among native-born Latinos, acculturation stress increases alcohol abuse and dependence with migration and first-generation populations. Ethnicity and socioeconomic status are also tied to the level of drinking.


Currently, women have nearly the same rates of alcohol dependence as men. This is in contrast with 1940, when men were more than twice as likely to be dependent on alcohol. Of interest, women often have a more severe disease course—perhaps due to reduced access to care, a greater time period before seeking treatment, or both.


Despite common misperceptions, the extent of drinking among Native Americans varies tremendously by tribe. The proportion of Native Americans who reported being current drinkers ranged from a low of 30% to a high of 84%. This wide range of reported drinking behavior is indicative of considerable variance between the alcohol use in Native American tribes. Furthermore, it has been reported that Northern reservations have a higher incidence of hospital admittance for an alcohol-related medical problem than Southern reservations (111/1000 versus 11/1000, respectively). On some Native American reservations, high quantities of alcohol are consumed per episode, but the frequency of binge drinking is low.


Location also matters. Urban and suburban dwellers have higher rates of dependence compared with their rural counterparts. Drinking styles also differ.


Religion appears to be an important determinant for drinking. Jews, Episcopalians, and Baptists living in rural areas show low rates of alcohol dependence compared with the general population.




Clinical Picture


Alcoholism can present in a multitude of ways, and at times its clinical effects can be subtle. Although there is no typical clinical pattern for an individual’s progression from excessive drinking to alcohol dependence, there are certain themes that prevail. These are based on the pathophysiology of alcohol.


An early manifestation of excessive drinking is intoxication. This can begin with one’s peers or by the influence of an older individual or family member. Some individuals note stress, depressed mood, or negative affect as a driving force, although at times it is elation. For others, there is an urge to drink, or craving. Although the concept of craving appears simple, the craving literature has found it difficult to define with consensus. When alcohol consumption leads to repeated bouts of intoxication and becomes a fixed pattern of behavior, the likelihood of alcohol-related problems increases.


As the body adapts to excessive alcohol consumption, tolerance develops. With tolerance, an increasingly greater amount of alcohol consumption is needed to obtain the same physiological effects. This can manifest as worsening grades or sick days among college students and workers and, for both, an increase in stress within interpersonal relationships, often characterized by greater irritability and moodiness. Furthermore, driving while under the influence of alcohol becomes more likely, and can lead to legal complications as well as morbidity and mortality to drivers, passengers, and other bystanders.


Heavy drinking can lead to blackouts, a failure to recall the events around the intoxication, due to the brain’s inability to process and lay down the memory in the hippocampus.


Hangovers, which are associated with headaches and nausea, can manifest the next morning after a bout of heavy drinking. Often, as duties and responsibilities lapse, attention to hygiene can wane, and the chronic drinker’s demeanor and behavior change. Memory lapses or forgetfulness may become more evident. In addition, the chronic excessive drinker may report guilt, remorse, and self-loathing after consuming alcohol and might conceal his or her drinking in order to avoid dealing with others. Such individuals tend to minimize the severity of their drinking behavior and its impact on others.


When drinking is being concealed, social isolation tends to occur, and to block or dampen guilt and anxiety, “relief drinking” can happen. Relief drinking may serve not only to temper these feelings but also to transiently reduce the resulting insomnia. Relief drinking might also temporarily ameliorate withdrawal symptoms upon drinking cessation (often starting within a few hours), which are the consequence of sympathetic nervous system hyperactivity. These symptoms can include tremulousness and anxiety and can proceed to a spectrum of serious withdrawal patterns, including delirium tremens. Despite any painful consequences such as loss of relationships, employment, legal entanglements, and physical and psychological complications, drinking can become the individual’s sole goal. The physical features of the disease are described below.




Signs and Symptoms


Cardiovascular System


Although it has been consistently shown that light-to-moderate drinking reduces the risk of coronary artery disease, there still remain severe risks to the cardiovascular system for people who are heavy alcohol drinkers. Cardiovascular conditions that may result from heavy drinking include hypertension, cardiac arrhythmias, and dilated cardiomyopathy.


The relationship between hypertension and heavy alcohol use has been known for more than three decades. Although a mechanism has yet to be elucidated, several clinical studies have confirmed this relationship. Clinicians in all fields of medicine should be aware that hypertension can be the result of heavy and chronic alcohol consumption.


The incidence of cardiac arrhythmias following excessive alcohol consumption is commonly known as “holiday heart phenomenon” following the observation that supraventricular arrhythmias in alcoholics most often occur on Mondays or between Christmas and New Year’s Day. Although the direct cause of arrhythmias following heavy drinking is not explicitly known, it has been suggested that it could be due to myocardial damage, vagal reflexes, electrolyte or metabolic effects, or changes in conduction and refractory periods. Regardless of the root cause, the incidence of cardiac arrhythmias doubles for heavy drinkers compared with light drinkers.


Dilated cardiomyopathy is characterized by an enlarged heart with weakened contraction. Sustained heavy alcohol use is thought to be a major contributing factor to dilated cardiomyopathy. Although the prevalence of alcohol-induced dilated cardiomyopathy is not fully known, it is estimated that up to 40% of dilated cardiomyopathy cases are a result of excessive alcohol consumption. The clinical picture may initially involve nonspecific electrocardiographic findings and possible rhythm disturbances but may progress to congestive heart failure, chronic rhythm disturbances, and even death.


Gastrointestinal System


Excessive alcohol consumption can cause gastroesophageal reflux disease, gastritis, or ulcers in the lining of the stomach. These can manifest as a burning in the throat or stomach or complaints of dark stools (i.e., melena). In individuals who present with a long history of gastroesophageal reflux disease, there is an increased incidence of Barrett’s esophagus, a metaplastic conversion of the mucosa of the lower esophagus; it is a well-known precursor lesion for esophageal cancer.


Chronic excessive alcohol consumption can cause varices, both gastric and esophageal. When varices rupture, often during severe retching, the individual may present with bright red blood. Bleeding varices are life-threatening medical emergencies. Mallory-Weiss tears from esophageal varices often require monitoring in intensive care settings due to their risk for re-bleeding with a high rate of blood loss.


Hepatic System


Chronic excessive alcohol consumption is associated with an increased risk for the development of liver disease. In the United States, 2 million people have alcoholic liver disease, ranging in severity from fatty liver to alcoholic hepatitis and end-stage cirrhosis.


Fatty liver is the accumulation of fatty acids in the liver. The pathogenesis of fatty liver is due to the overproduction of protonated nicotinamide adenine dinucleotide from alcohol dehydrogenase, which, in turn, leads to the inhibition of fatty acid oxidation, the citric acid cycle, and gluconeogenesis. It is the inhibition of fatty acid oxidation, as well as an increased synthesis of triglycerides, followed by the inhibition of the secretion of lipoprotein from the liver, which all contribute to fatty liver.


Alcoholic hepatitis causes inflammation of the liver along with areas of fibrosis and necrosis. In the United States, approximately 10%–35% of heavy drinkers develop alcoholic hepatitis. It can take months to years to develop this condition, and the only method to arrest its progress is through abstinence. Nevertheless, even with the cessation of alcohol consumption, the resulting scarring of the liver and any other collateral damage remain. The mortality rate in individuals with alcoholic hepatitis is 15%–20%, and even despite abstinence, many cases progress to cirrhosis .


Cirrhosis is characterized by progressive scarring of the liver due to the toxic effects of excessive alcohol use and alcohol’s metabolites. Cirrhosis, the most advanced form of alcoholic liver disease, is the leading cause of death among alcoholics. In 2010, approximately 490,000 deaths occurred due to alcohol-related liver disease, which represented 0.9% of all global deaths.


More than 15,000 Americans die each year from cirrhosis due to excessive alcohol use. Individuals with a diagnosis of both alcoholic hepatitis and cirrhosis have a death rate of more than 60% over a 4-year period. Most individuals die within the first 12 months of receiving the diagnosis. Although the progression of cirrhosis might be halted by abstinence, cirrhosis is very difficult to treat, and the damage to the liver cannot be reversed.


Endocrine System


Pancreatitis, both acute and chronic, is another complication of excessive alcohol use. Pancreatic insufficiency or malabsorption presents with gray, foul-smelling stools that float. Pancreatitis typically manifests with pain in the center of the abdomen that radiates to the back. Pancreatitis ranges from an uncomfortable but stable condition to a medical emergency, depending on the severity of the event. Individuals with chronic pancreatitis may have calcifications that can be seen on a plain radiographic film.


Diabetes, both type 1 and type 2, can be a consequence of excessive alcohol use. The development of type 1 diabetes is rare and is due to almost complete destruction of the pancreas. Type 2 diabetes is more common and due to weight gain from carbohydrate ingestion. Hypogonadism and osteoporosis are other complications. Thyroid disease also can be a sequela of excessive alcohol use, abuse, or dependence.


Rheumatic and Immune System


Chronic excessive alcohol consumption has been linked with an increase in illness and death from infectious diseases. Due to alcohol’s immunosuppressive effects, there is an increased susceptibility to bacterial pneumonia, pulmonary tuberculosis, and hepatitis C. There is even some speculation that chronic excessive alcohol users are at increased risk for HIV infection due to lowered immune response, and that those with HIV may have a quicker progression from HIV to full-blown AIDS.


Gout is a common complication of chronic excessive alcohol consumption. Podagra (gout in the big toe) is a typical complaint. Alcohol use appears to mitigate certain autoimmune conditions such as systemic lupus erythematosus and rheumatoid arthritis.


Hematological/Hematopoietic System


Anemias, both macrocytic and microcytic, are possible. Macrocytic anemia can be due to folate or vitamin B 12 deficiency. An increased mean corpuscular volume can reflect macrocytic anemia. Of note, an increased mean corpuscular volume can also be a result of liver disease when the lipid bilayers that hold the red cell do not form correctly. When liver disease is severe, platelets can be destroyed or can sequester in an enlarged spleen. Microcytic anemias are related to active bleeding or blood loss and should prompt evaluation for a gastrointestinal disorder or lesion. Sideroblastic anemia can also occur.


Central Nervous System


The brain is sensitive to alcohol’s toxic effects. Areas that are particularly sensitive include the hippocampus and the cerebellum, which can result in memory deficits and dementias as well as abnormal gait and intention tremors. Rarely, central pontine myelinolysis can occur. These central nervous system deficits are discussed in detail in subsequent text of this chapter.


Peripheral Neurological System


Changes in position and vibration sense occur after prolonged excessive alcohol use and are due to vitamin B 12 or folate deficiencies, or both. Myopathy can be a rare manifestation of alcohol dependence.


Integumentary System (Skin)


Psoriasis vulgaris, acne rosacea, and erythropoietic protoporphyria are all common skin conditions associated with excessive alcohol use. With liver disease, spider nevi, telangiectasias, palmar erythema (reddened palms), spider angiomas, and hepatic porphyrias, particularly porphyria cutanea tarda (bullous erosions, blistering, crusting lesions, and scarred healing with hyperpigmentation or depigmentation on the face, the side of the neck, and the back of the hands), might be found.


Nutritional Status


Low levels of potassium, magnesium, and phosphorus are common in individuals with severe alcohol dependence. Hypophosphatemia and hypomagnesemia also can be complications of severe nutritional deficiency. A refeeding syndrome that can lead to diaphragmatic paralysis and respiratory failure can occur. On many blood chemistries, magnesium and phosphorus are not part of the panel. Therefore, it is prudent to check these electrolytes in an alcohol-dependent individual who appears nutritionally compromised. Low levels of potassium can cause additional medical complications (particularly cardiovascular) if not replaced; however, this can be difficult to achieve in the setting of low magnesium. Therefore, magnesium and potassium need to be replenished simultaneously. As noted previously, thiamine replacement is also often required.


Oncology


An increasing number of cancers are being associated with excessive alcohol use or dependence. Traditionally, alcohol-related cancers include oropharyngeal, esophageal, gastric, pancreatic, and rectal cancers. In women, alcohol abuse has been reported to contribute to the etiology of breast cancer.


Fetal Development


The consumption of alcohol during pregnancy has been linked with poor birth outcomes, the potential for long-term developmental disabilities, and the manifestation of fetal alcohol spectrum disorder, which includes fetal alcohol syndrome. According to the CDC, 1 in 10 pregnant women reported consuming alcohol in the past 30 days and 1 in 33 reported binge drinking in 2011–2013. Whereas among nonpregnant women the prevalence rate of any alcohol use was 53.6%, pregnant women had a rate of 10.2%.


It has been estimated that the annual cost of care for those diagnosed with fetal alcohol spectrum disorders is $3.6 billion and that the lifetime cost for a single individual is $2.9 million. These numbers are staggering considering that maternal alcohol use during pregnancy is the leading cause of preventable birth defects and neurodevelopmental disabilities in the United States. The health care community continues to emphasize prevention and stresses abstinence from alcohol for women who are pregnant or considering becoming pregnant. Research into the clinical management of persons diagnosed with fetal alcohol spectrum disorders is still emerging, but human studies using behavioral intervention are encouraging.


The clinical manifestations of fetal alcohol exposure fall under the classification of fetal alcohol spectrum disorders. Fetal alcohol spectrum disorders can be further subdivided into four categorical syndromes: (1) fetal alcohol syndrome; (2) partial fetal alcohol syndrome; (3) alcohol-related neurodevelopmental disorder; and (4) alcohol-related birth defects. In a study of first grade children, the authors reported an estimated prevalence of fetal alcohol syndrome between 1 and 9 per 1000 and an estimated prevalence of combined fetal alcohol syndrome plus partial fetal alcohol syndrome to be much higher at 17–26 per 1000. This rate is significantly higher when compared to CDC data, which estimates a prevalence of 0.3 per 1000 children.


A clinical diagnosis of fetal alcohol syndrome requires alcohol exposure, a recognizable facial pattern that includes short palpebral fissures (<10th percentile), thin upper vermilion lip, and smooth philtrum, evidence of growth retardation or malformation, and evidence of neurocognitive defects. Newborns with fetal alcohol syndrome may exhibit irritability, tremors, hypotonia, and even withdrawal symptoms. Partial fetal alcohol syndrome is diagnosed when there is confirmation of alcohol consumption during pregnancy and, although not all the features of fetal alcohol syndrome are present, neurocognitive and some craniofacial features are present. Children diagnosed with alcohol-related neurodevelopmental disorder do not typically have the growth retardation or facial features characteristic of fetal alcohol syndrome, but the resulting neurocognitive defects are more pronounced. A diagnosis of alcohol-related birth defect requires some of the facial features characteristic of fetal alcohol syndrome, but it is the behavioral features or structural abnormalities that are more prominent.


In addition to the physical impairments inflicted by alcohol, there is a spectrum of cognitive problems that children who are diagnosed with fetal alcohol spectrum disorders exhibit. These problems include difficulties with hyperactivity, sustained and focused attention, cognitive flexibility, learning and memory, and social understanding. Aside from cognitive deficits, these children can also exhibit psychological and behavioral difficulties such as psychiatric problems, inappropriate sexual behavior, and alcohol and/or drug abuse. In fact, 90% of children diagnosed with fetal alcohol spectrum disorders have some form of diagnosable psychiatric disorder, ranging from attention deficit disorder to depression to schizophrenia. Fifty percent have been confined in either a mental health or criminal justice institution.


Although perinatal exposure to alcohol is known to be detrimental to fetal development, there is some debate as to whether it is ethanol or its metabolite acetaldehyde that causes the developmental abnormalities found in fetal alcohol syndrome. Acetaldehyde is 10 times more teratogenic than alcohol. However, this differential in teratogenicity is, perhaps, countered by the fact that blood ethanol concentration is 10 times higher than acetaldehyde in the typical person.


Acetaldehyde levels in excess of 35 μg can cause damage to a fetus, but acetaldehyde is rapidly metabolized by the placenta, and, after the third month of pregnancy, no acetaldehyde is detectable in the fetus. The placenta is, however, permeable to ethanol, and the fetus does not have ethanol dehydrogenase, the enzyme required to break down ethanol. It is, therefore, reasonable to propose that an hour or two following alcohol ingestion, the ethanol concentration in the mother’s blood may be falling while the ethanol concentration of the fetus may be rising. Although it is not clear whether it is alcohol itself or its metabolite acetaldehyde that is responsible for the developmental abnormalities found in fetal alcohol spectrum disorders, the physical findings in fetal alcohol syndrome do point to an interesting fact: it is not the disruption of developing tissues but rather the reduction in the number of cells and the subsequent cell migration abnormalities, particularly of the central nervous system, that causes the anomalies found in fetal alcohol syndrome.

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Jan 19, 2020 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Alcohol: Clinical Aspects
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