What are mutation and mutagenesis?

Definitions

A mutation is any change in the genetic material that can be inherited by the next generation of cells or progeny. A mutation can occur at any time in the life of any cell in the body. If a mutation occurs in a reproductive cell, the change can be passed to an offspring through the egg or sperm. The new mutation could then affect the phenotype of the offspring and be passed on to later generations. However, if the mutation occurs in cells of the skin, muscle, blood, or other somatic (body) tissue, the new mutation will be passed on to other body cells only when that cell divides. This can produce a mosaic group of cells carrying the new genetic change. Most of these are undetectable and have no effect on the carrier. An important exception is a somatic mutation that causes the affected cell to lose control of the cell cycle and divide uncontrollably, resulting in cancer. Many environmental chemicals and agents that cause mutations (such as x-rays and ultraviolet radiation) are therefore capable of causing cancer.

Mutation can also have an important, beneficial role in natural populations of all organisms. The ability of a species to adapt to changes in its environment, combat new diseases, or respond to new competitors is dependent on genetic diversity in the population’s gene pool. Without sufficient resources of variability, a species faced with a serious new stress can become extinct. The reduced population sizes in rare and endangered species can result in reduced genetic diversity and a loss of the capacity to respond to selection pressures. Zoo breeding programs often take data on genetic diversity into account when planning the captive breeding of endangered species. The creation of new agricultural crops or of animal breeds with economically desirable traits also depends on mutations that alter development in a useful way. Therefore, mutation can have both damaging and beneficial effects.

The Role of Mutations in Cell Activity and Development

The genetic information in a cell is encoded in the sequence of subunits, or nucleotides, that make up a molecule of DNA. A mutation is a change in the nucleotide sequence of DNA, and it can range from changing just a single nucleotide in the DNA molecule to altering long pieces of DNA. To appreciate how such changes can affect an organism, it is important to understand how information is encoded in DNA and how it is translated to produce a specific protein. There are four different nucleotides
in the DNA molecule: adenine (A), guanine (G), thymine (T), and cytosine (C). The DNA molecule is composed of two complementary strands linked together by hydrogen bonding, a process called base-pairing. Guanine (G) and adenine (A) are purine bases, which pair up with pyrimidine bases thymine (T) and cytosine (C). For example, an adenine on one strand should always pair with a thymine on the other strand (A-T), and a guanine on one strand should always pair with a cytosine on the other strand (G-C). When the expression of a gene is activated, one of the two strands of DNA is used as a template for the synthesis of a single-stranded molecule called messenger RNA (mRNA). The completed mRNA molecule is then transported out of the nucleus, where it binds with ribosomes (small structures in the cytoplasm of the cell), and a protein is made using the mRNA’s nucleotide sequence as its coded message. The nucleotides of the mRNA are read on the ribosome in triplets, with every three adjacent nucleotides (called a codon) corresponding to one of the twenty amino acids found in protein.

Thus the sequence of nucleotides eventually determines the order of amino acids that are linked together to form a specific protein. The amino acid sequence in turn determines how the protein will function, either as a structural part of a cell or as an enzyme that will catalyze a specific biochemical reaction. A gene is often at least one thousand base-pairs or longer, so there are many points at which a genetic change can occur. If a mutation takes place in an important part of the gene, even the change of a single amino acid can cause a major change in protein function. For example, sickle-cell disease is a good illustration of this. In sickle-cell disease, a single base substitution mutation in a gene causes the sixth codon in the mRNA to change from GAG to GUG. When this modified mRNA is used to create a protein, the amino acid valine is substituted for the normal glutamic acid in the sixth position in a string of 146 amino acids. This small change causes the protein to form crystals and thus deform cells when the amount of available oxygen is low. Since this protein is part of the oxygen-carrying hemoglobin molecule in red blood cells, this single DNA nucleotide change has potentially severe consequences for an affected individual.

Types of Mutation

Mutations are often categorized by the type of change that has occurred to the DNA, as well as the effect that the mutation has on the function of the encoded protein. For example, a point mutation is defined as a single change to the nucleotide sequence of DNA. The simplest kind of point mutation is a base substitution, whereby one base pair is replaced by another (for example, the replacement of an A-T base pair at one point in the DNA molecule by a C-G base pair). A more specific way of describing a base substitution mutation depends on the nature of the bases involved. For example, a transition mutation occurs when a purine replaces a purine, or a pyrimidine replaces another pyrimidine. A transversion mutation occurs when a purine replaces a pyrimidine, or vice versa. These mutations can change the sequence of the codon triplet used to build the protein, where consequently the wrong
amino acid is added to the protein at that point. This type of base substitution mutation that encodes a different amino acid is called a missense mutation. Similarly, if a single base substitution mutation changes a codon triplet to what is called a stop codon (these sequences normally occur only at the end of a gene to signal where the message ends), the protein stops production and the result is an incomplete or truncated protein. This type of base substitution mutation that encodes a stop codon is called a nonsense mutation. These point mutations often affect the function of the protein, at least in minor ways. However, some base substitutions do not change the nature of the amino acid. Since several different combinations of triplets can code for the same amino acid, not all base changes will result in an amino acid substitution, and these mutations are therefore called silent mutations.

Another category of mutations called frameshifts can have significant effects on protein structure. A frameshift mutation occurs when one or more nucleotides are added to, or lost from, the DNA strand when it is duplicated during cell division. Since translation of the mRNA is done by the ribosomes adding one amino acid to the growing protein for every three adjacent nucleotides, adding or deleting one nucleotide will effectively shift that reading frame so that all following triplet codons are different. By analogy, one can consider the following sentence of three-letter words: THE BIG DOG CAN RUN FAR. If a base (for example, a letter X, in this analogy) is added at the end of the second triplet, the “sentence” will still read three letters at a time during translation and the meaning will be completely altered. THE BIX GDO GCA NRU NFA R. In a cell, a nonfunctional protein is produced unless the frameshift is near the terminal end of the gene.

Some types of mutations, known as chromosome mutations, alter the structural integrity of DNA on a larger scale, affecting not only a single point in a gene but also one or more genes within a chromosome. There are four major kinds of mutations involving changes to genes at the chromosomal level. A deletion or deficiency is produced when two breaks occur in the chromosome but are repaired by leaving out the middle section. For example, if the sections of a chromosome are labeled with the letters ABCDEFGHIJKLMN and chromosome breaks occur at F-G and at K-L, the broken chromosome can be erroneously repaired by enzymes that link the ABCDEF fragment to the LMN fragment. The genes in the unattached middle segment, GHIJK, will be lost from the chromosome. Losing these gene copies can affect many different developmental processes and even cause the death of the organism. Chromosomal breaks and other processes can also cause some genes to be duplicated. A duplication is the converse of a deletion, and occurs when a gene sequence or chromosomal segment is repeated (for example, ABCDEFGHDEFGHIJKLMN). Gene duplication can result in the over-expression of genes, an event detrimental in such a case where an oncogene (a gene that promotes the growth of cancer when mutated or over-expressed) is duplicated. A third kind of chromosomal mutation, called an inversion, changes the orientation of the gene(s) when the segment between two chromosomal breaks is reattached backward (for example, ABCDJIHGFEKLMN). Chromosome segments can also be moved from one kind of chromosome to another in a structural change called a translocation. Some examples of heritable Down syndrome are caused by this type of chromosomal rearrangement, where part of chromosome 21 is translocated to another chromosome.

The loss or addition of an entire chromosome, a condition known as aneuploidy (characterized by having an abnormal number of chromosomes), is a significant source of genetic disorders in humans. Whole chromosomes can be lost or gained by errors during cell division. In animals, almost all examples of chromosome loss are so developmentally severe that the individual cannot survive to birth. On the other hand, since extra chromosomes provide an extra copy of each of their genes, the amount of each protein they code for is unusually high, and this, too, can create biochemical abnormalities for the organism. In humans, an interesting exception is changes in chromosome number that involve the sex-determining chromosomes, especially the X chromosome (the Y is relatively silent in development). Since normal males have one X and females have two, the cells in females inactivate one of the X chromosomes to balance gene
dosage. This dosage compensation mechanism can, therefore, also come into operation when one of the X chromosomes is lost or an extra one is inherited because of an error in cell division. The resulting conditions, such as Turner syndrome and Klinefelter syndrome, are much less severe than the developmental problems associated with other changes in chromosome number.

Mutation Rate

There are several different sources of genetic change. For example, errors can occur when the DNA molecule is being duplicated during cell division. In simple organisms such as bacteria, about one thousand nucleotides are added to the duplicating DNA molecule each second. The speed is not as great in plants and animals, but errors still occur when mispairing between A and T or between C and G nucleotides occurs. Additionally, some mutations are generated spontaneously, caused by changes or damage to DNA that occurs in the process of normal cell biochemistry. These kinds of alterations to the structure or composition of DNA (such as strand breaks or depurination) can be classified as DNA damage, or genetic damage. Other sources of damage can be traced to environmental factors that can increase mutation rates. Fortunately, almost all of this initial genetic damage is repaired by enzymes that recognize and correct errors in nucleotide pairing or DNA strand breaks. It is the unrepaired genetic damage that leads to new mutations.

Spontaneous mutation rates vary to some extent from one gene to another and from one organism to another, but one major source of variation in mutation rates comes from external agents called mutagens that act on the DNA to increase damage or inhibit repair. One of the most widely used techniques for measuring theactivity of a chemical mutagen
was developed in the 1970s by Bruce Ames. The Ames test uses bacteria that have a mutation that makes them unable to produce the amino acid histidine. These bacteria cannot survive in culture unless they are given histidine in the medium. To test whether a chemical increases the mutation rate, it is mixed with a sample of these bacteria, and they are placed on a medium without histidine. Any colonies that survive represent bacteria in which a new mutation has occurred to reverse the original defect (a back-mutation). Since many chemicals that cause mutations also cause cancer, this quick and inexpensive test is now used worldwide to screen potential carcinogenic, or cancer-causing, agents. Mutation rates in mice are measured by use of the specific-locus test. In this test, wild-type male mice are mated with females that are homozygous for up to seven visible, recessive mutations that cause changes in coat color, eye color, and shape of the ear. If no mutations occur in any of the seven genes in the germ cells of the male, the male offspring will all be wild type in appearance. However, a new mutation in any of the seven genes will yield a progeny with a mutant phenotype (for example, a new coat color). The same cross can also be used to identify new mutations in females. Since mice are mammals, they are a close model system to humans. Thus, results from mutation studies in mice have helped identify agents that are likely to be mutagenic in humans.

Types of Mutagens

Mutagens can cause a change in the genetic material. One primary way that mutations are generated in cells occurs when the nucleotide bases (A, T, C, or G) are modified or damaged in a way that makes their original identity unrecognizable during DNA replication. There are several different types of mutagens characterized by their mutagenic effects on cells. One type of mutagen involves compounds that mimic nucleotide bases, called base analogs. These compounds share similar properties with nucleotide bases that allow them to substitute for nucleotide bases in DNA. However, base analogs tend to base-pair during DNA replication incorrectly, resulting in the generation of a mutation in the new strand of DNA. A well-known example of a base analog is 5-bromo-uracil, an analog of thymine (T) that base-pairs with guanine (G) instead of the correct nucleotide adenine (A). 5-bromo-uracil therefore ultimately causes a transition mutation, where a T-A base-pair is replaced with C-G.

Other types of mutagens can modify nucleotide bases by altering their chemical makeup. For example, nitrous acid produced by the metabolism of nitrites in the diet causes the deamination (removal of the amino group) of cytosine, guanine, or adenine. This modification changes the identity of the original nucleotide base so that its base-pairing properties are altered during DNA replication, promoting the incorporation of the wrong nucleotide base in the newly synthesized strand of DNA.

Chemicals that are capable of intercalating DNA are also mutagens. Intercalating agents, such as ethidium bromide or acridines, are planar ringed compounds that interact with DNA and insert themselves into open spaces, causing the DNA to expand. During DNA replication, the expanded base is read as two instead of one, thus resulting in the addition of an extra base into the new DNA strand, causing a frameshift mutation.

Other mutagens with severe consequences are those that alter the size and structure of nucleotide bases. Chemical agents such as benzo[a]pyrene, a compound found in products of combustion and cigarette smoke, can be metabolically activated in cells to produce reactive compounds that attach to DNA and form bulky adducts on nucleotide bases. Damaged nucleotide bases formed by these mutagens are capable of blocking or halting DNA replication when cells are undergoing division. Blocked replication, in turn, can stimulate cells to use several different pathways for continuing the replication of DNA past the damage, a process known as DNA damage tolerance. However, some types of DNA damage tolerance work at the expense of generating new mutations.

Mutagens can be used in genetic studies with model organisms to induce germinal mutations that can be inherited by offspring. Offspring organisms that exhibit interesting phenotypes can then be further studied to identify which gene mutation caused the phenotype, an experimental approach called forward genetics. Mutagens are and will continue to be useful for studying the process of mutagenesis.

The Use of Mutations to Study Development

Mutations offer geneticists a powerful tool to analyze development. By understanding the way development is changed by a mutation, one can determine the role the normal gene plays. Although most people tend to think of mutations as causing some easily visible change in the appearance of a plant or animal (such as wrinkled pea seeds or white mouse fur), some mutations are actually lethal when present in two copies (homozygous). These lethal mutations affect some critical aspect of cell structure or other fundamental aspect of development or function. Genes turn on and off at specific times during development, and by studying the abnormalities that begin to show when a lethal mutation carrier dies, a geneticist can piece together a picture of the timing and role of important gene functions.

Another useful insight comes from mutations with effects that vary. A major source of genetic variation comes from polymorphisms, which comprise mutations that were selected for over multiple generations to become common in more than 1 percent of a population. Traits affected by polymorphisms are often reflected in the observable variation between individuals of a population, such as coat colors of animals or blood types of humans. Some mutations affect a single gene, yet exhibit multiple phenotypes, a characteristic termed as pleiotrophy. Pleiotrophy occurs when a gene has more than one function, and a mutation in that gene can therefore disrupt multiple biological processes. Other unique mutations can have phenotypic effects that depend on the conditions, such as temperature, in which the individual develops. An interesting example of such temperature sensitivity is the fur color of Siamese cats. A mutation causes the biochemical pathway for
pigmentation to be active at cool temperatures, but inactive at warmer body temperatures. For this reason, a Siamese cat will be pigmented only in the cooler parts such as the tips of the ears and tail.

It would be a mistake, however, to think that all mutations have large phenotypic effects. Many complex traits are produced by many genes working together and are affected by environmental variables. These are called quantitative traits because they are measured on some kind of scale, such as size, number, or intensity. The mutations that affect quantitative traits are not different, except perhaps in the magnitude of their individual effects, from other kinds of gene mutation. Mutations in quantitative traits are a major source of heritable variation on which natural and artificial selection can act to change a phenotype.

Impact and Applications

It will probably never be possible to eliminate all mutation events because many mutations are caused by small errors in normal DNA duplication when cells divide. Learning how mutations affect cell division and cell function can help one to understand processes such as cancer and birth defects that can often be traced to genetic change. Some explanations of processes such as aging have focused on mutation in somatic cells. Mutation is also the source of genetic variation in natural populations, and the long-term survival of a species depends on its ability to draw on this variation to adapt to new environmental conditions.

Two aspects of mutagenesis will continue to grow in importance. First, environmental and human-made mutagens will continue to be a source of concern as technological advances occur. Many scientists are working to monitor and correct potential mutagenic hazards. Second, geneticists have developed invaluable molecular tools for utilizing genetic engineering to produce preplanned mutations. For example, site-directed mutagenesis is a technique used to introduce specific mutations into DNA using short strands of single-stranded DNA (called primers) carrying a specific mutation of interest. The primers carrying the mutation are machine-made and are used in a reaction containing DNA polymerase to “prime” and synthesize the mutated version of the gene, carried on a vector. The resulting mutated DNA can be propagated and used to transform the cells of an organism that can use the mutated gene as a template for generating protein. This tool offers
several advantages for studying the effects of specific mutations. Directed mutagenesis of DNA may also offer a way to correct preexisting genetic defects or alter phenotypes in planned ways. Mutation is, therefore, a double-edged sword, both a source of problems and a source of promise.

Key terms




alleles


:

different forms of a gene characterized by sequence variation at the same genetic locus of a chromosome





gene pool


:

the collective set of alleles carried by members of a species or population of organisms; multiple alleles in the gene pool provide the variation that allows adaptation to new conditions




genome

:

the complete hereditary information of an organism encoded in DNA




genotype

:

the set of alleles an organism possesses in its genome




germinal mutation

:

a mutation in a reproductive cell (gamete), which can be passed from a parent to its offspring




mutagen

:

a chemical, physical, or biological agent that causes an increased rate of mutation




mutagenesis

:

the process of producing a change in the nucleotide sequence of DNA




mutant

:

an individual carrying a mutation; this term typically refers to a genetic change that causes a phenotype different from wild type




mutation rate

:

the probability of a mutation occurring in the genetic material over a given time period, such as a cell division cycle or a generation




phenotype

:

the observable effects of a gene; phenotypes include physical appearance, biochemical activity, cell function, or any other measurable factor




somatic mutation

:

a mutation that occurs in a body cell and may produce a group of mutant cells but is not transmitted to the next generation




wild type

:

the most common genetic makeup of an organism; a mutation alters the genotype of a wild type organism to produce a mutant phenotype





Bibliography

Braman, Jeff, ed. In Vitro Mutagenesis Protocols. 2nd ed. Totowa: Humana, 2002. Print.

Friedberg, Errol C., et al., eds. DNA Repair and Mutagenesis. 2nd ed. Washington: ASM, 2006. Print.

Hartl, Daniel L. Essential Genetics: A Genomics Perspective. 6th ed. Burlington: Jones, 2014. Print.

Kelly, Evelyn B. Encyclopedia of Human Genetics and Disease. 2 vols. Santa Barbara: Greenwood, 2013. Print.

Radman, Miroslav, and Robert Wagner. “The High Fidelity of DNA Duplication.” Scientific American 259 (1988). Print.

Schaefer, G. Bradley, and James N. Thompson Jr. Medical Genetics: An Integrated Approach. New York: McGraw-Hill, 2014. Print.

Smith, Paul J., and Christopher J. Jones, eds. DNA Recombination and Repair. New York: Oxford UP, 2000. Print.

Sobti, R. C., G. Obe, and P. Quillardet, eds. Trends in Environmental Mutagenesis. New Delhi: Tausco, 1999. Print.

Strachan, Tom, and Andrew P. Read. Human Molecular Genetics. 3rd ed. London: Garland Science, 2004. Print.

In Maniac Magee by Jerry Spineli, why did Maniac choose The Little Engine That Could as Grayson's first book?

Jerry Spinelli never writes why Maniac Magee chooses The Little Engine That Could.  Maniac never explains it either, so it is left up to the reader to hypothesize a reason.  

I think Maniac chose the book for a few reasons.  First, it is not a difficult read.  That is important though, because Grayson is learning to read for the first time in his life. Maniac needs a book that is accessible for a...

Jerry Spinelli never writes why Maniac Magee chooses The Little Engine That Could.  Maniac never explains it either, so it is left up to the reader to hypothesize a reason.  

I think Maniac chose the book for a few reasons.  First, it is not a difficult read.  That is important though, because Grayson is learning to read for the first time in his life. Maniac needs a book that is accessible for a beginning reader. 

Second, the book has a motivating message.  The engine keeps up positive thoughts and is eventually able to accomplish a large goal. That is the message that Maniac wants Grayson to learn.  Reading may seem like a daunting task, but if Grayson continues to think that he can do it, then he will be able to really do it. 

What is osteoarthritis? |

Causes and Symptoms

There are several causes of osteoarthritis (OA), including traumatic injuries,
joint overuse or repetitive movement of a joint, obesity, congenital bone
deformities, and genetic or metabolic diseases such as diabetes or
Paget's
disease of the bone. Other risk factors include old age and
female gender. The most commonly affected joints are in the hands, hips, knees,
and spine. An inherited genetic defect in the production of collagen leads to
defective cartilage and to more rapid joint deterioration. OA in the
hands or hips may be hereditary. OA in the knees and hips is linked to excess
weight, which puts added stress on these joints. Muscle weakness can also
predispose one to OA; thigh strengthening exercises can reduce one's risk of
developing OA in the knees.

In healthy joints, cartilage containing synovial fluid and elastic tissue reduces
friction as joints move. Osteoarthritis develops when the cartilage wears away and
bone rubs against bone. The most prominent symptom of osteoarthritis is joint
pain. Other symptoms include morning stiffness or stiffness after long periods of
immobility. Early in the disease, individuals may experience joint pain after
strenuous exercise. As the disease progresses, joints stiffen and diminished joint
mobility is experienced even with slight activity. As joint mobility decreases,
the muscles surrounding the joint weaken, thereby increasing the likelihood of
further injury to the joint. As the cartilage wears away, crepitus can often be
heard and a grating sensation can be felt as bone moves against bone. The
development of Heberden’s nodes on the distal interphalangeal joints and
Bouchard’s nodes on the proximal interphalangeal joints of the hands is not
uncommon.

Confirmation of osteoarthritis is based on a history of joint pain and physical
findings that indicate arthritic changes in the joints. In a physical examination,
a doctor may check for swelling and joint tenderness under pressure, as well as a
loss of the joint's range of mobility. An X-ray can show a loss of joint space,
osteophytes, bone cysts, and sclerosis of subchondrial bone. Sometimes, a
computed
tomography (CT) scan or magnetic resonance imaging (MRI) may
be helpful in confirming the presence of osteoarthritis and can show the loss of
cartilage.

Treatment and Therapy

The goal of treatment for OA is to preserve physical function and reduce pain.
Education, physical therapy, and occupational
therapy are instrumental in maintaining independence and
improving muscle strength around affected joints. Pacing activities to avoid
overexertion of the affected joints is an effective means to prevent further pain
and injury. Heat therapies such as warm soaks, paraffin, and mud treatments may
help to lessen the discomfort in tender joints. Moderate exercise such as walking,
swimming, strength training, and stretching all may help to maintain mobility in
arthritic joints and to improve posture and balance. Relaxation techniques, stress
reduction activities, and biofeedback may also be helpful.

Over-the-counter topical analgesic ointments may help to reduce joint swelling and
pain. Acetaminophen is very effective for controlling OA pain. However, persons
who take blood-thinning medicines, have liver disease, or consume large amounts of
alcohol should use acetaminophen with caution. Nonsteroidal anti-inflammatory
drugs (NSAIDs) such as ibuprofen and naproxen are also
effective for pain relief, but they may cause gastrointestinal bleeding. This
class of drugs selectively blocks the enzyme COX-2, thus controlling the
production of prostaglandins, natural chemicals that contribute to body
inflammation and cause the pain and swelling of arthritis.
Since they do not block the COX-1 enzyme cyclooxygenase-1, which is present in the
stomach and inflammation sites, the natural mucous linings of the stomach and
intestine are protected, thereby reducing the incidence of upset, ulceration, or
bleeding; however, COX-2 selective inhibitors increase the rate of cardiovascular
events such as heart attacks and stroke. Any medication used to treat OA should be
taken under the direction of a health care provider.

Glucosamine and chondroitin naturally occur in the body. Both have been promoted for the treatment of OA. Glucosamine may promote the formation and repair of cartilage, while chondroitin may promote water retention and elasticity in cartilage and prevent cartilage breakdown. However, recent studies indicate that taking glucosamine for arthritis may increase a patient's risk of developing glaucoma.

When interventions to relieve symptoms of OA no longer work, an orthopedic surgeon
may inject cortisone or hyaluronic acid into joint spaces. Hyaluronic acid is used
to replace the synovial fluid that a joint has lost in order to maintain knee
movement without pain. Cortisone may be injected into affected joint spaces to
provide temporary relief of joint pain. Surgical intervention to trim torn and
damaged cartilage from joint spaces, to partially or totally replace severely
damaged joints in the knees and hips, or to fuse bones together are effective
treatments in the most severe, debilitating stages of OA. Realignment of a joint
(osteotomy) and joint replacement surgery other possible procedures.

Perspective and Prospects

Arthritis comprises more than one hundred diseases and conditions and is the major
cause of disability in the United States. The incidence of OA increases with age,
but it can affect individuals as young as eighteen. According to the Arthritis
Foundation, approximately twenty-seven million people in the United States have
OA, and it is the most common form of arthritis. OA affects nearly 14 percent of
US adults over the age of twenty-five and more than 33 percent of adults over the
age of sixty-five, according to the US Centers for Disease Control and Prevention.
In 2010, hip and knee OA ranked as the eleventh highest contributor to global
disability. OA is three times more common among women, although before forty-five
years of age, it is more common in men. There is no cure for OA, but a healthy
diet, regular exercise and physical therapy, weight control, and the use of
medications are measures that can slow its progress and maintain joint function.

Bibliography

Ali, Naheed.
Arthritis and You: A Comprehensive Digest for Patients and
Caregivers. Lanham: Rowman, 2013. Print.

Brower, Anne C.
Arthritis in Black and White. Philadelphia: Elsevier
Saunders, 2012. Print.

Cross, Marita, et al. "The Global Burden of
Hip and Knee Osteoarthritis: Estimates from the Global Burden of Disease
2010 Study." Annals of the Rheumatic Diseases 73.7 (2014):
1323–30. Print.

Foltz-Gray, Dorothy.
The Arthritis Foundation’s Guide to Good Living with
Osteoarthritis. 2nd ed. Atlanta: Arthritis Foundation, 2004.
Print.

Juhl, C., et al. "Impact of Exercise Type and
Dose on Pain and Disability in Knee Osteoarthritis: A Systematic Review and
Meta-Regression Analysis of Randomized Controlled Trials." Arthritis
and Rheumatology 66.3 (2014): 622–36. Print.

Lane, Nancy E., and
Daniel J. Wallace. All about Osteoarthritis: The Definitive Resource
for Arthritis Patients and Their Families. New York: Oxford UP,
2002. Print.

Firestein, Gary S., et al.
Kelley's Textbook of Rheumatology. 9th ed. Philadelphia:
Elsevier, 2013. Print.

Nelson, Miriam E., et
al. Strong Women and Men Beat Arthritis. New York:
Putnam’s, 2002. Print.

Sayce, Valerie, and
Ian Fraser. Exercise Beats Arthritis: An Easy to Follow Program of
Exercises. Palo Alto: Bull, 1998. Print.

Sutton, Amy L., ed.
Arthritis Sourcebook: Basic Consumer Health Information About
Osteoarthritis, Rheumatoid Arthritis, Other Rheumatic Disorders,
Infectious Forms of Arthritis, and Diseases with Symptoms Linked to
Arthritis. 2nd ed. Detroit: Omnigraphics, 2004.
Print.

Yelin, E. “The
Economics of Osteoarthritis.” Osteoarthritis. Ed. K.
Brandt, M. Doherty, and L. Lohmander. New York: Oxford UP, 1998.
Print.

What does Hamlet mean when he says "The play's the thing/Wherein I'll catch the conscience of the king."?

This rhymed couplet sums up the plan that Hamlet decides to pursue at the end of Act II.

Hamlet isn't entirely certain that Claudius killed Hamlet's father, so he is going to test Claudius. He is going to stage a play for Claudius to watch, a thinly-disguised dramatization of Claudius's supposed murder of Hamlet's father. If, after watching the play, Claudius betrays emotions of guilt or otherwise behaves suspiciously, Hamlet will have confirmed that his...

This rhymed couplet sums up the plan that Hamlet decides to pursue at the end of Act II.

Hamlet isn't entirely certain that Claudius killed Hamlet's father, so he is going to test Claudius. He is going to stage a play for Claudius to watch, a thinly-disguised dramatization of Claudius's supposed murder of Hamlet's father. If, after watching the play, Claudius betrays emotions of guilt or otherwise behaves suspiciously, Hamlet will have confirmed that his uncle did, in fact, kill his father.

If you read the approximately 18 lines leading up to these words, you can observe Hamlet hatch this plan. The others have left; Hamlet is thinking aloud. And he recalls something:

"Fie upon't! foh! About, my brain! I have heard
That guilty creatures sitting at a play
Have by the very cunning of the scene
Been struck so to the soul that presently
They have proclaim'd their malefactions;
For murder, though it have no tongue, will speak
With most miraculous organ."

In other words, he's heard that people guilty of crimes have confessed their guilt after watching a play that portrays situations highly reminiscent of their own, criminal acts. Seeing their crimes acted out by others reminds them of their guilt, and so they give themselves away.

Having remembered this, Hamlet determines that he will write his own little drama -- one recreating the peculiar circumstances of the crimes he believes Claudius committed -- and have the actor's troupe perform it for the royal household. Then, to determine if Claudius is guilty, Hamlet says:

"… I'll observe his looks;
I'll tent him to the quick: if he but blench,
I know my course."

If Claudius reacts with so much as a flinch, Hamlet says, he will have the evidence he needs to confirm Claudius's guilt. This is crucial because Hamlet isn't sure he can trust what he was told by the spirit that had appeared to be his father's ghost. He's concerned that "the devil" might have taken the shape of his father and told him lies.

What is amenorrhea? |

Causes and Symptoms

Amenorrhea, or the absence of menses, can be physiologic, such as during pregnancy, or pathologic. Amenorrhea can be primary or secondary in nature. Primary amenorrhea is defined as the absence of menses by age sixteen, even in the presence of normal growth and secondary sexual characteristics. In girls with abnormal growth, primary amenorrhea is defined as the absence of menses by age fourteen. Causes of primary amenorrhea include abnormalities of the reproductive outflow tract that prevent the flow of menstrual blood. Examples include imperforate hymen, transverse vaginal septum, and Asherman’s syndrome, whereby scar tissue within the uterus prevents the outflow of menstrual fluid. Girls with these conditions may experience cyclic cramping and discomfort from the buildup of menstrual blood. Other causes of primary amenorrhea include genetic problems such as Turner syndrome, in which the individual has a single X chromosome, or androgen insensitivity syndrome, in which the individual appears female but is genetically male and lacks ovaries and a uterus. Turner syndrome and androgen insensitivity tend to be asymptomatic regarding their amenorrhea. Rare congenital causes of primary amenorrhea include Kallman syndrome and empty sella syndrome.

Secondary amenorrhea refers to the absence of menstrual periods after menstrual cycles have occurred previously. It is defined as the absence of menses for the duration of three regular menstrual cycles or six months. Physiological causes of secondary amenorrhea include pregnancy, the postpartum state, and the menopause. Pathologic causes of secondary amenorrhea include disorders of the central nervous system or hypothalamus, such as extreme stress or exercise and anorexia nervosa. Disorders of the pituitary gland, such as tumors, can cause secondary amenorrhea as well. These tumors may be accompanied by galactorrhea, from high levels of prolactin, or by visual impairment. Hormonal disturbances can also lead to secondary amenorrhea. One example is hypothyroidism, which is often accompanied by fatigue and cold intolerance. Polycystic ovary syndrome, an endocrinologic disorder characterized by insulin resistance and
hirsutism, may also lead to amenorrhea. Another cause of secondary amenorrhea is premature ovarian failure,
which may be attributable to radiation or chemotherapy. These individuals may experience the symptoms of early menopause, such as hot flashes and vaginal dryness.

Treatment and Therapy

The treatment for amenorrhea depends on the cause. If the disorder is the result of anatomic causes, then surgery may cure it. For instance, an imperforate hymen or transverse vaginal septum can be corrected surgically, allowing for normal outflow of menstrual fluid. If the disorder is the result of hormonal imbalances, then medications may be given, such as thyroid hormone for hypothyroidism or bromocriptine for hyperprolactinemia. In individuals with polycystic ovary syndrome, metoformin may be given to regulate the menstrual cycles. By correcting these hormonal imbalances, the resumption of regular menstrual cycles may occur, thus allowing for conception and pregnancy, if the individual so desires.

In cases of amenorrhea caused by extreme stress or exercise and anorexia nervosa, removal from the stressful conditions, a decrease in exercise levels, or an increase in caloric intake to maintain normal ideal body weight often remediates amenorrhea. Individuals who suffer from anorexia nervosa also require psychiatric treatment.

Individuals with genetic causes or premature ovarian failure leading to amenorrhea are unlikely to attain menstruation via medical therapy. For these individuals, therapy is aimed at preventing or treating the sequelae of estrogen deficiency that accompany amenorrhea. For instance, women with premature ovarian failure are at risk for the depletion of bone mineral density and osteoporosis. These individuals may benefit from hormone therapy in the form of estrogen and progesterone.

Perspective and Prospects

The cause for amenorrhea can often be found, since a vast array of diagnostic tests are available. Anatomic abnormalities may be detected on physical examination or via imaging of the reproductive structures such as ultrasound. Hormonal causes of amenorrhea can often be found through blood tests of hormones produced by the hypothalamus, pituitary gland, ovaries, thyroid gland, and adrenal glands. These tests can identify the hormone derangement and which organ is responsible. Genetic tests have allowed physicians to understand the basis of primary amenorrhea on a molecular level. While many cases of amenorrhea can be treated effectively once the cause has been identified, the future holds promise that better therapies with fewer side effects will be found.

Bibliography:

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

Kohnle, Diana, and Andrea Chisholm. "Absent Periods." Health Library, Sept. 27, 2012.

McPhee, Stephen J., and Maxine A. Papadakis, eds. Current Medical Diagnosis and Treatment. 50th ed. Los Altos: Lange Medical Pub, 2011.

Stenchever, Morton A., et al. Comprehensive Gynecology. 5th ed. St. Louis, Mo.: Mosby/Elsevier, 2007.

Vorvick, Linda J., and David Zieve. "Amenorrhea - Primary." MedlinePlus, May 31, 2012.

Vorvick, Linda J., and David Zieve. "Secondary Amenorrhea." MedlinePlus, May 31, 2012.

What are young adult cancers?

Risk factors: Researchers report no clear risk factors for cancer in young adults. Few studies have found any connection to environmental factors or inheritance. Most cases of young adult cancer appear sporadic and spontaneous with only 5 percent related to family history. Cancers that may be connected to environmental factors include melanoma, cervical cancer, Kaposi sarcoma, non-Hodgkin lymphoma, Hodgkin disease, and Burkitt lymphoma. Having a cancer in childhood may increase the risk of developing a second cancer as a young adult.

Etiology and the disease process: Because increased cancer occurrence is usually noted in older adults, cancer is often regarded as a disease of the elderly. However, cancer occurs in people of all ages. Historically, minimal research has been directed toward cancer in young adults, ages fifteen through twenty-nine, but that is changing. In 2006, the National Cancer Institute joined with the Lance Armstrong Foundation to identify barriers that face young adults with cancer and to develop approaches that can improve outcomes for this age group.

Young adults with cancer face many challenges because of their age and developmental tasks. In the teenage years, young people try to achieve mature relationships with others of both sexes, establish gender role identities, learn to accept their bodies, achieve emotional independence from their parents, prepare for marriage, gain education for a career, acquire values that govern behaviors, and become socially responsible. In early adulthood, young adults select a mate, establish a home, start a family, struggle to establish their identity, complete their education and training to work and provide financial support, express independence, and become comfortable with their sexuality. These milestones may be difficult with a chronic disease process that threatens financial security and brings changes in body image, social relationships, and sexuality. The stresses of the young adult differ from those of children or older adults.

Incidence: Young adult cancers account for only about 2 percent of all invasive cancers (excluding skin cancer) in the United States. However, each year about 70,000 young adults in the second or third decade of their lives learn they have some form of cancer. Young adults between the ages of fifteen and twenty-nine are 2.7 times as likely to develop cancer as they were before they turned fifteen. Young men between the ages of fifteen and twenty-nine have a higher incidence and a poorer prognosis than young women in this age group. The incidence of young adult cancers has experienced a steady increase. In 2011, over 69,000 adolescents and young adults between the ages of fifteen and thirty-nine were diagnosed with cancer.

According to the American Cancer Society in 2014, the three most predominant types of cancer in children and young adults is leukemia at 26 percent, brain and central nervous system cancers at 18 percent, and lymphoma at 14 percent.

Symptoms: Symptoms of young adult cancers are specific to the type cancer they have developed. The following are some common young adult cancers and symptoms:

Lymphoma symptoms include painless lumps in the neck, armpits, or groin; other possible signs are weight loss of up to 10 percent of total body weight, high infrequent fevers, loss of appetite, weakness and fatigue, generalized itchiness over the body, red irritated patches of skin, excessive sweating at night, and coughing or breathlessness with swelling of the face and neck.

Melanomas present in moles that change in size (become bigger), shape (especially with an irregular edge), color (get darker or multicolored), become itchy or painful, bleed or become crusty, or appear inflamed or irritated.

Thyroid cancer symptoms are a lump or nodule on the neck; pain in the neck, jaw, and ear; difficulty swallowing; a tickle in the throat; or hoarseness.

Leukemia symptoms vary by type but most are vague and nonspecific, such as fatigue or general weakness; malaise (general uncomfortable feeling throughout the body); abnormal bleeding and excessive bruising; reduced tolerance for exercise; an enlarged spleen, liver, or lymph nodes; joint or bone pain; increased infection and fever; and abdominal pain or fullness. A blood test will most likely show anemia, leukopenia (low white cell count), and thrombocytopenia (low blood-clotting cell count).

Cervical cancer is a silent disease in its early stages, with later symptoms such as abnormal vaginal bleeding, heavy vaginal discharge, pelvic pain, pain during urination, or bleeding after intercourse, between menses, or after douching.

Brain tumors may present with signs of increased intracranial pressure such as headaches, vomiting especially on waking, mental changes such as drowsiness or sluggishness, seizures, and loss of coordination with clumsy movement. Depending on the tumor location, symptoms can also include buzzing or ringing in the ears, dizziness, blindness in one side, language disorders, loss of smell, or impaired vision.

Spinal cord tumors manifest with symptoms such as neck, arm, or leg pain; weakness; muscle wasting; spasms; sensory changes; or decrease in bowel and bladder control.

Screening and diagnosis: Because young people are generally healthy, screening and diagnosis of cancer in young adults may be delayed. Young people may not recognize symptoms or may ignore their body’s signs of illness. They may think that symptoms are related to their lifestyle choices. Most screening procedures are recommended for middle-age or older adults, not for young adults. Health care providers may overlook cancer as a possibility because of the person’s youth and misdiagnose the disease.

Young adults in school or college may be covered by their parents’ health insurance or have school health insurance with limited coverage; some may have no health insurance due to limited financial resources. They may delay dealing with symptoms because of the costs associated with health care providers, clinics, and testing. When they do seek help, they may encounter a complicated health care system and become frustrated with the process.

Treatment and therapy: Cancer treatment for young adults will be specific to the location, type, and stage of the cancer. If there is a malignant tumor or mass, surgery may be the best option. With or without surgery, chemotherapy (the use of drugs to kill cancer cells) may be used by the oncology physician to treat the cancer. Some cancers respond to radiation therapy, in which a high level of energy targets the cancer site to kill cancer cells. Immunotherapy may be used to stimulate the immune system to fight the cancer. Hormone therapy might be employed in certain cancers. Targeted therapy may be a treatment for metastasis of the cancer. A stem cell transplant might be useful in treatment. Joining a clinical trial directed to the young adult’s specific cancer may prove beneficial.

Choosing a physician to provide cancer treatment and therapy is critical for young adults. The first consideration is to contact an oncologist, a doctor that specializes in cancer. Because cancer is less common in young adults, not all oncology physicians are familiar with this age-related specialty. They may not know about current treatment options and available support groups or resources for young adults. One example is that young adults with leukemia sometimes have better outcomes when treated with a regimen designed for children rather than the normal protocol for leukemia treatment in adults. Hence, young adults may need to consult specialists in pediatric oncology. However, practitioners who treat adults for cancers like breast, colon, or melanoma may provide the best treatment for young adults with these cancers.

Prognosis, prevention, and outcomes: The prognosis for young adults varies with their specific cancer. While overall survival rates for adults and children with cancer have improved over the past few years, the same is not true for young adults. The National Cancer Institute reports that in 2011, cancer was the leading causes of disease-related death among adolescents and young adults, with accidents, suicides, and homicides claiming more lives than cancer. Furthermore, it was reported that both cancer incidence rates and five-year survival rates were highest among white young adults, while African American young adults have moderate cancer incidence levels but low five-year survival rates. Asian/Pacific Islander young adults had the lowest cancer incidence rates.

Some studies suggest that young adult cancers can develop after previous childhood cancers. Research is currently examining lymphoma, leukemia, and testicular cancer, as these are diseases that affect children and young adults. Though no study has established why the second cancer occurs, some scientists believe that treatments such as chemotherapy and radiation therapy used to treat the first cancer may suppress the patient’s immune systems as well as damage normal cells. Key to decreasing second cancers is determining the factors that might contribute and minimizing exposure.

One cancer on the rise among young adults is nonmelanoma skin cancers, which are preventable. Simple precautions can prevent skin cancer in young adults. The American Cancer Society has several recommendations to prevent skin cancer:

• Avoid extended exposure to sunlight from 10 a.m. to 4 p.m.





• Wear a hat, sunglasses, and clothes that cover the skin when in direct sunlight.





• Use sunscreen with a sun protection factor (SPF) of at least 15.





• Avoid tanning booths.





• Check skin often for any unusual moles, spots, or blemishes. Note any change in size, shape, or color.





• See a health care provider immediately if any suspicious spots or moles occur.
  Young adult cancers
  
  

"Adolescents and Young Adults with Cancer." National Cancer Institute. US Dept. of Health and Human Services, n.d. Web. 29 Jan. 2015.

American Cancer Society. "Special Section: Childhood and Adolescent Cancers." Cancer Facts and Figures 2014. Atlanta: Amer. Cancer Society, 2014. 25–42.

Bleyer, A., M. O’Leary, R. Barr, and L. A. G. Ries, eds. Cancer Epidemiology in Older Adolescents and Young Adults Fifteen to Twenty-nine Years of Age, Including SEER Incidence and Survival: 1975-2000. Bethesda, Md.: National Cancer Institute, 2006.

Eden, T. O. B., et al., eds. Cancer and the Adolescent. 2d ed. Malden, Mass.: Blackwell, 2005.

Grinyer, Anne. Cancer in Young Adults: Through Parents’ Eyes. Philadelphia: Open University Press, 2002.

Robison, Leslie L., and Melissa M. Hudson. "Survivors of Childhood and Adolescent Cancer: Life-long Risks and Responsibilities."  Nature Reviews Cancer 14.1 (2014): 61–70. Print.

"'Stranger,' he grumbled back from his brutal heart, 'you must be a fool, stranger, or come from nowhere, telling me to fear the gods or avoid...

A. Monsters are stronger than the Greek gods.

In this particular passage, it seems as though option A is the best answer.  Polyphemus, the Cyclops, believes himself to be stronger than even the most powerful of the Olympian gods.  Though he turns out to be wrong, Polyphemus, son of Poseidon, continues to believe that his race has the superior power.  Odysseus has referenced Zeus and Zeus's protection of travelers because Odysseus would expect to be...

A. Monsters are stronger than the Greek gods.

In this particular passage, it seems as though option A is the best answer.  Polyphemus, the Cyclops, believes himself to be stronger than even the most powerful of the Olympian gods.  Though he turns out to be wrong, Polyphemus, son of Poseidon, continues to believe that his race has the superior power.  Odysseus has referenced Zeus and Zeus's protection of travelers because Odysseus would expect to be treated with great hospitality. The ancient Greeks felt that there was, thus, a religious imperative to offer a hearty welcome, with food and lodging and even gifts, if the host could manage it (and Polyphemus certainly can).  Therefore, option A seems to best describe Polyphemus's feelings about his relative power compared to the gods.  However, elsewhere in the text and in Greek life, while monsters could do a great deal of damage, they were not believed to be stronger than the immortal gods.

What is the relationship between hospitals and infectious disease?

Definition

Infections acquired in hospitals and health care facilities effect about one in every twenty-five patients admitted to acute-care or long-term-care facilities in the United States according to the Centers for Disease Control and Prevention (CDC). In 2011 this meant approximately 722,000 people in acute-care hospitals had healthcare-associated infections (HAIs), also called nosocomial infections, leading to about 75,000 deaths. To be diagnosed as nosocomial, the infection must not be associated with the admitting diagnosis and must occur because of a patient’s exposure to the surrounding pool of infectious agents. The infection usually becomes clinically evident after forty-eight hours (and during hospitalization) or within thirty days of discharge. These infectious agents can colonize a person’s skin, respiratory tract, genitourinary tract, gastrointestinal tract, and bloodstream.

Causes

Most hospital acquired infections are caused by bacteria, viruses, or parasites. The causative organisms can be introduced through endotracheal (ET) intubation, catheterization, gastric drainage tubes, and intravenous procedures for medication delivery, blood transfusions, or nutrition supplementation. Infection also occurs through surgical procedures and by health care workers’ failing to wash their hands before procedures and between encountering patients. Other risk factors for hospital acquired infections include prolonged hospitalization, the severity of the patient’s underlying illness, the prevalence of antibiotic-resistant bacteria from the prolonged use or overuse of antibiotics, contaminated air-conditioning systems, contaminated water systems, lack of an appropriate ratio of nurses to patients, and overcrowding of beds. Later studies suggested that the uniforms and laboratory coats of hospital personnel may also help transfer pathogens. Also, it has been suggested that the shedding of epithelial tissues from the patients onto their hospital clothing may contribute to infections. Other reservoirs of contamination include stethoscopes, blood pressure cuffs, bed pans, water pitchers, telephones, and other objects. Airborne infections in hospitals may contribute to infections that include tuberculosis and herpes varicella.

Among the most common hospital acquired infections are pneumonia and urinary tract infections. In terms of the latter, the common procedure of placing a catheter into the bladder for delivery of medication, for measuring urinary output, for the relief of pressure, or for other medical reasons creates a port of entry for infectious agents. The healthy bladder is normally sterile; it contains no harmful bacteria or other organisms. The catheter can pick up bacteria or organisms from the urethra, providing an easy route to the bladder. This infection can occur because of improper sterilization techniques,which creates a mechanical entry for infection through, for example, multiple tries to insert the catheter; even the composition of the catheter can lead to infection of the bladder. It is now recognized that a major cause of nosocomial infection is the picking up of bacteria, such as Escherichia coli (E. coli), or other organisms from the intestinal tract and transferring them to the bladder. Irritation from the catheter’s insertion and prolonged use of the catheter can transfer bacteria (and a fungus called Candida). An infection caused by an indwelling catheter will need long-term treatment with antibiotics; this long-term treatment can compromise the patient’s immune system, thereby causing further harm.

Nosocomial pneumonia is another leading hospital-acquired infection, accounting for about 157,500 cases in US acute-care hospitals in 2011. Bacteria and other microorganisms enter the respiratory system through procedures treating respiratory illnesses. The placement of ET tubes for mechanical ventilation is of primary concern. If ETtubes are inserted (such as by a paramedic) while the patient is outside a hospital or even in an emergency room, the risk of infection is greater. The introduction of aids for ensuring adequate ventilation often lead to infection. Aspiration from the nose, throat, and lungs is a direct pathway for introduction of microorganisms.

Surgery accounts for similar numbers of all US nosocomial infections. Agents of infection include contaminated surgical equipment, the contaminated hands of health care providers, contaminated dressings, trauma wounds, burn wounds, and pressure sores from prolonged bed rest or wheel chair use. The continuous delivery of medications, transfusions, antibiotics, or nutrients through the bloodstream by intravenous (IV) routes is yet another common cause of infection. Improper technique causes bacteria to enter the body at the placement of IVs and increases the risk of infection the longer the IVs are in place. Infections in the blood are of special concern because they can produce disseminating infections. Gastrointestinal procedures, such as colonoscopy; obstetric procedures; and kidney dialysis can also lead to major infections.

Antibiotic
resistance has led to an increase in several other nosocomial
infections, including superinfections. Generally, the major causative pathogens
for hospital acquired infections relate to the location of the involved body
system or systems, except for the bloodstream, which when infected can cause
dissemination of the infection to all major organs. By classifying major pathogens
according to the organ systems they affect, one can differentiate among these
varying pathogens. The major pathogens for the genitourinary system are
gram-negative enterics, fungi, and enterococci. Bloodstream infectious agents are
usually coagulase-negative staphylococci, enterococci, fungi,
Staphylococcus aureus, Enterobacter species,
Pseudomonas, and Acinetobacter baumannii
(which causes substantial antimicrobial resistance). Surgical-site infections
include S. aureus, Pseudomonas,
coagulase-negative staphylococci, and (rarely) enterococci, fungi,
Enterobacter species, and E. coli.

Ventilator-associated pneumonia (VAP) is designated as either early or late onset. Early onset begins within the first three to four days of mechanical ventilation. The infections are usually antibiotic-sensitive and are most often caused by S. pneumoniae, H. influenza, or S. aureus. Late-onset infections that are antibiotic-resistant and are main causative agents are those caused by Ps. aeruginosa, Actinobacter spp., and Enterobacter spp. Other pneumonias caused by gram-negative bacterium are Klebsiella pneumoniae, Legionella, or methicillin-resistant Staphyloccocus aureus (MRSA), known as the superbug.

A relatively new hospital-acquired infection is colitis, caused by the organism
Clostridium difficile
. This gram-positive, anaerobic, spore-forming bacillus is responsible for antibiotic-associated diarrhea and colitis. The infection is caused by a disturbance of the normal bacterial flora in the colon, precipitated by antibiotic therapy. The colonization of C. difficile releases two toxins: toxin A, an endotoxin, and toxin B, a cytotoxin, leading to mucosal inflammation and damage of the colon.

Risk Factors

Although all hospital patients are susceptible to nosocomial infections, young children, especially those in the neonatal intensive care unit (ICU); adult ICU patients; the elderly; and patients with compromised immune systems are more likely to acquire these infections. Other risk factors include having underlying diseases such as chronic lung disease, diabetes, or cardiac disease; being obese; being malnourished; having a malignancy; having a remote infection; using prophylactic antibiotics; and hospitalization before surgery (especially for twelve hours or longer), which increases the patient’s exposure to the reservoir of infectious agents.

Symptoms

The primary sign of infection is fever. A person’s
admission temperature and those temperatures recorded at the time of
hospitalization and after hospitalization are paramount for recognizing a
developing infection. Other symptoms of infection include an increased respiratory
rate; increased pulse rate; sweating, especially at night; chest pain; productive
phlegm with coughing or an inability to cough; pain and discharge from the nose or
mouth; fatigue; difficulty and pain with swallowing; nausea; vomiting; excessive
diarrhea; pain with urination or blood present in urine; reduced urine output;
redness and swelling with pustular discharge around surgical wounds or openings in
sutures from skin closures with exposure to subcutaneous tissues; and the
development of skin rashes.

Screening and Diagnosis

The foregoing signs and symptoms suggest infection. One should consult a doctor immediately if any of these symptoms are present during or after hospitalization. The first diagnostic tool is a complete physical examination, which includes laboratory studies and X rays. Other tests include extensive blood testing, with a complete blood count that looks for an increase in infection-fighting white blood cells; a complete urinalysis that includes culture and checks for a sensitivity to antibiotics; two blood samples drawn twenty minutes apart for culture and sensitivity; sputum for culture and sensitivity; and wound cultures for culture and sensitivity. Ancillary tests include abdominal X rays or computed tomography (CT) scans (detailed X rays that identify abnormalities of fine tissue structure); kidney X rays; kidney, liver, and pancreas function tests; blood gas tests; and tests for fungus infective agents.

Treatment and Therapy

While waiting for the laboratory culture and sensitivity results, which may
take up to forty-eight hours to complete, one should begin broad-spectrum
antibiotic therapy. This usually includes penicillin,
cephalosporins, tetracycline, or erythromycin, and
supplemental oxygen if needed. The doctor will need to know if the patient is
allergic to certain antibiotics or if the patient has been on prolonged antibiotic
therapy. It is usual to combine antibiotics for therapy, so, for best results, the
doctor must determine if the infecting organism is gram-positive or gram-negative
or whether it is anaerobic bacteria, resistant bacteria, or fungi. Once the
causative agent for infection has been identified, aggressive therapy begins.
Recommended treatments include vancomycin, imipenem plus cilastatin, meropenem,
azteonam, piperacillin plus tazobactam, ceftazidme, and cefepime. If MRSA is
suspected, limezoid can be used.

Other treatments that can be used to supplement antibiotic therapy include pulmonary hygiene and respiratory treatments, aggressive wound care, fever control until the antibiotics show evidence of effectiveness, body cleansing, changing of hospital garments, and extreme sterile techniques when treating the patient (which may include putting the patient in reverse isolation for protection of further exposure to infections). Close monitoring of cardiac status, urine output, and pulmonary functions is recommended. The changing of catheters, IV lines, gastrointestinal (GI) tubes, and other invasive forms of exposure may also be ordered by the doctor. The hospital’s medical team and infectious disease control team will monitor the patient’s status and present complete documentation of the case.

Prevention and Outcomes

The recommendations for the prevention of infections acquired in hospitals and other health care facilities cover a broad geographic, demographic, cultural, and ecological spectrum. The recommendations are based on the type of causative agents as precursors for disease in the associated populations. Requirements, although based on sound science, can sometimes be misinterpreted or even ignored. A good foundation for practice is to bring together basic infection-control measures and the history of epidemiology. Historically, this practice could be said to have begun in the nineteenth century with Florence Nightingale, who believed respiratory secretions could be dangerous, and with Ignaz Semmelweis, a nineteenth century obstetrician who demonstrated that routine handwashing could prevent the spread of puerperal fever. Joseph Lister, a nineteenth century professor of surgery, was the first to realize the connection between the suppuration of wounds and the discoveries of the fermentation process (by chemist and microbiologist Louis Pasteur) in the mid-nineteenth century. Lister published his findings in 1867 and was credited with helping to start the practice sterilizing operating rooms with carbolic acid.

The CDC began hospital surveillance in the United States in the 1960s. The 1970s saw the introduction of training courses in disease prevention and the establishment of the CDC’s Division of Healthcare Quality and Promotion for hospital infection programs and the National Nosocomial Infections Surveillance System. The Study on the Efficacy of Nosocomial Infection Control was conducted in the early 1970s. The Healthcare Infection Control Practices Advisory Committee was formed in 1991 and, in 2005, hospitals began contributing surveillance to the National Healthcare Safety Network, which was reworked with a comparison study in 2007. The initiatives created by these agencies and programs provide guidelines for improvement in the prevention of hospital acquired infections.

These guidelines include adopting infection control programs in accordance with the CDC to track trends in infection rates, ensuring that one practitioner is available for every two hundred beds in hospitals and other health care facilities, identifying high-risk medical procedures, strict adherence by medical staff and visitors to handwashing policies, and other sterilization techniques. These include using sterile gowns, gloves, masks, and barriers; sterilizing reusable equipment, including ventilators, humidifiers, or other respiratory equipment that comes in contact with a patient’s respiratory tract; frequently changing wound dressings and using antimicrobial ointments; removing nasalgastric and endotracheal tubes as soon as possible; using antibacterial-coated venous catheters; preventing infection by airborne microbes through wearing masks (by hospital personnel and patients); limiting the use of high-risk procedures such as urinary catheterization; isolating patients with known infections; and reducing the general use of antibiotics.

Bibliography

Clancy, Carolyn. “Simple Steps Can Reduce Health Care-Associated Infections: Navigating the Health Care System.” Rockville, Md.: Agency for Healthcare Research and Quality, 2008. Available at http://www.ahrq.gov/consumer/cc/cc070108.htm.

"Healthcare-Associated Infections (HAIs): Data and Statistics. CDC. Centers for Disease Control and Prevention, 15 Oct 2015 Web. 31 Dec. 2015.

Helms, Brenda, et al. “Improving Hand Hygiene Compliance: A Multidisciplinary Approach.” American Journal of Infection Control 38, no. 7 (2010): 572-574. Print.

Heymann, David L., ed. Control of Communicable Diseases Manual. 19th ed. Washington, D.C.: American Public Health Association, 2008. Print.

Kuehnert, Matthew J., et al. “Methicillin-Resistant Staphylococcus aureus Hospitalizations, United States.” Emerging Infectious Diseases 11, no. 6 (2005). Print.

Kushner, Thomasine Kimbrough. Surviving Healthcare: A Manual for Patients and Their Families. New York: Cambridge University Press, 2010. Print.

Peleg, Anton Y., and David C. Hooper. “Hospital-Acquired Infections Due to Gram-Negative Bacteria.” New England Journal of Medicine 362, no. 19 (2010): 1804-1813. Print.

Turnock, Bernard, J. Public Health: What It Is and How It Works. 3d ed. Sudbury, Mass.: Jones and Bartlett, 2004. Print.

Weber, David J., et al. “Role of Hospital Surfaces in the Transmission of Emerging Health Care-Associated Pathogens: Norovirus, Clostridium difficile, and Acinetobacter Species.” American Journal of Infection Control 38, no. 5, suppl. (2010): S25-S33. Print.

What is leprosy? |

Causes and Symptoms

Leprosy, also known as Hansen’s disease, is caused by the bacterium Mycobacterium leprae (M. leprae). Humans are the only natural host for this bacterium; it can be found only in leprosy victims. Most people who are exposed to this bacterium are unaffected by it; in the remainder, the bacterium grows inside skin and nerve cells, causing a wide range of symptoms that depend upon the person’s immune response to the growth of the bacteria.

M. leprae is an obligate intracellular parasite, which means that it can grow only inside other cells. M. leprae has a unique waxy coating that helps to protect it while it is growing inside human skin and nerve cells. The bacterium grows very slowly, dividing once every twelve days, whereas the average bacterium will divide every twenty to sixty minutes. M. leprae grows best at temperatures slightly below body temperature (37 degrees Celsius). The leprosy bacterium is the only bacterium known to destroy peripheral nerve tissue (nerves that are not a part of the central nervous system) and will also destroy skin and mucous membranes. This bacterium is closely related to the bacterium that causes tuberculosis: Mycobacterium tuberculosis.

Leprosy is not very contagious. Several attempts to infect human volunteers with the bacteria have been unsuccessful. It is believed that acquiring leprosy from an infected person requires prolonged intimate contact with that person, such as living in the same house for a long time. Although the precise mode of transmission of M. leprae bacteria is unclear, it is highly probable that the bacteria are transferred from the nasal or respiratory secretions of the victim to the nasal passages or a skin wound of the recipient.

Once inside a person, M. leprae will grow and reproduce inside skin and nerve cells and destroy tissue. The exact mechanism of tissue destruction is not understood, but it probably results from a combination of nerve damage, massive accumulation of bacteria, and immunological reactions. Because the bacteria grow so slowly, the length of time from infection to appearance of the symptoms (the incubation period) is quite long. The average incubation period is two to seven years, but incubation can range from three months to forty years. Since the bacteria prefer temperatures slightly lower than normal body temperature, symptoms appear first in the cooler parts of the body, such as the hands, fingers, feet, face, nose, and earlobes. In severe cases, symptoms also appear in the eyes and the respiratory tract.

The symptoms associated with leprosy can range from very mild to quite severe, and the symptoms that a person gets depend heavily on that person’s ability to mount a cellular immune response against the bacteria. In a normal infection, the human body is capable of defending itself through two processes of the immune system; the humoral immune response and the cellular immune response. The humoral response produces chemicals called antibodies that can attack and destroy infectious agents that are present in body fluids such as the blood. The cellular response produces white blood cells that can destroy infectious agents that are associated with cells. Since M. leprae hides and grows inside human cells, a cellular response is the only type of immune response that can be of any help in fighting the infection. The ability to generate a cellular immune response against M. leprae is dependent upon the genetic makeup and overall health of the victim, as well as the number of infecting bacteria and their ability to invade the body and cause disease. A quick and strong cellular response by a person infected with M. leprae will result in no symptoms or in the mild form of the disease: tuberculoid leprosy. A
slow or weak cellular response by a person exposed to leprosy may result in the more severe form of the disease: lepromatous leprosy.

Only one in two hundred people exposed to leprosy will get some form of the disease. The earliest symptom is a slightly bleached, flat lesion several centimeters in diameter that is usually found on the upper body or on the arms or legs. About three-fourths of all patients with an early solitary lesion heal spontaneously; the rest progress to tuberculoid or lepromatous leprosy or to one of the many forms that fall between these two extremes.

Tuberculoid leprosy is characterized by flat skin lesions five to twenty centimeters in diameter. The lesions are lighter in color than the surrounding skin and are sometimes surrounded by nodules (lumps). The lesions contain only a few bacteria, and they, along with the surrounding tissue, are numb. These lesions are caused by a hypersensitive cellular immune response to the bacteria in the nerves and skin. In an attempt to destroy the bacteria, the immune system overreacts, and some of the surrounding nerve and skin tissue is damaged while the bacteria are being killed. This causes the areas of the skin to lose pigment as well as sensation. Often, tuberculoid leprosy patients can experience more extensive physical damage if the numbness around the lesions leads to accidental loss of digits, skin, and so forth. Leprosy victims may burn and cut themselves unknowingly, since they have no feeling in certain areas of their bodies.

In lepromatous leprosy, the bacteria grow unchecked because of the weak cellular immune response. Often, there are more than 100 million bacterial cells present per square centimeter of tissue. These bacteria cause the formation of tumorlike growths called lepromas as well as tissue destruction of the skin and mucous membranes. Also, the presence of so many bacteria causes large numbers of antibacterial antibodies to be produced, but these antibodies are of no benefit in fighting off the infection. Instead, they can contribute to the formation of lesions and tissue damage both internally and on the skin through a process called immune complex hypersensitivity. This is a process whereby the large number of antibodies bind to the large number of bacteria in the body and form immune complexes. These complexes can be deposited in various parts of the body and trigger a chemical reaction that destroys the surrounding tissue. The large number of bacteria puts pressure on the nerves and destroys nerve tissue, which causes loss of sensation and tissue death.

The initial symptoms of lepromatous leprosy are skin lesions that can be spread out or nodular and are found on the cooler parts of the body, such as the inside of the nose, the front part of the eye, the face, the earlobes, the hands, and the feet. Often, the victim loses all facial features because the nodules enlarge the face, and the eyebrows and nose deteriorate, giving the victim a characteristic lionlike appearance. Severe lepromatous leprosy erodes bones; thus, fingers and toes become needlelike, pits form in the skull, nasal bones are destroyed, and teeth fall out. Also, the limbs become twisted and the hands become clawed. The destruction of the nerves leads to the inability to move the hands or feet, deformity of the feet, and chronic ulceration of the limbs. In addition, as is the case with tuberculoid leprosy, destruction of the small peripheral nerves leads to self-inflicted trauma and secondary infection (infection by another bacterium or virus). As the disease progresses, the growth of bacteria in the respiratory tract
causes larynx problems and difficult breathing. Deterioration of the optic nerve leads to blindness. Bacteria can invade the bloodstream and spread infection throughout the whole body except the central nervous system. Death associated with leprosy usually results from respiratory obstruction, kidney failure, or secondary infection.

Treatment and Therapy

A physician can tell whether a person has leprosy by looking for characteristic symptoms (light-colored and numb lesions, nodules, and so forth) and by determining whether the patient may have been exposed to someone with leprosy. In addition, samples of scrapings from skin lesions, nasal secretions, fluid from nodules, or other tissue secretions can be examined for the presence of M. leprae. Samples are treated with a procedure called the acid-fast technique. Because of M. leprae’s waxy coating, these bacteria retain a pink stain after being washed in an acid-alcohol mixture, whereas all other bacteria lose the pink stain. Therefore, pink, rod-shaped bacteria observed in samples treated with the acid-fast technique indicate the presence of M. leprae. It is easy to find the acid-fast M. leprae in lepromatous leprosy patients because they have so many bacteria in their lesions, but the bacteria are more difficult to find in the lesions of tuberculoid leprosy patients.

The lepromin test was originally developed to be used as a diagnostic tool for leprosy, in the same way that the tuberculin test is used as a diagnostic tool for tuberculosis. Lepromin, which is heat-killed M. leprae taken from nodules, is injected under the skin in the lepromin test. Two reactions are possible: an early reaction that appears twenty-four to forty-eight hours later and a late reaction that appears three to four weeks later. In both reactions, a hard red lump at the injection site indicates a positive lepromin test. This test is not specific for leprosy, however, because a person who has been exposed to M. leprae, M. tuberculosis, or the tuberculosis vaccine,
Bacillus Calmette-Guérin (BCG), will show a positive early reaction. Even though this test is not useful as a diagnostic tool, it is useful in determining whether a patient has a strong or a weak cellular immune response to M. leprae. Tuberculoid leprosy patients show both the early and late reactions, while lepromatous leprosy patients show no reaction at all.

Leprosy can be treated with antibiotics. The antibiotic dapsone began to be used on a wide scale in the treatment of leprosy in 1950. Since that time, however, many dapsone-resistant strains of M. leprae have appeared. This means that, for some victims, this drug is no longer helpful in fighting the disease. In 1981, in response to the problem of dapsone-resistant strains, the World Health Organization (WHO) recommended a multidrug regimen for leprosy victims. For lepromatous leprosy patients, dapsone, rifampin, and clofazimine are recommended, whereas tuberculoid leprosy patients need take only dapsone and rifampin. For patients who are intolerant of one or more of the standard antibiotics or who suffer from infections unresponsive to these medications, doxycycline and moxifloxacin are additional antibiotics that have been found to be effective. Treatment is expected to continue until skin smears are free from acid-fast bacteria, which can last from two years up to the lifetime of the patient. Since 1989, the US recommendations for tuberculoid leprosy are six months of rifampin and dapsone daily, then dapsone alone for three years. For lepromatous leprosy, the recommendation is to use rifampin and dapsone daily for three years, then dapsone only for the rest of the person’s life.

Often, antibiotics are given to family members of leprosy patients to prevent them from contracting the disease. Antibiotic therapy can make a leprosy victim noncontagious, stop the progress of the disease, and in some cases cause a reversal of some of the symptoms. Until treatment is complete, however, it is recommended that patients sleep in separate bedrooms, use their own linens and utensils, and not live in a house with children. Thus, leprosy victims can lead nearly normal lives without fear of infecting others in the community.

The best ways to keep from getting leprosy are to avoid exposure to leprosy bacteria and to receive antibiotic therapy following exposure. It should be possible to control and, eventually, eliminate leprosy. If every case of leprosy were treated, the disease could not spread and the bacteria would die out with the last leprosy victim. Progress in this direction is slow, however, because of ignorance, superstition, poverty, and overpopulation in areas with many leprosy cases. The first strategy in controlling leprosy is to treat all leprosy cases with antibiotics. As of 1991, about 50 percent of all leprosy victims were not receiving drug therapy. Second, the early detection and rigid isolation of lepromatous leprosy patients are important, as is preventive antibiotic therapy for individuals in close contact with those patients. Finally, even in the early twenty-first century, too many countries lack adequate basic health resources, and too many patients disabled by leprosy are not receiving adequate care. The development of a vaccine for leprosy would aid control efforts.

A global effort for the production of a vaccine for leprosy is being made under the auspices of WHO. The first problem with vaccine development is that, until recently, it was not possible to grow M. leprae bacteria outside a leprosy victim; therefore, not much is known about the nature of the bacteria. Even though this bacterium was the first to be associated with a disease, it cannot be grown on an artificial laboratory medium, whereas nearly all other bacteria known can be grown artificially. It was not until 1960 that scientists at the Centers for Disease Control (CDC) discovered that the bacterium could be grown in the footpads of mice. Finally, in 1969, scientists at the National Hansen’s Disease Center in Carville, Louisiana, found that the bacteria would grow in the tissues of the nine-banded armadillo. Several potential vaccines for leprosy have been tested since that time. One vaccine being tested is BCG, a live bacterial vaccine of the bacteria Mycobacterium bovis, which is a close relative of M. leprae. In four major trials with BCG, a range of 20 to 80 percent protection from leprosy was obtained. It is not known why there was such a wide variation in results. Recent strategies for vaccine development include making a modified BCG that contains M. leprae cell wall antigens. It is more advantageous to use BCG than M. leprae in a vaccine because BCG is much easier to grow. In addition, scientists are trying to find a way to grow M. leprae artificially so that larger quantities will be available to be used for a vaccine. In 1999, WHO set up a strategic plan titled “The Final Push Toward Leprosy Elimination: 2000–2005” and the Global Alliance for the Elimination of Leprosy was launched.

Perspective and Prospects

Leprosy is one of the oldest known diseases. References to leprosy are contained in Indian writings that are more than three thousand years old. The Bible refers to leprosy and the isolation of lepers, although the term refers to other skin diseases as well. The examination of ancient skeletons has provided insights into how leprosy spread in past centuries. Early evidence suggests that the disease was highly contagious and that leprosy was widespread in Europe during the Middle Ages. Leprosy was so prevalent, in fact, that both governments and churches moved to deal with the problem. At that time, the cause of leprosy was unknown, and the disease was generally believed to be a punishment for some personal sin. Lepers were treated as outcasts and required to shout “unclean.” They were required to wear gloves and distinctive clothes and carry a bell or clapper to warn people of their approach. They were forbidden to drink from public fountains, speak loudly, eat with healthy people, or attend church. Some lepers were even pronounced legally dead, burned at the stake, or buried alive. Later, they were isolated in asylums called leprosaria, and at one time about nineteen thousand leprosaria existed—mostly in France.

There was a sharp decrease in the number of leprosy cases in the sixteenth century. Several factors may have contributed to this decline, including the isolation of lepers, a better diet, warmer clothes, the plague epidemic, and the increase in tuberculosis, which may have provided resistance to leprosy. Leprosy is no longer as deadly or contagious as it once was, yet the stigma attached to this disease has remained. In an effort to alleviate the social stigma, the Fifth International Congress on Leprosy in 1948 banned the use of the word leper and encouraged the use of the term Hansen’s disease instead of leprosy. M. leprae, the causative agent of leprosy, was first identified in the tissues of leprosy patients by the Norwegian physician Gerhard Armauer Hansen in 1873—hence the alternate name, Hansen’s disease. Today, victims of leprosy are referred to as Hansenites or Hansenotic.

From the 1960s to the 1980s, estimates of the number of cases of leprosy worldwide ranged from 10 to 12 million. In 2001, at the Fifty-fourth World Health Assembly, it was announced that the global prevalence of leprosy had fallen to below one case per ten thousand by the end of 2000 and health experts believed that eliminating leprosy in all countries was an attainable goal by the year 2005. More than 600,000 new cases of leprosy were reported globally in 2002. A new combination of drugs known as multidrug therapy has been used to treat and completely cure patients. The drugs are donated free through foundations, and since these donations began in 2000, millions of the “blister packs,” each of which provides one month’s treatment to one patient, have been shipped. By 2008, some countries had achieved elimination, but leprosy remained endemic in others. And, although the disease has not been completely eliminated, its incidence has decreased dramatically. The World Health Organization reports that, worldwide, about 219,000 new cases of leprosy were reported in 2011 and that about 182,000 people had the disease in early 2012.

Leprosy is prevalent in tropical areas such as Africa, Southeast Asia, and South America. In the United States, most cases occur in Hawaii and small parts of Texas, California, Louisiana, and Florida. The number of new cases in the United States annually—mostly from foreign-born immigrants from leprosy-prone areas—has been very low in the last several decades.

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