History.

After World War II, German aviation was severely curtailed, and military aviation was completely forbidden after the "Luftwaffe" of the Third Reich had been disbanded in August 1946 by the Allied Control Commission. This changed in 1955 when West Germany joined NATO, as the Western Allies believed that Germany was needed to counter the increasing military threat posed by the Soviet Union and its Warsaw Pact allies. Therefore, on 9 January 1956, a new German Air Force called "Luftwaffe" was founded as a branch of the new "Bundeswehr".  Many well-known fighter pilots of the "Wehrmacht"'s "Luftwaffe" joined the new post-war air force and underwent refresher training in the US before returning to West Germany to upgrade on the latest U.S.-supplied hardware. These included Erich Hartmann, Gerhard Barkhorn, Günther Rall and Johannes Steinhoff. Steinhoff became commander-in-chief of the "Luftwaffe", with Rall as his immediate successor. Another pilot of World War II, Josef Kammhuber, also made a significant career in the post-war "Luftwaffe", retiring in 1962 as "Inspekteur der Luftwaffe" (Chief Inspector of the Air Force).  Despite the partial reliance of the new air force on airmen who had served in the "Wehrmacht"'s air arm, there was no organizational continuity between the old and the new "Luftwaffe". This is in line with the policy of the "Bundeswehr" on the whole, which does not consider itself a successor of the "Wehrmacht" and does not follow the traditions of any other previous German military organization.

First years.

The first volunteers of the "Luftwaffe" arrived at the Nörvenich Air Base in January 1956. In the same year, the "Luftwaffe" was provided with its first aircraft, the US-made Republic F-84 Thunderstreak. At first, the "Luftwaffe" was divided into two operational commands, one in Northern Germany, aligned with the British-led Second Allied Tactical Air Force, and the other in Southern Germany, aligned with the American-led Fourth Allied Tactical Air Force.  In 1957, the "Luftwaffe" took command of the Army Air Defence Troops located in Rendsburg and began the expansion of its own air defence missile capabilities. The first squadron to be declared operational was the Air Transport Wing 61 at Erding Air Base, followed by the 31st Fighter-Bomber Squadron at Büchel Air Base. In 1958, the "Luftwaffe" received its first conscripts. In 1959, the "Luftwaffe" declared the 11th Missile Group in Kaufbeuren armed with MGM-1 Matador surface-to-surface tactical nuclear cruise missiles operational. The same year "Jagdgeschwader 71" (Fighter Wing 71) equipped with Canadair CL-13 fighters became operational at Ahlhorner Heide Air Base. All aircraft sported—and continue to sport—the Iron Cross on the fuselage, harking back to the pre-March 1918 days of World War I, while the national flag of West Germany is displayed on the tail.

Cold War.

In 1963, the "Luftwaffe" saw its first major reorganization. The two operational Air Force Group Commands – Command North and Command South were both split into two mixed Air Force divisions containing flying and air defence units and one Support division. Additionally, a 7th Air Force division was raised in Schleswig-Holstein containing flying units, missile units, support units and the German Navy's naval aviation and placed under command of Allied Forces Baltic Approaches.  In 1960, the "Luftwaffe" received it first Lockheed F-104 Starfighter jets. The Starfighter remained in service for the entire duration of the Cold War, with the last being taken out of service in 1991. The "Luftwaffe" received 916 Starfighters, 292 of which crashed, resulting in the deaths of 116 pilots. The disastrous service record of the Starfighter led to the Starfighter crisis in 1966 as a reaction to 27 Starfighter crashes with 17 casualties in 1965 alone. The West German public referred to the Starfighter as the "Witwenmacher" (widow-maker), "fliegender Sarg" (flying coffin), "Fallfighter" (falling fighter) and "Erdnagel" (tent peg, literally "ground nail").  On 25 August 1966, the German Defence Minister Kai-Uwe von Hassel relieved the "Inspekteur der Luftwaffe" "Generalleutnant" Werner Panitzki, and transferred Colonel Erich Hartmann, commanding officer of the 71st Fighter Squadron, as both had publicly criticized the acquisition of the Starfighter as a "purely political decision". On 2 September 1966, Johannes Steinhoff, with Günther Rall as deputy, became the new "Inspekteur der Luftwaffe". Steinhoff and his deputy Günther Rall noted that the non-German F-104s proved much safer. The Americans blamed the high loss rate of the "Luftwaffe" F-104s on the extreme low-level and aggressive flying of German pilots rather than any faults in the aircraft. Steinhoff and Rall went to America to learn to fly the Starfighter under Lockheed instruction and noted some specifics in the training (a lack of mountain and foggy-weather training), combined with handling capabilities (rapidly initiated, high G turns) of the aircraft that could cause accidents. Steinhoff and Rall therefore changed the training regimen for the F-104 pilots, and the accident rates fell to those comparable or better than other air forces. They also brought about the high level of training and professionalism seen today throughout the "Luftwaffe", and the start of a strategic direction for "Luftwaffe" pilots to engage in tactical and combat training outside of Germany. However, the F-104 never lived down its reputation as a "widow-maker", and was replaced by the "Luftwaffe" with the McDonnell Douglas F-4 Phantom II fighter and the Panavia Tornado fighter-bomber in many units much earlier than in other national air forces.  On Steinhoff's initiative, the "Luftwaffe" opened the German Air Force Command USA/Canada ("Deutsches Luftwaffenkommando USA/Kanada") in Fort Bliss, where the "Luftwaffe" trained its missile and air defence troops, and pilots received their basic training. At the same time, the "Luftwaffe" opened a Tactical Training Command in Beja, Portugal, where pilots were trained in Close Air Support missions.  Between 1967 and 1970, the "Luftwaffe" undertook a major reorganization of its forces. The two operational commands were disbanded and the four mixed Air Force divisions were divided into two flying divisions and two air defence divisions. The remainder of the units were divided into functional commands:  Over the next decade, the "Luftwaffe" received large amounts of new equipment, including in 1968 the first C-160 Transall transport planes, in 1974 the F-4 Phantom II fighter-bombers, in 1978 the first Alpha Jet Version A light attack jets and in 1979 the first of 212 Panavia Tornado fighters.  In 1986, the air defense forces began to replace their Nike Hercules missile systems with state of the art surface-to-air missile systems: first to arrive was the MIM-104 Patriot system, followed one year later by Roland short range missile system.

Nuclear sharing.

Germany is participating in NATO's nuclear sharing concept. Nuclear sharing is a concept that involves member countries without nuclear weapons of their own in the planning for the use of nuclear weapons by NATO, and in particular provides for the armed forces of these countries to be involved in delivering these weapons in the event of their use.  Soon after its founding, the German Air Force began to train with the US Seventeenth Air Force in handling, arming and delivering nuclear weapons. At first, the F-104 Starfighter was intended to be used solely as a nuclear delivery platform, armed with nuclear air-to-air and air-to-surface missiles, as well as nuclear bombs. The Tornado was the second air force plane fielded that was capable of delivering nuclear ammunition, although it was limited to delivering B61 nuclear bombs.  From 1965 through 1970, Missile Wings 1 and 2 fielded 16 Pershing 1 missile systems with nuclear warheads under U.S. Army custody. In 1970, the system was upgraded to Pershing 1a with 72 missiles. Although not directly affected by the 1988 Intermediate-Range Nuclear Forces Treaty, the "Luftwaffe" unilaterally removed the Pershing 1a missiles from its inventory in 1991, and the missiles were destroyed. At the end of the Cold War, more than 100,000 soldiers served in the "Luftwaffe".  The United States still lends nuclear weapons for hypothetical use by the "Luftwaffe" under the nuclear sharing agreement. In 2007, 22 B61 nuclear bombs were still kept in Germany, stored at the Büchel Air Base for use with Tornado IDS fighter-bombers of "Jagdbombergeschwader" 33. The American nuclear weapons formerly stored at Nörvenich Air Base, Ramstein Air Base and Memmingen Air Base were all withdrawn from Germany during the mid-and-late-1990s.  By international treaties between Germany and the "Big Four" powers in Europe (that formerly occupied Germany), East Germany is a nuclear-free zone. The Big Four powers are the United States, Russia, the United Kingdom, and France, and with the latter three having no nuclear weapons in Germany anymore.

Reunification.

After German reunification in October 1990, the aircraft and personnel of the former GDR air force, the "Luftstreitkräfte der NVA" were taken. The remnants of the East German Air Force were placed under the newly formed "5. Luftwaffendivision" (5th Air Force Division) in Strausberg. In 1993, the division was renamed "3. Luftwaffendivision", moved to Gatow in Berlin and in 1995 assigned to NATO. By 1990, the East German plane markings had been replaced by the Air Force Iron Cross, the first time Soviet-built aircraft had served in a NATO air force. However, as the "Luftstreitkräfte der NVA" were supplied exclusively with Eastern Bloc-produced aircraft, such as the Sukhoi Su-17, MiG-21, MiG-23 and MiG-29 fighters, most of the equipment was not compatible with the West German NATO equipment and therefore taken out of service and sold or given to new members of NATO in Eastern Europe, such as Poland and the Baltic states.  An exception to this was the "Jagdfliegergeschwader 3" "Vladimir Komarov" (Fighter Wing 3 "Vladimir Komarov") in Preschen Air Base. The "Jagdfliegergeschwader 3" flew brand new MiG-29 fighters. On 1 June 1993, the wing was renamed "Jagdgeschwader 73" (Fighter Wing 73) and on 1 October 1994 completed its move to its new home at Laage Air Base. The pilots of JG 73 were some of the most experienced MiG-29 pilots in the world. One of their primary duties was to serve as aggressor pilots, training other pilots in dissimilar combat tactics. The United States sent a group of fighter pilots to Germany during the "Red October" exercise to practice tactics against the aircraft they were most likely to meet in real combat. The MiG-29s of JG 73 were fully integrated into the "Luftwaffe"'s air defence structure and the first Soviet Bloc aircraft to be declared operational within NATO. With the introduction of the Eurofighter Typhoon imminent, the decision was taken to withdraw the MiG-29. All German MiG-29s, save one, were sold to Poland for the symbolic price of €1 apiece. On 9 August 2004, the last MiG-29s landed in Poland where they continue to serve in the 41st Tactical Squadron of the Polish Air Force.

Operations in the Balkans.

The "Luftwaffe" experienced combat action for first time since World War II during September 1995 in the course of Operation Deliberate Force, when six IDS Tornado fighter-bombers, equipped with forward looking infrared devices, and escorted by eight ECR Tornados, supported NATO's artillery missions on positions of the Bosnian Serbs around Sarajevo, Bosnia & Herzegovina.  In March 1999, the "Luftwaffe" became involved in direct combat role as part of the Kosovo War along with the other NATO powers. This event was noted as significant in the British press with "The Sun" running the headline ""Luftwaffe" and the RAF into battle side by side". The "Luftwaffe" sent in Fighter Bomber Wing 32, equipped with ECR Tornados, which flew missions to suppress enemy air defences in and around Kosovo.  These fighter-bombers were equipped with an electronic countermeasures pod, one AIM-9 Sidewinder air-to-air missile for self-defence, and an AGM-88 HARM air-to-ground missile (anti-radar). The bomber wing flew 2108 hours and 446 sorties, firing 236 HARM missiles at hostile targets. No manned "Luftwaffe" planes were lost in combat during this campaign.

2000s.

In 2005 and 2008, "Luftwaffe" F-4F "Phantom II" fighter planes took part in the Baltic Air Policing operation (of NATO), and these fighters were supplemented in 2009 by units flying the "Typhoon".  In 2006, to support military operations in Afghanistan, the "Luftwaffe" sent over several Panavia Tornado reconnaissance planes from "Aufklärungsgeschwader" 51 "Immelmann" (the 51st Reconnaissance Wing "Immelmann"), stationed in Mazar-i-Sharif, Northern Afghanistan. There have also been assorted German Army helicopters flying from the "Luftwaffe" Air Base in Mazar-i-Sharif. Also, "Luftwaffe" C-160 Transall have flown transport plane missions in and around Afghanistan.  Since the 1970s, the West German (and, post reunification, German) "Luftwaffe" (as well as many other European air forces) has actively pursued the construction of European internationally made warplanes, such as the Panavia Tornado and the Eurofighter Typhoon introduced into the "Luftwaffe" in 2006.  On 13 January 2004, the Minister of Defence, Peter Struck, announced major changes in the future of the German armed forces. A major part of this announcement was a plan to cut the number of fighter planes from 426 in early 2004, to 265 by 2015. Assuming that the plans to order 180 Typhoons is carried out in full, and all of the F-4 Phantoms are removed from service, this would cut the number of Tornado fighter-bombers down to just 85.  In the past, the Bundesmarine's naval air wing (the "Marineflieger") received 112 Tornado IDS planes. However, during late 2004, the last unit of Bundesmarine Tornados was disbanded. The entire maritime combat role was assigned to the "Luftwaffe", one unit of which has had its Tornado fighters equipped to carry Kormoran II missiles and American HARM missiles.

2010s.

As of 2014, a significant proportion of Germany's military aircraft was reported to be unserviceable. It has been reported that the Sea Lynx helicopters have experienced cracking in their tails, that around half of the Eurofighters and Tornados are not currently airworthy, and that the aging C-160 fleet remains in limited service while awaiting the introduction of the Airbus A400M, the first of which was delivered in December 2014. Ursula von der Leyen admitted that, due to the poor state of the "Bundeswehr"'s equipment, Germany was no longer able to fulfill its NATO commitments.  The German Air Force was one of the founding members of the European Air Transport Command headquartered in Eindhoven - The Netherlands and most of the Transport & Tanker assets have been transferred under EATC management. Replacement of the current four Airbus A310 MRTT by the Airbus A330 MRTT was approved in 2018 by joining the acquisition of four by the Royal Netherlands Air Force.  Future plans are the replacement of the ageing Sikorsky CH-53 Sea Stallion, which were acquired in the 1970s, by 40-70 Boeing CH-47 Chinook or Sikorsky CH-53K King Stallion from 2022 onwards.  The "Luftwaffe" participated in the Israeli Air Force exercise “Blue Flag”, the country's largest international air combat exercise, designed to simulate extreme combat scenarios. The German Air Force's six Eurofighter Typhoon fighter jets were from Tactical Air Force Squadron 73 Steinhoff from Rostock. It is the first German participation in the Blue Flag exercise.  In 2018, the Air Force issued a request for information from manufacturers about four potential aircraft to replace the aging Panavia Tornados - the Eurofighter Typhoon, F-15 Advanced Eagle, F/A-18E/F Super Hornet and F-35 Lightning. In January 2019, it was announced that the F-35 Lightning had been dropped from the shortlist, with the Eurofighter Typhoon and Boeing F/A-18 Super Hornet under consideration. In April 2020, Germany selected F/A-18E/F Super Hornets, 15 EA-18G Growlers and 55 Eurofighter Typhoons as replacements for the Tornado fleet. The Super Hornet was selected due to its compatibility with nuclear weapons and availability of an electronic attack version. As of March 2020, the Super Hornet is not certified for the B61 nuclear bombs, but Dan Gillian, head of Boeing's Super Hornet program, previously stated that "We certainly think that we, working with the U.S. government, can meet the German requirements there on the [German's] timeline."  Due to the problems with the A400M, and in service limitations, the German Air Force will acquire three C130J Super Hercules Transport and three KC-130J Tanker Aircraft (delivery planned 2020-2021), which will be jointly operated with the French Air Force's two C-130J and two KC-130J Aircraft (delivery planned 2018-2019).

Structure.

The current commander of the German Air Force is Lieutenant General Ingo Gerhartz. The Inspector of the Air Force ("Inspekteur der Luftwaffe") is the commander of Air Force Command ("Kommando Luftwaffe"), a body created in 2013 by the merger of the Air Force Office ("Luftwaffenamt"), German Air Staff ("Führungsstab der Luftwaffe"), and Air Force Forces Command ("Luftwaffenführungskommando"). Similar to the Air Staff of the United States Air Force, the German Air Force Command is a force providing command, not an operational command. The Air Force Command is tasked with ensuring the combat readiness of the German Air Force combat units, which during operations would either be commanded by a NATO command or the Joint Operations Command of the "Bundeswehr". The Air Force command directly controls three higher commands.  The creation of the Air Force Command was part of a reorganization of the "Bundeswehr" as a whole, announced by Thomas de Maizière in 2011, which also involved the Air Force shrinking to 23,000 soldiers and thus undergoing major restructuring at all levels. In addition to the higher command authorities, the three air divisions, the Air Force Training Command, and Air Force Weapon Systems Command, were disbanded. The three surface-to-air missile units will merge into a single wing in Husum in Northern Germany. The wing fields 14 MIM-104 Patriot and 4 MANTIS systems. The three air transport wings will be merged into a single wing based at Wunstorf Air Base, which will field 40 A400M Atlas transport planes. The "Luftwaffe" will field three Multirole Eurofighter Wings, each with two squadrons for a total of 143 Eurofighter Typhoon. A fighter-bomber wing fielding Panavia Tornado IDS planes remains in service at Büchel Air Base. The Reconnaissance Wing 51 will remain in service at Schleswig Air Base and add one drone squadron to its Panavia Tornado ECR squadron.  The "Kommando Luftwaffe" has two main elements subordinate to it:  Individual Air Force units are either part of the Air Force Operational Forces Command or the Support Forces Command. They only fall under the command of the Air Operations Center when on deployment or attached to EU or NATO organizations.

Air Operations Center.

The main subordinate elements of the Air Operations Center are:

Air Force Forces Command.

The main subordinate elements of the Air Force Operational Forces Command are:  Directly subordinated institutions:  Subordinated flying units:  Subordinated ground based units:  Subordinated support units:

North American training centers.

In light of the destroyed infrastructure of West Germany post–World War II, the restrictions on aircraft production placed on Germany and the later restrictive flying zones available for training pilots, the reconstructed "Luftwaffe" trained most of its pilots tactically away from Germany, mainly in the United States and Canada where most of its aircraft were sourced.  During the 1960s and 1970s, a very large number of "Luftwaffe" jet crashes—the "Luftwaffe" suffered a 36 percent crash rate for F-84F Thunderstreaks and an almost 30 percent loss of F-104 Starfighters—created considerable public demand for moving "Luftwaffe" combat training centers away from Germany.  As a result, the "Luftwaffe" set up two tactical training centres: one, like those of many of the NATO forces, at the Royal Canadian Air Force base at Goose Bay; and the second in a unique partnership with the United States Air Force at Holloman Air Force Base in New Mexico (F-104 pilots had already been trained at Luke Air Force Base, Arizona, since 1964). Both facilities provide access to large unpopulated areas, where tactical and combat training can take place without danger to large populations. On 1 May 1996, the "Luftwaffe" established the German Air Force Tactical Training Center (TTC) in concert with the United States Air Force 20th Fighter Squadron at Holloman Air Force Base in New Mexico, which provides aircrew training in the F-4F Phantom II. The TTC serves as the parent command for two German air crew training squadrons. The F-4 Training Squadron oversees all German F-4 student personnel affairs and provides German instructor pilots to cooperate in the contracted F-4 training program provided by the U.S. Air Force (20th Fighter Squadron). A second TTC unit, the Tornado Training Squadron, provides academic and tactical flying training, by German air force instructors, for German Tornado aircrews.  The first contingent of Tornado aircraft arrived at Holloman in March 1996. More than 300 German air force personnel are permanently assigned at Holloman to the TTC, the only unit of its kind in the United States. The German Air Force Flying Training Center activated on 31 March 1996, with German Air Force Chief of Staff Gen. Portz and U.S. Air Force Chief of Staff Gen. Michael Ryan present. The "Luftwaffe" has since stationed up to 800 personnel at Holloman for training exercises, due to limited training space in Europe.  In September 2004, the "Luftwaffe" announced a reduction in its training program by about 20%. By the end of 2006, 650 "Luftwaffe" personnel and 25 Tornado aircraft were assigned to Holloman.

Air bases.

In 2018, the Air Force uses 16 air bases, six of which host no flying units. Furthermore, the Air Force has a presence at two civil airports:

Personnel.

In 2012, the Air Force had an authorized strength of 44,565 active soldiers and 4,914 reservists. The civil personnel within the Air Force is being reduced to 5,950 officials and employees. Most of the civilian employees work in maintenance and the Air Force Fire Department. On 20 September 2011 defense minister Thomas de Maizière announced that the Air Force would shrink to 23,000 soldiers.

Training.

The "Luftwaffe" has set up a total of 5 training institutions, namely the "Offizierschule der Luftwaffe", "Unteroffizierschule der Luftwaffe", "Luftwaffenausbildungsbataillon", "Fachschule der Luftwaffe" and "Technische Ausbildungszentrum der Luftwaffe", for training catering both personnel in active service and civilians willing to enter the "Luftwaffe".

Symbols, emblems and uniform.

Roundel and serial number.

Originally German Air Force aircraft carried an Iron Cross — appearing to be closely modeled on that used by the 1916-17 era Imperial German "Luftstreitkräfte" through the spring of 1918, but no longer having the white border around the crosses' "ends" (thusly resembling the orthogonal white "flanks" of the earlier, 1918-1945 era "Balkenkreuz" national marking) — as an identifying feature on all four wing positions and on both sides on the rear of the fuselage and a small tricolor "schwarz-rot-gold" German flag painted on the vertical stabilizer. Each aircraft also carried a serial number consisting of 2 letters, which identified the service and combat wing, followed by three numbers identifying the squadron and the number of the plane within the squadron, almost graphically resembling the USAF's own buzz numbers of the same period.  This system was changed in 1968. The large Iron Cross and serial numbers have since been replaced on all aircraft by a four number registration code, appearing somewhat in the manner of the earlier alphanumeric "Geschwaderkennung" combat wing code characters used by their World War II predecessor — separated by an Iron Cross in the middle: the first two numbers identify the type of aircraft and the second two numbers are a sequential for each type. When writing the registration number the Iron Cross is written as a "+". I.e. the Tornado IDS of the Air Force are numbered from 43+01 to 46+22, while the Tornado ECR of the Air Force are numbered from 46+23 to 46+57. The numbers from 30+01 to 33+99 are being used for the Eurofighter.

Uniform.

The ranks of the Air Force are identical to the ranks of the German Army. The Air Force field dress is the same as the army field dress. The dress uniform of the Air Force is dark blue with gold-yellow wings as collar patches. As headdress a dark blue side cap or dark blue peaked cap can be worn. Members of the German Air Force Regiment wear a dark blue beret.

Aircraft.

Current inventory.

NOTE: Four Airbus A330 MRTT’s are on order to support NATO’s multinational multi-role tanker transport fleet.

Selected bibliography.

Hundreds of books, magazines and articles have been written about the Luftwaffe. A select few are listed here.

The German Air Force (, ) is the aerial warfare branch of the "Bundeswehr", the armed forces of Germany. With a strength of 27,620 personnel (April 2020), it is the third largest air force within the European Union, after the Italian Air Force and French Air Force. The German Air Force (as part of the "Bundeswehr") was founded in 1956 during the era of the Cold War as the aerial warfare branch of the armed forces of then West Germany. After the reunification of West and East Germany in 1990, it integrated parts of the air force of the former German Democratic Republic, which itself had been founded in 1956 as part of the National People's Army. There is no organizational continuity between the current German Air Force and the former "Luftwaffe" of the "Wehrmacht" founded in 1935, which was completely disbanded in 1945/46 after World War II. The term "Luftwaffe" that is used for both the historic and the current German air force is the German-language generic designation of any air force.

德国联邦国防军空军()是指德意志联邦共和国的空军部队。


B细胞慢性淋巴细胞白血病

Signs and symptoms.

Most people are diagnosed as having CLL based on the result of a routine blood test that shows a high white blood cell count, specifically a large increase in the number of circulating lymphocytes. These people generally have no symptoms. Less commonly, CLL may present with enlarged lymph nodes. This is referred to as small lymphocytic lymphoma. Less commonly the disease comes to light only after the cancerous cells overwhelm the bone marrow resulting in low red blood cells, neutrophils, or platelets. Or there is fever, night sweats, weight loss, and the person feels tired.  CLL is, in virtually all cases, preceded by a particular subtype of monoclonal B-cell lymphocytosis (MBL). This subtype, termed chronic lymphocytic leukemia/small lymphocyte lymphoma MBL (CLL/SLL MBL) is an asymptomatic, indolent, and chronic disorder in which individuals exhibit an increase in the number of circulating B-cell lymphocytes. These B-cells are abnormal: they are monoclonal, i.e. produced by a single ancestral B-cell, and have some of the same cell marker proteins, chromosome abnormalities, and gene mutations found in CLL. CLL/SLL MBL consist of two groups: low-count CLL/SLL MBL has monoclonal B-cell blood counts of <0.5x cells/liter (i.e. 0.5x/L) while high-count CLL/SLL MBL has blood monoclonal B-cell counts ≥0.5x/L but <5x10/L. Individuals with blood counts of these monoclonal B-cells >5x/L are diagnosed as having CLL. Low-count CLL/SLLL MBL rarely if ever progresses to CLL while high-count CLL/SLL MBL does so at a rate of 1-2% per year. Thus, CLL may present in individuals with a long history of having high-count CLL/SLL MBL. There is no established treatment for these individuals except monitoring for development of the disorder's various complications (see treatment of MBL complications) and for their progression to CLL.

Complications.

Complications include a low level of antibodies in the bloodstream (hypogammaglobulinemia) leading to recurrent infection, warm autoimmune hemolytic anemia in 10–15% of patients, and bone marrow failure. Chronic lymphocytic leukemia may also transform into Richter's syndrome, the development of fast-growing diffuse large B cell lymphoma, prolymphocytic leukemia, Hodgkin's lymphoma, or acute leukemia in some patients. Its incidence is estimated to be around 5% in patients with CLL.  Gastrointestinal (GI) involvement can rarely occur with chronic lymphocytic leukemia. Some of the reported manifestations include intussusception, small intestinal bacterial contamination, colitis, and others. Usually, GI complications with CLL occur after Richter transformation. Two cases to date have been reported of GI involvement in chronic lymphocytic leukemia without Richter's transformation.

Cause.

CLL is caused by multiple genetic mutations and epigenetic changes. Men are about twice as likely to get CLL as women, and risk increases with age. It is relatively rare among Asians. Some relevant genetic mutations may be inherited; in around 9% of CLL cases a parent had CLL. Exposure to Agent Orange increases the risk of CLL, and exposure to hepatitis C virus may increase the risk. There is no clear association between ionizing radiation exposure and the risk of developing CLL. Blood transfusions have been ruled out as a risk factor.

Diagnosis.

CLL is usually first suspected by a diagnosis of lymphocytosis, an increase in a type of white blood cell, on a complete blood count test. This frequently is an incidental finding on a routine physician visit. Most often the lymphocyte count is greater than 5000 cells per microliter (μl) of blood, but can be much higher. The presence of lymphocytosis in an elderly individual should raise strong suspicion for CLL, and a confirmatory diagnostic test, in particular flow cytometry, should be performed unless clinically unnecessary.  A peripheral blood smear showing an abundance of damaged cells known as "smudge cells" or "basket cells" can also indicate the presence of the disease (smudge cells are due to cancer cells lacking in vimentin, a cytoskeletal protein).  The diagnosis of CLL is based on the demonstration of an abnormal population of B lymphocytes in the blood, bone marrow, or tissues that display an unusual but characteristic pattern of molecules on the cell surface. This atypical molecular pattern includes the coexpression of cell surface markers clusters of differentiation 5 (CD5) and 23. In addition, all the CLL cells within one individual are clonal, that is, genetically identical. In practice, this is inferred by the detection of only one of the mutually exclusive antibody light chains, kappa or lambda, on the entire population of the abnormal B cells. Normal B lymphocytes consist of a stew of different antibody-producing cells, resulting in a mixture of both kappa- and lambda-expressing cells. The lack of the normal distribution of these B cells is one basis for demonstrating clonality, the key element for establishing a diagnosis of any B cell malignancy (B cell non-Hodgkin lymphoma).  The combination of the microscopic examination of the peripheral blood and analysis of the lymphocytes by flow cytometry to confirm clonality and marker molecule expression is needed to establish the diagnosis of CLL. Both are easily accomplished on a small amount of blood. A flow cytometer instrument can examine the expression of molecules on individual cells in fluids. This requires the use of specific antibodies to marker molecules with fluorescent tags recognized by the instrument. In CLL, the lymphocytes are genetically clonal, of the B cell lineage (expressing marker molecules clusters of differentiation 19 and 20), and characteristically express the marker molecules CD5 and CD23. These B cells resemble normal lymphocytes under the microscope, although slightly smaller, and are fragile when smeared onto a glass slide, giving rise to many broken cells, which are called "smudge" or "smear" cells. The Matutes's CLL score allows the identification of a homogeneous subgroup of classical CLL, that differs from atypical/mixed CLL for the five markers' expression (CD5, CD23, FMC7, CD22, and immunoglobulin light chain) Matutes's CLL scoring system is very helpful for the differential diagnosis between classical CLL and the other B cell chronic lymphoproliferative disorders, but not for the immunological distinction between mixed/atypical CLL and mantle cell lymphoma (MCL malignant B cells). Discrimination between CLL and MCL can be improved by adding non-routine markers such as CD54 and CD200. Among routine markers, the most discriminating feature is the CD20/CD23 mean fluorescence intensity ratio. In contrast, FMC7 expression can surprisingly be misleading for borderline cases.

Clinical staging.

Staging, determining the extent of the disease, is done with the Rai staging system or the Binet classification (see details) and is based primarily on the presence of a low platelet or red cell count. Early-stage disease does not need to be treated. CLL and SLL are considered the same underlying disease, just with different appearances.  Rai staging system  Binet classification

Array-based karyotyping.

Array-based karyotyping is a cost-effective alternative to FISH for detecting chromosomal abnormalities in CLL. Several clinical validation studies have shown >95% concordance with the standard CLL FISH panel.

Related diseases.

In the past, cases with similar microscopic appearance in the blood but with a T cell phenotype were referred to as T-cell CLL. However, these are now recognized as a separate disease group and are currently classified as T-cell prolymphocytic leukemias.  CLL should not be confused with acute lymphoblastic leukemia, a highly aggressive leukemia most commonly diagnosed in children, and highly treatable in the pediatric setting.

Differential diagnosis.

Hematologic disorders that may resemble CLL in their clinical presentation, behavior, and microscopic appearance include mantle cell lymphoma, marginal zone lymphoma, B cell prolymphocytic leukemia, and lymphoplasmacytic lymphoma.  All the B cell malignancies of the blood and bone marrow can be differentiated from one another by the combination of cellular microscopic morphology, marker molecule expression, and specific tumor-associated gene defects. This is best accomplished by evaluation of the patient's blood, bone marrow, and occasionally lymph node cells by a pathologist with specific training in blood disorders. A flow cytometer is necessary for cell marker analysis, and the detection of genetic problems in the cells may require visualizing the DNA changes with fluorescent probes by FISH.

Treatment.

CLL treatment focuses on controlling the disease and its symptoms rather than on an outright cure. In those without or only minimal symptoms watchful waiting is generally appropriate.  CLL is treated by chemotherapy, radiation therapy, biological therapy, or bone marrow transplantation. Symptoms are sometimes treated surgically (splenectomy – removal of enlarged spleen) or by radiation therapy ("de-bulking" swollen lymph nodes).  Initial CLL treatments vary depending on the exact diagnosis and the progression of the disease, and even with the preference and experience of the health care practitioner. Any of dozens of agents may be used for CLL therapy.

Decision to treat.

While it is generally considered incurable, CLL progresses slowly in most cases. Many people with CLL lead normal and active lives for many years—in some cases for decades. Because of its slow onset, early-stage CLL is, in general, not treated since it is believed that early CLL intervention does not improve survival time or quality of life. Instead, the condition is monitored over time to detect any change in the disease pattern.  The decision to start CLL treatment is taken when the person's symptoms or blood counts indicate that the disease has progressed to a point where it may affect quality of life.  Clinical "staging systems" such as the Rai four-stage system and the Binet classification can help to determine when and how to treat the patient.  Determining when to start treatment and by what means is often difficult; no survival advantage is seen in treating the disease very early. The National Cancer Institute Working Group has issued guidelines for treatment, with specific markers that should be met before it is initiated.

Chemotherapy.

Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:  Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy, no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.  Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness. This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of patients with CLL.  Alkylating agents approved for CLL include bendamustine and cyclophosphamide.

Targeted therapy.

Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells. Targeted drugs used in CLL include venetoclax (a Bcl-2 inhibitor), ibrutinib (a Bruton's tyrosine kinase inhibitor), idelalisib and duvelisib (inhibitors of some forms of the enzyme phosphoinositide 3-kinase), as well as monoclonal antibodies against CD20 (rituximab, ofatumumab and obinutuzumab) and CD52 (alemtuzumab).

Stem cell transplantation.

Autologous stem cell transplantation, using the recipient's own cells, is not curative. Younger individuals, if at high risk for dying from CLL, may consider allogeneic hematopoietic stem cell transplantation (HSCT). Myeloablative (bone marrow killing) forms of allogeneic stem cell transplantation, a high-risk treatment using blood cells from a healthy donor, may be curative, but treatment-related toxicity is significant. An intermediate level, called reduced-intensity conditioning allogeneic stem cell transplantation, may be better tolerated by older or frail patients.

Refractory CLL.

"Refractory" CLL is a disease that no longer responds favorably to treatment. In this case, more aggressive therapies, including lenalidomide, flavopiridol, and bone marrow (stem cell) transplantation, are considered. The monoclonal antibody alemtuzumab (directed against CD52) may be used in patients with refractory, bone marrow-based disease.

During pregnancy.

Leukemia is rarely associated with pregnancy, affecting only about one in 10,000 pregnant women. Treatment for chronic lymphocytic leukemias can often be postponed until after the end of the pregnancy. If treatment is necessary, then giving chemotherapy during the second or third trimesters is less likely to result in pregnancy loss or birth defects than treatment during the first trimester.

Prognosis.

Prognosis depends on the subtype. Some subtypes have a median survival of 6–8 years, while others have a median survival of 22 years (which is a normal lifespan for older patients). Telomere length has been suggested to be a valuable prognostic indicator of survival.

Epidemiology.

CLL is primarily a disease of older adults, with a median age of 70 years at the time of diagnosis. Though less common, CLL sometimes affects people between 30 and 39 years of age. The incidence of CLL increases very quickly with increasing age.  In the United States during 2014, about 15,720 new cases are expected to be diagnosed, and 4,600 patients are expected to die from CLL. Because of the prolonged survival, which was typically about 10 years in past decades, but which can extend to a normal life expectancy, the prevalence (number of people living with the disease) is much higher than the incidence (new diagnoses). CLL is the most common type of leukemia in the UK, accounting for 38% of all leukemia cases. Approximately 3,200 people were diagnosed with the disease in 2011.  In Western populations, subclinical "disease" can be identified in 3.5% of normal adults, and in up to 8% of individuals over the age of 70. That is, small clones of B cells with the characteristic CLL phenotype can be identified in many healthy elderly persons. The clinical significance of these cells is unknown.  In contrast, CLL is rare in Asian countries, such as Japan, China, and Korea, accounting for less than 10% of all leukemias in those regions. A low incidence is seen in Japanese immigrants to the US, and in African and Asian immigrants to Israel.  Of all cancers involving the same class of blood cell, 7% of cases are CLL/SLL.  Rates of CLL are somewhat elevated in people exposed to certain chemicals. Under U.S. Department of Veterans' Affairs regulations, Vietnam veterans who served in-country or in the inland waterways of Vietnam and who later develop CLL are presumed to have contracted it from exposure to Agent Orange and may be entitled to compensation.

Research directions.

Research in 2008 is comparing different forms of bone marrow transplants to determine which patients are the best candidates and which approach is best in different situations. Researchers at the Abramson Cancer Center of the University of Pennsylvania School of Medicine reported preliminary success in the use of gene therapy, through genetically modified T cells, to treat CLL. The findings, which were published in August 2011, were based on data from three patients who had modified T cells injected into their blood. The T cells had been modified to express genes that would allow the cells to proliferate in the body and destroy B cells including those causing the leukemia. Two patients went into remission, while the presence of leukemia in the third patient reduced by 70%.  One of the patients had been diagnosed with CLL for 13 years, and his treatment was failing before he participated in the clinical trial. One week after the T cells were injected, the leukemia cells in his blood had disappeared. The T cells were still found in the bloodstream of the patients six months after the procedure, meaning they would be able to fight the disease should leukemia cells return. This was the first time scientists "have used gene therapy to successfully destroy cancer tumors in patients with advanced disease".  Research is also investigating therapies targeting B cell receptor signalling. Syk inhibitor fostamatinib is in trials. The trial of a combination of ibrutinib and venetoclax had encouraging results in a small number of people.

Chronic lymphocytic leukemia (CLL) is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell). Early on there are typically no symptoms. Later non-painful lymph node swelling, feeling tired, fever, night sweats, or weight loss for no clear reason may occur. Enlargement of the spleen and low red blood cells (anemia) may also occur. It typically worsens gradually over years. Risk factors include having a family history of the disease. Exposure to Agent Orange and certain insecticides might also be a risk. CLL results in the buildup of B cell lymphocytes in the bone marrow, lymph nodes, and blood. These cells do not function well and crowd out healthy blood cells. CLL is divided into two main types: those with a mutated IGHV gene and those without. Diagnosis is typically based on blood tests finding high numbers of mature lymphocytes and smudge cells. Management of early disease is generally with watchful waiting. Infections should more readily be treated with antibiotics. In those with significant symptoms, chemotherapy or immunotherapy may be used. As of 2019 ibrutinib is often the initial medication recommended. The medications fludarabine, cyclophosphamide, and rituximab were previously the initial treatment in those who are otherwise healthy. CLL affected about 904,000 people globally in 2015 and resulted in 60,700 deaths. The disease most commonly occurs in people over the age of 50. Males are affected more often than females. It is much less common in people from Asia. Five-year survival following diagnosis is approximately 83% in the United States. It represents less than 1% of deaths from cancer.

慢性淋巴细胞性白血病,Chronic lymphocytic leukemia,简称CLL,这是一种最常见的白血病 主要影响B细胞。B细胞来自于骨髓,在淋巴结中发育,它主要的功能是产生抗体。


Bone structure.

The skeleton is a large organ that is formed and degraded throughout life in the air-breathing vertebrates. The skeleton, often referred to as the skeletal system, is important both as a supporting structure and for maintenance of calcium, phosphate, and acid-base status in the whole organism. The functional part of bone, the "bone matrix", is entirely extracellular. The bone matrix consists of protein and mineral. The protein forms the "organic matrix." It is synthesized and then the mineral is added. The vast majority of the organic matrix is collagen, which provides tensile strength. The matrix is mineralized by deposition of hydroxyapatite (alternative name, hydroxylapatite). This mineral is hard, and provides compressive strength. Thus, the collagen and mineral together are a composite material with excellent tensile and compressive strength, which can bend under a strain and recover its shape without damage. This is called elastic deformation. Forces that exceed the capacity of bone to behave elastically may cause failure, typically bone fractures.

Bone remodeling.

Bone is a dynamic tissue that is constantly being reshaped by osteoblasts, which produce and secrete matrix proteins and transport mineral into the matrix, and osteoclasts, which break down the tissues.

Osteoblasts.

Osteoblasts are the major cellular component of bone. Osteoblasts arise from mesenchymal stem cells (MSC). MSC give rise to osteoblasts, adipocytes, and myocytes among other cell types. Osteoblast quantity is understood to be inversely proportional to that of marrow adipocytes which comprise marrow adipose tissue (MAT). Osteoblasts are found in large numbers in the periosteum, the thin connective tissue layer on the outside surface of bones, and in the endosteum.  Normally, almost all of the bone matrix, in the air breathing vertebrates, is mineralized by the osteoblasts. Before the organic matrix is mineralized, it is called the osteoid. Osteoblasts buried in the matrix are called osteocytes. During bone formation, the surface layer of osteoblasts consists of cuboidal cells, called "active osteoblasts". When the bone-forming unit is not actively synthesizing bone, the surface osteoblasts are flattened and are called "inactive osteoblasts". Osteocytes remain alive and are connected by cell processes to a surface layer of osteoblasts. Osteocytes have important functions in skeletal maintenance.

Osteoclasts.

Osteoclasts are multinucleated cells that derive from hematopoietic progenitors in the bone marrow which also give rise to monocytes in peripheral blood. Osteoclasts break down bone tissue, and along with osteoblasts and osteocytes form the structural components of bone. In the hollow within bones are many other cell types of the bone marrow. Components that are essential for osteoblast bone formation include mesenchymal stem cells (osteoblast precursor) and blood vessels that supply oxygen and nutrients for bone formation. Bone is a highly vascular tissue, and active formation of blood vessel cells, also from mesenchymal stem cells, is essential to support the metabolic activity of bone. The balance of bone formation and bone resorption tends to be negative with age, particularly in post-menopausal women, often leading to a loss of bone serious enough to cause fractures, which is called osteoporosis.

Osteogenesis.

Bone is formed by one of two processes: endochondral ossification or intramembranous ossification. Endochondral ossification is the process of forming bone from cartilage and this is the usual method. This form of bone development is the more complex form: it follows the formation of a first skeleton of cartilage made by chondrocytes, which is then removed and replaced by bone, made by osteoblasts. Intramembranous ossification is the direct ossification of mesenchyme as happens during the formation of the membrane bones of the skull and others.  During osteoblast differentiation, the developing progenitor cells express the regulatory transcription factor Cbfa1/Runx2. A second required transcription factor is Sp7 transcription factor. Osteochondroprogenitor cells differentiate under the influence of growth factors, although isolated mesenchymal stem cells in tissue culture may also form osteoblasts under permissive conditions that include vitamin C and substrates for alkaline phosphatase, a key enzyme that provides high concentrations of phosphate at the mineral deposition site.

Bone morphogenetic proteins.

Key growth factors in endochondral skeletal differentiation include bone morphogenetic proteins (BMPs) that determine to a major extent where chondrocyte differentiation occurs and where spaces are left between bones. The system of cartilage replacement by bone has a complex regulatory system. BMP2 also regulates early skeletal patterning. transforming growth factor beta (TGF-β), is part of a superfamily of proteins that include BMPs, which possess common signaling elements in the TGF beta signaling pathway. TGF-β is particularly important in cartilage differentiation, which generally precedes bone formation for endochondral ossification. An additional family of essential regulatory factors is the fibroblast growth factors (FGFs) that determine where skeletal elements occur in relation to the skin

Steroid and protein hormones.

Many other regulatory systems are involved in the transition of cartilage to bone and in bone maintenance. A particularly important bone-targeted hormonal regulator is parathyroid hormone (PTH). Parathyroid hormone is a protein made by the parathyroid gland under the control of serum calcium activity. PTH also has important systemic functions, including to keep serum calcium concentrations nearly constant regardless of calcium intake. Increasing dietary calcium results in minor increases in blood calcium. However, this is not a significant mechanism supporting osteoblast bone formation, except in the condition of low dietary calcium; further, abnormally high dietary calcium raises the risk of serious health consequences not directly related to bone mass including heart attack and stroke. Intermittent PTH stimulation increases osteoblast activity, although PTH is bifunctional and mediates bone matrix degradation at higher concentrations.  The skeleton is also modified for reproduction and in response to nutritional and other hormone stresses; it responds to steroids, including estrogen and glucocorticoids, which are important in reproduction and energy metabolism regulation. Bone turnover involves major expenditures of energy for synthesis and degradation, involving many additional signals including pituitary hormones. Two of these are adrenocorticotropic hormone (ACTH) and follicle stimulating hormone. The physiological role for responses to these, and several other glycoprotein hormones, is not fully understood, although it is likely that ACTH is bifunctional, like PTH, supporting bone formation with periodic spikes of ACTH, but causing bone destruction in large concentrations. In mice, mutations that reduce the efficiency of ACTH-induced glucocorticoid production in the adrenals cause the skeleton to become dense (osteosclerotic bone).

Organization and ultrastructure.

In well-preserved bone studied at high magnification via electron microscopy, individual osteoblasts are shown to be connected by tight junctions, which prevent extracellular fluid passage and thus create a bone compartment separate from the general extracellular fluid. The osteoblasts are also connected by gap junctions, small pores that connect osteoblasts, allowing the cells in one cohort to function as a unit. The gap junctions also connect deeper layers of cells to the surface layer ("osteocytes" when surrounded by bone). This was demonstrated directly by injecting low molecular weight fluorescent dyes into osteoblasts and showing that the dye diffused to surrounding and deeper cells in the bone-forming unit. Bone is composed of many of these units, which are separated by impermeable zones with no cellular connections, called cement lines.

Collagen and accessory proteins.

Almost all of the organic (non-mineral) component of bone is dense collagen type I, which forms dense crosslinked ropes that give bone its tensile strength. By mechanisms still unclear, osteoblasts secrete layers of oriented collagen, with the layers parallel to the long axis of the bone alternating with layers at right angles to the long axis of the bone every few micrometers. Defects in collagen type I cause the commonest inherited disorder of bone, called osteogenesis imperfecta.  Minor, but important, amounts of small proteins, including osteocalcin and osteopontin, are secreted in bone's organic matrix. Osteocalcin is not expressed at significant concentrations except in bone, and thus osteocalcin is a specific marker for bone matrix synthesis. These proteins link organic and mineral component of bone matrix. The proteins are necessary for maximal matrix strength due to their intermediate localization between mineral and collagen.  However, in mice where expression of osteocalcin or osteopontin was eliminated by targeted disruption of the respective genes (knockout mice), accumulation of mineral was not notably affected, indicating that organization of matrix is not significantly related to mineral transport.

Bone versus cartilage.

The primitive skeleton is cartilage, a solid avascular (without blood vessels) tissue in which individual cartilage-matrix secreting cells, or chondrocytes, occur. Chondrocytes do not have intercellular connections and are not coordinated in units. Cartilage is composed of a network of collagen type II held in tension by water-absorbing proteins, hydrophilic proteoglycans. This is the adult skeleton in cartilaginous fishes such as sharks. It develops as the initial skeleton in more advanced classes of animals.  In air-breathing vertebrates, cartilage is replaced by cellular bone. A transitional tissue is mineralized cartilage. Cartilage mineralizes by massive expression of phosphate-producing enzymes, which cause high local concentrations of calcium and phosphate that precipitate. This mineralized cartilage is not dense or strong. In the air breathing vertebrates it is used as a scaffold for formation of cellular bone made by osteoblasts, and then it is removed by osteoclasts, which specialize in degrading mineralized tissue.  Osteoblasts produce an advanced type of bone matrix consisting of dense, irregular crystals of hydroxyapatite, packed around the collagen ropes. This is a strong composite material that allows the skeleton to be shaped mainly as hollow tubes. Reducing the long bones to tubes reduces weight while maintaining strength.

Mineralization of bone.

The mechanisms of mineralization are not fully understood. Fluorescent, low-molecular weight compounds such as tetracycline or calcein bind strongly to bone mineral, when administered for short periods. They then accumulate in narrow bands in the new bone. These bands run across the contiguous group of bone-forming osteoblasts. They occur at a narrow (sub-micrometer) mineralization front. Most bone surfaces express no new bone formation, no tetracycline uptake and no mineral formation. This strongly suggests that facilitated or active transport, coordinated across the bone-forming group, is involved in bone formation, and that only cell-mediated mineral formation occurs. That is, dietary calcium does not create mineral by mass action.  The mechanism of mineral formation in bone is clearly distinct from the phylogenetically older process by which cartilage is mineralized: tetracycline does not label mineralized cartilage at narrow bands or in specific sites, but diffusely, in keeping with a passive mineralization mechanism.  Osteoblasts separate bone from the extracellular fluid by tight junctions by regulated transport. Unlike in cartilage, phosphate and calcium cannot move in or out by passive diffusion, because the tight osteoblast junctions isolate the bone formation space. Calcium is transported across osteoblasts by facilitated transport (that is, by passive transporters, which do not pump calcium against a gradient). In contrast, phosphate is actively produced by a combination of secretion of phosphate-containing compounds, including ATP, and by phosphatases that cleave phosphate to create a high phosphate concentration at the mineralization front. Alkaline phosphatase is a membrane-anchored protein that is a characteristic marker expressed in large amounts at the apical (secretory) face of active osteoblasts.  At least one more regulated transport process is involved. The stoichiometry of bone mineral basically is that of hydroxyapatite precipitating from phosphate, calcium, and water at a slightly alkaline pH:  In a closed system as mineral precipitates, acid accumulates, rapidly lowering the pH and stopping further precipitation. Cartilage presents no barrier to diffusion and acid therefore diffuses away, allowing precipitation to continue. In the osteon, where matrix is separated from extracellular fluid by tight junctions, this cannot occur. In the controlled, sealed compartment, removing H drives precipitation under a wide variety of extracellular conditions, as long as calcium and phosphate are available in the matrix compartment. The mechanism by which acid transits the barrier layer remains uncertain. Osteoblasts have capacity for Na/H exchange via the redundant Na/H exchangers, NHE1 and NHE6. This H exchange is a major element in acid removal, although the mechanism by which H is transported from the matrix space into the barrier osteoblast is not known.  In bone removal, a reverse transport mechanism uses acid delivered to the mineralized matrix to drive hydroxyapatite into solution.

Osteocyte feedback.

Feedback from physical activity maintains bone mass, while feedback from osteocytes limits the size of the bone-forming unit. An important additional mechanism is secretion by osteocytes, buried in the matrix, of sclerostin, a protein that inhibits a pathway that maintains osteoblast activity. Thus, when the osteon reaches a limiting size, it deactivates bone synthesis.

Morphology and histological staining.

Hematoxylin and eosin staining (H&E) shows that the cytoplasm of active osteoblasts is slightly basophilic due to the substantial presence of rough endoplasmic reticulum. The active osteoblast produces substantial collagen type I. About 10% of the bone matrix is collagen with the balance mineral. The osteoblast's nucleus is spherical and large. An active osteoblast is characterized morphologically by a prominent Golgi apparatus that appears histologically as a clear zone adjacent to the nucleus. The products of the cell are mostly for transport into the osteoid, the non-mineralized matrix. Active osteoblasts can be labeled by antibodies to Type-I collagen, or using naphthol phosphate and the diazonium dye fast blue to demonstrate alkaline phosphatase enzyme activity directly.

Osteoblasts (from the Greek combining forms for "bone", ὀστέο-, "osteo-" and βλαστάνω, "blastanō" "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts function in groups of connected cells. Individual cells cannot make bone. A group of organized osteoblasts together with the bone made by a unit of cells is usually called the osteon.

成骨细胞(英语:Osteoblast),名称来自希腊语“ὀστέο”(骨),和“βλαστάνω”(发芽)的组合形式,是具有单核的细胞,它们可以合成骨骼。 然而,在成骨作用中,成骨细胞的功能则是连接细胞。 单个细胞不能制造骨骼。 一组有组织的成骨细胞与由一个细胞单元组成的骨骼通常称为骨单位 。


Club career.

Early career.

Vonlanthen played as a junior for BSC Young Boys in Switzerland. In the 2001–02 season, he made his debut as a 16-year-old in the Swiss Super League starting eight games and appearing once as a substitute. In the summer of 2003, he was transferred to the Dutch Eredivisie club PSV Eindhoven. On 21 June 2004, Vonlanthen became the youngest goalscorer when he scored for Switzerland vs France in Coimbra, Portugal at the age of 18 years and 141 days old. He made a good initial impression and helped PSV qualify for the UEFA Champions League. After a good first season, he began to lose form and as a consequence was loaned out to Italian side Brescia Calcio for the last six months of the 2004–05 season. He was again loaned out to NAC Breda for the 2005–06 season.

Red Bull Salzburg.

At the start of the 2006–07 season, Vonlanthen transferred to Red Bull Salzburg in the Austrian Bundesliga.  On 13 July 2009, FC Zürich signed the Swiss forward on a season long loan deal. The move was not made permanent, and Vonlanthen returned to Salzburg for the start of the 2010–11 season.

Initial retirement and return.

On 30 May 2012, Vonlanthen announced his retirement at age 26. According to him, he 'could not face the prospect of undergoing a knee operation'.  However, on 13 June 2013, Vonlanthen came out of retirement to join Grasshoppers, signing a one-year deal with an option for a further two years.  On 27 December 2013, Vonlanthen was loaned out to Swiss second division side Schaffhausen, due to a lack of playtime at Grasshoppers.

International career.

On 6 June 2004, Vonlanthen made his senior debut for the Swiss National Team against Liechtenstein. He came on as a substitute in the 81st minute to replace Alexander Frei. Switzerland went on to beat Liechtenstein 1–0.  At Euro 2004, Vonlanthen became the second youngest player to play in the tournament when he came on as a substitute against England. On 21 June 2004, Vonlanthen became the youngest scorer ever in the European Championships when he equalised against France, beating Wayne Rooney's record – which had only been set four days before – by three months.  Since the European Championships in Portugal, Vonlanthen has managed to hold a regular position in the national team and as well as playing frequently in the under 21s side. He was part of the squad that very narrowly lost out to Spain on a place in the 2009 European Championships. He had scored the equaliser in the first leg in a 2–1 win but the Spanish came back to win 3–1 in the second leg and 4–3 on aggregate.  Vonlanthen was called up to the Swiss squad to play in 2006 World Cup, but was unable to participate due to a hamstring injury. He was also called up for Euro 2008.

Johan Vonlanthen Benavídez (born 1 February 1986) is a Swiss former professional footballer who played as a winger. His stepfather is a Swiss national, giving him the right to play for that country.

约翰·冯兰腾(Johan Vonlanthen Benavidez,1986年-2月1日)是一名瑞士足球运动员,可担任前锋和进攻中场,因严重伤病已退役。


Early life.

Vladislaus Henry was the second son of Duke Vladislaus II from his second marriage with Judith of Thuringia, thereby the younger brother of Ottokar I. He grew up during a frivolous time, for the complex personal relationship his father had with the emperor, Frederick Barbarossa, was leading to a tragic termination. During the late 12th century struggles within the Přemyslid dynasty, he supported his older brother Ottokar when he seized the Bohemian duchy in 1192. In turn, Ottokar appointed Vladislaus, Prince of Brno and Znojmo since 1191, a margrave of Moravia with the consent of Emperor Henry VI. However, the two never paid the demanded sum and so were again deposed in June 1193 by a decision of the Imperial Diet at Worms, which appointed their cousin, the Prague bishop Henry Bretislaus, as duke. Vladislaus was summoned to Prague Castle, where he had to spend the following years suspiciously eyed by Duke Bretislaus.

Reign.

After the death of Emperor Henry VI and Bretislaus in 1197, Vladislaus was released and elected duke on 22 June 1197, with his brother in attendance. Faced with an uprising in favour of Ottokar, Vladislaus abdicated a few months later, on 6 December. The brothers then very nearly came to war, but, their armies encamped facing each other, the two met and negotiated a solution whereby Ottokar took the Bohemian throne–though without imperial approval–and compensated Vladislaus with the hereditary margravial title of near-autonomous Moravia. By his repudiation of the throne, Vladislaus helped to bring an end to the destructive dynastic wars of the Přemyslids, which had lasted for over twenty-five years from the death of his father. His status as a Prince of the Holy Roman Empire was acknowledged in the 1212 Golden Bull of Sicily.  Vladislaus held Moravia until his death twenty five years thence, in close co-operation with his brother. He reinforced his rule, when he had the rivalling claimant Prince Spytihněv III of Brno blinded and installed his own confessor, Daniel Milík, as Bishop of Prague, the first investiture by a reigning prince in Bohemia. Daniel played a vital role in the reconciliation between Vladislaus and Ottokar; despite several protests to the Roman Curia, he held the see until 1214 without receiving imperial nomination. In 1205, Vladislaus founded the Cistercian abbey of Velehrad as a family monastery and burial ground of the Moravian margraves.  Vladislaus was married with one Heilwida (Hedwig), of unknown origin. He died without issue at his court in Znojmo, whereafter the Moravian margraviate fell back to King Ottokar I, who enfeoffed it to his younger son Vladislaus II. Vladislaus was buried at Velehrad Abbey.

Sources.

Vladislaus Henry (; – 12 August 1222), a member of the Přemyslid dynasty, was elected Duke of Bohemia (as "Vladislaus III") in 1197 and Margrave of Moravia from 1197 until his death. He only served as duke during the year 1197 and was indeed the last ruler of Bohemia to hold that title. It was his brother Ottokar I, whose forces overthrew him, who finally achieved the elevation of the Duchy of Bohemia to the status of a kingdom starting in 1198.

弗拉迪斯拉夫三世(,?-1222年-8月12日),普热米斯尔王朝的第25任及最后一任波希米亚公爵(1197年)。波希米亚国王弗拉迪斯拉夫一世之子、奥托卡一世的弟弟。


Complexity.

Although more practical than Karnaugh mapping when dealing with more than four variables, the Quine–McCluskey algorithm also has a limited range of use since the problem it solves is NP-complete. The running time of the Quine–McCluskey algorithm grows exponentially with the number of variables. For a function of "n" variables the number of prime implicants can be as large as 3ln("n"), e.g. for 32 variables there may be over 534 × 10 prime implicants. Functions with a large number of variables have to be minimized with potentially non-optimal heuristic methods, of which the Espresso heuristic logic minimizer was the de facto standard in 1995.  Step two of the algorithm amounts to solving the set cover problem; NP-hard instances of this problem may occur in this algorithm step.

Example.

Input.

In this example, the input is a Boolean function in four variables, formula_1 which evaluates to formula_2 on the values formula_3 and formula_4, evaluates to an unknown value on formula_5 and formula_6, and to formula_7 everywhere else (where these integers are interpreted in their binary form for input to formula_8 for succinctness of notation). The inputs that evaluate to formula_2 are called'minterms'. We encode all of this information by writing  This expression says that the output function f will be 1 for the minterms formula_3 and formula_4 (denoted by the'm' term) and that we don't care about the output for formula_5 and formula_6 combinations (denoted by the 'd' term).

Step 1: finding prime implicants.

First, we write the function as a table (where 'x' stands for don't care):  One can easily form the canonical sum of products expression from this table, simply by summing the minterms (leaving out don't-care terms) where the function evaluates to one:  which is not minimal. So to optimize, all minterms that evaluate to one are first placed in a minterm table. Don't-care terms are also added into this table (names in parentheses), so they can be combined with minterms:  At this point, one can start combining minterms with other minterms. If two terms differ by only a single digit, that digit can be replaced with a dash indicating that the digit doesn't matter. Terms that can't be combined any more are marked with an asterisk (*). For instance codice_1 and codice_2 can be combined to give codice_3, indicating that both minterms imply the first digit is codice_4 and the next two are codice_5.  When going from Size 2 to Size 4, treat codice_6 as a third bit value. For instance, codice_7 and codice_8 can be combined to give codice_9, as can codice_7 and codice_11 to give codice_11, but codice_7 and codice_14 cannot because codice_7 is implied by codice_16 while codice_14 is not. (Trick: Match up the codice_6 first.)  Note: In this example, none of the terms in the size 4 implicants table can be combined any further. In general this process should be continued (sizes 8, 16 etc.) until no more terms can be combined.

Step 2: prime implicant chart.

None of the terms can be combined any further than this, so at this point we construct an essential prime implicant table. Along the side goes the prime implicants that have just been generated, and along the top go the minterms specified earlier. The don't care terms are not placed on top—they are omitted from this section because they are not necessary inputs.  To find the essential prime implicants, we run along the top row. We have to look for columns with only one "✓". If a column has only one "✓", this means that the minterm can only be covered by one prime implicant. This prime implicant is "essential".  For example: in the first column, with minterm 4, there is only one "✓". This means that m(4,12) is essential. So we place a star next to it. Minterm 15 also has only one "✓", so m(10,11,14,15) is also essential. Now all columns with one "✓" are covered.  The second prime implicant can be 'covered' by the third and fourth, and the third prime implicant can be 'covered' by the second and first, and neither is thus essential. If a prime implicant is essential then, as would be expected, it is necessary to include it in the minimized boolean equation. In some cases, the essential prime implicants do not cover all minterms, in which case additional procedures for chart reduction can be employed. The simplest "additional procedure" is trial and error, but a more systematic way is Petrick's method. In the current example, the essential prime implicants do not handle all of the minterms, so, in this case, the essential implicants can be combined with one of the two non-essential ones to yield one equation:  or  Both of those final equations are functionally equivalent to the original, verbose equation:

The Quine–McCluskey algorithm (QMC), also known as the method of prime implicants, is a method used for minimization of Boolean functions that was developed by Willard V. Quine in 1952 and extended by Edward J. McCluskey in 1956. As a general principle this approach had already been demonstrated by the logician Hugh McColl in 1878, was proved by Archie Blake in 1937, and was rediscovered by Edward W. Samson and Burton E. Mills in 1954 and by Raymond J. Nelson in 1955. Also in 1955, Paul W. Abrahams and John G. Nordahl as well as Albert A. Mullin and Wayne G. Kellner proposed a decimal variant of the method.

奎因-麦克拉斯基算法(Quine-McCluskey算法)是最小化布尔函数的一种方法。它在功能上等同于卡诺图,但是它具有文字表格的形式,因此它更适合用于电子设计自动化算法的实现,并且它还给出了检查布尔函数是否达到了最小化形式的确定性方法。


Life.

The details of Priscian's life are largely unknown. Priscian was born and raised in the North-African city of Caesarea (modern Cherchell, Algeria) the capital of the Roman province of Mauretania Caesariensis. According to Cassiodorus, he taught Latin at Constantinople in the early sixth century. His minor works include a panegyric to Anastasius (491—518), written about 512, which helps establish his time period. In addition, the manuscripts of his "Institutes" contain a subscription to the effect that the work was copied (526, 527) by Flavius Theodorus, a clerk in the imperial secretariat.

Works.

Priscian's most famous work, the "Institutes of Grammar" (), is a systematic exposition of Latin grammar. The dedication to Julian probably indicates the consul and patrician, not the author of a well-known epitome of Justinian's "Novellae", who lived somewhat later than Priscian. The grammar is divided into eighteen books, of which the first sixteen deal mainly with sounds, word-formation and inflexions; the last two, which form from a fourth to a third of the whole work, deal with syntax.  Priscian's grammar is based on the earlier works of Herodian and Apollonius. The examples it includes to illustrate the rules preserve numerous fragments from Latin authors which would otherwise have been lost, including Ennius, Pacuvius, Accius, Lucilius, Cato and Varro. But the authors whom he quotes most frequently are Virgil, and, next to him, Terence, Cicero, Plautus; then Lucan, Horace, Juvenal, Sallust, Statius, Ovid, Livy and Persius.  The grammar was quoted by several writers in Britain of the 8th century - Aldhelm, Bede, Alcuin - and was abridged or largely used in the next century by Hrabanus Maurus of Fulda and Servatus Lupus of Ferrières. About a thousand manuscripts exist, all ultimately derived from the copy made by Theodorus. Most copies contain only books I—XVI; these are sometimes known as the "Priscianus Major" ("Greater Priscian"). Others contain only books XVII and XVIII along with the three books to Symmachus; these are known as his work "On Construction" ("") or the "Priscianus Minor" ("Lesser Priscian"). A few copies contain both parts. The earliest manuscripts are from the 9th century, though a few fragments are somewhat earlier.  Priscian's minor works include:

Legacy.

Books XVII & XVIII of the "Institutes", his work "On Construction", was part of the core curriculum of the University of Paris in the 13th century and Roger Bacon's lectures for the class were the probable origin of his own "Overview of Grammar", one of the first expositions on the idea of a universal grammar. Dante places Priscian in Hell among sodomites.

Editions and translations.

Editions  German Translations  French translations

References.

Attribution

Priscianus Caesariensis (), commonly known as Priscian ( or ), was a Latin grammarian and the author of the "Institutes of Grammar" which was the standard textbook for the study of Latin during the Middle Ages. It also provided the raw material for the field of speculative grammar.

普里西安(英语:Priscian),约活动于公元6世纪前后。拉丁文语法作家之一,他的著作成为中世纪学习相关语法知识的重要材料。早年事迹待考,后长期于宫廷中供职。他著有反映拉丁文的语法的大量作品,计十八卷,为后世学者提供了极为重要的拉丁文语法研究资料。


History.

Origin.

It is believed that "Arirang" originated in Jeongseon, Gangwon Province. According to a legend, the name is derived from the story of a bachelor and a maiden who fell in love while picking Camellia blossoms near the wharf at Auraji (). There are two versions of this story. In the first one, the bachelor cannot cross the Auraji to meet the maiden because the water is too high and so, they sing a song to express their sorrow. In the second version, the bachelor attempts to cross the Auraji and drowns, singing the sorrowful song after he dies.  Other theories on the origin of the name "Arirang" point to Lady Aryeong, wife of the first king of Silla; "arin," the Jurchen word for "hometown"."  According to, "Arirang" originated in the mountainous regions of Jeongseon and the first mention of the song was found in a 1756 manuscript.  According to Pete Seeger, who sang the song in concert in the 1960s, the song goes back to the 1600s when a despotic emperor was imprisoning people right and left who had opposed him. He hung these prisoners from tall pine trees on top of the hill of Arirang, located outside Seoul. Legend states that one of the prisoners condemned to death, walked his final miles singing of how much he loved his country, and how much he hated to say goodbye to it. It was soon picked up by the other prisoners, where it became a Korean tradition that any man had the right to sing this song before his execution.

First recording.

The first known recording of "Arirang" was made in 1896 by American ethnologist Alice C. Fletcher. At her home in Washington, D.C., Fletcher recorded three Korean students singing a song she called "Love Song: Ar-ra-rang." One source suggests that the students belonged to noble Korean families and were studying abroad at Howard University during the period in which the recording was made. The recordings are currently housed in the U.S. Library of Congress.

Resistance anthem.

During the Japanese occupation of Korea from 1910 to 1945, when singing was proscribed and it became a criminal offense for anyone to be singing any patriotic song including the national anthem of Korea, Arirang became an unofficial anthem. "Arirang" became a resistance anthem against Imperial Japanese rule. Korean protesters sang "Arirang" during the March 1 Movement, a Korean demonstration against the Japanese Empire in 1919. Many of the variations of "Arirang" that were written during the occupation contain themes of injustice, the plight of labourers, and guerrilla warfare. It was also sung by the mountain guerrillas who were fighting against the fascists.  The most well-known lyrics to "Arirang" first appeared in the 1926 silent film "Arirang," directed by Na Woon-gyu. "Arirang" is now considered a lost film but various accounts say the film was about a Korean student who became mentally ill after being imprisoned and tortured by the Japanese. The film was a hit upon its release and is considered the first Korean nationalist film.

Popularity in Japan.

During the Japanese occupation of Korea, Japan experienced a craze for Korean culture and for "Arirang", in particular. Over 50 Japanese versions of "Arirang" were released between 1931 and 1943, in genres including pop, jazz, and mambo. Some of the former Japanese Imperial soldiers remember and sing "Arirang" from the memories they recollect from their service in Japanese Korea, or from the Korean comfort women (sex slaves) or the Korean forcefully-inscripted labourers and soldiers.

Musical score.

<score vorbis="1"> \relative c' { \key f \major \time 9/8 \tempo "Lento" 4 = 140 \set Staff.midiInstrument = #"violin" c4. ~ c4 d8 c4 ( d8 ) | f4. ~ f4 g8 f4 ( g8 ) | a4. g8 a g f4 ( d8 ) | c4. ~ ( c4 d8 c d ) r8 |\break f4. ~ f4 g8 f4 ( g8 ) | a4 ( g8 ) f4 ( d8 ) c4 ( d8 ) | f4. ~ f4 g8 f4.| f4. ~ f4. r4. |\break c'4. ~ c c | c4. a4. g4. | a4. g4 a8 f4 ( d8 ) | c4. ~ ( c4 d8 c d ) r8 |\break \addlyrics { 아 리 랑 아 리 랑 아 라 - - 리 요 아 리 랑 고 개 로 넘 어 간 다 나 를 버 리 고 가 시 는 님 은 \addlyrics { 아 리 랑 아 리 랑 아 라 - - 리 요 아 리 랑 고 개 로 넘 어 간 다 청 천 하 늘 엔 별 도 - 많 고 \addlyrics { 아 리 랑 아 리 랑 아 라 - - 리 요 아 리 랑 고 개 로 넘 어 간 다 저 기 저 산 이 백 두 산 이라 지 </score>

Lyrics.

All versions of "Arirang" include a refrain similar to, "Arirang, arirang, arariyo ()." The word "arirang" itself is nonsensical and does not have a precise meaning in Korean. While the other lyrics vary from version to version, the themes of sorrow, separation, reunion, and love appear in most versions.  The table below includes the lyrics of "Standard Arirang" from Seoul. The first two lines are the refrain. The refrain is followed by three verses.

Variations.

There are an estimated 3,600 variations of 60 different versions of "Arirang." Titles of different versions of "Arirang" are usually prefixed by their place of origin.  While "Jeongseon Arirang" is generally considered to be the original version of the song, "Bonjo Arirang" (literally: Standard Arirang) from Seoul is one of the most famous versions. This version was first made popular when it was used as the theme song of the influential 1926 film "Arirang".  Other famous variations include "Jindo Arirang" from South Jeolla Province, a region known for being the birthplace of Korean folk music genres pansori and sinawi; and "Miryang Arirang" from South Gyeongsang Province.

Official status.

UNESCO.

Both South Korea and North Korea submitted "Arirang" to be included on the UNESCO Intangible Cultural Heritage list. South Korea successfully submitted the song for inclusion in 2012. North Korea successfully submitted the song for inclusion in 2014.

South Korea.

In 2015, the South Korean Cultural Heritage Administration added the "Arirang" to its list of important intangible cultural assets.

U.S. Army.

The U.S. Army's 7th Infantry Division adopted "Arirang" as its official march song in May 1956, after receiving permission from Syngman Rhee, the first president of South Korea. The division had been stationed in Korea from 1950 to 1953, during the Korean War.

In popular culture.

Music.

Pete Seeger sang the song, with an English translation in a concert in the 1960s.

"Arirang" (; ) is a Korean folk song that is often considered to be the anthem of Korea. There are about 3,600 variations of 60 different versions of the song, all of which include a refrain similar to, "Arirang, arirang, arariyo ()" It is estimated the song is more than 600 years old.

《阿里郎》(亦称做阿里岚等其他译名)是著名的朝鲜族民歌,它在不同地方有不同版本,最常听到的是流行于京畿道一带的本调阿里郎,此版本是因1926年同名电影的主题曲而成名,该电影为韩国第一出剧情片。


History.

As a start-up company, SRAM introduced the Grip Shift (or twist shift) gear-change method and technology to the road bike market in 1988. That technology was then adapted for mountain bikes in 1991.  In 1990, the company sued Shimano for unfair business practices, noting that Shimano offered, in effect, a 10-percent discount to bicycle manufacturers specifying an all-Shimano drivetrain and that few companies in the highly competitive industry would be willing to forgo such a discount to specify Grip Shift components. SRAM received an unspecified out-of-court settlement from Shimano in 1991. More importantly, all Shimano competitors won the right to compete in the lucrative OEM bicycle components arena.  The years after the Shimano settlement were marked by dramatic growth for the company, as it increased sales greatly and added other companies to its portfolio. SRAM is an example of a recent trend within the high-end cycle-component segment of the bicycle industry, where companies seek a position as a "one-stop shopping center" for bicycle frame manufacturers/bicycle brand owners, supplying all or most of the parts needed to build a complete bike. SRAM now incorporates the former bicycle divisions of Fichtel & Sachs, Sachs-Huret, and acquired component makers RockShox, Avid, Truvativ, Zipp, and QUARQ.  In 1995, SRAM introduced their first mountain bike rear derailleur, dubbed “ESP”, that featured a 1:1 cable actuation ratio that was more tolerant of cable contamination. The new derailleur was compatible with SRAM's ESP Grip Shifters. This was a critical first step for SRAM toward producing a complete shifting system. By 1997, SRAM was ready to make its first acquisition, Sachs. This acquisition provided SRAM with a group of experienced metallurgists and engineers as well as a successful chain and internally geared hub production line.  SRAM's released its first “X.O” rear derailleur in 2001. It was a complete redesign of SRAM's existing ESP derailleurs, however it still made use of SRAM's proprietary 1:1 shift actuation ratio for improved shifting performance with worn or contaminated cables. Made from forged aluminum, the introduction of SRAM's first high-end derailleur marked a turning point for the company's mountain bike shifting groups. The introduction of X.O also marked the first time trigger shifters were available as a shifting option for SRAM rear derailleurs.  In 2002, SRAM acquired suspension manufacturer, RockShox, after RockShox had defaulted on a loan from SRAM. In 2005, SRAM developed a new fork damper technology dubbed “Motion Control” that allowed users to adjust compression and rebound of the suspension, including a switch to greatly firm up the suspension. Motion Control was a market success and RockShox continues to use variants of the Motion Control damper on select models.  Avid was SRAM's next acquisition in spring of 2004. Avid produced popular hydraulic disc brakes and gave SRAM one more means to compete with Shimano. Later that same year SRAM purchased Truvativ, a crank, bottom bracket, and chainring manufacturer based out of San Luis Obispo, California. With Truvativ as part of the SRAM family, the company could finally sell a complete drivetrain package to OEM customers.  Although SRAM began as a manufacturer of road bike shifters, the company had largely left the road market in 1993 in favor of the rapidly growing mountain bike market. By 2004, SRAM planned a return to the road and began development of two new road groupsets, Force and Rival, which it brought to market in 2006. Force was raced in the Tour de France for the first time the following year. The group made use of a new proprietary shifting technology known as DoubleTap. The technology allows the rider to shift a derailleur in both directions using a single shifter paddle.  In 2007, SRAM acquired the bicycle component company Zipp. In 2008, SRAM introduced a new premium road groupset, SRAM RED.  SRAM acquired power meter crank manufacturer Quarq in 2011. By 2012, SRAM had incorporated power meters into its high-end RED road group. Also in 2012 SRAM introduced wide range 1x11 mountain bike shifting with its XX1 groupset. The new groupset made use of a 10-42 cassette and a patented single front chainring that made use of both narrow and specially shaped wide teeth to retain the chain without a chain guide. The rear derailleur for the groupset uses a parallelogram that moves only laterally, known as X-Horizon, which is intended to improve shifting precision and chain retention.  By 2014, this same technology was adapted for use on cyclocross bikes with the introduction of SRAM Force CX1. The group was expanded in 2015 to use chainrings (up to 54-teeth) for other applications such as TT/Tri, road, and fitness bikes. With the expanded applications SRAM simplified the naming of the group to Force 1. The same year the company also developed a lower price point 1x11 road groupset option with similar features, Rival 1. In August 2015, SRAM announced that it would release its 11-speed wireless electronic road groupset, SRAM RED eTap. The group utilizes derailleurs with self-contained batteries to shift using wireless signals sent from the shift levers. Benefits of the system include more precise shifting, faster setup, and lower maintenance compared to a traditional mechanically activated shifting arrangement.  The company announced a hydraulic disc brake version of its wireless road group called SRAM RED eTap HRD in May 2016. The new brakes make use of a hydraulic lever design with both lever reach adjustment and lever contact point adjustment. In May 2016 SRAM also released their new 1x12 drivetrain technology dubbed Eagle in both XX1 and X01 variants. It has received many awards globally in its first year of public availability from cycling publications due to its simplicity, versatility, and usable rider benefits. The new 1x12 drivetrain has a 500% gear range that is comparable to many 2x drivetrains on the market today. In October 2016 SRAM released the WiFLi version of its eTap rear derailleur which is compatible with a wider range of gears than a standard rear derailleur.  In 2017 SRAM launched the 1x12 GX Eagle drivetrain, intended to be more affordable than the similar existing Eagle XX1 and X01 drivetrains.  February 6, 2019 SRAM released three new wireless electronic groupsets. This release included one road groupset, RED eTap AXS, and two mountain bike groupsets, XX1 Eagle AXS and X01 Eagle AXS. All of the AXS groups have BLE connectivity and an optional free mobile app called AXS that offers users the ability to reassign and customize button functions.  The new RED groupset features a 12-speed cassette with wider gear range and smaller steps between gears in addition to many other innovations such as chainrings with power meter integration, a fluid damper for the rear derailleur pulley cage, and both 2x and 1x chainring drivetrain variants.  For the new mountain bike groups, in addition to their wireless electronic operation, they can also connect with sister brand RockShox’ Reverb AXS dropper post. SRAM's AXS app makes this possible by enabling users to reassign button functions between the Reverb seat post and the XX1 or X01 derailleur controller. The same AXS app also opens the option of using RED eTap AXS drop bar levers with an Eagle AXS drivetrain and a Reverb AXS dropper post. Conversely, drop bar bikes can be simply retrofitted with mountain bike handlebars using the Eagle AXS derailleur controller with RED eTap AXS drivetrain.

Event sponsorships.

SRAM has made significant efforts to support racing through sponsorships made in partnership with race promoters. Examples of this include the Amgen Tour of California, Ironman, the Sea Otter Classic, and Crankworks.  At the Amgen Tour of California (ATOC) SRAM is the neutral race support sponsor for both the women's and men's races and a title sponsor for the entire women's race. SRAM is also a sponsor of specific stages within the men's ATOC race.  SRAM is the neutral race support sponsor for numerous professional Ironman events including the US National Championships, European Championships, and World Championships. As a title sponsor for the Sea Otter Classic in Monterey, California for roughly a decade, SRAM provides neutral race support for entrants and hosts large product display and technical service tents in the event's expo area.  SRAM is also a supporter of the Crankworks festival held at the Whistler Bike Park in British Columbia, Canada.

Triathlon.

In the late 1980s and early 90s SRAM Grip Shifters were quickly adopted by triathletes. Grip Shift's aim to allow riders to shift without removing their hands from the bars made the product uniquely suited to the needs of triathletes. These racers needed to maintain an aero tuck with their hands extended on aero extensions, a place where Grip Shifters were designed to perch. It offered both SRAM and the athletes a competitive advantage at a time when there were few aerodynamic shifting options available.  Today SRAM sponsors a number of top triathletes including Ironman World Champ, Jan Frodeno. Other notable athletes sponsored by SRAM include Sebastien Kienle, Javier Gomez, Mirinda Carfrae, Alistair and Jonathan Brownlee, Caroline Steffen, Jordan Rapp, and Non Stanford.

Women's cycling.

SRAM is a standout among component manufacturers that has consistently assigned equal value to women's cycling. Products and technologies that reflect that commitment to the broad range of female riders’ needs include shifter Reach Adjust, Quarq cranksets available in down to 162.5mm lengths, and 36 cm wide Zipp handlebars.  SRAM is also an ardent supporter of women's professional cycling. SRAM is a title sponsor for the Women's Amgen Tour of California empowered with SRAM. The company also sponsors many top teams in the women's World Tour including CANYON//SRAM Racing, Boels-Dolmans Cycling Team, Twenty20 p/b SHO-AIR, and Rally Cycling Team.  Top female athletes sponsored by SRAM include 2015 UCI Road World Champion Lizzie Armitstead, 2015 UCI Junior Road and Time Trial World Champion Chloe Dygert, 2014 UCI Elite Time Trial Champion Lisa Brennauer, and 2015 Amgen Tour of California empowered with SRAM winner Trixie Worrack.

Brands.

SRAM has purchased a number of companies, enabling it to offer a full set of components rather than develop them from scratch. At the forefront of the company is the SRAM marque which is used for most of its groupsets. Companies SRAM has purchased and converted into marque brands include Rockshox, Truvativ, Sachs, Avid and Zipp.

Sachs Bicycle Components.

In November 1997, SRAM acquired Sachs Bicycle Components, including a significant hub gear production line, from Mannesmann Sachs AG, a unit of German telecommunications group Mannesmann AG. Sachs had 1,250 employees and annual revenues of more than $125 million. In 2013 production of internal gear hubs moved from Germany to Taiwan. In 2015 the former Sachs Schweinfurt factory was converted for use as a SRAM research and development center as well as a warehouse for European distribution. The remainder of the Sachs company (ZF Sachs) is now owned by ZF Friedrichshafen AG. ZF Sachs mainly deals in parts for motorized vehicles.  In 2017 SRAM announced it would end production of its internal gear hubs due to declining sales, a lack of interest on the part of its suppliers, and competition from e-bikes.

RockShox.

SRAM purchased RockShox on February 19, 2002. They were one of the first companies to introduce a bicycle suspension fork for consumer use. Marketing and sales departments were relocated to Chicago, while product development remained in Colorado Springs. A SRAM factory in Taichung, Taiwan was converted to RockShox production after the acquisition. RockShox is responsible for producing bicycle suspension products including front suspension forks for both mountain biking (MTB) and pavement usage, rear suspension, suspension lockout remotes, maintenance products and a dropper seatpost called the Reverb.

Avid.

On March 1, 2004, SRAM purchased Avid, a well-known designer and manufacturer of bicycle brake components. Its current line-up includes mechanical disc brakes, rim brakes, levers, cables and maintenance products for a range of uses including MTB and cyclocross. They also produce two road bike disc brakes. As with RockShox, Avid's product development continued in Colorado Springs while marketing and sales divisions were moved to Chicago.

Truvativ.

SRAM purchased Truvativ in 2004 from Micki Kozuschek, providing SRAM with a line of cranks, bottom brackets, handlebars, stems, pedals, seatposts and chain retention systems. This allowed SRAM to offer a complete drivetrain with the first SRAM branded road groupsets being released the following year. Following the acquisition, product development for cranksets and bottom brackets remained in San Luis Obispo, California.

Zipp.

On November 6, 2007, SRAM acquired Zipp Speed Weaponry, a company designing and manufacturing high-end carbon wheelsets for use on road racing bicycles, as well as other high-end components such as cranksets, handlebars, stems and wheels. The company operates out of Indianapolis, Indiana and produces all of its carbon fiber rims at the company's US factory.

Quarq.

In 2011, SRAM acquired power meter crank manufacturer, Quarq. Based out of Spearfish, South Dakota, Quarq was founded by Jim and Mieke Meyer. The company is best known for its crank based power meters, but it is venturing out into new areas with its Quarq Race Intelligence product, a live telemetry system aimed at race promoters, race officials, and media. Following the pattern set by other SRAM acquisitions, Quarq continues to operate out of its Spearfish location.

SRAM groupsets.

SRAM currently has nine road bike groupsets (in descending order of price):  SRAM currently has 18 mountain bike groupsets, divided by field of application, from more to less expensive:  Cross Country: Downhill: Enduro: Trail riding: Budget groupsets: E-MTB specific:

Corporate.

In 2008, the company received a strategic investment from Trilantic Capital Partners, formerly known as Lehman Brothers Merchant Banking, the buyout arm of Lehman Brothers. The firm invested $234.8 million in SRAM in a deal that closed Sept. 30, 2008. On May 12, 2011, the company announced in a filing that it intended to raise up to $300 million in an IPO. Shortly later, the company consolidated its debt to pay off the assets owned by the private equity firm. Those plans were put on hold due to volatility in the stock market. SRAM reported net sales of $524.1 million in 2010, and has grown at a rate of about 16 percent annually in the four years prior to 2010. The company has estimated that it holds about 15 percent of the $3.5 billion bicycle components market.

SRAM Cycling Fund.

The SRAM Cycling Fund is the advocacy and philanthropy arm of SRAM LLC. The Fund invested $10M over 6 years from 2009 to 2014. Grants for infrastructure at the national levels in both Europe and the U.S. helped leverage co-investment by other cycling industry companies to spur billions in public funding for cycling infrastructure. From 2015 through the present, the Fund continues to support People for Bikes, IMBA, IMBA Europe, and the European Cycling Federation. The Fund also continues to support local efforts near SRAM's US offices as well as Portugal, Taiwan, Australia and Germany.

SRAM LLC is a privately owned bicycle component manufacturer based in Chicago, Illinois, United States, founded in 1987. SRAM is an acronym comprising the names of its founders, Scott, Ray, and Sam, (where Ray is the middle name of the company's first CEO, Stan Day). The company is known for producing cycling components, including some internally developed, such as Grip Shift, EAGLE (1x12), DoubleTap, dedicated 1x11 mountain and road drivetrains and SRAM Red eTap.

速联公司(,简称SRAM)是一家由私人经营的自行车零部件制造商,总部设在芝加哥,成立于1987年。SRAM是一个首字母缩略词,包括其创始人Scott、Ray和Sam的名字(其中Ray是公司总裁Stan Day的中间名)。该公司以生产自行车部件闻名,其中包括一些内部开发,如Grip Shift、DoubleTap、专用的1x11山地和道路传动系统,以及无线电子组SRAM Red eTap。