What is childbirth? |

Process and Effects

In humans, pregnancy lasts an average of forty weeks, counting from the first day of the woman’s last menstrual cycle. Actually, ovulation, and therefore conception and the start of pregnancy, does not normally occur until about two weeks after the beginning of the last menstrual period, but because there is no good external indicator of the time of ovulation, obstetricians and other health care providers typically count the weeks of pregnancy using the easily observed last period of menstrual bleeding as a reference point. Because of the uncertainty about the actual time of ovulation and conception, the calculated due date for an infant’s birth may be inaccurate by as much as two weeks in either direction.

There is incomplete understanding of the processes that determine the timing and initiation of childbirth. Near the end of pregnancy, the uterus undergoes changes that prepare it for the birth process: The cervix softens and becomes stretchy, the cells in the uterus acquire characteristics that enable them to contract in a coordinated fashion, and the uterus becomes more responsive to hormones that cause contractions.

A number of substances are involved in the preparation of the uterus for birth, including the hormones
estrogen and progesterone (produced within the placenta), the hormone relaxin (from the maternal ovary and/or uterus), and
prostaglandins (produced within the uterus). The fetus participates in this preparation, since it provides precursors necessary for the uterine synthesis of estrogens. In addition, the amnion and chorion (the placenta and umbilical cord), two membranes surrounding the fetus, are capable of producing prostaglandins that assist in the preparation of the uterus.

Once labor begins, the hormone oxytocin (from the maternal pituitary gland) and uterine prostaglandins cause uterine contractions. It is not known what triggers the onset of labor or how the preparatory hormones and prostaglandins work together. However, a 2009 study indicated that labor may be triggered by elevated levels of placental corticotrophin-release hormone (CRH), which promotes the production of a steroid hormone called DHEAS by the fetal adrenal gland. The placenta is then thought to convert the steroid hormone into estriol, and the increasing imbalance between estriol and estradiol (both estrogens) may be responsible for inducing labor. Typically, estradiol blocks estriol's actions, but as the imbalance between these two estrogens increases, estriol is able to activate proteins in the uterine muscles, which then produce prostaglandins that promote muscle cell contraction.

In humans, the onset of labor is indicated by one or more of three signs: the beginning of regular, rhythmic uterine contractions; the rupture of the amniotic membrane, a painless event that is usually accompanied by the leakage of clear fluid from the vagina; and the expulsion of a slightly bloody mucus plug from the cervix, which is an indication that the cervix is beginning to dilate. These signs may appear in any order, or occasionally one sign may be absent or unnoticed. For example, the amniotic membrane may fail to rupture spontaneously; in this case, the attendant will usually pierce the membrane to facilitate the birth.

Uterine contractions are the most prominent indication of labor, which is divided into three stages. In the first stage of labor, the contractions have the effect of dilating the cervix from its initial size of only a few millimeters to full dilation of 10 centimeters, large enough to permit the passage of the fetus. When the first stage of labor starts, the contractions may be up to twenty minutes apart, with each contraction of relatively short duration. As the first stage progresses, the contractions become longer and closer together, so that by the end of the first stage there may be only a minute between contractions. There is no downward movement of the fetus during the first stage of labor, but the contractions do force the fetus against the cervix, and this force is important in causing cervical dilation. This first stage lasts for an average of eleven hours in women giving birth for the first time, but up to twenty hours is considered normal. The average length of the first stage of labor in women who have previously delivered is reduced to seven hours, with a norm of up to fourteen hours.

In the second stage of labor, the fetus moves downward through the fully dilated cervix and then into the vagina as a result of the force exerted by the continuing uterine contractions. Voluntary contractions of the abdominal muscles by the mother can help shorten this stage of labor by applying additional force, but in the absence of voluntary contractions (as with an anesthetized mother), the uterine contractions are usually sufficient to cause delivery. In approximately 96 percent of human births, the fetus is situated so that the head is downward and thus is first to pass through the birth canal. Because the vagina does not lie in the same line as the cervix and uterus, the head of the fetus must flex and rotate as the fetus progresses downward past the mother’s pelvic bones. The final barrier to the birth of the fetus is the soft tissue surrounding the vaginal opening; once the head of the fetus passes through and stretches this opening, the rest of the body usually slips out readily. The average duration of this second stage of labor in women delivering for the first time is slightly more than one hour; the average duration is shortened to twenty-four minutes in women who have previously delivered. Most women agree that the
actual birth of the child during the second stage is less uncomfortable than the strong uterine contractions that occur at the very end of the first stage of labor, when the cervix is dilating the last centimeter or so.

Most infants begin to take regular, deep breaths immediately upon delivery. These breaths serve to inflate the lungs with air for the first time. The infant now becomes dependent on breathing to supply oxygen to the blood, whereas oxygen had been supplied to the fetal blood by circulation through the placenta.

Following delivery of the infant, the mother enters the third stage of labor, during which continued uterine contractions serve to reduce the size of the uterus and expel the placenta. The placenta usually separates from the uterus and is expelled five to fifteen minutes after the birth of the infant.

Uterine contractions do not end with the delivery of the placenta; they continue, with decreasing frequency and intensity, for as long as six weeks following childbirth. These later contractions, known as afterpains, serve to reduce bleeding from the site of placental attachment and to return the uterus and cervix to their prepregnancy condition.

Another significant process that occurs in the mother’s body following delivery is the onset of milk production. During pregnancy, the breasts are prepared for later milk production by a number of hormones, but actual milk production does not begin until about the second day after delivery. It appears that the decrease in progesterone levels caused by the removal of the placenta at birth allows milk production to commence.

Most obstetrical attendants agree that the ideal childbirth situation is a labor and delivery with a minimum of medical intervention. If all goes well, the role of the attendant will be primarily that of a support person. Most women are admitted to a hospital or birthing center during the first stage of labor. The mother’s blood pressure and temperature will be checked frequently. In addition, the strength and timing of contractions will be assessed either by a hand placed lightly on the abdomen or by an electronic monitor that detects uterine activity through a sensor belt placed around the abdomen. The fetal heart rate will be measured with a stethoscope or by this same electronic monitor placed on the mother’s abdomen. Fetal well-being may also be monitored by an electrode placed on the scalp of the fetus through the cervix. This scalp pH probe indicates whether the fetus is tolerating labor well or is in distress. Cervical dilation can be assessed by a vaginal examination: The attendant will insert one or more fingers into the cervix to determine its state of dilation. It is also important that the attendant provide emotional support and reassurance to the mother throughout the delivery.

During the second stage of labor, the attendant will monitor the progress of the fetus through the birth canal. By inserting a hand into the vagina and feeling for the fetal skull bones, the attendant can determine the exact placement of the fetus within the birth canal. As the infant’s head appears at the vaginal opening, an incision called an
episiotomy is usually performed to prevent accidental tearing of these tissues. Many physicians believe that episiotomy should be done to prevent possible vaginal tearing, since a planned incision is easier to repair than an accidental tear. Another advantage of episiotomy is that it tends to speed the expulsion of the infant, which may be an advantage to both the mother and the child at this stage. The episiotomy incision is made after the injection of a local anesthetic to numb the area, and the incision is stitched closed following the delivery of the placenta.

Once the infant’s head has emerged from the vagina, the attendant uses a suction device to clear the infant’s nose and mouth of fluid. As the rest of the infant emerges, the attendant supports the body; a quick examination is conducted at this time to determine whether the infant has any major health problems. The umbilical cord that joins the infant to the placenta is usually cut within a few minutes after birth. When the placenta is delivered, the attendant will examine it for completeness and then will perform a thorough examination of the mother and child to ensure that all is well.

Complications and Disorders

If the labor and delivery do not progress normally, the attendant has available a number of medical interventions that will promote the safety of both the mother and the baby. For example, labor may be induced by administration of oxytocin through an intravenous catheter. Such induction is performed if the amniotic membrane ruptures without the spontaneous onset of uterine contractions, if the pregnancy progresses well beyond the due date, or in response to maternal indicators such as hypertension. The induction of labor has been found to be safe, but careful monitoring of the progress of labor is required.

Another fairly common procedure is the use of forceps to assist delivery. These tonglike instruments have two large loops that are placed on the sides of the fetal head when the head is in the birth canal. Forceps are not used to pull the fetus from the birth canal; instead, they are used to guide the fetus through the birth canal and to assist in the downward movement of the fetus during contractions. The use of forceps can help to speed the second stage of labor, and injury to the fetus or the mother is minimal when the forceps are not applied until the fetal head is well within the birth canal, as is the convention. Some type of anesthesia is always used with a forceps delivery. In some areas, vacuum extraction of the fetus is preferred. As the name implies, vacuum extraction makes use of a suction cup on the end of a vacuum hose; the suction cup is affixed to the fetal scalp.

Many women require some type of pain relief during labor, although this need can be reduced by thorough education and preparedness during the pregnancy. A wide range of pain-reducing drugs (analgesics), sedatives, and tranquilizers is available for use during the first stage of labor. These are typically administered by injection; they work at the level of the brain to alter the perception of pain and to promote relaxation. The goal is to use the minimum drug dose that allows the woman to be comfortable. The main danger is that these drugs reach the fetus through the placental circulation; side effects in the infant, which can persist for many hours after delivery, may include depressed respiration, irregular heart rhythm or rate, and sleepiness accompanied by poor suckling response.

Anesthetics that numb pain-carrying nerves in the mother may also be used during the first and second stages of labor. Two routes of delivery are in common use: epidural and spinal, both of which involve the injection of anesthetic drugs into or near the membranes around the mother’s spinal cord. The epidural route of injection places the anesthetic in a space that lies outside the spinal cord membranes; with spinal anesthesia, the injection is made slightly deeper into the membranous layers. An advantage of both methods is that the mother remains awake during the delivery and can assist by pushing during the second stage.

Although the disadvantages of both anesthetics, and especially of epidurals, have been downplayed, these procedures do impose restrictions on the mother. Once an epidural has been given, for example, a woman must stay in bed because it will be difficult for her to move her legs; some hospitals do offer “mobile epidurals,” which use a type of drug that blocks the pain while still allowing the woman to walk around, but these are the exception. Because walking helps to stimulate labor, the use of epidurals can be counterproductive. The use of epidurals is also associated with a prolongation of the second stage of labor and with increased need for forceps to assist delivery. Headaches, backaches, low blood pressure, nausea, and other side effects may result in the mother following the use of anesthetics. Moreover, contrary to past evidence, recent studies have suggested that the drugs in epidurals do cross the placenta to the baby, causing health risks.

General anesthesia refers to the use of drugs that induce sleep; they may be administered by inhalation or by injection. Because of profound side effects in both the mother and child, most physicians use general anesthesia only in an emergency situation requiring an immediate cesarean section.

Cesarean section refers to the delivery of the fetus through an incision made in the mother’s abdominal and uterine walls. (The name derives from an unsubstantiated legend that Julius Caesar was delivered in this way.) Cesarean deliveries may be planned in advance, as when a physician notes that the fetus is in a difficult-to-deliver position, such as breech (buttocks downward) or transverse (sideways). Multiple fetuses may also be delivered by cesarean section in order to spare the mother and her infants excessive stress. Alternatively, cesarean delivery may be performed as an emergency measure, perhaps after labor has started. As fetal monitoring techniques have improved, problems are noted more quickly and with greater frequency, leading to a larger number of cesarean sections. One indication of the need for emergency cesarean delivery is fetal distress, a condition characterized by an abnormal fetal heart rate and rhythm. Fetal distress is thought to be an indication of reduced blood flow to the placenta, which may be life-threatening to the fetus. Cesarean section may be performed using spinal or epidural anesthesia, as well as general anesthesia. A woman who delivers one child by cesarean section does not necessarily require a cesarean for later deliveries; each pregnancy is evaluated separately. Attempted vaginal births after cesareans (AVBACs) are still being done but are decreasing in frequency due to increased likelihood of problems.

Perspective and Prospects

Prior to 1800, most women were attended during childbirth by female midwives. In some areas, a midwife was provided a salary by the town or region; her contract might stipulate that she provide services to all women regardless of financial or social status. In other areas, midwives worked for fees paid by the clients. Midwives of this time had little, if any, formal training and learned about birth practices from other women. Because birth was considered a natural event requiring little intervention on the part of the attendant, the midwife’s medical role was limited and the few doctors available were consulted only in difficult cases. Although birth statistics were not kept at the time, anecdotal accounts from the diaries of midwives and doctors suggest that the births were most often successful, with rare cases of maternal or infant deaths.

The nineteenth century saw a gradual shift away from the use of midwives to a preference for formally trained male doctors. This shift was made possible by the establishment of medical schools that provided scientific training in obstetrics. Because these schools were generally closed to women, only men received this training and had access to the instruments and anesthesia that were coming into use.

Maternity hospitals came into being during the nineteenth century but were at first used primarily by poor or unmarried women. Women of higher social status still preferred to deliver their children in the privacy of their homes. Indeed, home birth was safer than hospital birth, since the building of hospitals had outpaced the knowledge of how to sanitize them. Rates of infection and maternal and infant death were higher in hospitals than in homes.

By the 1930s, the situation had reversed: Hospital births had become safer than home births, because sanitation and surgical procedures had improved. There followed an increasing trend for women to enter hospitals for delivery, so that the percentage of women giving birth in hospitals increased from about 25 percent in 1930 to almost 100 percent by 1960. In the same period, maternal and infant mortality showed a dramatic reduction. The shift to hospital birth had coincided with an interventionist philosophy: Most women were anesthetized during delivery, and forceps deliveries and episiotomy became more common.

By the 1960s, the older idea of “natural” childbirth—that is, a birth that encourages active labor and the use of drug-free types of pain relief with as little medical intervention as possible—had regained popularity. This change in attitude was brought about in part by recognition that analgesic and anesthetic drugs often had profound effects on the infant and often prevented strong mother-infant bonding in the immediate hours after delivery.

It was also brought about by the Lamaze method of childbirth, conceived by French doctor Fernand Lamaze and introduced to the United States with Marjorie Karmel’s book Thank You, Dr. Lamaze (1959). In this method, women learn controlled breathing techniques to relax and to cope with contractions during labor. A labor coach, who is often the baby’s father, helps to initiate and facilitate these techniques. Because natural childbirth must be learned, usually through childbirth classes offered in hospitals during the last trimester of pregnancy, it is also called prepared childbirth. As an extension of natural childbirth, the LeBoyer method has been proposed, allowing for delivery to take place underwater, so that the fetus is expelled from the fluid-filled amniotic sac into a warm, peaceful, fluid-filled environment, allowing for an easier transition to extrauterine life.

By the latter part of the twentieth century, a compromise between the more radical approaches of the past seemed to have been reached, with common practice in obstetrics being to allow the birth to proceed naturally when possible, but with the advantage of having refined drugs, diagnostics, and surgical techniques available if needed. The midwife has been reinstated as a specially trained advanced practice nurse (certified nurse midwife) who provides comprehensive health care to pregnant and nonpregnant women, and who conducts deliveries under a variety of settings, collaborating with physician colleagues as necessary for medically complicated labor and birth.

Bibliography

Ammer, Christine. The New A to Z of Women’s Health: A Concise Encyclopedia. 6th ed. New York: Checkmark Books, 2009.

Beckmann, Charles R. B., et al., eds. Obstetrics and Gynecology. 7th ed. Baltimore: Lippincott Williams & Wilkins, 2013.

Creasy, Robert K., et al., eds. Creasy & Resnik's Maternal-Fetal Medicine: Principles and Practice. 6th ed. Philadelphia: W. B. Saunders, 2008.

Cunningham, F. Gary, et al., eds. Williams Obstetrics. 23d ed. New York: McGraw-Hill, 2010.

DeCherney, Alan, et al., eds. Current Diagnosis & Treatment: Obstetrics & Gynecology. 11th ed. New York: McGraw Hill, 2012.

Klaus, Marshall H., John H. Kennell, and Phyllis H. Klaus. Doula Book: How a Trained Labor Companion Can Help You Have a Shorter, Easier, and Healthier Birth. 2d ed. Reading, Mass.: Perseus, 2002.

Klein, M. C., et al. “Why Do Women Go Along with This Stuff?” Birth 33, no. 3 (September, 2006): 245–250.

"Labor and Birth." US Department of Health and Human Services Office on Women's Health, September 27, 2010.

Lees, Christoph, and Grainne McCarten. Pregnancy and Birth: Your Questions Answered. Rev. ed. New York: DK, 2012.

Quilligan, Edward J., and Frederick P. Zuspan, eds. Current Therapy in Obstetrics and Gynecology. 5th ed. Philadelphia: W. B. Saunders, 2000.

Simkin, Penny, et al. Pregnancy, Childbirth, and the Newborn: The Complete Guide. 4th ed. Minnetonka, Minn.: Meadowbrook Press, 2010.

What is pityriasis rosea? |

Causes and Symptoms

Pityriasis rosea is primarily a skin

disease of children and young adults, with females being more commonly affected than males. The initial lesion is a characteristic eruption seen on the trunk called the herald or mother patch, as it signals the onset of lesions to come. This is a scaly pink plaque which is around one to two centimeters in diameter, slightly raised above the surface, with central salmon-colored wrinkles. This lesion should be differentiated from that of syphilis and ringworm.

The herald patch is followed in about two weeks by a crop of similar but smaller lesions all over the trunk. The pink scaly oval papules are distributed along the skin tension lines in the trunk and result in a so-called Christmas tree distribution. The lesions may be mild to moderately pruritic (itchy) and will resolve spontaneously in four to six weeks, without any specific treatment. Other symptoms may involve mild aches and fatigue.

The exact cause of this exanthem (eruptive disease) is not known, but it is believed to result from exposure to various viruses. Most patients appear to have a positive recent history of influenza or an upper respiratory tract infection. The eruption typically appears in spring and fall and appears to cluster among close contacts; however, it is not believed to be highly contagious.

Treatment and Therapy

There is no specific treatment for pityriasis rosea, and usually none is required, as the disease is self-limited and resolves without treatment in four to six weeks. Pruritus is usually mild and can be treated with antihistamines and calamine lotion. If itching is severe, then topical steroids and a short, tapered dose of systemic
steroids may be administered. Ultraviolet B (UVB) radiation is another treatment option. Patients are also advised to avoid hot showers and strenuous activity, as sweat and water appear to exacerbate the rash.

Perspective and Prospects

The term pityriasis is derived from the Greek pityron, meaning “scales.” The term, initially applied to include all those skin disorders that were characterized by fine scales, is presently used only with modifiers such as rosea, alba, or versicolor. Rosea means “pink,” and therefore pityriasis rosea describes pink-colored, fine, scaly lesions.

It is important clinically to distinguish the herald patch from other skin conditions. Therefore, a blood test for syphilis should be included for differential diagnosis. Also, ringworm, which requires treatment with antifungal agents, should be ruled out.

About 3 percent of the patients with pityriasis rosea experience recurrences, and no systemic manifestations have been demonstrated.

Bibliography

Chuh, Antonio A. T. “Pityriasis Rosea: Roles of the Dermatology Nurse.” Dermatology Nursing 16, no. 2 (April 1, 2004): 130–136.

Parker, James N., and Philip M. Parker. Pityriasis Rosea: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, Calif.: ICON Health Publications, 2004.

Kasper, Dennis L., et al., eds. Harrison’s Principles of Internal Medicine. 18th ed. New York: McGraw-Hill, 2012.

Montemayor-Quellenberg, Marjorie. "Pityriasis Rosea." Health Library, September 26, 2012.

Rakel, Robert E., ed. Textbook of Family Practice. 8th ed. Philadelphia: W. B. Saunders, 2011.

Tapley, Donald F., et al., eds. The Columbia University College of Physicians and Surgeons Complete Home Medical Guide. Rev. 3d ed. New York: Crown, 1995.

Vorvick, Linda J. "Pityriasis Rosea." MedlinePlus, October 14, 2012.

What is colic? |

Causes and Symptoms

The term “colic,” when unmodified, generally refers to infantile colic. Infantile
colic is a group of behaviours displayed by young infants that includes crying,
facial grimacing, drawing-up of the legs over the abdomen, and clenching of the
fists, which are not caused by a medical problem and typically resolve by four
months of age. Infantile colic was once believed to be caused by abdominal spasm,
gastrointestinal obstruction, or twisting of an abdominal organ, but there is no
known underlying medical cause for colicky behaviors in infants. The term biliary
colic refers to cramplike pain caused by a stone obstructing the bile ducts, and
renal colic can refer to a stone obstructing the urinary tract.

The crying of colicky infants tends to be more prominent in the evening, although
they cry more than other infants at other times of day. The “rule of threes” of
infantile colic holds that infants with colic cry for more than three hours per
day for more than three days per week for more than three weeks. The associated
gestures suggest to some that the infant is experiencing abdominal pain and is
responsible for the use of the term “colic” to describe the condition. Colic
describes crying and fussy behaviors in an otherwise health infant without
condition that may elicit prolonged crying; for example, colicky crying persists
in the absence of organic disease, hunger, or neglect.

Several causes of infantile colic have been postulated, but conclusive evidence is
lacking for any of them. This combination of behaviors has been interpreted as
abdominal pain, leading to the idea that cramping somewhere in the intestine is
the cause. Neurobehavioral explanations have been offered. The most common is that
colic represents a state of agitation that may not require a noxious stimulus for
agitation and crying to continue. Rarely is colic the result of organic disease,
and the prevailing opinion is that it is a variant of normal infant behavior.
Almost all babies display colicky symptoms to varying degrees. It appears to be
unrelated to caregiving style or intensity. Other proposed mechanisms include
difficult temperament, sleep disturbance, diarrhea, child abuse, and
irritable
bowel syndrome (IBS). Intestinal
gas, either from air swallowed during feeding or crying or
from fermentation of incompletely absorbed carbohydrates in the colon, has also
been investigated. Parents of colicky infants frequently describe flatulence as an
associated symptom.

Treatment and Therapy

The medical treatment of the infant with colic begins with a thorough medical history and a careful physical examination. While the likelihood of finding a cause of the infant’s symptoms are slight, the thoroughness of this approach provides an effective basis for reassurance and demonstrates that the parents’ complaint is taken seriously.

Infantile colic virtually always resolves spontaneously, leaving the infant
healthy and thriving. The essentials of therapy are demystification, reassurance,
and support for the haggard and anxious parents. Demystification is the
explanation of the source of the infant’s distress, which alleviates the anxiety
attendant on diagnostic hypotheses that occur to or are suggested to the parents.
It is important for pediatricians to deal with the anxiety aroused by the infant’s
symptoms with reassurance, pointing out that the baby will be fine.

Quick, superficial attempts to solve the problem with formula changes or
medications, particularly when not accompanied by patient demystification and
reassurance, reinforce the parents’ suspicion that there is something wrong with
the child, ultimately increasing parental perception of the child’s vulnerability.
Dietary changes are generally not recommended as a treatment for colic, as many
controlled studies have indicated that most cases of colic are not related to
diet.

More frequent, smaller feedings may help, as may increased carrying (called
“walking the floor”) and rocking. One theory holds that mimicking the environment
in the womb is reassuring, which can be achieved through closeness to a warm
person with a detectable heartbeat (sometimes called “kangaroo care”), swaddling
(wrapping the baby in a blanket to restrict movement of the extremities and
prevent the baby from becoming overstimulated), and rhythmic stimulation provided
by background music, white noise, and car or stroller rides. One commonly used
method involves placing the baby in an infant bouncer, thus exposing the infant to
constant vibration. Care must be taken to stay with the baby or to secure the
infant seat to prevent injury resulting from a fall. Caretakers should experiment
to see which methods best soothe their crying infant. Many colicky infants have
excessive gas, and gas pains have long been suspected as being responsible for
colic, although the gas may be due to excessive air intake from prolonged crying.
Since virtually all the gas in the intestine is swallowed air, minimizing air
swallowing and maximizing burping after feedings are important measures in
reducing colic. Identifying and then avoiding the dietary triggers of colic and
learning how to comfort the infant during crying episodes will help to soothe the
infant until the symptoms of colic subside, typically at three to four months of
age.

Perspective and Prospects

One theory holds that infantile colic is related to a familial prevalence of irritable bowel syndrome, also called irritable colon or spastic colon, although the evidence for this theory is limited. Diagnosis of colic is made after carefully reviewing the familial history of the infant and performing a thorough physical examination to rule out any organic causes. Although treatment is limited, most babies outgrow the symptoms of colic by three to four months of age. In the absence of an organic disease or unexplained weight loss, colic is self-limited with no long-term adverse effects on the child's development or future health.

Bibliography

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Walling, Anne D.
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Prudhomme, et al. “Behavioral and Physiological Responsivity, Sleep, and
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Child Development 71.4 (2000): 862–77. Print.

What fatal flaws does Creon show?

Pride

Creon's chief flaw, and ultimately his downfall, lies in his refusal to admit that he is wrong. By the time that he does, it is already too late to save Antigone. He only admits to his pride at the very end, when he decides to free Antigone.

Creon: That is true…. It troubles me. Oh it is hard to give in! but it is worse to risk everything for stubborn pride.

Selfishness

Creon doesn't think of his son, who is engaged to Antigone, or his son's happiness. He justifies his actions to Haimon by telling him that she wouldn't have been good for him in the end.

Creon: So you are right
Not to lose your head over this woman. Your pleasure with her would soon grow cold, Haimon,
And then you’d have a hellcat in bed and elsewhere. Let her find her husband in Hell!

Anger 

During Creon's argument with his son, Haimon, he allows his anger to cloud his reason. He even childishly repeats Haimon's question to make his own point.

Creon: Then she is not a criminal?

Haimon: The City proposes to teach me how to rule?

Creon: And the City proposes to teach me how to rule?

Haimon: Ah. Who is it that’s talking like a boy now?

Hypocrisy

Creon professes to be a leader who is committed to doing the right thing for the people. However, he allows himself to be corrupted by his own biases and desires. He expresses the following value during his initial monologue:

Creon: I say to you at the very outset that I have nothing but contempt for the kind of Governor who is afraid, for whatever reason, to follow the course that he knows is best for the State....

Creon's professed values as a leader contrast with the way he actually led, which caused dissent among his people. His anger and pride blinded him to the reality that he made the wrong choice until it was too late. His selfish behavior ultimately led to the death of Antigone, Haimon, and Euridice.

Are the female characters in King Lear not realistically portrayed women but, instead, caricatures of good and evil?

While one hesitates to call any Shakespeare character a "caricature," this is an interesting question to consider. I would never call Cordelia a caricature, as she is a fully developed character, but I can see elements of caricature in Goneril and Regan, the evil sisters. They are not simply caricatures, but they come closer to that role than Cordelia.

At the beginning of the play, Shakespeare makes clear that Cordelia's frustration with her sisters' over-the-top...

While one hesitates to call any Shakespeare character a "caricature," this is an interesting question to consider. I would never call Cordelia a caricature, as she is a fully developed character, but I can see elements of caricature in Goneril and Regan, the evil sisters. They are not simply caricatures, but they come closer to that role than Cordelia.

At the beginning of the play, Shakespeare makes clear that Cordelia's frustration with her sisters' over-the-top flattery of their father leads her to moderate her own comments to him. When asked to declare her love for her father, Cordelia responds genuinely, telling her father she loves him but feeling it would make her dirty to use the false flattery her sisters use. Cordelia is so disgusted with her sisters that she refuses to mimic their behavior, a very human response.

In contrast, we don't get much psychological explanation as to why Goneril and Regan behave as they do. We tend to group them together as an undifferentiated twosome (look at online character analyses of the two and you find them yoked: Goneril-and-Regan), which suggests they are less than fully-developed characters.

At least initially, however, there's some psychological justification for Goneril and Regan's desire to curtail Lear, repulsed as we may be by how stunningly quickly they, especially Goneril, turn from words of utter devotion to rude cruelty that seems unnecessarily harsh and humiliating. In the sisters' defense, Lear does behave erratically and with poor judgment in banning Cordelia and Kent from the kingdom. He does come across as capricious and possibly senile. His truth-telling Fool even tells him he is behaving foolishly.

When Goneril and Regan lock their father out of the castle in Act II, scene 2, they have adopted a level of cruelty that does arguably border on caricature because it is not justified by what Lear has done. If we put this play together with Macbeth as joint commentaries on women behaving with ruthless cruelty to achieve their aims, you could argue that it is cruel behavior itself that becomes a crude caricature of wise power and that Shakespeare wants his audiences to see it that way.

Please provide a chapter-wise summary of the novel Three Men in a Boat.

The book contains 29 chapters, originally marked by Roman numerals. Here is a summary of the main points of each one.

I – The three men -- narrator J., George, and Harris -- discuss their health issues. As a remedy for being overworked, they decide to go on a boat trip along the River Thames.

II – The friends begin to make plans. They decide to camp out in good weather and to use hotels and inns and pubs in wet weather. J. tells us more about Montmorency, the fox terrier.

III – J. relates the story of his Uncle Podger. The men make a list of supplies for the trip. They decide to use a boat with a cover as a tent. They decide about clothing.

IV – They decide about food to take, and they choose to take a “methylated spirit stove” and whiskey. J. relates a lengthy story about cheese. J. packs the equipment and clothes, and George and Harris packs the food hamper.

V – The first day of the trip. They get up late. J. talks about weather and barometers. He and Harris take the train and get into the boat at Kingston.

VI – J. and Harris start out. In the meantime, J. tells stories about Kingston, a boy named Stivvings, carved oak staircases, antiques, the year 2000 and beyond. Harris relates the story of getting lost in the Hampton Court maze.

VII – They reach Moulsey Lock. J. talks about clothing, especially about the clothing women wear for boating trips. Harris falls into the hamper in an attempt to get his drink.

VIII – They have lunch at Kempton Park. Harris wants to sing comic songs. J. relates the story of the German singer. They reach Sunbury lock. They go along the river, past graveyards, and pick up George, who has a banjo and an instruction book.

IX – J. relates two stories about tow ropes, including one where a couple is so engrossed in conversation that they don’t know they’ve lost the boat behind them. The men continue through locks. J. tells story of watching for Wallingford lock once, and not knowing that it was long gone.

X – They tie up at Picnic Point. George and Harris get tangled up as they try to put up the canvas and hoops tent. They eat supper and make tea. They relax and go to sleep under the stars.

XI – The second day of the trip. George tells the story of his stopped watch. J. goes swimming and gets George’s shirt wet. Harris tries to make scrambled eggs. The landscape reminds J. of the year 1215, King John, and the Magna Carta.

XII – They go over to Magna Carta Island. They interrupt a couple courting. J. and George remember a time when they were looking for an inn at Datchet. They lunch below Monkey Island. There’s no mustard, and they can’t open a can of pineapple. J. talks about sailing.

XIII – They reach Marlow and Boham Abbey. Montmorency is stared down by a cat. The men go shopping. J. talks negatively about steam launches. Harris tumbles into grass.

XIV – They pass the villages of Warame, Waxwoos, Sonning, and Shiplake. George makes Irish stew. Montmorency donates a water rat for the stew and argues with a tea kettle. George gets out his banjo. J. tells the story of Young Jefferson and his bagpipes. Harris gets drunk and supposedly fights off rogue swans.

XV – J. discusses work and who does most of it. He also addresses his experiences with water-related activities: rafting, learning to row, “punting” with a pole, and sailing.

XVI – They pass the town of Reading. They are pulled along by a launch owned by J’s friends. J. tells the story of a dead woman in the water.

XVII – The men wash their clothes in the river, unsuccessfully. They pay a washerwoman in Streatley to do the job instead. They spend two days in Streatley. J. tells fish stories, including the incident when he and George see the mounted trout in an inn, and they meet the many men who had caught it.

XVIII – The fourth or fifth day of the trip. J. talks about locks and tells the story of once getting caught in a lock, posing for a photographer. They pass Wallingford, Dorchester, and Abington.

XIX – They spend two days in Oxford. They begin the journey home, but it’s raining and miserable. They decide inside to take a train back to London, to eat a good dinner, and to go to a show.

What is bronchoalveolar lung cancer?

Related conditions:
Pleural effusion, pneumonia

Definition:

Bronchoalveolar lung cancer is a type of NSCLC that arises in the alveoli (air sacs of the lung). It can begin as either a single site or multiple sites, or spread rapidly as a pneumonic form. Bronchoalveolar lung cancer is less likely than other types of NSCLC to spread beyond the lungs.

Risk factors: The most common cause of lung cancer is smoking cigarettes. Another major cause is exposure to secondhand smoke. Other risk factors include exposure to radon gas or asbestos, environmental pollution, tuberculosis, lung disease, and an inherited predisposition to lung cancer.

Etiology and the disease process: With bronchoalveolar lung cancer, cells in the alveoli begin to grow wildly. As they grow, they progress along the alveolar walls. Multiple sites may develop and then converge to consolidate some areas of the lungs. An obstructed area of the lung may become pneumonic.

Incidence: NSCLCs account for about 75 percent of all lung cancers. Bronchoalveolar lung cancer makes up about 2 to 3 percent of this group. Although 10 percent of patients with lung cancer in the United States are nonsmokers, 25 to 30 percent of patients with bronchoalveolar lung cancer are nonsmokers. It is more common in women.

Symptoms: The symptoms of bronchoalveolar cancer are coughing, shortness of breath, wheezing, chest pain, large amounts of watery sputum, and hemoptysis (coughing up blood). On physical examination, the lungs are dull to percussion (tapping on the chest wall), and breath sounds may be weak or absent on auscultation (listening with a stethoscope). If the tumor is pressing on a nerve, it can cause shoulder pain or hoarseness.

Screening and diagnosis: Currently, there is no accurate, inexpensive screening test for bronchoalveolar lung cancer. Researchers are working to develop such a test by looking at a marker in the blood and also at breath analysis.

To diagnose lung cancer, pulmonary function tests and a chest X ray may be performed. Chest X rays can demonstrate most lung cancers, except the very small. More sensitive tests are computed tomography (CT) scans, magnetic resonance imaging (MRI), and positron emission tomography (PET) scans.

To differentiate between the types of lung cancer, a biopsy of the tumor must be performed. Bronchoscopy, thoracoscopy, or mediastinoscopy may be performed to examine pulmonary secretions and the lymph nodes of the lung. If the cancer exists on the periphery of the lung, it may be necessary to perform a needle biopsy through the chest wall. If none of these procedures is effective in determining the type of lung cancer, a surgical procedure called a thoracotomy (opening the chest) can be performed.

The actual diagnosis of bronchoalveolar lung cancer is made by the pathologist, who examines the tumor cells under a microscope. The pathologist identifies the type of lung cancer and stages the cancer. All NSCLCs are staged in the same way, using a combination of numeric tumor grading and the TNM (tumor/lymph node/metastasis) stages. The stages are as follows:

• Stage IA, T1 N0 M0: The tumor is less than 3 centimeters (cm) and there is no lymph node involvement or metastases.





• Stage IB, T2 N0 M0: The tumor is greater than 3 cm, but it has not spread beyond the lung.





• Stage IIA, T1 N1 M0: The tumor is less than 3 cm, and there is spread to local lymph nodes.





• Stage IIB, T2 N1 M0, or T3 N0 M0: Either the tumor is greater than 3 cm, or it has spread into the outside of the lungs, the chest cavity, or the pericardium (sac around the heart).





• Stage IIIA, T 1-3 N2 M0, or T3 N1 M0: Either the cancer has spread to distant lymph nodes but has not metastasized, or the cancer has spread into adjacent tissues and muscles and has spread to local lymph nodes.





• Stage IIIB, T4 N3 M0: Either the cancer has spread to nearby organs or it has spread to distant lymph nodes but has not metastasized.





• Stage IV, M1: The cancer has metastasized to distant organs.

Treatment and therapy: Treatment of lung cancer can include surgery, chemotherapy, and radiation. To remove a bronchoalveolar tumor, the surgeon can perform a wedge resection, a lobectomy, or a pneumonectomy. Chemotherapy for lung cancers is effective only 35 percent of the time. The most commonly used drugs are combinations of cisplatin (Platinol), carboplatin (Paraplatin), vinorelbine (Navelbine), vincristine (Oncovin), vinblastine (Velban), paclitaxel (Taxol), docetaxel (Taxotere), and gemcitabine (Gemzar). Newer chemotherapy drugs that interfere with cell growth and reproduction as well as angiogenesis (formation of new blood vessels) are being used. They are gefitinib (Iressa), erlotinib (Tarceva), and bevacizumab (Avastin).

Radiation therapy for bronchoalveolar lung cancer is not effective as a cure, so it is reserved for treatment when surgery is not possible.

Prognosis, prevention, and outcomes: Patients with lower stage cancers survive longer than those with high-stage cancers. Research has shown that patients who have never smoked respond better to treatments for bronchoalveolar cancer. The best way to avoid lung cancer is by not smoking and by avoiding exposure to secondhand smoke.

Houlihan, Nancy G. Lung Cancer. Pittsburgh: Oncology Nursing Soc., 2004. Print.

Hunt, Ian, Martin Muers, and Tom Treasure. ABC of Lung Cancer. Malden: Blackwell, 2008. Print.

Leary, Alison. Lung Cancer: A Multidisciplinary Approach. Chichester: Wiley, 2012. Print.

Pass, Harvey I. Principles and Practice of Lung Cancer: The Official Reference Text of the International Association for the Study of Lung Cancer. Philadelphia: Lippincott, 2010. Print.

Roth, Jack A., James D. Cox, and Waun Ki Hong, eds. Lung Cancer. 3rd ed. Malden: Blackwell, 2008. Print.

West, Howard. "Basics of Bronchioloalveolar Carcinoma (BAC)." Global Resource for Advancing Cancer Education. GRACE, 9 July 2010. Web. 8 Sep. 2014.

What is ataxia telangiectasia? |

Risk Factors

According to the Genetics Home Reference, the prevalence of ataxia telangiectasia is estimated to be 1 in 40,000 to 1 in 100,000, as of 2013, and about 1 percent of the population is heterozygous for an ataxia telangiectasia mutation (carriers). These individuals have an increased risk of cancer.

Etiology and Genetics

The ataxia telangiectasia mutated (ATM) gene is about 150 kilobase pairs (kbp) long, containing sixty-six exons, coding for a 13 kbp mature transcript with a 9,168 nucleotide-long open reading frame that translates into a protein of approximately 370 kilodaltons (kDa). The ATM protein is a serine/threonine protein kinase (enzyme that adds a phosphate group to other proteins) with multiple functions and protein targets. Many different proteins are phosphorylated and thereby regulated by the ATM kinase. Lack of functioning ATM protein leads to defects in DNA repair, cancer, and neurodegeneration. ATM kinase activates repair proteins in response to double-stranded breaks in DNA. If there is too much DNA damage for the repair system, then ATM activates p53 and Chk1 to cause cell-cycle arrest or programmed cell death (apoptosis).

Ataxia telangiectasia patients have lack-of-function mutations because of truncated ATM proteins or splice-site mutations that result in short, unstable ATM proteins. Because patients have a decreased ability to repair double-strand DNA breaks, they are very sensitive to ionizing radiation (x-rays and gamma rays). In the normal immune system, rearrangements of DNA occur to create immunoglobins (for example, VDJ recombination in B and T cells). ATM kinase plays a role in the breaks that occur in this rearrangement process. Individuals who lack functioning ATM will have immunodeficiencies. Deficiencies in DNA repair and loss of regulation of the cell cycle can result in cancer. These deficiencies also lead to degeneration of postmitotic neurons of the cerebellum, the part of the brain that controls voluntary body movements.

Individuals who are carriers for ataxia telangiectasia—that is, who have a single defective copy of the ATM gene—have an increased risk of developing breast, lung, and blood cancers.

Symptoms

Since ataxia telangiectasia may show incomplete penetrance; severity of symptoms or age of occurrence of symptoms varies. Symptoms include developmental delay of motor skills in the young child, difficulty in coordinating movements, and poor balance. As patients age, the problems with motor control progressively worsen and also include lack of control of limb movements. Patients may have slurred speech and difficulty swallowing. Telangiesctasias (visible blood vessels) in the eyes typically occur by age five, though not all patients develop them. The neck and extremities may also develop telangiesctasias. About 60 to 80 percent of ataxia telangiectasia patients have frequent infections, especially of the sinuses and lungs, as a result of immune system defects. Patients have an increased risk of developing cancers, especially lymphomas and leukemias.

Screening and Diagnosis

Patients with ataxia telangiectasia are generally diagnosed between the ages of two and seven. A clinical diagnosis is based on the observation of ataxia and telangiectasia of the eyes. Patients have elevated serum levels of alpha-fetoprotein. Tests include sensitivity of cells to x-ray damage, chromosome instability in the patient’s lymphocytes, an antibody for the protein, and sequencing of the ATM gene. Cerebellar atrophy may be seen in magnetic resonance imaging (MRI) or computed tomography (CT) scans. General indicators of ataxia telangiectasia are increased ionizing radiation sensitivity and lack of the ATM protein.

Treatment and Therapy

There is no cure for ataxia telangiectasia, nor are there treatments that are able to slow the progression of the disease. Symptoms are treated. Antibiotics and gammaglobulins are given to fight recurrent respiratory infections. Physical therapy helps the patient maintain flexibility. Speech therapy may be indicated for individuals who develop slurred speech. Psychological counseling may help individuals with ataxia telangiectasia. Patients generally have normal intelligence but may not perform well on tests that require visual-motor coordination. Because of the hypersensitivity to ionizing radiation, patients should limit exposure to x-rays. Diagnostic x-rays should be used only when there is no alternative to obtain a diagnosis.

Prevention and Outcomes

Patients with ataxia telangiectasia are often confined to wheelchairs by the age of ten but generally survive at least into their mid-to-late twenties, though some even live into their fifties, as reported by pathologist Richard Gatti. According to the National Institute of Neurological Disorders and Stroke, 35 percent develop some form of cancer, especially leukemias and lymphomas. A-T patients often die from recurring respiratory infections and lung failure. Couples with the ATM gene in their families can receive genetic counseling. Prenatal testing can be done to determine if a fetus has a mutated ATM gene. Following a family with the ATM mutation, linkage analysis and microsatellite markers are used to screen the fetus. Direct testing for the mutated gene (from known ataxia telangiectasia patients in the family) is used to determine whether the fetus has A-T

Bibliography

Gatti, Richard. "Ataxia-Telangiectasia." GeneReviews. U of Washington, Seattle, 11 Mar. 2010. Web. 21 July 2014.

Genetics Home Reference. "Ataxia-Telangiectasia." Genetics Home Reference. US National Library of Medicine, Jan. 2013. Web. 21 July 2014.

Gorospe, Myriam, and Rafael de Cabo. “AsSIRTing the DNA Damage Response.” Trends in Cell Biology 18.2 (2008): 77–83. Print.

Lavin, Martin F. “Ataxia-Telangiectasia: From a Rare Disorder to a Paradigm for Cell Signalling and Cancer.” Nature Reviews: Molecular Cell Biology 9 (2008): 759–69. Print.

National Institute of Neurological Disorders and Stroke. "NINDS Ataxia Telangiectasia Information Page." National Institute of Neurological Disorders and Stroke. US Dept. of Health and Human Services, National Institutes of Health, 27 Dec. 2013. Web. 21 July 2014.

NORD. "Ataxia Telangiectasia." RareDiseases.org. National Organization for Rare Disorders, 17 Aug. 2007. Web. 21 July 2014.

Staropoli, John F. “Tumorigenesis and Neurodegeneration: Two Sides of the Same Coin?” BioEssays 30 (2008): 719–27. Print.

Turnpenny, Peter, and Sian Ellard. Emery’s Elements of Medical Genetics. 14th ed. Philadelphia: Elsevier, 2012. Print.

What is benzene? Is it a carcinogen?

Exposure routes: Inhalation, skin contact, and oral ingestion are the most toxic and dangerous routes.

Where found: Benzene is an industrial chemical that is widely used as a solvent and used in inks, rubber, lacquers, paint removers, gas additives, glue backing for carpeting, high-solvent paints, some furniture wax, automobile exhaust, tobacco smoke, secondhand smoke, taxidermy, firefighting, metal preparation and pouring, petroleum refining, industrial cleaning, drinking water, and closed processes to synthesize organic chemicals. It is also used to make dyes and insecticides and in the processing of numerous chemicals.

At risk: Children and pregnant woman are at higher risk. However, anyone exposed to benzene is at risk. For example, the presence of benzene in gasoline makes exposure to it a risk for anyone filling an automobile gas tank.

Etiology and symptoms of associated cancers:According to the American Cancer Society, benzene causes chromosomal damage to the bone marrow, the blood-forming tissue, which can then lead to leukemias and lymphomas. The US Centers for Disease Control and Prevention reported in 2013 that benzene can also cause insufficient red blood cell production and alter antibody levels. Exposure to as little as less than one part per million can lower white blood cell counts, as reported in a 2004 study by Qing Lan et al. in the journal Nature.

Symptoms of leukemias and lymphomas include fever, night sweats, fatigue, bleeding and easy bruising, bone pain, frequent infections, swollen lymph nodes, and weight loss.

History: Benzene is a natural component of crude oil. In 1825 Michael Faraday performed distillation experiments and extracted a gas from the oil. The gas burned, and he named it “bicarburet of hydrogen.” The chemical structure of benzene remained elusive until 1865, when Friedrich August Kekulé von Stradonitz hypothesized a hexagonal structure.

Benzene was derived from the distillation of coal by A. W. Hoffman in 1846. The uses of and demand for benzene increased along with oil exploration as its usefulness in many industrial applications became apparent.

Linus Pauling, the Nobel Prize–winning physicist, was one of many scientists to attempt to elucidate the unique hybrid structure of benzene that was confirmed in 1931.

The main use of benzene prior to World War I was in gasoline blending, as it increased octane. It was used extensively in industry in World War II, and almost all organic chemistry–related industry involves petroleum (benzene-containing) products.

"Benzene." Cancer.org. Amer. Cancer Soc., 9 Dec. 2013. Web. 4 Sept. 2014.

Chilcott, R. P. HPA Compendium of Chemical Hazards: Benzene. Health Protection Agency, 2011. PDF file.

"Facts about Benzene." CDC.gov. Centers for Disease Control and Prevention, 14 Feb. 2013. Web. 4 Sept. 2014.

Lan, Qing, et al. "Hematotoxicity in Workers Exposed to Low Levels of Benzene." Nature 306.5702 (2004): 1774–76. PDF file.

Snyder, Robert. "Leukemia and Benzene." International Journal of Environmental Research and Public Health 9.8 (2012): 2875–93. PDF file.

US Department of Health and Human Services, Public Health Service, National Toxicology Program. 12th Report on Carcinogens. Research Triangle Park: US Dept. of Health and Human Services, 2011. Print.

How would you describe the men from Old Sarum in Chapter 15 of Harper Lee's To Kill a Mockingbird?

In Chapter 15, Jem, Dill, and Scout search for Atticus, who happens to be sitting outside of Tom Robinson's jail cell. Atticus wants to make sure that no one will harm Tom before the trial, and shortly after the children locate Atticus, they witness a group of dusty cars arrive from the Meridian highway. The cars stop right in front of the Maycomb jailhouse and a group of men known as the Old Sarum bunch...

In Chapter 15, Jem, Dill, and Scout search for Atticus, who happens to be sitting outside of Tom Robinson's jail cell. Atticus wants to make sure that no one will harm Tom before the trial, and shortly after the children locate Atticus, they witness a group of dusty cars arrive from the Meridian highway. The cars stop right in front of the Maycomb jailhouse and a group of men known as the Old Sarum bunch encircle Atticus. They are there to lynch Tom Robinson and the leader of the mob, Walter Cunningham, tells Atticus to move out of the way. Atticus tells them to go home, and Scout runs out from her hiding place. When she enters the circle of men, she mentions that they smelled like stale whiskey and pigpen. Jem follows Scout out of the shadows and Atticus also tells him to go home. When Jem refuses, one of the members of the Old Sarum bunch grabs him by the collar and yanks Jem off of his feet. Scout kicks the man in the crotch and Atticus continues to plead with his son to go home. Scout looks around at the mob and mentions that they are dressed in overalls and denim shirts buttoned up to the collars, with their sleeves rolled down and buttoned at the cuffs. They also wear their hats low to disguise their identity. Scout recognizes Walter Cunningham's father and attempts to carry on a conversation. She eventually gets his attention, and Walter realizes the error in his decision. Walter then tells the mob that it's time to leave, and they get in their cars and drive home.

The Old Sarum bunch was a group of racist hillbillies who wished to lynch Tom Robinson. Judging from their dusty cars, country dialect, and attire, one can tell that they are poor, uneducated farmers. The Old Sarum bunch obviously has violent tendencies because they are there to harm Tom, and one of the members is quick to grab Jem. The Old Sarum bunch has a reputation for getting drunk and disturbing the peace throughout the county, which is exactly what they do in Chapter 15. They also seem to follow Walter's lead and do not make individual decisions on their own.

What are restriction enzymes? |

Discovery and Role of Restriction Enzymes in Bacteria

Nucleases are a broad class of enzymes that destroy nucleic acids by breaking the sugar-phosphate backbone of the molecule. Until 1970, the only known nucleases were those that destroyed nucleic acids nonspecifically—that is, in a random fashion. For this reason, these enzymes were of limited usefulness for working with nucleic acids such as DNA and RNA. In 1970, molecular biologist Hamilton O. Smith discovered a type of nuclease that could fragment DNA molecules in a specific and therefore predictable pattern. This nuclease, HindII, was the first restriction endonuclease, or restriction enzyme. Smith was working with the bacterium Haemophilus influenzae (H. influenzae) when he discovered this enzyme, which is capable of destroying DNA from other bacterial species but not the DNA of H. influenzae itself. The term “restriction” refers to the apparent role these enzymes play in destroying the DNA of invading bacteriophages
(bacterial viruses) while leaving the bacterial cell’s own DNA untouched. A bacterium with such an enzyme was said to “restrict” the host range of the bacteriophage.

As more restriction enzymes from a wide variety of bacterial species were discovered in the 1970s, it became increasingly clear that these enzymes could be useful for creating and manipulating DNA fragments in unique ways. What was not clear was how these enzymes were able to distinguish between bacteriophage DNA and the bacterial cell’s own DNA. A chemical comparison between DNA that could and could not be fragmented revealed that the DNA molecules differed slightly at the restriction sites (the locations the enzyme recognized and cut). Nucleotides at the restriction site were found to have methyl functional groups (–CH3) attached to them, giving this phenomenon the name DNA methylation.

The conclusion was that the methylation somehow protected the DNA from attack, which could account for Smith’s observation that H. influenzae DNA was not destroyed by its own restriction enzyme; presumably the enzyme recognized a specific methylation pattern on the DNA molecule and left it alone. Foreign DNA, such as that from another species, would not have the correct methylation pattern, or might not be methylated at all, and could therefore be fragmented by the restriction enzyme. Hence, restriction enzymes are now regarded as part of a simple yet effective bacterial defense mechanism to guard against foreign DNA, which can enter bacterial cells with relative ease.

Mechanism of Action

To begin the process of cleaving a DNA molecule, a restriction enzyme must first recognize the appropriate place on the molecule. The recognition site for most restriction enzymes involves a short, usually four- to six-nucleotide palindromic sequence. A palindrome is a word or phrase that reads the same backward and forward, such as “Otto” or “madam”; in terms of DNA, a palindromic sequence is one that reads the same on each strand of DNA but in opposite directions. EcoRI, derived from the bacterium Escherichia coli, is an example of an enzyme that has a recognition site composed of nucleotides arranged in a palindromic sequence:
——GAATTC————CTTAAG——

Whether the top sequence is read from left to right or the bottom sequence is read from right to left, it is always GAATTC.

An additional consideration in the mechanism of restriction-enzyme activity is the type of cut that is made. When a restriction enzyme cuts DNA, it is actually breaking the “backbone” of the molecule, which consists of a chain of sugar and phosphate molecules. This breakage occurs at a precise spot on each strand of the double-stranded DNA molecule. The newly created ends of the DNA fragments are informally referred to as either “sticky ends” or “blunt ends,” depending on whether or not single-stranded regions of DNA are generated by the cutting activity of the restriction enzyme. For example, the enzyme EcoRI is a sticky-end cutter; when the cuts are made at the recognition site, the result is:
—GAATTC—  —G  AATTC—
→  
—CTTAAG—  —CTTAA  G—

The break in the DNA backbone is made just after the G in each strand; this helps weaken the connections between the nucleotides in the middle of the site, and the DNA molecule splits into two fragments. The single-stranded regions, where the bases TTAA are not paired with their complements (AATT) on the other strand, are called overhangs; however, the bases in one overhang are still capable of pairing with the bases in the other overhang, as they did before the DNA strands were cut. The ends of these fragments will readily stick to each other if brought close together—hence the name “sticky ends.”

Enzymes that create blunt ends make a flush cut and do not leave any overhangs, as demonstrated by the cutting site of the enzyme AluI:
——AGCT——  ——AG  CT——
→  
——TCGA——  ——TC  GA——

Because of the lack of overhanging single-strand regions, these two DNA fragments will not readily rejoin. In practice, either type of restriction enzyme may be used, but enzymes that produce sticky ends are generally favored over blunt-end cutters because of the ease with which the resulting fragments can be rejoined.

Impact and Applications

It is no exaggeration to say that the entire field of genetic engineering would have been impossible without the discovery and widespread use of restriction enzymes. On the most basic level, restriction enzymes allow scientists to create recombinant DNA
molecules (hybrid molecules containing DNA from different sources, such as humans and bacteria). No matter what the source, DNA molecules can be cut with restriction enzymes to produce fragments that can then be rejoined in new combinations with DNA fragments from other molecules. This technology has led to advances such as the production of human insulin by bacterial cells such as Escherichia coli.

The DNA of most organisms is relatively large and complex; in fact, it is usually so large that it becomes difficult to manipulate and study the DNA of some organisms, such as humans. Restriction enzymes provide a convenient way to cut large DNA molecules very specifically into smaller fragments that can then be used more easily in a variety of molecular genetics procedures.

Another area of genetic engineering that is possible because of restriction enzymes is the production of restriction maps. A restriction map is a diagram of a DNA molecule showing where particular restriction enzymes cut the molecule and the molecular sizes of the fragments that are generated. The restriction sites can then be used as markers for further study of the DNA molecule and to help geneticists locate important genetic regions. Use of restriction enzymes has also revealed other interesting and useful markers of the human genome, called restriction fragment length polymorphisms (RFLP). The name refers to changes in the size of restriction fragments caused by mutations in the recognition site for a particular restriction enzyme. The recognition site is mutated so that the restriction enzyme no longer cuts there, resulting in one long fragment where, before the mutation, there would have been two shorter fragments. These changes in fragment length can then be used as markers for the region of DNA in question. Because they result from mutations in the DNA sequence, they are inherited from one generation to the next. Thus, these mutations have been a valuable tool for molecular biologists mapping human DNA and for those scientists involved in “fingerprinting” individuals by means of their DNA.

Key Terms




enzyme


:

a molecule, usually a protein, that is used by cells to facilitate and speed up a chemical reaction




methylation

:

the process of adding a methyl functional group (one carbon atom and three hydrogen atoms) to a particular molecule, such as a DNA nucleotide




nuclease

:

a type of enzyme that breaks down the sugar-phosphate backbone of nucleic acids such as DNA and RNA





nucleotides


:

the building blocks of nucleic acids, composed of a sugar, a phosphate group, and a nitrogen-containing base





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