What is West Nile virus?

Causes and Symptoms

For most of the twentieth century following its discovery in Uganda, West Nile virus, an organism that can cause severe inflammation of the spinal cord and brain, was known only in Africa, southeast Europe, and southwest Asia. As the century came to a close, however, the potentially fatal disease emerged in the Western Hemisphere, in the New York City metropolitan area. Since then, it has spread across the continental United States, seven Canadian provinces, Mexico, the Caribbean, and parts of Central America. One of the hallmarks of the disease is dead birds, such as crows, who are also susceptible to the virus.

The first North American cases of the mosquito-borne West Nile virus were found in patients from New York in 1999, and its resurgence in following summers indicates that this disease has become established. The virus is a member of the Japanese encephalitis complex most closely related to St. Louis encephalitis, which also occurs in North America. This group of encephalitis viruses includes the Japanese, Murray Valley, and Stratford complex of viruses. The West Nile virus is also called West Nile encephalitis or West Nile meningitis.

The West Nile virus is called an arbovirus, which is an abbreviation for “arthropod-borne virus.” Mosquitoes are the only known agents of transmission of the virus. Other blood-feeding animals, such as ticks and flies, may carry the virus, but so far none of them has been shown to transmit the viral disease to humans. The disease cannot be transmitted from one person to another or between animals and humans other than through a vector mosquito.

A potential transmission cycle begins when a mosquito becomes infected with the disease by feeding on an infected animal, usually a bird or mammal. The virus enters the mosquito’s bloodstream and is eventually carried to its salivary glands. The virus incubates within the salivary glands for an unknown period of time. During the mosquito’s next blood meal, some of the saliva containing the virus may be injected. Once inside the individual, the virus multiplies and is carried via the bloodstream to all the tissues of the body. In about 1 in 150 individuals, some of the virus makes its way past the blood-brain barrier and into the brain. In humans, the pathology of the West Nile virus disease manifests as a type of encephalitis, a swelling of the meninges, or tissue linings, of the brain.

The first symptoms of infection usually appear within three to fifteen days following exposure, and they may include fever, headache, general body aches, swollen lymph glands, and sometimes a skin rash. In more serious cases, symptoms such as high fever, stiffness, disorientation, stupor, coma, tremors, convulsions, and muscle weakness and paralysis may progressively occur.

Treatment and Therapy

Severely infected individuals are hospitalized and treated with a battery of life-support therapies, including intravenous fluids, ventilation to aid breathing, and inoculations to prevent the occurrence of pneumonia and other secondary infections. In many cases, the symptoms may last several weeks. In severe cases, brain damage and other neurological disorders may be permanent. Fatalities result from swelling of the brain and associated neurological pathologies. At present, there is no treatment for the disease.

Perspective and Prospects

West Nile virus is a classic emerging disease. It was first isolated in 1937 in the West Nile Valley of Uganda in humans and animals, notably horses and birds. The virus quickly spread throughout much of interior Africa, following the course of the Nile River southward into Uganda and neighboring countries, then westward into the Republic of the Congo, then still farther south into Botswana and Zimbabwe. Spreading northward along the Nile River, the virus reached Egypt in 1950, then spread across the Middle East, Eurasia, and Oceania. By 1997, the virus was documented in Italy, France, and Romania. The first cases of West Nile virus in North America were reported in the early summer of 1999 in New York. Twelve states reported cases in 2001, and all states but Alaska and Hawaii had reported the disease by 2005. The numbers of both infections and fatalities in the United States decreased between 2008 and 2011. However, in 2012, there were over 5,600 reported cases of West Nile in the United States, including over 280 deaths—the deadliest year on record for this disease in the United States. After this spike, the numbers subsequently declined again, with around 2,500 cases in 2013 and around 2,100 in 2014. The number of reported cases in Canada in 2003 reached about 1,400; by 2005, only 200 persons were diagnosed. In 2012, approximately 450 cases of West Nile were reported in Canada. Canadian cases of the disease also declined after 2012, with the number reaching twenty-one in 2014.

The transmission and fatality rates in humans are actually very low, for several reasons. First, the incidence of infected mosquitoes in an area is typically small, generally on the order of about 1 percent or less, even in regions that have had a long history of West Nile virus. Second, acquiring the virus from the bite of an infected mosquito is not certain, as particles of the virus may or may not be transmitted into the human bloodstream during the blood meal. Finally, small amounts of virus may not produce the “full-blown” disease in humans. The Centers for Disease Control and Prevention (CDC) suggest that about 1 in 150 people bitten by an infected mosquito becomes severely ill with the disease. Healthy people may simply fight off the viral infection without manifesting any symptoms at all. Others experience a variety of generally mild, flulike symptoms, which may include malaise, aching bones, and headaches.

CDC estimates of fatality rates are uncertain but suggest that one in one thousand infected people actually dies from the disease, but some estimates place the fatality rate at 3 to 15 percent. As with many viral diseases, the effect of West Nile virus increases with age; the young and healthy seem to develop very few symptoms and almost no residual traces of the disease, but people fifty and older or individuals with compromised immune systems are most at risk. Individuals who survive exposure apparently develop a long-term immunity to the virus.

At present, the only way to prevent becoming infected with West Nile virus is to avoid being outdoors in areas where mosquitoes are plentiful or, alternately, to confine outdoor activities to midday hours, when mosquitoes are least active. When outdoors, one should use a recommended mosquito repellant and wear long pants and a long-sleeved shirt.

Among mammals, horses seem most susceptible to the West Nile virus, but the virus has also been documented in dogs, cats, rabbits, skunks, bats, chipmunks, mice, and squirrels. At least seventy species of birds have been found with the disease, of which sparrows, ducks, pigeons, starlings, and crows are the best-known examples. Of these animals, crows seem most at risk, or at least seem to show the highest incidence of infection and mortality, but this may reflect their size and coloration, both factors making them easily seen. Despite public concern over the incidence of West Nile virus in birds and other mammals, tests have shown that the virus cannot be transmitted simply by handling dead birds. There are no records of animal-to-animal or animal-to-human transmission of West Nile virus. However, it is always advisable to wear gloves and avoid the animal’s body fluids when handling animals found dead or known to be infected with West Nile virus.

Bibliography:

De Filette, Marina C., Sebastian Ulbert, Mike Diamond, and Niek N. Sanders. "Recent Progress in West Nile Virus Diagnosis and Vaccination." Veterinary Research 43.1 (2012): 16. Print.

Despommier, Dickson D. West Nile Story. New York: Apple Tree, 2001. Print.

Emerging Infectious Diseases Journal 7.4 (August, 2001). Print.

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Neale, Todd. "West Nile Virus 'Stumps' CDC." medpagetoday.com . 27 Sept. 2012. Web. 4 Jun. 2013.

Patterson, Brittany. "As Earth Warms, West Nile Spreads." Atlantic. Atlantic Monthly, 9 May 2014. Web. 12 May. 2015.

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White, Dennis J., and Dale L. Morse, eds. West Nile Virus: Detection, Surveillance, and Control. New York: New York Academy of Sciences, 2003. Print.

What is Paget disease of bone?

Related conditions:
Metabolic and endocrine bone diseases

Definition:

Paget disease of bone (osteitis deformans) is a bone disorder in which excessive bone resorption is followed by excessive bone formation. The primary disturbance is an exaggeration of activity by a cell called the osteoclast, which is responsible for removing bone in the remodeling process. Frenzied osteoclastic activity results in localized bone loss followed by a period of hectic bone formation. The osteoblast cell responds by regenerating new bone that is primitive (woven), disorganized, and weaker. The resultant effect of this cycle is a net gain in bone mass; however, the newly formed bone is structurally unsound. The disease process also results in extensive vascularity (increased number of blood vessels and blood flow) and increased fibrous connective tissue within the adjacent bone marrow space. Paget disease can produce a variety of skeletal, neuromuscular, and cardiovascular complications.

Risk factors: Although the exact cause of Paget disease remains unknown, being older than forty-five years and having a family history of the disease are the only known risk factors. Of patients with Paget disease, 15 to 30 percent have a family history. Family studies suggest that a person with a first-degree relative has a seven times higher risk of developing this condition. In families with early-onset or severe Paget disease, the risk is even greater.

Etiology and the disease process: Named after the nineteenth-century English surgeon Sir James Paget, Paget disease was first described in 1876 as an inflammatory condition that affects the normal biological processes of bone. The exact cause or mechanism of this disease process remains unknown. Scientists have discovered several genes that appear linked to this disorder. Other investigators believe Paget is related to a viral infection in the bone cells that may be present for many years before problems appear.

As living tissue, bone is engaged in a continual process of renewal; old bone is removed and replaced by new bone. This process of remodeling is disrupted in Paget disease. In the initial, or lytic, phase, old bone starts breaking down faster because of the erratic and accelerated activity of osteoclast cells. The body responds by generating new bone at a faster than normal rate. This mixed phase is devoted to osteoblastic cell activity. In the final osteosclerotic phase, the exhausted cells become quiescent. A mosaic pattern of bone is identifiable. The new bone is coarsely thickened but soft, porous, and lacking structural stability. These microscopic aspects make the bone vulnerable to deformation and to fracture under stress.

A variety of tumors and tumor-like conditions develop in the chaotic activity associated with pagetic bone. The most dreaded complication is the development of sarcomas (bone cancers), which occurs in 5 to 10 percent of patients with severe disease. The prognosis of patients who develop secondary sarcomas is exceedingly poor, but in the absence of malignant transformation, Paget disease usually follows a relatively benign course.

Incidence: Paget disease usually begins in the fifth decade of life, becomes progressively more common thereafter, and has a slight male predominance. There is a striking variation in prevalence both within certain countries and throughout the world. Paget disease is relatively common in England, France, Austria, regions of Germany, Australia, and New Zealand, affecting 5 to 11 percent of the populations in these countries. In the United States, Paget disease is estimated to occur in 1 to 3 percent of people over the age of forty-five. Paget disease is rare before the age of twenty; the estimated incidence among individuals older than eighty is 10 percent. In contrast, Paget disease is rare in the native populations of Scandinavia, China, Japan, and Africa.

Symptoms: Paget disease affects each person differently. Most people with Paget disease have no symptoms. Initial discovery may be the result of a screening X ray for other purposes. When symptoms do occur, they may be widespread but typically arise in the areas affected by the disease, which include bones, joints, and nerves.

The most common bone sites include the spine, pelvis, skull, femur (involved in up to 80 percent of cases), and tibia. Patients will complain of bone pain characterized as constant, aching, deep, and most severe at night. Skull involvement may produce enlargement of the head (frontal bossing). Deafness may result from disease of the temporal bone or ossicles (bones of the middle ear). Involvement at the base of the skull can lead to compression of the brain stem, resulting in symptoms of ataxia (difficulty walking), weakness, or respiratory compromise. Compression fractures of the spine can result in spinal cord injury and spinal deformity.

Hip and knee joints are commonly affected. The cartilage lining the joints near affected bones is damaged. This additional factor coupled with normal wear and tear leads to accelerated osteoarthritis, which may cause joint pain, swelling, and stiffness.

Enlarged bones can compress the spinal cord or the nerves exiting from the brain or spinal cord. Pain resulting from nerve compression is often more severe than bone pain. The location of the pain caused by nerve compression depends on the nerve that is affected. If lumbar nerves from the spine are compromised, this leads to radiating pain from the lower back and into the legs (sciatica). Nerve compression can result in limb weakness, pain, or paralysis. Nerve compression has been implicated in hearing and vision loss along with facial weakness and numbness.

Screening and diagnosis: Diagnosis depends on the following tests:

• Blood test: Specifically, an alkaline phosphatase test. Alkaline phosphatase is a chemical substance produced by bone cells that are responsible for forming new bone, and its serum level is elevated in Paget disease.





• X ray: The first indication of Paget disease usually is an abnormality found on an X ray. X-ray images delineate areas of bone reabsorption, enlargement of bones, and bone deformities.





• Bone scan: In some cases, bone scans can pick up Paget disease before it is seen on an X ray. In a bone scan, radioactive tracers are injected into the body. The tracers are preferentially taken up by areas of the bone that are metabolically active. Areas of pagetoid bone are seen as darker than areas of normal bone.





• Bone biopsy: Biopsy of the bone provides definitive evidence of the disease. Slides of the sectioned tissue show the classic mosaic pattern of bone. Biopsy can also be useful in staging the disease process.

Treatment and therapy: Asymptomatic patients may not need treatment. Treatment is recommended when the disease is active (indicated by elevated serum levels of alkaline phosphatase). Treatment can help alleviate pain and may halt the damage done to the bones. In many cases, treatment can cause a remission of the disease although not a cure. Medications, surgery, and self-care remain the essential elements in most treatment regimens.

Drug therapy incorporates the use of nonsteroidal anti-inflammatory medications, analgesics, and muscle relaxants that lessen pain and discomfort but do not alter the natural course of the disease. The two major pharmaceuticals employed are calcitonin (a hormone that inhibits osteoclast activity and affects extent of bone resorption, provides relief of acute symptom, and lowers alkaline phosphatase levels) and the bisphosphonates, which are the most effective agents in reducing bone resorption.

Surgery, in rare cases, may be required to stabilize a fracture or to replace a damaged joint. If Paget disease affects the spine or skull, decompressive surgery (removal of excess bone) is needed to reduce the pressure on the nerves, thereby restoring normal neurologic function.

Prognosis, prevention, and outcomes: In most cases, Paget disease progresses slowly. The condition can be managed effectively in nearly all people and is rarely fatal. A nutritional diet, regular exercise, and maintaining a healthy weight are important aspects of any treatment protocol. Certain individuals may require a corset or brace to relieve back pain and provide support. If symptoms become severe, the use of analgesics and muscle relaxants is recommended. Medical supervision and examination are necessary since major complications of this disease can include fractures, osteoarthritis, heart failure, and cancer.

Kumar, V., A. Abbas, N. Fausto, and R. Mitchels, eds. Robbins Basic Pathology. 8th ed. Philadelphia: Saunders, 2007. Print.

McDermott, Michael T. Endocrine Secrets. 6th ed. Philadelphia: Elsevier, 2013. Print.

Rosen, Clifford J., R. Bouillon, Juliet Compston, and Vicki Rosen. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. Hoboken: Wiley, 2013. Print.

Schwamm, H. A., and C. L. Millward. Histologic Differential Diagnosis of Skeletal Lesions. New York: Igaku-Shoin, 1996. Print.

Singer, F. “Paget’s Disease of the Bone.” In Endocrinology, edited by L. J. DeGroot. Philadelphia: Saunders, 1995. Print.

Waldman, Steven D. Atlas of Uncommon Pain Syndromes. 3rd ed. Philadelphia: Saunder, 2014. Print.

What are circadian rhythms? |

Introduction

Circadian rhythms are a fundamental characteristic of life. The term circadian was coined by Franz Halberg and refers to rhythms that are about a day in length (from the Latin circa, “about,” and dies, “day”). Although historically many of the early observations were made on plants and animals, later research has shown a remarkable similarity in the structure and functioning of the circadian clock across different species. Circadian rhythms are ubiquitous and are exhibited by most physiological, biochemical, and molecular events that occur in organisms and share common mechanisms of operation.

The most obvious rhythm of human activity is the sleep-wake cycle. Human beings are most active during the daylight hours and sleep for much of the dark period. A species with this schedule is called diurnal (animals active during the dark period are termed nocturnal). Human beings are essentially diurnal except for the adaptations that come with work, travel, and other circumstances.

It is known that the sleep-wake cycle is not determined as rigidly as many other physiological rhythms. For example, one can choose not to sleep for several days and thereby temporarily abolish the pattern. A more fundamental and less easily modified rhythm is the circadian rhythm of core body temperature. In this case, there is a daily fluctuation of slightly more than 1 degree Celsius over the course of twenty-four hours, with the lowest body temperature occurring between 4:00 and 5:00 a.m., when a person is deep in sleep. The temperature rhythm continues its fluctuation, although somewhat dampened, even if a person stays awake for several days. This condition is called desynchronization of rhythms—in this case, the temperature rhythm and the sleep-wake rhythm are desynchronized from each other.

One of the first discoveries made on circadian rhythms is that they are endogenous in nature—the rhythmic activities are engendered and controlled from within the organism rather than being influenced or controlled by external agents such as the changing light and dark cycles or changes in temperature. Isolating human beings under constant conditions, where natural changes to day and night or fluctuations in temperature are absent, do not lead to abolition of rhythmicity. Even in the absence of external time cues, human beings are able to tell time because of the presence of an endogenous clock. The daily rhythmic occurrence of events (such as the time interval between the onset of sleep or the time interval between the occurrences of temperature minima) is measured by period. Under normal conditions, the period is close to twenty-four hours because the rhythms are synchronized or “entrained” by the light-dark cycles and other cues afforded by nature. However, if human beings are kept under constant conditions, they exhibit a period called a free-running rhythm that deviates slightly from twenty-four hours.

Free-running rhythms are observed in humans if the individual lives for many days or weeks in an isolated cave or bunker, where possible time cues such as the light-dark cycle or other factors have been eliminated. The famous cave explorer Michel Siffre found that he had a sleep-wake cycle of twenty-four hours and thirty-one minutes when he lived alone in a cave for two months without time cues. Similar studies in the more controlled environments of World War II bunkers were carried out by the German scientist Jürgen Aschoff. In each case, it was found that the body’s rhythms gradually drifted out of phase with the actual time of day when watches and the natural cycle of light changes were eliminated. Aschoff termed factors that maintain a circadian periodicity Zeitgebers, or time givers. Individual subjects were found to have their own unique period, or length, for their free-running rhythms—for example, 24.3, 24.5, 24.7, or 24.9 hours. It has been well documented that various rhythms such as the sleep-wake cycle, body temperature, blood pressure, respiration rate, and urinary excretion of sodium, under constant conditions, will show slightly different period lengths and will therefore become desynchronized. Desynchronization, which may occur in the elderly under normal living conditions, is thought by some scientists to lead to various disease states. For example, episodes of mania in people with bipolar disorder can be triggered by travel to a geographical zone with increased sunlight.

Various mental abilities in humans have been shown to be subject to circadian variations. A person’s ability to estimate time duration varies during the day inversely to the daily change in temperature. The ability to memorize numbers is better in the morning than in the afternoon, and the ability to add random numbers is better in the morning than in the afternoon. Eye-hand coordination changes with a circadian rhythm, with skills better during the day and performance reduced at night. The existence of these rhythms has many implications, and the further study of such rhythmic factors remains a vital common ground between physiology and psychology.

Two small nuclei, suprachiasmatic nuclei (SCN), situated just below the optic chiasma in the hypothalamus of the brain, are implicated to be crucial for the generation and sustenance of rhythmic behavior. They are called the core circadian clock, and their removal abolishes an array of rhythmic activities, including sleep-wake and temperature cycles. The hypothalamus, located just above the pituitary gland in the brain, is thought to regulate many human rhythms. Its cell clusters, or nuclei, receive input from various sense organs and brain areas. In response, they secrete releasing hormones, which travel to glands in the body and stimulate the release of second and third downstream hormonal systems that modulate body processes. These hypothalamic nuclei and secondary hormones are active in many cyclical patterns. For example, female sex hormones from the pituitary gland follow characteristic circadian patterns—monthly patterns that develop the female ovum (egg) and regulate each menstrual cycle—and lifetime patterns that initiate sexual maturation and menopause.

Genetic and Molecular Basis

In 1971, Ronald J. Konopka and Seymour Benzer isolated mutations in the fruit fly, Drosophila melanogaster, with consistent differences in their periods (such as short-period mutants and long-period mutants) and identified three alleles of the Period gene (PER) as being responsible for the changes.
Understanding of the components and the functioning of circadian clocks at the molecular level has increased tremendously. More than ten genes have been shown to be responsible for proper functioning of the circadian clock (core clock genes) and several others have been indicated as clock-controlled genes. At least three period genes (PER1, PER2, and PER3) have been identified in mammals as components of the core clock. These, along with other identified circadian clock genes such as Cryptochrome 1 and 2 (CRY 1, CRY 2), CLOCK, BMAL1, and REV-ERB alpha, generate the twenty-four-hour rhythmicity of the circadian clock through a series of transcriptional and translational events. The mechanism of their action involves an interlocking positive and negative feedback loop (turning the expression of certain genes on and off at given intervals of time, while having their own expression turned on and off at given intervals of time). Such molecular oscillations are observed in the SCN as well as in several other peripheral organs like the liver and the brain. The molecular mechanism of the circadian clock function is remarkably similar among different species, including fungi, insects, rodents, and humans.

Manipulating Circadian Rhythms

The most familiar way humans apply their understanding of body clocks is to adjust to external changes in the sleep-wake cycle. A person can willfully avoid sleep for hours without a parallel increase in fatigue, as is attested by students who get a “second wind” once they study past 3:00 or 4:00 a.m. Some researchers envision an underlying circadian rhythm of alertness and fatigue that enhances a person’s ability to awaken in the morning and to fall asleep in the late evening. In general, it is easier to awaken in the morning when the body temperature is increasing, and it is easier to fall asleep in the late evening when body temperature is falling. So-called owls and larks do exist in the human population; people who fall into these two groups differ as to when their body temperature peaks, with larks peaking earlier.

In human beings, such manipulations are a bit tricky because the sleep-wake cycle can be modified by alcohol, drugs, and social interactions, among other factors. However, studies on a specific population in Utah found people who have an inherently shifted period. Individuals in this population had their sleep phase advanced by about four to six hours a day. This is called familial advanced sleep phase syndrome (FASPS). FASPS manifests itself in early childhood as a dramatic advance in the sleep schedule, and with advances in age it gets even worse. This syndrome is in contrast to the delayed sleep phase syndrome (DSPS) observed in many adolescents. Extensive genetic studies identified alterations in hPER2, (human period 2), a critical core circadian clock gene, in the affected population. Several clock genes, including hPER3, arylalkylamine N-acetyltransferase, and hCLOCK have been linked to DSPS.

The detailed makeup of sleep also shows periodicity. Brain waves measured with an electroencephalograph (EEG) record four distinct waves, each associated with a type and depth of sleep that repeats two to five times each night. The pattern changes with age; children sleep most deeply on initiation of sleep, while adults sleep most deeply just before waking. Rapid eye movement (REM) sleep, associated with dreaming, occurs more frequently later during the sleep period. Most major cities now have sleep laboratories in which scientists monitor the sleep of patients and apply theories involving circadian rhythms to improve the type and timing of medications.

Shift Work and Jet Lag

When people are forced to change their sleep-wake schedule for either work or travel, shift-work problems and jet lag can result. Shift work is required in circumstances in which around-the-clock services are either essential or economically beneficial. These include medical, police, military, utility, transportation, and other essential services, as well as tasks in the chemical, steel, petroleum, and various other manufacturing industries. Work is done and days off are given according to many different schedules. A number of catastrophic events, such as the Three Mile Island nuclear accident (1979), the chemical explosion in Bhopal, India (1984), and the Chernobyl nuclear accident (1986) happened during the late-evening or night shift, when fatigue of ill-adapted workers may have been a factor. Within the population, there are owls who can adapt to night shift work without the physical problems experienced by their peers. It is known that physiological and behavioral rhythms will shift to a new schedule only if the schedule is kept the same for a period of weeks. Shift workers who stay on their schedule of night work and day sleep will quickly shift their sleep-wake cycle and eventually shift their various behavioral and more fundamental physiological rhythms such as body temperature. Because the body’s circadian rhythms are more than twenty-four hours in length, it is easier to start work later on successive days than it is to start work earlier.

What later became known as jet lag was first experienced by Wiley Post and Harold Gatty on their 1931 around-the-world airplane trip. By the 1950s, increasing numbers of tourists, diplomats, flight crews, and pilots were suffering from the general malaise, headaches, fatigue, disruptions of the sleep-wake cycle, and gastrointestinal disorders that can occur when people cross several time zones within a few hours. The effects are worse on eastward flights than on westward flights, perhaps because the circadian rhythms can undergo an adjustment to a lengthening in timing better than to a shortening. A night flight from New York to Paris results in a six-hour time shift, with breakfast coming six hours early according to nonshifted circadian rhythms. Within a few days, the sleep-wake cycle adjusts, but deeper physiological rhythms may take two or more weeks to shift to the new time zone.

There is mounting evidence to suggest that jet lag and shift-work sleep disorders are due to disturbances in the circadian phase of plasma melatonin levels. Melatonin, the so-called hormone of sleep, is available for shifting the phase of sleep (phase shifting) and to synchronize sleep patterns. Melatonin is widely used for treating problems related to jet lag and shift work. The hormone melatonin binds to its receptors—melatonin receptors 1 and 2, called MT1 and MT2. Both of these receptors are located in the SCN region of the brain. The administered dose of melatonin changes depending on the duration of the travel time. Longer travel requires starting of the treatment regimen a few days in advance of the travel, while shorter travel can bypass this step. Drugs that bind to the melatonin receptor and activate it are being tested in clinical settings.

Seasonal Affective Disorder

Another application of chronobiology is in the study and treatment of seasonal affective disorder (SAD). People with SAD typically experience clinical depression in March and April, at the end of the winter months of shorter daylight. This depression is unlike the more common melancholic depression, which is characterized by loss of sleep and appetite, in that it is accompanied by increased eating, particularly of carbohydrates, and increased sleep, up to sixteen hours per day. It is also distinguished from the winter blues, which occur in one of four individuals, usually earlier in the winter. Although SAD is not considered a variant of bipolar disorder, it resembles bipolar disorder in the type of depressive symptoms and its relationship to sunlight. Many highly creative individuals, such as artist Vincent Van Gogh, writers Tennessee Williams and Edgar Allan Poe, President Abraham Lincoln, and many others have suffered either bipolar illness or SAD, describing the “seasons of the mind” in their work.

Circadian rhythms are fundamental to the pathophysiology and treatment of SAD. Response to daylight is modulated by the pineal gland, a pea-sized organ midline under the cerebral hemispheres of the brain. In darkness, the pineal gland secretes melatonin and possibly other substances. Information about light, transmitted along specific nerve pathways from the eyes, inhibits release of melatonin. Although it is not clear exactly how loss of daylight leads to seasonal depression, bright light therapy can reverse or prevent it, possibly by altering circadian rhythms such as those influencing mood, sleep, and appetite via secondary effects of melatonin. The standard light therapy involves exposure to approximately 1,500 lux (the unit of measurement for light) at a frequency that mimics sunlight. For mood disorders, patients are exposed to 10,000 lux light intensity daily for twenty to thirty minutes, preferably in the morning as nighttime treatments have been known to cause insomnia. Although the majority of light therapy products filter or completely block harmful UV light, individuals should not look directly at the light but instead have it nearby so that the light is absorbed through peripheral vision.

The severity of other illnesses also follows a circadian rhythm. Stomach acid secretion peaks in the late afternoon and just after midnight, leading to worsened symptoms of peptic ulcers at these times. Drugs that inhibit acid secretion are given at night to take advantage of this phenomenon. Similarly, asthma exacerbations tend to occur at night; predictably, oral medications for asthma produce better results if given before bedtime. Some types of high blood pressure peak at night, others in the morning; again, drugs should be given so that peak drug levels coincide with peak blood pressure readings.

There has been tremendous progress in the understanding of the cellular and molecular mechanisms dictating the functioning of a normal circadian clock. Associations of pathophysiology of diseases to disruptions in circadian clock functions are being investigated. Many clock genes have been implicated in complex mental illnesses such as major depression, bipolar, and schizophrenia, in addition to insomnia and SAD. Modifications of treatments based on the understanding of circadian rhythms have become a reality. For example, chemotherapy is given for cancer at more exact times to coincide with the most vulnerable period of cancer cell division, allowing for lower doses, fewer side effects, and better treatment results. As circadian rhythms are better understood, many aspects of health and daily life may be managed with greater ease.

Circadian Rhythm Research

In 1729, French astronomer Jean Jacques d’Ortous de Mairan reported his observations on the leaf movements of a “sensitive” heliotrope plant that continued to open and close its leaves approximately every twenty-four hours even when it was kept in continuous dark. This was the first demonstration of a free-running rhythm. Studies on humans included those by Sanctorius, who in the seventeenth century constructed a huge balance on which he was seated in a chair and studied circadian rhythms in body weight. Julian-Joseph Virey, a Parisian pharmacist, postulated endogenous biological clocks modified by environmental input in his 1814 doctoral thesis and is credited with formally establishing the field of chronobiology. Yet despite these early studies, it was the 1950’s before circadian rhythms were more widely studied and research on humans began to be more common.

In psychology, Nathaniel Kleitman and Eugene Aserinsky in the 1940’s discovered rapid eye movement, or REM, sleep. The rhythmic patterns in REM sleep and their relation to the circadian sleep-wake cycle have remained an active area for research. The psychobiologist Curt Richter carried out work on the activity rhythms in rats. Richter also identified the general area in which the suprachiasmatic nuclei are found as a region of the hypothalamus important in controlling circadian rhythms. Simon Folkard and colleagues have studied various human performance tests and have found numerous circadian rhythms. They found that the circadian rhythms in memory tests peaked at different times, depending on the complexity of the number to be memorized. There remains a need for more research by psychologists who incorporate variation due to circadian rhythm into their research design.

The research on the genetics of circadian rhythms was initiated by Konopka and Benzer in 1971, using a forward genetic approach. The Period gene was first identified in Drosophila, and its orthologs in mammals were identified in 1997. Another important clock gene, Clock was identified through genetic studies in 1994 and was subsequently cloned in 1997. Two other important genes, the cryptochromes, CRY1 and CRY2 were identified in the same year, and the molecular mechanism involving the positive and negative feedback loops was uncovered subsequently. Research on this field focuses not only on further details and missing elements of the circadian clock, but also on how alterations in these identified genes could be related to various disease states.

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Shaw, Paul, Medhi Tafti, and Michael J. Thorpy. The Genetic Basis of Sleep and Sleep Disorders. New York: Cambridge UP, 2013. Print.

Terman, Michael, and Ian McMahan. Chronotherapy: Resetting Your Inner Clock to Boost Mood, Alertness, and Quality Sleep. New York: Penguin, 2012. Print.

Toh, K. L., et al. “An hPER2 Phosphorylation Site Mutation in Familial Advanced Sleep Phase Syndrome.” Science 291 (2001): 1040-1043. This article showed that mutations in a single gene (hPER2) caused alterations in sleep behavior. The study was conducted in a small population in Utah. This is the first identification in humans of a single gene mutation affecting as complex a behavior as sleep.

What is opioid abuse? |

Causes

Opioids produce a quick, intense feeling of pleasure (euphoria) followed by a sense of well-being and calm drowsiness. Opioid drugs produce their effects by binding to the opioid receptors of the central nervous system, which respond to the body’s intrinsic opioids known as endorphins to naturally block or suppress the sensation of pain. When opioid drugs are used repeatedly, the level of natural endorphins in the body is diminished and the brain is likely to become dependent on the drug. Opioids are highly addictive.

Risk Factors

Risk factors that increase the chances of developing opioid addiction include a history of abuse of other types of drugs and the presence of a mood or anxiety disorders. Men between the ages of twenty and twenty-nine are also at a greater risk of developing opioid abuse.

Symptoms

There are several symptoms of opioid abuse. One symptom is tolerance, or the need to increase the dose in order to achieve the same effect. Another symptom is increased amounts of time spent drug-seeking. Other symptoms include the interference of drug or drug-seeking behavior with social, occupational, or school functioning; the continued use of drugs despite social, legal, occupational, or interpersonal consequences stemming from drug use; desire or efforts made to decrease or stop drug use without success; and withdrawal, the adverse symptoms that occur when the drug is not taken.

Symptoms of withdrawal are many, such as aching, fever, leg tremors, sweating, chills, and craving the drug. Some other symptoms of withdrawal are diarrhea, nausea, and vomiting; sleeplessness; abdominal pain and muscle aches; restlessness; tearing eyes and runny nose; yawning; panic; and irritability.

Screening and Diagnosis

A diagnosis by a medical expert will include questions about the symptoms of opioid abuse as well as questions pertaining to a patient’s medical history. A physical examination is also performed. Urine and blood tests may also be conducted.

Treatment and Therapy

The treatment options for opioid abuse consist of detoxification, rehabilitation programs, support groups, behavioral therapy, inpatient and outpatient programs, and medications. In rehab programs, people with opioid abuse stay in a controlled environment for anywhere from a few days to several months. The length of stay is determined not by medical necessity or patient desire but by insurance companies. Many programs require that an individual detoxes from the drug before attending or being admitted. Some programs have detox units and areas incorporated in the facility so that individuals can easily transition from one phase of rehab to the next. One support group, Narcotics Anonymous, is a twelve-step program that many find helpful in maintain sobriety. Substance use disorder, especially in relation to opioid addiction, does not have a "one size fits all" cure. Recovery is a long and arduous road to travel and a multi-faceted and multi-pronged approach is the most effective.

Behavioral therapy is another valuable treatment option. Behavioral therapy is designed to modify people’s attitudes and behaviors related to opioid abuse. In therapy, a person will learn how to avoid and cope with situations in which he or she is most likely to use drugs.

Medicines that have been shown to be effective in reducing withdrawal symptoms are methadone, buprenorphine (Subutex), and buprenorphine and naloxone (Suboxone). When combined with therapy, these medicines can help an individual adjust to not using drugs. They may also help an individual go through withdrawal at home, rather than at an inpatient facility.

Prevention

The best way to prevent this condition is to never use opioids. For persons taking prescription opioid medications for pain management, it is important to use the drug only at the prescribed dosages in order to prevent the development of drug dependence.

Bibliography

Edlund, M., et al. “Risk Factors for Clinically Recognized Opioid Abuse and Dependence Among Veterans Using Opioids for Chronic Non-Cancer Pain.” Pain 129.3 (2007): 355–62. Print.

Hall, Wayne, Chris Doran, Louisa Degenhardt, and Donald Shepard. “Illicit Opiate Abuse.” Disease Control Priorities in Developing Countries. 2nd ed. Ed. D. T. Jamison, et al. Washington: World Bank, 2006. Print.

“Mind Over Matter: Opiates.” National Institute on Drug Abuse: NIDA for Teens. National Institutes of Health. 2012. Web. 30 Mar. 2012.

Smith, Janna Malamud. "A Multipronged Approach to the Addiction Epidemic Has to Include Empathy." Cognoscenti. WBUR/National Public Radio, 29 Oct. 2015. Web. 30 Oct. 2015.

What is palsy? |

Causes and Symptoms

In general, the term “palsy” describes any type of dysfunction of the motor nerves that impairs or reduces the conscious control of muscles. The paralysis or loss of motor control is usually accompanied or followed by weakness and wasting of the muscles in the affected area.

The most common type of palsy is Bell’s palsy, a paralysis of the seventh cranial nerve, or facial nerve, often accompanied by pain over part or all of the affected area. The number of muscles involved varies. The paralysis usually occurs on one side of the face at a time, with the result that the undamaged muscles of the opposite side pull the facial skin to that side. Typically, the eye on the affected side remains open all the time because the muscles that close it have been affected; attempts by the patient to close the eye merely result in the eyeball rotating upward. The rest of the face on the affected side generally droops but remains flat; the brow fails to wrinkle, and the cheeks never thicken. Smiles and other facial expressions are asymmetrically contorted.

Thorough neurological testing is needed to assess how much damage has been done and which branches of the facial nerve have been affected. If the damage affects either hearing or taste, this finding indicates that the damage is closer to the root of the facial nerve, and the patient’s chances for recovery are correspondingly much lower. If only a few muscles are involved, it indicates that the damage is farther from the root of the nerve, which usually forecasts a better chance of recovery. In most cases, Bell’s palsy is thought to arise from a reduced blood supply to the affected nerves. Viral infection by
herpes simplex or
herpes zoster (shingles) is also a frequent cause; the viral infections are believed to cause demyelination (deterioration of the myelin sheath that insulates nerves) of the affected parts of the facial nerve. Other causes include injuries to the area just below or in front of the external ear resulting from blows to the head, surgery in this region, or other types of trauma.

Another common type of palsy is
cerebral palsy, an impairment of movement and posture caused in most cases by injury, malformation, or other damage to the immature brain. Cerebral palsy is actually a group of paralytic disorders that begin during intrauterine development, at birth, or in early infancy. The extent of the paralysis may vary, often involving large groups of muscles while sparing others. Those muscles that are not totally paralyzed are often uncoordinated in their movements or poorly controlled; this is especially true of large muscle movements such as those of the limbs. In many cases, the patient exhibits a “scissors gait” in which the lower limbs are crossed and the one behind must be swung sideways before it is placed in front of the other limb. In addition to the lack of muscular control of the limbs, other symptoms variously include spasms, athetoid (slow, rhythmic, and wormlike) movements, or muscular rigidity. Speech is in many cases difficult or unclear if the muscles used in speaking are affected.

Mental deterioration may occur in some cases but not in others: Some patients with cerebral palsy are intellectually disabled, while others have managed to display brilliant artistic or literary talents with the use of whatever muscles still function in their bodies. Some cerebral palsy patients also suffer from seizure disorders such as
epilepsy. Almost all cases of cerebral palsy are accompanied by some other type of neurological impairment, the nature of which varies greatly. In general, cerebral palsy is a nonprogressive type of disease; that is, it does not continually worsen. Afflicted individuals generally experience a normal life span, though with impaired motor functions.

The most common types of cerebral palsy are those that occur in infancy or earlier. Of this group, injuries received at birth (during forceps delivery, for example) form one of the largest and most well defined groups. Cerebral hemorrhage, a cause of many cerebral palsies, may occur either during intrauterine life or at birth. Cerebral palsy may also result from embryonic malformations, from injuries received during intrauterine life, or from injuries or other damage during the first two years of life. In addition to birth trauma, many other factors may contribute to a risk of cerebral palsy: premature delivery, breech delivery, toxemia of pregnancy, impairment of the baby’s oxygen supply, maternal infection (especially rubella, also called German measles), premature detachment of the placenta during the birth process, and incompatibility between the Rh blood types of mother and child. Brain injuries caused by low oxygen levels (anoxia or hypoxia) can arise before, during, or after birth and can result from damage to the blood vessels, birth trauma, or infectious diseases such as meningitis or encephalitis.

Cerebral palsies are classified into two general types: pyramidal (or spastic) and extrapyramidal (or nonspastic). The pyramidal or spastic types show muscular spasms and other symptoms that persist with age and hardly vary with changes in emotion, tension, movement, or sleep. The pyramidal tracts of the brain stem are damaged in these forms of cerebral palsy. The extrapyramidal or nonspastic types are more variable and are subdivided into several subtypes according to the types of movement exhibited: none (rigid type), weak (dystonic type), rhythmic and wormlike (athetoid type), or uncoordinated shaking (ataxic type). The extrapyramidal tracts of the brain stem are damaged in all these forms of the disease. Most forms of cerebral palsy can also be described as hemiplegia (involving both extremities on one side of the body only), diplegia (involving both legs more than the arms), bilateral hemiplegia (involving the arms more than the legs), or
quadriplegia (involving all four extremities more or less equally). Attempts to group the various forms of cerebral palsy by their causes have generally resulted in a lack of agreement among experts. One scheme divides the causes into subependymal hemorrhage among premature infants, damage from oxygen deprivation to the growing brain (the vast majority of cases), and developmental abnormalities of the nervous system.

The most common form of cerebral palsy is infantile spastic hemiplegia, which accounts for about one-third of all cerebral palsies. Most cases of
spastic hemiplegia (about 65 percent) are thought to result from birth trauma, either from forceps delivery or from the difficult passage of a very large head through the mother’s pelvic girdle. Another 30 percent arise after birth, during the first year of life, either from head injury or from infections such as meningitis and encephalitis. Only 5 percent of spastic hemiplegias arise before birth from embryonic malformations or from toxemia of pregnancy. The rate at which cerebral palsy occurs is higher for babies born prematurely than for those born at term. It is also higher for large babies that may suffer injury during a difficult passage through the birth canal. In the United States, there is a somewhat higher incidence rate among Caucasians than among African Americans.

Parkinson’s disease (also called paralysis agitans or shaking palsy) is a progressive or degenerative type of palsy. The disease usually produces a tremor that includes a distinctive “pill-rolling” movement of the thumb and forefinger; this tremor usually stops if a voluntary movement of some other kind is begun. Muscle weakness, stiffness, and muscular rigidity are common but with intermittent symptoms that come and go; movements generally become slow and difficult. The muscles involved in chewing and swallowing are often affected in Parkinson’s disease, so patients are often advised to eat high-calorie, semisoft foods that require no chewing and are more easily swallowed than liquids. Involvement of the muscles of facial expression results in a masklike expression that does not alter with changes in emotion. Patients suffering from Parkinson’s disease often have difficulty in initiating voluntary movements; this difficulty is often described by patients as a feeling of “being frozen in place.”

The walking gait of Parkinson’s disease patients is also very characteristic: The body above the waist leans forward, the head and shoulders droop, the feet shuffle slowly (and are barely lifted from the ground), and the arms are generally held slightly flexed and motionless rather than swinging. Many patients break into a trot or a run when they attempt to walk; as a result, patients often fall, most often forward. To prevent such falls, they frequently shuffle forward in very small steps. The shuffling gait is believed to result from a partial paralysis of the extrapyramidal motor system of neurons, which is generally responsible for controlling posture and coordinating motor activities.

Parkinson’s disease is known to result from a disorder in the production of dopamine, a neurotransmitter chemical normally secreted by certain parts of the brain. The affected parts of the brain are the basal ganglia deep within the cerebral hemispheres, and especially the substantia nigra, a deeper structure that sends dopamine-secreting nerve fibers to the basal ganglia. In patients with Parkinson’s disease, cells of the substantia nigra are often degenerate and pale from the loss of normal pigments, but this may be a result, rather than a cause, of the primary defect: an impairment of the brain’s ability to convert dopa (dihydroxyphenylalanine) into the neurotransmitter dopamine.

The chemical n-methyyl-4-phenyl-1,2,3,4-tetrahydropyridine has been found to produce in experimental animals a disease very similar to Parkinson’s disease. For this reason, many researchers suspect that the disease has an environmental cause that leads to the production of a related toxic chemical, one that presumably interferes with the production of dopamine.

Parkinson’s disease is uncommon before the age of forty, but it becomes so common in people over sixty that it is the leading neurological disorder in this age group. In the United States, the incidence rate is about 130 per 100,000 in the general population and is roughly the same in all races and ethnic groups. About 10 to 15 percent of patients show mental deterioration (dementia) as the disease progresses. Patients often experience depression, social withdrawal, and generalized apathy.

Other, less common palsies include brachial birth palsy, Erb’s palsy, Klumpke’s palsy, true or progressive bulbar palsy, pseudobulbar palsy, Féréol-Graux palsy, posticus palsy, lead palsy, scrivener’s palsy, pressure palsy, compression palsy, and creeping or wasting palsy.

Brachial birth palsy is a paralysis of the infant’s arm resulting from an injury received at birth, involving the whole arm, the upper arm only (Erb’s palsy), or the lower arm only (Klumpke’s palsy). Erb’s palsy, a brachial birth palsy of the upper arm, is caused by an injury at birth to the brachial plexus or the posterior roots of the fifth and sixth cervical nerves; the muscles involved generally include the deltoideus, biceps brachii, and brachialis, impairing the raising of the upper arm, flexion of the elbow, or supination movements involving the forearm. In Klumpke’s palsy, which results from an injury at birth, the muscles of the forearm and the small muscles of the hand undergo atrophy; this form is often accompanied by paralysis of the cervical sympathetic nerves.

True or progressive bulbar palsy, a palsy and progressive
atrophy of the muscles of the tongue, lips, palate, pharynx, and larynx, often occurs late in life and is caused by degeneration of the motor neurons leading to these muscles. Twitching or atrophy of the tongue and other affected muscles causes drooling, difficulties in swallowing, and ultimately a respiratory paralysis that results in death. Many experts consider true bulbar palsy to be a manifestation of the same disease that causes amyotrophic lateral sclerosis (ALS), which is popularly known as Lou Gehrig’s disease.

Pseudobulbar palsy (“laughing sickness”) is a paralysis of the lips and tongue that mimics true or progressive bulbar palsy, but it arises in the brain itself and is accompanied by difficulties in swallowing and by spasmodic laughter at inappropriate times. Féréol-Graux palsy, a one-sided (unilateral) paralysis of the motor nucleus of the lateral rectus muscle of one eye and the medial rectus muscle of the other eye, results from damage to the medial longitudinal fasciculus and impairs the ability to direct either eye toward the affected side. Posticus palsy is a paralysis of the posterior cricoarytenoideus muscle (cricoarytenoideus posticus), resulting in the vocal cords being held close to the midline.

Lead palsy is a paralysis of the extensor muscles of the wrist resulting from lead poisoning, while scrivener’s palsy (“writer’s cramp”) is a repetitive motion disorder resulting in damage to the nerve controlling the small muscles of the hand. Pressure palsy is a paralysis caused by repeated or persistent compression of a nerve or nerve trunk. Compression palsy results from nerve compression, especially of the arm, caused by pressure from the use of a crutch (crutch palsy) or from compression of a nerve during sleep. Creeping palsy and wasting palsy are general terms for progressive muscle atrophy, such as that associated with ALS.

Treatment and Therapy

Bell’s palsy is treated by various methods, including the application of warmth, the avoidance of cold drafts, or the administration of vasodilating drugs such as cortisone or antiviral drugs such as acyclovir. In unusual cases, surgery is performed to enlarge the passages through which the facial nerve passes, thus relieving compression on the nerve. In past generations, physicians often recommended treating eyes that could not be closed by taping them shut, especially in sleep. This treatment is no longer recommended. Instead, physicians usually advise patients who cannot close an affected eye to wear dark glasses during the day.

Many patients with Bell’s palsy recover spontaneously on their own. The chances that a particular individual will spontaneously recover depend on the location of the damage and the extent of muscle involvement; the cases with the most favorable outcomes are those in which the damage is more peripheral and fewer muscles are involved. Frequent, repeated testing of each small group of facial muscles is needed to assess the extent of damage and the extent of any recovery.

Diagnosis of cerebral palsy is best made by a trained neurologist through observation of the patient’s spontaneous motor movements and reflex actions. Infants who exhibit any reflex that persists beyond its appropriate age range, or any voluntary motor pattern that fails to develop at the appropriate age, should be examined more carefully for signs of nerve damage. For example, most babies can lift their heads by one month of age and their chests by two months. By three months of age, most babies can raise themselves up on their elbows, and by four months on their wrists. Newborn babies exhibit reflexes such as the Moro reflex, a flexion and “embracing” reflex in reaction to a sudden noise or other sudden stimulus or “startle”; however, the persistence of this reflex beyond six months of age (or its asymmetrical performance) may be indicative of some form of cerebral palsy. Another reflex often used in diagnosis is the “fencer” reflex, or asymmetric tonic neck reflex: Turning the baby’s head toward one side usually causes extension movements in both the arm and leg on the side toward which the chin faces, while flexion movements usually take place on the opposite side of the body. This reflex is present at birth and disappears in a few months; its persistence after six months of age should be considered suspicious.

There is no cure for cerebral palsy. Treatment generally consists of physical rehabilitation and training the patient to use whatever muscles are still capable of being consciously controlled. This is a difficult form of therapy that must be tailored to the needs of each patient because individuals experience unique combinations of motor abilities and disabilities. Few patients with cerebral palsy are capable of walking on their own. Depending on the extent of impairment of muscle movements, some patients may require crutches or braces, while others use motorized wheelchairs. In cases in which there is speech impairment, speech therapy may also be needed to teach the patient to speak more clearly. Most types of cerebral palsy are already present during infancy; therapy for these types is always rather difficult because the patient is learning the necessary motor skills (such as walking or speaking) for the first time. Palsies that arise during adolescence or adulthood respond differently to therapy because the patient is relearning skills that had already been mastered.

Treatment for Parkinson’s disease includes the administration of a number of drugs that are chemically related to dopamine, the missing neurotransmitter. The drug most often used is levodopa, or L-dopa, a derivative of a naturally occurring amino acid in the brain. The drug carbidopa is also given to help deliver most of the levodopa into the brain. Dopamine agonists (enhancers) such as bromocriptine and pergolide are frequently given. The antiviral drug amantadine has also been shown to have effects that counter the disease.

Bloom, Floyd E., M. Flint Beal, and David J. Kupfer, eds. The Dana Guide to Brain Health. New York: Dana Press, 2006.

Carson-DeWitt, Rosalyn. "Parkinson's Disease." Health Library, September 10, 2012.

Chipps, Esther, Norma J. Clanin, and Victor G. Campbell. Neurologic Disorders. St. Louis, Mo.: Mosby Year Book, 1992.

Daube, Jasper R., ed. Clinical Neurophysiology. 3d ed. New York: Oxford University Press, 2009.

Kliegman, Robert M., and Waldo E. Nelson, eds. Nelson Textbook of Pediatrics. 19th ed. Philadelphia: Saunders/Elsevier, 2011.

Iansek, Robert, and Meg. E. Morris, eds. Rehabilitation in Movement Disorders. Cambridge: Cambridge University Press, 2013.

Stanley, Fiona J., Eva Alberman, and Eva Blair. Cerebral Palsies: Epidemiology and Causal Pathways. New York: Cambridge University Press, 2000.

Stanton, Marion. The Cerebral Palsy Handbook. London: Vermilion, 2002.

United Cerebral Palsy. http://www.ucp.org.

Victor, Maurice, and Allan H. Ropper. Adams and Victor’s Principles of Neurology. 9th ed. New York: McGraw-Hill, 2009.

Waxman, Stephen G. Correlative Neuroanatomy. 25th ed. New York: Lange Medical Books/McGraw-Hill, 2002.

Weiner, William J., Lisa M. Shulman, and Anthony E. Lang. Parkinson's Disease: A Complete Guide for Patients and Families, 3d ed. Baltimore, Md.: Johns Hopkins University Press, 2013.

What are plasmid relationships and applications?

Plasmid Structure

The structure of plasmids is usually circular, although linear forms do exist. Their size ranges from a few thousand base pairs to hundreds of thousands of base pairs. They are found primarily in bacteria but have also been found in fungi, plants, and even humans.

In its commensal relationship with its host, the plasmid can be thought of as a molecular parasite whose primary function is to maintain itself within its host and to spread itself as widely as possible to other hosts. The majority of genes that are present on a plasmid will be dedicated to this function. Researchers have discovered that despite the great diversity of plasmids, most of them have similar genes, dedicated to this function. This relative simplicity of plasmids makes them ideal models of gene function, as well as useful tools for molecular biology. Genes of interest can be placed on a plasmid, which can easily be moved in and out of cells. Using plasmids isolated from the wild, molecular biologists have designed many varieties of artificial plasmids, which have greatly facilitated research in molecular biology.

Plasmid Replication

To survive and propagate, a plasmid must be able to copy itself, or replicate. The genes that direct this process are known as the replication genes. These genes do not carry out all the functions of replication, but instead coopt the host’s replication machinery to replicate the plasmid. Replication allows the plasmid to propagate by creating copies of itself that can be passed to each daughter cell when the host divides. In this manner, the plasmid propagates along with the host.

A second function of the replication genes is to control the copy number of the plasmid. The number of copies of a plasmid that exist inside a host can vary considerably. Plasmids can exist at a very low copy number (one or two copies per cell) or at a higher copy number, with dozens of copies per cell. Adjusting the copy number is an important consideration for a plasmid. Plasmid replication is an expensive process that consumes energy and resources of the host cell. A plasmid with a high copy number can place a significant energy drain on its host cell. In environments where the nutrient supply is low, a plasmid-bearing cell may not be able to compete successfully with other, non-plasmid-containing cells. Wild plasmids often exist at a low copy number, or create a high copy number for only a brief period of time.

Plasmid Partitioning

Because the presence of a plasmid is expensive in terms of energy, a cell harboring a plasmid will grow more slowly than a similar cell with no plasmid. This can cause a problem for a plasmid if it fails to partition properly during its host’s division. If the plasmid does not partition properly, then one of the host’s daughter cells will not contain a plasmid. Since this cell does not have to spend energy replicating a plasmid, it will gain an ability to grow faster, as will all of its offspring. In such a situation, the population of non-plasmid-containing cells could outgrow the population of plasmid-containing cells and use up all the nutrients in the environment. To avoid this problem, plasmids have evolved strategies to prevent improper partitioning. One strategy is for the plasmid to contain partitioning genes. Partitioning genes encode proteins that actively partition plasmids into each daughter cell during the cell division of the host. Active partitioning greatly reduces the errors in partitioning that might occur if partitioning were left to chance.

A second strategy that plasmids use to prevent partitioning errors is the plasmid addition system. In this strategy, genes on the plasmid direct the production of both a toxin and an antidote. The antidote protein is very unstable and degrades quickly, but the toxin is quite stable. As long as the plasmid is present, the cytoplasm of the cell will be full of toxin and antidote. Should a daughter cell fail to receive a plasmid during division, the residual antidote and toxin present in the cytoplasm from the mother cell will begin to degrade, since there is no longer a plasmid present to direct the synthesis of either toxin or antidote. Since the antidote is very unstable, it will degrade first, leaving only toxin, which will kill the cell.

Plasmid Transfer Between Cells

Propagation of plasmids can occur through the spread of plasmids from parent cells to their offspring (referred to as vertical transfer), but propagation can also occur between two different cells (referred to as horizontal transfer). Many plasmids are able to transfer themselves from one host to another through the process of conjugation. Conjugal plasmids contain a collection of genes that direct the host cell that contains them to attach to other cells and transfer a copy of the plasmid. In this manner, the plasmid can spread itself to other hosts and is not limited to spreading itself only to the descendants of the original host cell.

One of the first plasmids to be identified was discovered because of its ability to conjugate. This plasmid, known as the F plasmid, or F factor, is a plasmid found in the bacterium
Escherichia coli
. Cells harboring the F plasmid are designated F+ cells and can transfer their plasmid to other E. coli cells that do not contain the F plasmid (called F- cells).

Conjugal plasmids can be very specific and transfer only between closely related members of the same species (such as the F plasmid), or they can be very promiscuous and allow transfer between unrelated species. An extreme example of cross-species transfer is the Ti plasmid of the bacterial species Agrobacterium tumefaciens. The Ti plasmid is capable of transferring part of itself from A. tumefaciens into the cells of dicotyledonous plants. Plant cells that receive parts of the Ti plasmid are induced to grow and form a tumorlike structure, called a gall, that provides a hospitable environment for A. tumefaciens.

Host Benefits from Plasmids

In most commensal relationships, there is an exchange of benefits between the two partners. The same is true for plasmids and their hosts. In many cases, plasmids provide their host cells with a collection of genes that enhance the ability of the host cell to survive. Enhancements include the ability to metabolize a wider range of materials for food and the ability to survive in hostile environments. One particular hostile environment in which plasmids can provide the ability to survive is the human body. A number of pathogenic microorganisms gain their ability to inhabit the human body, and thus cause disease, from genes contained on plasmids. An example of this is Bacillus anthracis, the agent that causes anthrax. Many of the genes that allow this organism to cause disease are contained on one of two plasmids, called pXO1 and pXO2. Yersinia pestis, the causative agent of bubonic plague, also gains its disease-causing ability from plasmids.

R Factors

Another example of plasmids conferring on their hosts the ability to survive in a hostile environment is antibiotic resistance. Plasmids known as R factors contain genes that make their bacterial hosts resistant to antibiotics. These R factors are usually conjugal plasmids, so they can move easily from cell to cell. Because the antibiotic resistance genes they carry are usually parts of transposons, they can readily copy themselves from one piece of DNA to another. Two different R factors that happened to be together in one cell could exchange copies of each other’s antibiotic resistance genes. A number of R factors exist that contain multiple antibiotic resistance genes. Such plasmids can result in the formation of “multidrug resistant” (MDR)
strains of pathogenic bacteria, which are difficult to treat. There is much evidence to suggest that the widespread use of antibiotics has contributed to the development of MDR pathogens, which are emerging as an important health concern.

Role of Plasmids in Evolution

Through conjugation, plasmids can transfer genetic information from one species of bacterial cell to another. During its stay in a particular host, a plasmid may acquire some of the chromosomal genes of the host, which it then carries to a new host by conjugation. These genes can then be transferred from the plasmid to the chromosome of the new host. If the new host and the old host are different species, this gene transfer can result in the introduction of new genes, and thus new traits, into a cell. Bacteria, being asexual, produce daughter cells that are genetically identical to their parent. The existence of conjugal plasmids, which allow for the transfer of genes between bacterial species, may represent an important mechanism by which bacteria generate diversity and create new species.

Genetic Engineering of Plasmids

The identification of restriction endonuclease sites within plasmids allowed scientists to manipulate the organization and makeup of these molecules. Researchers were now able to insert genes of interest into these restriction sites within the plasmids and have the recombined plasmid vector taken up by bacteria through the process of transformation. Transcription of the inserted gene by the host bacterium is dependent on an upstream promoter that is active in that bacterial strain. The use of genetic engineering and the creation of artificial plasmid vectors have revolutionized basic research and have led to the creation of modern industrial microbiology. Because bacteria containing the vector are able to express proteins encoded by the inserted gene(s) at a high level, mass quantities of desired proteins can be produced on an industrial scale. Vectors have been used to express medically important proteins such as insulin, human growth hormone, and human factor IX, a blood-clotting factor. Vectors have also been used to express proteins within eukaryotic cells. Additional DNA elements are necessary for the optimal production of proteins in these cells. Viral or mammalian promoters recognized by host RNA polymerases, as well as enhancer sequences, allow proteins to be expressed from the vector. Poly-adenylation sequences are added downstream of the inserted gene for proper messenger RNA (mRNA) expression.

The ability to express proteins within mammalian cells has enabled the development of DNA vaccines
in which antigenic proteins are expressed from plasmids. These plasmids are taken up by cells following introduction into the animal or human subject by injection or alternate means of inoculation. Expression of these proteins in the cell then allows for an immunological response by the vaccine. Expression of cytokine or other immunomodulatory molecules from the same plasmid has been explored as a means of enhancing the immune response to the coexpressed antigenic protein using DNA vaccines. Plasmid DNA itself can sometimes have immunostimulatory effects due to the presence of CpG dinucleotides. Clinical trials using DNA vaccines targeting cancer have demonstrated the immunogenicity of these vaccines in humans. Veterinary applications of DNA vaccines have been approved for use.

Plasmids have also been used as delivery vehicles for the expression of double-stranded RNAs (dsRNAs) in order to suppress specific mRNAs by RNA interference (RNAi). Because of the abbreviated length (about 21 nucleotides) and need for a distinction termination point of these dsRNAs, RNA polymerase III promoters and the accompanying termination signals have often been included on the plasmids to express these transcripts within cells. Delivery of the RNAi expression plasmids to the desired location within the body remains a challenge for the development of this technology.

Key terms




commensalism


:

a relationship in which two organisms rely on each other for survival





gene


:

a region of DNA containing instructions for the manufacture of a protein





transposon


:

a piece of DNA that can copy itself from one location to another





Bibliography

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Bower, D. M., and K. L. J. Prather. “Engineering of Bacterial Strains and Vectors for the Production of Plasmid DNA.” Applied Microbiology and Biotechnology 82.5 (2009): 805–13. Print.

Dale, Jeremy, and Simon F. Park. Molecular Genetics of Bacteria. 5th ed. Chichester: Wiley, 2010. Print.

Kroll, Jens, et al. “Plasmid Addiction Systems: Perspectives and Applications in Biotechnology.” Microbial Biotechnology 3.6 (2010): 634–57. Print.

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Van Gaal, E. V. B., W. E. Hennink, D. J. A. Crommelin, and E. Mastrobattista. “Plasmid Engineering for Controlled and Sustained Gene Expression for Nonviral Gene Therapy.” Pharmaceutical Research 23.6 (2006): 1053–074. Print.

When did the Articles of Confederation reign, and when did the Constitution become the law of the land?

Technically speaking, the Articles of Confederation “reigned” beginning on March 1, 1781.  They were replaced by the Constitution of the United States, which became “the law of the land” almost exactly 8 years later, on March 4, 1789.

The Articles of Confederation were the first constitution for the United States.  They were written before the country had won the Revolutionary War and become independent in the eyes of the world.  They were actually written and...

Technically speaking, the Articles of Confederation “reigned” beginning on March 1, 1781.  They were replaced by the Constitution of the United States, which became “the law of the land” almost exactly 8 years later, on March 4, 1789.

The Articles of Confederation were the first constitution for the United States.  They were written before the country had won the Revolutionary War and become independent in the eyes of the world.  They were actually written and finalized in October of 1777 and sent to the states to be ratified in the next month.  However, the Articles would not become binding until all of the states formally ratified them.  Therefore, they did not officially go into effect until Maryland became the last state to ratify them in March of 1781.  From 1777 to 1781, then, the US government was without a formal constitution.  During that time, the structure of government was set by the Articles of Confederation even though the Articles had not actually been ratified.  So, we might argue that the Articles “reigned” from 1777 on, but they were not technically in effect until March of 1781.

After the Revolution, Americans soon came to think that the Articles were flawed.  They wanted a stronger central government than the one the Articles had created.  Therefore, they convened a convention that ended up writing a new constitution, the Constitution of the United States.  That document was written in 1787 and finally ratified on June 21, 1788.  However, it did not formally take effect until March 4, 1789.

What is guilt? |

Introduction

The concept of guilt has played an important role in the development of human behavior and culture since the early days of civilization. More recently, there has been a focus on the psychological understanding of guilt. One of the first people to write extensively about the psychological meaning of guilt was the Austrian founder of psychoanalysis, Sigmund Freud
. His writings from the 1890s to the 1930s provide the basic foundation of the contemporary understanding of guilt. Guilt is the feeling of tension when one feels that one has violated a moral code by thought, action, or nonaction. It is considered to be a type of anxiety. The unpleasant feeling of guilt usually prompts the guilty person to take some type of action to relieve the tension.

Freud believed that guilt starts in early childhood as a result of the child’s fear of being punished or of losing the love of the parent through misbehavior. Freud stressed that the most significant event in establishing guilt is the Oedipus complex. At the age of four or five, Freud hypothesized, the male child wants to kill his father and have sex with his mother. In the counterpart to this, sometimes called the Electra complex, the female child wants to kill her mother and have sex with her father. The child becomes anxious with these thoughts and attempts to put them out of his or her consciousness. As a result of the Oedipus complex, the child develops a conscience, which represents inner control and morality. There is the ability to recognize right from wrong and to act on the right and refrain from doing wrong. Freud would later use the concept of the superego
to explain conscience. The superego represents the parental thoughts and wishes that have been internalized in the child. Now the internal superego can monitor the morality of the child, and guilt can be generated when the superego is displeased.

An important distinction is to be made between normal guilt and neurotic guilt. Normal guilt is experienced when one has acted in such a way as to violate one’s moral code. A person then usually takes some action to relieve the guilt. Neurotic guilt relates to thoughts or wishes that are unacceptable and cause anxiety. These thoughts are pushed out of consciousness, so that the person feels guilt-ridden but is not aware of the source of the guilt. There is no relief from the guilt. In neurotic guilt, the thought is equated with the deed.

Origin

The origin of guilt can be traced back to childhood. In human development there is a long period in which the baby is dependent on the parent. The young baby cannot survive without someone providing for its care. As the baby begins to individuate and separate from the parent, ambivalent feelings are generated. Ambivalent feelings are opposing feelings, typically love and hate, felt for the same person. The child begins to worry that these hateful feelings will cause the parents to punish him or her or remove their love. With this fear of parental retaliation, the child becomes guilty when thinking or acting in a way that might displease the parents.

The Oedipus complex dramatically changes this situation. The dynamics of this complex are based on the play by the Greek playwright Sophocles, in which Oedipus murders his father and takes his mother as his wife, unaware that they are his parents. When Oedipus finds out the truth, he blinds himself and goes into exile. Freud believed the Oedipal situation to be a common theme in literature. He also discussed the play Hamlet (1603) by the English playwright William Shakespeare. At the beginning of the play, Hamlet’s uncle has killed Hamlet’s father and married Hamlet’s mother. There is the question as to why Hamlet hesitates in killing his uncle, and Freud attributed this indecision to Hamlet’s Oedipus complex. Freud argued that Hamlet had thoughts of killing his father and having sex with his mother, and Hamlet’s uncle only put into action what Hamlet had thought. Hamlet’s guilty desires prevent him from taking any action. Freud believed that the Oedipus complex can exist throughout one’s life. People can feel guilty about separating from their parents or achieving more than their parents, as this can unconsciously represent killing them off.

Freud’s examination of neurotic guilt led him to the concept of unconscious guilt. Neurotics experience guilt but are not sure what they are guilty about. Freud first noticed this attitude in obsessive patients. These patients tended to be perfectionistic and overly conscientious, and yet they were wracked by guilt. Freud believed them to be feeling guilty about thoughts and wishes they had pushed out of consciousness, that is, Oedipal wishes. Freud observed the paradox that the more virtuous a person, the more the person experiences self-reproach and guilt as temptations increase.

Freud’s final writings on guilt highlighted its importance for civilization. He wrote that guilt enabled people to get along with others and form groups, institutions, and nations. Without the ability to curb impulses, particularly aggression, society would suffer. Freud did feel that humans pay a price for this advance in civilization, in that there is a loss of personal happiness due to the heightening of the sense of guilt.

History

Writing in the 1930s, child psychoanalyst Melanie Klein
argued that the Oedipus complex started much earlier in the child’s development than Freud had suggested. She believed that it started toward the end of the first year of life and centered primarily on the mother. The baby hates the mother for withdrawing the breast during feeding. The baby then feels guilty and worries that the mother will no longer breast-feed. Klein felt that the baby would want to relieve its guilt by making amends to the mother, causing it to show concern and care for the mother. Klein felt that this was the most crucial step in human development, the capacity to show concern for someone else. Guilt is thus seen as a critical ingredient in the ability to love.

The psychoanalyst Franz Alexander
further advanced understanding of guilt. He wrote that feeling guilty can interfere with healthy assertiveness. The guilty person may need excessive reassurance from other people. When the guilty person is assertive, he or she fears retaliation from others. Alexander also wrote about the concept of guilt projection. This term refers to situations in which people who tend to be overly critical induce guilt in other people.

The psychoanalyst Erik H. Erikson
also wrote on the theme of guilt interfering with assertiveness. He formulated a theory of eight stages of human development, focusing primarily on early development. The fourth stage of development, around the age of four to five, is called guilt/initiative. The child must successfully repress Oedipal wishes to avoid feeling excessive guilt. The child can then proceed with normal initiative.

Another perspective on guilt is the concept of existential guilt, discussed by American psychiatrist James Knight. Existential guilt is the failure to live up to one’s expectations and potentialities. It can lead to questioning one’s existence and to states of despair until personal meaning can be established.

Erich Fromm
expanded the concept of guilt in order to better understand group psychology. He wrote that there are essentially two types of conscience: authoritarian and humanistic. Authoritarian conscience is the voice of internalized external authority. It is based on fear and danger. It is afraid of displeasing authority and actively seeks to please authority. Authoritarian conscience can lead to immoral acts committed as the individual conscience is given over to this higher authority. Humanistic conscience is one’s own voice expressing one’s own true self. It is the essence of one’s moral experience in life. It includes integrity and self-awareness.

Current Status

Since 1960, there has been a significant change in the views of psychoanalytic theory on guilt. The psychoanalyst Hans Loewald wrote extensively about guilt. He considered that guilt does not necessarily lead to punishment; sometimes punishment is sought to evade guilt. Bearing the burden of guilt makes it possible to master guilt by achieving a reconciliation of conflicting feelings. Guilt is thus seen not as a troublesome feeling but as one of the driving forces in the organization of the self. Guilt plays a critical part in developing self-responsibility and integrity.

The American psychoanalyst Stephen Mitchell, writing in 2000, expanded on Loewald’s ideas. Mitchell concerned himself with the concept of genuine guilt. He believes it is important to tolerate, accept, and use this feeling. People need to take responsibility for the suffering they have caused others and themselves. People particularly hurt those they love, but by taking personal responsibility for their behavior, they can repair and deepen their love.

Guilt and Shame

Throughout the 1990s, there were a number of writings about the concept of shame and its relation to guilt. Shame is experienced as a feeling of inadequacy in the self. There can be physical, psychological, or emotional shame.

The American psychoanalyst Helen Lewis wrote extensively about this topic. She believed that shame includes dishonor, ridicule, humiliation, and embarrassment, while guilt includes duty, obligation, responsibility, and culpability. A person can feel both guilt and shame.

Bibliography

Akhtar, Salman, ed. Guilt: Origins, Manifestations, and Management. Lanham: Aronson, 2013. Print.

Carveth, Donald L. The Still Small Voice: Psychoanalytic Reflections on Guilt and Conscience. London: Karnac, 2013. Print.

Freeman, Lucy, and Herbert S. Strean. Understanding and Letting Go of Guilt. Northvale: Aronson, 1995. Print.

Joseph, Fernando. “The Borrowed Sense of Guilt.” International Journal of Psychoanalysis 81.3 (2000): 499–512. Print.

Lewis, Michael. The Rise of Consciousness and the Development of Emotional Life. New York: Guilford, 2014. Print.

Piers, Gerhart, and Milton B. Singer. Shame and Guilt: A Psychoanalytic and a Cultural Study. New York: Norton, 1971. Print.

Reilly, Patrick. The Literature of Guilt: From Gulliver to Golding. Iowa City: U of Iowa P, 1988. Print.

Rodogno, Raffaele. "Gender and Shame: A Philosophical Perspective." Gender and Emotion. Ed. Ioana Latu, Marianne Schmid Mast, and Susanne Kaiser. Bern: Lang, 2013. 155–70. Print.

Tangney, June Price, and Ronda L. Dearing. Shame and Guilt. New York: Guilford, 2004. Print.

Tournier, Paul. Guilt and Grace: A Psychological Study. San Francisco: Harper, 1983. Print.