<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Combat stress reaction and can you explain it in depth? [/INST] Combat stress reaction (CSR) is acute behavioral disorganization as a direct result of the trauma of war. Also known as "combat fatigue", "battle fatigue", or "battle neurosis", it has some overlap with the diagnosis of acute stress reaction used in civilian psychiatry. It is historically linked to shell shock and can sometimes precurse post-traumatic stress disorder.
Combat stress reaction is an acute reaction that includes a range of behaviors resulting from the stress of battle that decrease the combatants fighting efficiency. The most common symptoms are fatigue, slower reaction times, indecision, disconnection from ones surroundings, and the inability to prioritize. Combat stress reaction is generally short-term and should not be confused with acute stress disorder, post-traumatic stress disorder, or other long-term disorders attributable to combat stress, although any of these may commence as a combat stress reaction. The US Army uses the term/acronym COSR (Combat Stress Reaction) in official medical reports. This term can be applied to any stress reaction in the military unit environment. Many reactions look like symptoms of mental illness (such as panic, extreme anxiety, depression, and hallucinations), but they are only transient reactions to the traumatic stress of combat and the cumulative stresses of military operations.In World War I, shell shock was considered a psychiatric illness resulting from injury to the nerves during combat. The horrors of trench warfare meant that about 10% of the fighting soldiers were killed (compared to 4.5% during World War II) and the total proportion of troops who became casualties (killed or wounded) was about 57%. Whether a person with shell-shock was considered "wounded" or "sick" depended on the circumstances.  When faced with the phenomenon of a minority of soldiers mentally breaking down, there was an expectation that the root of this problem lay in character of the individual soldier, not because of what they experienced on the front lines during the war.  The large proportion of World War I veterans in the European population meant that the symptoms were common to the culture.

Signs and symptoms
Combat stress reaction symptoms align with the symptoms also found in psychological trauma, which is closely related to post-traumatic stress disorder (PTSD). CSR differs from PTSD (among other things) in that a PTSD diagnosis requires a duration of symptoms over one month, which CSR does not.

Fatigue-related symptoms
The most common stress reactions include:

Autonomic nervous system – Autonomic arousal
Battle casualty rates
The ratio of stress casualties to battle casualties varies with the intensity of the fighting. With intense fighting, it can be as high as 1:1. In low-level conflicts, it can drop to 1:10 (or less).
Modern warfare embodies the principles of continuous operations with an expectation of higher combat stress casualties.The World War II European Army rate of stress casualties of 1 in 10 (101:1,000) troops per annum is skewed downward from both its norm and peak by data by low rates during the last years of the war.

Diagnosis
The following PIE principles were in place for the "not yet diagnosed nervous" (NYDN) cases:

Proximity – treat the casualties close to the front and within sound of the fighting.
Immediacy – treat them without delay and not wait until the wounded were all dealt with.
Expectancy – ensure that everyone had the expectation of their return to the front after a rest and replenishment.United States medical officer Thomas W. Salmon is often quoted as the originator of these PIE principles. However, his real strength came from going to Europe and learning from the Allies and then instituting the lessons. By the end of the war, Salmon had set up a complete system of units and procedures that was then the "worlds best practice". After the war, he maintained his efforts in educating society and the military. He was awarded the Distinguished Service Medal for his contributions.Effectiveness of the PIE approach has not been confirmed by studies of CSR, and there is some evidence that it is not effective in preventing PTSD.US services now use the more recently developed BICEPS principles:

Brevity
Immediacy
Centrality or contact
Expectancy
Proximity
Simplicity

Between the wars
The British government produced a Report of the War Office Committee of Inquiry into "Shell-Shock", which was published in 1922. Recommendations from this included:

In forward areas
No soldier should be allowed to think that loss of nervous or mental control provides an honorable avenue of escape from the battlefield, and every endeavor should be made to prevent slight cases leaving the battalion or divisional area, where treatment should be confined to provision of rest and comfort for those who need it and to heartening them for return to the front line.
In neurological centers
When cases are sufficiently severe to necessitate more scientific and elaborate treatment they should be sent to special Neurological Centers as near the front as possible, to be under the care of an expert in nervous disorders.  No such case should, however, be so labelled on evacuation as to fix the idea of nervous breakdown in the patients mind.
In base hospitals
When evacuation to the base hospital is necessary, cases should be treated in a separate hospital or separate sections of a hospital, and not with the ordinary sick and wounded patients.  Only in exceptional circumstances should cases be sent to the United Kingdom, as, for instance, men likely to be unfit for further service of any kind with the forces in the field.  This policy should be widely known throughout the Force.
Forms of treatment
The establishment of an atmosphere of cure is the basis of all successful treatment, the personality of the physician is, therefore, of the greatest importance.  While recognizing that each individual case of war neurosis must be treated on its merits, the Committee are of opinion that good results will be obtained in the majority by the simplest forms of psycho-therapy, i.e., explanation, persuasion and suggestion, aided by such physical methods as baths, electricity and massage.  Rest of mind and body is essential in all cases.The committee are of opinion that the production of deep hypnotic sleep, while beneficial as a means of conveying suggestions or eliciting forgotten experiences are useful in selected cases, but in the majority they are unnecessary and may even aggravate the symptoms for a time.
They do not recommend psycho-analysis in the Freudian sense.In the state of convalescence, re-education and suitable occupation of an interesting nature are of great importance.  If the patient is unfit for further military service, it is considered that every endeavor should be made to obtain for him suitable employment on his return to active life.
Return to the fighting line
Soldiers should not be returned to the fighting line under the following conditions:(1) If the symptoms of neurosis are of such a character that the soldier cannot be treated overseas with a view to subsequent useful employment.
(2) If the breakdown is of such severity as to necessitate a long period of rest and treatment in the United Kingdom.
(3) If the disability is anxiety neurosis of a severe type.
(4) If the disability is a mental breakdown or psychosis requiring treatment in a mental hospital.
It is, however, considered that many of such cases could, after recovery, be usefully employed in some form of auxiliary military duty.
Part of the concern was that many British veterans were receiving pensions and had long-term disabilities.
By 1939, some 120,000 British ex-servicemen had received final awards for primary psychiatric disability or were still drawing pensions – about 15% of all pensioned disabilities – and another 44,000 or so were getting pensions for soldiers heart or Effort Syndrome.  There is, though, much that statistics do not show, because in terms of psychiatric effects, pensioners were just the tip of a huge iceberg."War correspondent Philip Gibbs wrote:

Something was wrong.  They put on civilian clothes again and looked to their mothers and wives very much like the young men who had gone to business in the peaceful days before August 1914.  But they had not come back the same men.  Something had altered in them.  They were subject to sudden moods, and queer tempers, fits of profound depression alternating with a restless desire for pleasure.  Many were easily moved to passion where they lost control of themselves, many were bitter in their speech, violent in opinion, frightening.
One British writer between the wars wrote:

There should be no excuse given for the establishment of a belief that a functional nervous disability constitutes a right to compensation.  This is hard saying.  It may seem cruel that those whose sufferings are real, whose illness has been brought on by enemy action and very likely in the course of patriotic service, should be treated with such apparent callousness.  But there can be no doubt that in an overwhelming proportion of cases, these patients succumb to shock because they get something out of it.  To give them this reward is not ultimately a benefit to them because it encourages the weaker tendencies in their character.  The nation cannot call on its citizens for courage and sacrifice and, at the same time, state by implication that an unconscious cowardice or an unconscious dishonesty will be rewarded.

World War II
American
At the outbreak of World War II, most in the United States military had forgotten the treatment lessons of World War I. Screening of applicants was initially rigorous, but experience eventually showed it to lack great predictive power.
The US entered the war in December 1941. Only in November 1943 was a psychiatrist added to the table of organization of each division, and this policy was not implemented in the Mediterranean Theater of Operations until March 1944. By 1943, the US Army was using the term "exhaustion" as the initial diagnosis of psychiatric cases, and the general principles of military psychiatry were being used. General Pattons slapping incident was in part the spur to institute forward treatment for the Italian invasion of September 1943. The importance of unit cohesion and membership of a group as a protective factor emerged.
John Appel found that the average American infantryman in Italy was "worn out" in 200 to 240 days and concluded that the American soldier "fights for his buddies or because his self respect wont let him quit". After several months in combat, the soldier lacked reasons to continue to fight because he had proven his bravery in battle and was no longer with most of the fellow soldiers he trained with. Appel helped implement a 180-day limit for soldiers in active combat and suggested that the war be made more meaningful, emphasizing their enemies plans to conquer the United States, encouraging soldiers to fight to prevent what they had seen happen in other countries happen to their families. Other psychiatrists believed that letters from home discouraged soldiers by increasing nostalgia and needlessly mentioning problems soldiers could not solve. William Menninger said after the war, "It might have been wise to have had a nation-wide educational course in letter writing to soldiers", and Edward Strecker criticized "moms" (as opposed to mothers) who, after failing to "wean" their sons, damaged morale through letters.Airmen flew far more often in the Southwest Pacific than in Europe, and although rest time in Australia was scheduled, there was no fixed number of missions that would produce transfer out of combat, as was the case in Europe. Coupled with the monotonous, hot, sickly environment, the result was bad morale that jaded veterans quickly passed along to newcomers. After a few months, epidemics of combat fatigue would drastically reduce the efficiency of units. Flight surgeons reported that the men who had been at jungle airfields longest were in bad shape:

Many have chronic dysentery or other disease, and almost all show chronic fatigue states. … They appear listless, unkempt, careless, and apathetic with almost mask-like facial expression. Speech is slow, thought content is poor, they complain of chronic headaches, insomnia, memory defect, feel forgotten, worry about themselves, are afraid of new assignments, have no sense of responsibility, and are hopeless about the future.

British
Unlike the Americans, the British leaders firmly held the lessons of World War I. It was estimated that aerial bombardment would kill up to 35,000 a day, but the Blitz killed only 40,000 in total. The expected torrent of civilian mental breakdown did not occur. The Government turned to World War I doctors for advice on those who did have problems. The PIE principles were generally used. However, in the British Army, since most of the World War I doctors were too old for the job, young, analytically trained psychiatrists were employed. Army doctors "appeared to have no conception of breakdown in war and its treatment, though many of them had served in the 1914–1918 war." The first Middle East Force psychiatric hospital was set up in 1942. With D-Day for the first month there was a policy of holding casualties for only 48 hours before they were sent back over the Channel. This went firmly against the expectancy principle of PIE.Appel believed that British soldiers were able to continue to fight almost twice as long as their American counterparts because the British had better rotation schedules and because they, unlike the Americans, "fight for survival" – for the British soldiers, the threat from the Axis powers was much more real, given Britains proximity to mainland Europe, and the fact that Germany was concurrently conducting air raids and bombarding British industrial cities. Like the Americans, British doctors believed that letters from home often needlessly damaged soldiers morale.

Canadian
The Canadian Army recognized combat stress reaction as "Battle Exhaustion" during the Second World War and classified it as a separate type of combat wound. Historian Terry Copp has written extensively on the subject. In Normandy, "The infantry units engaged in the battle also experienced a rapid rise in the number of battle exhaustion cases with several hundred men evacuated due to the stress of combat. Regimental Medical Officers were learning that neither elaborate selection methods nor extensive training could prevent a considerable number of combat soldiers from breaking down."

Germans
In his history of the pre-Nazi Freikorps paramilitary organizations, Vanguard of Nazism, historian Robert G. L. Waite describes some of the emotional effects of World War I on German troops, and refers to a phrase he attributes to Göring: men who could not become "de-brutalized".In an interview, Dr Rudolf Brickenstein stated that:

... he believed that there were no important problems due to stress breakdown since it was prevented by the high quality of leadership.  But, he added, that if a soldier did break down and could not continue fighting, it was a leadership problem, not one for medical personnel or psychiatrists.  Breakdown (he said) usually took the form of unwillingness to fight or cowardice.
However, as World War II progressed there was a profound rise in stress casualties from 1% of hospitalizations in 1935 to 6% in 1942. Another German psychiatrist reported after the war that during the last two years, about a third of all hospitalizations at Ensen were due to war neurosis. It is probable that there was both less of a true problem and less perception of a problem.

Finns
The Finnish attitudes to "war neurosis" were especially tough. Psychiatrist Harry Federley, who was the head of the Military Medicine, considered shell shock as a sign of weak character and lack of moral fibre. His treatment for war neurosis was simple: the patients were to be bullied and harassed until they returned to front line service.Earlier, during the Winter War, several Finnish machine gun operators on the Karelian Isthmus theatre became mentally unstable after repelling several unsuccessful Soviet human wave assaults on fortified Finnish positions.

Post-World War II developments
Simplicity was added to the PIE principles by the Israelis: in their view, treatment should be brief, supportive, and could be provided by those without sophisticated training.

Peacekeeping stresses
Peacekeeping provides its own stresses because its emphasis on rules of engagement contains the roles for which soldiers are trained. Causes include witnessing or experiencing the following:

Constant tension and threat of conflict.
Threat of land mines and booby traps.
Close contact with severely injured and dead people.
Deliberate maltreatment and atrocities, possibly involving civilians.
Cultural issues.
Separation and home issues.
Risk of disease including HIV.
Threat of exposure to toxic agents.
Mission problems.
Return to service.

Pathophysiology
SNS activation
Many of the symptoms initially experienced by people with CSR are effects of an extended activation of the human bodys fight-or-flight response. The fight-or-flight response involves a general sympathetic nervous system discharge in reaction to a perceived stressor and prepares the body to fight or run from the threat causing the stress. Catecholamine hormones, such as adrenaline or noradrenaline, facilitate immediate physical reactions associated with a preparation for violent muscular action. Although the flight-or-fight-response normally ends with the removal of the threat, the constant mortal danger in combat zones likewise constantly and acutely stresses soldiers.

General adaptation syndrome
The process whereby the human body responds to extended stress is known as general adaptation syndrome (GAS). After the initial fight-or-flight response, the body becomes more resistant to stress in an attempt to dampen the sympathetic nervous response and return to homeostasis. During this period of resistance, physical and mental symptoms of CSR may be drastically reduced as the body attempts to cope with the stress. Long combat involvement, however, may keep the body from homeostasis and thereby deplete its resources and render it unable to normally function, sending it into the third stage of GAS: exhaustion. Sympathetic nervous activation remains in the exhaustion phase and reactions to stress are markedly sensitized as fight-or-flight symptoms return. If the body remains in a state of stress, then such more severe symptoms of CSR as cardiovascular and digestive involvement may present themselves. Extended exhaustion can permanently damage the body.

Treatment
7 Rs
The British Army treated Operational Stress Reaction according to the 7 Rs:
Recognition – identify that the individual has an Operational Stress Reaction
Respite – provide a short period of relief from the front line
Rest – allow rest and recovery
Recall – give the individual the chance to recall and discuss the experiences that have led to the reaction
Reassurance – inform them that their reaction is normal and they will recover
Rehabilitation – improve the physical and mental health of the patient until they no longer show symptoms
Return – allow the soldier to return to their unit

BICEPS
Modern front-line combat stress treatment techniques are designed to mimic the historically used PIE techniques with some modification. BICEPS is the current treatment route employed by the U.S. military and stresses differential treatment by the severity of CSR symptoms present in the service member. BICEPS is employed as a means to treat CSR symptoms and return soldiers quickly to combat.
The following subsections on the BICEPS program are adapted from the USMC combat stress handbook:

Brevity
Critical Event Debriefing should take 2 to 3 hours. Initial rest and replenishment at medical CSC (Combat Stress Control) facilities should last no more than 3 or 4 days. Those requiring further treatment are moved to the next level of care. Since many require no further treatment, military commanders expect their service members to return to duty rapidly.

Immediacy
CSC should be done as soon as possible when operations permit. Intervention is provided as soon as symptoms appear.

Centrality/Contact
Service members requiring observation or care beyond the unit level are evacuated to facilities in close proximity to, but separate from the medical or surgical patients at the BAS, surgical support company in a central location (Marines) or forward support/division support or area support medical companies (Army) nearest the service members unit. It is best to send service members who cannot continue their mission and require more extensive respite to a central facility other than a hospital, unless no other alternative is possible. The service member must be encouraged to continue to think of themselves as a war fighter, rather than a patient or a sick person. The chain of command remains directly involved in the service members recovery and return to duty. The CSC team coordinates with the units leaders to learn whether the over-stressed individual was a good performer prior to the combat stress reaction, or whether they were always a marginal or problem performer whom the team would rather see replaced than returned. Whenever possible, representatives of the unit, or messages from the unit, tell the casualty that they are needed and wanted back. The CSC team coordinates with the unit leaders, through unit medical personnel or chaplains, any special advice on how to assure quick reintegration when the service member returns to their unit.

Expectancy
The individual is explicitly told that he is reacting normally to extreme stress and is expected to recover and return to full duty in a few hours or days. A military leader is extremely effective in this area of treatment. Of all the things said to a service member experiencing combat stress, the words of his small-unit leader have the greatest impact due to the positive bonding process that occurs during combat. Simple statements from the small-unit leader to the service member that he is reacting normally to combat stress and is expected back soon have positive impact. Small-unit leaders should tell service members that their comrades need and expect them to return. When they do return, the unit treats them as every other service member and expects them to perform well. Service members suffering and recovering from combat stress disorder are no more likely to become overloaded again than are those who have not yet been overloaded. In fact, they are less likely to become overloaded than inexperienced replacements.

Proximity
In mobile war requiring rapid and frequent movement, treatment of many combat stress cases takes place at various battalion or regimental headquarters or logistical
units, on light duty, rather than in medical units, whenever possible. This is a key factor and another area where the small-unit leader helps in the treatment. CSC and follow-up care for combat stress casualties are held as close as possible to and maintain close association with the members unit, and are an integral part of the entire healing process. A visit from a member of the individuals unit during restoration is effective in keeping a bond with the organization. A service member experiencing combat stress reaction is having a crisis, and there are two basic elements to that crisis working in opposite directions. On the one hand, the service member is driven by a strong desire to seek safety and to get out of an intolerable environment. On the other hand, the service member does not want to let their comrades down. They want to return to their unit. If a service member starts to lose contact with their unit when he enters treatment, the impulse to get out of the war and return to safety takes over. They feel that theyve failed their comrades who have already rejected them as unworthy. The potential is for the service member to become more and more emotionally invested in keeping their symptoms so they can stay in a safe environment. Much of this is done outside the service members conscious awareness, but the result is the same. The more out of touch the service member is with their unit, the less likely they will recover. They are more likely to develop a chronic psychiatric illness and get evacuated from the war.

Simplicity
Treatment is kept simple. CSC is not therapy. Psychotherapy is not done. The goal is to rapidly restore the service members coping skills so that he functions and returns to duty again. Sleep, food, water, hygiene, encouragement, work details, and confidence-restoring talk are often all that is needed to restore a service member to full operational readiness. This can be done in units in reserve positions, logistical units or at medical companies. Every effort is made to reinforce service members identity. They are required to wear their uniforms and to keep their helmets, equipment, chemical protective gear, and flak jackets with them. When possible, they are allowed to keep their weapons after the weapons have been cleared. They may serve on guard duty or as members of a standby quick reaction force.

Predeployment preparation
Screening
Historically, screening programs that have attempted to preclude soldiers exhibiting personality traits thought to predispose them to CSR have been a total failure. Part of this failure stems from the inability to base CSR morbidity on one or two personality traits. Full psychological work-ups are expensive and inconclusive, while pen and paper tests are ineffective and easily faked. In addition, studies conducted following WWII screening programs showed that psychological disorders present during military training did not accurately predict stress disorders during combat.

Cohesion
While it is difficult to measure the effectiveness of such a subjective term, soldiers who reported in a WWII study that they had a "higher than average" sense of camaraderie and pride in their unit were more likely to report themselves ready for combat and less likely to develop CSR or other stress disorders. Soldiers with a "lower than average" sense of cohesion with their unit were more susceptible to stress illness.

Training
Stress exposure training or SET is a common component of most modern military training. There are three steps to an effective stress exposure program.
Providing knowledge of the stress environmentSoldiers with a knowledge of both the emotional and physical signs and symptoms of CSR are much less likely to have a critical event that reduces them below fighting capability. Instrumental information, such as breathing exercises that can reduce stress and suggestions not to look at the faces of enemy dead, is also effective at reducing the chance of a breakdown.
Skills acquisitionCognitive control strategies can be taught to soldiers to help them recognize stressful and situationally detrimental thoughts and repress those thoughts in combat situations. Such skills have been shown to reduce anxiety and improve task performance.
Confidence building through application and practiceSoldiers who feel confident in their own abilities and those of their squad are far less likely to develop combat stress reaction. Training in stressful conditions that mimic those of an actual combat situation builds confidence in the abilities of themselves and the squad. As this training can actually induce some of the stress symptoms it seeks to prevent, stress levels should be increased incrementally as to allow the soldiers time to adapt.

Prognosis
Figures from the 1982 Lebanon war showed that with proximal treatment, 90% of CSR casualties returned to their unit, usually within 72 hours. With rearward treatment, only 40% returned to their unit. It was also found that treatment efficacy went up with the application of a variety of front line treatment principles versus just one treatment. In Korea, similar statistics were seen, with 85% of US battle fatigue casualties returned to duty within three days and 10% returned to limited duties after several weeks.Though these numbers seem to promote the claims that proximal PIE or BICEPS treatment is generally effective at reducing the effects of combat stress reaction, other data suggests that long term PTSD effects may result from the hasty return of affected individuals to combat. Both PIE and BICEPS are meant to return as many soldiers as possible to combat, and may actually have adverse effects on the long-term health of service members who are rapidly returned to the front-line after combat stress control treatment. Although the PIE principles were used extensively in the Vietnam War, the post traumatic stress disorder lifetime rate for Vietnam veterans was 30% in a 1989 US study and 21% in a 1996 Australian study. In a study of Israeli Veterans of the 1973 Yom Kippur War, 37% of veterans diagnosed with CSR during combat were later diagnosed with PTSD, compared with 14% of control veterans.

Controversy
There is significant controversy with the PIE and BICEPS principles. Throughout a number of wars, but notably during the Vietnam War, there has been a conflict among doctors about sending distressed soldiers back to combat. During the Vietnam War this reached a peak with much discussion about the ethics of this process. Proponents of the PIE and BICEPS principles argue that it leads to a reduction of long-term disability but opponents argue that combat stress reactions lead to long-term problems such as post-traumatic stress disorder.
The use of psychiatric drugs to treat people with CSR has also attracted criticism, as some military psychiatrists have come to question the efficacy of such drugs on the long-term health of veterans. Concerns have been expressed as to the effect of pharmaceutical treatment on an already elevated substance abuse rate among former people with CSR.Recent research has caused an increasing number of scientists to believe that there may be a physical (i.e., neurocerebral damage) rather than psychological basis for blast trauma. As traumatic brain injury and combat stress reaction have very different causes yet result in similar neurologic symptoms, researchers emphasize the need for greater diagnostic care.

See also
Acute stress disorder
Eye movement desensitization and reprocessing (modern treatment)
Lack of Moral Fibre
Shell shock
Social alienation – among returning war veterans

References
Further reading
West, Rebecca (1918). The Return of the Soldier. Garden City, NY: Garden City Pub. Co.
Woolf, Virginia (1925). Mrs Dalloway.
Barker, Pat (1991). Regeneration </s>


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<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Gestational choriocarcinoma and can you explain it in depth? [/INST] Gestational choriocarcinoma is a form of gestational trophoblastic neoplasia, which is a type of gestational trophoblastic disease (GTD), that can occur during pregnancy. It is a rare disease where the trophoblast, a layer of cells surrounding the blastocyst, undergoes abnormal developments, leading to trophoblastic tumors. The choriocarcinoma can metastasize to other organs, including the lungs, kidney, and liver. The amount and degree of choriocarcinoma spread to other parts of the body can vary greatly from person to person.Gestational choriocarcinoma can happen during and after any type of pregnancy event, though risk of the disease is higher in and after complete or partial molar pregnancies. Risk of disease may also be higher in those experiencing pregnancy at younger or older ages that average, such as below 15 years old or above 45 years old. Those with gestational choriocarcinoma may experience abnormal vaginal bleeding, abdominal pain, and have high levels of human chorionic gonadotropin (hCG), in addition to history of molar pregnancy or other metastatic cancer. A combination of history, symptoms, human chorionic gonadotropin levels, and imaging can be used in the diagnosis process, with ultrasonography being commonly used to image. Approximately 50% of those with gestational choriocarcinoma have experienced molar pregnancy, approximately 25% developed the disease after a regular, term pregnancy, and other situations have included history of ectopic pregnancy, where the pregnancy does not occur in the uterus.Guidelines from the Federation of Gynecologists and Obstetricians (FIGO), Royal College of Obstetricians and Gynaecologists (RCOG), European Society for Medical Oncology (ESMO), and Royal Australian and New Zealand College of Obstetricians and Gynaecologists (RANZCOG) exist to evaluate risk and treatment of the disease. There are generally three levels of risk: low risk, high risk, and ultrahigh risk. The primary form of treatment is chemotherapy with one or more agents. Duration can go upwards of six weeks following return of human chorionic gonadotropin levels to the normal range. Depending on the risk of gestational trophoblastic disease (GTD) development, such as in certain people with mole pregnancies, chemotherapy has been used in a preventative manner in the past. However, this type of use is now advised against due to risk of toxicity and resistance to agents that may be needed in future treatment of the disease, on top of medical costs. Guidelines also detail options for salvage therapies in the situation of resistance to preferred choice of chemotherapy and surgical procedures possible in the situation of drug-resistant tumors.

Signs and symptoms
Vaginal bleeding is a common symptom of gestational choriocarcinoma. In the event the gestational choriocarcinoma has already spread to other parts of the body, bleeding events in other organs may be the first symptom. If the choriocarcinoma has metastasized to the lungs, one of the most common organs of metastasis, then symptoms may include abnormally quick breathing, coughing, and chest pain. However, it is also possible for there to be none of these symptoms and only a difference in biomarkers in an individual instead.Uterine enlargement as seen in an ultrasound can be a presenting sign of gestational choriocarcinoma. Transvaginal ultrasounds may also be used in screening for the disease, with the positron emission tomography (PET) scan, computed tomography (CT), and magnetic resonance imaging (MRI) in locations such as the abdomen, pelvis, and brain being other imaging options. Chest x-rays may also be used to see if gestational choriocarcinoma has potentially spread to the lungs.Human chorionic gonadotropin is a hormone produced by the trophoblast and can be measured in both urine and blood. Another option of measuring this biomarker level is through lumbar puncture, which can show fluid-to-serum ratio of human chorionic gonadotropic and reflect whether the disease has potentially spread to the central nervous system. Elevated or rising human chorionic gonadotropin can be a sign of gestational choriocarcinoma, though it is also used as a biomarker in other types of gestational trophoblastic diseases (GTD). It is useful not only for diagnosis but also for monitoring disease progression, treatment response, and potential of recurring gestational choriocarcinoma.

Causes
Gestational choriocarcinoma (GC) is the most aggressive form of trophoblastic tumor; it most commonly arises from certain fertilization defects, such as molar pregnancy, which results in increased level of growth factors and uncontrolled proliferation of trophoblasts in the uterus. Statistics from clinical cases have shown that GC is associated with any pregnancy events, with 50% of GC arise from hydatidiform moles, 25% from gestation, and 25% from abortion or tubal pregnancy.

Risk factors
The exact underlying causes for this disease are still not fully elucidated, part of the reasons being that this condition is very rare and it is clinically hard to distinguish it from invasive mole, which are other type of trophoblastic tumor  that present some similarities as GC.  But several risk factors have been reported to have association with gestational choriocarcinoma.

Maternal age. This is one of the two well-established risk factors for GC. Many studies have shown that the risk of developing GC increased very rapidly in gestational women older than 40 years old.
Prior history of complete hydatidiform mole. This is another well-established risk factor for GC. It has been showed that the risk of having GC after a complete hydatidiform mole is significantly higher than after a live birth.
Others risk factors such as reproductive factors, use of oral contraceptives, diet and environmental factors were also reported. But because of data inconsistency, such associations are still questionable. For example, there is a case-control study showed that theres a significant association of GC in women having more than 5 births. But other studies had showed no association when corrected for age.

Pathogenesis
At the cellular level, any abnormalities in the placental trophoblastic proliferation could potentially contribute to molar pregnancy and tumor development. There are three different types of trophoblasts: cytotrophoblasts, syncytiotrophoblasts, and intermediate trophoblasts. Each of them possesses distinct specialized functions to support a developing embryo. Cytotrophoblasts are the germinating cells that forms the chorion villi and can be differentiated into syncytiotrophoblasts which produce hCG and can intrude to the inner muscle layer of the uterus to help embed the developing embryo, and intermediate trophoblasts which spread throughout the chorion villi to support maternal-fetal circulation. Malignant cellular transformation of all of these three trophoblastic cells contribute to the development of gestational choriocarcinoma. Common pathological features of GC include abnormal trophoblastic enlargement, loss of trophoblastic specialized features and functions, absence of villi in the placenta, abnormal bleeding, and necrosis.Many efforts have been made to try to understand the mechanism of how non-malignant mole could become invasive. It is suspected that activation of certain oncogenes (such as up-regulations of MDM2, c-ERB2, and BLC2) and inactivation of tumor suppressor genes (such as up-regulations of p53, p21) were involved in the processes of genetic changes in this malignant transformation.  But trophoblastic cells, by nature, are highly active in cell division, the increased activities of those genes are also necessary to maintain their normal cell function. Therefore, it is still unclear how significantly these genetic changes are in the pathogenesis of gestational choriocarcinoma.
Recent research in the role of long non-coding RNAs (lncRNAs) in the GC development is believed to bring hope in this field. Long non-coding RNAs are groups of RNAs that do not code for protein expression and are usually over 200 nucleotides long; they are increasingly recognized to have essential role in many aspects of cellular function, like transcriptional regulation, sub-cellular protein localization, and epigenetic remodeling. To date, several types of lncRNAs are reported to have role in GC pathogenesis, which are metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), H19, maternally expressed gene 3 (MEG3), prostate cancer antigen 3 (PCA3), the long intergenic non-coding RNA 00261 (LINC00261), etc.. However, as many of these studies are still in the preliminary stages, more investigation is needed to fully understand the underlying mechanism.

Diagnosis
Common characteristic manifestations of gestational choriocarcinoma include irregular vaginal bleeding and hydatidiform moles. A hydatidiform mole is a red hemorrhagic mass with various sizes in the uterus. Often, diagnosis is presumptive. It is based on clinical findings and the identification of a malignant trophoblast. One prevalent symptom is vaginal bleeding after a pregnancy, abortion, or hydatidiform mole. In the presence of choriocarcinoma, a pregnancy test will be positive even if there is no embryo/fetus.A confirmed diagnosis usually happens after the disease has progressed to a late clinical stage. This is partly due to the wide spectrum and rare clinical presentations of the disease. Individuals presented with the disease are mostly in their reproductive years.Similar to other non-gestational tumors, gestational choriocarcinoma can be reflected via an elevated level in serum hCG concentration. Besides the change in serum hCG levels, the diagnosis of gestational choriocarcinoma also focuses on the presence of metastases after any types of pregnancy events. Based on the International Federation of Gynecology and Obstetrics (FIGO)s updated guidelines on gestational trophoblastic disease management, the diagnostic criteria of a post-gestational trophoblastic neoplasia (GTN) is as follows:
Over a period of 3 weeks or longer (day 1, 7, 14, 21), there are 4 or more plateaued hCG levels.
Over a period of 2 weeks or longer (day 1, 7, 14), there are 3 consecutive weekly measurements of rising hCG levels.
A histological diagnosis of choriocarcinoma.There are currently different guidelines available in terms of diagnosing and recommending treatment options for gestational trophoblastic neoplasia (GTN). The 4 guidelines identified are: the Royal College of Obstetricians and Gynecologists (RCOG), the International Federation of Gynecology and Obstetrics (FIGO), the European Society for Medical Oncology (ESMO), and the Royal Australian and New Zealand College of Obstetricians and Gynecologists (RANZCOG). The differences in GTN diagnosis between the guidelines are as follows:
To differentiate gestational choriocarcinoma from other tumors such as lung or brain cancers, a genetic test is usually completed on top of a pathological diagnosis. DNA genotyping is a powerful tool that helps with the differentiation. The technique can accurately determine the time that it takes to develop the observed tumor and the type of index gestation, which includes term pregnancy, molar gestation, or non-molar abortion.

Treatment
Due to the susceptability of choriocarcinomas to chemotherapy, it is the first line treatment for this disease. Treatment course depends on the FIGO Scoring System for GTN, which has various prognostic factors, and categorizes based on low risk with a score of 0-6 and high risk with a score of 7 and above.

Low risk
Individuals with low risk GTN are usually treated with single agent chemotherapy, such as methotrexate and folinic acid (MTX/FA) or actinomycin D (ActD). Other treatment options for those with low risk include hysterectomy and surgical removal of the tumor if possible.

High risk
Those with high risk GTN receive a multi-agent chemotherapy regimen, usually consisting of a weekly rotation of etopside, methotrexate, and actinomycin D given one week and cyclophosphamide and vincristine given the following week, with variations to treatment occurring on a patient-specific basis.  In individuals who relapse, secondary chemotherapy is needed where treatment may vary from the original regimen. The treatment includes a platinum-etopside combination given with other chemotherapy medications, such as methotrexate and actinomycin D (EMA-EP), bleomycin (BEP), or ifosfamide (VIP, ICE) </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Microcephaly and can you explain it in depth? [/INST] Microcephaly (from New Latin microcephalia, from Ancient Greek μικρός mikrós "small" and κεφαλή kephalé "head") is a medical condition involving a smaller-than-normal head. Microcephaly may be present at birth or it may develop in the first few years of life. Since brain growth is correlated with head growth, people with this disorder often have an intellectual disability, poor motor function, poor speech, abnormal facial features, seizures and dwarfism.The disorder is caused by a disruption to the genetic processes that form the brain early in pregnancy, though the cause is not identified in most cases. Many genetic syndromes can result in microcephaly, including chromosomal and single-gene conditions, though almost always in combination with other symptoms. Mutations that result solely in microcephaly (primary microcephaly) exist but are less common. External toxins to the embryo, such as alcohol during pregnancy or vertically transmitted infections, can also result in microcephaly. Microcephaly serves as an important neurological indication or warning sign, but no uniformity exists in its definition. It is usually defined as a head circumference (HC) more than two standard deviations below the mean for age and sex. Some academics advocate defining it as head circumference more than three standard deviations below the mean for the age and sex.There is no specific treatment that returns the head size to normal. In general, life expectancy for individuals with microcephaly is reduced, and the prognosis for normal brain function is poor. Occasional cases develop normal intelligence and grow normally (apart from persistently small head circumference). It is reported that in the United States, microcephaly occurs in 2 to 12 babies per 10,000 births.

Signs and symptoms
There are a variety of symptoms that can occur in children. Infants with microcephaly are born with either a normal or reduced head size. Subsequently, the head fails to grow, while the face continues to develop at a normal rate, producing a child with a small head and a receding forehead, and a loose, often wrinkled scalp. As the child grows older, the smallness of the skull becomes more obvious, although the entire body also is often underweight and dwarfed.Severely impaired intellectual development is common, but disturbances in motor functions may not appear until later in life. Affected newborns generally have striking neurological defects and seizures. Development of motor functions and speech may be delayed. Hyperactivity and intellectual disability are common occurrences, although the degree of each varies. Convulsions may also occur. Motor ability varies, ranging from clumsiness in some to spastic quadriplegia in others.

Causes
Microcephaly is a type of cephalic disorder. It has been classified in two types based on the onset:

Congenital
Isolated
Familial (autosomal recessive) microcephaly
Autosomal dominant microcephaly
X-linked microcephaly
Chromosomal (balanced rearrangements and ring chromosome)
Syndromes
Chromosomal
Poland syndrome
Down syndrome
Edward syndrome
Patau syndrome
Unbalanced rearrangements
Contiguous gene deletion
4p deletion (Wolf–Hirschhorn syndrome)
5p deletion (Cri-du-chat)
7q11.23 deletion (Williams syndrome)
22q11 deletion (DiGeorge syndrome)
Single gene defects
Smith–Lemli–Opitz syndrome
Seckel syndrome
Cornelia de Lange syndrome
Holoprosencephaly
Primary microcephaly 4
Wiedemann-Steiner syndrome
Acquired
Disruptive injuries
Ischemic stroke
Hemorrhagic stroke
Death of a monozygotic twin
Vertically transmitted infections
Congenital cytomegalovirus infection
Toxoplasmosis
Congenital rubella syndrome
Congenital Varicella Syndrome
Zika virus (see Zika fever#Microcephaly)
Drugs
Fetal hydantoin syndrome
Fetal alcohol syndrome
Other
Radiation exposure to mother
Maternal malnutrition
Maternal phenylketonuria
Poorly controlled gestational diabetes
Hyperthermia
Maternal hypothyroidism
Placental insufficiency
Craniosynostosis

Postnatal onset
Genetic
Inborn errors of metabolism
Congenital disorder of glycosylation
Mitochondrial disorders
Peroxisomal disorder
Glucose transporter defect
Menkes disease
Congenital disorders of amino acid metabolism
Organic acidemia
Syndromes
Contiguous gene deletion
17p13.3 deletion (Miller–Dieker syndrome)
Single gene defects
Rett syndrome (primarily girls)
Nijmegen breakage syndrome
X-linked lissencephaly with abnormal genitalia
Aicardi–Goutières syndrome
Ataxia telangiectasia
Cohen syndrome
Cockayne syndrome
Acquired
Disruptive injuries
Traumatic brain injury
Hypoxic-ischemic encephalopathy
Ischemic stroke
Hemorrhagic stroke
Infections
Congenital HIV encephalopathy
Meningitis
Encephalitis
Toxins
Chronic kidney failure
Deprivation
Hypothyroidism
Anemia
Congenital heart disease
MalnutritionGenetic mutations cause most cases of microcephaly. Relationships have been found between autism, duplications of genes and macrocephaly on one side. On the other side, a relationship has been found between schizophrenia, deletions of genes and microcephaly. Several genes have been designated "MCPH" genes, after microcephalin (MCPH1), based on their role in brain size and primary microcephaly syndromes when mutated. In addition to microcephalin, these include WDR62 (MCPH2), CDK5RAP2 (MCPH3), KNL1 (MCPH4), ASPM (MCPH5), CENPJ (MCPH6), STIL (MCPH7), CEP135 (MCPH8), CEP152 (MCPH9), ZNF335 (MCPH10), PHC1 (MCPH11) and CDK6 (MCPH12). Moreover, an association has been established between common genetic variants within known microcephaly genes (such as MCPH1 and CDK5RAP2) and normal variation in brain structure as measured with magnetic resonance imaging (MRI)—i.e., primarily brain cortical surface area and total brain volume.The spread of Aedes mosquito-borne Zika virus has been implicated in increasing levels of congenital microcephaly by the International Society for Infectious Diseases and the US Centers for Disease Control and Prevention. Zika can spread from a pregnant woman to her fetus. This can result in other severe brain malformations and birth defects. A study published in The New England Journal of Medicine has documented a case in which they found evidence of the Zika virus in the brain of a fetus that displayed the morphology of microcephaly.

Microlissencephaly
Microlissencephaly is microcephaly combined with lissencephaly (smooth brain surface due to absent sulci and gyri). Most cases of microlissencephaly are described in consanguineous families, suggesting an autosomal recessive inheritance.

Historical causes of microcephaly
After the dropping of atomic bombs "Little Boy" on Hiroshima and "Fat Man" on Nagasaki, several women close to ground zero who had been pregnant at the time gave birth to children with microcephaly. Microcephaly was present in 7 children from a group of 11 pregnant women at 11–17 weeks of gestation who survived the blast at less than 1.2 km (0.75 mi) from ground zero. Due to their proximity to the bomb, the pregnant womens in utero children received a biologically significant radiation dose that was relatively high due to the massive neutron output of the lower explosive-yielding Little Boy. Researchers studied 286 additional children who were in utero during the atomic bombings, and after a year they found these children had a higher incidence of microcephaly and mental retardation.

Other relations
Intracranial volume also affects this pathology, as it is related with the size of the brain.

Pathophysiology
Microcephaly generally is due to the diminished size of the largest part of the human brain, the cerebral cortex, and the condition can arise during embryonic and fetal development due to insufficient neural stem cell proliferation, impaired or premature neurogenesis, the death of neural stem cells or neurons, or a combination of these factors. Research in animal models such as rodents has found many genes that are required for normal brain growth. For example, the Notch pathway genes regulate the balance between stem cell proliferation and neurogenesis in the stem cell layer known as the ventricular zone, and experimental mutations of many genes can cause microcephaly in mice, similar to human microcephaly. Mutations of the abnormal spindle-like microcephaly-associated (ASPM) gene are associated with microcephaly in humans and a knockout model has been developed in ferrets that exhibits severe microcephaly. In addition, viruses such as cytomegalovirus (CMV) or Zika have been shown to infect and kill the primary stem cell of the brain—the radial glial cell, resulting in the loss of future daughter neurons </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Couvade and can you explain it in depth? [/INST] Couvade is a term which was coined by anthropologist E. B. Tylor in 1865 to refer to certain rituals in several cultures that fathers adopt during pregnancy.
Couvade can be traced to Ancient Egypt as a "sacred birth custom, of when a child is born, the man experiences the ritual of "labor" in which he takes to his bed, and undergoes periods of fasting and purification, and the observance of certain taboos".The term "couvade" is borrowed from French (where it is derived from the verb couver "to brood, hatch"); the use in the modern sense derives from a misunderstanding of an earlier idiom faire la couvade, which meant "to sit doing nothing."An example of couvade is that the Cantabri people had a custom in which the father, during or immediately after the birth of a child, took to bed, complained of having labour pains, and was accorded the treatment usually shown to women during pregnancy or after childbirth. Similarly, in Papua New Guinea, fathers built a hut outside the village and mimicked the pains of labour until the baby is born </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Ullrich congenital muscular dystrophy and can you explain it in depth? [/INST] Ullrich congenital muscular dystrophy is a form of congenital muscular dystrophy. It is associated with variants of type VI collagen, it is commonly associated with muscle weakness and respiratory problems, though cardiac issues are not associated with this type of CMD. It is named after Otto Ullrich, who is also known for the Ullrich-Turner syndrome.

Signs and symptoms
The presentation of Ullrich congenital muscular dystrophy in an affected individual is as follows:
Muscle weakness
Difficulty walking
Contractures (predominantly in proximal muscles, e.g. neck)
Joint looseness (predominantly in distal joints)

Genetics
In terms of the genetics of Ullrich congenital muscular dystrophy, there are mutations in the genes COL6A1, COL6A2, and COL6A3. This sub-type of muscular dystrophy is autosomal recessive in nature.COL6A1 plays an important part in maintaining the human bodys integrity of various tissues. Alpha 1 subunit of type VI collagen is the encoded protein.

Diagnosis
In terms of the diagnosis of Ullrich congenital muscular dystrophy upon inspection follicular hyperkeratosis, may be a dermatological indicator, additionally also serum creatine kinase may be mildly above normal. Other exams/methods to ascertain if the individual has Ullrich congenital muscular dystrophy are:
MRI
Biopsy muscle
Genetic testing

Differential diagnosis
This includes

Treatment
Treatment for Ullrich congenital muscular dystrophy can consist of physical therapy and regular stretching to prevent and reduce contractures. Respiratory support may be needed at some point by the affected individual.Though cardiac complications are not a concern in this type of CMD, in regards to respiratory issues ventilation via a tracheostomy is a possibility in some cases.

Prognosis
The prognosis of this sub-type of MD indicates that the affected individual may eventually have feeding difficulties. Surgery, at some point, might be an option for scoliosis.Scoliosis, which is a sideways curve of the persons vertebrate, is determined by a variety of factors, including the degree (mild or severe), in which case if possible a brace might be used by the individual.

Research
In terms of possible research for Ullrich congenital muscular dystrophy one source indicates that cyclosporine A might be of benefit to individuals with this CMD type.According to a review by Bernardi, et al., cyclosporin A (CsA) used to treat collagen VI muscular dystrophies demonstrates a normalization of mitochondrial reaction to rotenone.

See also
Muscular dystrophy
Congenital muscular dystrophy

References
Further reading
Ph.D, Evelyn B. Kelly (2013-01-07). Encyclopedia of Human Genetics and Disease [2 volumes]. ABC-CLIO. ISBN 9780313387142.
Carakushansky, Gerson; Ribeiro, Marcia Gonçalves; Kahn, Evelyn (2011). "Moderately progressive Ullrich congenital muscular dystrophy". Jornal de Pediatria. 88 (1): 93–96. doi:10.2223/JPED.2112. ISSN 0021-7557. PMID 22016142.
"National Guideline Clearinghouse | Evidence-based guideline summary: evaluation, diagnosis, and management of congenital muscular dystrophy: report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular and Electrodiagnostic Medicine". www.guideline.gov. Archived from the original on 2016-04-08. Retrieved 2016-05-12.
Hicks, D.; Lampe, A. K.; Laval, S. H.; Allamand, V.; Jimenez-Mallebrera, C.; Walter, M </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Periapical cyst and can you explain it in depth? [/INST] Commonly known as a dental cyst, the periapical cyst is the most common odontogenic cyst.  It may develop rapidly from a periapical granuloma, as a consequence of untreated chronic periapical periodontitis.Periapical is defined as "the tissues surrounding the apex of the root of a tooth" and a cyst is "a pathological cavity lined by epithelium, having fluid or gaseous content that is not created by the accumulation of pus."Most frequently located in the maxillary anterior region, the cyst is caused by pulpal necrosis secondary to dental caries or trauma. Its lining is derived from the epithelial cell rests of Malassez which proliferate to form the cyst. Such cysts are very common. Although initially asymptomatic, they are clinically significant because secondary infection can cause pain and damage. In radiographs, the cyst appears as a radiolucency (dark area) around the apex of a tooths root.

Signs and symptoms
Periapical cysts begin as asymptomatic and progress slowly. Subsequent infection of the cyst causes swelling and pain. Initially, the cyst swells to a round hard protrusion, but later on the body resorbs some of the cyst wall, leaving a softer accumulation of fluid underneath the mucous membrane.Secondary symptoms of periapical cysts include inflammation and infection of the pulp causing dental caries. This infection is what causes necrosis of the pulp.Larger cysts may cause bone expansion or displace roots. Discoloration of the affected tooth may also occur. Patient will present negative results to electric and ice test of the affected tooth but will be sensitive to percussion. Surrounding gingival tissue may experience lymphadenopathy. The alveolar plate may exhibit crepitus when palpated.

Complications
Expansion of the cyst causes erosion of the floor of the maxillary sinus. As soon as it enters the maxillary antrum, the expansion rate increases due to available space for expansion. Performing a percussion test by tapping the affected teeth will cause shooting pain. This is often clinically diagnostic of pulpal infection.

Causes
Dental cysts are usually caused due to root infection involving tooth decay. Untreated dental caries then allow bacteria to reach the level of the pulp, causing infection. The bacteria gains access to the periapical region of the tooth through deeper infection of the pulp, traveling through the roots. The resulting pulpal necrosis causes proliferation of epithelial rests of Malassez which release toxins at the apex of the tooth. The bodys inflammatory response will attack the source of the toxins, leading to periapical inflammation. The many cells and proteins that rush to an area of infection create osmotic tension in the periapex which is the source of internal pressure increase at the cyst site.
These lesions can grow large because they apply pressure over the bone, causing resorption.  The toxins released by the breakdown of granulation tissue are one of the common causes of bone resorption.
There are two schools of thought regarding cyst expansion.
Complementary response to inflammation
Chemical reaction with Interleukin and Prostaglandin

Mechanisms
Periapical cysts develop due to an inflammatory stimulus in 3 stages:
Initial stage: Epithelial cells from the rests of Malassez at the apex of the roots of a non-vital tooth (one where the nerve and blood supply in the tooth have degenerated and no longer exist) become stimulated due to the bodys inflammatory response to bacterial endotoxins infecting the pulp or as a direct response to necrotic pulp tissue, therefore re-entering the growth phase. Bacterial byproducts then are able to seep into the periapical region through the infected pulp.
Cyst development stage:  Epithelial cells form strands and are attracted to the area which contains exposed connective tissue and foreign substances. Several strands from each rest converge and surround the abscess or foreign body.
Cyst growth stage: Fluid flows into the cavity where the forming cyst is growing due to the increased osmolality of the cavity in relation to surrounding serum in capillaries. Pressure and size increase.The definitive mechanism by which cysts grow is under debate; several theories exist.

Biomechanical theory
Pressure and concentration differences between the cystic cavity and the growth surroundings influence fluid movement into the cyst, causing size increase.

Biochemical theories
a. Collagenase (breakdown of collagen) in the jaw bone leads to bone degeneration, providing room for cysts to develop. Substances released by the bodys immune system as a result of the connective tissue breakdown, such as cytokines and growth factors, contribute to the mobilization and proliferation of epithelial cells in the area.
b. Bone resorption caused by metabolism of acidic substances produced by cysts contributes to cyst growth. Such substances include Prostaglandin-2 and Interleukin-1 which are both produced by the cyst itself.

Nutritional deficiency theory
Epithelial cells will form a mass inside the cavity and the innermost cells become deprived of nutrients because they are far from the source of nutrients (the blood vessels). The innermost cells die and form an aggregate of dead tissue.  The inner cells undergo ischemic liquefactive necrosis which creates the cavity space surrounded by growing epithelial cells. This theory is unlikely in the absence of malignant transformation of epithelial cells as it does not follow the existing relationship between connective tissue and epithelium.

Abscess theory
Epithelial cells have an inherent quality to reproduce and cover any connective tissue that is not already lined with epithelia. Formation of an abscess must precede the epithelial proliferation in order for the cells to carry out this tendency. This theory explains why cysts are lined in epithelia but not why the initial cysts itself forms.

Diagnosis
A non-vital tooth is necessary for the diagnosis of a periapical cyst, meaning the nerve has been removed by root canal therapy.

Oral examination
The surrounding intraoral anatomical structures should be palpated to identify the presence of bone expansion or displacement of tooth roots as well as crepitus noises during examination, indicating extensive bone damage. Bulging of the buccal or lingual cortical plates may be present. Age of occurrence in the patient, the location of the cyst, the edges of cystic contours, and the impact that the cyst has on adjacent structures must all be considered for proper diagnosis.

Radiology
Several lesions can appear similarly in radiographic appearance. Intraoral X-rays or a 3-D cone beam scan of the affected area can be used to obtain radiological images and confirm diagnosis of cysts in the periapical area. Circular or ovoid radiolucency surrounding the root tip of approximately 1-1.5 cm in diameter is indicative of the presence of a periapical cyst. The border of the cyst is seen as a narrow opaque margin contiguous with the lamina dura. In cysts that are actively enlarging, peripheral areas of the margin may not be present. Periapical cysts have a characteristic  unilocular shape on radiographs. There is also a severe border of cortication between the cyst and surrounding bone. Pseudocysts, on the other hand, have a fluid filled cavity but are not lined by epithelium, therefore they have a less severe and more blurred border between the fluid and bony surroundings.

Histopathology
In light microscopy, periapical cysts show:
Stratified squamous epithelium of variable thickness, except when originating in a maxillary sinus where there is respiratory epithelium (pseudostratified ciliated columnar epithelium).
A fibrous capsule of varying thickness, with chronic inflammatory cells, wherein a plasma cells may be abundantThey sometimes have the following features:
Rushton hyaline bodies, which are amorphic, eosinophilic, linear to crescent-shaped bodies in the cyst epithelium, present in 10% of periapical cysts.
Scattered ciliated cells
Cholesterol clefts in the cyst lining.

Classification
Periapical cysts exist in two structurally distinct classes:

Periapical true cysts - cysts containing cavities entirely surrounded in epithelial lining.  Resolution of this type of cyst requires surgical treatment such as a cystectomy.
Periapical pocket cysts - epithelium lined cavities that have an opening to the root canal of the affected tooth.  Resolution may occur after traditional root canal therapy.

Differentiation
Radiographically, it is virtually impossible to differentiate granuloma from a cyst. If the lesion is large it is more likely to be a cyst. Radiographically, both granulomas and cysts appear radiolucent. Many lesions of the mandible in particular appear cystlike in appearance. It is often necessary to obtain a biopsy and evaluate the tissue under a microscope to accurately identify the lesion.

Treatment
The infected tissue of the periapical cyst must be entirely removed, including the epithelium of the cyst wall; otherwise, a relapse is likely to occur. Root canal treatment should be performed on the tooth if it is determined that previous therapy was unsuccessful. Removal of the necrotic pulp and the inflamed tissue as well as proper sealing of the canals and an appropriately fitting crown will allow the tooth to heal under uninfected conditions.Surgical options for previously treated teeth that would not benefit from root canal therapy include cystectomy and cystostomy </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Autoimmune neutropenia and can you explain it in depth? [/INST] Autoimmune neutropenia (AIN) is a form of neutropenia which is most common in infants and young children where the body identifies the neutrophils as enemies and makes antibody to destroy them.
Primary autoimmune neutropenia, another name for autoimmune neutropenia, is an autoimmune disease first reported in 1975 that primarily occurs in infancy. In autoimmune neutropenia, the immune system produces autoantibodies directed against the neutrophilic protein antigens in white blood cells known as granulocytic neutrophils, granulocytes, segmented neutrophils, segs, polysegmented neutrophils, or polys. These antibodies, IgG antibodies, destroy granulocytic neutrophils. Consequently, patients with autoimmune neutropenia have low levels of granulocytic neutrophilic white blood cells causing a condition of neutropenia. Neutropenia causes an increased risk of infection from organisms that the body could normally fight easily.
Primary autoimmune neutropenia has been reported as early as the second month of life although most cases are diagnosed in children between 5 and 15 months of age. Girls have a slightly higher risk of developing AIN than boys as well as do people of Caucasian background. In neutropenia discovered at birth or shortly after birth, a diagnosis of allo-immune neutropenia (from maternal white blood cell antibodies passively transferred to the infant) is more likely.
In infants neutropenia is defined by absolute neutrophil counts less than 1000/uL </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Knuckle pads and can you explain it in depth? [/INST] Knuckle pads (also known as "Heloderma", meaning similar to the skin of the Gila monster lizard for which it is named) are circumscribed, keratotic, fibrous growths over the dorsa of the interphalangeal joints. They are described as well-defined, round, plaque-like, fibrous thickening that may develop at any age, and grow to be 10 to 15mm in diameter in the course of a few weeks or months, then go away over time.Knuckle pads are sometimes associated with Dupuytrens contracture and camptodactyly,: 595  and histologically, the lesions are fibromas.: 595  Knuckle pads are generally non-responsive to treatment, including corticosteroids, and tend to recur after surgery; however, there has been some effectiveness with intralesional fluorouracil.

See also
Skin lesion
List of cutaneous conditions
Garrods pad

References
Further reading
Guberman D;  et al. (1996). ""Knuckle pads-a forgotten skin condition " report of a case and review of the literature". Cutis. 57 (4): 241–242. PMID 8727774.
Ly Y;  et al. (2003). "A novel mutation of keratin 9 in epidermolytic palmoplantar keratoderma combined with knuckle pads" </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Antisynthetase syndrome and can you explain it in depth? [/INST] Anti-synthetase syndrome  is an autoimmune disease associated with interstitial lung disease, dermatomyositis, and polymyositis.

Signs and symptoms
As a syndrome, this condition is poorly defined </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Aggressive fibromatosis and can you explain it in depth? [/INST] Aggressive fibromatosis or desmoid tumor is a rare condition.  Desmoid tumors arise from cells called fibroblasts, which are found throughout the body and provide structural support, protection to the vital organs, and play a critical role in wound healing. These tumors tend to occur in women in their thirties, but can occur in anyone at any age. They can be either relatively slow-growing or malignant. However, aggressive fibromatosis is locally aggressive and can cause life-threatening problems or even death when they compress vital organs such as intestines, kidneys, lungs, blood vessels, or nerves. Most cases are sporadic, but some are associated with familial adenomatous polyposis (FAP). Approximately 10% of individuals with Gardners syndrome, a type of FAP with extracolonic features, have desmoid tumors.The World Health Organization reclassified desmoid tumors (termed desmoid-type fibromatosis) as a specific type of tumor in the category of intermediate (locally aggressive) fibroblastic and myofibroblastic tumors.Histologically they resemble very low-grade fibrosarcomas, but they are very locally aggressive and tend to recur even after complete resection. There is a tendency for recurrence in the setting of prior surgery; in one study, two-thirds of patients with desmoid tumors had a history of prior abdominal surgery.

Risk factor
Risk factors for desmoid disease amongst FAP patients include female sex, a 3 APC mutation, a positive family history, and a history of previous abdominal surgery.

Diagnosis
Classification
Desmoid tumors may be classified as extra-abdominal, abdominal wall, or intra-abdominal (the last is more common in patients with FAP). It is thought that the lesions may develop in relation to estrogen levels or trauma/operations.A 3 APC mutation is the most significant risk factor for intra-abdominal desmoid development amongst FAP patients. FAP patients presenting with an abdominal wall desmoid pre-operatively are at an increased risk of developing an intra-abdominal desmoid post-operatively.Desmoid tumours of the breast are rare. Although benign, they can mimic breast cancer
on physical examination, mammography and breast ultrasound and can also be locally invasive </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Copper deficiency and can you explain it in depth? [/INST] Copper deficiency, or hypocupremia,  is defined either as insufficient copper to meet the needs of the body, or as a serum copper level below the normal range. Symptoms may include fatigue, decreased red blood cells, early greying of the hair, and neurological problems presenting as numbness, tingling, muscle weakness, and ataxia. The neurodegenerative syndrome of copper deficiency has been recognized for some time in ruminant animals, in which it is commonly known as "swayback". Copper deficiency can manifest in parallel with vitamin B12 and other nutritional deficiencies.

Overview
The most common cause of copper deficiency is a remote gastrointestinal surgery, such as gastric bypass surgery, due to malabsorption of copper, or zinc toxicity. On the other hand, Menkes disease is a genetic disorder of copper deficiency involving a wide variety of symptoms that is often fatal.Copper is required for the functioning of many enzymes, such as cytochrome c oxidase, which is complex IV in the mitochondrial electron transport chain, ceruloplasmin, Cu/Zn superoxide dismutase, and in amine oxidases.  These enzyme catalyze reactions for oxidative phosphorylation, iron transportation, antioxidant and free radical scavenging and neutralization, and neurotransmitter synthesis, respectively. Diets vary in the amount of copper they contain, but may provide about 5 mg/day, of which only 20-50% is absorbed. The diet of the elderly may have a lower copper content than the recommended daily intake. Dietary copper can be found in whole grain cereals, legumes, oysters, organ meats (particularly liver), cherries, dark chocolate, fruits, leafy green vegetables, nuts, poultry, prunes, and soybean products like tofu.Copper deficiency can have many hematological consequences, such as myelodysplasia, anemia, low white blood cell count, and low count of neutrophils (a type of white blood cell that is often called "the first line of defense" of the immune system). Copper deficiency has long been known as a cause of myelodysplasia (when a blood profile has indicators of possible future leukemia development), but it was not until 2001 that copper deficiency was associated with neurological manifestations like sensory ataxia (irregular coordination due to proprioceptive loss), spasticity, muscle weakness, and more rarely visual loss due to damage in the peripheral nerves, myelopathy (disease of the spinal cord), and rarely optic neuropathy.

Signs and symptoms
Blood symptoms
The characteristic hematological (blood) effects of copper deficiency are anemia (which may be microcytic, normocytic or macrocytic) and neutropenia. Thrombocytopenia (low blood platelets) is unusual.The peripheral blood and bone marrow aspirate findings in copper deficiency can mimic myelodysplastic syndrome. Bone marrow aspirate in both conditions may show dysplasia of blood cell precursors and the presence of ring sideroblasts (erythroblasts containing multiple iron granules around the nucleus). Unlike most cases of myelodysplastic syndrome, the bone marrow aspirate in copper deficiency characteristically shows cytoplasmic vacuoles within red and white cell precursors, and karyotyping in cases of copper deficiency does not reveal cytogenetic features characteristic of myelodysplastic syndrome.Anemia and neutropenia typically resolve within six weeks of copper replacement.

Neurological symptoms
Copper deficiency can cause a wide variety of neurological problems including myelopathy, peripheral neuropathy, and optic neuropathy.

Myelopathy
Copper deficiency myelopathy in humans was discovered and first described by Schleper and Stuerenburg in 2001. They described a patient with a history of gastrectomy and partial colonic resection who presented with severe tetraparesis and painful paraesthesias and who was found on imaging to have dorsomedial cervical cord T2 hyperintensity. Upon further analysis, it was found that the patient had decreased levels of serum coeruloplasmin, serum copper, and CSF copper. The patient was treated with parenteral copper and the patients paraesthesias did resolve. Since this discovery, there has been heightened and increasing awareness of copper-deficiency myelopathy and its treatment, and this disorder has been reviewed by Kumar.
Patients typically present difficulty walking (gait difficulty) caused by sensory ataxia (irregular muscle coordination) due to dorsal column dysfunction or degeneration of the spinal cord (myelopathy). Patients with ataxic gait have problems balancing and display an unstable wide walk. They often feel tremors in their torso, causing sideways jerks and lunges.In brain MRI, there is often an increased T2 signalling at the posterior columns of the spinal cord in patients with myelopathy caused by copper deficiency. T2 signalling is often an indicator of some kind of neurodegeneration. There are some changes in the spinal cord MRI involving the thoracic cord, the cervical cord or sometimes both. Copper deficiency myelopathy is often compared to subacute combined degeneration (SCD). Subacute combined degeneration is also a degeneration of the spinal cord, but instead vitamin B12 deficiency is the cause of the spinal degeneration. SCD also has the same high T2 signalling intensities in the posterior column as copper deficient patient in MRI imaging.

Peripheral neuropathy
Another common symptom of copper deficiency is peripheral neuropathy, which is numbness or tingling that can start in the extremities and can sometimes progress radially inward towards the torso. In an Advances in Clinical Neuroscience & Rehabilitation (ACNR) published case report, a 69-year-old patient had progressively worsened neurological symptoms. These symptoms included diminished upper limb reflexes with abnormal lower limb reflexes, sensation to light touch and pin prick was diminished above the waist, vibration sensation was lost in the sternum, and markedly reduced proprioception or sensation about the selfs orientation. Many people with the neurological effects of copper deficiency complain about very similar or identical symptoms as the patient. This numbness and tingling poses danger for the elderly because it increases their risk of falling and injuring themselves. Peripheral neuropathy can become very disabling leaving some patients reliant on wheelchairs or walking canes for mobility if there is a lack of correct diagnosis. Rarely can copper deficiency cause major disabling symptoms. The deficiency will have to be present for an extensive amount of time until such disabling conditions manifest.

Optic neuropathy
Some patients with copper deficiency have shown signs of vision and color loss. The vision is usually lost in the peripheral views of the eye. The bilateral vision loss is usually very gradual. An optical coherence tomography (OCT) shows some nerve fiber layer loss in most patients, suggesting the vision loss and color vision loss was secondary to optic neuropathy or neurodegeneration.

Causes
Surgery
Bariatric surgery is a common cause of copper deficiency. Bariatric surgery, such as gastric bypass surgery, is often used for weight control of the morbidly obese. The disruption of the intestines and stomach from the surgery can cause absorption difficulties not only as regards copper but also for iron and vitamin B12 and many other nutrients. The symptoms of copper deficiency myelopathy may take up to decades to develop.

Zinc toxicity
Increased consumption of zinc is another cause of copper deficiency.  Zinc is often used for the prevention or treatment of common colds and sinusitis (inflammation of sinuses due to an infection), ulcers, sickle cell disease, celiac disease, memory impairment, and acne. Zinc is found in many common vitamin supplements and is also found in denture creams. Recently, several cases of copper deficiency myeloneuropathy were found to be caused by prolonged use of denture creams containing high quantities of zinc. A literature review found two cases of copper deficiency myelopathy secondary to parenteral zinc supplementation during chronic dialysis.Metallic zinc is the core of all United States currency coins, including copper-coated pennies. People who ingest a large number of coins will have elevated zinc levels, leading to zinc-toxicity-induced copper deficiency and the associated neurological symptoms. This was the case for a 57-year-old woman diagnosed with schizophrenia. The woman consumed over 600 coins, and started to show neurological symptoms such as unsteady gait and mild ataxia.

Hereditary disorders
Menkes disease is a congenital disease that is a cause of copper deficiency. Menkes disease is a hereditary condition caused by a defective gene involved with the metabolism of copper in the body. Menkes disease involves a wide variety of symptoms including floppy muscle tone, seizures, abnormally low temperatures, and a peculiar steel color hair that feels very rough. Menkes disease is usually a fatal disease with most children dying within the first ten years of life.

Other
It is rarely suggested that excess iron supplementation causes copper deficiency myelopathy.
Another rarer cause of copper deficiency is celiac disease, probably due to malabsorption in the intestines.
Still, a large percentage, around 20%, of cases have unknown causes.

Pathophysiology
Copper functions as a prosthetic group, which permits electron transfers in key enzymatic pathways like the electron transport chain. Copper is integrated in the enzymes cytochrome c oxidase, which is involved in cellular respiration and oxidative phosphorylation, Cu/Zn dismutase, which is involved in antioxidant defense, and many more listed in the table below.

Neurological
Cytochrome c oxidase
There have been several hypotheses about the role of copper and some of its neurological manifestations. Some suggest that disruptions in cytochrome c oxidase, also known as Complex IV, of the electron transport chain is responsible for the spinal cord degeneration.

Methylation cycle
Another hypothesis is that copper deficiency myelopathy is caused by disruptions in the methylation cycle. The methylation cycle causes a transfer of a methyl group (-CH3) from methyltetrahydrofolate to a range of macromolecules by the suspected copper dependent enzyme methionine synthase. This cycle is able to produce purines, which are a component of DNA nucleotide bases, and also myelin proteins. The spinal cord is surrounded by a layer of protective protein coating called myelin (see figure). When this methionine synthase enzyme is disrupted, the methylation decreases and myelination of the spinal cord is impaired. This cycle ultimately causes myelopathy.

Hematological cause
Iron transportation
The anemia caused by copper deficiency is thought to be caused by impaired iron transport. Hephaestin is a copper containing ferroxidase enzyme located in the duodenal muscosa that oxidizes iron and facilitates its transfer across the basolateral membrane into circulation. Another iron transporting enzyme is ceruloplasmin. This enzyme is required to mobilize iron from the reticuloendothelial cell to plasma.  Ceruloplasmin also oxidizes iron from its ferrous state to the ferric form that is required for iron binding. Impairment in these copper dependent enzymes that transport iron may cause the secondary iron deficiency anemia. Another speculation for the cause of anemia is involving the mitochondrial enzyme cytochrome c oxidase (complex IV in the electron transport chain). Studies have shown that animal models with impaired cytochrome c oxidase failed to synthesize heme from ferric iron at the normal rate. The lower rate of the enzyme might also cause the excess iron to clump, giving the heme an unusual pattern. This unusual pattern is also known as ringed sideroblastic anemia cells.

Cell growth halt
The cause of neutropenia is still unclear; however, the arrest of maturing myelocytes, or neutrophil precursors, may cause the neutrophil deficiency.

Zinc intoxication
Zinc intoxication may cause anemia by blocking the absorption of copper from the stomach and duodenum. Zinc also upregulates the expression of chelator metallothionein in enterocytes, which are the majority of cells in the intestinal epithelium </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Monocephalus and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Osteochondropathy and can you explain it in depth? [/INST]  </s>