healthy life always

2010-06-28T12:36:00.000-07:00

Yunis Varon syndrome

2009-07-05T12:46:00.000-07:00

Yunis Varon syndrome
Classification and external resources
ICD-10	Q 87.8
OMIM	216340
DiseasesDB	33830

Yunis-Varon syndrome (YVS)^[1] is an extremely rare^[2] autosomal recessive^[3] multisystem congenital disorder^[4] which affects the skeletal system, ectodermal tissue and cardiorespiratory systems.

Presentation

Symptoms include growth retardation before and after birth, defective growth of the bones of the skull along with complete or partial absence of the shoulder blades and characteristic facial features.^[2]^[5] Additional symptoms may include abnormalities of the fingers and/or toes.^[5]^[6] In most cases, infants with this disorder experience severe feeding problems and respiratory difficulties. In addition, affected infants may have heart defects.

Genetic prevalence

Yunis-Varon syndrome has an autosomal recessive pattern of inheritance.

This syndrome is inherited as an autosomal recessive genetic trait.^[5]^[7] The disease has been described relatively recently in the 1980s and since then less than 15 cases have been reported around the world. Many of the infants did not survive beyond one year of age.^[6]^[7]

Young Simpson syndrome

2009-07-05T12:42:00.003-07:00

Young Simpson syndrome (YSS), is a rare congenital disorder with symptoms including hypothyroidism, heart defects, facial dysmorphism, cryptorchidism in males, hypotonia, mental retardation and postnatal growth retardation.^[1]^[2]

Other symptoms include transient hypothyroidism, macular degeneration and torticollis.^[3] The condition was discovered in 1987 and the name arose from the individuals who first reported the syndrome.^[4]^[5] A individual with YSS has been identified with having symptoms to a similar syndrome known as Ohdo Blepharophimosis syndrome showing that it is quite difficult to diagnose the correct condition based on the symptoms present.^[6] Some doctors therefore consider the syndrome to be the same. ^[7]

The mode of inheritance has had mixed findings based on studies undertaken.^[5]^[8] One study showed that the parents of an individual with YSS are unrelated and phenotypically normal, indicating a sporadic mutation, thus making it difficult to base the cause of the condition on genetic make up alone.^[5] Another study however with an individual of YSS had first cousins as parents, giving the possibility of autosomal recessive inheritance.

Endodermal sinus tumor

2009-07-05T12:42:00.002-07:00

Endodermal sinus tumor (EST), also known as yolk sac tumor (YST), is a member of the germ cell tumor group of cancers. It is the most common testicular tumor in children under 3, and is also known as infantile embryonal carcinoma. This age group has a very good prognosis. In contrast to the pure form typical of infants, adult endodermal sinus tumors are often found in combination with other kinds of germ cell tumor, particularly teratoma and embryonal carcinoma. While pure teratoma is usually benign, endodermal sinus tumor is

Diagnosis

The histology of EST is variable, but usually includes malignant endodermal cells. These cells secrete alpha-fetoprotein (AFP), which can be detected in tumor tissue, serum, cerebrospinal fluid, urine and, in the rare case of fetal EST, in amniotic fluid. When there is incongruence between biopsy and AFP test results for EST, the result indicating presence of EST dictates treatment.^[1] This is because EST often occurs as small "malignant foci" within a larger tumor, usually teratoma, and biopsy is a sampling method; biopsy of the tumor may reveal only teratoma, whereas elevated AFP reveals that EST is also present. GATA-4, a transcription factor, also may be useful in the diagnosis of EST.^[2] Schiller-Duval bodies on histology are pathognomonic.

Diagnosis of EST in pregnant women and in infants is complicated by the normal extremely high levels of AFP in those two groups. Tumor surveillance by monitoring AFP requires accurate correction for gestational age in pregnant women, and age in infants.^{[citation needed]} In pregnant women, this can be achieved simply by testing maternal serum AFP rather than tumor marker AFP. In infants, the tumor marker test is used, but must be interpreted using a reference table or graph of normal AFP in infants.

Treatment

Most treatments involve some combination of surgery and chemotherapy.

Before modern chemotherapy, this type of neoplasm was highly lethal, but the prognosis has significantly improved since.

When treated promptly with surgery and chemotherapy, death from endodermal sinus tumors is exceedingly rare ^[3].

Yersinia pestis

2009-07-05T12:42:00.001-07:00

Yersinia pestis

A scanning electron micrograph depicting a mass of Yersinia pestis bacteria

Scientific classification

Kingdom:	Eubacteria
Phylum:	Proteobacteria
Class:	Gammaproteobacteria
Order:	Enterobacteriales
Family:	Enterobacteriaceae
Genus:	Yersinia
Species:	Y. pestis

Binomial name

Yersinia pestis
(Lehmann & Neumann, 1896)
van Loghem 1944

Yersinia pestis (formerly Pasteurella pestis) is a Gram-negative rod-shaped bacterium belonging to the family Enterobacteriaceae. It is a facultative anaerobe that can infect humans and other animals.

Human Y. pestis infection takes three main forms: pneumonic, septicemic, and the notorious bubonic plagues.^[1] All three forms have been responsible for high mortality rates in epidemics throughout human history, including the Black Death (a bubonic plague) that accounted for the death of at least one-third of the European population in 1347 to 1353.

Recently Y. pestis has gained attention as a possible biological warfare agent and the CDC has classified it as category A pathogen requiring preparation for a possible terrorist attack.

History

Y. pestis was discovered in 1894 by Alexandre Yersin, a Swiss/French physician and bacteriologist from the Pasteur Institute, during an epidemic of plague in Hong Kong.^[2] Yersin was a member of the Pasteur school of thought. Shibasaburo Kitasato, a German-trained Japanese bacteriologist who practiced Koch's methodology was also engaged at the time in finding the causative agent of plague.^[3] However, it was Yersin who actually linked plague with Yersinia pestis. Originally named Pasteurella pestis, the organism was renamed in 1967.

Originally three biovars of Y. pestis were thought to correspond to one of the historical pandemics of bubonic plague.^[4] Biovar Antiqua is thought to correspond to the Plague of Justinian; it is not known whether this biovar also corresponds to earlier, smaller epidemics of bubonic plague, or whether these were even truly bubonic plague.^[5] Biovar Medievalis is thought to correspond to the Black Death. Biovar Orientalis is thought to correspond to the Third Pandemic and the majority of modern outbreaks of plague. Y. pestis was transmitted by fleas infesting rats. However, recent MLST data has shown that in fact Yersinia pestis is clonal, so this somewhat overthrows the 'biovar' hypothesis.

Every year thousands of cases of plague are still reported to the World Health Organization, although with proper treatment the prognosis for victims is now much better. A five to sixfold increase in cases occurred in Asia during the time of the Vietnam war, possibly due to the disruption of ecosystems and closer proximity between people and animals. Plague also has a detrimental effect on mammals other than humans. In the United States of America, endangered animals such as the black-tailed prairie dog and the black footed ferret are both under threat from the disease

Role in Black Death

DNA from Y. pestis has been found in the teeth of an individual who supposedly died from the Black Death, and medieval corpses who died from other causes have tested positive for Y. pestis.^[6]^[7] This suggests that Y. pestis was, at the very least, a contributing factor in some (though possibly not all) of the European plagues. It is possible that the selective pressures induced by the plague might have changed how the pathogen makes itself manifest in humans, selecting against the individuals or populations which were the most susceptible.

General characteristics

Y. pestis is a rod-shaped facultative anaerobe with bipolar staining (giving it a safety pin appearance).^[8] Similar to other Yersinia members, it tests negative for urease, lactose fermentation, and indole.^[9] The closest relative is the gastrointestinal pathogen Yersinia pseudotuberculosis, and more distantly Yersinia enterocolitica.

Genome

The complete genomic sequence is available for two of the three sub-species of Y. pestis: strain KIM (of biovar Medievalis),^[10] and strain CO92 (of biovar Orientalis, obtained from a clinical isolate in the United States)^[11]. As of 2006, the genomic sequence of a strain of biovar Antiqua has been recently completed.^[12] Similar to the other pathogenic strains, there are signs of loss of function. The chromosome of strain KIM is 4,600,755 base pairs long; the chromosome of strain CO92 is 4,653,728 base pairs long. Like its cousins Y. pseudotuberculosis and Y. enterocolitica, Y. pestis is host to the plasmid pCD1. In addition, it also hosts two other plasmids, pPCP1 (also called pPla or pPst) and pMT1 (also called pFra) which are not carried by the other Yersinia species. pFra codes for a phospholipase D that is important for the ability of Y. pestis to be transmitted by fleas^[13]. pPla codes for a protease, Pla, that activates plasminogen in human hosts and is a very important virulence factor for pneumonic plague^[14]. Together, these plasmids, and a pathogenicity island called HPI, encode several proteins which cause the pathogenesis for which Y. pestis is famous. Among other things, these virulence factors are required for bacterial adhesion and injection of proteins into the host cell, invasion of bacteria into the host cell, and acquisition and binding of iron harvested from red blood cells. Y. pestis is thought to be descendant from Y. pseudotuberculosis, differing only in the presence of specific virulence plasmids.

A comprehensive and comparative proteomics analysis of Y. pestis: strain KIM was performed in 2006;^[15] this analysis focused on the transition to a growth condition mimicking growth in

Pathogenics and immunity

In the urban and sylvatic cycles of Y. pestis most of the spreading occurs between rodents and fleas. In the sylvatic cycle the rodent is wild, unlike in the urban cycle, where the rodent is domestic. Additionally Y. pestis can spread from the urban environment and back again. Every infected animal can transmit the infection to humans through contact with skin tissue. Humans can also spread the bacteria to other humans through sneezing, coughing or direct contact with infected tissue.

In reservoir hosts

The reservoir commonly associated with Y. pestis are several species of rodents. In the steppes, the reservoir species is principally believed to be the marmot. In the United States, several species of rodents are thought to maintain Y. pestis. However, the case is not very clear because the expected disease dynamics have not been found in any rodent species. It is known that some individuals in a rodent population will have a different resistance, which could lead to a carrier status.^[16] There is some evidence that fleas from other mammals have a role in human plague outbreaks.^[17]

This lack of knowledge of the dynamics of plague in mammal species is also true among susceptible rodents such as the black-tailed prairie dog (Cynomys ludovicianus), in which plague can cause colony collapse resulting in a massive effect on prairie food webs.^[18] However, the transmission dynamics within prairie dogs does not follow the dynamics of blocked fleas; carcasses, unblocked fleas, or another vector could possibly be important instead.^[19]

In other regions of the world the reservoir of the infection is not clearly identified, which complicates prevention and early warning programs. One such example was seen in a 2003 outbreak in Algeria.^[20]

In vector

The transmission of Y. pestis by fleas is well characterized^[21]. Initial acquisition of Y. pestis by the vector occurs during feeding on an infected animal. Several proteins then contribute to the maintenance of the bacteria in the flea digestive tract, among them the hemin storage (Hms) system and Yersinia murine toxin (Ymt).

Although Ymt is highly toxic to rodents and was once thought to be produced to insure reinfection of new hosts, it has been demonstrated that murine toxin is important for the survival of Y. pestis in fleas.^[13]

The Hms system plays an important role in the transmission of Y. pestis back to a mammalian host^[22]. The proteins encoded by Hms genetic loci aggregate in the esophagus and proventriculus of the flea, which is a structure that ruptures blood cells. Aggregation of Hms proteins inhibits feeding and causes the flea to feel hungry. Transmission of Y. pestis occurs during the futile attempts of the flea to feed. Ingested blood is pumped into the esophagus, where it dislodges bacteria growing there and is regurgitated back into the host circulatory

In humans and other susceptible hosts

Pathogenesis due to Y. pestis infection of mammalian hosts is due to several factors including an ability of these bacteria to suppress and avoid normal immune system responses such as phagocytosis and antibody production. Flea bites allow for the bacteria to enter through the skin. Y. pestis expresses the yadBC gene, which is similar to adhesins in other Yersinia species, allowing for adherence and invasion of epithelial cells.^[23] Y. pestis expresses a plasminogen activator that is an important virulence factor for pneumonic plague and which might act on blood clots in order to facilitate systematic invasion. ^[14] Many of the bacteria's virulence factors are anti-phagocytic in nature. Two important anti-phagocytic antigens, named F1 (Fraction 1) and V or LcrV, are both important for virulence.^[8] These antigens are produced by the bacterium at normal human body temperature. Furthermore, Y. pestis survives and produces F1 and V antigens while it is residing within blood cells such as monocytes, but not in neutrophils. Natural or induced immunity is achieved by the production of specific opsonic antibodies against F1 and V antigens; antibodies against F1 and V induce phagocytosis by neutrophils.^[24]

Additionally, the Type III secretion system allows Y. pestis to inject proteins into macrophages and other immune cells. These T3SS-injected proteins are called YOPs (Yersinia Outer Proteins) and include Yop B/D which form pores in the host cell membrane and have been linked to cytolysis. YopO, YopH, YopM, YopT, YopJ and YopE are injected into the cytoplasm of host cells via T3SS into a pore created in part by YopB and YopD. ^[25] These injected Yop proteins limit phagocytosis and cell signaling pathways important in the innate immune system, as discussed below.

Yersinia pestis proliferates inside lymph nodes where it is able to avoid destruction by cells of the immune system such as macrophages. The ability of Yersinia pestis to inhibit phagocytosis allows it to grow in lymph nodes and cause lymphadenopathy. YopH is a protein tyrosine phosphatase that contributes to the ability of Yersinia pestis to evade immune system cells^[26]. In macrophages, YopH has been shown to dephosphorylate p130Cas, Fyb (Fyn binding protein) SKAP-HOM and Pyk, a tyrosine kinase homologous to FAK. YopH also binds the p85 subunit of phosphoinositide 3-kinase, the Gab1 and Gab2 adapter proteins, and the Vav guanine nucleotide exchange factor.

YopE functions as a GTPase activating protein for members of the Rho family of GTPases such as RAC1. YopT is a cysteine protease that inhibits RhoA by removing the isoprenyl group which is important for localizing the protein to the cell membrane. It has been proposed that YopE and YopT may function to limit YopB/D-induced cytolysis^[27]. This might limit the function of YopB/D to creating the pores used for Yop insertion into host cells and prevent YopB/D-induced rupture of host cells and release of cell contents that would attract and stimulate immune system responses.

YopJ is an acetyltransferase that binds to a conserved α-helix of MAPK kinases^[28]. YopJ acetylates MAPK kinases at serines and threonines that are normally phosphorylated during activation of the MAP kinase cascade^[29]. This disruption of host cell protein kinase activity causes apoptosis of macrophages and it has been proposed that this is important for the establishment of infection and for evasion of the host immune response. YopO is a protein kinase also known as Yersinia protein kinase A (YpkA). YopO is a potent inducer of human macrophage

Immunity

A formalin-inactivated vaccine once was available for adults at high risk of contracting the plague until removal from the market by the U.S. Food and Drug Administration. It was of limited effectiveness and may cause severe inflammation. Experiments with genetic engineering of a vaccine based on F1 and V antigens are underway and show promise; however, bacteria lacking antigen F1 are still virulent, and the V antigens are sufficiently variable, that vaccines composed of these antigens may not be fully protective^[31]. United States Army Medical Research Institute of Infectious Diseases (USAMRIID) have found that an experimental F1/V antigen based vaccine protect cynomolgus macaques, but fails to protect African green monkeys^[32]. A report found that Europeans were less likely to catch the plague, because they are the descendants of the survivors of the plagues that affected Europe in the medieval times.^[33]

Clinical aspects

Symptoms and disease progression

Bubonic plague
- Incubation period of 2–6 days, when the bacteria is actively replicating.
- Universally a general lack of energy
- Fever
- Headache and chills occur suddenly at the end of the incubation period. From this point the infection is resolved or lethal.
- Swelling of lymph nodes resulting in buboes, the classic sign of bubonic plague

Septicemic plague
- Hypotension
- Hepatosplenomegaly
- Delirium
- Seizures in children
- Shock
- Universally a general lack of energy
- Fever
- Symptoms of Bubonic or Pneumonic Plague, not always present

Pneumonic plague
- Fever
- Chills
- Cough
- Chest pain
- Dyspnea
- Hemoptysis
- Lethargy
- Hypotension
- Shock
- Symptoms of bubonic or septicemic plague, not always present ^[34]

If this occurs with the classic buboes, this is considered primary, while secondary occurs after symptoms of bubonic or pneumonic infection. Since the bacteria are blood-bourne, several organs can be affected including the spleen and brain. The diffuse infection can cause an immunologic cascade to occur, leading to DIC, which in turn results in bleeding and necrotic skin and tissue. Such a disseminated infection increases mortality to 22%.

Pneumonic plague can be spread from one human to another directly by aerosol. Rarely bubonic and even more rarely septicemic plague can gain pneumonic characteristics. As with the other forms of plague, after the incubation period there is a sudden onset of coughing, high temperature, and lack of energy. From this point the infection increases in severity. Due to its high replication rates, plague proves fatal in roughly 50% of cases even with medical treatment, and is almost universally fatal without treatment.^[35]

With the exception of the buboes, the initial symptoms of plague are very similar to many other disease, making diagnosis difficult^[36].

ICD-9 codes for the diseases caused by Y. pestis:

020.0 Bubonic plague
020.2 Septicemic plague
020.5 Unspecified pneumonic plague
020.3 Primary pneumonic plague
020.4 Secondary pneumonic plague

Clinical determination

Grams stains can confirm the presence of gram negative rods, and in some cases the identification of the double curved shape. More definitive test is a Anti-F1 serology test, which can differentiate between different species of Yersinia. coba

Treatment

The traditional first line treatment for Y. pestis has been streptomycin,^[37]^[38] chloramphenicol, tetracycline,^[39] and fluoroquinolones. There is also good evidence to support the use of doxycycline or gentamicin.^[40] Resistant strains have been isolated; treatment should be guided by antibiotic sensitivities where available. Antibiotic treatment alone is insufficient for some patients, who may also require circulatory, ventilator, or renal support.

In an emergency department setting, Harrison's Principles of Internal Medicine outlines the following treatment course^[41]. Antibiotics within the first 24 hours is very beneficial, with intravenous being preferred in pulmonary or advanced cases. Streptomycin or gentamicin are the first-line drugs, with chloramphenicol for critically ill patients, or rarely for suspected neuro-involvement.

Yersiniosis

2009-07-05T12:42:00.000-07:00

Yersiniosis is an infectious disease caused by a bacterium of the genus Yersinia. In the United States, most human illness is caused by Y. enterocolitica. Infection with Y. enterocolitica occurs most often in young children.

Yersiniosis is mentioned as a specific zoonotic disease to prevent outbreaks in European Council Directive 92/117/EEC.^[1]

It has been associated with chitterlings.^[2]

Symptoms

Infection with Y. enterocolitica can cause a variety of symptoms depending on the age of the person infected. Common symptoms in children are fever, abdominal pain, and diarrhea, which is often bloody. Symptoms typically develop 4 to 7 days after exposure and may last 1 to 3 weeks or longer. In older children and adults, right-sided abdominal pain and fever may be the predominant symptoms, and may be confused with appendicitis. In a small proportion of cases, complications such as skin rash, joint pains, or the spread of bacteria to the bloodstream (bacteremia) can occur.

Yellow nail syndrome

2009-07-05T12:39:00.000-07:00

Yellow nail syndrome (also known as "Primary lymphedema associated with yellow nails and pleural effusion"^[1]^:849) is a very rare medical syndrome that includes pleural effusions, lymphoedema and yellow dystrophic nails. Approximately 40% will also have bronchiectasis. It is also associated with chronic sinusitis and persistent coughing. It usually affects adults.^[2]^[3]^:665

Normal treatment for swelling and any respiratory problems is appropriate. Nutritional supplementation with Vitamin E in some studies has been shown to be effective in controlling nail changes.^[2]

Restated, yellow nail syndrome is characterized by marked thickening and yellow to yellow-green discoloration of the nails often associated with systemic disease, most commonly lymphedema and compromised respiration.[

Y chromosome microdeletion

2009-07-05T12:34:00.000-07:00

Y chromosome microdeletion (YCM) is a family of genetic disorders caused by missing gene(s) in the Y chromosome. Many men with YCM exhibit no symptoms and lead normal lives. However, YCM is also known to be present in a significant number of men with reduced fertility. Men with reduced sperm production (in up to 20% of men with reduced sperm count, some form of YCM has been detected^[1]) varies from oligozoospermia, significant lack of sperm, or azoospermia, complete lack of sperm.

Various genes shown to have some correlation with spermatogenesis in men with reduced fertility include^[2] RBM, DAZ, SPGY, and TSPY.

Content

Cause

The mechanism of mutation is not different for Y-chromosome microdeletion. However, the ability to repair it differs from other chromosomes. The human Y chromosome is passed directly from father to son, and is not protected against accumulating copying errors, whereas other chromosomes are error corrected by recombining genetic information from mother and father. This may leave natural selection as the primary repair mechanism for the Y chromosome.

Diagnosis

Y chromosome microdeletion is currently diagnosed by extracting DNA from leukocytes in a man's blood sample, mixing it with some of the about 300 known genetic markers for sequence-tagged sites (STS) on the Y chromosome, and then using polymerase chain reaction amplification and gel electrophoresis in order to test whether the DNA sequence corresponding to the selected markers is present in the DNA.

Such procedures can test only the integrity of a tiny part of the overall 23 million base pair long Y chromosome, therefore the sensitivity of such tests depends on the choice and number of markers used. Present diagnostic techniques can only discover certain types of deletions and mutations on a chromosome and give therefore no complete picture of genetic causes of infertility. They can only demonstrate the presence of some defects, but not the absence of any possible genetic defect on the chromosome.

The gold standard test for genetic mutation, namely complete DNA sequencing of a patient's Y chromosome, is still far too expensive for use in epidemiologic research or even clinical diagnostics.

Infertility

Microdeletions in the Y chromosome have been found at a much higher rate in infertile men than in fertile controls and the correlation found may still go up as improved genetic testing techniques for the Y chromosome are developed.

Ataxia-telangiectasia

2009-06-24T06:28:00.000-07:00

Ataxia-telangiectasia (A-T) (Boder-Sedgwick syndrome^[1] or Louis-Bar syndrome^[2]^:555) is a rare, neurodegenerative, inherited disease that affects many parts of the body and causes severe disability. Ataxia refers to poor coordination and telangiectasia to small dilated blood vessels, both of which are hallmarks of the disease.

A-T affects the cerebellum (the body's motor coordination control center) and also weakens the immune system in about 70% of the cases, leading to respiratory disorders and increased risk of cancer. It first appears in early childhood (the toddler stage) with symptoms such as lack of balance, slurred speech, and increased infections. Because all children at this age take time to develop good walking skills, coherent speech, and an effective immune system, it may be some years before A-T is properly diagnosed.

Classification

So far there appear to be three forms of A-T:

Pure A-T where patients present with all/most of the diagnostic symptoms.
Attenuated A-T where sufferers do not possess all of the diagnostic symptoms.
Carrier A-T where individuals with a single ATM mutation show an increased risk of cancer

These are sometimes classified into ‘types’ from I to IV.

Type I is the classic syndrome with all manifestations.
Type II lacks some of the typical findings but shows radiosensitivity.
Type III has the classic clinical findings but is not radiosensitive.
Type IV shows only some clinical features and is not radiosensitive.

Differential diagnosis

There are several other disorders with similar symptoms that physicians may consider when diagnosing A-T. These include:

Ataxia-telangiectasia like disorder (ATLD) is an extremely rare condition which could be considered in the differential diagnosis of A-T. ATLD patients are very similar to A-T patients in showing a progressive cerebellar ataxia, hypersensitivity to ionising radiation and genomic instability. However, ATLD can be distinguished from A-T by the absence of telangiectasias, normal immunoglobulin levels, a later onset of the condition and a slower progression of the disease. It is not known whether ATLD individuals are also predisposed to tumours. The gene mutated in ATLD is hMre11 and is located on chromosome 11q21.

Interestingly, the proteins expressed by the hMre11 (defective in ATLD) and Nbs1 (defective in NBS) genes exist in the cell as a complex, along with a third protein expressed by the hRad50 gene. This complex, known as the MRN complex, plays an important role in DNA damage repair and signaling and is required to recruit ATM to the sites of DNA double strand breaks. Mre11 and Nbs1 are also targets for phosphorylation by the ATM kinase. Thus, the similarity of the three diseases can be explained in part by the fact that the protein products of the three genes

Signs and Symptoms

A-T is characterised by:

Early-onset progressive cerebellar ataxia (difficulty with control of movement)
Telangiectasias of the eyes and skin
Immunodeficiency mostly thorough lowering of IgA, IgG and IgE levels.
Chromosomal instability
Hyper-sensitivity to ionising radiation
Increased incidence of malignancies (primarily hematologic).
Raised alpha-fetoprotein levels.^[3]

Initially it may be hard to be sure that anything is amiss and some children seem to improve from 3 to 5 years, but eventually it becomes obvious that balance control is abnormal. Towards the end of the first decade and the start of the second other problems come to light; these can be as handicapping as the loss of body balance control. Because A-T can have somewhat incomplete penetrance, some patients have a mild form of the disease that starts later and has less severe symptoms. An A-T diagnosis is one of exclusion. Because of the disease's rarity, many doctors aren't familiar with the symptoms, diagnosis methods, or treatment. It may take some time before doctors rule out other possible conditions, such as cancer (a high AFP level can lead doctors in the wrong direction), or Cerebral Palsy.

Ataxia

The first indications of A-T usually occur during the toddler years. These first signs indicate difficulty with control of the body posture and body movement (truncal ataxia). The child may start to walk later than usual (after 18 months), may be reluctant to let go of supporting people or objects, may continue to walk unsteadily for longer than normal, may be unable to stand still without tottering, and may fall frequently.

Walking becomes more strenuous and appears awkward, doors and walls are frequently used for support. Running may, for a time, seem less affected; this is because less balance is needed for quick movements than slower graceful ones. At the beginning of the second decade of their lives most people with A-T begin to use a wheelchair.

Co-ordination of limbs becomes abnormal (peripheral ataxia) later in the disease. Involuntary movements may start in some patients, and generally become worse over time. They may include small jerks of the hands and feet which look like fidgeting (chorea), slower twisting movements of the upper body (athetosis), adoption of stiff and twisted postures (dystonia), occasional uncontrolled jerks (myoclonic jerks), and shaking episodes of a limb which are like shivering (tremors).

Slurring of speech (dysarthria) may develop in the first decade, becoming worse for 5 to 10 years and then remaining a static problem. Patients generally can be understood, although conversation may be a slow process. Eye movements become restricted (vertical and horizontal sacchadic apraxia). Reading and following moving objects becomes difficult.

Telangiectasia

Prominent blood vessels in the whites of the eyes (telangiesctasias) usually occur by the age of 5 years. These are the ocular telangiectasia of the condition and resemble those vessels seen in the eyes of much older people. They can occasionally be present at birth yet in others may not develop until the teenage years. Although potentially a cosmetic problem they do not bleed or itch. It is their constant nature, not changing with time, weather or emotion, which marks them as different from other eye blood vessels.

Immune problems

About half the people with A-T have immune problems. These usually take the form of repeated colds and runny noses (sinopulmonary infections). The immune system is complex and difficult to assess, but if the child is suffering more than his/her fair share of infections a physician should undertake this assessment. Some people with A-T need additional immunizations (DPT, Hib and Pneumovax), others need continued antibiotics to provide "background cover" and some need injections of immunoglobulins (proteins that the body makes to fight infections). Others are never troubled. The impression is that bacterial, rather than viral, infections are the most trouble. Infections can be giving children IVIg on a regular basis. The doses should be determined by a medical doctor however.

Other features

People with A-T have an increased incidence (probably 1% risk per year) of tumors, particularly lymphomas and leukemia. It has been reported that there is a small increased risk of breast cancer in mothers of children with A-T. This finding is the subject of much debate and research at present. Mammography before 50 years however is not recommended unless there is a strong family history of breast cancer.

Although people with A-T have an increased sensitivity to ionizing radiation (X-rays and gamma rays), they cope with other forms of radiation normally, i.e. obtaining a suntan from ultraviolet light. Also, the tumors seen in A-T are not thought to be radiation induced. X-ray exposure should be limited only to cases where it is absolutely medically necessary, as exposing an A-T patient to ionizing radiation can mutate cells in such a way that the body can't repair them.

Mental retardation is not seen in A-T. However, many children seem to have slower thinking speed. Some children are placed in special schools while others remain in mainstream schools, even graduating from university.

A-T patients are often very thin. This may be due to a poor appetite, to the energy expended with involuntary movements, or the inherent characteristics of the disorder. Some people with A-T, both males and females, have a delayed puberty. This seems more common in those who are thin or are prone to infections.

Thymic hypoplasia may be present.^[4]

Genetics

A-T is inherited in an autosomal recessive fashion.

A-T usually runs in families. The mode of inheritance is autosomal recessive, so in a family with two parents who are carriers of the A-T allele, there is 1 chance in 4 that each child born to the parents will have the disorder. Prenatal diagnosis can be carried out in most families, but this is complex and must be arranged before conception.

A-T is caused by mutations in the ATM gene located on chromosome 11q22-23. ^[5] It was characterised in June 1995 and is made up of 66 exons spread across 150kb of genomic DNA. It encodes a 13kb mature transcript with an open reading frame of 9168 nucleotides. The ATM protein is about 370kDa and is ubiquitously expressed and is localised to the cell nucleus. The ATM protein is a large serine-threonine kinase thought to play a role in regulating cell cycle checkpoints, repair of double stranded DNA and meiosis (similar to the BRCA genes). ATM is also known to play a role in regulating p53, BRCA1 and CHEK2. Part of ATM’s role in DNA repair is known to be that of telomere repair as telomeres degrade more rapidly in people affected with A-T.

Mutations in the ATM gene are thought to come in two types:

Null mutations are those which cause complete loss of function of the protein and are therefore inherited in a recessive manner and cause A-T.
Missense mutations which produce stable, full sized protein with reduced function e.g. substitutions, short in-frame insertions and deletions etc. These mutations act by dominantly interfering with the normal copy of the protein.

The majority of A-T sufferers, 65-70%, have truncating mutations, with exon skipping mutations being particularly common. This results in very low or undetectable levels of ATM protein. Missense mutations are the most common type of mutation found in carriers with breast cancer. Individuals with two missense mutations are believed to have a milder form of AT, which may account for cases of attenuated A-T. Therefore it is thought that "subtle constitutional alterations of ATM may impart an increased risk of developing breast cancer and therefore act as a low penetrance, high prevalence gene in the general population" (Maillet et al. 2002).

Oculo-cutaneous telangiectasia combined with ataxia are the defining features of the condition. However, some patients with A-T, even those with two null mutations who produce no ATM protein at all, may never present with oculo-cutaneous telangiectasia.

[edit] ATM Carriers

Carriers of ATM missense mutations are believed to have a 60% penetrance by age 70 and a risk of breast cancer 16 times higher that of the normal population, with a 5-8 fold increased risk of cancer. On average carriers die 7–8 years earlier than the normal population, often from heart disease. Some papers state a lifetime risk for people with both null and missense mutations of 10-38%, which is still a hundredfold increase from population risk.

Individuals with a single ATM mutation are also at a higher risk from lung, gastric and lymphoid tumours, as well as breast cancer. S707P is known to be particularly common in breast cancer patients and F1463S is known to be associated with Hodgkin’s lymphoma. If pulmonary infections could be completely eradicated A-T is consistent with survival into the 5th or 6th decade.

Diagnosis

Diagnosis is usually achieved clinically by examination and identification of both ataxia and oculo-telangiectasia or skin telangiectasia. This is then followed by laboratory tests for serum AFP level, the response of white blood cells to X-rays and measurement of the level of ATM protein. Sufferers may also have a low lymphocyte count and other immunological abnormalities. This can then be followed by cytogenetic and molecular testing to confirm the diagnosis. MRI and CT scans may show signs of cerebellar atrophy. (MRI is the preferred method, as patients should limit exposure to any radiological diagnostic tests that use ionizing radiation)

Molecular diagnosis of A-T can be carried out by sequencing all 66 exon of the gene or by linkage if there is a significant family history. Protein functionality testing is also available. However A-T testing is usually carried out cytogenetically as specific breakpoints and cytogenetic instability are major characteristic features of the disorder. This must be carried out on lymphocytes. 10% of patients with A-T show balanced translocations, 2/3rds of which involve the immunoglobulin genes on chromosomes 7 and 14. Some patients show expansions in their immunoglobulin genes which can expand during mitosis resulting in prolymphocyte leukaemia.

Antenatal diagnosis can be carried out using linkage and microsatellite markers. However, direct gene analysis between known sufferers and the foetus is more common.

Pathophysiology

The responsible gene in AT, ataxia-telangiectasia mutated (ATM), was discovered in 1995 by Savitsky et al. ^[6] a team led by Yosef Shiloh of Tel Aviv University in Israel. Researchers linked the hyper-sensitivity of A-T patients to ionizing radiation (IR) and predisposition to cancer, to "chromosomal instability, abnormalities in genetic recombination, and defective signaling to programmed cell death and several cell cycle checkpoints activated by DNA damage".^[7] Earlier observations predicted that the gene altered in A-T played a role in DNA damage recognition. These predictions were confirmed when a single gene on chromosome 11 (11q 22-23) was discovered.^[6]^[8] Since its discovery, the protein product of the ATM gene has been shown to be a part of eukaryotic cell cycle control, DNA repair, and DNA recombination (Lavin, 2004). Specifically, the A-T gene serves as a tumor suppressor gene by contributing to a network of genes that link double stranded breaks in DNA to cell cycle arrest and apoptosis (programmed cell death). Patients with ATM have a defective A-T gene, which leaves them susceptible to contracting cancer. For example, female ATM patients have a two-fold higher chance of ever having breast cancer, which often occur before the age of 50. ATM patients must try avoiding x-rays at all costs since the radiation induces double-stranded breaks.

Management

Treatment is symptomatic and supportive. Physical and occupational therapy may help maintain flexibility. Speech therapy may also be needed. Gamma-globulin injections may be given to help supplement a weakened immune system. High-dose vitamin regimens may also be used. Antibiotics are used to treat infections. Some physicians recommend low doses of chemotherapy to reduce the risk of cancer but this is controversial. It is also recommended that heterozygote family members are regularly monitored for cancers. Recently deferoxamine was shown to increase the stability of A-T cells and may prove to be an effective treatment for the disorder.

People with A-T have an increased incidence (probably 1% risk per year) of tumours, particularly lymphomas and leukaemia, but due to sufferers' hyper-sensitivity to ionising radiation, radiotherapy and chemotherapy are rarely used.^[9]

Prognosis

Those with A-T usually die in their teens or early 20s although some individuals have been known to live to over 40. Mortality is mainly due to the compromised immune system which results in recurrent respiratory infections, predisposition to cancer, and the high rate of pulmonary problems which are associated with the disease.

Epidemiology

The incidence of A-T in Caucasians is about 3 per million so the disorder is very rare, with probably fewer than 200 affected people in the UK.

Society and Culture

All families in the United Kingdom with a child who has A-T have access to a specialist clinic in Nottingham where a multi-disciplinary team (involving a neurologist, a geneticist and therapists) has seen many families with A-T.^[10]

Asperger syndrome

2009-06-24T06:26:00.000-07:00

Asperger syndrome is an autism spectrum disorder (ASD), and people with it therefore show significant difficulties in social interaction, along with stereotypies and other restricted and repetitive patterns of behavior and interests. It differs from other ASDs by its relative preservation of linguistic and cognitive development. Although not required for diagnosis, physical clumsiness and atypical use of language are frequently reported.^[1]^[2]

Asperger syndrome (AS) is also called Asperger's syndrome, Asperger (or Asperger's) disorder, or just Asperger's. It is named after the Austrian pediatrician Hans Asperger who, in 1944, described children in his practice who lacked nonverbal communication skills, demonstrated limited empathy with their peers, and were physically clumsy.^[3] Fifty years later, AS was standardized as a diagnosis, but questions about many aspects remain.^[4] For example, there is lingering doubt about the distinction between AS and high-functioning autism (HFA);^[5] partly because of this, the prevalence of AS is not firmly established. The exact cause is unknown, although research supports the likelihood of a genetic basis; brain imaging techniques have not identified a clear common pathology.^[1]

There is no single treatment for Asperger syndrome, and the effectiveness of particular interventions is supported by only limited data.^[1] Intervention is aimed at improving symptoms and function. The mainstay of management is behavioral therapy, focusing on specific deficits to address poor communication skills, obsessive or repetitive routines, and physical clumsiness.^[6] Most individuals with AS can improve over time, but difficulties with communication, social adjustment and independent living continue into adulthood.^[4] Some researchers and people with AS have advocated a shift in attitudes toward the view that AS is a difference, rather than a disability that must be treated or cured.^[7]

Classification

Asperger syndrome is one of the autism spectrum disorders (ASD) or pervasive developmental disorders (PDD), which are a spectrum of psychological conditions that are characterized by abnormalities of social interaction and communication that pervade the individual's functioning, and by restricted and repetitive interests and behavior. Like other psychological development disorders, ASD begins in infancy or childhood, has a steady course without remission or relapse, and has impairments that result from maturation-related changes in various systems of the brain.^[8] ASD, in turn, is a subset of the broader autism phenotype (BAP), which describes individuals who may not have ASD but do have autistic-like traits, such as social deficits.^[9] Of the other four ASD forms, autism is the most similar to AS in signs and likely causes but its diagnosis requires impaired communication and allows delay in cognitive development, Rett syndrome and childhood disintegrative disorder share several signs with autism but may have unrelated causes, and pervasive developmental disorder not otherwise specified (PDD-NOS) is diagnosed when the criteria for a more specific disorder are unmet.^[10]

The extent of the overlap between AS and high-functioning autism (HFA—autism unaccompanied by mental retardation) is unclear.^[5]^[11]^[12] The current ASD classification may not reflect the true nature of the spectrum.^[13] A panel session at a 2008 diagnosis-related autism research planning conference noted problems with the classification of AS as a distinct subgroup of ASD, and two of three breakout groups recommended eliminating AS as a separate diagnosis in future versions of the Diagnostic and Statistical Manual of Mental Disorders and of the International Statistical Classification of Diseases and Related Health Problems.^[14]

Characteristics

A pervasive developmental disorder, Asperger syndrome is distinguished by a pattern of symptoms rather than a single symptom. It is characterized by qualitative impairment in social interaction, by stereotyped and restricted patterns of behavior, activities and interests, and by no clinically significant delay in cognitive development or general delay in language.^[15] Intense preoccupation with a narrow subject, one-sided verbosity, restricted prosody, and physical clumsiness are typical of the condition, but are not required for diagnosis.^[5]

[edit] Social interaction

Further information: Asperger syndrome and interpersonal relationships

The lack of demonstrated empathy is possibly the most dysfunctional aspect of Asperger syndrome.^[2] Individuals with AS experience difficulties in basic elements of social interaction, which may include a failure to develop friendships or to seek shared enjoyments or achievements with others (for example, showing others objects of interest), a lack of social or emotional reciprocity, and impaired nonverbal behaviors in areas such as eye contact, facial expression, posture, and gesture.^[1]

Unlike those with autism, people with AS are not usually withdrawn around others; they approach others, even if awkwardly. For example a person with AS may engage in a one-sided, long-winded speech about a favorite topic, while misunderstanding or not recognizing the listener's feelings or reactions, such as a need for privacy or haste to leave.^[5] This social awkwardness has been called "active but odd".^[1] This failure to react appropriately to social interaction may appear as disregard for other people's feelings, and may come across as insensitive.^[5]

The cognitive ability of children with AS often allows them to articulate social norms in a laboratory context,^[1] where they may be able to show a theoretical understanding of other people's emotions; however, they typically have difficulty acting on this knowledge in fluid, real-life situations.^[5] People with AS may analyze and distill their observation of social interaction into rigid behavioral guidelines, and apply these rules in awkward ways, such as forced eye contact, resulting in a demeanor that appears rigid or socially naive. Childhood desire for companionship can become numbed through a history of failed social encounters.^[1]

The hypothesis that individuals with AS are predisposed to violent or criminal behavior has been investigated but is not supported by data.^[1]^[16] More evidence suggests children with AS are victims rather than victimizers.^[17] A 2008 review found that an overwhelming number of reported violent criminals with AS had coexisting psychiatric disorders such as schizoaffective disorder.^[18]

Restricted and repetitive interests and behavior

People with Asperger syndrome often display behavior, interests, and activities that are restricted and repetitive and are sometimes abnormally intense or focused. They may stick to inflexible routines, move in stereotyped and repetitive ways, or preoccupy themselves with parts of objects.^[15]

Pursuit of specific and narrow areas of interest is one of the most striking features of AS.^[1] Individuals with AS may collect volumes of detailed information on a relatively narrow topic such as dinosaurs, trains or deep fat fryers, without necessarily having genuine understanding of the broader topic.^[1]^[5] For example, a child might memorize camera model numbers while caring little about photography.^[1] This behavior is usually apparent by grade school, typically age 5 or 6 in the United States.^[1] Although these special interests may change from time to time, they typically become more unusual and narrowly focused, and often dominate social interaction so much that the entire family may become immersed. Because narrow topics often capture the interest of children, this symptom may go unrecognized.^[5]

Stereotyped and repetitive motor behaviors are a core part of the diagnosis of AS and other ASDs.^[19] They include hand movements such as flapping or twisting, and complex whole-body movements.^[15] These are typically repeated in longer bursts and look more voluntary or ritualistic than tics, which are usually faster, less rhythmical and less often symmetrical.^[20]

Speech and language

Although individuals with Asperger syndrome acquire language skills without significant general delay and their speech typically lacks significant abnormalities, language acquisition and use is often atypical.^[5] Abnormalities include verbosity, abrupt transitions, literal interpretations and miscomprehension of nuance, use of metaphor meaningful only to the speaker, auditory perception deficits, unusually pedantic, formal or idiosyncratic speech, and oddities in loudness, pitch, intonation, prosody, and rhythm.^[1]

Three aspects of communication patterns are of clinical interest: poor prosody, tangential and circumstantial speech, and marked verbosity. Although inflection and intonation may be less rigid or monotonic than in autism, people with AS often have a limited range of intonation: speech may be unusually fast, jerky or loud. Speech may convey a sense of incoherence; the conversational style often includes monologues about topics that bore the listener, fails to provide context for comments, or fails to suppress internal thoughts. Individuals with AS may fail to monitor whether the listener is interested or engaged in the conversation. The speaker's conclusion or point may never be made, and attempts by the listener to elaborate on the speech's content or logic, or to shift to related topics, are often unsuccessful.^[5]

Children with AS may have an unusually sophisticated vocabulary at a young age and have been colloquially called "little professors", but have difficulty understanding figurative language and tend to use language literally.^[1] Children with AS appear to have particular weaknesses in areas of nonliteral language that include humor, irony, and teasing. Although individuals with AS usually understand the cognitive basis of humor they seem to lack understanding of the intent of humor to share enjoyment with others.^[12] Despite strong evidence of impaired humor appreciation, anecdotal reports of humor in individuals with AS seem to challenge some psychological theories of AS and autism.^[21]

Other

Individuals with Asperger syndrome may have signs or symptoms that are independent of the diagnosis, but can affect the individual or the family. These include differences in perception and problems with motor skills, sleep, and emotions.

Individuals with AS often have excellent auditory and visual perception.^[22] Children with ASD often demonstrate enhanced perception of small changes in patterns such as arrangements of objects or well-known images; typically this is domain-specific and involves processing of fine-grained features.^[23] Conversely, compared to individuals with high-functioning autism, individuals with AS have deficits in some tasks involving visual-spatial perception, auditory perception, or visual memory.^[1] Many accounts of individuals with AS and ASD report other unusual sensory and perceptual skills and experiences. They may be unusually sensitive or insensitive to sound, light, touch, texture, taste, smell, pain, temperature, and other stimuli, and they may exhibit synesthesia;^[24] these sensory responses are found in other developmental disorders and are not specific to AS or to ASD. There is little support for increased fight-or-flight response or failure of habituation in autism; there is more evidence of decreased responsiveness to sensory stimuli, although several studies show no differences.^[25]

Hans Asperger's initial accounts^[1] and other diagnostic schemes^[26] include descriptions of physical clumsiness. Children with AS may be delayed in acquiring skills requiring motor dexterity, such as riding a bicycle or opening a jar, and may seem to move awkwardly or feel "uncomfortable in their own skin". They may be poorly coordinated, or have an odd or bouncy gait or posture, poor handwriting, or problems with visual-motor integration.^[1]^[5] They may show problems with proprioception (sensation of body position) on measures of apraxia (motor planning disorder), balance, tandem gait, and finger-thumb apposition. There is no evidence that these motor skills problems differentiate AS from other high-functioning ASDs.^[1]

Children with AS are more likely to have sleep problems, including difficulty in falling asleep, frequent nocturnal awakenings, and early morning awakenings.^[27]^[28] AS is also associated with high levels of alexithymia, which is difficulty in identifying and describing one's emotions.^[29] Although AS, lower sleep quality, and alexithymia are associated, their causative relationship is unclear.^[28]

As with other forms of ASD, parents of children with AS have higher levels of stress.^[30]

Causes

Further information: Causes of autism

Hans Asperger described common symptoms among his patients' family members, especially fathers, and research supports this observation and suggests a genetic contribution to Asperger syndrome. Although no specific gene has yet been identified, multiple factors are believed to play a role in the expression of autism, given the phenotypic variability seen in this group of children.^[1]^[31] Evidence for a genetic link is the tendency for AS to run in families and an observed higher incidence of family members who have behavioral symptoms similar to AS but in a more limited form (for example, slight difficulties with social interaction, language, or reading).^[6] Most research suggests that all autism spectrum disorders have shared genetic mechanisms, but AS may have a stronger genetic component than autism.^[1] There is probably a common group of genes where particular alleles render an individual vulnerable to developing AS; if this is the case, the particular combination of alleles would determine the severity and symptoms for each individual with AS.^[6]

A few ASD cases have been linked to exposure to teratogens (agents that cause birth defects) during the first eight weeks from conception. Although this does not exclude the possibility that ASD can be initiated or affected later, it is strong evidence that it arises very early in development.^[32] Many environmental factors have been hypothesized to act after birth, but none has been confirmed by scientific investigation.^[33]

Mechanism

Further information: Mechanism of autism

Asperger syndrome appears to result from developmental factors that affect many or all functional brain systems, as opposed to localized effects.^[34] Although the specific underpinnings of AS or factors that distinguish it from other ASDs are unknown, and no clear pathology common to individuals with AS has emerged,^[1] it is still possible that AS's mechanism is separate from other ASD.^[35] Neuroanatomical studies and the associations with teratogens strongly suggest that the mechanism includes alteration of brain development soon after conception.^[32] Abnormal migration of embryonic cells during fetal development may affect the final structure and connectivity of the brain, resulting in alterations in the neural circuits that control thought and behavior.^[36] Several theories of mechanism are available; none is likely to provide a complete explanation.^[37]

Functional magnetic resonance imaging provides some evidence for both underconnectivity and mirror neuron theories.^[38]^[39]

The underconnectivity theory hypothesizes underfunctioning high-level neural connections and synchronization, along with an excess of low-level processes.^[38] It maps well to general-processing theories such as weak central coherence theory, which hypothesizes that a limited ability to see the big picture underlies the central disturbance in ASD.^[40] A related theory—enhanced perceptual functioning—focuses more on the superiority of locally oriented and perceptual operations in autistic individuals.^[41]

The mirror neuron system (MNS) theory hypothesizes that alterations to the development of the MNS interfere with imitation and lead to Asperger's core feature of social impairment.^[39]^[42] For example, one study found that activation is delayed in the core circuit for imitation in individuals with AS.^[43] This theory maps well to social cognition theories like the theory of mind, which hypothesizes that autistic behavior arises from impairments in ascribing mental states to oneself and others,^[44] or hyper-systemizing, which hypothesizes that autistic individuals can systematize internal operation to handle internal events but are less effective at empathizing by handling events generated by other agents.^[45]

Other possible mechanisms include serotonin dysfunction^[46] and cerebellar dysfunction.^[47]

Screening

Parents of children with Asperger syndrome can typically trace differences in their children's development to as early as 30 months of age.^[31] Developmental screening during a routine check-up by a general practitioner or pediatrician may identify signs that warrant further investigation.^[1]^[6] The diagnosis of AS is complicated by the use of several different screening instruments,^[6]^[26] including the Asperger Syndrome Diagnostic Scale (ASDS), Autism Spectrum Screening Questionnaire (ASSQ), Childhood Asperger Syndrome Test (CAST), Gilliam Asperger's Disorder Scale (GADS), Krug Asperger's Disorder Index (KADI),^[48] and the Autism Spectrum Quotient (AQ; with versions for children,^[49] adolescents^[50] and adults^[51]). None have been shown to reliably differentiate between AS and other ASDs.^[1]

Diagnosis

Main article: Diagnosis of Asperger syndrome

Standard diagnostic criteria require impairment in social interaction, and repetitive and stereotyped patterns of behavior, activities and interests, without significant delay in language or cognitive development. Unlike the international standard,^[8] U.S. criteria also require significant impairment in day-to-day functioning.^[15] Other sets of diagnostic criteria have been proposed by Szatmari et al.^[52] and by Gillberg and Gillberg.^[53]

Diagnosis is most commonly made between the ages of four and eleven.^[1] A comprehensive assessment involves a multidisciplinary team^[2]^[6]^[54] that observes across multiple settings,^[1] and includes neurological and genetic assessment as well as tests for cognition, psychomotor function, verbal and nonverbal strengths and weaknesses, style of learning, and skills for independent living.^[6] The current "gold standard" in diagnosing ASDs combines clinical judgment with the Autism Diagnostic Interview-Revised (ADI-R)—a semistructured parent interview—and the Autism Diagnostic Observation Schedule (ADOS)—a conversation and play-based interview with the child.^[4] Delayed or mistaken diagnosis can be traumatic for individuals and families; for example, misdiagnosis can lead to medications that worsen behavior.^[54] Many children with AS are initially misdiagnosed with attention-deficit hyperactivity disorder (ADHD).^[1] Diagnosing adults is more challenging, as standard diagnostic criteria are designed for children and the expression of AS changes with age.^[55] Conditions that must be considered in a differential diagnosis include other ASDs, the schizophrenia spectrum, ADHD, obsessive compulsive disorder, major depressive disorder, semantic pragmatic disorder, nonverbal learning disorder,^[54] Tourette syndrome,^[20] stereotypic movement disorder and bipolar disorder.^[31]

Underdiagnosis and overdiagnosis are problems in marginal cases. The cost of screening and diagnosis and the challenge of obtaining payment can inhibit or delay diagnosis. Conversely, the increasing popularity of drug treatment options and the expansion of benefits has motivated providers to overdiagnose ASD.^[56] There are indications AS has been diagnosed more frequently in recent years, partly as a residual diagnosis for children of normal intelligence who do not have autism but have social difficulties. There are questions about the external validity of the AS diagnosis. That is, it is unclear whether there is a practical benefit in distinguishing AS from HFA and from PDD-NOS;^[57] the same child can receive different diagnoses depending on the screening tool.^[6] The debate about distinguishing AS from HFA is partly due to a tautological dilemma where disorders are defined based on severity of impairment, so that studies that appear to confirm differences based on severity are to be expected.^[58]

Management

Further information: Autism therapies

Asperger syndrome treatment attempts to manage distressing symptoms and to teach age-appropriate social, communication and vocational skills that are not naturally acquired during development,^[1] with intervention tailored to the needs of the individual child, based on multidisciplinary assessment.^[59] Although progress has been made, data supporting the efficacy of particular interventions are limited.^[1]^[60]

Therapies

The ideal treatment for AS coordinates therapies that address core symptoms of the disorder, including poor communication skills and obsessive or repetitive routines. While most professionals agree that the earlier the intervention, the better, there is no single best treatment package.^[6] AS treatment resembles that of other high-functioning ASDs, except that it takes into account the linguistic capabilities, verbal strengths, and nonverbal vulnerabilities of individuals with AS.^[1] A typical program generally includes:^[6]

the training of social skills for more effective interpersonal interactions,^[61]
cognitive behavioral therapy to improve stress management relating to anxiety or explosive emotions,^[62] and to cut back on obsessive interests and repetitive routines,
medication, for coexisting conditions such as major depressive disorder and anxiety disorder,^[63]
occupational or physical therapy to assist with poor sensory integration and motor coordination,
social communication intervention, which is specialized speech therapy to help with the pragmatics of the give and take of normal conversation,^[64]
the training and support of parents, particularly in behavioral techniques to use in the home.

Of the many studies on behavior-based early intervention programs, most are case studies of up to five participants, and typically examine a few problem behaviors such as self-injury, aggression, noncompliance, stereotypies, or spontaneous language; unintended side effects are largely ignored.^[65] Despite the popularity of social skills training, its effectiveness is not firmly established.^[66] A randomized controlled study of a model for training parents in problem behaviors in their children with AS showed that parents attending a one-day workshop or six individual lessons reported fewer behavioral problems, while parents receiving the individual lessons reported less intense behavioral problems in their AS children.^[67] Vocational training is important to teach job interview etiquette and workplace behavior to older children and adults with AS, and organization software and personal data assistants to improve the work and life management of people with AS are useful.^[1]

Medications

No medications directly treat the core symptoms of AS.^[63] Although research into the efficacy of pharmaceutical intervention for AS is limited,^[1] it is essential to diagnose and treat comorbid conditions.^[2] Deficits in self-identifying emotions or in observing effects of one's behavior on others can make it difficult for individuals with AS to see why medication may be appropriate.^[63] Medication can be effective in combination with behavioral interventions and environmental accommodations in treating comorbid symptoms such as anxiety disorder, major depressive disorder, inattention and aggression.^[1] The atypical neuroleptic medications risperidone and olanzapine have been shown to reduce the associated symptoms of AS;^[1] risperidone can reduce repetitive and self-injurious behaviors, aggressive outbursts and impulsivity, and improve stereotypical patterns of behavior and social relatedness. The selective serotonin reuptake inhibitors (SSRIs) fluoxetine, fluvoxamine and sertraline have been effective in treating restricted and repetitive interests and behaviors.^[1]^[2]^[31]

Care must be taken with medications; abnormalities in metabolism, cardiac conduction times, and an increased risk of type 2 diabetes have been raised as concerns with these medications,^[68]^[69] along with serious long-term neurological side effects.^[65] SSRIs can lead to manifestations of behavioral activation such as increased impulsivity, aggression and sleep disturbance.^[31] Weight gain and fatigue are commonly reported side effects of risperidone, which may also lead to increased risk for extrapyramidal symptoms such as restlessness and dystonia^[31] and increased serum prolactin levels.^[70] Sedation and weight gain are more common with olanzapine,^[69] which has also been linked with diabetes.^[68] Sedative side-effects in school-age children^[71] have ramifications for classroom learning. Individuals with AS may be unable to identify and communicate their internal moods and emotions or to tolerate side effects that for most people would not be problematic.^[72]

Prognosis

There is some evidence that as many as 20% of children with AS "grow out" of it, and fail to meet the diagnostic criteria as adults.^[4] As of 2006, no studies addressing the long-term outcome of individuals with Asperger syndrome are available and there are no systematic long-term follow-up studies of children with AS.^[5] Individuals with AS appear to have normal life expectancy but have an increased prevalence of comorbid psychiatric conditions such as major depressive disorder and anxiety disorder that may significantly affect prognosis. Although social impairment is lifelong, outcome is generally more positive than with individuals with lower functioning autism spectrum disorders;^[1] for example, ASD symptoms are more likely to diminish with time in children with AS or HFA.^[73] Although most students with AS/HFA have average mathematical ability and test slightly worse in mathematics than in general intelligence, some are gifted in mathematics^[74] and AS has not prevented some adults from major accomplishments such as winning the Nobel Prize.^[75]

Children with AS may require special education services because of their social and behavioral difficulties although many attend regular education classes.^[5] Adolescents with AS may exhibit ongoing difficulty with self care, organization and disturbances in social and romantic relationships; despite high cognitive potential, most young adults with AS remain at home, although some do marry and work independently.^[1] The "different-ness" adolescents experience can be traumatic.^[76] Anxiety may stem from preoccupation over possible violations of routines and rituals, from being placed in a situation without a clear schedule or expectations, or from concern with failing in social encounters;^[1] the resulting stress may manifest as inattention, withdrawal, reliance on obsessions, hyperactivity, or aggressive or oppositional behavior.^[62] Depression is often the result of chronic frustration from repeated failure to engage others socially, and mood disorders requiring treatment may develop.^[1] Clinical experience suggests the rate of suicide may be higher among those with AS, but this has not been confirmed by systematic empirical studies.^[77]

Education of families is critical in developing strategies for understanding strengths and weaknesses;^[2] helping the family to cope improves outcomes in children.^[17] Prognosis may be improved by diagnosis at a younger age that allows for early interventions, while interventions in adulthood are valuable but less beneficial.^[2] There are legal implications for individuals with AS as they run the risk of exploitation by others and may be unable to comprehend the societal implications of their actions.^[2]

Epidemiology

Further information: Conditions comorbid to autism spectrum disorders

Prevalence estimates vary enormously. A 2003 review of epidemiological studies of children found prevalence rates ranging from 0.03 to 4.84 per 1,000, with the ratio of autism to Asperger syndrome ranging from 1.5:1 to 16:1;^[78] combining the average ratio of 5:1 with a conservative prevalence estimate for autism of 1.3 per 1,000 suggests indirectly that the prevalence of AS might be around 0.26 per 1,000.^[79] Part of the variance in estimates arises from differences in diagnostic criteria. For example, a relatively small 2007 study of 5,484 eight-year-old children in Finland found 2.9 children per 1,000 met the ICD-10 criteria for an AS diagnosis, 2.7 per 1,000 for Gillberg and Gillberg criteria, 2.5 for DSM-IV, 1.6 for Szatmari et al., and 4.3 per 1,000 for the union of the four criteria. Boys seem to be more likely to have AS than girls; estimates of the sex ratio range from 1.6:1 to 4:1, using the Gillberg and Gillberg criteria.^[80]

Anxiety disorder and major depressive disorder are the most common conditions seen at the same time; comorbidity of these in persons with AS is estimated at 65%.^[1] Depression is common in adolescents and adults; children are likely to present with ADHD.^[81] Reports have associated AS with medical conditions such as aminoaciduria and ligamentous laxity, but these have been case reports or small studies and no factors have been associated with AS across studies.^[1] One study of males with AS found an increased rate of epilepsy and a high rate (51%) of nonverbal learning disorder.^[82] AS is associated with tics, Tourette syndrome, and bipolar disorder, and the repetitive behaviors of AS have many similarities with the symptoms of obsessive-compulsive disorder and obsessive-compulsive personality disorder.^[83] Although many of these studies are based on psychiatric clinic samples without using standardized measures, it seems reasonable to conclude that comorbid conditions are relatively common.^[4]

History

Main article: History of Asperger syndrome

Named after the Austrian pediatrician Hans Asperger (1906–80), Asperger syndrome is a relatively new diagnosis in the field of autism.^[84] In 1944, Asperger described four children in his practice^[2] who had difficulty in integrating themselves socially. The children lacked nonverbal communication skills, failed to demonstrate empathy with their peers, and were physically clumsy. Asperger called the condition "autistic psychopathy" and described it as primarily marked by social isolation.^[6] Unlike today's AS, autistic psychopathy could be found in people of all levels of intelligence, including those with mental retardation.^[85] In the context of the Nazi eugenics policy of sterilizing and killing social deviants and the mentally handicapped, Asperger passionately defended the value of autistic individuals, writing "We are convinced, then, that autistic people have their place in the organism of the social community. They fulfil their role well, perhaps better than anyone else could, and we are talking of people who as children had the greatest difficulties and caused untold worries to their care-givers."^[3] Asperger also called his young patients "little professors",^[3] and believed some would be capable of exceptional achievement and original thought later in life.^[2] His paper was published during wartime and in German, so it was not widely read elsewhere.

Lorna Wing popularized the term Asperger syndrome in the English-speaking medical community in her 1981 publication^[86] of a series of case studies of children showing similar symptoms,^[84] and Uta Frith translated Asperger's paper to English in 1991.^[3] Sets of diagnostic criteria were outlined by Gillberg and Gillberg in 1989 and by Szatmari et al. in the same year.^[80] AS became a standard diagnosis in 1992, when it was included in the tenth edition of the World Health Organization's diagnostic manual, International Classification of Diseases (ICD-10); in 1994, it was added to the fourth edition of the American Psychiatric Association's diagnostic reference, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).^[6]

Hundreds of books, articles and websites now describe AS, and prevalence estimates have increased dramatically for ASD, with AS recognized as an important subgroup.^[84] Whether it should be seen as distinct from high-functioning autism is a fundamental issue requiring further study.^[2] There is little consensus among clinical researchers about the use of the terms Asperger's syndrome or Asperger's disorder, and there are questions about the empirical validation of the DSM-IV and ICD-10 criteria.^[5]

Arnold-Chiari

2009-06-24T06:24:00.000-07:00

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Arnold-Chiari
Classification and external resources
A T2-weighted sagittal MRI scan, from a patient with Chiari-like symptomatology, demonstrating tonsillar herniation less than 3 mm
ICD-10	Q 07.0
ICD-9	741.0
OMIM	207950
DiseasesDB	899
MeSH	D001139

Arnold-Chiari malformation is a malformation of the brain. It consists of a downward displacement of the cerebellar tonsils and the medulla^[1] through the foramen magnum, sometimes causing hydrocephalus as a result of obstruction of cerebrospinal fluid (CSF) outflow ^[2]. The cerebrospinal fluid outflow being caused by phase difference in outflow and influx of blood in the vasculature of the brain.

Terminology

Chiari malformation is the most frequently used term for these types of malformations. The use of the term Arnold-Chiari malformation has fallen somewhat out of favor over time, although it is used by some to refer to the type II malformation. Some sources use "Chiari malformation" to describe four specific grades of the condition, reserving the term "Arnold-Chiari" for type II only.^[3] Some sources use "Arnold-Chiari" for all four types.^[4] This article uses the latter convention.

Chiari malformation or Arnold-Chiari malformation should not be confused with Budd-Chiari syndrome,^[5] a hepatic condition also named for Hans Chiari.

Diagnosis

Chiari malformations are diagnosed with a sagittal T1 magnetic resonance imaging (MRI) scan of the posterior fossa of the skull. This displays the typical downward herniation of the cerebellar tonsils. A displacement of greater than 5 mm below the foramen magnum is deemed significant and will lead to a patient being diagnosed with Arnold-Chiari malformation. In some instances, MRI CSF flow studies are used to decide if a displacement is causing any damage.^[6]

The average age at diagnosis is about 27 and it is more common in women, but is also found in men.

Some characteristics are visible prenatally.^[7]

Incidence

The incidence of Chiari 1 malformation, defined as tonsilar herniations of 3 to 5 mm or greater, is approximately 1 in 1,200.^{[citation needed]} The incidence of symptomatic Chiari is less but unknown.

History and classification

The Austrian pathologist Hans Chiari in the late 1800s described seemingly related anomalies of the hindbrain, the so called Chiari malformations I, II and III. Later, other investigators added a fourth (Chiari IV) malformation. The scale of severity is rated I - IV, with IV being the most severe. Types III and IV are very rare.^[8]

Type	Presentation	Other notes
I	Is generally asymptomatic during childhood, but often manifests with headaches and cerebellar symptoms. Herniation of cerebellar tonsils.^[9]^[10]	The most common form.
II	Usually accompanied by a myelomeningocele^[11] leading to partial or complete paralysis below the spinal defect. Abnormal development of the cerebellar vermis and medulla oblongata occur, and they both descend into the foramen magnum. Hydrocephalus is also nearly always present.
III	Causes severe neurological defects. It is associated with an encephalocele.^[12]
IV	Involves a failure of brain development.^[13]

Other conditions sometimes associated with Chiari Malformation include hydrocephalus,^[14] syringomyelia, spinal curvature, and connective tissue disorders^[15] such as Ehlers-Danlos syndrome and Marfan Syndrome.

Symptoms

The brainstem, cranial nerves, and the lower portion of the cerebellum may be stretched or compressed. Therefore, any of the functions controlled by these areas may be affected. The blockage of Cerebro-Spinal Fluid (CSF) flow may also cause a syrinx to form, eventually leading to syringomyelia. Chiari is often associated with major headaches, sometimes mistaken for migraines. Chiari headaches usually include intense pressure in the back of the head, aggravated by Valsalva maneuvers, such as yawning, laughing, crying, coughing, sneezing or straining. Chiari also includes muscle weakness, facial pain, hearing problems, and extreme fatigue. It also can cause insomnia cycles of sleep deprivation followed by inabilities to remain awake cycling between them. 15% of patients with adult Chiari malfomation are asymptomatic.

Treatment

Once symptomatic onset occurs, a common treatment is decompression surgery,^[16] in which a neurosurgeon usually removes the first and part of the second and sometimes third cervical vertebrae and part of the occipital bone of the skull to allow the flow of spinal fluid and may be accompanied by a shunt. This treatment is well recognized and accepted with many studies published (involving a total of hundreds of patients) in well-respected peer-reviewed medical journals showing that about 80% of patients obtain improvement. Some authors advocate performing a transoral clivus-odontoid resection in cases with ventral brain-stem compression, as they feel these patients may potentially deteriorate with posterior fossa decompression alone.

A small number of neurological surgeons believe that detethering the spinal cord as an alternate approach relieves the compression of the brain against the skull opening (foramen magnum), obviating the need for decompression surgery and associated trauma. However, this approach is significantly less documented in the medical literature, with reports on only a handful of patients. It should be noted that the alternative spinal surgery is also not without risk.

Prognosis

The prognosis differs dependent on the type of malformation (i.e., type I, II, III, or IV). Types I and II are generally adult-onset variations and, while not curable, are treatable and non-fatal. Types I and II sufferers may also develop syringomyelia. Types III and IV are extremely rare and patients generally do not survive past the age of two or three.^[17]

History

An Austrian pathologist, Hans Chiari, first described these hindbrain malformations in the 1890s.^[18] A colleague of Professor Chiari, Dr. Julius Arnold, later contributed to the definition of the condition,^[19] and students of Dr. Arnold (Schwalbe and Gredig)^[20] suggested the term "Arnold-Chiari malformation" to henceforth refer to the condition.^[21]^[22]

Some sources credit the characterization of the condition to Cleland^[23]^[24] or Cruveilhier.^[25]

Notable people with the malformation

Rosanne Cash

Research

Considerable research has been directed towards improving methods used to diagnose Arnold-Chiari malformation. In particular, the traditional diagnosis method quantifying a 5 mm descent of the lower cerebellar tonsils through the foramen magnum may be insufficient for diagnosis in some patients. Research has been conducted to investigate the importance of cerebrospinal fluid velocities, other geometric parameters of the cranium, the importance of cranial and spinal canal compliance, and thickening of the filum terminale in assessment of Arnold-Chiari malformation.

Arachnoiditis

2009-06-24T06:23:00.000-07:00

Arachnoiditis
Classification and external resources
ICD-10	G 03.9
ICD-9	320-322
DiseasesDB	22543
eMedicine	radio/49
MeSH	D001100

Arachnoiditis is a neuropathic disease caused by the inflammation of the arachnoid, one of the membranes that surround and protect the nerves of the central nervous system, including the brain and spinal cord. The arachnoid can become severely inflamed because of adverse reactions to chemicals, blood, and/or steroids, infection from bacteria or viruses, as the result of direct injury to the spine, chronic compression of spinal nerves, or complications from spinal surgery or other invasive spinal procedures such as epidural steroid injections. Lumbar patches (also known as blood patches), which are often useful in relieving painful headaches associated with spinal taps and epidural anesthesia, have been found to be significant potential causative agents in some cases and may warrant avoidance of the procedure where possible. Multiple blood patches may amplify the probability of contracting arachnoiditis. It is also noteworthy that blood has been found to be a significant inflammatory agent in the nervous system. Inflammation can sometimes lead to the formation of scar tissue and adhesions which can cause the spinal nerves to "stick" together.

Symptoms

The swollen arachnoid can lead to a host of painful and debilitating symptoms. Chronic pain is common, including neuralgia. Numbness and tingling of the extremities is frequent in patients due to spinal cord involvement. Bowel, bladder, and sexual functioning can be affected if the lower part of the spinal cord is affected. While arachnoiditis has no consistent pattern of symptoms, it frequently affects the nerves that supply the legs and lower back. Many sufferers find themselves unable to sit for long (or even short) periods of time, often due to severe pain as well as efferent neurological symptoms, such as difficulties controlling limbs. This can be particularly problematic for those patients who exhibit difficulties standing or walking for protracted periods, as wheelchairs are not helpful for this group. Some sufferers benefit from relatively new inventions, such as the Segway or the less expensive Stand'n'Ride alternative. Standing wheelchairs are also available, although often quite expensive and limited compared to these alternatives. However, standing endurance and vibration tolerance should be taken into account before a motorized assistance device is selected.

It is critical for patients to realize that the symptoms of arachnoiditis are highly varied and are not all experienced by all sufferers. Consequently, while typically significantly life-altering, the outcome, especially with physical therapy, appropriate psychotherapy, and medication, may be better than many patients fear upon receiving the diagnosis.

Prognosis

Arachnoiditis is a chronic disorder and there is no known cure at this time. Pain management techniques may provide some relief to patients. Prognosis may be hard to determine because of the lack of correlation between the beginning of the disease and the start of symptoms. For many, arachnoiditis is a disabling disease that causes chronic pain and neurological deficits. It may also lead to other spinal cord conditions, such as syringomyelia.

Treatment

Arachnoiditis is a difficult condition to treat. Treatment is limited to alleviation of pain and other symptoms. Surgical intervention generally has a poor outcome and only provides temporary relief. Steroid injections administered either intrathecally or epidurally have been linked as a cause of the disease, therefore they are generally discouraged as a treatment and may even worsen the condition.

Current research

Recent research has indicated that a group of chemicals called cytokines that are produced by various cells in the body may be responsible for generating the pain response. Medications that affect the release of cytokines or block the action of cytokines may reduce the pain response. Various anti-cytokine medications are now being used to treat painful disease states such as Rheumatoid Arthritis and Crohn's Disease. In a recent study the anti-cytokine medication, Thalidomide, is being evaluated for its effect in treating pain associated with Arachnoiditis.

Global warming

2009-06-24T06:21:00.000-07:00

1) "Global warming" is a real phenomenon: Earth's temperature is increasing. (True/False)

Correct Answer: True

Today's temperature is probably higher than it's been in at least 1300 years - mostly due to human activities.

2) The "Greenhouse Effect" is real. (True/False)

Correct Answer: True

A background greenhouse effect is natural to the Earth. Without it, the Earth's average temperature would be an uninhabitable 0°F. But human activities have increased the greenhouse effect, causing rapid global warming.

3) The main cause of Global Warming is:

a) pollution from factories and automobiles
b) orbital eccentricities of Earth and variations in the Sun's output
c) the Greenhouse Effect

Correct Answer: a) pollution from factories and automobiles, and c) the Greenhouse Effect

Today's rapid global warming is caused by increased concentrations of greenhouse gases in the atmosphere. The additional greenhouse gases come from human activities such as industrial pollution and tropical deforestation. It is not caused by orbital eccentricities or variations in the Sun's output.

4) The Greenhouse Effect is caused primarily by:

a) water vapor
b) carbon dioxide
c) ozone-destroying aerosol sprays

Correct Answer: b) carbon dioxide

Although water vapor traps more heat than carbon dioxide (CO2), increasing greenhouse gases like CO2, not water vapor, is what drives global warming. Air warmed by CO2 holds more water vapor, enhancing the effect. To interrupt this vicious cycle and stop global warming, we must control the emission of greenhouse gases like CO2.

5) Which most accurately describes the effects of Global Warming in the United States over the last 100 years?

a) temperatures have risen > 5° C
b) temperatures have risen > 2° C
c) temperatures have risen < 1° C

Correct Answer: c) temperatures have risen < 1° C

Global temperatures have increased by about 0.75°C over the past 100 years (see this chart from NASA). U.S. temperatures have risen by nearly the same amount.

It may sound like a small number, but the impacts on Earth systems and global climate are already dramatic. Scientists predict much more warming in the future unless we cut greenhouse gas emissions.

6) How much carbon dioxide (CO2) is in Earth's atmosphere today?

a) 10% or greater
b) 2% to 10%
c) less than 1/10th of 1%

Correct Answer: c) less than 1/10th of 1%

CO2 is about 0.038 percent of the Earth's atmosphere. This sounds insignificant, but even small concentrations of greenhouse gases can have a large effect.

Since the start of the industrial revolution, CO2 levels have risen about 33 percent, and the level of methane (a more potent greenhouse gas) has more than doubled.

7) Carbon dioxide from coal-fired power plants damages forests. (True/False)

Correct Answer: True

Nearly 20 percent of global CO2 emissions come from cutting down forests, which certainly counts as damage!

Rising levels of CO2 from industrial emissions have a complex effect on forests and other plants. In the western U.S., warming and drying have encouraged widespread beetle outbreaks and increasing wildfires. Some plants respond to CO2 by growing more rapidly, but scientists also have found that many crops grown in high CO2 conditions have lower nutritional value.

8) Which answer below provides the best explanation for the following temperature record?

<>

a) Industrial pollution from factories, power plants, and cars caused global warming
b) Natural variations in global temperatures may occur in roughly 500-years cycles
c) Global cooling occurred as a result of the Renaissance Period

Correct Answer: N/A, data in graph not accurate

The actual temperature record is not depicted in this graph. The "Medieval Warm Period" wasn't as warm as temperatures are today, and it may not have been a global phenomenon. Like the "Little Ice Age", it's most prominent in records from Europe. Scientists think the cooler temperatures between the 14th and 19th centuries may have been caused by changes in solar energy and/or the Gulf Stream. But natural factors like these have not contributed much to today's warming trend.

9) Which of the following is not true about an increasing greenhouse effect?

a) the consensus of scientists is that the problem warrants drastic action
b) nighttime temperatures may increase, but daytime temperatures will not
c) the coldest, driest regions of the planet will warm first

Correct Answer: b) nighttime temperatures may increase, but daytime temperatures will not, and c) the coldest, driest regions of the planet will warm first

Both daytime and nighttime temperatures are already increasing. Northern areas are warming more quickly, but global warming is evident around the world. Scientists are calling for prompt action to cut greenhouse gas emissions.

10) Which temperature measuring method most accurately measures global warming?

a) ground-based thermometers
b) orbiting weather satellites
c) weather balloons

Correct Answer: a) ground-based thermometers, and b) orbiting weather satellites
Labels: Global warming
Global warming

Global warming is the increase in the average temperature of the Earth's near-surface air and oceans since the mid-twentieth century, and its projected continuation.

The average global air temperature near the Earth's surface increased 0.74 ± 0.18 °C (1.33 ± 0.32 °F) during the hundred years ending in 2005. The Intergovernmental Panel on Climate Change (IPCC) concludes "most of the observed increase in globally averaged temperatures since the mid-twentieth century is very likely due to the observed increase in anthropogenic (man-made) greenhouse gas concentrations" via the greenhouse effect. Natural phenomena such as solar variation combined with volcanoes probably had a small warming effect from pre-industrial times to 1950 and a small cooling effect from 1950 onward.

These basic conclusions have been endorsed by at least thirty scientific societies and academies of science, including all of the national academies of science of the major industrialized countries. While individual scientists have voiced disagreement with some findings of the IPCC, the overwhelming majority of scientists working on climate change agree with the IPCC's main conclusions.
Global mean surface temperature anomaly relative to 1961–1990
Global mean surface temperature anomaly relative to 1961–1990
Mean surface temperature anomalies during the period 1995 to 2004 with respect to the average temperatures from 1940 to 1980

Climate model projections summarized by the IPCC indicate that average global surface temperature will likely rise a further 1.1 to 6.4 °C (2.0 to 11.5 °F) during the twenty-first century. This range of values results from the use of differing scenarios of future greenhouse gas emissions as well as models with differing climate sensitivity. Although most studies focus on the period up to 2100, warming and sea level rise are expected to continue for more than a thousand years even if greenhouse gas levels are stabilized. The delay in reaching equilibrium is a result of the large heat capacity of the oceans.

Increasing global temperature will cause sea level to rise, and is expected to increase the intensity of extreme weather events and to change the amount and pattern of precipitation. Other effects of global warming include changes in agricultural yields, trade routes, glacier retreat, species extinctions and increases in the ranges of disease vectors.

Remaining scientific uncertainties include the amount of warming expected in the future, and how warming and related changes will vary from region to region around the globe. Most national governments have signed and ratified the Kyoto Protocol aimed at reducing greenhouse gas emissions, but there is ongoing political and public debate worldwide regarding what, if any, action should be taken to reduce or reverse future warming or to adapt to its expected consequences.

Thiroid

2009-06-24T06:20:00.000-07:00

The thioroid is a small gland located below the skin and muscles at the front of the neck, just at the spot where a bow tie would rest. It's brownish red, with left and right halves (called lobes) that look like a butterfly's wings. It's light like a butterfly, too, and usually weighs less than an ounce.

As small as it is, though, the thioroid has an enormously important job to do, especially for teens. It manufactures thehormones that help control metabolismand growth. To do its job, the thioroid needs a chemical element called iodine that the body absorbs from the foods you eat and the water you drink. The entire body contains about 50 milligrams of iodine. About 1/5 to 1/3 of that supply (10 to 15 milligrams) is stored in your thioroid. The thioroid combines the iodine with tyrosine (an essential amino acid) to make important hormones.

Thioroid hormones are released from the gland and travel through the bloodstream to your body's cells. They help control the growth and the structure of bones, sexual development (puberty), and many other body functions. By helping your cells convert oxygen and calories into the energy they need to work properly, these hormones are important in determining if your body will mature as it should. Thioroid hormones also directly affect how most of your organs function. So if your thioroid isn't operating properly, you can have problems in lots of other parts of your body.

What Is Thioroid Disease?

Thioroid disease occurs when the thioroid gland doesn't supply the proper amount of hormones needed by the body. If the thioroid is overactive, it releases too much thioroid hormone into the bloodstream, resulting in hyperthioroidism. ("Hyper" is from the Greek, meaning "over" or "above.") Hyperthioroidism causes the body to use up energy more quickly than it should, and chemical activity (like metabolism) in the cells speeds up.

An underactive thioroid produces too little thioroid hormone, resulting in hypothioroidism. ("Hypo" means "under" or "below.") When the amount of hormone released into the bloodstream is below normal, the body uses up energy more slowly, and chemical activity (metabolism) in the cells slows down.

Although they are two different conditions, in both hypothioroidism and hyperthioroidism the thioroid can become larger than normal. An enlarged thioroid gland is a lump that can be felt under the skin at the front of the neck. When it is large enough to see easily, it's called a goiter. People who don't get enough iodine in their diets also can get an enlarged thioroid, but this is rare in the United States because foods here usually supply enough iodine.

Hyperthioroidism

Hyperthioroidism can cause nervousness, irritability, increased perspiration, intolerance to heat, fatigue, difficulty sleeping, a fast heartbeat, irregular menstrual periods in girls, and muscle weakness. People with this problem might lose weight even though they're eating more than usual. The eyes may feel irritated or look like they're staring. Sometimes the tissues around the eyes become inflamed and swollen, and the eyes appear to bulge out, but this is less common in teens than in adults with hyperthioroidism.

Graves disease, an autoimmune disease, is the most common cause of hyperthioroidism. The condition makes a person's immune system produce abnormal types of antibodies (normally antibodies help the body fight infection). These abnormal antibodies make the thioroid gland produce more thioroid hormones. Eventually, the thioroid gland enlarges, which can result in a goiter. For reasons that doctors don't yet understand, autoimmune thioroid diseases like Graves disease are much more common in women and are most likely to occur in teens and young and middle-aged adults.

Doctors usually diagnose Graves disease based on a person's symptoms, a physical examination, and blood tests that show high levels of thioroid hormone in the blood.

Once the diagnosis is made, a teen with Graves disease will usually start taking an anti-thioroid medication, such as propylthiouracil or methimazole, which blocks the thioroid's production of thioroid hormones. Medication usually brings the hormone levels down to the normal range in 1 to 2 months.

However, in most cases, the disease doesn't go away. Some people continue taking medication for months or years to keep Graves disease under control, but it can be a hassle to take medication 1 to 3 times a day for a long period. So many doctors recommend a permanent treatment.

Radioactive iodine (RAI) is the most commonly recommended permanent treatment for teens with Graves disease today. It is usually given at a hospital, but doesn't require a hospital stay. RAI is considered safe for teens when given in the standard amount. It is taken in capsules or mixed with a glass of water. The thioroid gland quickly absorbs the RAI from the bloodstream and, within a few months, the gland shrinks and symptoms gradually disappear. RAI has been used to treat Graves disease successfully for more than 50 years.

The other permanent treatment for Graves disease is surgery to remove most of the thioroid gland (thioroidectomy). The operation is performed in a hospital under general anesthesia, meaning the person is asleep and feels nothing during the surgery. A small incision (cut) in the lower central part of the neck usually leaves a thin scar. After surgery, there typically is swelling in the area of the incision. People sometimes have a sore throat and some trouble swallowing following surgery, although they should be able to eat and drink normally. These symptoms usually disappear within a few days.

After treatment for hyperthioroidism, hormone production often slows down to hypothioroid (underactive) levels, so the person needs to take a thioroid hormone replacement tablet each day. This treatment is a lot easier to manage than taking pills to control the hyperthioroidism - fewer blood tests, doctor visits, and medication adjustments are necessary.

As the body adjusts to the hormone replacement tablets, a doctor may increase or reduce the dosage until the levels of thioroid hormone in a person's blood are normal. Once the doctor finds the proper dosage, people usually feel well and free of symptoms. However, the doctor will continue to check hormone levels to make sure the dosage is right, especially for growing teens whose levels might change over just a few months.

Hypothioroidism

A person with mild hypothioroidism may feel just fine - in fact, the condition might cause no symptoms at all. However, symptoms can become more obvious if hypothioroidism progresses.

People with underactive thioroids might feel depressed and sluggish. They might gain weight, even though they're not eating more or getting less exercise than usual. Teens with hypothioroidism also might have slow growth in height, slow sexual development, irregular menstrual periods in girls, muscle weakness, dry skin, hair loss, poor memory, and difficulty concentrating.

Hashimoto's thioroiditis (pronounced: hah-she-moe-toes thy-roy-dye-tiss) is also an autoimmune disease and is the most common cause of hypothioroidism in teens. In this condition, the body's immune system attacks the cells in the thioroid gland, preventing it from producing enough thioroid hormone. The thioroid responds by working harder to make enough hormones. This can make it become enlarged and may result in a goiter.

Hypothioroidism is usually easily diagnosed with a physical examination and blood tests, and treatment with thioroid hormone replacement pills can restore normal levels of thioroid hormone in the blood. This treatment is pretty simple, but it does require doctor visits once or twice a year for an examination, blood tests, and medication adjustments as needed.

Goiters and Thioroid Nodules

It can take months or years for a goiter to develop. In teens, goiters are usually caused by the autoimmune thioroid conditions discussed above, which might show no obvious symptoms until the goiter is visible as a swelling at the front of the neck. People with this problem might have the sensation that food is stuck in the throat, especially when they lie down or sleep on their backs.

Generally, treatment of the thioroid disease causing the goiter will decrease or control the enlargement. If the thioroid continues to get larger despite treatment and becomes large enough to cause discomfort or a lump in the neck, surgery may be required. However, surgery is not necessary for most people.

A thioroid nodule is a lump or enlarged area in the thioroid gland. Sometimes a nodule can appear in a healthy gland. It may feel like a lump in the throat, or there may be tenderness or pain in the front of the neck. If the nodule is large enough, it may be visible at the front of the neck.

Most thioroid nodules are harmless. A nodule may simply be an overgrowth of normal thioroid tissue, a swelling caused byinflammation (such as in autoimmune thioroid diseases) or a collection of fluid called a cyst.

The doctor usually discovers nodules by touch during a physical examination. If the doctor finds a nodule, blood tests might be needed to find out how the thioroid gland is working. A doctor may also take an ultrasound image of the gland to detect whether the nodule is a cyst or a solid growth or tumor. In addition to doing aphysical examination, the doctor will ask you about any concerns and symptoms you have, your past health, your family's health, any medications you're taking, any allergies you may have, and other issues. This is called the medical history.

Another test called a thioroid scan can tell the doctor what type of nodule a person has. For this test, a person swallows a pill containing a small amount of radioactive iodine or another radioactive substance. The thioroid absorbs the radioactive substance. Next, a special camera measures where the radioactive substance is taken up by the thioroid gland, giving the doctor a better picture of the location, size, and type of thioroid nodule.

In addition, a fine needle biopsy may be done to help determine whether a nodule is cancerous. During the biopsy, the doctor inserts a thin needle through the skin into the thioroid nodule (the skin is numbed with medication first). Through the needle, the doctor takes a sample of tissue or some fluid from a cyst. The tissue or fluid is then sent to a lab to be examined. In some cases, a person might need to have the nodule surgically removed for more detailed examination in the lab. Fortunately, cancer is rare in children and teens, and most thioroid cancers can be cured or controlled with treatment.

Thioroid Disease, Growth, and Puberty

Once puberty starts, the body goes through some very noticeable changes. Because thioroid hormones play an important role in this process, thioroid disease may slow down or interfere with a teen's physical development. But it's important to know that not everyone grows or develops at the same age or at the same rate. If your friend seems to grow 4 inches overnight and you haven't had a growth spurt yet, it doesn't mean there's something wrong with you or your thioroid.

A thioroid problem may also cause a girl to have changes in her periods. Girls with thioroid problems may have a decrease or increase in menstrual flow or there may be a shorter or longer time between periods than usual. However, because girls who are just starting to menstruate often have irregular periods for the first year or so, changes in periods are usually nothing to worry about and don't mean a person has thioroid disease.

People who are concerned that they might have a thioroid problem should visit the doctor. Chances are, the problem is something simpler. And if a person does have thioroid disease, diagnosing and treating it properly - including bringing the blood levels of thioroid hormones back to normal - will usually prevent or correct any problems.

Keratitis

2009-06-08T06:04:00.000-07:00


Keratitis Classification and external resources
An eye with non-ulcerative sterile keratitis.
ICD-10	H 16.
ICD-9	370
DiseasesDB	7150
MeSH	D007634

Keratitis is a condition in which the eye's cornea, the front part of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves impaired eyesight. ^[1]

Types

Superficial keratitis involves the superficial layers of the cornea. After healing, this form of keratitis does not generally leave a scar.

Deep keratitis involves deeper layers of the cornea, and the natural course leaves a scar upon healing that impairs vision if on or near the visual axis. This can be reduced or avoided with the use of topical steroid eyedrops.

Causes

Keratitis has multiple causes, one of which is an infection of a present or previous herpes simplex virus secondary to an upper respiratory infection, involving cold sores.

Pathogens

Amoebic keratitis. Amoebic infection of the cornea is the most serious corneal infection, usually affecting contact lens wearers.^[2] It is usually caused by Acanthamoeba. On May 25, 2007, the CDC issued a health advisory due to increased risk of Acanthamoeba keratitis (AK)infection associated with use of Advanced Medical Optics (AMO) Complete Moisture Plus Multi-Purpose eye solution. See CDC Advisory
Bacterial keratitis. Bacterial infection of the cornea can follow from an injury or from wearing contact lenses. The bacteriums usually involved are Staphylococcus aureus and for contact lens wearers Pseudomonas aeruginosa.
Fungal keratitis (cf. Fusarium, causing recent incidences of keratitis through the possible vector of Bausch & Lomb ReNu with MoistureLoc contact lens solution)
Viral keratitis

Herpes simplex keratitis. Viral infection of the cornea is often caused by the herpes simplex virus which frequently leaves what is called a 'dendritic ulcer'.
Herpes zoster keratitis

Onchocercal keratitis -- for which reason onchocerciasis is also named "river blindness"

Other

Exposure keratitis
Photokeratitis - keratitis due to intense ultraviolet radiation exposure (e.g. snow blindness or welder's arc eye.)
Ulcerative keratitis
Contact lens acute red eye (CLARE) - a non-ulcerative sterile keratitis associated with colonization of Gram-negative bacteria on contact lenses
Severe allergic response may lead to corneal inflammation and ulceration (i.e. vernal keratoconjunctivitis).
Feline Eosinophilic Keratitis - affecting cats and horses; possibly initiateded by feline herpesvirus-1 or other viral infection.

Diagnosis

Effective diagnosis is important in detecting this condition and subsequent treatment as keratitis is sometimes mistaken for an allergic conjunctivitis.

Treatment

Treatment depends on the cause of the keratitis

Infectious keratitis generally requires antibacterial, antifungal, or antiviral therapy to treat the infection. This treatment can involve prescription eye drops, pills, or even intravenous therapy. Over-the-counter eye drops are typically not helpful in treating infections. In addition, contact lens wearers are typically advised to discontinue contact lens wear and discarding contaminated contact lenses and contact lens cases. Antibacterial solutions include Quixin (levofloxacin), Zymar (gatifloxacin), Vigamox (moxifloxacin), Ocuflox (ofloxacin — available generically). Steroid containing medications should not be used for bacterial infections, as they may exacerbate the disease and lead to severe corneal ulceration and corneal perforation. These include Maxitrol (neomycin+polymyxin+dexamethasone — available generically), as well as other steroid medications.. One should consult an Optometrist or qualified Ophthalmologist for treatment of an eye condition.

Some infections may scar the cornea to limit vision. Others may result in perforation of the cornea, (an infection inside the eye), or even loss of the eye. With proper medical attention, infections can usually be successfully treated without long-term visual loss.

Binswanger's disease

2009-06-08T06:01:00.000-07:00

Binswanger's disease or subcortical leukoencephalopathy is a rare form of multi-infarct dementia caused by damage to white brain matter.^[1] It is characterized by loss of memory and intellectual function and by changes in mood.

It was described by Otto Binswanger in 1894.^[2] Alois Alzheimer first used the phrase "Binswanger's disease" in 1902.^[3]

It was more formally described by Olszewski in 1962.^[4]^[5]

The term is sometimes considered too imprecise for formal nosology.^[6]

Presentation

Binswanger's disease is one of the neurological syndromes associated with hypertension. It is uncommon, but obviously devastating. The histologic findings are diffuse, irregular loss of axons and myelin accompanied by widespread gliosis. Small infarcts may be seen in the frontal lobes. The pathologic mechanism may be damage caused by severe atherosclerosis.

A patient with long term severe hypertension develops progressive dementia. CT scans of the head demonstrate a diffuse loss of deep hemispheric white matter.

Prognosis

Binswanger's disease has no known treatment, let alone cure, although drugs used to treat high blood pressure, depression, arrhythmia and low blood pressure are used to treat the condition's symptoms.

Congenital diaphragmatic hernia

2009-05-16T09:37:00.000-07:00

Congenital diaphragmatic hernia (CDH) is a term applied to a variety of congenital birth defects that involve abnormal development of the diaphragm. The term is used most commonly in reference to Bochdalek hernia, however it can also apply to Morgagni's hernia, diaphragm eventration and central tendon defects of the diaphragm. A common theme in all scenarios is malformation of the diaphragm; this allows the abdominal contents to protrude into the chest thereby impeding proper lung formation. Newborns with CDH often have severe respiratory distress which can be life-threatening unless treated appropriately.

Bochdalek hernia

Main article: Bochdalek hernia

The Bochdalek hernia, also known as a postero-lateral diaphragmatic hernia, is the most common manifestation of CDH, accounting for more than 95% of cases.^[1]^[2] In this instance the diaphragm abnormality is characterized by a hole in the postero-lateral corner of the diaphragm which allows passage of the abdominal viscera into the chest cavity. The majority of Bochdalek hernias (80-85%) occur on the left side of the diaphragm, a large proportion of the remaining cases occur on the right side, and a small fraction are bilateral i.e., left and right sided defects. ^[3]^[4]

Pathophysiology

It involves three major defects.

A failure of the diaphragm to completely close during development.
Herniation of the abdominal contents into the chest
Pulmonary hypoplasia

Presentation and diagnosis

This condition can often be diagnosed before birth and fetal intervention can sometimes help, depending on the severity of the condition.^[5] Infants born with diaphragmatic hernia experience respiratory failure due to both pulmonary hypertension and pulmonary hypoplasia. The first condition is a restriction of blood flow through the lungs thought to be caused by defects in the lung. Pulmonary hypoplasia or decreased lung volume is directly related to the abdominal organs presence in the chest cavity which causes the lungs to be severely undersized, especially on the side of the hernia.

Survival rates for infants with this condition vary, but have generally been increasing through advances in neonatal medicine. Work has been done to correlate survival rates to ultrasound measurements of the lung volume as compared to the baby's head circumference. This figure known as the lung to head ratio (LHR).

Treatment

ECMO has been used as part of the treatment strategy at some hospitals.^[6]^[7]

Morbidity and mortality

Congenital Diaphragmatic Hernia has a mortality rate of 50%. This is an average rate of success, individual rates vary greatly dependent upon multiple factors; size of hernia, organs involved, additional birth defects or genetic problems, amount of lung growth, age and size at birth, type of treatments, timing of treatments, complications such as infections and lack of lung function. Each patient is different, therefore each patient has different chances of survival.

Morgagni's hernia

Morgagni's Hernia

This rare anterior defect of the diaphragm is variably referred to as Morgagni’s, retrosternal, or parasternal hernia. Accounting for approximately 2% of all CDH cases, it is characterised by herniation through the foramina of Morgagni which are located immediately adjacent to the xiphoid process of the sternum.^[8] The majority of hernias occur on the right side of the body and are generally asymptomatic; However newborns may present with respiratory distress at birth similar to Bochdalek hernia. Additionally, recurrent chest infections and gastrointestinal symptoms have been reported in those with previously undiagnosed Morgagni's hernia.^[9]^[10] In asymptomatic individuals laparoscopic surgical repair is still recommended as they are at risk of a strangulated intestine.

Diaphragm eventration

The diagnosis of congenital diaphragmatic eventration is used when there is abnormal displacement (i.e. elevation) of part or all of an otherwise intact diaphragm into the chest cavity. This rare type of CDH occurs because in the region of eventration the diaphragm is thinner, allowing the abdominal viscera to protrude upwards. This thinning is thought to occur because of incomplete muscularisation of the diaphragm, and can be found unilaterally or bilaterally. ^[11] Minor forms of diaphragm eventration are asymptomatic, however in severe cases infants will present with respiratory distress similar to Bochdalek hernia.^[12] Diaphragm eventration is typically repaired thoracoscopically, by a technique called plication of the diaphragm. ^[13] Plication basically involves a folding of the eventrated diaphragm which is then sutured in order to “take up the slack” of the excess diaphragm tissue.

Coeliac disease

2009-05-16T09:34:00.000-07:00


Coeliac disease Classification and external resources
Biopsy of small bowel showing coeliac disease manifested by blunting of villi, crypt hyperplasia, and lymphocyte infiltration of crypts
ICD-10	K 90.0
ICD-9	579.0
OMIM	212750
DiseasesDB	2922
MedlinePlus	000233
eMedicine	med/308 ped/2146 radio/652
MeSH	D002446

Coeliac disease (pronounced /ˈsiːli.æk/), also spelled celiac disease, is an autoimmune disorder of the small intestine that occurs in genetically predisposed people of all ages from middle infancy on up. Symptoms include chronic diarrhœa, failure to thrive (in children), and fatigue, but these may be absent, and symptoms in all other organ systems have been described. A growing portion of diagnoses are being made in asymptomatic persons as a result of increased screening.^[1]

Coeliac disease is caused by a reaction to gliadin, a gluten protein found in wheat (and similar proteins of the tribe Triticeae, which includes other cultivars such as barley and rye). Upon exposure to gliadin, the enzyme tissue transglutaminase modifies the protein, and the immune system cross-reacts with the small-bowel tissue, causing an inflammatory reaction. That leads to flattening of the lining of the small intestine (called villous atrophy). This interferes with the absorption of nutrients, because the intestinal villi are responsible for absorption. The only known effective treatment is a lifelong gluten-free diet. While the disease is caused by a reaction to wheat proteins, it is not the same as wheat allergy.

This condition has several other names, including: cœliac disease (with œ ligature), c(o)eliac sprue, non-tropical sprue, endemic sprue, gluten enteropathy or gluten-sensitive enteropathy, and gluten intolerance. The term coeliac derives from the Greek κοιλιακός (koiliakόs, "abdominal"), and was introduced in the 19th century in a translation of what is generally regarded as an ancient Greek description of the disease by Aretaeus of Cappadocia.^[2]

Signs and symptoms

Classic symptoms of coeliac disease include diarrhoea, weight loss (or stunted growth in children), and fatigue, but while coeliac disease is primarily a bowel disease, bowel symptoms may also be limited or even absent. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Given this wide range of possible symptoms, the classic triad is no longer a requirement for diagnosis.

Children between 9 and 24 months tend to present with bowel symptoms and growth problems shortly after first exposure to gluten-containing products. Older children may have more malabsorption-related problems and psychosocial problems, while adults generally have malabsorptive problems.^[3] Many adults with subtle disease only have fatigue or anaemia.^[1]

Gastrointestinal

The diarrhoea characteristic of coeliac disease is pale, voluminous and malodorous. Abdominal pain and cramping, bloatedness with abdominal distension (thought to be due to fermentative production of bowel gas) and mouth ulcers^[4] may be present. As the bowel becomes more damaged, a degree of lactose intolerance may develop. However, the variety of gastrointestinal symptoms that may be present in patients with coeliac disease is great, and some may have a normal bowel habit or even tend towards constipation. Frequently, the symptoms are ascribed to irritable bowel syndrome (IBS), only later to be recognised as coeliac disease; a small proportion of patients with symptoms of IBS have underlying coeliac disease, and screening may be justified.^[5]

Coeliac disease leads to an increased risk of both adenocarcinoma and lymphoma of the small bowel, which returns to baseline with diet. Longstanding disease may lead to other complications, such as ulcerative jejunitis (ulcer formation of the small bowel) and stricturing (narrowing as a result of scarring).^[6]

Malabsorption-related

The changes in the bowel make it less able to absorb nutrients, minerals and the fat-soluble vitamins A, D, E, and K.^[3]

The inability to absorb carbohydrates and fats may cause weight loss (or failure to thrive/stunted growth in children) and fatigue or lack of energy.
Anaemia may develop in several ways: iron malabsorption may cause iron deficiency anaemia, and folic acid and vitamin B12 malabsorption may give rise to megaloblastic anaemia.
Calcium and vitamin D malabsorption (and compensatory secondary hyperparathyroidism) may cause osteopenia (decreased mineral content of the bone) or osteoporosis (bone weakening and risk of fragility fractures).
A small proportion (10%) have abnormal coagulation due to deficiency of vitamin K and are slightly at risk for abnormal bleeding.
Coeliac disease is also associated with bacterial overgrowth of the small intestine, which can worsen malabsorption or cause malabsorption after treatment.^[7]

Miscellaneous

Coeliac disease has been linked with a number of conditions. In many cases, it is unclear whether the gluten-induced bowel disease is a causative factor or whether these conditions share a common predisposition.

IgA deficiency is present in 2% of patients with coeliac disease, and in turn, this condition features a tenfold increased risk of coeliac disease.^[8]^[9] Other features of this condition are an increased risk of infections and autoimmune disease.
Dermatitis herpetiformis; this itchy cutaneous condition has been linked to a transglutaminase enzyme in the skin, features small-bowel changes identical to those in coeliac disease^[10] and occurs more often (in 2%) in patients with coeliac disease.^[3]
Neurological associations: epilepsy, ataxia (coordination problems), myelopathy, peripheral neuropathy, and schizophrenia ^[11] have all been linked with coeliac disease, but the strength of these associations and the causality are still subject to debate.^[12]
Growth failure and/or pubertal delay in later childhood can occur even without obvious bowel symptoms or severe malnutrition. Evaluation of growth failure often includes coeliac screening.
Miscarriage and infertility.
Hyposplenism (a small and underactive spleen)—it is unclear whether this actually increases infection risk in the same way as in other people without a functioning spleen.^[13]
Other autoimmune disorders: diabetes mellitus type 1,^[14] autoimmune thyroiditis,^[15] primary biliary cirrhosis,^[16] and microscopic colitis.^[17]

Other grains

Wheat varieties or subspecies containing gluten and related species such as barley and rye also induce symptoms of coeliac disease.^[18] A small minority of coeliac patients also react to oats.^[19]^[20] It is most probable that oats produce symptoms due to cross contamination with other grains in the fields or in the distribution channels.^[3] Generally, oats are therefore not recommended^[18], though gluten-free oats are available in some locales and may be tried with caution.^[21] Other cereals such as maize (corn), quinoa, millet, sorghum, teff, amaranth, buckwheat, rice, and wild rice are safe for patients to consume.^[22] Non-cereal carbohydrate-rich foods such as potatoes and bananas do not contain gluten and do not trigger symptoms.

Diagnosis

There are several tests that can be used to assist in diagnosis. The level of symptoms may determine the order of the tests, but all tests lose their usefulness if the patient is already taking a gluten-free diet. Intestinal damage begins to heal within weeks of gluten being removed from the diet, and antibody levels decline over months. For those who have already started on a gluten-free diet, it may be necessary to perform a re-challenge with 10 g of gluten (four slices of bread) per day over 2–6 weeks before repeating the investigations. Those who experience severe symptoms (e.g. diarrhoea) earlier can be regarded as sufficiently challenged and can be tested earlier.^[3]

Combining findings into a prediction rule to guide use of endoscopy reported a sensitivity of 100% (it would identify all the cases) and specificity of 61% (it would be incorrectly positive in 39%). The prediction rule recommends that patients with high-risk symptoms or positive serology should undergo endoscopy. The study defined high-risk symptoms as weight loss, anaemia (haemoglobin less than 120 g/l in females or less than 130 g/l in males), or diarrhoea (more than three loose stools per day).^[23]

Blood tests

Antibody testing

Serological blood tests are the first-line investigation required to make a diagnosis of coeliac disease. Serology for anti-tTG antibodies has superseded older serological tests and has a high sensitivity (99%) and specificity (>90%) for identifying coeliac disease. Modern anti-tTG assays rely on a human recombinant protein as an antigen.^[24]

Because of the major implications of a diagnosis of coeliac disease, professional guidelines recommend that a positive blood test is still followed by an endoscopy/gastroscopy and biopsy. A negative serology test may still be followed by a recommendation for endoscopy and duodenal biopsy if clinical suspicion remains high due to the 1 in 100 "false-negative" result. As such, tissue biopsy is still considered the gold standard in the diagnosis of coeliac disease.^[3]^[6]

Historically three other antibodies were measured: anti-reticulin (ARA), anti-gliadin (AGA) and anti-endomysium (EMA) antibodies. Serology may be unreliable in young children, with anti-gliadin performing somewhat better than other tests in children under five.^[25] Serology tests are based on indirect immunofluorescence (reticulin, gliadin and endomysium) or ELISA (gliadin or tissue transglutaminase, tTG).^[26]

Guidelines recommend that a total serum IgA level is checked in parallel, as coeliac patients with IgA deficiency may be unable to produce the antibodies on which these tests depend ("false negative"). In those patients, IgG antibodies against transglutaminase (IgG-tTG) may be diagnostic.^[27]

Blood HLA tests for coeliac disease^[28]
Test	sensitivity	specificity
HLA-DQ2	94%	73%
HLA-DQ8	12%	81%

HLA genetic typing

Antibody testing and HLA testing have similar accuracies.^[28]

[edit] Endoscopy

Endoscopic still of duodenum of patient with coeliac disease showing scalloping of folds

Schematic of the Marsh classification of upper jejunal pathology in coeliac disease

An upper endoscopy with biopsy of the duodenum (beyond the duodenal bulb) or jejunum is performed. It is important for the physician to obtain multiple samples (four to eight) from the duodenum. Not all areas may be equally affected; if biopsies are taken from healthy bowel tissue, the result would be a false negative.^[6]

Most patients with coeliac disease have a small bowel that appears normal on endoscopy; however, five concurrent endoscopic findings have been associated with a high specificity for coeliac disease: scalloping of the small bowel folds (pictured), paucity in the folds, a mosaic pattern to the mucosa (described as a "cracked-mud" appearance), prominence of the submucosa blood vessels, and a nodular pattern to the mucosa.^[29]

Until the 1970s, biopsies were obtained using metal capsules attached to a suction device. The capsule was swallowed and allowed to pass into the small intestine. After x-ray verification of its position, suction was applied to collect part of the intestinal wall inside the capsule. One often-utilised capsule system is the Watson capsule. This method has now been largely replaced by fibre-optic endoscopy, which carries a higher sensitivity and a lower frequency of errors.^[30]

Pathology

The classic pathology changes of coeliac disease in the small bowel are categorised by the "Marsh classification":^[31]

Marsh stage 0: normal mucosa
Marsh stage 1: increased number of intra-epithelial lymphocytes, usually exceeding 20 per 100 enterocytes
Marsh stage 2: proliferation of the crypts of Lieberkuhn
Marsh stage 3: partial or complete villous atrophy
Marsh stage 4: hypoplasia of the small bowel architecture

The changes classically improve or reverse after gluten is removed from the diet, so many official guidelines recommend a repeat biopsy several (4–6) months after commencement of gluten exclusion.^[3]

In some cases, a deliberate gluten challenge, followed by biopsy, may be conducted to confirm or refute the diagnosis. A normal biopsy and normal serology after challenge indicates the diagnosis may have been incorrect.^[3] Patients are warned that one does not "outgrow" coeliac disease in the same way as childhood food intolerances.

Other diagnostic tests

Other tests that may assist in the diagnosis are blood tests for a full blood count, electrolytes, calcium, renal function, liver enzymes, vitamin B12 and folic acid levels. Coagulation testing (prothrombin time and partial thromboplastin time) may be useful to identify deficiency of vitamin K, which predisposes patients to hemorrhage. These tests should be repeated on follow-up, as well as anti-tTG titres.^[3]

Some professional guidelines^[3] recommend screening of all patients for osteoporosis by DXA/DEXA scanning.

Pathophysiology

Coeliac disease appears to be polyfactorial, both in that more than one genetic factor can cause the disease and that more than one factor is necessary for the disease to manifest in a patient.

Almost all coeliac patients have the variant HLA DQ2 allele.^[1] However, about 20–30% of people without coeliac disease have inherited an HLA-DQ2 allele.^[28] This suggests additional factors are needed for coeliac disease to develop. Furthermore, about 5% of those people who do develop coeliac disease do not have the DQ2 gene.^[1]

The HLA-DQ2 allele shows incomplete penetrance, as the gene alleles associated with the disease appear in most patients but are neither present in all cases nor sufficient by themselves to cause the disease.

Genetics

The vast majority of coeliac patients have one of two types of HLA-DQ.^[28] This gene is part of the MHC class II antigen-presenting receptor (also called the human leukocyte antigen) system and distinguishes cells between self and non-self for the purposes of the immune system. The gene is located on the short arm of the sixth chromosome, and as a result of the linkage, this locus has been labeled CELIAC1.

DQ α⁵-β² -binding cleft with a deamidated gliadin peptide (yellow), modified from PDB 1S9V^[32]

There are seven HLA DQ variants (DQ2 and DQ4–DQ9). Over 95% of coeliac patients have the isoform of DQ2 or DQ8, which is inherited in families. The reason these genes produce an increase in risk of coeliac disease is that the receptors formed by these genes bind to gliadin peptides more tightly than other forms of the antigen-presenting receptor. Therefore, these forms of the receptor are more likely to activate T lymphocytes and initiate the autoimmune process.^[1]

Most coeliac patients bear a two-gene HLA-DQ2 haplotype referred to as DQ2.5 haplotype. This haplotype is composed of two adjacent gene alleles, DQA1*0501 and DQB1*0201, which encode the two subunits, DQ α⁵ and DQ β². In most individuals, this DQ2.5 isoform is encoded by one of two chromosomes 6 inherited from parents. Most coeliacs inherit only one copy of this DQ2.5 haplotype, while some inherit it from both parents; the latter are especially at risk for coeliac disease, as well as being more susceptible to severe complications.^[33] Some individuals inherit DQ2.5 from one parent and portions of the haplotype (DQB1*02 or DQA1*05) from the other parent, increasing risk. Less commonly, some individuals inherit the DQA1*05 allele from one parent and the DQB1*02 from the other parent, called a trans-haplotype association, and these individuals are at similar risk for coeliac disease as those with a single DQ2.5-bearing chromosome 6, but in this instance, disease tends not to be familial. Among the 6% of European coeliacs that do not have DQ2.5(cis or trans) or DQ8 (encoded by the haplotype DQA1*03:DQB1*0302), 4% have the DQ2.2 isoform, and the remaining 2% lack DQ2 or DQ8.^[34]

The frequency of these genes varies geographically. DQ2.5 has high frequency in peoples of North and Western Europe (Basque Country and Ireland^[35] with highest frequencies) and portions of Africa and is associated with disease in India,^[36] but is not found along portions of the West Pacific rim. DQ8, spread more globally than DQ2.5, is more prevalent from South and Central America (up to 90% phenotype frequency).^[37]

Prolamins

The majority of the proteins in food responsible for the immune reaction in coeliac disease are the prolamins. These are storage proteins rich in proline (prol-) and glutamine (-amin) that dissolve in alcohols and are resistant to proteases and peptidases of the gut.^[38]^[1] One region of α-gliadin stimulates membrane cells, enterocytes, of the intestine to allow larger molecules around the sealant between cells. Disruption of tight junctions allow peptides larger than three amino acids to enter circulation.^[39]

Illustration of deamidated α-2 gliadin's 33mer, amino acids 56-88, showing the overlapping of three varieties of T-cell epitope^[40]

Membrane leaking permits peptides of gliadin that stimulate two levels of immune response, the innate response and the adaptive (T-helper cell mediated) response. One protease-resistant peptide from α-gliadin contains a region that stimulates lymphocytes and results in the release of interleukin-15. This innate response to gliadin results in immune-system signalling that attracts inflammatory cells and increases the release inflammatory chemicals.^[1] The strongest and most common adaptive response to gliadin is directed toward an α2-gliadin fragment of 33 amino acids in length.^[1] The response to 33mer occurs in most coeliacs who have a DQ2 isoform. This peptide, when altered by intestinal transglutaminase, has a high density of overlapping T-cell epitopes. This increases the likelihood that the DQ2 isoform will bind and stay bound to peptide when recognised by T-cells.^[40] Gliadin in wheat is the best-understood member of this family, but other prolamins exist, and hordein (from barley) and secalin (from rye) may contribute to coeliac disease.^[1]^[41] However, not all prolamins will cause this immune reaction, and there is ongoing controversy on the ability of avenin (the prolamin found in oats) to induce this response in coeliac disease.

Tissue transglutaminase

Anti-transglutaminase antibodies to the enzyme tissue transglutaminase (tTG) are found in an overwhelming majority of cases.^[42] Tissue transglutaminase modifies gluten peptides into a form that may stimulate the immune system more effectively.^[1]

Stored biopsies from suspected coeliac patients have revealed that autoantibody deposits in the subclinical coeliacs are detected prior to clinical disease. These deposits are also found in patients who present with other autoimmune diseases, anaemia or malabsorption phenomena at a much-increased rate over the normal population.^[43] Endomysial components of antibodies (EMA) to tTG are believed to be directed toward cell-surface transglutaminase, and these antibodies are still used in confirming a coeliac disease diagnosis. However, a 2006 study showed that EMA-negative coeliac patients tend to be older males with more severe abdominal symptoms and a lower frequency of "atypical" symptoms including autoimmune disease.^[44] In this study, the anti-tTG antibody deposits did not correlate with the severity of villous destruction. These findings, coupled with recent work showing that gliadin has an innate response component,^[45] suggests that gliadin may be more responsible for the primary manifestations of coeliac disease, whereas tTG is a bigger factor in secondary effects such as allergic responses and secondary autoimmune diseases. In a large percentage of coeliac patients, the anti-tTG antibodies also recognise a rotavirus protein called VP7. These antibodies stimulate monocyte proliferation, and rotavirus infection might explain some early steps in the cascade of immune cell proliferation.^[46] Indeed, earlier studies of rotavirus damage in the gut showed this causes a villous atrophy.^[47] This suggests that viral proteins may take part in the initial flattening and stimulate self-crossreactive anti-VP7 production. Antibodies to VP7 may also slow healing until the gliadin-mediated tTG presentation provides a second source of crossreactive antibodies.

Villous atrophy and malabsorption

The inflammatory process, mediated by T cells, leads to disruption of the structure and function of the small bowel's mucosal lining and causes malabsorption as it impairs the body's ability to absorb nutrients, minerals and fat-soluble vitamins A, D, E and K from food. Lactose intolerance may be present due to the decreased bowel surface and reduced production of lactase but typically resolves once the condition is treated.

Alternative causes of this tissue damage have been proposed and involve release of interleukin 15 and activation of the innate immune system by a shorter gluten peptide (p31–43/49). This would trigger killing of enterocytes by lymphocytes in the epithelium.^[1] The villous atrophy seen on biopsy may also be due to unrelated causes, such as tropical sprue, giardiasis and radiation enteritis. While positive serology and typical biopsy are highly suggestive of coeliac disease, lack of response to diet may require these alternative diagnoses to be considered.^[6]

Risk modifiers

There are various theories as to what determines whether a genetically susceptible individual will go on to develop coeliac disease. Major theories include infection by rotavirus^[48] or human intestinal adenovirus.^[49] Some research has suggested that smoking is protective against adult-onset coeliac disease.^[50]

A 2005 prospective and observational study found that timing of the exposure to gluten in childhood was an important risk modifier. People exposed to wheat, barley, or rye before the gut barrier has fully developed (within the first three months after birth) had five times the risk of developing coeliac disease relative to those exposed at four to six months after birth. Those exposed even later than six months after birth were found to have only a slightly increased risk relative to those exposed at four to six months after birth.^[51] However, a 2006 study with similar numbers found just the reverse, that early introduction of grains was protective.^[52] Breastfeeding may also reduce risk. A meta-analysis indicates that prolonging breastfeeding until the introduction of gluten-containing grains into the diet was associated with a 52% reduced risk of developing coeliac disease in infancy; whether this persists into adulthood is not clear.^[53]

Treatment

Diet

At present, the only effective treatment is a life-long gluten-free diet.^[18] No medication exists that will prevent damage or prevent the body from attacking the gut when gluten is present. Strict adherence to the diet allows the intestines to heal, leading to resolution of all symptoms in most cases and, depending on how soon the diet is begun, can also eliminate the heightened risk of osteoporosis and intestinal cancer.^[54] Dietician input is generally requested to ensure the patient is aware which foods contain gluten, which foods are safe, and how to have a balanced diet despite the limitations. In many countries, gluten-free products are available on prescription and may be reimbursed by health insurance plans, however gluten-free products are hard to find in Asian countries because Coeliac Disease is not a serious epidemic in these countries. Websites such as glutenfreemall.com helps Americans as well as others order gluten-free products domestically and internationally. More manufacturers are producing gluten-free products, some of which are almost indistinguishable from their gluten-containing counterparts.

The diet can be cumbersome; failure to comply with the diet may cause relapse. The term gluten-free is generally used to indicate a supposed harmless level of gluten rather than a complete absence.^[55] The exact level at which gluten is harmless is uncertain and controversial. A recent systematic review tentatively concluded that consumption of less than 10 mg of gluten per day is unlikely to cause histological abnormalities, although it noted that few reliable studies had been done.^[55] Regulation of the label gluten-free varies widely by country. For example, in the United States, the term gluten-free is not yet regulated.^[56] The current international Codex Alimentarius standard, established in 1981, allows for 50 mg N/100 g on dry matter,^[57] although a proposal for a revised standard of 20 ppm in naturally gluten-free products and 200 ppm in products rendered gluten-free has been accepted.^[58] Gluten-free products are usually more expensive and harder to find than common gluten-containing foods.^[59] Since ready-made products often contain traces of gluten, some coeliacs may find it necessary to cook from scratch.^[58]

Even while on a diet, health-related quality of life (HRQOL) may be lower in people with coeliac disease. Studies in the United States have found that quality of life becomes comparable to the general population after staying on the diet, while studies in Europe have found that quality of life remains lower, although the surveys are not quite the same.^[60] Men tend to report more improvement than women.^[61] Some have persisting digestive symptoms or dermatitis herpetiformis, mouth ulcers, osteoporosis and resultant fractures. Symptoms suggestive of irritable bowel syndrome may be present, and there is an increased rate of anxiety, fatigue, dyspepsia and musculoskeletal pain.^[62]

Refractory disease

A tiny minority of patients suffer from refractory disease, which means they do not improve on a gluten-free diet. This may be because the disease has been present for so long that the intestines are no longer able to heal on diet alone, or because the patient is not adhering to the diet, or because the patient is consuming foods that are inadvertently contaminated with gluten. If alternative causes have been eliminated, steroids or immunosuppressants (such as azathioprine) may be considered in this scenario.^[6]

[edit] Experimental treatments

Various other approaches are being studied that would reduce the need of dieting. All are still under development, and are not expected to be available to the general public for a while:^[1]

Genetically engineered wheat species, or wheat species that have been selectively bred to be minimally immunogenic. This, however, could interfere with the effects that gliadin has on the quality of dough.
A combination of enzymes (prolyl endopeptidase and a barley glutamine-specific cysteine endopeptidase (EP-B2)) that degrade the putative 33-mer peptide in the duodenum. This combination would enable coeliac disease patients to consume gluten-containing products.^[63]
Inhibition of zonulin, an endogenous signalling protein linked to increased permeability of the bowel wall and hence increased presentation of gliadin to the immune system.^[64]
Other treatments aimed at other well-understood steps in the pathogenesis of coeliac disease, such as the action of HLA-DQ2 or tissue transglutaminase and the MICA/NKG2D interaction that may be involved in the killing of enterocytes (bowel lining cells).

Screening and case finding

There is significant debate as to the benefits of screening. Some studies suggest that early detection would decrease the risk of osteoporosis and anaemia. In contrast, a cohort studied in Cambridge suggested that people with undetected coeliac disease had a beneficial risk profile for cardiovascular disease (less overweight, lower cholesterol levels).^[1]

Due to its high sensitivity, serology has been proposed as a screening measure, because the presence of antibodies would detect previously undiagnosed cases of coeliac disease and prevent its complications in those patients. Serology may also be used to monitor adherence to diet: in those who still ingest gluten, antibody levels remain elevated.^[3]^[6]

In the United Kingdom, the National Institute for Health and Clinical Excellence (NICE) recommends screening for coeliac disease in patients with newly diagnosed chronic fatigue syndrome^[65] and irritable bowel syndrome.^[66]

Other clinical scenarios in which screening may be justified include type 1 diabetes,^[14] unexplained iron-deficiency anaemia,^[67]^[68] Down's syndrome, Turner's syndrome, lupus, and autoimmune thyroid disease.^[69]

Epidemiology

The prevalence of clinically diagnosed disease (symptoms prompting diagnostic testing) is 0.05–0.27% in various studies. However, population studies from parts of Europe, India, South America, Australasia and the USA (using serology and biopsy) indicate that the prevalence may be between 0.33 and 1.06% in children (5.66% in one study of Sahrawi children^[70]) and 0.18–1.2% in adults.^[1] People of African, Japanese and Chinese descent are rarely diagnosed; this reflects a much lower prevalence of the genetic risk factors. Population studies also indicate that a large proportion of coeliacs remain undiagnosed; this is due to many clinicians being unfamiliar with the condition.^[71]

A large multicentre study in the U.S. found a prevalence of 0.75% in not-at-risk groups, rising to 1.8% in symptomatic patients, 2.6% in second-degree relatives of a patient with coeliac disease and 4.5% in first-degree relatives. This profile is similar to the prevalence in Europe.^[72] Other populations at increased risk for coeliac disease, with prevalence rates ranging from 5% to 10%, include individuals with Down and Turner syndromes, type 1 diabetes, and autoimmune thyroid disease, including both hyperthyroidism (overactive thyroid) and hypothyroidism (underactive thyroid).^[73]

Historically, coeliac disease was thought to be rare, with a prevalence of about 0.02%.^[73] Recent increases in the number of reported cases may be due to changes in diagnostic practice.^[74]

Social and religious issues

Christian churches & the Eucharist

Most mainstream Christian churches offer their communicants gluten-free alternatives to the sacramental bread, usually in the form of a rice-based cracker or gluten-free bread. These include United Methodist, Christian Reformed, Episcopal, Lutheran, The Church of Jesus Christ of Latter-day Saints, and many others.^[75]

Roman Catholic position

Roman Catholic doctrine states that for a valid Eucharist, the bread must be made from wheat. In 2002, the Congregation for the Doctrine of the Faith approved German-made low-gluten hosts, which meet all of the Catholic Church's requirements, for use in Italy; although not entirely gluten-free, they were also approved by the Italian Celiac Association.^[76] Some Catholic coeliac sufferers have requested permission to use rice wafers; such petitions have always been denied.^[77] The issue is more complex for priests. Though a Catholic (lay or ordained) receiving under either form is receiving Christ "whole and entire", his body, blood, soul, and divinity, the priest, who is acting in persona Christi, is required to receive under both species when offering Mass—not for the validity of his Communion, but for the fullness of the sacrifice of the Mass. On 22 August 1994, the Congregation for the Doctrine of the Faith apparently barred coeliacs from ordination, stating, "Given the centrality of the celebration of the Eucharist in the life of the priest, candidates for the priesthood who are affected by coeliac disease or suffer from alcoholism or similar conditions may not be admitted to holy orders." After considerable debate, the congregation softened the ruling on 24 July 2003 to "Given the centrality of the celebration of the Eucharist in the life of a priest, one must proceed with great caution before admitting to Holy Orders those candidates unable to ingest gluten or alcohol without serious harm."^[78]

As of January 2004, an extremely low-gluten host became available in the United States. The Benedictine Sisters of Perpetual Adoration in Clyde, Missouri, produce low-gluten hosts safe for celiacs and also approved by the Catholic Church for use at Mass. The hosts are made and packaged in a dedicated wheat-free, gluten-free environment. Gluten-content analysis found no detectable amount of gluten, though the reported gluten content is 0.01% as that was the lowest limit of detection possible with the utilized analysis technique. In an article from the Catholic Review (15 February 2004), Dr. Alessio Fasano was quoted as declaring these hosts "perfectly safe for celiac sufferers." ^[79]

[edit] Coeliacs and Passover

The Jewish festival of Pesach (Passover) may present problems with its obligation to eat matzo, which is unleavened bread made in a strictly controlled manner from wheat, barley, spelt, oats, or rye. This rules out many other grains that are normally used as substitutes for people with gluten sensitivity, especially for Ashkenazi Jews, who also avoid rice. Many kosher for Passover products avoid grains altogether and are therefore gluten-free. Potato starch is the primary starch used to replace the grains. Consuming matzo is mandatory on the first night of Pesach only. Jewish law holds that a person should not seriously endanger one's health in order to fulfill a commandment. Thus, a person with severe coeliac disease is not required, or even allowed, to eat any matzo other than gluten-free matzo. The most commonly used gluten-free matzo is made from oats.^[80]

History

Aretaeus of Cappadocia, living in the second century, recorded a malabsorptive syndrome with chronic diarrhoea. His "Cœliac Affection" (coeliac from Greek κοιλιακός koiliakos, "abdominal") gained the attention of Western medicine when Francis Adams presented a translation of Aretaeus's work at the Sydenham Society in 1856. The patient had stomach pain and was atrophied, pale, feeble and incapable of work. The diarrhoea manifested as loose stools that were white, malodorous and flatulent, and the disease was intractable and liable to periodic return. The problem, Aretaeus believed, was a lack of heat in the stomach necessary to digest the food and a reduced ability to distribute the digestive products throughout the body, this incomplete digestion resulting in the diarrhoea. He regarded this as an affliction of the old and more commonly affecting women, explicitly excluding children. The cause, according to Aretaeus, was sometimes either another chronic disease or even consuming "a copious draught of cold water".^[2]

The paediatrician Samuel Gee gave the first modern-day description of the condition in a lecture at Hospital for Sick Children, Great Ormond Street, London, in 1887. Gee acknowledged earlier descriptions and terms for the disease and adopted the same term as Aretaeus (coeliac disease). Unlike Aretaeus, he included children in the scope of the affliction, particularly those between one and five years old. Gee found the cause to be obscure and failed to spot anything abnormal during post-mortem examination (the lining of the small bowel quickly deteriorates on death).^[81] He perceptively stated, "If the patient can be cured at all, it must be by means of diet." Gee recognised that milk intolerance is a problem with coeliac children and that highly starched foods should be avoided. However, he forbade rice, sago, fruit and vegetables, which all would have been safe to eat, and he recommended raw meat as well as thin slices of toasted bread. Gee highlighted particular success with a child "who was fed upon a quart of the best Dutch mussels daily". However, the child could not bear this diet for more than one season.^[82]

Christian Archibald Herter, an American physician, wrote a book in 1908 on children with coeliac disease, which he called "intestinal infantilism". He noted their growth was retarded and that fat was better tolerated than carbohydrate. The eponym Gee-Herter disease was sometimes used to acknowledge both contributions.^[83]^[84] Sydney V. Haas, an American paediatrician, reported positive effects of a diet of bananas in 1924.^[85] This diet remained in vogue until the actual cause of coeliac disease was determined.

While a role for carbohydrates had been suspected, the link with wheat was not made until the 1940s by the Dutch paediatrician Dr Willem Dicke.^[86] It is likely that clinical improvement of his patients during the Dutch famine of 1944 (during which flour was sparse) may have contributed to his discovery.^[87] The link with the gluten component of wheat was made in 1952 by a team from Birmingham, England.^[88] Villous atrophy was described by British physician John W. Paulley in 1954.^[89] Paulley was able to examine biopsies taken from patients during abdominal operations.^[81] Dr Margo Shiner, working on Prof Sheila Sherlock's team at the Postgraduate Medical School in London, described the principles of small-bowel biopsy in 1956.^[90]

Throughout the 1960s other features of coeliac disease were elucidated. Its hereditary character was recognised in 1965.^[91] In 1966 dermatitis herpetiformis was linked to gluten sensitivity.^[10]

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