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Thalassemia

Thalassemias are inherited blood disorders that result in abnormal hemoglobin. Symptoms depend on the type of thalassemia and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin) as thalassemia can affect the production of red blood cells and also affect how long the red blood cells live. Symptoms of anemia include feeling tired and having pale skin. Other symptoms of thalassemia include bone problems, an enlarged spleen, yellowish skin, pulmonary hypertension, and dark urine. Slow growth may occur in children. Symptoms and presentations of thalassemia can change over time. Thalassemia is also known as Cooley's anemia or Mediterranean anemia.

Thalassemias are genetic disorders. There are two main types, alpha thalassemia and beta thalassemia. The severity of alpha and beta thalassemia depends on how many of the four genes for alpha globin or two genes for beta globin are missing. Diagnosis is typically by blood tests including a complete blood count, special hemoglobin tests, and genetic tests. Diagnosis may occur before birth through prenatal testing.

Treatment depends on the type and severity. Treatment for those with more severe disease often includes regular blood transfusions, iron chelation, and folic acid. Iron chelation may be done with deferoxamine, deferasirox or deferiprone. Occasionally, a bone marrow transplant may be an option. Complications may include iron overload from the transfusions with resulting heart or liver disease, infections, and osteoporosis. If the spleen becomes overly enlarged, surgical removal may be required. Thalassemia patients who do not respond well to blood transfusions can take hydroxyurea or thalidomide, and sometimes a combination of both. Hydroxyurea is the only FDA approved drug for thalassemia. Patients who took 10 mg/kg of hydroxyurea every day for a year had significantly higher hemoglobin levels, and it was a well-tolerated treatment for patients who did not respond well to blood transfusions. Other known hemoglobin-inducers include thalidomide, but it has not been tested in a clinical setting. The combination of thalidomide and hydroxyurea resulted in hemoglobin levels increasing significantly in transfusion-dependent and non-transfusion dependent patients

As of 2015, thalassemia occurs in about 280 million people, with about 439,000 having severe disease. It is most common among people of Greek, Italian, Middle Eastern, South Asian, and African descent. Males and females have similar rates of disease. It resulted in 16,800 deaths in 2015, down from 36,000 deaths in 1990. Those who have minor degrees of thalassemia, in common with those who have sickle-cell trait, have some protection against malaria, explaining why sickle-cell trait and thalassemia are more common in regions of the world where the risk of malaria is higher. An estimated 1/3 of people with thalassemia have "non-transfusion dependent thalassemia" and do not depend on regularly continuing blood transfusions to survive.

Signs and symptoms

 * Iron overload: People with thalassemia can get an overload of iron in their bodies, either from the disease itself or from frequent blood transfusions. Too much iron can result in damage to the heart, liver, and endocrine system, which includes glands that produce hormones that regulate processes throughout the body. The damage is characterized by excessive deposits of iron. Without adequate iron chelation therapy, almost all patients with beta-thalassemia accumulate potentially fatal iron levels.
 * Infection: People with thalassemia have an increased risk of infection. This is especially true if the spleen has been removed.
 * Bone deformities: Thalassemia can make the bone marrow expand, which causes bones to widen. This can result in abnormal bone structure, especially in the face and skull. Bone marrow expansion also makes bones thin and brittle, increasing the risk of broken bones.
 * Enlarged spleen: The spleen aids in fighting infection and filters unwanted material, such as old or damaged blood cells. Thalassemia is often accompanied by the destruction of a large number of red blood cells and the task of removing these cells causes the spleen to enlarge. Splenomegaly can make anemia worse, and it can reduce the life of transfused red blood cells. Severe enlargement of the spleen may necessitate its removal.
 * Slowed growth rates: anemia can cause the growth of a child to slow down. Puberty may also be delayed in children with thalassemia.
 * Heart problems: Diseases, such as congestive heart failure and abnormal heart rhythms, may be associated with severe thalassemia.

Hemoglobin structural biology
Normal human hemoglobins are tetrameric proteins composed of two pairs of globin chains, each of which contains one alpha-like (α-like) chain and one beta-like (β-like) chain. Each globin chain is associated with an iron-containing heme moiety. Throughout life, the synthesis of the alpha-like and the beta-like (also called non-alpha-like) chains is balanced so that their ratio is relatively constant and there is no excess of either type.

The specific alpha and beta-like chains that are incorporated into Hb are highly regulated during development:
 * Embryonic Hbs are expressed as early as four to six weeks of embryogenesis and disappear around the eighth week of gestation as they are replaced by fetal Hb. Embryonic Hbs include:
 * Hb Gower-1, composed of two ζ globins (zeta globins) and two ε globins (epsilon globins) (ζ2ε2)
 * Hb Gower-2, composed of two alpha globins and two epsilon globins (α2ε2)
 * Hb Portland I, composed of two zeta globins and two gamma globins (ζ2γ2)
 * Hb Portland II, composed of two zeta globins and two beta globins (ζ2β2)
 * Fetal Hb (Hb F) is produced from approximately eight weeks of gestation through birth and constitutes approximately 80 percent of Hb in the full-term neonate. It declines during the first few months of life and, in the normal state, constitutes <1 percent of total Hb by and past early childhood. Hb F is composed of two alpha globins and two gamma globins (α2γ2). Patients with β-thalassemia exhibit higher levels of gamma globulin, and thus more production of Hb F, to counteract the imbalance from not being able to produce beta chains.
 * Adult Hb (Hb A) is produced at low levels through embryonic and fetal life and is the predominant Hb in children by six months of age and onward; it constitutes 96-97% of total Hb in individuals without a hemoglobinopathy. It is composed of two alpha globins and two beta globins (α2β2).
 * Hb A2 is a minor adult Hb that normally accounts for approximately 2.5-3.5% of total Hb from six months of age onward. It is composed of two alpha globins and two delta globins (α2δ2).

Cause

Both α- and β-thalassemias are often inherited in an autosomal recessive manner. Cases of dominantly inherited α- and β-thalassemias have been reported, the first of which was in an Irish family with two deletions of 4 and 11 bp in exon 3 interrupted by an insertion of 5 bp in the β-globin gene. For the autosomal recessive forms of the disease, both parents must be carriers for a child to be affected. If both parents carry a hemoglobinopathy trait, the risk is 25% for each pregnancy for an affected child.

The genes involved in thalassemia control the production of healthy hemoglobin. Hemoglobin binds oxygen in the lungs and releases it when the red cells reach peripheral tissues, such as the liver. The binding and release of oxygen by hemoglobin are essential for survival.

Evolution
Having a single genetic variant for thalassemia may protect against malaria and thus can be an advantage.

People diagnosed with heterozygous (carrier) β-thalassemia have some protection against coronary heart disease.

Pathophysiology
Normally, the majority of adult hemoglobin (HbA) is composed of four protein chains, two α and two β-globin chains arranged into a heterotetramer. In thalassemia, patients have defects in either the α or β-globin chain, causing production of abnormal red blood cells.

The thalassemias are classified according to which chain of the hemoglobin molecule is affected. In α-thalassemias, production of the α-globin chain is affected, while in β-thalassemia, production of the β-globin chain is affected.

The β-globin chains are encoded by a single gene on chromosome 11; α-globin chains are encoded by two closely linked genes on chromosome 16. Thus, in a healthy person with two copies of each chromosome, two loci encode the β chain, and four loci encode the α chain. Deletion of one of the α loci has a high prevalence in people of African or Asian descent, making them more likely to develop α-thalassemia. β-thalassemias are not only common in Africans, but also in Greeks and Turks.

Alpha-thalassemias
The α-thalassemias involve the genes HBA1 and HBA2, inherited in a Mendelian recessive fashion. Two gene loci and so four alleles exist. Two genetic loci exist for α-globin, thus four alleles are in diploid cells. Two alleles are maternal and two alleles are paternal in origin. The severity of the α-thalassemias is correlated with the number of affected α-globin; alleles: the greater, the more severe will be the manifestations of the disease. Alpha-thalassemias result in decreased alpha-globin production; therefore, fewer alpha-globin chains are produced, resulting in an excess of β chains in adults and excess γ chains in newborns. The excess β chains form unstable tetramers (called hemoglobin H or HbH of 4 beta chains), which have abnormal oxygen dissociation curves. Alpha thalassemias often are found in people from Southeast Asia, the Middle East, China, and in those of African descent.

Beta-thalassemia
Beta thalassemias are due to mutations in the HBB gene on chromosome 11, also inherited in an autosomal, recessive fashion. The severity of the disease depends on the nature of the mutation and on the presence of mutations in one or both alleles.

Mutated alleles are called β+ when partial function is conserved (either the protein has a reduced function, or it functions normally but is produced in reduced quantity) or βo, when no functioning protein is produced.

The situation of both alleles determines the clinical picture:
 * β thalassemia major (Mediterranean anemia or Cooley anemia) is caused by a βo/βo genotype. No functional β chains are produced, and thus no hemoglobin A can be assembled. This is the most severe form of β-thalassemia;
 * β thalassemia intermedia is caused by a β+/βo or β+/β+ genotype. In this form, some hemoglobin A is produced;
 * β thalassemia minor is caused by a β/βo or β/β+ genotype. Only one of the two β globin alleles contains a mutation, so β chain production is not terribly compromised and patients may be relatively asymptomatic.

Beta thalassemia most often occurs in people of Mediterranean origin. To a lesser extent, Chinese, other Asians, and African Americans can be affected.

Delta-thalassemia
As well as alpha and beta chains present in hemoglobin, about 3% of adult hemoglobin is made of alpha and delta chains. Just as with beta thalassemia, mutations that affect the ability of this gene to produce delta chains can occur.

Combination hemoglobinopathies
Thalassemia can coexist with other hemoglobinopathies. The most common of these are:
 * Hemoglobin E/thalassemia: common in Cambodia, Thailand, and parts of India, it is clinically similar to β thalassemia major or thalassemia intermedia.
 * Hemoglobin S/thalassemia: common in African and Mediterranean populations, it is clinically similar to sickle-cell anemia, with the additional feature of splenomegaly.
 * Hemoglobin C/thalassemia: common in Mediterranean and African populations, hemoglobin C/βo thalassemia causes a moderately severe hemolytic anemia with splenomegaly; hemoglobin C/β+ thalassemia produces a milder disease.
 * Hemoglobin D/thalassemia: common in the northwestern parts of India and Pakistan (Punjab region).

Diagnosis
Thalassemia can be diagnosed via a complete blood count, hemoglobin electrophoresis or high-performance liquid chromatography, and DNA testing. Hemoglobin electrophoresis is not widely available in developing countries, but the Mentzer index can also be used for diagnosis of thalassemia; it is not a definitive test but it can suggest the possibility of thalassemia. The Mentzer index can be calculated from a complete blood count report.

Endocrine Complications in Thalassemia

1) Hypogonadism: iron overload in pituitary gonadotropic cells causes decreased gonadotrophin secretion which leads to delayed, slow or arrested puberty.

2) Hypoparathyroidism: chronic anemia causes hematopoiesis which results in bone reabsorption which decreases parathyroid secretion.

3) Adrenal insufficiency: Decreased growth of pubic and axillary hair in adolescent TM patients. This is due to excess iron deposition which causes adrenal dysfunction.

4) Hypothyroidism: Increase in weight and retarded growth in adolescent patients. Secondary is rare and majority suffers from primary hypothyroidism.

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Management
Given the range of severities, some people require no treatment (those who are asymptomatic) while some people require regular blood transfusions for survival. People with severe thalassemia require medical treatment and the main treatment is usually a red blood cell transfusion.

Red blood cell transfusions
Blood transfusions are the main treatment approach for prolonging life. The approach and frequency needed varies in each person depending on severity, age, if the person has stunted growth, presence of extramedullary erythropoiesis (pediatrics), if a person is pregnant, and heart health. Blood transfusions come with risks including making iron overload worse, the risk of infections, risk of red blood cell antibody formation, increased risk of the development of hypersensitivity reactions, and the risk of gall bladder inflammation (cholecystitis).

Multiple blood transfusions may result in iron overload. The iron overload related to thalassemia may be treated by chelation therapy with the medications deferoxamine, deferiprone, or deferasirox. These treatments have resulted in longer life expectancy for those with thalassemia major. Deferoxamine is only effective as a daily injection, complicating its long-term use. However, it is inexpensive and safe. Adverse effects include primary skin reactions around the injection site and hearing loss. Deferasirox and deferiprone are both oral medications, whose common side effects include nausea, vomiting and diarrhea. When comparing effectiveness, there is no evidence that deferasirox or deferiprone is superior, however, a long term comparison has not been performed. Deferasirox is not effective for all patients and may not be suitable for those with significant cardiac issues related to iron overload, while deferiprone appears to be the most effective agent when the heart is involved. Furthermore, the cost of deferasirox is also significant. Combining calcium channel blocker medications with iron chelation therapy is under study, however, the benefits are not clear from clinical trials conducted.

Growth hormone therapy
There is some evidence that growth hormone replacement therapy may help to increase the rate at which children with thalassemia grow taller.

Bone-marrow transplantation
Bone-marrow transplantation may offer the possibility of a cure in young people who have an HLA-matched donor. Success rates have reached the 80–90% range. Mortality from the procedure is about 3%. There are no randomized controlled trials that have tested the safety and efficacy of non-identical donor bone-marrow transplantation in persons with β- thalassemia who are dependent on blood transfusion.

Graft-versus-host diseases (GvHD) are one relevant side effect of bone-marrow transplantation. Further research is necessary to evaluate whether mesenchymal stromal cells can be used as prophylaxis or treatment for GvHD.

If the person does not have an HLA-matched compatible donor, bone-marrow transplantation from haploidentical mother to child (mismatched donor) may be attempted. In a study of 31 people, the thalassemia-free survival rate was 70%, rejection 23% and mortality 7%. The most positive results tend to occur with very young people.

Other treatments
Many treatments are being investigated with the goal of reducing the number of blood transfusions that a person requires. Foetal haemoglobin (HbF) inducer medications have been trialed with the goal of increasing hemoglobin and decreasing the person's reliance of a blood transfusion, however, the benefits are not clear and early results do not show a clinically meaningful benefit. Hydroxyurea treatment with the goal of reactivating gamma‐genes to produce HbF also does not have any high quality evidence supporting its effectiveness.

There is no evidence from randomized controlled trials to support zinc supplementation for those with thalassemia. Computer programs or mobile applications have been suggested as tools to help people manage thalassemia and follow their therapies including iron chelation therapy. The effectiveness of these applications has not been well investigated.

People with thalassemia are at a higher risk of osteoporosis. Treatment options include bisphosphonates and sometimes the addition of hormonal therapy. Other treatments have been suggested including calcitonin, zinc, hydroxyurea, and calcium supplementation. The effectiveness of bisphosphonates and zinc is not clear and further studies are required.

Dental care
Helping people with thalassemia with dental care and treating dental problems can be challenging due to the underlying condition. Overload of iron due to blood transfusions may lead to iron deposition in the teeth and discolouration, and there is an increased risk for infection. Treatment options for people with thalassemia need to be modified to ensure that the needs of the person are considered and early detection and early management of any problems is strongly suggested in order to reduce the risk of the person needing more complicated dental treatments. The evidence supporting the effectiveness of dental treatments on people with thalassemia is weak and higher quality clinical trials are needed.

Mild thalassemia
People with thalassemia traits do not require medical or follow-up care after the initial diagnosis is made. People with β-thalassemia trait should be warned that their condition can be misdiagnosed as the more common iron-deficiency anemia. They should avoid routine use of iron supplements, but iron deficiency may develop during pregnancy or from chronic bleeding. Genetic counseling is indicated for all persons with genetic disorders, especially when the family is at risk of a severe form of disease that may be prevented.

Prevention
The American College of Obstetricians and Gynecologists recommends all people thinking of becoming pregnant be tested to see if they have thalassemia. Genetic counseling and genetic testing are recommended for families who carry a thalassemia trait. Understanding the genetic risk, ideally before a family is started, would hopefully allow families to understand more about the condition and make an informed decision that is best for their family.

A screening policy exists in Cyprus to reduce the rate of thalassemia, which, since the program's implementation in the 1970s (also including prenatal screening and abortion), has reduced the number of children born with the disease from one of every 158 births to almost zero. Greece also has a screening program to identify people who are carriers.

In Iran as a premarital screening, the man's red cell indices are checked first. If he has microcytosis (mean cell hemoglobin < 27 pg or mean red cell volume < 80 fl), the woman is tested. When both are microcytic, their hemoglobin A2 concentrations are measured. If both have a concentration above 3.5% (diagnostic of thalassemia trait) they are referred to the local designated health post for genetic counseling.

Large-scale awareness campaigns are being organized in India both by government and non-government organizations to promote voluntary premarital screening, with marriage between carriers strongly discouraged.

Epidemiology
The beta form of thalassemia is particularly prevalent among Mediterranean peoples, and this geographical association is responsible for its original name. Thalassemia resulted in 25,000 deaths in 2013 down from 36,000 deaths in 1990.

In Europe, the highest concentrations of the disease are found in Greece, coastal regions in Turkey (particularly the Aegean Region such as İzmir, Balıkesir, Aydın, Muğla, and Mediterranean Region such as Antalya, Adana, Mersin), in southern Spain, in parts of Italy, particularly southern Italy. With the exception of the Balearics, the major Mediterranean Islands, such as Sicily, Sardinia, Malta, Corsica, Cyprus, and Crete are heavily affected. Other Mediterranean peoples, as well as those in the vicinity of the Mediterranean, also have high rates of thalassemia, including people from North Africa and West Asia. Far from the Mediterranean, South Asians are also affected, with the world's highest concentration of carriers (16–18% of the population) in the Maldives.

The disease is also found in populations living in Africa, the Americas, and in Tharu people in the Terai region of Nepal and India. It is believed to account for much lower rates of malaria illnesses and deaths, accounting for the historic ability of Tharus to survive in areas with heavy malaria infestation while others could not. Thalassemias are particularly associated with people of Mediterranean origin, Arabs (especially Palestinians and people of Palestinian descent), and Asians. The estimated prevalence is 16% in people from Cyprus, 1% in Thailand, and 3–8% in populations from Bangladesh, China, India, Malaysia and Pakistan.

Estimates suggest that approximately 1.5% of the global population (80 – 90 million people) are β-thalassemia carriers. However, exact data on carrier rates in many populations are lacking, particularly in developing areas of the world known or expected to be heavily affected. Because of the prevalence of the disease in countries with little knowledge of thalassemia, access to proper treatment and diagnosis can be difficult. While there are some diagnostic and treatment facilities in developing countries, in most cases these are not provided by government services and are available only to patients who can afford them. In general, poorer populations only have access to limited diagnostic facilities and blood transfusions. In some developing countries, there are virtually no facilities for diagnosis or management of thalassemia.

Etymology and synonym
The word thalassemia derives from the Greek  thalassa (θάλασσα), "sea", and Neo-Latin -emia (from the Greek compound stem -aimia (-αιμία), from haima (αἷμα), "blood"). It was coined because the condition called "Mediterranean anemia" was first described in people of Mediterranean ethnicities. "Mediterranean anemia" was renamed thalassemia major once the genetics were better understood. The word thalassemia was first used in 1932.

Gene therapy
Gene therapy is being studied for thalassemia. The procedure involves collecting hematopoietic stem cells (HSCs) from the affected person's blood. The HSCs then have a beta-globin gene added using a lentiviral vector. After destroying the affected person's bone marrow with a dose of chemotherapy (a myeloablative conditioning regimen), the altered HSCs are infused back into the affected person where they become engrafted in the bone marrow where they proliferate. This potentially results in a progressive increase in hemoglobin A2 synthesis in all subsequent developing red blood cells, with resultant resolution of the anemia.

While one person with beta thalassemia has no longer required blood transfusions following treatment within a research trial, it is not an approved treatment as of 2018.

HbF induction
HbF induction is an attempt to reactivate fetal globin gene transcription. Efforts involve trying to disrupt the fetal globin gene promoter.

title: Thalassemia


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Spoke–hub distribution paradigm

The spoke–hub distribution paradigm (also known as the hub-and-spoke system) is a form of transport topology optimization in which  traffic planners organize routes as a series of "spokes" that connect outlying points to a central "hub". Simple forms of this distribution/connection model contrast with point-to-point transit systems, in which each point has a direct route to every other point, and which modeled the principal method of transporting passengers and freight until the 1970s. Delta Air Lines pioneered the spoke–hub distribution model in 1955, and the concept revolutionized the transportation logistics industry after Federal Express demonstrated its value in the early 1970s. In the late 1970s the telecommunications and information technology sector subsequently adopted this distribution topology, dubbing it the star network network topology.

"Hubbing" involves "the arrangement of a transportation network as a hub-and-spoke model".

Benefits
The hub-and-spoke model, as compared to the point-to-point model, requires fewer routes. For a network of n nodes, only n − 1 routes are necessary to connect all nodes so the upper bound is n − 1, and the complexity is O(n). That compares favourably to the $$\frac{n(n-1)}{2}$$ routes, or O(n2), which would be required to connect each node to every other node in a point-to-point network. For example, in a system with 10 destinations, the spoke–hub system requires only 9 routes to connect all destinations, and a true point-to-point system would require 45 routes. However distance traveled per route will necessarily be more than with a point-to-point system (except where the route happens to have no interchange). Therefore, efficiency may be reduced. Conversely, for the same number of aircraft, having fewer routes to fly means each route can be flown more frequently and with higher capacity because the demand for passengers can be resourced from more than just one city (assuming the passengers are willing to change, which will of itself incur its own costs).

Complicated operations, such as package sorting and accounting, can be carried out at the hub rather than at every node, and this leads to economies of scale. As a result of this, spokes are simpler to operate, and so new routes can easily be created.

Drawbacks
In addition, the hub constitutes a bottleneck or single point of failure in the network. The total cargo capacity of the network is limited by the hub's capacity. Delays at the hub (such as from bad weather conditions) can result in delays throughout the network. Cargo must pass through the hub before reaching its destination and so require longer journeys than direct point-to-point trips. That may be desirable for freight, which can benefit from sorting and consolidating operations at the hub, but it is problematic for time-critical cargo, as well as for passengers. The necessity of baggage transfers at the hub also increases the risk of missing luggage, as compared to the point-to-point model.

Commercial aviation

In 1955, Delta Air Lines pioneered the hub-and-spoke system at its hub in Atlanta, Georgia, in an effort to compete with Eastern Air Lines. In the mid-1970s FedEx adopted the hub-and-spoke model for overnight package delivery. After the airline industry was deregulated in 1978, several other airlines adopted Delta's hub-and-spoke paradigm.

Airlines have extended the hub-and-spoke model in various ways. One method is to create additional hubs on a regional basis and to create major routes between them. That reduces the need to travel long distances between nodes near one another. Another method is to use focus cities to implement point-to-point service for high-traffic routes and to bypass the hub entirely.

Transportation
The spoke–hub model is applicable to other forms of transportation as well:
 * Sea transport in which feeder ships transport shipping containers from different ports to a central container terminal to be loaded onto larger vessels.
 * Cargo airlines: most UPS Airlines flights travel through its Worldport at Louisville International Airport, and many FedEx Express parcels are processed at its "SuperHub" at Memphis International Airport.
 * Freight rail transport in which cargo is hauled to a central exchange terminal. At the terminal, shipping containers are loaded from one freight car to another, and classification yards (marshalling yards) are used to sort freight cars into trains and divide them according to varying destinations. Intermodal freight is often loaded from one mode to another at central hubs.
 * Public transit uses various transport hubs to allow passengers to transfer between different lines or transportation modes. Often those hubs are intermodal linking buses, trams, local trains, subways and so on.

For passenger road transport, the spoke–hub model does not apply because drivers generally take the shortest or fastest route between two points. However, the road network as a whole likewise contains higher order roads like limited access highways and more local roads with most trips starting and ending at the latter but spending most of the distance on the former.

Industrial distribution
The hub-and-spoke model has also been used in economic geography theory to classify a particular type of industrial district. Economic geographer Ann Markusen theorized about industrial districts, with a number of key industrial firms and facilities acting as a hub, with associated businesses and suppliers benefiting from their presence and arranged around them like the spokes of a wheel. The chief characteristic of such hub-and-spoke industrial districts is the importance of one or more large companies, usually in one industrial sector, surrounded by smaller, associated businesses. Examples of cities with such districts include Seattle (where Boeing was founded), Silicon Valley (a high tech hub), and Toyota City, with Toyota.

East Asian relations
In the context of East Asian geopolitics, Victor Cha says the hub-and-spokes paradigm refers to the network of alliances the United States has built individually with other East Asian countries. The 1951 Security Treaty Between the United States and Japan, the 1953 U.S.–South Korea Status of Forces Agreement and the 1954 Mutual Defense Treaty between the United States and the Republic of China (later replaced by the Taiwan Relations Act) are some examples of such bilateral security relationships. The system creates a bilateral security architecture in East Asia that is different from the multilateral security architecture in Europe. The US acts as a "hub", and Asian countries like South Korea and Japan are its "spokes". There is a strong connection between the hub and the spoke, but weak or no connections between the spokes themselves.

In April 2014, all ten ASEAN defense chiefs and United States Secretary of Defense Chuck Hagel attended the US–ASEAN Defense Forum in Hawaii. The meeting was the first time the US hosted the forum and was part of a US attempt to get the countries to strengthen military ties between themselves.

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Spoke–hub distribution paradigm


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New Appomattox Court House

The Appomattox Courthouse is the current courthouse in Appomattox, Virginia built in 1892. It is located in the middle of the state about three miles (5 km) southwest of the Appomattox Court House National Historical Park, once known as Clover Hill—home of the original Old Appomattox Court House. The "new" Appomattox Courthouse is near the Appomattox Station and where the regional county government is located.

Before the Civil War, the railroad bypassed Clover Hill, now known as the Appomattox Court House National Historical Park. As a result the population of Clover Hill, where the Old Appomattox Courthouse once stood, never grew much over 150 while Appomattox town grew to the thousands. When the courthouse at the village of Clover Hill burned for the second time in 1892, it was not rebuilt and a new courthouse was built in West Appomattox. That sealed the fate of the village of Clover Hill. The county seat was formally moved to the town of West Appomattox in 1894 and the word "West" was dropped in time making the name of the town just Appomattox, Virginia.

There is a marker at the site of the "new" Appomattox Court House explaining the difference between the "new" and "old" court houses.

"This building, erected in 1892 when the county seat was moved to this location, should not be mistaken for the original, built in 1846 and destroyed by fire in 1892. Three miles northeast is old Appomattox Court House and the McLean House where Lee surrendered to Grant on April 9, 1865, thus ending the War between the States. The village of Old Appomattox Court House is now preserved as a national shrine by the Federal Government."

Two members of the United States House of Representatives, Henry D. Flood and his half-brother Joel West Flood, are entombed in a mausoleum on the courthouse green.

title: New Appomattox Court House


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Wenceslaus III

Wenceslaus III may refer to:

 * Wenceslaus III of Oława (1400–23), Duke of Oława (1419/20–23)
 * Wenceslaus III, Duke of Rybnik (c. 1442 – 1479)
 * Wenceslaus III Adam, Duke of Cieszyn (1524–1579), Duke of Cieszyn (1528–79)
 * Wenceslaus III of Bohemia (1289–1306), King of Hungary (1301–05), King of Bohemia and of Poland (1305–06)

title: Wenceslaus III


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User:Palestine liberator

This user is banned. All edits by this user will be reverted.

UserContributions:Palestine liberator

As ever, bans can be appealed by emailing jwales at bomis dot com

From: Jimmy Wales To: wikien-l@wikipedia.org Date: Mon, 4 Aug 2003 06:13:04 -0700

> A ban page is at User talk:Palestinian liberator/ban. Please > express your viewers whether here on the list or there on the > page. A decision is clearly needed quickly before the scale of > vandalism gets out of hand.

I'm convinced. Palestinian liberator is to be banned. Can someone take care of this for me?

It might be helpful -- though it is hard to say -- if someone who considers themselves generally or overwhelmingly pro-Palestinian but NPOV could write to this person explaining NPOV and what not, and explaining that contributions like that are just going to be deleted, and that a more effective way to help the cause is to contribute materials that is simple and factual and uncontroversial.

One of the advantages of NPOV is that all of us believe fervently that everyone would agree with us if only they had all the facts. So no matter what your POV, if you *really* believe in it, you will agree that simply laying out the facts, warts and all, will be sufficient to convince.

--Jimbo

 * Archive of the above post

title: User:Palestine liberator


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User talk:Whimsy~enwiki

Hello there, welcome to the 'pedia! I hope you like the place and decide to stay. If you need pointers on how we title pages visit Naming conventions or how to format them visit our manual of style. If you have any other questions about the project then check out Help or add a question to the Village pump. Cheers! --maveric149

Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Whimsy. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Whimsy~enwiki that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name. If you think you might own all of the accounts with this name and this message is in error, please visit Special:MergeAccount to check and attach all of your accounts to prevent them from being renamed.

Your account will still work as before, and you will be credited for all your edits made so far, but you will have to use the new account name when you log in.

Sorry for the inconvenience.

Yours, Keegan Peterzell Community Liaison, Wikimedia Foundation 03:37, 20 March 2015 (UTC)

Renamed
 This account has been renamed as part of single-user login finalisation. If you own this account you can |log in using your previous username and password for more information. If you do not like this account's new name, you can choose your own using this form after logging in: . -- Keegan (WMF) (talk) 20:28, 22 April 2015 (UTC)

title: User talk:Whimsy~enwiki


text:
User talk:Socrates99

Hello there, welcome to the 'pedia! I hope you like the place and decide to stay. If you need pointers on how we title pages visit Naming conventions or how to format them visit our manual of style. If you have any other questions about the project then check out Help or add a question to the Village pump. Cheers! --maveric149

title: User talk:Socrates99


text:
User talk:Automaton~enwiki

Hello there, welcome to the 'pedia! I hope you like the place and decide to stay. If you need pointers on how we title pages visit Naming conventions or how to format them visit our manual of style. If you have any other questions about the project then check out Help or add a question to the Village pump. Cheers! --maveric149

Image copyrights
Hi! Thanks for uploading Image:Ous-chamber.jpg and Image:Ousu.jpg. I notice they currently don't have image copyright tags. Could you add one to let us know its copyright status? (You can use if you release it under the GFDL, or  if you claim fair use, etc.) If you don't know what any of this means, just let me know where you got the images and I'll tag them for you. Thanks so much, Edwinstearns 21:23, 9 Dec 2004 (UTC)

Image:Hallquad.jpg listed for deletion
An image or media file that you uploaded or altered, Image:Hallquad.jpg, has been listed at. Please look there to see why this is (you may have to search for the title of the image to find its entry), if you are interested in it not being deleted. Thank you. User:Gay Cdn (talk) (Contr) 01:52, 20 April 2007 (UTC)

File:Oronhyatekha.jpg missing description details
Dear uploader: The media file you uploaded as File:Oronhyatekha.jpg is missing a description and/or other details on its image description page. If possible, please add this information. This will help other editors to make better use of the image, and it will be more informative for readers.

If you have any questions please see Help:Image page. Thank you. Sfan00 IMG (talk) 23:40, 4 May 2009 (UTC)

File source problem with File:Oronhyatekha.jpg
Thanks for uploading File:Oronhyatekha.jpg. I noticed that the file's description page currently doesn't specify who created the content, so the copyright status is unclear. If you did not create this file yourself, you will need to specify the owner of the copyright. If you obtained it from a website, then a link to the website from which it was taken, together with a restatement of that website's terms of use of its content, is usually sufficient information. However, if the copyright holder is different from the website's publisher, their copyright should also be acknowledged.

If you have uploaded other files, consider checking that you have specified their source and tagged them, too. You can find a list of files you have uploaded by following this link. Unsourced and untagged images may be deleted one week after they have been tagged, as described on criteria for speedy deletion. If the image is copyrighted under a non-free license (per Fair use) then the image will be deleted 48 hours after 17:51, 24 May 2009 (UTC). If you have any questions please ask them at the Media copyright questions page. Thank you. Papa November (talk) 17:51, 24 May 2009 (UTC)

Do not delete other people's talk
In a recent edit you deleted some of what I wrote on a talk page. Perhaps it happened accidentally. But you should know that it is considered very bad form to delete what another editor has written on any talk page (unless it is a grave violation of some policy). I'll assume it was inadvertant, but please be careful not to remove from talk pages what other editors have written, again. Slrubenstein  |  Talk 20:38, 10 April 2010 (UTC)

Your account will be renamed
Hello,

The developer team at Wikimedia is making some changes to how accounts work, as part of our on-going efforts to provide new and better tools for our users like cross-wiki notifications. These changes will mean you have the same account name everywhere. This will let us give you new features that will help you edit and discuss better, and allow more flexible user permissions for tools. One of the side-effects of this is that user accounts will now have to be unique across all 900 Wikimedia wikis. See the announcement for more information.

Unfortunately, your account clashes with another account also called Automaton. To make sure that both of you can use all Wikimedia projects in future, we have reserved the name Automaton~enwiki that only you will have. If you like it, you don't have to do anything. If you do not like it, you can pick out a different name. If you think you might own all of the accounts with this name and this message is in error, please visit Special:MergeAccount to check and attach all of your accounts to prevent them from being renamed.

Your account will still work as before, and you will be credited for all your edits made so far, but you will have to use the new account name when you log in.

Sorry for the inconvenience.

Yours, Keegan Peterzell Community Liaison, Wikimedia Foundation 22:21, 19 March 2015 (UTC)

Renamed
 This account has been renamed as part of single-user login finalisation. If you own this account you can |log in using your previous username and password for more information. If you do not like this account's new name, you can choose your own using this form after logging in: . -- Keegan (WMF) (talk) 10:47, 22 April 2015 (UTC)

title: User talk:Automaton~enwiki


text:
AFL

AFL may refer to:

Education

 * Angel Foundation for Learning, a Canadian Roman Catholic charity
 * Ankara Science High School, a high school in Ankara, Turkey, natively referred to as Ankara Fen Liesi
 * Assessment for learning

Military

 * Armed Forces of Liberia
 * Armée française de la Libération or French Liberation Army, the army of Free France from 1943 to 1945
 * Army of Free Lebanon, a 1970s splinter faction of the Lebanese Armed Forces

Organized labour

 * Alberta Federation of Labour, a provincial trade union centre chartered by the Canadian Labour Congress
 * American Federation of Labor, an 1886–1955 national trade union centre that merged into the AFL-CIO
 * Arbeidernes Faglige Landsorganisasjon or Workers' National Trade Union, former name of the Norwegian Confederation of Trade Unions, a national trade union centre

Politics and social advocacy

 * Actresses' Franchise League, a primarily English women's suffrage organization
 * Anglicans for Life, an anti-abortion advocacy group associated with the Anglican Church in North America
 * Anti-Federalist League, a 1990s British political party
 * Australian Freedom League, a 1910s anti-conscription organization

Science and technology

 * American Fuzzy Lop (software), a fuzzer
 * Astrobiology Field Laboratory, a cancelled robotic rover to be sent to Mars
 * Atrial flutter, a form of cardiac arrhythmia

Australian rules football

 * AFL (video game series), a series of Australian rules football video games
 * AFL (2011 video game), an Australian rules football video game for the Wii and iOS
 * Anti-Football League, an organization that bemoans the cultural saturation of Australian rules football
 * Australian Football League, an Australian rules football league that is the highest level of the sport
 * Australian rules football, a sport commonly referred to as AFL

Gridiron football

 * Alberta Football League, an amateur Canadian football league
 * American Football League, a name shared by several separate and unrelated professional American football leagues:
 * American Football League (1926) (a.k.a. "AFL I"), first rival of the National Football League (NFL) that competed in 1926
 * American Football League (1934), regional borderline-major league that competed in 1934
 * American Football League (1936) (a.k.a. "AFL II"), second rival of the NFL that competed in 1936 and 1937
 * American Football League (1938), minor professional league that changed its name to the American Professional Football Association in 1939
 * American Football League (1940) (a.k.a. "AFL III"), third rival of the NFL that competed in 1940 and 1941
 * American Football League (1944), offshoot of the Pacific Coast Professional Football League that competed in 1944
 * American Football League (1946), name adopted by the American Association minor American football league in 1946
 * American Football League (a.k.a. "AFL IV"), an American football league, active from 1960 to 1970
 * Arena Football League, an American indoor football league
 * Austrian Football League, the highest league of American football in Austria

Other uses in sport

 * African Football League, an association football competition run by the Confederation for African Football (CAF)
 * American Fencing League, an amateur standard fencing league
 * Arizona Fall League, an American off-season baseball league operated by Major League Baseball

Transportation

 * Adaptive front light, of an automobile
 * Aeroflot, ICAO airline code AFL
 * Alta Floresta Airport, IATA airport code AFL, in Alta Floresta, Brazil

Other uses

 * Abstract family of languages
 * Academic Free License, a software licence
 * Aflac, American insurance company (NYSE ticker: AFL)
 * After-fader listen

title: AFL


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User talk:Munford

Hello there, welcome to the 'pedia! I hope you like the place and decide to stay. If you need pointers on how we title pages visit Naming conventions or how to format them visit our manual of style. If you have any other questions about the project then check out Help or add a question to the Village pump. Cheers! --maveric149

Gardner / Mason
I noticed your edits to zh:厄爾·史丹利·賈德納. If you have any knowledge of the subject, could you add to that article or zh:佩瑞·梅森? Thanks. -  AjaxSmack    02:28, 2 October 2006 (UTC)

2008 unrest in Tibet
Hi there, I noticed the revert war going on between you and 75.152.153.240 in 2008 unrest in Tibet. I would encourage you two to stop that behavior. As far as my 5 cents on using the word rioters vs protesters, not all protesters in Tibet are rioters but it seems all rioters in Tibet are protesters and it fits better. Regardless if it is still a issue bring it up in Talk:2008 unrest in Tibet Zethus(talk) 04:48, 19 March 2008 (UTC)

Hi, I would also like to borrow this space to say that your comparison w/ this incident to the LA riots of 1992 was quite accurate. It all started with good intention yet executed poorly and ended up with a bad rep. TheAsianGURU (talk) 18:25, 20 March 2008 (UTC)

2008 Olympic torch relay
Hi. You've deleted the line about Der Spiegel, for the second time, without discussion. If you delete it a third time, I must inform you that I will report you for violation of the 3RR. Such editing (deleting content several times without discussion) is considered disruptive. If you would like to see the line removed, explain your reasons here, but do not delete it again yourself. Thank you. Aridd (talk) 10:58, 18 April 2008 (UTC)
 * I've replied to you on the talk page. Now we can discuss it rather than have an edit war. Aridd (talk) 21:21, 19 April 2008 (UTC)

File:Danba diaolou.jpg
Refering to this file, I doubt these are Diaolou, but more probably Himalayan Towers, see for instance here : http://www.sciencemag.org/cgi/content/summary/303/5666/1972a There is also an article in "Grands Reportages", with photos similar to your. --Rédacteur Tibet (talk) 18:58, 20 March 2010 (UTC)
 * en:Diaolou wasn't correctly named. It should be called Kaiping diaolou(I've just made this change). It's only local to that region of Kaiping in Guangdong, southern China. This style of Diaolou I took picture of is located in Sichuan province, southwest China. It's mainly built by Qiang ethnics. In addition, I'm not sure about the English name "Himalaya tower" is correct as well. I don't think this region can be called Himalayas. It's Qionglai Mountain range or Hengduan Mountains. I guess by calling it Himalaya tower gives it some mystic appeal. -munford (talk) 15:03, 21 March 2010 (UTC)

ArbCom elections are now open!
MediaWiki message delivery (talk) 08:53, 23 November 2015 (UTC)

title: User talk:Munford