<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 Erotomania and can you explain it in depth? [/INST] Erotomania, also known as de Clérambaults Syndrome, named after French psychiatrist Gaëtan Gatian de Clérambault, is listed in the DSM-5 as a subtype of a delusional disorder. It is a relatively uncommon paranoid condition that is characterized by an individuals delusions of another person being infatuated with them. This disorder is most often seen (though not exclusively) in female patients who are shy, dependent and sexually inexperienced. The object of the delusion is typically a male who is unattainable due to high social or financial status, marriage or uninterest. The object of obsession may also be imaginary, deceased or someone the patient has never met. Delusions of reference are common, as the erotomanic individual often perceives that they are being sent messages from the secret admirer through innocuous events such as seeing license plates from specific states, but has no proof. Commonly, the onset of erotomania is sudden, and the course is chronic.

Presentation
Erotomania is more common in women, but men are more likely to exhibit violent and stalker-like behaviors. The core symptom of the disorder is that the individual holds an unshakable belief that another person is secretly in love with them. In some cases, the person with the condition may believe several people at once are "secret admirers". Most commonly, the individual has delusions of being loved by an unattainable person who is usually an acquaintance or someone the person has never met. They may also experience other types of delusions concurrently with erotomania, such as delusions of reference, wherein the perceived admirer secretly communicates their love by subtle methods such as body posture, arrangement of household objects, colors, license plates on cars from specific states, and other seemingly innocuous acts (or, if the person is a public figure, through clues in the media). Some delusions may be extreme such as the conception, birth, and kidnapping of children that never existed. The delusional objects may be replaced by others over time, and some may be chronic in fixed forms. Denial is characteristic with this disorder as the patients do not accept the fact that their object of delusion may be married, unavailable, or uninterested. The phantom lover may also be imaginary or deceased.
Erotomania has two forms: primary and secondary. Primary erotomania is also commonly referred to as de Clerambaults syndrome and Old Maids Insanity and it exists alone without comorbidities, has a sudden onset and a chronic outcome. The secondary form is found along with mental disorders like paranoid schizophrenia, often includes persecutory delusions, hallucinations, and grandiose ideas, and has a more gradual onset. Patients with a "fixed" condition are more seriously ill with constant delusions and are less responsive to treatment. These individuals are usually timid, dependent women that are often sexually inexperienced. In those with a more mild, recurrent condition, delusions are shorter-lived and the disorder can exist undetected by others for years. Problematic behaviors include actions like calling, sending letters and gifts, making unannounced house visits and other persistent stalking behaviors.

Cause
Erotomania may present as a primary mental disorder, or as a symptom of another psychiatric illness. With secondary erotomania, the erotomanic delusions are due to other mental disorders such as bipolar I disorder or schizophrenia. Symptoms may also be precipitated by alcoholism and the use of antidepressants. There may be a potential genetic component involved as family histories of first degree relatives with histories of psychiatric disorders are common. Sigmund Freud explained erotomania as a defense mechanism to ward off homosexual impulses which can lead to strong feelings of paranoia, denial, displacement and projection. Similarly, it has been explained as a way to cope with severe loneliness or ego deficit following a major loss. Erotomania may also be linked to unsatiated urges dealing with homosexuality or narcissism. Some research shows brain abnormalities occurring in patients with erotomania such as heightened temporal lobe asymmetry and greater volumes of lateral ventricles than those with no mental disorders.

Treatment
Prognosis differs from person to person, and the ideal treatment is not completely understood. Treatment for this disorder gains the best results when tailored specifically for each individual. To date, the mainline pharmacological treatments have been pimozide (a typical antipsychotic which was also approved for treating Tourettes Syndrome), and atypical antipsychotics like risperidone and clozapine. Non-pharmacologic treatments that have shown some degree of efficacy are electroconvulsive therapy (ECT), supportive psychotherapy, family and environment therapy, rehousing, risk management and treating underlying disorders in cases of secondary erotomania. ECT may provide temporary remission of delusional beliefs; antipsychotics help attenuate delusions and reduce agitation or associated dangerous behaviors, and SSRIs may be used to treat secondary depression. In delusional disorder there is some evidence that pimozide has superior efficacy compared with other antipsychotics. Psychosocial psychiatric interventions can enhance the quality of life through allowing some social functioning, and treating comorbid disorders is a priority for secondary erotomania. Family therapy, adjustment of socio-environmental factors, and replacing delusions with something positive may be beneficial to all. In most cases, harsh confrontation should be avoided. Structured risk assessment helps to manage risky behaviors in those individuals more likely to engage in actions that include violence, stalking, and crime. For particularly troublesome cases, neuroleptics and enforced separation may be moderately effective.

History
Early references to the condition can be found in the work of Hippocrates, Freud (1911), G.G. de Clérambault (1942), Erasistratus, Plutarch and Galen. Parisian physician, Bartholomy Pardoux (1545-1611) covered the topics of nymphomania and erotomania. In 1623, erotomania was referred to in a treatise by Jacques Ferrand (Maladie damour ou Mélancolie érotique) and has been called "erotic paranoia" and "erotic self-referent delusion" until the common usage of the terms erotomania and de Clérambaults syndrome. In 1971 and 1977, M.V. Seeman referred to the disorder as "phantom lover syndrome" and "psychotic erotic transference reaction and delusional loving". Emil Kraepelin and Bernard also wrote of erotomania and more recently, Winokur, Kendler, and Munro have contributed to knowledge on the disorder.G. E. Berrios and N. Kennedy outlined in Erotomania: a conceptual history (2002) several periods of history through which the definition of erotomania has changed considerably:

Classical times – early eighteenth century: General disease caused by unrequited love
Early eighteenth-beginning of nineteenth century: Practise of excess physical love (akin to nymphomania or satyriasis)
Early nineteenth century – beginning twentieth century: Unrequited love as a form of mental disease
Early twentieth century – present: Delusional belief of "being loved by someone else"In one case, erotomania was reported in a patient who had undergone surgery for a ruptured cerebral aneurysm.

Well-known cases
In his paper that described the syndrome, de Clérambault referenced a patient he had counselled who was obsessed with British monarch George V. She had stood outside Buckingham Palace for hours at a time, believing that the king was communicating his desire for her by moving the curtains.Parallels were drawn between this and a 2011 case where the body of a homeless American man was found on a secluded island in St James Park, within sight of Buckingham Palace. The man had sent hundreds of "strange and offensive" packages to Queen Elizabeth II over the previous fifteen years.The attempted assassination of United States president Ronald Reagan by John Hinckley Jr. has been reported to have been driven by an erotomaniac fixation on actress Jodie Foster, whom Hinckley was attempting to impress.
Late-night TV entertainer David Letterman and former astronaut Story Musgrave were both stalked by Margaret Mary Ray, who had erotomania.Michael David Barrett allegedly had erotomania, stalking ESPN correspondent Erin Andrews across the country, trying to see her and taking lewd videos.Many cases of obsession or stalking can be linked to erotomania but do not always necessarily go hand in hand.

In media
Nurse Betty (2000)
A main character in Orange Is the New Black, Lorna Morello, exhibits erotomanic behavior towards a man she has delusions of being engaged to.
He Loves Me... He Loves Me Not (2002)
A 2011 episode (Series 5, Episode 3) of the British TV series Lewis features a character with erotomania, referred to in the show as de Clérambaults syndrome.
Enduring Love (1997)
Criminal Minds Season 1, Episode 5: Broken Mirror.
Doc Martin Season 6, Episode 3: The Tameness of a Wolf

See also
Further reading
Remington GJ, Jeffries JJ (1994). "Erotomanic delusions and electroconvulsive therapy: a case series". J Clin Psychiatry. 55 (7): 306–8. PMID 8071292.
Anderson CA, Camp J, Filley CM (1998). "Erotomania after aneurysmal subarachnoid hemorrhage: case report and literature review". J Neuropsychiatry Clin Neurosci. 10 (3): 330–7. doi:10.1176/jnp.10.3.330. PMID 9706541.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Frank Bruni, Behind the Jokes, a Life Of Pain and Delusion; For Letterman Stalker, Mental Illness Was Family Curse and Scarring Legacy, New York Times, November 22, 1998
Foster, David & Levinson, Arlene. Suicide on a railroad track ends a celebrity-stalkers inner agony Archived 2011-06-14 at the Wayback Machine., Associated Press, October 11, 1998
Berrios GE, Kennedy N (2002). "Erotomania: a conceptual history". Hist Psychiatry. 13 (52): 381–400. doi:10.1177/0957154X0201305202. PMID 12638595. S2CID 24663481.
Helen K. Gediman (14 December 2016). Stalker, Hacker, Voyeur, Spy: A Psychoanalytic Study of Erotomania, Voyeurism, Surveillance, and Invasions of Privacy. Karnac Books. pp. 21–34. ISBN 978-1-78181-706-3.

References
Notes
Bibliography
Anderson CA, Camp J, Filley CM (1998). "Erotomania after aneurysmal subarachnoid hemorrhage: case report and literature review". J Neuropsychiatry Clin Neurosci. 10 (3): 330–70. doi:10.1176/jnp.10.3.330. PMID 9706541.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Berrios GE, Kennedy N (2002). "Erotomania: a conceptual history". History of Psychiatry. 13 (52): 381–400. doi:10.1177/0957154X0201305202. PMID 12638595. S2CID 24663481.
Helen K. Gediman (14 December 2016). Stalker, Hacker, Voyeur, Spy: A Psychoanalytic Study of Erotomania, Voyeurism, Surveillance, and Invasions of Privacy. Karnac Books. pp. 21–34. ISBN 978-1-78181-706-3.
Jordan H.W., Lockert E.W., Johnson-Warren M., Cabell C., Cooke T., Greer W., Howe G. (2006). "Erotomania revisisted: Thirty-four years later". Journal of the National Medical Association. 98 (5): 787–93. PMC 2569288. PMID 16749657.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Kelly B.D. (2005). "Erotomania: Epidemiology and management". CNS Drugs. 19 (8): 657–669. doi:10.2165/00023210-200519080-00002. PMID 16097848.
McDonnell, Margaux, and Mike McPadden. "9 Stalkers That Make Us Glad Were Not Famous." CrimeFeed, 12 Nov. 2013, crimefeed.com/2013/10/9-stalkers-that-make-us-glad-were-not-famous/.
Oliveira C., Alves S., Ferreira C., Agostinho C., Avelino M.J. (2016). "Erotomania-A review of De Clerambaults Syndrome". The Journal of the European Psychiatric Association. 33: S664.{{cite journal}}:  CS1 maint: multiple names: authors list (link)
Seeman M.V. (2016). "Erotomania and recommendations for treatment". Psychiatric Quarterly </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 Neuroglycopenia and can you explain it in depth? [/INST] Neuroglycopenia is a shortage of glucose (glycopenia) in the brain, usually due to hypoglycemia. Glycopenia affects the function of neurons, and alters brain function and behavior. Prolonged or recurrent neuroglycopenia can result in loss of consciousness, damage to the brain, and eventual death.

Signs and symptoms
Abnormal mentation, impaired judgment
Nonspecific dysphoria, anxiety, moodiness, depression, crying, fear of dying, suicidal thoughts
Negativism, irritability, belligerence, combativeness, rage
Personality change, emotional lability
Fatigue, weakness, apathy, lethargy, daydreaming
Confusion, amnesia, dizziness, delirium
Staring, "glassy" look, blurred vision, double vision
Automatic behavior
Difficulty speaking, slurred speech
Ataxia, incoordination, sometimes mistaken for "drunkenness"
Focal or general motor deficit, paralysis, hemiparesis
Paresthesia, headache
Stupor, coma, abnormal breathing
Generalized or focal seizures
Plasma glucose 20 mg/dL (1.1 mmol/L) or lowerNot all of the above manifestations occur in every case of hypoglycemia. There is no consistent order to the appearance of the symptoms. Specific manifestations vary by age and by the severity of the hypoglycemia. In older children and adults, moderately severe hypoglycemia can resemble mania, mental illness, drug intoxication, or drunkenness. In the elderly, hypoglycemia can produce focal stroke-like effects or a hard-to-define malaise. The symptoms of a single person do tend to be similar from episode to episode.
In the large majority of cases, hypoglycemia severe enough to cause seizures or unconsciousness can be reversed without obvious harm to the brain. Cases of death or permanent neurological damage occurring with a single episode have usually involved prolonged, untreated unconsciousness, interference with breathing, severe concurrent disease, or some other type of vulnerability. Nevertheless, brain damage or death has occasionally resulted from severe hypoglycemia.

Metabolic responses
Most neurons have the ability to use other fuels besides glucose (e.g. lactic acid, ketones) </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 Pneumoperitoneum and can you explain it in depth? [/INST] Pneumoperitoneum is pneumatosis (abnormal presence of air or other gas) in the peritoneal cavity, a potential space within the abdominal cavity. The most common cause is a perforated abdominal organ, generally from a perforated peptic ulcer, although any part of the bowel may perforate from a benign ulcer, tumor or abdominal trauma. A perforated appendix seldom causes a pneumoperitoneum.
Spontaneous pneumoperitoneum is a rare case that is not caused by an abdominal organ rupture. This is also called an idiopathic spontaneous pneumoperitoneum when the cause is not known.
In the mid-twentieth century, an "artificial" pneumoperitoneum was sometimes intentionally administered as a treatment for a hiatal hernia.  This was achieved by insufflating the abdomen with carbon dioxide.  The practice is currently used by surgical teams in order to aid in performing laparoscopic surgery.

Causes
Perforated duodenal ulcer – The most common cause of rupture in the abdomen. Especially of the anterior aspect of the first part of the duodenum.
Perforated peptic ulcer
Bowel obstruction
Ruptured diverticulum
Penetrating trauma
Ruptured inflammatory bowel disease (e.g., megacolon)
Necrotising enterocolitis/pneumatosis coli
Bowel cancer
Ischemic bowel
Steroids
After laparotomy
After laparoscopy
Breakdown of a surgical anastomosis
Bowel injury after endoscopy
Peritoneal dialysis (PD), although the prevalence of pneumoperitoneum is estimated to be less than 4% among people with PD in a more recent study in the United Kingdom.
Vaginal insufflation (air enters via the fallopian tubes; e.g., water-skiing, oral sex)
Colonic or peritoneal infection
From chest (e.g., bronchopleural fistula)
Non-invasive PAP (positive airway pressure) can force air down duodenum as well as down trachea.

Spontaneous pneumoperitoneum
A spontaneous pneumoperitoneum is a rare case that is not caused by an abdominal organ rupture. This is also called an idiopathic spontaneous pneumoperitoneum when the cause is not known </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 Larynx and can you explain it in depth? [/INST] The larynx (), commonly called the voice box, is an organ in the top of the neck involved in breathing, producing sound and protecting the trachea against food aspiration. The opening of larynx into pharynx known as the laryngeal inlet is about 4–5 centimeters in diameter. The larynx houses the vocal cords, and manipulates pitch and volume, which is essential for phonation. It is situated just below where the tract of the pharynx splits into the trachea and the esophagus. The word ʻlarynxʼ (plural ʻlaryngesʼ) comes from the Ancient Greek word  lárunx ʻlarynx, gullet, throat.ʼ

Structure
The triangle-shaped larynx consists largely of cartilages that are attached to one another, and to surrounding structures, by muscles or by fibrous and elastic tissue components. The larynx is lined by a ciliated columnar epithelium except for the vocal folds. The cavity of the larynx extends from its triangle-shaped inlet, to the epiglottis, and to the circular outlet at the lower border of the cricoid cartilage, where it is continuous with the lumen of the trachea. The mucous membrane lining the larynx forms two pairs of lateral folds that project inward into its cavity. The upper folds are called the vestibular folds. They are also sometimes called the false vocal cords for the rather obvious reason that they play no part in vocalization. The lower pair of folds are known as the vocal cords, which produce sounds needed for speech and other vocalizations. The slit-like space between the left and right vocal cords, called the rima glottidis, is the narrowest part of the larynx. The vocal cords and the rima glottidis are together designated as the glottis. The laryngeal cavity above the vestibular folds is called the vestibule. The very middle portion of the cavity between the vestibular folds and the vocal cords is the ventricle of the larynx, or laryngeal ventricle. The infraglottic cavity is the open space below the glottis.

Location
In adult humans, the larynx is found in the anterior neck at the level of the cervical vertebrae C3–C6. It connects the inferior part of the pharynx (hypopharynx) with the trachea. The laryngeal skeleton consists of nine cartilages: three single (epiglottic, thyroid and cricoid) and three paired (arytenoid, corniculate, and cuneiform). The hyoid bone is not part of the larynx, though the larynx is suspended from the hyoid. The larynx extends vertically from the tip of the epiglottis to the inferior border of the cricoid cartilage. Its interior can be divided in supraglottis, glottis and subglottis.

Cartilages
There are nine cartilages, three unpaired and three paired (3 pairs=6), that support the mammalian larynx and form its skeleton.
Unpaired cartilages:

Thyroid cartilage: This forms the Adams apple (also called the laryngeal prominence). It is usually larger in males than in females. The thyrohyoid membrane is a ligament associated with the thyroid cartilage that connects it with the hyoid bone. It supports the front portion of the larynx.
Cricoid cartilage: A ring of hyaline cartilage that forms the inferior wall of the larynx. It is attached to the top of the trachea. The median cricothyroid ligament connects the cricoid cartilage to the thyroid cartilage.
Epiglottis: A large, spoon-shaped piece of elastic cartilage. During swallowing, the pharynx and larynx rise. Elevation of the pharynx widens it to receive food and drink; elevation of the larynx causes the epiglottis to move down and form a lid over the glottis, closing it off.Paired cartilages:

Arytenoid cartilages: Of the paired cartilages, the arytenoid cartilages are the most important because they influence the position and tension of the vocal cords. These are triangular pieces of mostly hyaline cartilage located at the posterosuperior border of the cricoid cartilage.
Corniculate cartilages: Horn-shaped pieces of elastic cartilage located at the apex of each arytenoid cartilage.
Cuneiform cartilages: Club-shaped pieces of elastic cartilage located anterior to the corniculate cartilages.

Muscles
The muscles of the larynx are divided into intrinsic and extrinsic muscles. The extrinsic muscles act on the region and pass between the larynx and parts around it but have their origin elsewhere; the intrinsic muscles are confined entirely within the larynx and have their origin and insertion there.The intrinsic muscles are divided into respiratory and the phonatory muscles (the muscles of phonation). The respiratory muscles move the vocal cords apart and serve breathing. The phonatory muscles move the vocal cords together and serve the production of voice. The main respiratory muscles are the posterior cricoarytenoid muscles. The phonatory muscles are divided into adductors (lateral cricoarytenoid muscles, arytenoid muscles) and tensors (cricothyroid muscles, thyroarytenoid muscles).

Intrinsic
The intrinsic laryngeal muscles are responsible for controlling sound production.

Cricothyroid muscle lengthen and tense the vocal cords.
Posterior cricoarytenoid muscles abduct and externally rotate the arytenoid cartilages, resulting in abducted vocal cords.
Lateral cricoarytenoid muscles adduct and internally rotate the arytenoid cartilages, increase medial compression.
Transverse arytenoid muscle adduct the arytenoid cartilages, resulting in adducted vocal cords.
Oblique arytenoid muscles narrow the laryngeal inlet by constricting the distance between the arytenoid cartilages.
Thyroarytenoid muscles narrow the laryngeal inlet, shortening the vocal cords, and lowering voice pitch. The internal thyroarytenoid is the portion of the thyroarytenoid that vibrates to produce sound.Notably the only muscle capable of separating the vocal cords for normal breathing is the posterior cricoarytenoid.  If this muscle is incapacitated on both sides, the inability to pull the vocal cords apart (abduct) will cause difficulty breathing. Bilateral injury to the recurrent laryngeal nerve would cause this condition.  It is also worth noting that all muscles are innervated by the recurrent laryngeal branch of the vagus except the cricothyroid muscle, which is innervated by the external laryngeal branch of the superior laryngeal nerve (a branch of the vagus).
Additionally, intrinsic laryngeal muscles present a constitutive Ca2+-buffering profile that predicts their better ability to handle calcium changes in comparison to other muscles. This profile is in agreement with their function as very fast muscles with a well-developed capacity for prolonged work. Studies suggests that mechanisms involved in the prompt sequestering of Ca2+ (sarcoplasmic reticulum Ca2+-reuptake proteins, plasma membrane pumps, and cytosolic Ca2+-buffering proteins) are particularly elevated in laryngeal muscles, indicating their importance for the myofiber function and protection against disease, such as Duchenne muscular dystrophy. Furthermore, different levels of Orai1 in rat intrinsic laryngeal muscles and extraocular muscles over the limb muscle suggests a role for store operated calcium entry channels in those muscles functional properties and signaling mechanisms.

Extrinsic
The extrinsic laryngeal muscles support and position the larynx within the mid-cervical cereal region.
thumb|Extrinsic laryngeal muscles

Sternothyroid muscles depress the larynx. (Innervated by ansa cervicalis)
Omohyoid muscles depress the larynx. (Ansa cervicalis)
Sternohyoid muscles depress the larynx. (Ansa cervicalis)
Inferior constrictor muscles. (CN X)
Thyrohyoid muscles elevates the larynx. (C1)
Digastric elevates the larynx. (CN V3, CN VII)
Stylohyoid elevates the larynx. (CN VII)
Mylohyoid elevates the larynx. (CN V3)
Geniohyoid elevates the larynx. (C1)
Hyoglossus elevates the larynx. (CN XII)
Genioglossus elevates the larynx. (CN XII)

Nerve supply
The larynx is innervated by branches of the vagus nerve on each side. Sensory innervation to the glottis and laryngeal vestibule is by the internal branch of the superior laryngeal nerve. The external branch of the superior laryngeal nerve innervates the cricothyroid muscle.  Motor innervation to all other muscles of the larynx and sensory innervation to the subglottis is by the recurrent laryngeal nerve. While the sensory input described above is (general) visceral sensation (diffuse, poorly localized), the vocal cords also receives general somatic sensory innervation (proprioceptive and touch) by the superior laryngeal nerve.
Injury to the external branch of the superior laryngeal nerve causes weakened phonation because the vocal cords cannot be tightened. Injury to one of the recurrent laryngeal nerves produces hoarseness, if both are damaged the voice may or may not be preserved, but breathing becomes difficult.

Development
In newborn infants, the larynx is initially at the level of the C2–C3 vertebrae, and is further forward and higher relative to its position in the adult body. The larynx descends as the child grows.

Laryngeal cavity
The laryngeal cavity (cavity of the larynx) extends from the laryngeal inlet downwards to the lower border of the cricoid cartilage where it is continuous with that of the trachea.It is divided into two parts by the projection of the vocal folds, between which is a narrow triangular opening, the rima glottidis.
The portion of the cavity of the larynx above the vocal folds is called the laryngeal vestibule; it is wide and triangular in shape, its base or anterior wall presenting, however, about its center the backward projection of the tubercle of the epiglottis.
It contains the vestibular folds, and between these and the vocal folds are the laryngeal ventricles.
The portion below the vocal folds is called the infraglottic cavity. It is at first of an elliptical form, but lower down it widens out, assumes a circular form, and is continuous with the tube of the trachea.

Function
Sound generation
Sound is generated in the larynx, and that is where pitch and volume are manipulated. The strength of expiration from the lungs also contributes to loudness.
Manipulation of the larynx is used to generate a source sound with a particular fundamental frequency, or pitch.  This source sound is altered as it travels through the vocal tract, configured differently based on the position of the tongue, lips, mouth, and pharynx.  The process of altering a source sound as it passes through the filter of the vocal tract creates the many different vowel and consonant sounds of the worlds languages as well as tone, certain realizations of stress and other types of linguistic prosody. The larynx also has a similar function to the lungs in creating pressure differences required for sound production; a constricted larynx can be raised or lowered affecting the volume of the oral cavity as necessary in glottalic consonants.
The vocal cords can be held close together (by adducting the arytenoid cartilages) so that they vibrate (see phonation). The muscles attached to the arytenoid cartilages control the degree of opening. Vocal cord length and tension can be controlled by rocking the thyroid cartilage forward and backward on the cricoid cartilage (either directly by contracting the cricothyroids or indirectly by changing the vertical position of the larynx), by manipulating the tension of the muscles within the vocal cords, and by moving the arytenoids forward or backward. This causes the pitch produced during phonation to rise or fall. In most males the vocal cords are longer and have a greater mass than most females vocal cords, producing a lower pitch.
The vocal apparatus consists of two pairs of folds, the vestibular folds (false vocal cords) and the true vocal cords. The vestibular folds are covered by respiratory epithelium, while the vocal cords are covered by stratified squamous epithelium. The vestibular folds are not responsible for sound production, but rather for resonance. The exceptions to this are found in Tibetan chanting and Kargyraa, a style of Tuvan throat singing. Both make use of the vestibular folds to create an undertone. These false vocal cords do not contain muscle, while the true vocal cords do have skeletal muscle.

Other
The most important role of the larynx is its protective function, the prevention of foreign objects from entering the lungs by coughing and other reflexive actions.  A cough is initiated by a deep inhalation through the vocal cords, followed by the elevation of the larynx and the tight adduction (closing) of the vocal cords.  The forced expiration that follows, assisted by tissue recoil and the muscles of expiration, blows the vocal cords apart, and the high pressure expels the irritating object out of the throat.  Throat clearing is less violent than coughing, but is a similar increased respiratory effort countered by the tightening of the laryngeal musculature.  Both coughing and throat clearing are predictable and necessary actions because they clear the respiratory passageway, but both place the vocal cords under significant strain.Another important role of the larynx is abdominal fixation, a kind of Valsalva maneuver in which the lungs are filled with air in order to stiffen the thorax so that forces applied for lifting can be translated down to the legs.  This is achieved by a deep inhalation followed by the adduction of the vocal cords.  Grunting while lifting heavy objects is the result of some air escaping through the adducted vocal cords ready for phonation.Abduction of the vocal cords is important during physical exertion.  The vocal cords are separated by about 8 mm (0.31 in) during normal respiration, but this width is doubled during forced respiration.During swallowing, elevation of the posterior portion of the tongue levers (inverts) the epiglottis over the glottis opening to prevent swallowed material from entering the larynx which leads to the lungs, and provides a path for a food or liquid bolus to "slide" into the esophagus; the hyo-laryngeal complex is also pulled upwards to assist this process. Stimulation of the larynx by aspirated food or liquid produces a strong cough reflex to protect the lungs.
In addition, intrinsic laryngeal muscles are spared from some muscle wasting disorders, such as Duchenne muscular dystrophy,  may facilitate the development of novel strategies for the prevention and treatment of muscle wasting in a variety of clinical scenarios. ILM have a calcium regulation system profile suggestive of a better ability to handle calcium changes in comparison to other muscles, and this may provide a mechanistic insight for their unique pathophysiological properties

Clinical significance
Disorders
There are several things that can cause a larynx to not function properly. Some symptoms are hoarseness, loss of voice, pain in the throat or ears, and breathing difficulties.

Acute laryngitis is the sudden inflammation and swelling of the larynx. It is caused by the common cold or by excessive shouting. It is not serious. Chronic laryngitis is caused by smoking, dust, frequent yelling, or prolonged exposure to polluted air. It is much more serious than acute laryngitis.
Presbylarynx is a condition in which age-related atrophy of the soft tissues of the larynx results in weak voice and restricted vocal range and stamina. Bowing of the anterior portion of the vocal colds is found on laryngoscopy.
Ulcers may be caused by the prolonged presence of an endotracheal tube.
Polyps and vocal cord nodules are small bumps caused by prolonged exposure to tobacco smoke and vocal misuse, respectively.
Two related types of cancer of the larynx, namely squamous cell carcinoma and verrucous carcinoma, are strongly associated with repeated exposure to cigarette smoke and alcohol.
Vocal cord paresis is weakness of one or both vocal cords that can greatly impact daily life.
Idiopathic laryngeal spasm.
Laryngopharyngeal reflux is a condition in which acid from the stomach irritates and burns the larynx. Similar damage can occur with gastroesophageal reflux disease (GERD).
Laryngomalacia is a very common condition of infancy, in which the soft, immature cartilage of the upper larynx collapses inward during inhalation, causing airway obstruction.
Laryngeal perichondritis, the inflammation of the perichondrium of laryngeal cartilages, causing airway obstruction.
Laryngeal paralysis is a condition seen in some mammals (including dogs) in which the larynx no longer opens as wide as required for the passage of air, and impedes respiration. In mild cases it can lead to exaggerated or "raspy" breathing or panting, and in serious cases can pose a considerable need for treatment.
Duchenne muscular dystrophy, intrinsic laryngeal muscles (ILM) are spared from the lack of dystrophin and may serve as a useful model to study the mechanisms of muscle sparing in neuromuscular diseases. Dystrophic ILM presented a significant increase in the expression of calcium-binding proteins. The increase of calcium-binding proteins in dystrophic ILM may permit better maintenance of calcium homeostasis, with the consequent absence of myonecrosis. The results further support the concept that abnormal calcium buffering is involved in these neuromuscular diseases.

Treatments
Patients who have lost the use of their larynx are typically prescribed the use of an electrolarynx device.  Larynx transplants are a rare procedure.  The worlds first successful operation took place in 1998 at the Cleveland Clinic, and the second took place in October 2010 at the University of California Davis Medical Center in Sacramento.

Other animals
Pioneering work on the structure and evolution of the larynx was carried out in the 1920s by the British comparative anatomist Victor Negus, culminating in his monumental work The Mechanism of the Larynx (1929). Negus, however, pointed out that the descent of the larynx reflected the reshaping and descent of the human tongue into the pharynx. This process is not complete until age six to eight years </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 Hallermann–Streiff syndrome and can you explain it in depth? [/INST] Hallermann–Streiff syndrome is a congenital disorder that affects growth, cranial development, hair-growth, and dental development. There are fewer than 200 people with the syndrome worldwide. One notable organization that is supporting people with Hallermann–Streiff syndrome is the Germany-based "Schattenkinder e.V".

Presentation
Patients with this syndrome are shorter than the average person and may not develop hair in many places, including in the facial, leg and pubic areas. Patients also have eye problems including reduced eye size, bilateral cataracts and glaucoma. The syndrome can be associated with sleep apnea. The physical characteristics of the syndrome can result in difficult intubation by medical professionals. Intelligence is usually normal.

Cause
The genetic cause of Hallermann–Streiff syndrome has not been conclusively determined. It is most likely due to a de novo mutation, and it may be associated with the GJA1 gene.

Diagnosis
Diagnosis is based on the physical characteristics and symptoms </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 Portal vein thrombosis and can you explain it in depth? [/INST] Portal vein thrombosis (PVT) is a vascular disease of the liver that occurs when a blood clot occurs in the hepatic portal vein, which can lead to increased pressure in the portal vein system and reduced blood supply to the liver. The mortality rate is approximately 1 in 10.An equivalent clot in the vasculature that exits the liver carrying deoxygenated blood to the right atrium via the inferior vena cava, is known as hepatic vein thrombosis or Budd-Chiari syndrome.

Signs and symptoms
Portal vein thrombosis causes upper abdominal pain, possibly accompanied by nausea and an enlarged liver and/or spleen; the abdomen may be filled with fluid (ascites). A persistent fever may result from the generalized inflammation. While abdominal pain may come and go if the thrombus forms suddenly, long-standing clot build-up can also develop without causing symptoms, leading to portal hypertension before it is diagnosed.Other symptoms can develop based on the cause. For example, if portal vein thrombosis develops due to liver cirrhosis, bleeding or other signs of liver disease may be present. If portal vein thrombosis develops due to pylephlebitis, signs of infection such as fever, chills, or night sweats may be present.

Causes
Slowed blood flow due to underlying cirrhosis or congestive heart failure is often implicated. The prevalence of PVT in patients with cirrhosis is unclear, with a wide variety of incidence claimed by various researchers (estimated to be 1 in 100 by some while others believe it affects nearly 1 in 4).Thrombophilia (including inherited conditions such as factor V Leiden deficiency, protein C or S deficiency, or antiphospholipid antibody syndrome) is another common cause. Nearly one-third of patients have a myeloproliferative disorder (e.g. polycythemia vera or primary thrombocytosis), most commonly due to a Janus kinase 2 (JAK2) gene mutation. Oral contraceptive use or pregnancy are other non-inherited tendencies for thrombosis.Alternatively, the portal vein may be injured as a result of pancreatitis, diverticulitis, cholangiocarcinoma, hepatocellular carcinoma (HCC), or abdominal surgery/trauma. Red flags for cancerous growth as a cause are elevated alpha fetoprotein levels, portal vein diameter greater than 2.3 cm, pulsatility on Doppler ultrasound imaging, or hyperintense hepatic arterial phase (HAP) on CT scan with contrast.PVT is also a known complication of surgical removal of the spleen. During the last several years, myeloproliferative neoplasms (MPNs) have emerged as a leading systemic cause of splanchnic vein thromboses (which include PVT).

Mechanism
The main portal vein is formed by the union of the splenic vein and superior mesenteric vein (SMV). It is responsible for approximately three-fourths of the liver’s blood flow, transported from much of the gastrointestinal system as well as the pancreas, gallbladder, and spleen. Cirrhosis alters bleeding pathways thus patients are simultaneously at risk of uncontrolled bleeding and forming clots. A long-standing hindrance in flow as in chronic PVT, also known as portal cavernoma, can cause an increase in the hepatic venous pressure gradient (portal hypertension) and increased blood flow through subsidiary veins. This may lead to ascites or bleeding from varices.An infected thrombus may become septic, known as pylephlebitis; if blood cultures are positive for growth at this time, the most common organism is Bacteroides.

Diagnosis
The diagnosis of portal vein thrombosis is usually made with imaging confirming a clot in the portal vein; ultrasound is the least invasive method and the addition of Doppler technique shows a filling defect in blood flow </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 Coronary occlusion 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 Visual agnosia and can you explain it in depth? [/INST] Visual agnosia is an impairment in recognition of visually presented objects. It is not due to a deficit in vision (acuity, visual field, and scanning), language, memory, or intellect. While cortical blindness results from lesions to primary visual cortex, visual agnosia is often due to damage to more anterior cortex such as the posterior occipital and/or temporal lobe(s) in the brain.[2] There are two types of visual agnosia: apperceptive agnosia and associative agnosia.
Recognition of visual objects occurs at two primary levels. At an apperceptive level, the features of the visual information from the retina are put together to form a perceptual representation of an object. At an associative level, the meaning of an object is attached to the perceptual representation and the object is identified. If a person is unable to recognize objects because they cannot perceive correct forms of the objects, although their knowledge of the objects is intact (i.e. they do not have anomia), they have apperceptive agnosia. If a person correctly perceives the forms and has knowledge of the objects, but cannot identify the objects, they have associative agnosia.

Symptoms and signs
While most cases of visual agnosia are seen in older adults who have experienced extensive brain damage, there are also cases of young children with less brain damage during developmental years acquiring the symptoms. Commonly, visual agnosia presents as an inability to recognize an object in the absence of other explanations, such as blindness or partial blindness, anomia, memory loss, etc.. Other common manifestations of visual agnosia that are generally tested for include difficulty identifying objects that look similar in shape, difficulty with identifying line drawings of objects, and recognizing objects that are shown from less common views, such as a horse from a top-down view.Within any given patient, a variety of symptoms can occur, and the impairment of ability is not only binary but can range in severity. For example, Patient SM is a prosopagnosic with a unilateral lesion to left extrastriate cortex due to an accident in his twenties who displays behavior similar to congenital prosopagnosia. Although he can recognize facial features and emotions – indeed he sometimes uses a standout feature to recognize a face – face recognition is almost impossible purely from visual stimuli, even for faces of friends, family, and himself. The disorder also affects his memory of faces, both in storing new memories of faces and recalling stored memories.Nevertheless, it is important to note the reach of symptoms to other domains. SMs object recognition is similarly impaired though not entirely; when given line drawings to identify, he was able to give names of objects with properties similar to the drawing, implying that he is able to see the features of the drawing.  Similarly, copying a line drawing of a beach scene led to a simplified version of the drawing, though the main features were accounted for. For recognition of places, he is still impaired but familiar places are remembered and new places can be stored into memory.

Pathophysiology
Visual agnosia occurs after damage to visual association cortex or to parts of the ventral stream of vision, known as the "what pathway" of vision for its role in object recognition.  This occurs even when no damage has been done to the eyes or optic tract that leads visual information into the brain; in fact, visual agnosia occurs when symptoms cannot be explained by such damage. Damage to specific areas of the ventral stream impair the ability to recognize certain categories of visual information, such as the case of prospagnosia.  Patients with visual agnosia generally do not have damage to the dorsal stream of vision, known as the "where pathway" of vision because of its role determining objects position in space, allowing individuals with visual agnosia to show relatively normal visually guided behavior.For example, patient DF had lesions to the ventral surface that gave her apperceptive agnosia. One of the tasks she was tested on required her to place a card through a thin slot that could be rotated into all orientations. As an apperceptive agnosic, it would be expected that since she cannot recognize the slot, she should not be able to correctly place the card into the slot. Indeed, when she was asked to give the direction of the slot, her responses were no better than chance. Yet, when she was asked to place the card into the slot, her success was almost to the level of the controls. This implies that in the event of a ventral stream deficit, the dorsal stream can help with processing of special information to aid movement regardless of object recognition.More specifically, the lateral occipital complex appears to respond to many different types of objects.  Prosopagnosia (inability to recognize faces) is due to damage of the fusiform face area (FFA). An area in the fusiform gyrus of the temporal lobe that has been strongly associated with a role in facial recognition.  However, this area is not exclusive to faces; recognition of other objects of expertise are also processed in this area. The extrastriate body cortex (EBA) was found to be activated by photographs, silhouettes, or stick drawings of human bodies.  The parahippocampal place area (PPA) of the limbic cortex has been found to be activated by the sight of scenes and backgrounds.  Cerebral achromatopsia (the inability to discriminate between different hues) is caused by damage to the V8 area of the visual association cortex.The left hemisphere seems to play a critical role in recognizing the meaning of common objects.

Diagnosis
Classification
Broadly, visual agnosia is divided into apperceptive and associative visual agnosia.Apperceptive agnosia is failure of object recognition even when the basic visual functions (acuity, color, motion) and other mental processing, such as language and intelligence, are normal. The brain must correctly integrate features such as edges, light intensity, and color from sensory information to form a complete percept of an object. If a failure occurs during this process, a percept of an object is not fully formed and thus it cannot be recognized. Tasks requiring copying, matching, or drawing simple figures can distinguish the individuals with apperceptive agnosia because they cannot perform such tasks.Associative agnosia is an inability to identify objects even with apparent perception and knowledge of them. It involves a higher level of processing than apperceptive agnosia. Individuals with associative agnosia can copy or match simple figures, indicating that they can perceive objects correctly. They also display the knowledge of objects when tested with tactile or verbal information. However, when tested visually, they cannot name or describe common objects. This means that there is an impairment in associating the perception of objects with the stored knowledge of them.Although visual agnosia can be general, there exist many variants that impair recognition of specific types. These variants of visual agnosia include prosopagnosia (inability to recognize faces), pure word blindness (inability to recognize words, often called "agnosic alexia" or "pure alexia"), agnosias for colors (inability to differentiate colors), agnosias for the environment (inability to recognize landmarks or difficulty with spatial layout of an environment, i.e. topographagnosia) and simultanagnosia (inability to sort out multiple objects in a visual scene).

Categories and subtypes of visual agnosia
The two main categories of visual agnosia are:

Apperceptive visual agnosia, impaired object recognition. Individuals with apperceptive visual agnosia cannot form a whole percept of visual information.
Associative visual agnosia, impaired object identification. Individuals with associative agnosia cannot give a meaning to a formed percept. The percept is created, but it would have no meaning for individuals who have an associative agnosia.

Subtypes of associative visual agnosia
Achromatopsia, an inability to distinguish different colors.
Prosopagnosia, an inability to recognize human faces. Individuals with prosopagnosia know that they are looking at faces, but cannot recognize people by the sight of their face, even people whom they know well.
Simultagnosia, an inability to recognize multiple objects in a scene, including distinct objects within a spatial layout and distinguishing between "local" objects and "global" objects, such as being able to see a tree but not the forest or vice versa.
Topographagnosia, an inability to process the spatial layout of an environment, including landmark agnosia, difficulty recognizing buildings and places; difficulty building mental maps of a location or scene; and/or an inability to discern the orientation between objects in space.
Pure alexia, an inability to read.
Orientation agnosia: an inability to judge or determine orientation of objects.
Pantomime agnosia: an inability to understand pantomimes (gestures). It appears that the inferior cortical visual cortex is critical in recognizing pantomimes.

Patient CK
Background
Patient C.K. was born in 1961 in England and emigrated to Canada in 1980. In January 1988, C.K. sustained a head injury from a motor vehicle accident while out for a jog. Following the accident, C.K. experienced many cognitive issues, mood swings, poor memory, and temper outbursts. C.K. also had motor weakness on the left side and a left homonymous hemianopia. He recovered well, retaining normal intelligence and normal visual acuity. He was able to complete a masters degree in history, later working as a manager at a large corporation. Although his recovery was successful in other areas of cognition, C.K. still struggles to make sense of the visual world.

Associative visual agnosia
Magnetic resonance imaging (MRI) showed bilateral thinning of C.K.s occipital lobe which resulted in associative visual agnosia. Patients that have visual agnosia are unable to identify visually presented objects. They can identify these objects through other modalities such as touch but if presented visually, they are unable to. Associative agnosic patients cannot create a detailed representation of the visual world in their brains, they can only perceive elements of whole objects. They also cannot form associations between objects or assign meaning to objects.C.K. makes many mistakes when trying to identify objects. For example, he called an abacus "skewers on a kebab" and a badminton racquet a "fencers mask". A dart was a "feather duster" and a protractor was mistaken for a "cockpit". Despite this impairment in visual object recognition, C.K. retained many abilities such as drawing, visual imagery, and internal imagery. As a native of England, he was tasked with drawing England, marking London and where he was born. His accurate drawing of England is just one example of his excellent drawing abilities.As aforementioned, C.K. is able to identify parts of objects but cannot generate a whole representation. It should not be surprising then that his visual imagery for object size, shape, and color is intact. For example, when shown a picture of an animal, he can correctly answer questions such as "are the ears up or down?" and "is the tail long or short?" He can correctly identify colors, for example that the inside of a cantaloupe is orange. Finally, C.K. can generate internal images and perceive these generated objects. For example, Finke, Pinker, and Farah instructed C.K. to imagine a scenario where a B is rotated 90 degrees to the left, a triangle is put below, and the line in the middle is removed. C.K. can correctly identify this object as a heart by picturing this transformation in his head.

Evidence for double dissociation between face and object processing
Patient C.K. provided evidence for a double dissociation between face processing and visual object processing. Patients with prosopagnosia have damage to the Fusiform Face Area (FFA) and are unable to recognize upright faces. C.K. has no difficulty with face processing and matches the performance of controls when tasked with identifying upright famous faces. When shown inverted faces of famous people, C.K. performs significantly worse than controls. This is because processing inverted faces involves a piecemeal strategy. C.K.s performance is compared to patients with prosopagnosia who are impaired in face processing but perform well identifying inverted faces. This was the first evidence for a double dissociation between face and object processing suggesting a face-specific processing system.

In popular culture
A famous report on this condition is the title essay of Oliver Sacks book, The Man Who Mistook His Wife for a Hat.
The murder suspect in the Picket Fences episode "Strangers" supposedly had agnosia.
The patient in the House episode "Adverse Events" had agnosia.
In the graphic novel Preacher, the character Lorie has an extreme version of agnosia resulting from being born with a single eye. For example, she perceives Arseface, a man with severe facial deformities, as resembling a young James Dean.
Val Kilmers character has visual agnosia in the film At First Sight.
In "Folie à Deux", a fifth-season episode of The X-Files, Mulder succumbs to the same belief as telemarketer Gary Lambert, that his boss Greg Pincus is a monster who disguises his true appearance by means of hypnosis. Scully, although believing this notion preposterous, suggests that what Mulder describes is analogous to an induced visual agnosia.
The short story "Liking What You See: A Documentary" by Ted Chiang examines the cultural effects of a noninvasive medical procedure that induces a visual agnosia toward physical beauty.
In the manga and anime Odd Taxi, the main character Odokawa has agnosia, which causes him to see himself and everyone around him as an animal.

See also
References
Further reading
Cant JD, Goodale MA (March 2007). "Attention to form or surface properties modulates different regions of human occipitotemporal cortex". Cereb. Cortex. 17 (3): 713–31. doi:10.1093/cercor/bhk022. PMID 16648452.
Cavina-Pratesi C, Kentridge RW, Heywood CA, Milner AD (February 2010). "Separate processing of texture and form in the ventral stream: evidence from FMRI and visual agnosia". Cereb. Cortex. 20 (2): 433–46. doi:10.1093/cercor/bhp111. PMID 19478035.
Goodale MA; Milner AD (2004). Sight Unseen: An Exploration of Conscious and Unconscious Vision. Oxford UK: Oxford University Press. pp </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 Immature teratoma and can you explain it in depth? [/INST] An immature teratoma is a teratoma that contains anaplastic immature elements, and is often synonymous with malignant teratoma. A teratoma is a tumor of germ cell origin, containing tissues from more than one germ cell line, It can be ovarian or testicular in its origin. and are almost always benign. An immature teratoma is thus a very rare tumor, representing 1% of all teratomas, 1% of all ovarian cancers, and 35.6% of malignant ovarian germ cell tumors. It displays a specific age of incidence, occurring most frequently in the first two decades of life and almost never after menopause. Unlike a mature cystic teratoma, an immature teratoma contains immature or embryonic structures. It can coexist with mature cystic teratomas and can constitute of a combination of both adult and embryonic tissue. The most common symptoms noted are abdominal distension and masses. Prognosis and treatment options vary and largely depend on grade, stage and karyotype of the tumor itself.

Diagnosis
At CT and MRI, an immature teratoma possesses characteristic appearance. It is typically large (12–25 cm) and has prominent solid components with cystic elements. It is usually filled with lipid constituents and therefore demonstrates fat density at CT and MRI. Ultrasound appearance of an immature teratoma is nonspecific. It is highly heterogeneous with partially solid lesions and scattered calcifications.

Stage
Traditionally, comprehensive surgical staging is performed via exploratory laparotomy with cytologic washings, peritoneal biopsies, an omental assessment (either biopsy or rarely a full omentectomy), and both pelvic and aortic lymph node dissection. Laproscopy is often suggested as an alternative to surgically stage patients with immature teratoma.Ovarian cancer is staged using the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy via midline laparotomy, unilateral (or bilateral) salpingo-oophorectomy, pelvic (peritoneal) washings, assessment of retroperitoneal lymph nodes and/or appendectomy. The  AJCC staging system, identical to the FIGO staging system, describes the extent of tumor (T), the presence of absences of metastases to lymph nodes (N), the presence or absence of distant metastases (M).

Pathology
An immature teratoma contains varying compositions of adult and embryonic tissue. The most common embryonic component identified in immature teratomas is the neuroectoderm. Occasionally, tumors may present neuroepithelium that resemble neuroblasts. Tumors may also present embryonic components such as immature cartilage and skeletal muscle of mesodermal origin. Immature teratomas composed of embryonic endodermal derivatives are rare.Often a mature cystic teratoma is misdiagnosed as its immature counterpart due to the misinterpretation of mature neural tissue as immature. While mature neural cells have nuclei with uniformly dense chromatin and neither exhibit apoptotic or mitotic activity, immature neural cells have nuclei with vesicular chromatin and exhibit both apoptotic and mitotic activity. A recent study has identified the use of Oct-4 as a reliable biomarker for the diagnosis of highly malignant cases of immature teratomas.

Grade
Thurlbeck and Scully devised a grading system for “pure” immature teratomas on the basis of differentiation of the cellular elements of the tumor. The proportion of immature tissue elements defines the grade of immaturity. This was later modified by Norris et al. (1976), who added a quantitative aspect to the degree of immaturity.

Karyotype
An ovarian immature teratoma is karyotypically normal 46,XX or near-normal. Grade 1 or 2 tumors exhibit 46,XX normal karyotype, whereas grade 3 tumors show a variety of abnormal karyotypes. Though immature teratoma cells show a normal karyotype, there may still be detectable alterations in the gene level and that these aberrations may influence the stability of chromosome status.

Genetics
Ovarian immature teratomas have been classified as among the least mutated of all solid cancers. Immature teratomas originate from germ cells that undergo one of several meiotic failures, leading to a tumor genome with high levels of copy neutral loss of heterozygosity.

Prognosis
Though several studies have shown that size and stage of the primary tumor are related to survival, the grade of the tumor is the best determinant of prognosis prior to peritoneal spread. Once peritoneal spread has occurred, the grade of metastatic lesions or implants is the best determinant of prognosis. Multiple sections of the primary tumor and wide sampling of the implants are necessary to properly grade the tumor. In most cases, the implants are better differentiated than the primary tumors. Gliomatosis peritonei, a rare condition often associated with immature ovarian teratoma, is characterized by the presence of mature glial implants in the peritoneum. Yoon et al. (2012), reported that immature ovarian teratoma patients with Gliomatosis peritonei have larger tumors, more frequent recurrence and higher CA-125 levels than immature ovarian teratoma patients without gliomatosis peritonei.A high degree of immaturity in the primary tumor, one that corresponds with a grade 3 diagnosis is a sign of poor prognosis. Grade 3 tumors often display chromosomal abnormalities, also an indication of poor prognosis. Tumor grade is the most important factor for relapse in immature teratomas. Vicus et al. (2011), reported that grade 2 or 3 tumors are associated with a greater chance of relapse that can be fatal, predominantly within 2 years of diagnosis. Among grade 3 patients, the stage was significantly associated with relapse.In the past, survival rates were low for high-grade immature teratomas. Norris et al. (1976), reported a survival rate of 82% for patients with grade 1 tumors, 62% for grade 2 and 30% for grade 3 tumors. However, these results antedate the use of multi-agent chemotherapy. With the advent of multiagent chemotherapy after surgical resection, long-term remission and increased survival rates have been achieved. Pashankar et al. (2016), reported that the estimated 5-year overall survival rate for grade 3 Stage I and II disease was 91%  compared with 88% for grade 3, Stage III and IV disease.

Treatment
Histologic grade and fertility desires of the patient are key considerations in determining treatment options. In adult women postoperative adjuvant chemotherapy is standard except for stage I /grade 1 disease. In pediatric patients, surgery alone is standard.

Surgery
Since the occurrence of immature teratoma is very rarely bilateral, current standard of care of unilateral salpingo-oophorectomy with wide sampling of peritoneal implants. Total abdominal hysterectomy with bilateral salpingo-oophorectomy are not indicated as they do not influence outcomes. Fertility-sparing surgery in the form of unilateral salpingo-oophorectomy is the primary treatment modality in young patients. Some physicians recommend ovarian cystectomy alone, rather than a unilateral salpingo-oophorectomy for patients with an early stage low grade disease. Zhao et al. (2017), reported no significant differences in survival rates or post-operative fertility outcomes between the two treatment options. However, others caution against such an approach.

Chemotherapy
Norris et al </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 Oculofaciocardiodental syndrome 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 Folliculitis nares perforans 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 Pseudopterygium 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 Smokeless tobacco keratosis and can you explain it in depth? [/INST] Smokeless tobacco keratosis (STK) is a condition which develops on the oral mucosa (the lining of the mouth) in response to smokeless tobacco use. Generally it appears as a white patch, located at the point where the tobacco is held in the mouth. The condition usually disappears once the tobacco habit is stopped. It is associated with slightly increased risk of mouth cancer.
There are many types of smokeless tobacco. Chewing tobacco is shredded, air-cured tobacco with flavoring. Dipping tobacco ("moist snuff") is air or fire-cured, finely cut tobacco. Dry snuff is ground or pulverised tobacco leaves. In the Indian subcontinent, the Middle-East and South-East Asia, tobacco may be combined in a quid or paan with other ingredients such as betel leaf, Areca nut and slaked lime. Use of Areca nut is associated with oral submucous fibrosis. An appearance termed Betel chewers mucosa describes morsicatio buccarum with red-staining of mucosa due to betel quid ingredients. In Scandinavian countries, snus, a variant of dry snuff, is sometimes used. In the United States of America, the most common form of smokeless tobacco is dipping tobacco, although chewing tobacco is sometimes used by outdoor workers and dry snuff is common among females in the Southern states. The overall prevalence of smokeless tobacco use in the USA is about 4.5%, but this is higher in Mid-Western and Southern states.

Signs and symptoms
STK typically occurs in the buccal sulcus (inside the cheek) or the labial sulcus (between the lips and the teeth) and corresponds to the site where the tobacco is held in the mouth. It is painless.The appearance of the lesion is variable depending upon the type of tobacco used, and the frequency and duration of use. It takes about 1-5 years of smokeless tobacco use for the lesion to appear. Early lesions may appear as thin, translucent and granular or wrinkled mucosa. The later lesion may appear thicker, more opaquely white and hyperkeratotic with fissures and folds. Oral snuff causes more pronounced changes in the oral mucosa than tobacco chewing. Snuff dipping is associated more with verrucous keratosis.As well as the white changes of the oral mucosa, there may be gingival recession (receding gums) and staining of tooth roots in the area where the tobacco is held.

Diagnosis
Diagnosis is mainly clinical, based on the history and clinical appearance. The differential diagnosis includes other oral white lesions such as Leukoplakia, squamous cell carcinoma, oral candidiasis, lichen planus, white sponge nevus and contact stomatitis. In contrast to pseudomembraneous candidiasis, this white patch cannot be wiped off. Tissue biopsy is sometimes carried out to rule out other lesions, although biopsy is not routinely carried out for this condition.

Treatment
Apart from stopping the habit, no other treatment is indicated </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 Left posterior fascicular block 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 Laryngotracheitis 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 Hutchinsons sign 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 Adenocarcinoma of the lung and can you explain it in depth? [/INST] Adenocarcinoma of the lung is the most common type of lung cancer, and like other forms of lung cancer, it is characterized by distinct cellular and molecular features. It is classified as one of several non-small cell lung cancers (NSCLC), to distinguish it from small cell lung cancer which has a different behavior and prognosis. Lung adenocarcinoma is further classified into several subtypes and variants. The signs and symptoms of this specific type of lung cancer are similar to other forms of lung cancer, and patients most commonly complain of persistent cough and shortness of breath.
Adenocarcinoma is more common in patients with a history of cigarette smoking, and is the most common form of lung cancer in younger women and Asian populations. The pathophysiology of adenocarcinoma is complicated, but generally follows a histologic progression from cells found in healthy lungs to distinctly dysmorphic, or irregular cells. There are several distinct molecular and genetic pathways that contribute to this progression. Like many lung cancers, adenocarcinoma of the lung is often advanced by the time of diagnosis. Once a lesion or tumor is identified with various imaging modalities, such as computed tomography (CT) or X-ray, a biopsy is required to confirm the diagnosis.
Treatment of this lung cancer is based upon the specific subtype and the extent of spread from the primary tumor. Surgical resection, chemotherapy, radiotherapy, targeted therapy and immunotherapy are used in attempt to eradicate the cancerous cells based upon these factors.

Signs and symptoms
The majority of patients who are diagnosed with lung cancer usually present with locally advanced or metastatic disease. Only about one third of patients have stage I disease when diagnosed. The symptoms that the patient exhibits usually reflect the extent of the cancers spread. Lung cancers that are discovered early may cause symptoms localized to the respiratory system. However, lung cancer that is advanced will cause patients to experience additional signs and symptoms secondary to the cancer spreading to other organ systems. In order of highest frequency, the most common signs of lung cancer include:
cough that does not go away or gets worse
weight loss
dyspnea (shortness of breath or difficulty breathing)
chest pain, which may be aggravated by deep breathing, coughing, or laughing
hemoptysis (coughing up blood or rust-colored phlegm)
bone pain
clubbing
fever
generally feeling tired or weak
superior vena cava obstruction- facial, neck, upper torso swelling. This is caused by compression of vasculature by the lung tumor that restricts blood return from the upper body.
dysphagia (trouble swallowing or the sensation that something is caught in the throat) and hoarseness
new onset of wheezing without history of asthmaClinicians should have a high level of suspicion for lung cancer, especially in patients with a smoking history. Patients with recurring or unresolving lung infections (e.g. bronchitis and pneumonia) that are unresponsive to antibiotics should also be further evaluated for lung cancer. In nonsmokers, women and East Asians are more likely to present with symptoms of an underlying lung cancer at younger ages.
Importantly, many of these signs are commonly due to other causes that are not cancer. A detailed medical history should be obtained from each patient to determine the relevance of further diagnostic workup and management.

Extrapulmonary manifestations
Adenocarcinoma, like other forms of lung cancer, is usually advanced or metastatic at time of diagnosis. Patients may complain of signs or symptoms outside of the respiratory tract that represent a hematologic or metabolic complication of the malignancy without, however, resulting necessarily from obstruction or metastasis. These go under the name of paraneoplastic syndromes, which often indicate advanced disease and worse prognosis. The most common paraneoplastic syndromes associated with adenocarcinoma of the lung are described below:

Hypercalcemia of malignancy is more common in squamous cell carcinoma of the lung, but can occur in adenocarcinoma as well. Parathyroid hormone-related peptide (PTHrP) is produced by tumor cells and functions similarly to parathyroid hormone (PTH). The production of this hormonally active peptide by cancer cells causes increased bone resorption via upregulation of osteoclasts, one of the cells responsible for bone remodeling. When bone is broken down, calcium is released into the bloodstream, resulting in hypercalcemia. The signs and symptoms of elevated calcium in the blood include: thirst, fatigue, constipation, polyuria (increased urination), and nausea. It is important to rule out boney metastases in patients with NSCLC because they also present with hypercalcemia.
Hypertrophic pulmonary osteoarthropathy (HPO) is fairly rare in adenocarcinoma. Less than 1% of patients with adenocarcinoma of the lung will exhibit this finding, but when it does occur, it is a poor prognostic factor. The exact mechanism of HPO is unknown but it thought to be hormonal or neurogenic in etiology. The triad of HPO includes distal clubbing, arthritis, and bilateral symmetrical periosteal formation.

Causes
Risk factors
According to the Nurses Health Study, the risk of pulmonary adenocarcinoma increases substantially after a long duration of tobacco smoking: smokers with a previous smoking duration of 30–40 years are more than twice as likely to develop lung adenocarcinoma compared to never-smokers (relative risk of approximately 2.4); a duration of more than 40 years increases relative risk to 5.This cancer usually is seen peripherally in the lungs, as opposed to small cell lung cancer and squamous cell lung cancer, which both tend to be more centrally located, although it may also occur as central lesions. For unknown reasons, it often arises in relation to peripheral lung scars. The current theory is that the scar probably occurred secondary to the tumor, rather than causing the tumor. The adenocarcinoma has an increased incidence in smokers, and is the most common type of lung cancer seen in non-smokers and women. Deeper inhalation of cigarette smoke results in peripheral lesions that are often the case in adenocarcinomas of the lung. Generally, adenocarcinoma grows more slowly and forms smaller masses than the other subtypes. However, it tends to metastasize at an early stage.

Mechanism
Pathogenesis
Large scale studies such as The Cancer Genome Atlas (TCGA) have systematically characterized recurrent somatic alterations likely driving lung adenocarcinoma initiation and development.

Gene mutations and copy number alterations
Since smoking is a strong mutagenic factor, lung adenocarcinoma is one of the tumor types with the highest number of mutations. Common somatic mutations in lung adenocarcinoma affect many oncogenes and tumor suppressor genes, including TP53 (mutated in 46% of cases), EGFR (27%), KRAS (32%), KEAP1, STK11 and NF1. EGFR and KRAS mutations tend to appear in a mutually exclusive fashion. KRAS mutations are associated with smoking habits, whereas EGFR mutations occur more frequently in females, people of Asian ethnicity and never-smokers.Copy number amplifications in oncogenes such as TERT, MDM2, EGFR, MET, and MYC have been reported, as well as deletions of tumor suppressor genes such as CDKN2A.Frequent alterations occur in genes belonging to the receptor tyrosine kinase pathway, of which EGFR is the most prominent example. This pathway is involved in cell proliferation and survival and it is often deregulated in cancer. As a consequence, targeted therapies have been developed to inhibit mutant pathway components.

Chromosomal rearrangements
Three membrane associated tyrosine kinase receptors are recurrently involved in fusions or rearrangements in adenocarcinomas: ALK, ROS1, and RET, and more than eighty other translocations have also been reported in adenocarcinomas of the lung.In ALK rearrangements, the most common partner gene is EML4. EML4-ALK fusions tend to occur in tumors that do not carry EGFR or KRAS mutations and have also a lower frequency of TP53 mutations. ALK and ROS fusions offer opportunities for targeted therapies with tyrosine kinase inhibitors.

Pathophysiology
The respiratory tract can be divided into two main components: the conducting airways and the gas exchange airways. The gas exchange airways are made of alveoli, small microscopic air sacs that are responsible for the exchange of oxygen and carbon dioxide during normal breathing. Alveoli are composed of two cell types, type I and type II pneumocytes. Type I pneumocytes cover 95% of alveolar surfaces, and are not able to regenerate. Type II pneumocytes are more common, making up 60% of the cells within alveolar epithelium, but constitute only 3% of the alveolar surface.There are several factors that contribute to the transformation of normal alveolar epithelium into dysplastic, or pre-cancerous, lesions. Adenocarcinoma of the lung develops in a step-wise progression as type II pneumocytes undergo consecutive molecular changes that disrupt normal cell regulation and turnover. Atypical adenomatous hyperplasia (AAH) is considered a pre-cancerous lesion, and is thought to further progress to adenocarcinoma in situ and invasive adenocarcinoma of the lung. The lesions of AAH are <5 mm, can be single or multiple, and have a ground glass appearance on CT imaging. As more genetic mutations and dysregulation of normal cell signaling pathways accumulate, AAH can progress to adenocarcinoma in situ (AIS). AIS lesions are classified as small tumors <3 cm with abnormal type II pneumocyte cell growth that is limited to the alveolar spaces i.e. without invasion into the stroma, pleura, or vasculature. This type of growth is termed "lepidic" and is characteristic of adenocarcinoma of the lung in its earliest stages.

Diagnosis
A diagnosis of lung cancer may be suspected on the basis of typical symptoms, particularly in a person with smoking history. Symptoms such as coughing up blood and unintentional weight loss may prompt further investigation, such as medical imaging.

Classification
The majority of lung cancers can be characterized as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). Lung adenocarcinoma is one of the three major subtypes of NSCLC, which also include squamous carcinoma and large cell carcinoma.Historically, there has been much debate in the most accurate method of describing adenocarcinoma of the lung and several revisions of classification systems have been published. Most recently, the International Multidisciplinary Classification of Lung Adenocarcinoma was published in 2011 and represents the consensus of several organizations to more accurately describe this specific type of lung cancer. The current classification system aims to more reliably predict prognosis and determination of therapeutic management.The tumor size, pattern of cell growth, and depth of cell invasion into normal lung tissue are considered in determining classification. The following names represent a step-wise pathologic progression in the natural course of adenocarcinoma development; Adenocarcinoma in situ (AIS), Minimally invasive adenocarcinoma (MIA), and Invasive adenocarcinoma. Invasive adenocarcinoma of the lung includes a heterogenous mixture of subtypes and variants.
The 2011 consensus describes five subtypes of invasive adenocarcinomas based on the cell pattern that is most predominant. These subtypes are described below:

lepidic predominant
acinar predominant
papillary predominant
micropapillary predominant
solid predominant with mucin production Cell patterns identifying subtypes are associated with prognosis, ranging from favorable (lepidic) to intermediate (acinar and papillary) to poor (micropapillary and solid).Four discrete variants of invasive adenocarcinomas not assignable to these five subtypes are also included in the current classification:

invasive mucinous adenocarcinoma
colloid adenocarcinoma
fetal adenocarcinoma
primary pulmonary enteric adenocarcinoma

Imaging
A chest x-ray (radiograph) is often the first imaging test performed when a person presents with cough or chest pain, particularly in the primary care setting. A chest radiograph may detect a lung nodule/mass that is suggestive of cancer, although sensitivity and specificity are limited.CT imaging provides better evaluation of the lungs, with higher sensitivity and specificity for lung cancer compared to chest radiograph (although still significant false positive rate). Computed tomography (CT) that is specifically aimed at evaluating lung cancer includes the chest and the upper abdomen. This allows for evaluation of other relevant anatomic structures such as nearby lymph nodes, adrenal glands, liver, and bones which may show evidence of metastatic spread of disease. Indeed, the US Preventative Services Task Force recommends annual screening with low-dose CT in adults aged 55 to 80 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years, with certain caveats (see Lung cancer screening).Nuclear medicine imaging, such as PET/CT and bone scan, may also be helpful to diagnose and detect metastatic disease elsewhere in the body. PET/CT uses a metabolically active tracer that allows clinicians to identify areas of the body that are hypermetabolic. Increased uptake of the tracer occurs in malignant cells and areas of inflammation or infection. Integrating the imaging reflective of metabolic activity with normal CT imaging allows for higher sensitivity and specificity compared to PET alone.MRI is reserved for patients with advanced disease where intracranial, or brain, involvement is likely. It is also helpful for evaluating the extent of chest wall, diaphragmatic, brachial plexus (such as in the case of superior sulcus tumors), or spine involvement.

Histopathology
If possible, a biopsy of any suspected lung tumor is performed in order to make a microscopic evaluation of the cells involved and is ultimately required to confirm diagnosis. Biopsy should be attempted in distant lesions first to establish a histologic diagnosis and to simultaneously confirm metastatic staging. The biopsy material is also used to analyze whether the tumor express any specific mutations suitable for tageted therapy (e.g. EGFR mutation or ALK mutation). Biopsy can be accomplished via bronchoscopy, transthoracic needle biopsy, and video-assisted thorascopic surgery (VATS).While sputum cytology has been shown to have limited utility, thoracentesis, or aspiration of pleural fluid with an ultrasound-guided needle, should be performed when pleural effusion is present. When malignant cells are identified in the pleural aspirate of patients highly suspect for lung cancer, a definitive diagnosis and staging (stage IV adenocarcinoma of the lung) is established.Adenocarcinoma of the lung tends to stain mucin positive as it is derived from the mucus-producing glands of the lungs. Similar to other adenocarcinoma, if this tumor is well differentiated (low grade) it will resemble the normal glandular structure. Poorly differentiated adenocarcinoma will not resemble the normal glands (high grade) and will be detected by seeing that they stain positive for mucin (which the glands produce). Adenocarcinoma can also be distinguished by staining for TTF-1, a cell marker for adenocarcinoma.As discussed previously, the category of adenocarcinoma includes are range of subtypes, and any one tumor tends to be heterogeneous in composition. Several major subtypes are currently recognized by the World Health Organization (WHO) and the International Association for the Study of Lung Cancer (IASLC) / American Thoracic Society (ATS) / European Respiratory Society (ERS): lepidic predominant adenocarcinoma, acinar predominant adenocarcinoma, papillary predominant adenocarcinoma, micropapillary predominant adenocarcinoma, solid predominant adenocarcinoma, and solid predominant with mucin production. In as many as 80% of these tumors, components of more than one subtype will be recognized. Surgically resected tumors should be classified by comprehensive histological subtyping, describing patterns of involvement in increments of 5%. The predominant histologic subtype is then used to classify the tumor overall. The predominant subtype is prognostic for survival after complete resection.To reveal the adenocarcinomatous lineage of the solid variant, demonstration of intracellular mucin production may be performed. Foci of squamous metaplasia and dysplasia may be present in the epithelium proximal to adenocarcinomas, but these are not the precursor lesions for this tumor. Rather, the precursor of peripheral adenocarcinomas has been termed atypical adenomatous hyperplasia (AAH). Microscopically, AAH is a well-demarcated focus of epithelial proliferation, containing cuboidal to low-columnar cells resembling club cells or type II pneumocytes. These demonstrate various degrees of cytologic atypia, including hyperchromasia, pleomorphism, prominent nucleoli. However, the atypia is not to the extent as seen in frank adenocarcinomas. Lesions of AAH are monoclonal, and they share many of the molecular aberrations (like KRAS mutations) that are associated with adenocarcinomas.Signet ring and clear cell adenocarcinoma are no longer histological subtypes, but rather cytological features that can occur in tumour cells of multiple histological subtypes, most often solid adenocarcinoma.

Treatment
The treatment of adenocarcinoma of the lung depends on several factors including stage, resectability, performance status, histology and genomic alterations acquired by the individual tumor. As in most cancer types, treatment approaches can be broadly divided into 5 categories: surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy.

Surgery
Early stage (I, II and IIIA) lung adenocarcinomas are typically treated surgically to remove the tumor with pneumonectomy or lobectomy, if it is found to be resectable with imaging studies and biopsies and if the patient is considered able to tolerate surgery. Video-assisted thorascopic surgery (VATS) is often adopted, which consists in the insertion of a thorascope inside a small incision made in the chest; a lobe can be removed via the scope through this small incision.

Chemotherapy
For advanced (stage IV) and unresectable lung tumors, the first-line therapy is platinum-based doublet chemotherapy, combining cisplatin or carboplatin with another cytotoxic agent. Regimens strongly depend on each patient performance status and response, and when the risk of adverse events could worsen quality of life significantly, basic supportive care is more recommended. Chemotherapy is also used as an adjuvant therapy following surgery to kill remaining cancer cells in patients with stage IIA, IIB and IIIA NSCLC.

Radiotherapy
Adenocarcinoma is a non-small cell lung carcinoma, and it is not as responsive to radiation therapy compared to small cell lung carcinoma. However, radiotherapy may be used as an adjuvant therapy for patients who have undergone a resection surgery to reduce the risk of lung cancer relapse. It may also benefit inoperable tumors that are localized to the chest and be part of palliative care to improve quality of life in patients not responding to surgery or chemotherapy.

Targeted therapy
Targeted therapy is available for lung adenocarcinomas with certain molecular characteristics. Tyrosine kinase inhibitors (TKIs) have been developed to target mutant components of the receptor tyrosine kinase pathway such as EGFR, ALK and ROS1, which show frequent alterations in lung adenocarcinomas.
First-generation EGFR TKIs, including gefitinib and erlotinib, have been shown to be more effective in treating EGFR-mutated patients with respect to cytotoxic chemotherapy. Second-generation inhibitors such as afatinib and dacomitinib provided a broader scope of application as they are able to target not only the protein EGFR itself but also other members of the EGFR family, such as HER2 and HER4 (also known as ERBB2 and ERBB4), and they have shown improved progression-free survival compared to gefitinib. As the most common cause of acquired resistance to first-generation TKIs is a second EGFR mutation on codon 790, a third-generation EGFR TKI, osimertinib, has been developed to target this new mutation as well. MET amplification is another known mechanism of acquired resistance.ALK inhibitors such as crizotinib showed to be effective against tumors harboring ALK fusions. Most patients previously treated with crizotinib benefited from second-generation ALK inhibitors including ceritinib, alectinib and brigatinib. Resistance to ALK inhibitors can occur with novel acquired ALK mutations or amplifications.Also ROS1-positive tumors have shown high sensitivity to ALK inhibitors due to the high homology between the kinase domains of ROS1 and ALK.

Immunotherapy
Immune response can be prevented via activation of immune checkpoints, which consist in the binding of a ligand protein (e.g. PD-L1) to a receptor (e.g </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 Nicotine poisoning and can you explain it in depth? [/INST] Nicotine poisoning describes the symptoms of the toxic effects of nicotine following ingestion, inhalation, or skin contact. Nicotine poisoning can potentially be deadly, though serious or fatal overdoses are rare. Historically, most cases of nicotine poisoning have been the result of use of nicotine as an insecticide. More recent cases of poisoning typically appear to be in the form of Green Tobacco Sickness, or due to unintended ingestion of tobacco or tobacco products or consumption of nicotine-containing plants.Standard textbooks, databases, and safety sheets consistently state that the lethal dose of nicotine for adults is 60 mg or less (30–60 mg), but there is overwhelming data indicating that more than 0.5 g of oral nicotine is required to kill an adult.Children may become ill following ingestion of one cigarette; ingestion of more than this may cause a child to become severely ill. The nicotine in the e-liquid of an electronic cigarette can be hazardous to infants and children, through accidental ingestion or skin contact. In some cases children have become poisoned by topical medicinal creams which contain nicotine.People who harvest or cultivate tobacco may experience Green Tobacco Sickness (GTS), a type of nicotine poisoning caused by skin contact with wet tobacco leaves. This occurs most commonly in young, inexperienced tobacco harvesters who do not consume tobacco.

Signs and symptoms
Nicotine poisoning tends to produce symptoms that follow a biphasic pattern. The initial symptoms are mainly due to stimulatory effects and include nausea and vomiting, excessive salivation, abdominal pain, pallor, sweating, hypertension, tachycardia, ataxia, tremor, headache, dizziness, muscle fasciculations, and seizures. After the initial stimulatory phase, a later period of depressor effects can occur and may include symptoms of hypotension and bradycardia, central nervous system depression, coma,  muscular weakness and/or paralysis, with difficulty breathing or respiratory failure.From September 1, 2010 to December 31, 2014, there were at least 21,106 traditional cigarette calls to US poison control centers. During the same period, the ten most frequent adverse effects to traditional cigarettes reported to US poison control centers were vomiting (80.0%), nausea (9.2%), drowsiness (7.8%), cough (7.2%), agitation (6.6%), pallor (3.0%), tachycardia (2.5%), diaphoresis (1.5%), dizziness (1.5%), and diarrhea (1.4%). 95% of traditional cigarette calls were related to children 5 years old or less. Most of the traditional cigarette calls were a minor effect.Calls to US poison control centers related to e-cigarette exposures involved inhalations, eye exposures, skin exposures, and ingestion, in both adults and young children. Minor, moderate, and serious adverse effects involved adults and young children. Minor effects correlated with e-cigarette liquid poisoning were tachycardia, tremor, chest pain and hypertension. More serious effects were bradycardia, hypotension, nausea, respiratory paralysis, atrial fibrillation and dyspnea. The exact correlation is not fully known between these effects and e-cigarettes. 58% of e-cigarette calls to US poison control centers were related to children 5 years old or less. E-cigarette calls had a greater chance to report an adverse effect and a greater chance to report a moderate or major adverse effect than traditional cigarette calls. Most of the e-cigarette calls were a minor effect.From September 1, 2010 to December 31, 2014, there were at least 5,970 e-cigarette calls to US poison control centers. During the same period, the ten most frequent adverse effects to e-cigarettes and e-liquid reported to US poison control centers were vomiting (40.4%), eye irritation or pain (20.3%), nausea (16.8%), red eye or conjunctivitis (10.5%), dizziness (7.5%), tachycardia (7.1%), drowsiness (7.1%), agitation (6.3%), headache (4.8%), and cough (4.5%).E-cigarette exposure cases in the US National Poison Data System increased greatly between 2010 and 2014, peaking at 3,742 in 2014, fell in 2015 though 2017, and then between 2017 and 2018 e-cigarette exposure cases increased from 2,320 to 2,901. The majority of cases (65%) were in children under age five and 15% were in ages 5-24. Approximately 0.1% of cases developed life-threatening symptoms.

Toxicology
The LD50 of nicotine is 50 mg/kg for rats and 3 mg/kg for mice. 0.5–1.0 mg/kg can be a lethal dosage for adult humans, and 0.1 mg/kg for children. However the widely used human LD50 estimate of 0.5–1.0 mg/kg was questioned in a 2013 review, in light of several documented cases of humans surviving much higher doses; the 2013 review suggests that the lower limit causing fatal outcomes is 500–1000 mg of ingested nicotine, corresponding to 6.5–13 mg/kg orally. An accidental ingestion of only 6 mg may be lethal to children.It is unlikely that a person would overdose on nicotine through smoking alone. The US Food and Drug Administration (FDA) stated in 2013: "There are no significant safety concerns associated with using more than one [over the counter] OTC [nicotine replacement therapy] NRT at the same time, or using an OTC NRT at the same time as another nicotine-containing product—including a cigarette." Ingestion of nicotine pharmaceuticals, tobacco products, or nicotine containing plants may also lead to poisoning. Smoking excessive amounts of tobacco has also led to poisoning; a case was reported where two brothers smoked 17 and 18 pipes of tobacco in succession and were both fatally poisoned. Spilling an extremely high concentration of nicotine onto the skin can result in intoxication or even death since nicotine readily passes into the bloodstream following skin contact.The recent rise in the use of electronic cigarettes, many forms of which are designed to be refilled with nicotine-containing "e-liquid" supplied in small plastic bottles, has renewed interest in nicotine overdoses, especially the possibility of young children ingesting the liquids. A 2015  Public Health England report noted an "unconfirmed newspaper report of a fatal poisoning of a two-year old child" and two published case reports of children of similar age who had recovered after ingesting e-liquid and vomiting. They also noted case reports of suicides by nicotine, where adults drank liquid containing up to 1,500 mg of nicotine. They recovered (helped by vomiting), but an ingestion apparently of about 10,000 mg was fatal, as was an injection. They commented that "Serious nicotine poisoning seems normally prevented by the fact that relatively low doses of nicotine cause nausea and vomiting, which stops users from further intake." Four adults died in the US and Europe, after intentionally ingesting liquid. Two children, one in the US in 2014 and another in Israel in 2013, died after ingesting liquid nicotine.The discrepancy between the historically stated 60-mg dose and published cases of nicotine intoxication has been noted previously (Matsushima et al. 1995; Metzler et al. 2005). Nonetheless, this value is still widely accepted over the 500mg figure as the basis for safety regulations of tobacco and other nicotine-containing products (such as the EU wide TPD, set at a maximum of 20mg.

Pathophysiology
The symptoms of nicotine poisoning are caused by effects at nicotinic cholinergic receptors. Nicotine is an agonist at nicotinic acetylcholine receptor which are present in the central and autonomic nervous systems, and the neuromuscular junction. At low doses nicotine causes stimulatory effects on these receptors, however, higher doses or more sustained exposures can cause inhibitory effects leading to neuromuscular blockade.It is sometimes reported that people poisoned by organophosphate insecticides experience the same symptoms as nicotine poisoning </s>


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