<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 Chronic cerebrospinal venous insufficiency controversy and can you explain it in depth? [/INST] Chronic cerebrospinal venous insufficiency (CCSVI or CCVI) is a term invented by Italian researcher Paolo Zamboni in 2008 to describe compromised flow of blood in the veins draining the central nervous system. Zamboni hypothesized that it might play a role in the cause or development of multiple sclerosis (MS). Zamboni also devised a surgical procedure which the media nicknamed a liberation procedure or liberation therapy, involving venoplasty or stenting of certain veins. Zambonis ideas about CCSVI are very controversial, with significantly more detractors than supporters, and any treatments based on his ideas are considered experimental.There is no scientific evidence that CCSVI is related to MS, and there is no good evidence that the surgery helps MS patients.  Zambonis first published research was neither blinded nor did it have a comparison group. Zamboni also did not disclose his financial ties to Esaote, the manufacturer of the ultrasound specifically used in CCSVI diagnosis. The "liberation procedure" has been criticized for possibly resulting in serious complications and deaths, while its purported benefits have not been proven. In 2012, the United States Food and Drug Administration states that it is not clear if CCSVI exists as a clinical entity and that these treatments may cause more harm. In 2017 they emphasized that this use of balloon angioplasty is not an approved use. In a 2017 study Zamboni et al. stated "Venous PTA cannot be recommended for patients with relapsing-remitting multiple sclerosis." In 2018 a study in Neurology concluded "Our data do not support the continued use of venoplasty of extracranial jugular and/or azygous venous narrowing to improve patient-reported outcomes, chronic MS symptoms, or the disease course of MS."Research on CCSVI was fast-tracked, but researchers have been unable to find a connection between CCSVI and MS. This has raised serious objections to the hypothesis of CCSVI originating multiple sclerosis. Additional research investigating the CCSVI hypothesis is underway. A 2013 study found that CCSVI is equally rare in people with and without MS, while narrowing of the cervical veins is equally common.

Hypothesis
Proposed consequences of CCSVI syndrome include intracranial hypoxia, delayed perfusion, reduced drainage of catabolites, increased transpulmonary pressure, and iron deposits around the cerebral veins. Multiple sclerosis has been proposed as a possible outcome of CCSVI.

Pathophysiology
Zamboni and colleagues claimed that in MS patients diagnosed with CCSVI, the azygos and IJV veins are stenotic (abnormally narrowed) in around 90% of cases. Zamboni theorized that malformed blood vessels cause increased deposition of iron in the brain, which in turn triggers autoimmunity and degeneration of the nerves myelin sheath. While the initial article on CCSVI claimed that abnormal venous function parameters were not seen in healthy people, others have noted that this is not the case. In the report by Zamboni none of the healthy participants met criteria for a diagnosis of CCSVI while all patients did. Such outstanding results have raised suspicions of a possible spectrum bias, which originates on a diagnostic test not being used under clinically significant conditions.Further studies of the relationship between CCSVI and MS have had variable results, with many failing to reproduce the association between MS and CCSVI. Moreover, the greatest predictor of positive results is researchers involvement in the administration of the "liberation procedure". This effect goes to the extent that, when only fully independent studies are considered, no association at all is found. The poor reproducibility across studies and diagnostic modalities has led some authors to conclude that CCVSI might be nothing more than a clinically irrelevant sonographic construct.Already by 2010, there were "a growing number of papers that raise serious questions about its (CCSVI) validity", although evidence had been "both for and against the controversial hypothesis". It was agreed that it was urgent to perform appropriate epidemiological studies to define the possible relationship between CCSVI and MS, although existing data did not support CCSVI as the cause of MS.

Venous malformations
Most of the venous problems in MS patients have been reported to be truncular venous malformations, including azygous stenosis, defective jugular valves and jugular vein aneurysms. Problems with the innominate vein and superior vena cava have also been reported to contribute to CCSVI. A vascular component in MS had been cited previously.Several characteristics of venous diseases make it difficult to include MS in this group. In its current form, CCSVI cannot explain some of the epidemiological findings in MS. These include risk factors such as Epstein-Barr infection, parental ancestry, date of birth and geographic location. MS is also more common in women, while venous diseases are more common in men. Venous pathology is commonly associated with hypertension, infarcts, edema and transient ischemia, and occurs more often with age, however these conditions are hardly ever seen in MS and the disease seldom appears after age 50. Finally, an organ-specific immune response is not seen in any other kind of venous disease.

Iron deposits
Iron deposition as a cause of MS received support when a relationship between venous pressure and iron depositions in MS patients was found in a neuroimaging study, and criticism as other researchers found normal ferritin levels in the cerebrospinal fluid of MS patients. Additionally iron deposition occurs in different neurological diseases such as Alzheimers disease or Parkinsons disease that are not associated with CCSVI. Evidence linking CCSVI and iron deposition is lacking, and dysregulation of iron metabolism in MS is more complex than simply iron accumulation in the brain tissue.

Genetics
A small genetic study looked at fifteen MS patients who also had CCSVI. It found 234 specific copy number variations in the human leukocyte antigen focus. Of these, GRB2, HSPA1L and HSPA1A were found to be specifically connected to both MS and angiogenesis, TAF11 was connected to both MS and artery passage, and HLA-DQA2 was suggestive of having an implication for angiogenesis as it interacts with CD4. A study in 268 MS patients and 155 controls reported more a frequency of CCSVI in the MS group that was more than twice as high as in the controls group and was also higher in the progressive MS group than in the non-progressive MS group. This study found no relationship between CCSVI and HLA DRB1*1501, a genetic variation that has been consistently linked to MS.

Diagnosis
CCSVI was first described using specialized extracranial and transcranial doppler sonography. Five ultrasound criteria of venous drainage have been proposed to be characteristic of the syndrome, although two are considered sufficient for diagnosis of CCSVI:
reflux in the internal jugular and vertebral veins,
reflux in the deep cerebral veins,
high-resolution B-mode ultrasound evidence of stenosis of the internal jugular vein,
absence of flow in the internal jugular or vertebral veins on Doppler ultrasound, and
reverted postural control of the main cerebral venous outflow pathways.It is still not clear whether magnetic resonance venography, venous angiography, or Doppler sonography should be considered the gold standard for the diagnosis of CCSVI. Use of magnetic resonance venography for the diagnosis of CCSVI in MS patients has been proposed by some to have limited value, and should be used only in combination with other techniques. Others have stated that magnetic resonance venography is a valid measure which has advantages over Doppler including the fact that results are more operator-independent.Diagnostic criteria have been criticized. Both the number of criteria and the need of being positive for two of them as enough for diagnosis are arbitrary ideas. Moreover, experienced groups in the use of ultrasound have not been able to show intracranial or extracranial reflux in MS patients or even healthy controls whereas the criterion of absence of flow and the criterion regarding stenosis are considered not valid since they are related to normal physiological processes and not pathology. These problems in the criteria have led some researchers to consider the criteria inadequate and more generally the concept of CCSVI flawed.

Treatment
All proposed treatments are experimental
Treatment based on the idea of CCSVI is considered experimental.
Further trials are required to determine if the benefits, if any, of the procedure outweigh its risks. Most experts, and medical and patients organizations, including the National Multiple Sclerosis Society of the USA or the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), recommend not using the proposed treatment outside clinical trials until its effectiveness is confirmed by controlled studies. Moreover, the CIRSE has stated that treatment research should begin by a small, placebo-controlled, prospective randomised trial which should be monitored by an independent organization. An exception has been the Society of Interventional Radiology in the US and Canada, which considered research on the effectiveness of CCSVI intervention to be inconclusive as of 2010. In March 2013 a press release indicated that the first prospective, placebo-controlled study of balloon angioplasty for MS had not shown any benefit of the therapy. The study, a phase II clinical trial designed to evaluate safety and efficacy of endovascular treatment, enrolled initially 10 patients that received the treatment and 20 more afterwards that were either allocated to receive angioplasty or a placebo intervention.Kuwait became the first country in the world where treatment of CCSVI, as of 2010, was explicitly allowed by the medical authorities and paid by the state health system. As of 2010, the procedure was performed privately in 40 countries, and, despite existing recommendations, as of 2013 it is believed that over 30,000 patients have undergone the procedure.

Procedures
Balloon angioplasty and stenting have been proposed as treatment options for CCSVI in MS. The proposed treatment has been termed "liberation therapy" though the name has been criticized for suggesting unrealistic results.Balloon angioplasty in a preliminary, uncontrolled, unblinded study by Zamboni improved symptoms in MS in a minority of treated people. Although the procedure pushes the vein open temporarily, the effect does not persist, supporters advise against using stents.Venous percutaneous transluminal angioplasty (PTA) has proven to be safe but due to its ineffectiveness is not recommended.

Adverse effects
While the procedure has been reported to be generally safe for MS patients, severe complications related to the angioplasty and stenting that have been reported include intracranial hemorrhage, stent migration into a renal vein, thrombosis and nerve compression syndrome of cranial nerves XI and XII. One death case appeared in the scientific literature, while 3 other deaths have been related to CCSVI treatment in the media. Some United States hospitals have banned the surgical procedure outside clinical trials due to safety concerns until more evidence to support its use is available.In May 2012 the U.S. Food and Drug Administration issued a safety communication on CCSVI, stating that MS patients undergoing angioplasty and/or stenting to treat CCSVI risk serious injuries or death. Furthermore, it also noted that the benefits of these experimental procedures have not been proven and that studies exploring a link between MS and CCSVI are inconclusive.

History
Venous pathology has been associated with MS for more than a century. Pathologist Georg Eduard Rindfleisch noted in 1863 that the inflammation-associated lesions were distributed around veins. Later, in 1935, Tracy Putnam was able to produce similar lesions in dogs blocking their veinsThe term "chronic cerebrospinal venous insufficiency" was coined in 2008 by Paolo Zamboni, who described it in patients with multiple sclerosis. According to Zamboni, CCSVI had a high sensitivity and specificity differentiating healthy individuals from those with multiple sclerosis. Zambonis results were criticized because his study was not blinded and his results needed to be verified by further studies. Zamboni had become interested in CCSVI in 1999 when his wife was diagnosed with MS.

Society and culture
Conflict of interest
Paolo Zamboni has patents related to the highly sensitive ultrasound diagnostic systems manufactured by Esaote which, he proposes, should be used to diagnose CCSVI. Moreover, Zambonis research center has also received support in the form of equipment and technical assistance from this manufacturer. These are potential conflicts of interest that he has never disclosed when publishing scientific articles, which would be against ethical practices of some countries such as the United States.

Media
CCSVI has received a great deal of attention in all media, the scientific literature and on the Internet. Moreover, the CCSVI case has been considered a good example of how new communication technologies and social media are modifying the traditional relationship between science, politics, medicine, and the general public. In this sense they have played a key role in effectively promoting the theory.Media coverage has been perceived by some as "hype", with exaggerated claims that have led to excessive expectations. This has been partially attributed to some of the investigators of the theory. Mainstream media initial approximations to Zambonis theory were enthusiastic and emphasized Zambonis effort to find a cure for his wife, along with the improvement of some patients after its alleged treatment. Initial difficulty reproducing results connecting MS and CCSVI, combined with reports of secondary effects of the surgical procedure, led to a more cautious discourse proposing that more investigation in the relationship between CCSVI and MS was needed. The first fatality related to CCSVI treatment was a pivotal development in this trend towards a less optimistic media view of the theory.The Internet has been extensively used by patient groups to obtain and disseminate information on CCSVI. People with MS often read extensively about the CCSVI theory and its development on Internet sites, and a search for "liberation procedure" in Google as of August 2010 yielded more than 2.5 million hits. The Internet has also been used to advertise places where stenting for CCSVI is performed, and to more generally disseminate all the information on CCSVI. Social media have served patient groups in their attempt to pressure official bodies to make decisions favoring funding of clinical trials, or the public coverage of stenting and venoplasty as treatments of MS. Likewise, social media have been accused of creating a division between CCSVI supporters and those who say it does not work. Indeed, they have been repeatedly used by advocates of the CCSVI theory to attack those who were more critical or cautious, most commonly with accusations of being tainted due to commercial relationships with pharmaceutical companies.Many patients who have had the surgical procedure report their improvements on social media websites such as structured patient databases and YouTube. Such stories are only anecdotal evidence of efficacy, and do not constitute a scientific proof of the efficacy of the treatment since, for example, those who have had a positive result are more prone to post their cases than those who had little or no improvement, and the reported improvements in patients condition can be attributed to the placebo effect. Patients reasons for not publishing negative results may include embarrassment about the money spent in the procedure without effect and the negative reaction they expect from other people with MS. Caution has been recommended regarding patients self-reports found on the web.Scientists and physicians transmitted their arguments regarding CCSVI inadequately, especially after the initial rising of the hypothesis. Their communication was characterized by an excessive hesitation and a lack of clear statements, as opposed to CCSVI proponents, who "won the communication battle, at least in the early rounds." A positive effect of the important media coverage may be that it forces the world of medical research to be self-critical and give appropriate responses to the questions that globalization of the theory raises, especially among people with MS.

Reception in Canada
While reasons are not completely clear, the CCSVI theory was received differently in Canada than other places. The public interest and number of media appearances were much greater than elsewhere, including Italy, and debate has been heated regarding funding. As an example, by the end of 2009, a public petition to the country health authorities in support of the "liberation treatment" had received over 17,000 signatures. The debate regarding funding in Canada has been considered to be specially informative as an example of extreme involvement of politics, due to public pressure, in decisions usually governed by scientific evidence.In 2009, the Multiple Sclerosis Society of Canada committed to funding research on the connection between CCSVI and MS, although later in 2010 it came under criticism for opposing clinical trials of CCSVI therapy. The MS Society of Canada in September 2010 reserved one million dollars toward CCSVI research "when a therapeutic trial is warranted and approved."At a political level there have been contradictory positions, with some provinces funding trials, others stating that since therapy is unproven they should wait, and others urging for a pan-Canadian trial. British Columbia, Alberta, and Newfoundland and Labrador funded observational studies in which patients who had already received the treatment were included. Over 2 million dollars were allocated to these studies. The province of Saskatchewan was more aggressive and provided 2.2 million dollars for some of its residents to be included in a clinical trial.The Canadian Institutes of Health Research (CIHR), the federal agency responsible for funding health research, recommended in 2010 against funding a pan-Canadian trial of liberation therapy because there was a lack of evidence on the safety or efficacy of the procedure. It suggested a scientific expert working group made up of the principal investigators for the seven MS Society-sponsored studies. The health minister accepted the CIHR recommendation and said that Canada was not going to fund clinical trials. The expert panel was created by the end of 2010 together between the CIHR and the MS Society of Canada. It has been proposed that the creation of this expert panel was partly directed to cope with the high levels of social pressure the CCSVI theory had raised and at the same time try to maintain a scientific perspective in the funding and investigation of CCSVI. The main task of the panel was to monitor the results of the ongoing studies in the relationship between CCSVI and MS and recommend the funding of a clinical trial in case that there was evidence of a true relationship between the two. In 2011, the Canadian federal government announced that they would fund clinical trials of the procedure to widen the veins since CIHR considered that evidence of venous abnormalities in MS was enough for small treatment trials. It has been proposed that the recommendation to fund phase I and II trials instead of a big study was a compromise between the high levels of social and political pressure and the low level of evidence on the theory.Two qualitative studies have investigated the motives and experiences of Canadian patients traveling abroad to get the "liberation procedure". One of the studies identified three factors contributing to patients going abroad seeking treatment: a loss of faith in the Canadian health system when it did not provide access to CCSVI treatment in Canada, hope in the new treatment as a solution for their worsening health, and trust in the MS community and the organizations, clinics and doctors facilitating or providing the desired operation. Conversely, the other study concluded that sense of community and cooperation (from family, MS groups and the general population) was a key motivating factor </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 Adjustment disorder and can you explain it in depth? [/INST] Adjustment disorder is a maladaptive response to a psychosocial stressor. It is classified as a mental disorder. The maladaptive response usually involves otherwise normal emotional and behavioral reactions that manifest more intensely than usual (considering contextual and cultural factors), causing marked distress, preoccupation with the stressor and its consequences, and functional impairment.Diagnosis of adjustment disorder is common. Lifetime prevalence estimates for adults range from five percent to 21%. Adult women are diagnosed twice as often as men. Among children and adolescents, girls and boys are equally likely to be diagnosed with an Adjustment disorder.Adjustment disorder was introduced into the Diagnostic and Statistical Manual of Mental Disorders in 1980 (DSM-III).Other names for adjustment disorder are stress response syndrome (new name as of 2013) and situational depression since it is one of the most common symptoms.

Signs and symptoms
Some emotional signs of adjustment disorder are: sadness, hopelessness, lack of enjoyment, crying spells, nervousness, anxiety, desperation, feeling overwhelmed and thoughts of suicide, performing poorly in school/work etc.Common characteristics of Adjustment disorder include mild depressive symptoms, anxiety symptoms, and traumatic stress symptoms or a combination of the three. According to the DSM-5, there are six types of Adjustment disorder, which are characterized by the following predominant symptoms: depressed mood, anxiety, mixed depression and anxiety, disturbance of conduct, mixed disturbance of emotions and conduct, and unspecified. However, the criteria for these symptoms are not specified in greater detail. Adjustment disorder may be acute or chronic, depending on whether it lasts more or less than six months. According to the DSM-5, if the Adjustment disorder lasts less than six months, then it may be considered acute. If it lasts more than six months, it may be considered chronic. Moreover, the symptoms cannot last longer than six months after the stressor(s), or its consequences, have terminated.: 679  However, the stress-related disturbance does not only exist as an exacerbation of a pre-existing mental disorder.Unlike major depression, the disorder is caused by an outside stressor and generally resolves once the individual is able to adapt to the situation. The condition is different from anxiety disorder, which lacks the presence of a stressor, or post-traumatic stress disorder and acute stress disorder, which usually are associated with a more intense stressor.
Suicidal behavior is prominent among people with Adjustment disorder of all ages, and up to one-fifth of adolescent suicide victims may have an adjustment disorder. Bronish and Hecht (1989) found  that 70% of a series of patients with Adjustment disorder attempted suicide immediately before their index admission and they remitted faster than a comparison group with major depression. Asnis et al. (1993) found that Adjustment disorder patients report persistent ideation or suicide attempts less frequently than those diagnosed with major depression. According to a study on 82 Adjustment disorder patients at a clinic, Bolu et al. (2012) found that 22 (26.8%) of these patients were admitted due to suicide attempt, consistent with previous findings. In addition, it was found that 15 of these 22 patients chose suicide methods that involved high chances of being saved. Henriksson et al. (2005) states statistically that the stressors are of one-half related to parental issues and one-third in peer issues.One hypothesis about Adjustment disorder is that it may represent a sub-threshold clinical syndrome.

Subtypes and Their Symptoms
Adjustment disorder has six different subtypes, and they are all based on what the main symptoms are.Those subtypes are as follows:
With depressed mood: depression, hopelessness, lack of interest or joy from previously enjoyed hobbies, tearfulness
With anxiety: anxiousness, being overwhelmed, trouble concentrating, worry, separation anxiety (common in children)
With anxiety and depressed mood: combination of symptoms from both subtypes above
With disturbance of conduct: acting destructive, reckless behavior, rebellious
With mixed disturbance of emotions and conduct: combination of symptoms from both subtypes above
Unspecified: symptoms that do not fall into above subtypes; often include physical symptoms and withdrawal from everyday activities

Risk factors
Those exposed to repeated trauma are at greater risk, even if that trauma is in the past. Age can be a factor due to young children having fewer coping resources and because they are less likely to realize the consequences of a potential stressor.A stressor is generally an event of a serious, unusual nature that an individual or group of individuals experience. Adjustment disorders can come from a wide range of stressors that can be traumatic or relatively minor, like the loss of a girlfriend/boyfriend, a poor report card, or moving to a new neighborhood. It is thought that the more often the stressor occurs, the more likely it is to produce Adjustment disorder. The objective nature of the stressor is of secondary importance. A stressor gains its pathogenic potential when the patient perceives it as stressful. The identification of a causal stressor is necessary if a diagnosis of adjustment disorder is to be made.There are certain stressors that are more common in different age groups:Adulthood:

Marital conflict
Financial conflict
Health issues with oneself, partner, or dependent children
Personal tragedy such as death or personal loss
Loss of job or unstable employment conditions e.g., corporate takeover or redundancyAdolescence and childhood:

Family conflict or parental separation
School problems or changing schools
Sexuality issues
Death, illness, or trauma in the familyIn a study conducted from 1990 to 1994 on 89 psychiatric outpatient adolescents, 25% had attempted suicide in which 37.5% had misused alcohol, 87.5% displayed aggressive behaviour, 12.5% had learning difficulties, and 87.5% had anxiety symptoms.

Diagnosis
DSM-5 classification
The basis of the diagnosis is the presence of a precipitating stressor and a clinical evaluation of the possibility of symptom resolution on removal of the stressor due to the limitations in the criteria for diagnosing Adjustment disorder. In addition, the diagnosis of Adjustment disorder is less clear when patients are exposed to stressors long-term, because this type of exposure is associated with Adjustment disorder and major depressive disorder (MDD) and generalized anxiety disorder (GAD).Some signs and criteria used to establish a diagnosis are important. First, the symptoms must clearly follow a stressor. The symptoms should be more severe than would be expected. There should not appear to be other underlying disorders. The symptoms that are present are not part of a normal grieving for the death of family member or other loved one.Adjustment disorders have the ability to be self-limiting. Within five years of when they are originally diagnosed, approximately 20–50% go on to be diagnosed with psychiatric disorders that are more serious.

ICD-11 classification
International Statistical Classification of Diseases and Related Health Problems (ICD), assigns codes to classify diseases, symptoms, complaints, social behaviors, injuries, and such medical-related findings.
ICD-11 classifies Adjustment disorder (6B43) under "Disorders specifically associated with stress".

Treatment
Individuals with an adjustment disorder and depressive or anxiety symptoms may benefit from treatments usually used for depressive or anxiety disorders. The use of different therapies can be beneficial for any age group. There is also a list of medications that can be used to help people with adjustment disorder whose symptoms are too severe for therapy alone. If a person is considering taking medication, they should talk to their doctor.
Specific treatment is based on factors of each individual separately. These factors include but are not limited to age, severity of symptoms, type of adjustment disorder, and personal preference.Different ways to help with the disorder include:

Individual Psychotherapy
Family Therapy
Peer Group Therapy
Medication (used only when the symptoms are severe or with a doctors approval)In addition to professional help, parents and caregivers can help their children with their difficulty adjusting by:

offering encouragement to talk about their emotions
offering support and understanding
reassuring the child that their reactions are normal
involving the childs teachers to check on their progress in school
letting the child make simple decisions at home, such as what to eat for dinner or what show to watch on TV
having the child engage in a hobby or activity they enjoy

Criticism
Like many of the items in the DSM, adjustment disorder receives criticism from a minority of the professional community as well as those in semi-related professions outside the healthcare field. First, there has been criticism of its classification. It has been criticized for its lack of specificity of symptoms, behavioral parameters, and close links with environmental factors. Relatively little research has been done on this condition.An editorial in the British Journal of Psychiatry described adjustment disorder as being so "vague and all-encompassing… as to be useless," but it has been retained in the DSM-5 because of the belief that it serves a useful clinical purpose for clinicians seeking a temporary, mild, non-stigmatizing label, particularly for patients who need a diagnosis for insurance coverage of therapy.In the US military there has been concern about its diagnosis in active duty military personnel.

Adjustment Disorder and the COVID-19 pandemic
A study was conducted in Poland, during the first phase of the pandemic. The study used self-report surveys to measure the prevalence and severity of symptoms of adjustment disorder compared to PTSD, depression, and anxiety. The data was collected in the first quarantine period between March 25 to April 27, 2020.Results from the study
The current COVID-19 pandemic was a highly stressful event for 75% of the participants and the most powerful predictor of adjustment disorder.
49% reported an increase in adjustment disorder symptoms, which were more common among females and those without a full-time job. 14% of the sample met the criteria for a diagnosis of adjustment disorder.
A significant proportion of the sample was also positive for generalized anxiety (44%) and depression (26%): the presumptive diagnosis rate of PTSD was 2.4%

References
Further reading
First, Michael B., ed. (2014). "Differential Diagnosis by the Trees". DSM-5 Handbook of Differential Diagnosis (1st ed.). Arlington, VA: American Psychiatric Publishing </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 Relapsing polychondritis and can you explain it in depth? [/INST] Relapsing polychondritis is a multi-systemic condition characterized by repeated episodes of inflammation and deterioration of cartilage. The often painful disease can cause joint deformity and be life-threatening if the respiratory tract, heart valves, or blood vessels are affected. The exact mechanism is poorly understood, but it is thought to be related to an immune-mediated attack on particular proteins that are abundant in cartilage.
The diagnosis is reached on the basis of the symptoms and supported by investigations such as blood tests and sometimes other investigations. Treatment may involve symptomatic treatment with painkillers or anti-inflammatory medications, and more severe cases may require suppression of the immune system.

Signs and symptoms
Though any cartilage in the body may be affected in persons with relapsing polychondritis, in many cases the disease affects several areas while sparing others. The disease may be variable in its signs and symptoms, resulting in a difficult diagnosis which may leads to delayed recognition for several months, years or decades.
Joint symptoms are often one of the first signs of the disease with cartilage inflammation initially absent in nearly half the cases.

Associated diseases
There are several other overlapping diseases associated with RP, that should also be taken into account. About one-third of people with RP might be associated with other autoimmune diseases, vasculitides and hematologic disorders. Systemic vasculitis is the most common association with RP, followed by rheumatoid arthritis and systemic lupus erythematosus.
The following table displays the main diseases in association with RP.

Cartilage inflammation
Cartilage inflammation (technically known as chondritis) that is relapsing is very characteristic of the disease and is required for the diagnosis of RP. These recurrent episodes of inflammation over the course of the disease may result in breakdown and loss of cartilage. The signs and symptoms of cartilage inflammation in various parts of the body will be described first.

Ear
Inflammation of the cartilage of the ear is a specific symptom of the disease and affects most people. It is present in about 20% of persons with RP at presentation and in 90% at some point. Both ears are often affected but the inflammation may alternate between either ear during a relapse. It is characteristic for the entire outer part of the ear except the earlobe to be swollen, red, or less often purplish, warm and painful to light touch.The inflammation of the ear usually lasts a few days or more, rarely a few weeks, and then resolves spontaneously and recurs at various intervals. Because of the loss of cartilage, after several flares cauliflower ear deformity may result. The outer part of the ear may be either floppy or hardened by calcifications of the scar tissue that replaces the cartilage. These cauliflower ear deformities occur in about 10% of persons with RP.

Nose
The inflammation of the cartilage of the nose involves the bridge of the nose and is often less marked than the ears. Statistics show that this clinical manifestation is present in 15% of persons with RP and occurs at some point in 65% of persons with RP.Nasal obstruction is not a common feature. Atrophy may eventually develop secondarily during the disease, this appears gradual and is not easily noticed. This can result in collapse of the nasal septum with saddle-nose deformity, which is painless but irreversible.

Respiratory tract
Inflammation occurs in the laryngeal, tracheal and bronchial cartilages. Both of these sites are involved in 10% of persons with RP at presentation and 50% over the course of this autoimmune disease, and is more common among females.
The involvement of the laryngotracheobronchial cartilages may be severe and life-threatening; it causes one-third of all deaths among persons with RP.
Laryngeal chondritis is manifested as pain above the thyroid gland and, more importantly, as dysphonia with a hoarse voice or transient aphonia. Because this disease is relapsing, recurrent laryngeal inflammation may result in laryngomalacia or permanent laryngeal stenosis with inspiratory dyspnea that may require emergency tracheotomy as a temporary or permanent measure.Tracheobronchial involvement may or may not be accompanied with laryngeal chondritis and is potentially the most severe manifestation of RP.The symptoms consist of dyspnea, wheezing, a nonproductive cough, and recurrent, sometimes severe, lower respiratory tract infections.
Obstructive respiratory failure may develop as the result of either permanent tracheal or bronchial narrowing or chondromalacia with expiratory collapse of the tracheobronchial tree. Endoscopy, intubation, or tracheotomy has been shown to hasten death.

Ribs
Involvement of the rib cartilages results in costochondritis. Symptoms include chest wall pain or, less often, swelling of the involved cartilage. The involvement of the ribs is seen in 35% of persons with RP but is rarely the first symptom.

Other manifestations
Relapsing polychondritis may affect many different organ systems of the body.  At first, some people with the disease may have only nonspecific symptoms such as fever, weight loss, and malaise.

Joint
The second most common clinical finding of this disease is joint pain with or without arthritis, after chondritis.
All synovial joints may be affected.At presentation, around 33% of people have joint symptoms that involve Polyarthralgia and/or polyarthritis or oligoarthritis that affects various parts of the body and often appears to be episodic, asymmetric, migratory and non-deforming. The most common sites of involvement are the metacarpophalangeal joints, proximal interphalangeal joints and knees. After which is followed by the ankles, wrists, metatarsophalangeal joints and the elbows. Any involvement of the axial skeleton is considered to be very rare. Tests for rheumatoid factor are negative in affected persons with RP, unless there is a co-morbidity with RA.Less often it has been reported that persons may experience arthralgia, monoarthritis, or chronic polyarthritis that mimics rheumatoid arthritis, leading to a difficult diagnosis for this disease. The appearance of erosions and destruction, however, is exceedingly rare and this may point instead to rheumatoid arthritis as a cause.Diseases and inflammation of tendons have been reported in small numbers of people with RP. During the course of the disease, around 80% of people develop joint symptoms.

Eye
Involvement of the eye is rarely the initial symptom but develops in 60% of persons with RP. The most common forms of ocular involvement are usually mild and often consist of unilateral or bilateral episcleritis and/or scleritis, that is often anterior and could be lingering or relapsing. Scleritis that is necrotizing is found to be exceedingly rare. Less often, conjunctivitis occurs.
There are also other ocular manifestations that occur in persons with RP, these include keratoconjunctivitis sicca, peripheral keratitis (rarely with ulcerations), anterior uveitis, retinal vasculitis, proptosis, lid edema, keratoconus, retinopathy, iridocyclitis and ischemic optic neuritis that can lead to blindness.Cataract also is reported in relation to either the disease or to glucocorticoid exposure.

Neurological
The involvement of the peripheral or central nervous system is relatively rare and only occurs in 3% of persons affected with RP, and is sometimes seen in a relation with concomitant vasculitis.
The most common neurological manifestation are palsies of the cranial nerves V and VII. Also hemiplegia, ataxia, myelitis and polyneuropathy have been reported in scientific literature.
Very rare neurological manifestations include aseptic meningitis, meningoencephalitis, stroke, focal or generalized seizures and intracranial aneurysm.
Magnetic Resonance Imaging of the brain shows multifocal areas of enhancement consistent with cerebral vasculitis in some cases.

Kidney
The involvement of the kidney can be caused by primary renal parenchymal lesions, or an underlying vasculitis, or another associated autoimmune disease. Actual kidney involvement is quite rare, elevated creatinine levels are reported in approximately 10% of people with RP, and abnormalities in urinalysis in 26%. Involvement of the kidney often indicates a worse prognosis, with a 10-year survival rate of 30%.
The most common histopathologic finding is mild mesangial proliferation, that is followed by focal and segmental necrotizing glomerulonephritis with crescents. Other abnormalities that are found include glomerulosclerosis, IgA nephropathy and interstitial nephritis. Immunofluorescence studies most often reveal faint deposits of C3, IgG or IgM in the primarily mesangium.

Constitutional symptoms
These symptoms could consist of asthenia, fever, anorexia, and weight loss. They mostly occur during a severe disease flare.

Others
Skin and mucous membranes: 20 to 30% of people with relapsing polychondritis have skin involvement, including aphthous ulcers, genital ulcers, and a number of non-specific skin rashes including erythema nodosum, livedo reticularis, hives, and erythema multiforme.
Cardiovascular system: Relapsing polychrondritis may cause inflammation of the aorta. It can also cause leaky heart valves (aortic valve regurgitation in 4 to 10%, mitral valve regurgitation in 2%).

Causes
Relapsing polychondritis is an autoimmune disease in which the bodys immune system begins to attack and destroy the cartilage tissues in the body. It has been postulated that both cell-mediated immunity and humoral immunity are responsible.Reasons for disease onset are not known, but there is no evidence of a genetic predisposition to developing relapsing polychondritis. However, there are cases where multiple members of the same family have been diagnosed with this illness. Studies indicate that some genetic contribution to susceptibility is likely.

Diagnosis
There is no specific test for relapsing polychondritis.  Some people may exhibit abnormal lab results while others may have completely normal labs even during active flares.

Diagnostic criteria
There are several clinical criteria used to diagnose this disease. McAdam et al. introduced the clinical criteria for RP in 1976. These clinical criteria have later been expanded by Damiani et al. in 1979 and finally Michet et al. modified them in 1986. See the following table for these diagnostic clinical criteria and the number of conditions required for an official diagnosis.

Laboratory findings
Patients presenting with acute episodes often have high levels of inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein, ESR or CRP. Patients often have cartilage-specific antibodies present during acute relapsing polychondritis episodes. Antinuclear antibody reflexive panel, rheumatoid factor, and antiphospholipid antibodies are tests that may assist in the evaluation and diagnosis of autoimmune connective-tissue diseases.

Imaging studies
FDG positron emission tomography (PET) may be useful to detect the condition early. Other imaging studies including MRI, CT scans, and X-rays may reveal inflammation and/or damaged cartilage facilitating diagnosis.

Special tests
Biopsy
Biopsy of the cartilage tissue (for example, ear) may show tissue inflammation and destruction, and may help with the diagnosis. The Biopsy of cartilage in patients with relapsing polychondritis may demonstrate chondrolysis, chondritis, and perichondritis.

Pulmonary function tests
It is useful to do a full set of pulmonary function tests, including inspiratory and expiratory flow-volume loops. Patterns consistent with either extrathoracic or intrathoracic obstruction (or both) may occur in this disease. Pulmonary function tests (flow-volume loops) provide a useful noninvasive means of quantifying and following the degree of extrathoracic airway obstruction in relapsing polychondritis.

Differential diagnosis
A differential diagnosis should be taken into account with the following main RP manifestations.

Treatment
There are no prospective randomized controlled trials studying therapies for relapsing polychondritis. Evidence for efficacy of treatments is based on many case reports and series of small groups of patients. There are case reports that non-steroidal anti-inflammatories are effective for mild disease and that corticosteroids are effective for treatment of severe relapsing polychondritis. There are multiple case reports that dapsone is effective in doses from 25 mg/day to 200 mg/day. Corticosteroid-sparing medications such as azathioprine or methotrexate may be used to minimize steroid doses and limit the side effects of steroids.  For severe disease cyclophosphamide is often given in addition to high dose intravenous steroids.

Prognosis
Many individuals have mild symptoms, which recur infrequently, while others may have persistent problems that become debilitating or life-threatening.

Epidemiology
Relapsing polychondritis occurs as often in men as in women.  In a Mayo Clinic series, the annual incidence was about 3.5 cases per million. The highest incidence is between the ages of 40 and 50 years, but it may occur at any age.

History
In 1923, Rudolf Jaksch von Wartenhorst first discovered relapsing polychondritis while working in Prague and initially named it Polychondropathia.

His patient was a 32-year-old male brewer who presented with fever, asymmetric polyarthritis, and the ears and nose showed signs of swelling, deformity and were painful. Biopsy of nasal cartilage revealed loss of the cartilage matrix and a hyperplastic mucous
membrane. Jaksch von Wartenhorst considered this was an undescribed degenerative disorder of cartilage and named it Polychondropathia.
He even took his patients occupation into consideration, and related the cause to excessive alcohol intake.Since then, the disease has received many names. The following table shows the history of the nomenclature of relapsing polychondritis. The current name, Relapsing Polychondritis (RP), was introduced by Pearson and his colleagues in 1960 to emphasize the episodic course of the disease.

Research
There has been little research on neurological problems related to RP. If these cartilage structures get inflamed, they could press against nerves and cause a variety of problems that is seen in RP like peripheral neuropathy and many more.

References
Further reading
Sanders, Lisa (14 November 2021) [10 November 2021 (online)]. "A Doctor Asks Two Strange Questions That Reveal a Mysterious Disease". The New York Times Magazine. p. 22. Retrieved 10 November 2021.
Trentham DE, Le CH (July 1998) </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 Woolly hair nevus 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 Spinocerebellar ataxia type-13 and can you explain it in depth? [/INST] Spinocerebellar ataxia type 13 (SCA13) is a rare autosomal dominant disorder, which, like other types of SCA, is characterized by dysarthria, nystagmus, and ataxia of gait, stance and the limbs due to cerebellar dysfunction. Patients with SCA13 also tend to present with epilepsy, an inability to run, and increased reflexes. This cerebellar dysfunction is permanent and progressive. SCA13 is caused by mutations in KCNC3, a gene encoding a voltage-gated potassium channel KV3.3. There are two known mutations in this gene causative for SCA13. Unlike many other types of SCA, these are not polyglutamine expansions but, rather, point mutations resulting in channels with no current or altered kinetics.

Signs and symptoms
SCA13 is typified by early onset, mildly progressive cerebellar ataxia with accompanying dysarthria, mental retardation, and nystagmus </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 Subcutaneous emphysema and can you explain it in depth? [/INST] Subcutaneous emphysema (SCE, SE) occurs when gas or air accumulates and seeps under the skin, where normally no gas should be present. Subcutaneous refers to the subcutaneous tissue, and emphysema refers to trapped air pockets resembling the pneumatosis seen in pulmonary emphysema.  Since the air generally comes from the chest cavity, subcutaneous emphysema usually occurs around the upper torso, such as on the chest, neck, face, axillae and arms, where it is able to travel with little resistance along the loose connective tissue within the superficial fascia. Subcutaneous emphysema has a characteristic crackling-feel to the touch, a sensation that has been described as similar to touching warm Rice Krispies. This sensation of air under the skin is known as subcutaneous crepitation, a form of Crepitus.
Numerous etiologies of subcutaneous emphysema have been described. Pneumomediastinum was first recognized as a medical entity by Laennec, who reported it as a consequence of trauma in 1819. Later, in 1939, at The Johns Hopkins Hospital, Dr. Louis Hamman described it in postpartum woman; indeed, subcutaneous emphysema is sometimes known as Hammans syndrome. However, in some medical circles, it can instead be more commonly known as Macklins Syndrome after L. Macklin, in 1939, and M.T. and C.C. Macklin, in 1944, who cumulatively went on to describe the pathophysiology in more detail.Subcutaneous emphysema can result from puncture of parts of the respiratory or gastrointestinal systems.  Particularly in the chest and neck, air may become trapped as a result of penetrating trauma (e.g., gunshot wounds or stab wounds) or blunt trauma. Infection  (e.g., gas gangrene) can cause gas to be trapped in the subcutaneous tissues. Subcutaneous emphysema can be caused by medical procedures and medical conditions that cause the pressure in the alveoli of the lung to be higher than that in the tissues outside of them.  Its most common causes are pneumothorax or a chest tube that has become occluded by a blood clot or fibrinous material.  It can also occur spontaneously due to rupture of the alveoli, with dramatic presentation.  When the condition is caused by surgery it is called surgical emphysema. The term spontaneous subcutaneous emphysema is used when the cause is not clear.
Subcutaneous emphysema is not typically dangerous in and of itself, however it can be a symptom of very dangerous underlying conditions, such as pneumothorax.  Although the underlying conditions require treatment, subcutaneous emphysema usually does not; small amounts of air are reabsorbed by the body.  However, subcutaneous emphysema can be uncomfortable and may interfere with breathing, and is often treated by removing air from the tissues, for example by using large bore needles, skin incisions or subcutaneous catheterization.

Symptoms and signs
Signs and symptoms of spontaneous subcutaneous emphysema vary based on the cause, but it is often associated with swelling of the neck and chest pain, and may also involve sore throat, neck pain, difficulty swallowing, wheezing and difficulty breathing. Chest X-rays may show air in the mediastinum, the middle of the chest cavity. A significant case of subcutaneous emphysema is easy to detect by touching the overlying skin; it feels like tissue paper or Rice Krispies.  Touching the bubbles causes them to move and sometimes make a crackling noise.  The air bubbles, which are painless and feel like small nodules to the touch, may burst when the skin above them is palpated.  The tissues surrounding SCE are usually swollen.  When large amounts of air leak into the tissues, the face can swell considerably.  In cases of subcutaneous emphysema around the neck, there may be a feeling of fullness in the neck, and the sound of the voice may change. If SCE is particularly extreme around the neck and chest, the swelling can interfere with breathing. The air can travel to many parts of the body, including the abdomen and limbs, because there are no separations in the fatty tissue in the skin to prevent the air from moving.

Causes
Trauma
Conditions that cause subcutaneous emphysema may result from both blunt and penetrating trauma; SCE is often the result of a stabbing or gunshot wound.
Subcutaneous emphysema is often found in car accident victims because of the force of the crash.
Chest trauma, a major cause of subcutaneous emphysema, can cause air to enter the skin of the chest wall from the neck or lung. When the pleural membranes are punctured, as occurs in penetrating trauma of the chest, air may travel from the lung to the muscles and subcutaneous tissue of the chest wall.  When the alveoli of the lung are ruptured, as occurs in pulmonary laceration, air may travel beneath the visceral pleura (the membrane lining the lung), to the hilum of the lung, up to the trachea, to the neck and then to the chest wall. The condition may also occur when a fractured rib punctures a lung; in fact, 27% of patients who have rib fractures also have subcutaneous emphysema.  Rib fractures may tear the parietal pleura, the membrane lining the inside of chest wall, allowing air to escape into the subcutaneous tissues.Subcutaneous emphysema is frequently found in pneumothorax (air outside of the lung in the chest cavity) and may also result from air in the mediastinum, pneumopericardium (air in the pericardial cavity around the heart).  A tension pneumothorax, in which air builds up in the pleural cavity and exerts pressure on the organs within the chest, makes it more likely that air will enter the subcutaneous tissues through pleura torn by a broken rib.  When subcutaneous emphysema results from pneumothorax, air may enter tissues including those of the face, neck, chest, armpits, or abdomen.Pneumomediastinum can result from a number of events.  For example, foreign body aspiration, in which someone inhales an object, can cause pneumomediastinum (and lead to subcutaneous emphysema) by puncturing the airways or by increasing the pressure in the affected lung(s) enough to cause them to burst.Subcutaneous emphysema of the chest wall is commonly among the first indications that barotrauma, damage caused by excessive pressure, has occurred; it suggests that the lung was subjected to significant barotrauma. Thus the phenomenon may occur in diving injuries.Trauma to parts of the respiratory system other than the lungs, such as rupture of a bronchial tube, may also cause subcutaneous emphysema. Air may travel upward to the neck from a pneumomediastinum that results from a bronchial rupture, or downward from a torn trachea or larynx into the soft tissues of the chest. It may also occur with fractures of the facial bones, neoplasms, during asthma attacks, when the Heimlich maneuver is used, and during  childbirth.Injury with pneumatic tools, those that are driven by air, is also known to cause subcutaneous emphysema, even in extremities (the arms and legs).  It can also occur as a result of rupture of the esophagus; when it does, it is usually as a late sign.

Medical treatment
Subcutaneous emphysema is a common result of certain types of surgery; for example it is not unusual in chest surgery.  It may also occur from surgery around the esophagus, and is particularly likely in prolonged surgery. Other potential causes are positive pressure ventilation for any reason and by any technique, in which its occurrence is frequently unexpected. It may also occur as a result of oral surgery, laparoscopy, and cricothyrotomy.  In a pneumonectomy, in which an entire lung is removed, the remaining bronchial stump may leak air, a rare but very serious condition that leads to progressive subcutaneous emphysema. Air can leak out of the pleural space through an incision made for a thoracotomy to cause subcutaneous emphysema.  On infrequent occasions, the condition can result from dental surgery, usually due to use of high-speed tools that are air driven.  These cases result in usually painless swelling of the face and neck, with an immediate onset, the crepitus (crunching sound) typical of subcutaneous emphysema, and often with subcutaneous air visible on X-ray.One of the main causes of subcutaneous emphysema, along with pneumothorax, is an improperly functioning chest tube.  Thus subcutaneous emphysema is often a sign that something is wrong with a chest tube; it may be clogged, clamped, or out of place. The tube may need to be replaced, or, when large amounts of air are leaking, a new tube may be added.Since mechanical ventilation can worsen a pneumothorax, it can force air into the tissues; when subcutaneous emphysema occurs in a ventilated patient, it is an indication that the ventilation may have caused a pneumothorax. It is not unusual for subcutaneous emphysema to result from positive pressure ventilation.  Another possible cause is a ruptured trachea.  The trachea may be injured by tracheostomy or tracheal intubation; in cases of tracheal injury, large amounts of air can enter the subcutaneous space. An endotracheal tube can puncture the trachea or bronchi and cause subcutaneous emphysema.

Infection
Air can be trapped under the skin in necrotizing infections such as gangrene, occurring as a late sign in gas gangrene, of which it is the hallmark sign. Subcutaneous emphysema is also considered a hallmark of fournier gangrene. Symptoms of subcutaneous emphysema can result when infectious organisms produce gas by fermentation. When emphysema occurs due to infection, signs that the infection is systemic, i.e. that it has spread beyond the initial location, are also present.

Pathophysiology
Air is able to travel to the soft tissues of the neck from the mediastinum and the retroperitoneum (the space behind the abdominal cavity) because these areas are connected by fascial planes.  From the punctured lungs or airways, the air travels up the perivascular sheaths and into the mediastinum, from which it can enter the subcutaneous tissues.Spontaneous subcutaneous emphysema is thought to result from increased pressures in the lung that cause alveoli to rupture. In spontaneous subcutaneous emphysema, air travels from the ruptured alveoli into the interstitium and along the blood vessels of the lung, into the mediastinum and from there into the tissues of the neck or head.

Diagnosis
Significant cases of subcutaneous emphysema are easy to diagnose because of the characteristic signs of the condition. In some cases, the signs are subtle, making diagnosis more difficult. Medical imaging is used to diagnose the condition or confirm a diagnosis made using clinical signs. On a chest radiograph, subcutaneous emphysema may be seen as radiolucent striations in the pattern expected from the pectoralis major muscle group. Air in the subcutaneous tissues may interfere with radiography of the chest, potentially obscuring serious conditions such as pneumothorax. It can also reduce the effectiveness of chest ultrasound.  On the other hand, since subcutaneous emphysema may become apparent in chest X-rays before a pneumothorax does, its presence may be used to infer that of the latter injury. Subcutaneous emphysema can also be seen in CT scans, with the air pockets appearing as dark areas. CT scanning is so sensitive that it commonly makes it possible to find the exact spot from which air is entering the soft tissues.  In 1994, M.T. Macklin and C.C. Macklin published further insights into the pathophysiology of  spontaneous Macklins Syndrome occurring from a severe asthmatic attack.
The presence of subcutaneous emphysema in a person who appears quite ill and febrile after bout of vomiting followed by left chest pain is very suggestive of the diagnosis of Boerhaaves syndrome, which is a life-threatening emergency caused by rupture of the distal esophagus.
Subcutaneous emphysema can be a complication of CO2 insufflation with laparoscopic surgery.  A sudden rise in end-tidal CO2 following the initial rise that occurs with insufflation (first 15-30 min) should raise suspicion of subcutaneous emphysema. Of note, there are no changes in the pulse oximetry or airway pressure in subcutaneous emphysema, unlike in endobronchial intubation, capnothorax, pneumothorax, or CO2 embolism.

Treatment
Subcutaneous emphysema is usually benign. Most of the time, SCE itself does not need treatment (though the conditions from which it results may); however, if the amount of air is large, it can interfere with breathing and be uncomfortable. It occasionally progresses to a state "Massive Subcutaneous Emphysema" which is quite uncomfortable and requires surgical drainage. When the amount of air pushed out of the airways or lung becomes massive, usually due to positive pressure ventilation, the eyelids swell so much that the patient cannot see. Also the pressure of the air may impede the blood flow to the areolae of the breast and skin of the scrotum or labia. This can lead to necrosis of the skin in these areas. The latter are urgent situations requiring rapid, adequate decompression. Severe cases can compress the trachea and do require treatment.In severe cases of subcutaneous emphysema, catheters can be placed in the subcutaneous tissue to release the air. Small cuts, or "blow holes", may be made in the skin to release the gas.  When subcutaneous emphysema occurs due to pneumothorax, a chest tube is frequently used to control the latter; this eliminates the source of the air entering the subcutaneous space </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 Lymphoid leukemia and can you explain it in depth? [/INST] Lymphoid leukemias are a group of leukemias affecting circulating lymphocytes, a type of white blood cell. The lymphocytic leukemias are closely related to lymphomas of the lymphocytes, to the point that some of them are unitary disease entities that can be called by either name (for example, adult T-cell leukemia/lymphoma). Such diseases are all lymphoproliferative disorders. Most lymphoid leukemias involve a particular subtype of lymphocytes, the B cells.

Classification
Historically, they have been most commonly divided by the stage of maturation at which the clonal (neoplastic) lymphoid population stopped maturing:
Acute lymphoblastic leukemia
Chronic lymphocytic leukemiaHowever, the influential WHO Classification (published in 2001) emphasized a greater emphasis on cell lineage. To this end, lymphoid leukemias can also be divided by the type of cells affected:

B-cell leukemia
T-cell leukemia
NK-cell leukemiaThe most common type of lymphoid leukemia is B-cell chronic lymphocytic leukemia.

B-cell leukemias
B-cell leukemia describes several different types of lymphoid leukemia which affect B cells.

Other types include (with ICD-O code):

9826/3 – Acute lymphoblastic leukemia, mature B-cell type
9833/3 – B-cell prolymphocytic leukemia
9940/3 – Hairy cell leukemia

T-cell leukemias
T-cell leukemia describes several different types of lymphoid leukemias which affect T cells.The most common T-cell leukemia is precursor T-cell lymphoblastic leukemia. It causes 15% of acute leukemias in childhood, and also 40% of lymphomas in childhood. It is most common in adolescent males. Its morphology is identical to that of precursor B-cell lymphoblastic leukemia. Cell markers include TdT, CD2, CD7. It often presents as a mediastinal mass because of involvement of the thymus. It is highly associated with NOTCH1 mutations.Other types include:

Large granular lymphocytic leukemia
Adult T-cell leukemia/lymphoma
T-cell prolymphocytic leukemiaIn practice, it can be hard to distinguish T-cell leukemia from T-cell lymphoma, and they are often grouped together.

NK cell leukemia
Aggressive NK-cell leukemia (ANKL) is a lymphoid leukemia that is a deficiency NK cells. Not very much is known about this disease due to its rarity, but it is highly aggressive. Most patients will die within 2 years.

Diagnosis
The requirements for diagnosing ANKL are as follows:
Immature-looking NK cells
Certain immunophenotypes
Germline configuration genes: TCR-β and IgH
Restricted cytotoxicityThe T-cell receptor (TCR) is an important factor when ANKL is being diagnosed along with T-cell leukemia. The TCR gene transcripts are normally positive for ANKL.  Current Research is attempting to find the causation of ANKL. So far, the researchers have concluded that lineage of the T-cell receptor gene does not predict the behavior of the disease.

Treatment
ANKL is treated similarly to most B-cell lymphomas </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 Lichen nitidus 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 Glycine encephalopathy and can you explain it in depth? [/INST] Glycine encephalopathy  is a rare autosomal recessive disorder of glycine metabolism. After phenylketonuria, glycine encephalopathy is the second most common disorder of amino acid metabolism. The disease is caused by defects in the glycine cleavage system, an enzyme responsible for glycine catabolism. There are several forms of the disease, with varying severity of symptoms and time of onset. The symptoms are exclusively neurological in nature, and clinically this disorder is characterized by abnormally high levels of the amino acid glycine in bodily fluids and tissues, especially the cerebrospinal fluid.
Glycine encephalopathy is sometimes referred to as "nonketotic hyperglycinemia" (NKH), as a reference to the biochemical findings seen in patients with the disorder, and to distinguish it from the disorders that cause "ketotic hyperglycinemia" (seen in propionic acidemia and several other inherited metabolic disorders). To avoid confusion, the term "glycine encephalopathy" is often used, as this term more accurately describes the clinical symptoms of the disorder.

Signs and symptoms
It typically presents as a severe encephalopathy with myoclonic seizures, is rapidly progressive and eventually results in respiratory arrest. Standard evaluation for inborn errors of metabolism and other causes of this presentation does not reveal any abnormality (no acidosis, no hypoglycaemia, or hyperammonaemia and no other organ affected). Pronounced and sustained hiccups in an encephalopathic infant have been described as a typical observation in non-ketotic hyperglycinaemia.

Genetics
Glycine encephalopathy has an estimated incidence of 1 in 60,000, making it the second most common disorder of amino acid metabolism, after phenylketonuria. It is caused by a defect in the glycine cleavage system (GCS), which is made up of four protein subunits. Each of these four subunits is encoded by a separate gene. Defects in three of these four genes have been linked to glycine encephalopathy.: 790
There is a fourth unit in the complex, dihydrolipoamide dehydrogenase or GCSL. However, to date there have been no mutations in GCSL found to be associated with glycine encephalopathy.
A small percentage of affected individuals do not have detectable mutations in any of the three genes (listed above) that are typically associated with the disease. However, they still show defective glycine-cleavage enzymatic activity. It is thought that these patients may have mutations in the genes encoding one of the cofactors associated with the GCS complex.Defects in the GCS proteins can prevent the complex from functioning properly or can prevent the GCS complex from forming entirely. When the complex is unable to metabolize glycine properly, this causes excess glycine to build up to toxic levels in the bodys organs and tissues. Damage caused by elevated levels of glycine in the brain and cerebrospinal fluid is responsible for the characteristic seizures, breathing difficulties, movement disorders, and intellectual disability.This disorder is inherited in an autosomal recessive pattern. The term "autosomal" signifies that the gene associated with the disorder is located on an autosome. In an autosomal recessive inheritance pattern, two defective copies of the gene (one inherited from each parent) are required in order for a child to be born with the disorder. Therefore, each parent of an individual with an autosomal recessive disorder has at least one defective copy of the gene. With autosomal recessive disorders, individuals with only one copy of a defective gene (heterozygotes) are considered "carriers" for the disorder. Carriers usually do not show signs or symptoms of the disorder.

Pathophysiology
Glycine is the simplest amino acid, having no stereoisomers. It can act as a neurotransmitter in the brain, act as an inhibitor in the spinal cord and brain stem, while having excitatory effects in the cortex of the brain. Glycine is metabolized to final end products of ammonia and carbon dioxide through the glycine cleavage system (GCS), an enzyme complex made up of four protein subunits. Defects in these subunits can cause glycine encephalopathy, although some causes of the disease are still unknown. Normally, GCS shows its highest enzymatic activity in liver, brain and placental tissue. One of its main functions is to maintain normal glycine levels in the brain. Defects in GCS cause an increase of glycine concentration in blood plasma and cerebrospinal fluid. The exact pathophysiology of the disorder is not known, but it is considered likely that buildup of glycine in the brain is responsible for the symptoms.All forms of glycine encephalopathy show elevated levels of glycine in the plasma, as well as in cerebral spinal fluid (CSF).: 793   Glycine concentrations in the CSF of affected patients are typically more markedly elevated than in plasma, leading to a corresponding elevation in the ratio of glycine concentrations in the cerebral spinal fluid to that in the plasma. This ratio can also be slightly elevated in patients receiving valproic acid.: 811 Glycine encephalopathy (nonketotic hyperglycinemia, or NKH) should not be confused with other metabolic disorders that can produce elevated glycine levels. For example, certain inherited organic acidurias (aka organic acidemias) can produce elevated glycine in plasma and urine, although these disorders are not caused by defects in the glycine cleavage system, and they are not typically accompanied by corresponding elevations of glycine in cerebrospinal fluid (CSF). Glycine encephalopathy is unique in the fact that levels of glycine are disproportionately elevated in CSF (in addition to elevations in blood and urine), whereas CSF glycine levels are normal or near-normal in patients with inherited organic acidurias.

Glycine metabolism
Glycine is metabolized in the bodys cells to end products of carbon dioxide and ammonia. The glycine cleavage system, which is responsible for glycine metabolism in the mitochondria is made up of four protein subunits, the P-protein, H-protein, T-protein and L-protein.: 793

Diagnosis
Classification
There are several different forms of glycine encephalopathy, which can be distinguished by the age of onset, as well as the types and severity of symptoms. All forms of glycine encephalopathy present with only neurological symptoms, including intellectual disability (IQ scores below 20 are common), hypotonia, apneic seizures, and brain malformations.: 811 With the classical, or neonatal presentation of glycine encephalopathy, the infant is born after an unremarkable pregnancy, but presents with lethargy, hypotonia, apneic seizures and myoclonic jerks, which can progress to apnea requiring artificial ventilation, and often death. Apneic patients can regain spontaneous respiration in their second to third week of life. After recovery from the initial episode, patients have intractable seizures and profound intellectual disability, remaining developmentally delayed. Some mothers comment retrospectively that they noticed fetal rhythmic "hiccuping" episodes during pregnancy, most likely reflecting seizure episodes in utero. Patients with the infantile form of glycine encephalopathy do not show lethargy and coma in the neonatal period, but often have a history of hypotonia. They often have seizures, which can range in severity and responsiveness to treatment, and they are typically developmentally delayed </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 Prolonged labor and can you explain it in depth? [/INST] Prolonged labor is the inability of a woman to proceed with childbirth upon going into labor. Prolonged labor typically lasts over 20 hours for first time mothers, and over 14 hours for women that have already had children. Failure to progress can take place during two different phases; the latent phase and active phase of labor. The latent phase of labor can be emotionally tiring and cause fatigue, but it typically does not result in further problems. The active phase of labor, on the other hand, if prolonged, can result in long term complications.It is important that the vital signs of the woman and fetus are being monitored so preventive measures can be taken if prolonged labor begins. Women experiencing prolonged labor should be under supervision of a surgically equipped doctor. Prolonged labor is determined based on the information that is being collected regarding the strength and time between contractions. Medical teams track this data using intrauterine pressure catheter placement (IUPC) and continuous electronic fetal monitoring (EFM). IUPC is a straw that is inserted into the womb with a monitor that reads when contractions are coming and how strong they are. EFMs are used to track the fetal heart rate. If either devices indicate that vital signs are off and prolonged labor is beginning, it is important that the medical team begin discussing treatment and alternative options for delivery.
Prolonged labor can result from a variety of different issues, such as fetal malpresentation, issues with uterine contractions, cervical dystocia  or stenosis, and cephalopelvic disproportion. Both fetal malpresentation and cervical dystocia may result in obstructed labor. The cause of prolonged labor will determine the medical intervention that needs to take place. Medical professionals can either engage in preventive measures or turn to surgical methods of removing the fetus. If not handled properly or immediately treated, both the woman and the fetus can suffer a variety of long term complications, the most serious of which is death. There is no "quick fix" to prolonged labor, but there are preventive measures that can be taken, such as oxytocin infusions. In order to properly and safely deliver the baby, doctors will often intervene in child birth and conduct assisted vaginal delivery through the use of forceps or a vacuum extractor, or perform a Caesarean section.

Signs and symptoms
Symptoms include:
Labor extends beyond 18 hours
Dehydration and exhaustion of the mother
Pain around the back, sides, and thighs of the mother as a result of extreme muscle pressure
Severe pain when labor begins
Increased heart rate of the mother
Swollen large intestine on either side of the uterus as a result of gas build up
Uterus sensitivity
Ketosis
Distress of the fetus
Uterine ruptures

Complications
Distress to the fetus as a result of decreasing oxygen levels
Internal bleeding of the fetuss head (intracranial hemorrhage)
Higher chance of operative delivery
Risks of long-term injuries to the infant such as hypoxic-ischemic encephalopathy (HIE) or cerebral palsy
Infection of the uterus
Damage to the birth canal
Postpartum infection
Postpartum hemorrhage

Prolonged latent labor
The term describes labor that occurs very slowly. This does not necessarily mean that the woman or fetuss health is being compromised, but it is painful and is an important indication for doctors to pay attention to warning signs of prolonged labor.

Prolonged active labor
The phase of labor that extends into multiple hours (at least 14). The cervix usually dilates to over 4 cm before active labor occurs. When it first begins, it is encouraged that women stand up, walk around, and eat or drink. If failure to progress extends beyond this point, preventive measures need to be taken.

Causes
Fetal malpresentations
Fetal malpresentations are irregular positions of the crown of the fetal head in relation to the mothers pelvis (the fetus is in an abnormal position). Some important ways to manage fetal malpresentation are making rapid evaluations of the condition of the women pertaining to vital signs as well as the heart rate of the fetus. If fetal heart rate is abnormal, and if membranes have ruptured and amniotic fluid is atypical, it is important for medical professionals to determine the presenting part of the fetus and the position of the fetal head. Possible delivery methods, if this is the case, are compound presentation, vaginal breech delivery, or caesarean section for breech presentation depending upon the severity of the malposition.

Uterine contractions
This refers to uterine conditions that result in the uterus not having enough coordination or strength to dilate the cervix and push the baby through the birth canal. Issues with uterine contractions are the main cause of prolonged labor during the latent phase. Contractions may not occur as of a result of uterine tumors. In addition, if the uterus is stretched, usually due to previous pregnancies or multiple gestation, contractions may be difficult. Irregular or weak contractions can be fixed through stimulation of the uterus or oxytocin infusions. Lack of contractions may be caused by an overwhelming amount of painkillers or anesthesia, by which the medications should be discontinued. In this case, it is appropriate for assisted vaginal delivery to be conducted.

Cervical stenosis
Cervical dystocia, or stenosis, occurs when the cervix fails to dilate after a practical amount of time during positive uterine pains. The main problems in cervical dystocia is the lack of uterine inertia and cervical abnormalities, which prevent the cervix from fully dilating. It is very typical of patients that have hypopituitarism. There are many preexisting complications that may result in stenosis. Common conditions that lead to stenosis are tumors, a full bladder, large size of the infant, multiple pregnancies, delay in rupture of membranes, or problems with the cervix. High stress may interfere with the progression of pregnancy in cases such as these, leading to prolonged labor.

Cephalopelvic disproportion
Cephalopelvic disproportion is the issue that arises when the fetus body or head is too large to pass through the woman’s pelvis. Common conditions that lead to CPD are diabetes, multiple pregnancies, small or abnormally shaped pelvis, atypical fetal positions, hereditary factors, and first time pregnancies. Medical professionals can usually estimate if fetal size is too large based on ultrasounds, but they are not always entirely accurate. Doctors typically determine CPD when labor begins and the use of oxytocin is not effective. The safest way for delivery to take place when CPD is a factor is through Caesarean sections.

Prevention
If the woman is being closely monitored and begins to show signs of prolonged labor, medical professionals can take preventive measures to better the chances of delivery within 24 hours. A precise initial diagnosis of prolonged labor based on signs and symptoms is extremely important in applying proper precautionary treatment. Oxytocin infusions upon an initial amniotomy is typically used to move normal labor back on track. The application of oxytocin is only effective if administered on the basis of fetal distress. This treatment method only pertains to specific states of the fetus. If the baby is experiencing malpresentation, for example, the only safe and reliable method to proceed with childbirth is medical interference.

Management
In terms of medical care, preventive treatment or assisted delivery are typically the first options doctors consider. There is usually no quick fix to prolonged labor, especially if preventive measures do not revert the mother back to normal labor. Often, medical professionals resort to intervention methods. If the state of the fetus and mother are not especially serious or threatening to their health, doctors will perform assisted vaginal deliveries.

Assisted vaginal delivery
There are two different methods of assisted vaginal delivery that medical professionals typically utilize to aid in delivery in order to avoid surgical methods of fetal extraction. These procedures are only applied if a vaginal delivery has proven to still be safe to the woman and the baby, based on their vital signs. Assisted vaginal delivery is usually only used in the latent phase. Delivery during the active phase is usually associated with more complications for the woman. One approach to assisted vaginal delivery is the use of forceps. The forceps doctors use resemble two large salad spoons and are inserted into the cervix, around the babys head and help to guide it out of the birth canal. The other option is the use of vacuum extraction. Vacuums used have a cup on the end and are inserted into the cervix. The cup attaches to the fetuss head by suction and aids in guiding delivery. The choice between forceps and vacuum extraction is usually made by the doctor based on preference </s>