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Effects of Lack of Sleep to Students of Philippine State College Essay Sample

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Effects of Lack of Sleep to Students of Philippine State College Essay Sample

A person may not receive the recommend amount of sleep in a night. School, friends, family, and social events can all be factors in reducing a person’s amount of sleep. It may not seem a whole lot to miss out on just a couple hours a night, but lacking a proper amount of sleep can hurt us in our day to day activities. Sleep is an essential life process. It is as important to our well-being as the food we eat, the water we drink, and the air we breathe. Unfortunately, it is easy to take sleep for granted. Busy people sometimes regard sleep as a waste of time. As college students, many of us have grown used to sleepless nights, be it as a result of long nights of studying, doing assignments we have put off until the last minute, or partying a bit too hard. Regardless of the reasons, we have all experienced the effects of sleepless nights although the effects are not always immediately apparent. Many of us do not really understand the dynamics of sleep nor do we recognize the purpose and the importance of sleep. Sleep is also the body’s way of rejuvenating itself. This process helps replenish the energy stores we have depleted throughout the day, as well as give our organs the opportunity to rest.

Sleep relaxes us and helps with the overall health of the central nervous system. Lack of sleep can lead to decrease in concentration, reaction time and overall alertness. Of course, these effects are of great importance for students in all majors, but more so for aeronautics you feel the next day. If you wake up irritable, tired and unenergetic, you probably are not getting all of the sleep you need. Sleep deprivation or a reduction in the amount of sleep we require is cumulative; however, the fact still remains that one good night of sleep will make up for several nights of lost sleep. Typically, an average person sleeps seven to eight hours each night. How do you then explain those who sleep less than the average? These people are generally more active, sociable, ambitious and extroverted, while those who sleep more than eight hours a night have been found to be introverted, critical and significant worriers. Sleeping too much or too little may be one of the warning signs of physical, emotional or behavioural problems.

Common causes of sleep difficulties, Sleep problems or insomnia are traditionally classified as non-specific medical problems, which may have many causes. Lack of sleep can lead to deficiency, lack of concentration, lack of overall alertness and reaction time. Emotional factors such as anxiety, depression, life stressors, or disturbing thoughts at bedtime may create sleep disorders. Of course, these effects are of great importance for students in all majors especially to those aeronautical students who have flight responsibilities. This research has been made to identify the relationship between lack of sleep and the quality of the performances done by the students of Philippine State College of Aeronautics. Students will benefit from this research for this may help in informing them why they should take enough sleep. This may also show the direct relationship that the quality of sleep received by the students affects their performance and participation in school.

Related Studies
Lack of sleep (Sleep Deprivation)
Sleep deprivation is the condition of not having enough sleep; it can be either chronic or acute. A chronic sleep-restricted state can cause fatigue, daytime sleepiness, clumsiness and weight loss or weight gain. It adversely affects the brain and cognitive function. Few studies have compared the effects of acute total sleep deprivation and chronic partial sleep restriction Effects on the Brain

Sleep deprivation can adversely affect the brain and cognitive function.[17] A 2000 study, by the UCSD School of Medicine and the Veterans Affairs Healthcare System in San Diego, used functional magnetic resonance imaging (fMRI) technology to monitor activity in the brains of sleep-deprived subjects performing simple verbal learning tasks.[18] The study showed that regions of the brain’s prefrontal cortex, an area that supports mental faculties such as working memory and logical and practical (“means-ends”) reasoning, displayed more activity in sleepier subjects. Researchers interpreted this result as indicating that the brain of the average sleep-deprived subject had to work harder than that of the average non-sleep-deprived subject to accomplish a given task, and from this indication they inferred the conclusion the brains of sleep-deprived subjects were attempting to compensate for adverse effects caused by sleep deprivation.The temporal lobe , which is known to be a brain region involved in language processing, was activated during verbal learning in rested subjects but not in sleep-deprived subjects. The parietal lobe, not activated in rested subjects during the verbal exercise, was more active when the subjects were deprived of sleep. Although memory performance was less efficient with sleep deprivation, greater activity in the parietal region was associated with better short term memory.

A 2001 study at Chicago Medical Institute suggested that sleep deprivation may be linked to serious diseases, such as heart disease and mental illness including psychosis andbipolar disorder.[citation needed] The link between sleep deprivation and psychosis was further documented in 2007 through a study at Harvard Medical School and the University of California at Berkeley. The study revealed, using MRI scans, that sleep deprivation causes the brain to become incapable of putting an emotional event into the proper perspective and incapable of making a controlled, suitable response to the event. Sleep deprivation may have been the underlying cause of the overdose deaths of celebrities Heath Ledger andAnna Nicole Smith. A study tested 17 right-handed civilian males, between the ages of 21–29 years (mean 24.7 ± 2.8 years), with no history of medical, neurological, psychiatric, or sleep disorder conditions. Their histories also included 7–8 hours of nightly sleep on a regular basis, no nicotine use, and low caffeine use (less than 100 mg/day). The negative effects of sleep deprivation on alertness and cognitive performance suggest decreases in brain activity and function, primarily in the thalamus, structure involved in alertness and attention, and in the prefrontal cortex, a region sub-serving alertness, attention, and higher-order cognitive processes.

This study used a combination of positron emission tomography (PET) and Fluorine-2-deoxyglucose (FDG), a marker for regional cerebral metabolic rate for glucose (CMRglu) and neuronal synaptic activity. A time series design was used, with progressive sleep deprivation as the independent variable. Repeated measures of absolute regional CMRglu, cognitive performance, alertness, mood, and subjective experiences were collected after 0, 24, 48, and 72 h of sleep deprivation. Additional measures of alertness, cognitive performance, and mood were collected at fixed intervals throughout the sleep deprivation period. These measures were included to place the performance results associated with the PET scans in the context of the circadian rhythm of cognitive performance, as well as to impose a moderate-to-heavy near continuous workload on the subjects as might be anticipated in a real-world sustained operation. A noted 2002 University of California animal study indicated that non-rapid eye movement sleep (NREM) is necessary for turning off neurotransmitters and allowing their receptors to “rest” and regain sensitivity which allows monoamines (norepinephrine, serotonin and histamine) to be effective at naturally produced levels. This leads to improved regulation of mood and increased learning ability.

The study also found that rapid eye movement sleep (REM) deprivation may alleviate clinical depression because it mimics selective serotonin reuptake inhibitors (SSRIs). This is because the natural decrease in monoamines during REM is not allowed to occur, which causes the concentration of neurotransmitters in the brain that are depleted in clinically depressed persons, to increase. Sleep outside of the REM phase may allow enzymes to repair brain cell damage caused by free radicals. High metabolic activity while awake damages the enzymes themselves preventing efficient repair. This study observed the first evidence of brain damage in rats as a direct result of sleep deprivation. Scientists Find Brain Areas Affected By Lack of Sleep

Nov. 14, 2003 — Lack of sleep can affect an individual’s memory, ability to perform simple daily tasks, and attention span. Recent studies that help decipher the basic mechanism of sleep may help in the development of drugs that reduce the need for sleep in military combat or other circumstances.In other research, investigators have found that sleeping only a few hours a night over a long period of time impairs memory and alertness. Another study shows that sleep deprivation for a short period may actually enhance memory for some tasks. Still another study provides a glimpse into what areas of the brain are impaired by sleep deprivation and how this in turn affects decision-making. Giulio Tononi, MD, PhD, and his group have used a molecular approach to investigate what happens during sleep. They have screened more than 15,000 genes to identify all those whose expression changes during sleep compared to waking, and also after sleep deprivation. Work published by several laboratories last year showed that expression of many genes in Drosophila and mice changes in the brain depending on the time of day (e.g., 4 am versus 4 pm). These cycling genes that work according to circadian time are involved in many cellular functions. However, it was not known to what extent changes in gene expression between day and night depend on circadian time versus when an individual is actually asleep or awake, whether it be day or night.

Tononi and his colleagues set up an experiment to identify gene expression changes related to sleep and wakefulness per se, as opposed to simply day and night. To do so, they placed electrodes on the skulls of rats–who are nocturnal animals–to detect their sleep and assigned them to three groups: Rats who were allowed to sleep spontaneously were sacrificed at 6 pm during their usual sleep period; sleep-deprived rats were killed at the same circadian time after having been kept awake by playing with them for eight hours; spontaneously awake rats were killed at 6 am during their usual waking period. The investigators found that while 10 percent of genes expressed in the cerebral cortex do change in their level of expression between day and night, about half of them do so not because of circadian time but because of wakefulness and sleep, regardless of time of day. “We even found there are molecular correlates of sleep and wakefulness in brain structures not known to sleep, such as the cerebellum,” said Tononi. “This suggests that sleep may serve some cellular function even when it has not been observed electrophysiologically.”

The investigators found specific categories of genes that are selectively expressed in the sleeping and in the awake of the brain. The genes associated with wakefulness include mitochondrial genes involved in energy metabolism, those involved in acquiring new memories, and stress response genes. Sleep-related genes were found to be involved in consolidation of memories and initiation of protein synthesis, as had been found in previous studies, and in membrane trafficking, which had not been shown before. “Our study shows that sleep, far from being a quiescent state of global inactivity, may actively favor specific cellular functions,” Tononi said. In other molecular work, Yoshihiro Urade, PhD, found that mice deficient in prostaglandin D2 synthase (PGD2S) (the enzyme that produces prostaglandin D2 in the brain), prostaglandin D2 receptor (PGD2R), or adenosine A2A receptor could not rebound–that is, regain their functioning through deeper sleep–after being deprived of sleep for a long time. Prostaglandin D2 is a sleep hormone that initiates the signal for sleep by binding its receptor, PGD2R. This signal is then transmitted to VLPO, a sleep center, via adenosine by way of adenosine A2A receptor. Adenosine A2A receptor is believed to be a target of caffeine, which inhibits sleepiness. The phenomenon of rebounding after sleep deprivation is what occurs when you wake up much earlier in the morning than usual or when you work until midnight.

You will naturally be sleepy the next day and will try to sleep much longer and deeper than usual. The researchers deprived both wild-type mice and PGD2S, PGD2R, or A2A knockout mice of sleep for six hours by gently touching their face and body with a cotton pad. They then analyzed sleep profiles during a recovery period by measuring electroencephalogram data. All the wild-type mice showed an increase in non-REM and REM sleep during the recovery period. But all the knockout mice showed almost no non-REM sleep rebound and shorter REM sleep rebound than wild-type mice. “Drugs that can increase prostaglandin D2 receptor or adenosine A2A receptor activity will be a new type of sleeping pill,” said Urade, “while those that inhibit their activity may help suppress sleepiness and enhance wakefulness.” In another line of work, Daniel Press, MD, and his colleagues at Beth Israel Deaconess Medical Center in Boston sought to determine the effects of chronic sleep restriction on cognitive functioning, in particular on working memory. Working memory is the maintenance of information in a short-term buffer for later manipulation to guide behavior. Working memory is similar to RAM in a computer–it is able to perform different tasks for a short time, then empty itself to perform the next task.

The investigators studied the working memory capacities of individuals who were restricted to four hours of sleep per night for nine days. Seven of the twelve participants in the study slept four hours each night, and five slept for eight hours. Each morning, participants completed a computer task to measure how quickly they could access a list of numbers they had been asked to memorize. The list could be one, three, or five items long. Then participants were presented with a series of single digits and asked to answer “yes” or “no” to indicate whether each digit was one they had memorized. The speed of their responses was measured. The longer it took an individual to respond, the less efficient their working memory. As had been shown previously, it took longer for participants to respond when they had to keep five items in working memory than when they had to keep only one. This measure allowed the researchers to eliminate motor slowing as a factor in the less efficient working memory. If fatigue made people slower at pushing the buttons to answer yes or no, their response times for one-, two-, or five-item tasks would have decreased equally over time, because the only difference between the tasks is the amount of working memory required. Individuals who slept eight hours a night steadily increased their working memory efficiency on this task.

But participants who slept only four hours a night failed to show any improvement in memory efficiency. Motor skill did not change across days for either group of participants. “Even relatively minor degrees of sleep restriction can impair alertness and performance,” Press said. “Continued research on the specific skills affected by different levels of sleep deprivation is crucial to our understanding of how sleep can influence performance on the tasks we encounter in our daily lives.” A surprising finding by Ilana Hairston, PhD, from Craig Heller and Robert Sapolsky’s groups at Stanford University is that sleep-deprived rats actually performed better in a task that required localization of an easily detectable cue than did non-sleep-deprived rats. By contrast, sleep deprivation impaired performance of rats in a task requiring spatial navigation.

Lack of Sleep Takes Toll on Brain Power
By Daniel J. DeNoon
WebMD Health News
Feb. 9, 2000 (Atlanta) — A sleepy person’s brain works harder — and accomplishes less. A study using real-time, state-of-the-art imaging shows that sleep deprivation has dramatic effects on the brain and how well it performs.Researchers expected to find only sluggish activity in the brains of healthy young people who took a simple word test after staying awake for 35 hours. They found instead that while parts of the sleep-deprived brains churned with activity during the test, another part of the brain — the language center — shut down. “Sleep deprivation is bad for your brain when you are trying to do high-level [thinking] tasks,” study co-author J. Christian Gillin, MD, tells WebMD. “It may have serious consequences both on performance and on the way your brain functions.”Gillin’s team at the University of California, San Diego, and the San Diego VA Medical Center found that the brains of some sleep-deprived study participants tried to overcome the language-center shut-down by shifting activity to another part of the brain. These individuals performed better on the memory test than their sleep-deprived peers, but not as well as they did when rested. “What this shows is that the brain is very flexible,” Monte S. Buchsbaum, MD, professor of psychiatry at Mount Sinai School of Medicine, tells WebMD.

“This shows that the brain can move a task from one area to the other when you are sleep deprived, or when you get old.” Jim Horne, PhD, director of the sleep research laboratory at Loughborough University in England, notes in a commentary accompanying the study that the part of the brain that overworks in the sleep-deprived people normally is one of the most active areas of the brain. It is involved in complex functions such as updating working memory, planning, attention, sense of time, dealing with novel situations, and verbal fluency. “Some years ago, we suspected that if sleep offers some sort of recovery process, then the parts of the cortex that work hardest during wakefulness may be those that suffer the deprivation initially,” he tells WebMD.

“But what seems to be happening is that the functional part of the brain appears to be working even harder during compensation — to no avail, because performance shows deterioration.” However, Horne says that this part of the brain gets its rest during the earlieststages of sleep. “Not all of sleep is for recovery. A particular part of sleep occurring in the early part of sleep is most important for [brain] recovery, and the latter part is not so important in that regard,” he says. “As we can eat more food than we require and drink more fluids than we require, we may sleep more than we require. Rather than trying to extend one’s sleep ? perhaps we should take short naps instead.”

Effects on growth
A 1999 study found that sleep deprivation resulted in reduced cortisol secretion the next day, driven by increased subsequent slow-wave sleep. Sleep deprivation was found to enhance activity on the hypothalamic-pituitary-adrenal axis (which controls reactions to stress and regulates body functions such as digestion, the immune system, mood, sex, or energy usage) while suppressing growth hormones. The results supported previous studies, which observed adrenal insufficiency in idiopathic hyper insomnia. Sleep deprivation can have significant and important effects on the secretion of hormones from endocrine glands, especially those that follow a circadian pattern. A classic example includes the effect of sleep loss or disruption in children and the impact on growth. Growth hormone is secreted during slow-wave sleep, which is more common in the early part of the night in children. When this sleep is disrupted, either through inadequate sleep or from disorders such as sleep apnoea, the amount of growth hormone released is compromised. As a result, children may not reach their full growth potential, becoming shorter than they otherwise would have been. Sleep deprivation also seems to affect the activity of the thyroid gland. It is thought that the increased energy needs while staying awake for too long demand more work from the thyroid.

Effects on healing process

Sleep Deprivation Delays Wound Healing
Yahoo.com (December 17, 2007)

Without proper sleep, the body cannot recovery and rejuvenate for the next day. Sleep deprivation is a stress induced complication but can also lead to additional stress upon the body. For individuals who suffer from injury, sleep deprivation can have an adverse affect on the healing and recovery process. Wound healing is a complex physiological process that engages protein changes, cell division and replication, and promotes the release of growth hormones. With sleep, these processes are vastly improved. When sleep deprived, the body is unable to engage in the wound healing processes as it is actively working to maintain normal bodily functions. With sleep deprivation, the most significant complication involves the loss of growth hormone secretion which not only impairs wound healing, it impairs total body function. If you suffer from an injury that involves a wound, either internal or external, it is important to understand the impact your sleep may have on your recovery. In many cases, pain and other wound healing complications impede the ability of the sufferer from gaining quality sleep. As a result, pain medications prescribed often include both a pain alleviating component but also a sleeping aide. As you work through your recovery, it is important to ask your physician to guide you through the processes that involve sleep and to reduce the risk for sleep deprivation.

In addition to the actual wound healing process, quality sleep also serves to promote improvement in the immune system. With improved immune system, you can reduce your risk for additional injury, infection and improve your mental state of mind. These dynamics are also important to the wound and injury healing process .The timing of your sleep deprivation may also play an impact on the wound healing process. As a general train of thought, the first five days following your injury may result in some degree of sleep deprivation but this sleep deprivation does not adversely affect your wound healing process. It is the sleep deprivation that occurs in the period beginning after day six that may have the greater long term impact on your wound healing. Therefore, management of your wound healing and sleep deprivation should be highly focused well past day five. As sleep disorders continue to be a leading focus of many healthcare initiatives, much focus is turned to the reduction of sleep deprivation in individuals who suffer from wound healing complications. When treating for an injury, ask your healthcare professional about the medications and methods you can utilize to aide in a restful and quality sleep for the weeks after your injury occurs.

Attention and working memory
Among the numerous physical consequences of sleep deprivation, deficits in attention and working memory are perhaps the most important; such lapses in mundane routines can lead to unfortunate results, from forgetting ingredients while cooking to missing a sentence while taking notes. Working memory is tested by such methods as choice-reaction time tasks. The intentional lapses also extend into more critical domains in which the consequences can be life-or-death; car crashes and industrial disasters can result from inattentiveness attributable to sleep deprivation. To empirically measure the magnitude of attention deficits, researchers typically employ the psychomotor vigilance task (PVT) which requires the subject to press a button in response to a light at pseudo-random intervals. Failure to press the button in response to the stimulus (light) is recorded as an error, attributable to the micro sleeps that occur as a product of sleep deprivation. Crucially, individuals’ subjective evaluations of their fatigue often do not predict actual performance on the PVT.

While totally sleep-deprived individuals are usually aware of the degree of their impairment, lapses from chronic (lesser) sleep deprivation can build up over time so that they are equal in number and severity to the lapses occurring from total (acute) sleep deprivation. Chronically sleep-deprived people, however, continue to rate themselves considerably less impaired than totally sleep-deprived participants. Since people usually evaluate their capability on tasks like driving subjectively, their evaluations may lead them to the false conclusion that they are able to perform tasks that require constant attention when their abilities are in fact impaired. Sleep deprivation: Impact on cognitive performance

(October 2007)
The two most widely studied cognitive domains in SD research are attention and working memory, which in fact are interrelated. Working memory can be divided into four subsystems: phonological loop, visuospatial sketchpad, episodic buffer and central executive (Baddeley and Hitch 1974; Baddeley 2000). The phonological loop is assumed to temporarily store verbal and acoustic information (echo memory); the sketchpad, to hold visuospatial information (iconic memory), and the episodic buffer to integrate information from several different sources. The central executive controls them all. Executive processes of working memory play a role in certain attention functions, such as sustained attention (Baddeley et al 1999), which is referred to here as vigilance. Both attention and working memory are linked to the functioning of frontal lobes (for a review, see Naghavi and Nyberg 2005). Since the frontal brain areas are vulnerable to SD (Harrison et al 2000; Thomas et al 2000), it can be hypothesized that both attention and working memory are impaired during prolonged wakefulness. The decrease in attention and working memory due to SD is well established. Vigilance is especially impaired, but a decline is also observed in several other attentional tasks (Table 1).

These include measures of auditory and visuo-spatial attention, serial addition and subtraction tasks, and different reaction time tasks (Table 1). The most frequently used task is the psychomotor vigilance test (PVT, lasts usually 10 min) (Dinges and Powell 1985), which is sensitive to sleep loss effects and provides information about both reaction speed and lapses. In working memory, the tests have varied from n-back style tasks with different demand levels to choice-reaction time tasks with a working memory component (Table 1). However, some studies have also failed to find any effect. After one night of SD, no difference was observed between deprived and non-deprived subjects in simple reaction time, vigilance, or selective attention tasks in one study (Forest and Godbout 2000). Performance on the Wisconsin Card Sorting Test, a measure of frontal lobe function, also remained even (Binks et al 1999;Forest and Godbout 2000). These results may be partly biased because of small sample sizes, inadequate control of the subjects’ sleep history or the use of stimulants before the study. Impairment of ability

The dangers of sleep deprivation are apparent on the road; the American Academy of Sleep Medicine (AASM) reports that one in every five serious motor vehicle injuries is related to driver fatigue, with 80,000 drivers falling asleep behind the wheel every day and 250,000 accidents every year related to sleep, though the National Highway Traffic Safety Administration suggests the figure for traffic accidents may be closer to 100,000. The AASM recommends pulling off the road and taking a 15- or 20-minute nap to alleviate drowsiness. According to a 2000 study published in the British Medical Journal, researchers in Australia and New Zealand reported that sleep deprivation can have some of the same hazardous effects as being drunk. People who drove after being awake for 17–19 hours performed worse than those with a blood alcohol level of .05 percent, which is the legal limit for drunk driving in most western European countries and Australia. Another study suggested that performance begins to degrade after 16 hours awake, and 21 hours awake was equivalent to a blood alcohol content of .08 percent, which is the blood alcohol limit for drunk driving in Canada, the U.S., and the U.K. In addition, as a result of continuous muscular activity without proper rest time, effects such as cramping are much more frequent in sleep-deprived individuals. Extreme cases of sleep deprivation have been reported to be associated with hernias, muscle fascia tears, and other such problems commonly associated with physical overexertion.

A 2006 study has shown that while total sleep deprivation for one night caused many errors, the errors were not significant until after the second night of total sleep deprivation. However, combining alcohol with acute sleep deprivation results in a trebled rate of driving off the road when using a simulator. The National Sleep Foundation identifies several warning signs that a driver is dangerously fatigued, including rolling down the window, turning up the radio, trouble keeping eyes open, head-nodding, drifting out of the lane, and daydreaming. At particular risk are lone drivers between midnight and 6 a.m. Sleep deprivation can negatively impact performance in professional fields as well, potentially jeopardizing lives. Due largely to the February 2009 crash of a regional jet in Buffalo, NY, which killed 50 people and was partially attributed to pilot fatigue, which caused the FAA to review its procedures to ensure pilots are sufficiently rested. A 2004 study also found medical residents with less than four hours of sleep a night made more than twice as many errors as residents who slept for more than seven hours a night, an especially alarming trend given that less than 11% of surveyed residents were sleeping more than seven hours a night.

Twenty-four hours of continuous sleep deprivation results in the choice of less difficult math tasks without decreases in subjective reports of effort applied to the task. Naturally caused sleep loss affects the choice of everyday tasks such that low effort tasks are mostly commonly selected. Adolescents who experience less sleep show a decreased willingness to engage in sports activities that require effort through fine motor coordination and attention to details. Great sleep deprivation mimics psychosis: distorted perceptions can lead to inappropriate emotional and behavioural responses. Astronauts have reported performance errors and decreased cognitive ability during periods of extended working hours and wakefulness as well as due to sleep loss caused by circadian rhythm disruption and environmental factors.

Lack of Sleep Affects Immune System
A lack of sleep could have an impact on more than just your mood, according to a new study led by the Surrey Sleep Research Centre.Researchers found that just one week of poor sleep could affect up to 700 different genes associated with the immune system, metabolism, and stress responses.Researchers say disrupting the genes increases the risk of heart disease, diabetes, obesity, and stress. Prof. Derk-Jan Dijk, director of the Surrey Sleep Research Centre at Surrey University, said that not getting enough sleep does more than “just make you tired,” The Guardian reported.”The surprise for us was that a relatively modest difference in sleep duration leads to these kinds of changes,” Dijk said. Previous studies have shown that people who get less than five hours sleep a night are at a 15 percent higher risk of death from a variety of causes than their counterparts who get a full night’s sleep.

Reference:

http://en.wikipedia.org/wiki/Sleep_deprivation#Effects_on_the_brain http://www.sciencedaily.com/releases/2003/11/031113065511.htm http://www.webmd.com/sleep-disorders/news/20000209/lack-of-sleep-takes-toll-on-brain-power http://www.cbn.com/cbnnews/healthscience/2013/February/Lack-of-Sleep-Affects-Immune-System/ http://voices.yahoo.com/sleep-deprivation-delays-wound-healing-706061.html http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2656292/

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2869.1992.tb00043.x/

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