<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 Acute pancreatitis and can you explain it in depth? [/INST] Acute pancreatitis (AP) is a sudden inflammation of the pancreas. Causes in order of frequency include: 1) a gallstone impacted in the common bile duct beyond the point where the pancreatic duct joins it; 2) heavy alcohol use; 3) systemic disease; 4) trauma; 5) and, in minors, mumps. Acute pancreatitis may be a single event; it may be recurrent; or it may progress to chronic pancreatitis.
Mild cases are usually successfully treated with conservative measures: hospitalization, pain control, nothing by mouth, intravenous nutritional support, and intravenous fluid rehydration. Severe cases often require admission to an intensive care unit to monitor and manage complications of the disease. Complications are associated with a high mortality, even with optimal management.

Signs and symptoms
Common
severe epigastric pain (upper abdominal pain) radiating to the back in 50% of cases
nausea
vomiting
loss of appetite
fever
chills (shivering)
hemodynamic instability, including shock
tachycardia (rapid heartbeat)
respiratory distress
peritonitis
hiccupAlthough these are common symptoms, frequently they are not all present; and epigastric pain may be the only symptom.

Uncommon
The following are associated with severe disease:

Grey-Turners sign (hemorrhagic discoloration of the flanks)
Cullens sign (hemorrhagic discoloration of the umbilicus)
Pleural effusions (fluid in the bases of the pleural cavity)
Grünwald sign (appearance of ecchymosis, large bruise, around the umbilicus due to local toxic lesion of the vessels)
Körtes sign (pain or resistance in the zone where the head of pancreas is located (in epigastrium, 6–7 cm above the umbilicus))
Kamenchiks sign (pain with pressure under the xiphoid process)
Mayo-Robsons sign (pain while pressing at the top of the angle lateral to the erector spinae muscles and below the left 12th rib (left costovertebral angle (CVA))
Mayo-Robsons point – a point on border of inner 2/3 with the external 1/3 of the line that represents the bisection of the left upper abdominal quadrant, where tenderness on pressure exists in disease of the pancreas. At this point the tail of pancreas is projected on the abdominal wall.

Complications
Locoregional complications include pancreatic pseudocyst (most common, occurring in up to 25% of all cases, typically after 4–6 weeks) and phlegmon/abscess formation, splenic artery pseudoaneurysms, hemorrhage from erosions into splenic artery and vein, thrombosis of the splenic vein, superior mesenteric vein and portal veins (in descending order of frequency), duodenal obstruction, common bile duct obstruction, progression to chronic pancreatitis, pancreatic ascites, pleural effusion, sterile/infected pancreatic necrosis.Systemic complications include ARDS, multiple organ dysfunction syndrome, DIC, hypocalcemia (from fat saponification), hyperglycemia and insulin dependent diabetes mellitus (from pancreatic insulin-producing beta cell damage), malabsorption due to exocrine failure

MetabolicHypocalcemia, hyperglycemia, hypertriglyceridemiaRespiratoryHypoxemia, atelectasis, Effusion, pneumonitis, Acute respiratory distress syndrome (ARDS)Renal
Renal artery or vein thrombosis
Kidney failure
Circulatory
Arrhythmias
Hypovolemia and shock
myocardial infarction
Pericardial effusion
vascular thrombosis
Gastrointestinal
Gastrointestinal hemorrhage from stress ulceration;
gastric varices (secondary to splenic vein thrombosis)
Gastrointestinal obstruction
 Hepatobiliary
Jaundice
Portal vein thrombosis
Neurologic
Psychosis or encephalopathy (confusion, delusion and coma)
Cerebral Embolism
Blindness (angiopathic retinopathy with hemorrhage)
Hematologic
Anemia
DIC
Leucocytosis
Dermatologic
Painful subcutaneous fat necrosis
Miscellaneous
Subcutaneous fat necrosis
Arthalgia

Causes
Most common
Biliary pancreatitis due to gallstones or constriction of ampulla of Vater in 40% of cases
Alcohol in 30% of cases
Idiopathic in 15-25% of cases
Metabolic disorders: hereditary pancreatitis, hypercalcemia, elevated triglycerides, malnutrition
Post-ERCP
Abdominal trauma
Penetrating ulcers
Carcinoma of the head of pancreas, and other cancer
Drugs: diuretics (e.g., thiazides, furosemide), gliptins (e.g., vildagliptin, sitagliptin, saxagliptin, linagliptin), tetracycline, sulfonamides, estrogens, azathioprine and mercaptopurine, pentamidine, salicylates, steroids, Depakote
Infections: mumps, viral hepatitis, coxsackie B virus, cytomegalovirus, Mycoplasma pneumoniae, Ascaris
Structural abnormalities: choledochocele, pancreas divisum
Radiotherapy
Autoimmune pancreatitis
Severe hypertriglyceridemia

Less common
Scorpion venom
Chinese liver fluke
Ischemia from bypass surgery
Heart valve surgery
Fat necrosis
Pregnancy
Infections other than mumps, including varicella zoster
Hyperparathyroidism
Valproic acid
Cystic fibrosis
Anorexia or bulimia
Codeine phosphate reaction

Pathology
Pathogenesis
Acute pancreatitis occurs when there is abnormal activation of digestive enzymes within the pancreas. This occurs through inappropriate activation of inactive enzyme precursors called zymogens (or proenzymes) inside the pancreas, most notably trypsinogen. Normally, trypsinogen is converted to its active form (trypsin) in the first part of the small intestine (duodenum), where the enzyme assists in the digestion of proteins. During an episode of acute pancreatitis, trypsinogen comes into contact with lysosomal enzymes (specifically cathepsin), which activate trypsinogen to trypsin. The active form trypsin then leads to further activation of other molecules of trypsinogen. The activation of these digestive enzymes lead to inflammation, edema, vascular injury, and even cellular death. The death of pancreatic cells occurs via two main mechanisms: necrosis, which is less organized and more damaging, or apoptosis, which is more controlled. The balance between these two mechanisms of cellular death is mediated by caspases which regulate apoptosis and have important anti-necrosis functions during pancreatitis: preventing trypsinogen activation, preventing ATP depletion through inhibiting polyADP-ribose polymerase, and by inhibiting the inhibitors of apoptosis (IAPs). If, however, the caspases are depleted due to either chronic ethanol exposure or through a severe insult then necrosis can predominate.

Pathophysiology
The two types of acute pancreatitis are mild and severe, which are defined based on whether the predominant response to cell injury is inflammation (mild) or necrosis (severe). In mild pancreatitis, there is inflammation and edema of the pancreas. In severe pancreatitis, there is necrosis of the pancreas, and nearby organs may become injured.
As part of the initial injury there is an extensive inflammatory response due to pancreatic cells synthesizing and secreting inflammatory mediators: primarily TNF-alpha and IL-1. A hallmark of acute pancreatitis is a manifestation of the inflammatory response, namely the recruitment of neutrophils to the pancreas. The inflammatory response leads to the secondary manifestations of pancreatitis: hypovolemia from capillary permeability, acute respiratory distress syndrome, disseminated intravascular coagulations, renal failure, cardiovascular failure, and gastrointestinal hemorrhage.

Histopathology
The acute pancreatitis (acute hemorrhagic pancreatic necrosis) is characterized by acute inflammation and necrosis of pancreas parenchyma, focal enzymic necrosis of pancreatic fat and vessel necrosis (hemorrhage). These are produced by intrapancreatic activation of pancreatic enzymes. Lipase activation produces the necrosis of fat tissue in pancreatic interstitium and peripancreatic spaces as well as vessel damage. Necrotic fat cells appear as shadows, contours of cells, lacking the nucleus, pink, finely granular cytoplasm. It is possible to find calcium precipitates (hematoxylinophilic). Digestion of vascular walls results in thrombosis and hemorrhage. Inflammatory infiltrate is rich in neutrophils. Due to the pancreas lacking a capsule, the inflammation and necrosis can extend to include fascial layers in the immediate vicinity of the pancreas.

Diagnosis
Acute pancreatitis is diagnosed using clinical history and physical examination, based on the presence of at least 2 of 3 criteria: abdominal pain, elevated serum lipase or amylase, and abdominal imaging findings consistent with acute pancreatitis. Additional blood studies are used to identify organ failure, offer prognostic information, and determine if fluid resuscitation is adequate and whether ERCP is necessary.

Blood investigations – complete blood count, kidney function tests, liver function, serum calcium, serum amylase and lipase
Imaging – A triple phase abdominal CT and abdominal ultrasound are together considered the gold standard for the evaluation of acute pancreatitis. Other modalities including the abdominal x-ray lack sensitivity and are not recommended. An important caveat is that imaging during the first 12 hours may be falsely reassuring as the inflammatory and necrotic process usually requires 48 hours to fully manifest.

Differential diagnosis
The differential diagnosis includes:
Perforated peptic ulcer
Biliary colic
Acute cholecystitis
Pneumonia
Pleuritic pain
Myocardial infarction

Biochemical
Elevated serum amylase and lipase levels, in combination with severe abdominal pain, often trigger the initial diagnosis of acute pancreatitis. However, they have no role in assessing disease severity.
Serum lipase rises 4 to 8 hours from the onset of symptoms and normalizes within 7 to 14 days after treatment.
Serum amylase may be normal (in 10% of cases) for cases of acute or chronic pancreatitis (depleted acinar cell mass) and hypertriglyceridemia.
Reasons for false positive elevated serum amylase include salivary gland disease (elevated salivary amylase), bowel obstruction, infarction, cholecystitis, and a perforated ulcer.
If the lipase level is about 2.5 to 3 times that of amylase, it is an indication of pancreatitis due to alcohol.Decreased serum calcium
GlycosuriaRegarding selection on these tests, two practice guidelines state:

"It is usually not necessary to measure both serum amylase and lipase. Serum lipase may be preferable because it remains normal in some nonpancreatic conditions that increase serum amylase including macroamylasemia, parotitis, and some carcinomas. In general, serum lipase is thought to be more sensitive and specific than serum amylase in the diagnosis of acute pancreatitis""Although amylase is widely available and provides acceptable accuracy of diagnosis, where lipase is available it is preferred for the diagnosis of acute pancreatitis (recommendation grade A)"Most, but not all individual studies support the superiority of the lipase. In one large study, there were no patients with pancreatitis who had an elevated amylase with a normal lipase. Another study found that the amylase could add diagnostic value to the lipase, but only if the results of the two tests were combined with a discriminant function equation.While often quoted lipase levels of 3 or more times the upper-limit of normal is diagnostic of pancreatitis, there are also other differential diagnosis to be considered relating to this rise.

Computed tomography
Regarding the need for computed tomography, practice guidelines state:
CT is an important common initial assessment tool for acute pancreatitis. Imaging is indicated during the initial presentation if:

the diagnosis of acute pancreatitis is uncertain
there is abdominal distension and tenderness, fever >102 F (38,9 C), or leukocytosis
there is a Ranson score > 3 or APACHE score > 8
there is no improvement after 72 hours of conservative medical therapy
there has been an acute change in status: fever, pain, or shockCT is recommended as a delayed assessment tool in the following situations:

acute change in status
to determine therapeutic response after surgery or interventional radiologic procedure
before discharge in patients with severe acute pancreatitisAbdominal CT should not be performed before the first 12 hours of onset of symptoms as early CT (<12 hours) may result in equivocal or normal findings.
CT findings can be classified into the following categories for easy recall:

Intrapancreatic – diffuse or segmental enlargement, edema, gas bubbles, pancreatic pseudocysts and phlegmons/abscesses (which present 4 to 6 wks after initial onset)
Peripancreatic / extrapancreatic – irregular pancreatic outline, obliterated peripancreatic fat, retroperitoneal edema, fluid in the lessar sac, fluid in the left anterior pararenal space
Locoregional – Gerotas fascia sign (thickening of inflamed Gerotas fascia, which becomes visible), pancreatic ascites, pleural effusion (seen on basal cuts of the pleural cavity), adynamic ileus, etc.The principal value of CT imaging to the treating clinician is the capacity to identify devitalised areas of the pancreas which have become necrotic due to ischaemia. Pancreatic necrosis can be reliably identified by intravenous contrast-enhanced CT imaging, and is of value if infection occurs and surgical or percutaneous debridement is indicated.

Magnetic resonance imaging
While computed tomography is considered the gold standard in diagnostic imaging for acute pancreatitis, magnetic resonance imaging (MRI) has become increasingly valuable as a tool for the visualization of the pancreas, particularly of pancreatic fluid collections and necrotized debris. Additional utility of MRI includes its indication for imaging of patients with an allergy to CTs contrast material, and an overall greater sensitivity to hemorrhage, vascular complications, pseudoaneurysms, and venous thrombosis.Another advantage of MRI is its utilization of magnetic resonance cholangiopancreatography (MRCP) sequences. MRCP provides useful information regarding the etiology of acute pancreatitis, i.e., the presence of tiny biliary stones (choledocholithiasis or cholelithiasis) and duct anomalies. Clinical trials indicate that MRCP can be as effective a diagnostic tool for acute pancreatitis with biliary etiology as endoscopic retrograde cholangiopancreatography, but with the benefits of being less invasive and causing fewer complications.

Ultrasound
On abdominal ultrasonography, the finding of a hypoechoic and bulky pancreas is regarded as diagnostic of acute pancreatitis.

Treatment
Initial management of a patient with acute pancreatitis consists of supportive care with fluid resuscitation, pain control, nothing by mouth, and nutritional support.

Fluid replacement
Aggressive hydration at a rate of 5 to 10 mL/kg per hour of isotonic crystalloid solution (e.g., normal saline or lactated Ringers solution) to all patients with acute pancreatitis, unless cardiovascular, renal, or other related comorbid factors preclude aggressive fluid replacement. In patients with severe volume depletion that manifests as hypotension and tachycardia, more rapid repletion with 20 mL/kg of intravenous fluid given over 30 minutes followed by 3 mL/kg/hour for 8 to 12 hours.Fluid requirements should be reassessed at frequent intervals in the first six hours of admission and for the next 24 to 48 hours. The rate of fluid resuscitation should be adjusted based on clinical assessment, hematocrit and blood urea nitrogen (BUN) values.
In the initial stages (within the first 12 to 24 hours) of acute pancreatitis, fluid replacement has been associated with a reduction in morbidity and mortality.

Pain control
Abdominal pain is often the predominant symptom in patients with acute pancreatitis and should be treated with analgesics.
Opioids are safe and effective at providing pain control in patients with acute pancreatitis. Adequate pain control requires the use of intravenous opiates, usually in the form of a patient-controlled analgesia pump. Hydromorphone or fentanyl (intravenous) may be used for pain relief in acute pancreatitis. Fentanyl is being increasingly used due to its better safety profile, especially in renal impairment. As with other opiates, fentanyl can depress respiratory function. It can be given both as a bolus as well as constant infusion.
Meperidine has been historically favored over morphine because of the belief that morphine caused an increase in sphincter of Oddi pressure. However, no clinical studies suggest that morphine can aggravate or cause pancreatitis or cholecystitis. In addition, meperidine has a short half-life and repeated doses can lead to accumulation of the metabolite normeperidine, which causes neuromuscular side effects and, rarely, seizures.

Bowel rest
In the management of acute pancreatitis, the treatment is to stop feeding the patient, giving them nothing by mouth, giving intravenous fluids to prevent dehydration, and sufficient pain control. As the pancreas is stimulated to secrete enzymes by the presence of food in the stomach, having no food pass through the system allows the pancreas to rest. Approximately 20% of patients have a relapse of pain during acute pancreatitis. Approximately 75% of relapses occur within 48 hours of oral refeeding.The incidence of relapse after oral refeeding may be reduced by post-pyloric enteral rather than parenteral feeding prior to oral refeeding. IMRIE scoring is also useful.

Nutritional support
Recently, there has been a shift in the management paradigm from total parenteral nutrition (TPN) to early, post-pyloric enteral feeding (in which a feeding tube is endoscopically or radiographically introduced to the third portion of the duodenum). The advantage of enteral feeding is that it is more physiological, prevents gut mucosal atrophy, and is free from the side effects of TPN (such as fungemia). The additional advantages of post-pyloric feeding are the inverse relationship of pancreatic exocrine secretions and distance of nutrient delivery from the pylorus, as well as reduced risk of aspiration.
Disadvantages of a naso-enteric feeding tube include increased risk of sinusitis (especially if the tube remains in place greater than two weeks) and a still-present risk of accidentally intubating the trachea even in intubated patients (contrary to popular belief, the endotracheal tube cuff alone is not always sufficient to prevent NG tube entry into the trachea).

Oxygen
Oxygen may be provided in some patients (about 30%) if Pao2 levels fall below 70mm of Hg.

Antibiotics
Up to 20 percent of people with acute pancreatitis develop an infection outside the pancreas such as bloodstream infections, pneumonia, or urinary tract infections. These infections are associated with an increase in mortality. When an infection is suspected, antibiotics should be started while the source of the infection is being determined. However, if cultures are negative and no source of infection is identified, antibiotics should be discontinued.
Preventative antibiotics are not recommended in people with acute pancreatitis, regardless of the type (interstitial or necrotizing) or disease severity (mild, moderately severe, or severe)

ERCP
In 30% of those with acute pancreatitis, no cause is identified. ERCP with empirical biliary sphincterotomy has an equal chance of causing complications and treating the underlying cause, therefore, is not recommended for treating acute pancreatitis.
If a gallstone is detected, Endoscopic retrograde cholangiopancreatography (ERCP), performed within 24 to 72 hours of presentation with successful removal of the stone, is known to reduce morbidity and mortality. The indications for early ERCP are:

Clinical deterioration or lack of improvement after 24 hours
Detection of common bile duct stones or dilated intrahepatic or extrahepatic ducts on abdominal CTThe risks of ERCP are that it may worsen pancreatitis, it may introduce an infection to otherwise sterile pancreatitis, and bleeding.

Surgery
Surgery is indicated for (i) infected pancreatic necrosis and (ii) diagnostic uncertainty and (iii) complications. The most common cause of death in acute pancreatitis is secondary infection. Infection is diagnosed based on 2 criteria

Gas bubbles on CT scan (present in 20 to 50% of infected necrosis)
Positive bacterial culture on FNA (fine needle aspiration, usually CT or US guided) of the pancreas.Surgical options for infected necrosis include:

Minimally invasive management – necrosectomy through small incision in skin (left flank) or abdomen
Conventional management – necrosectomy with simple drainage
Closed management – necrosectomy with closed continuous postoperative lavage
Open management – necrosectomy with planned staged reoperations at definite intervals (up to 20+ reoperations in some cases)

Other measures
Pancreatic enzyme inhibitors are proven not to work.
The use of octreotide has been shown not to improve outcomes.

Classification by severity: prognostic scoring systems
Acute pancreatitis patients recover in majority of cases.
Some may develop abscess, pseudocyst or duodenal obstruction.
In 5 percent cases, it may result in ARDS (acute respiratory distress syndrome), DIC (disseminated intravascular coagulation)
Acute pancreatitis can be further divided into mild and severe pancreatitis.
Mostly the Ranson Criteria are used to determine severity of acute pancreatitis. In severe pancreatitis serious amounts of necrosis determine the further clinical outcome. About 20% of the acute pancreatitis are severe with a mortality of about 20%. This is an important classification as severe pancreatitis will need intensive care therapy whereas mild pancreatitis can be treated on the common ward.
Necrosis will be followed by a systemic inflammatory response syndrome (SIRS) and will determine the immediate clinical course. The further clinical course is then determined by bacterial infection. SIRS is the cause of bacterial (Gram negative) translocation from the patients colon.
There are several ways to help distinguish between these two forms. One is the above-mentioned Ranson Score.
In predicting the prognosis, there are several scoring indices that have been used as predictors of survival. Two such scoring systems are the Ranson criteria and APACHE II (Acute Physiology and Chronic Health Evaluation) indices. Most, but not all studies report that the Apache score may be more accurate. In the negative study of the APACHE-II, the APACHE-II 24-hour score was used rather than the 48-hour score. In addition, all patients in the study received an ultrasound twice which may have influenced allocation of co-interventions. Regardless, only the APACHE-II can be fully calculated upon admission. As the APACHE-II is more cumbersome to calculate, presumably patients whose only laboratory abnormality is an elevated lipase or amylase do not need assessment with the APACHE-II; however, this approach is not studied. The APACHE-II score can be calculated at www.sfar.org.
Practice guidelines state:

2006: "The two tests that are most helpful at admission in distinguishing mild from severe acute pancreatitis are APACHE-II score and serum hematocrit. It is recommended that APACHE-II scores be generated during the first 3 days of hospitalization and thereafter as needed to help in this distinction. It is also recommended that serum hematocrit be obtained at admission, 12 h after admission, and 24 h after admission to help gauge adequacy of fluid resuscitation."2005: "Immediate assessment should include clinical evaluation, particularly of any cardiovascular, respiratory, and renal compromise, body mass index, chest x ray, and APACHE II score"

Ranson score
The Ranson score is used to predict the severity of acute pancreatitis. They were introduced in 1974.

At admission
age in years > 55 years
white blood cell count > 16000 cells/mm3
blood glucose > 11.1 mmol/L (> 200 mg/dL)
serum AST > 250 IU/L
serum LDH > 350 IU/L

At 48 hours
Calcium (serum calcium < 2.0 mmol/L (< 8.0 mg/dL)
Hematocrit fall >10%
Oxygen (hypoxemia PO2 < 60 mmHg)
BUN increased by 1.8 or more mmol/L (5 or more mg/dL) after IV fluid hydration
Base deficit (negative base excess) > 4 mEq/L
Sequestration of fluids > 6 LThe criteria for point assignment is that a certain breakpoint be met at any time during that 48 hour period, so that in some situations it can be calculated shortly after admission. It is applicable to both gallstone and alcoholic pancreatitis.
Alternatively, pancreatitis can be diagnosed by meeting any of the following:[2]

Alternative Ranson score
Ransons score of ≥ 8
Organ failure
Substantial pancreatic necrosis (at least 30% glandular necrosis according to contrast-enhanced CT)
Interpretation
If the score ≥ 3, severe pancreatitis likely.
If the score < 3, severe pancreatitis is unlikely
Or
Score 0 to 2 : 2% mortality
Score 3 to 4 : 15% mortality
Score 5 to 6 : 40% mortality
Score 7 to 8 : 100% mortality

APACHE II score
"Acute Physiology And Chronic Health Evaluation" (APACHE II) score > 8 points predicts 11% to 18% mortality
Hemorrhagic peritoneal fluid
Obesity
Indicators of organ failure
Hypotension (SBP <90 mmHG) or tachycardia > 130 beat/min
PO2 <60 mmHg
Oliguria (<50 mL/h) or increasing BUN and creatinine
Serum calcium < 1.90 mmol/L (<8.0 mg/dL) or serum albumin <33 g/L (<3.2.g/dL)>

Balthazar score
Developed in the early 1990s by Emil J. Balthazar et al., the Computed Tomography Severity Index (CTSI) is a grading system used to determine the severity of acute pancreatitis. The numerical CTSI has a maximum of ten points, and is the sum of the Balthazar grade points and pancreatic necrosis grade points:
Balthazar grade

Necrosis score

CTSIs staging of acute pancreatitis severity has been shown by a number of studies to provide more accurate assessment than APACHE II, Ranson, and C-reactive protein (CRP) level. However, a few studies indicate that CTSI is not significantly associated with the prognosis of hospitalization in patients with pancreatic necrosis, nor is it an accurate predictor of AP severity.

Glasgow score
The Glasgow score is valid for both gallstone and alcohol induced pancreatitis, whereas the Ranson score is only for alcohol induced pancreatitis. If a patient scores 3 or more it indicates severe pancreatitis and the patient should be considered for transfer to ITU. It is scored through the mnemonic, PANCREAS:

P - PaO2 <8kPa
A - Age >55-years-old
N - Neutrophilia: WCC >15x10(9)/L
C - Calcium <2 mmol/L
R - Renal function: Urea >16 mmol/L
E - Enzymes: LDH >600iu/L; AST >200iu/L
A - Albumin <32g/L (serum)
S - Sugar: blood glucose >10 mmol/L

BISAP score
Predicts mortality risk in pancreatitis with fewer variables than Ransons criteria. Data should be taken from the first 24 hours of the patients evaluation.

BUN >25 mg/dL (8.9 mmol/L)
Abnormal mental status with a Glasgow coma score <15
Evidence of SIRS (systemic inflammatory response syndrome)
Patient age >60 years old
Imaging study reveals pleural effusionPatients with a score of zero had a mortality of less than one percent, whereas patients with a score of five had a mortality rate of 22 percent </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 Cyanide poisoning and can you explain it in depth? [/INST] Cyanide poisoning is poisoning that results from exposure to any of a number of forms of cyanide. Early symptoms include headache, dizziness, fast heart rate, shortness of breath, and vomiting. This phase may then be followed by seizures, slow heart rate, low blood pressure, loss of consciousness, and cardiac arrest. Onset of symptoms usually occurs within a few minutes. Some survivors have long-term neurological problems.Toxic cyanide-containing compounds include hydrogen cyanide gas and a number of cyanide salts. Poisoning is relatively common following breathing in smoke from a house fire. Other potential routes of exposure include workplaces involved in metal polishing, certain insecticides, the medication sodium nitroprusside, and certain seeds such as those of apples and apricots. Liquid forms of cyanide can be absorbed through the skin. Cyanide ions interfere with cellular respiration, resulting in the bodys tissues being unable to use oxygen.Diagnosis is often difficult. It may be suspected in a person following a house fire who has a decreased level of consciousness, low blood pressure, or high lactic acid. Blood levels of cyanide can be measured but take time. Levels of 0.5–1 mg/L are mild, 1–2 mg/L are moderate, 2–3 mg/L are severe, and greater than 3 mg/L generally result in death.If exposure is suspected, the person should be removed from the source of exposure and decontaminated. Treatment involves supportive care and giving the person 100% oxygen. Hydroxocobalamin (vitamin B12a) appears to be useful as an antidote and is generally first-line. Sodium thiosulphate may also be given. Historically cyanide has been used for mass suicide and by the Nazis for genocide.

Signs and symptoms
Acute exposure
If hydrogen cyanide is inhaled it can cause a coma with seizures, apnea, and cardiac arrest, with death following in a matter of seconds.  At lower doses, loss of consciousness may be preceded by general weakness, dizziness, headaches, vertigo, confusion, and perceived difficulty in breathing. At the first stages of unconsciousness, breathing is often sufficient or even rapid, although the state of the person progresses towards a deep coma, sometimes accompanied by pulmonary edema, and finally cardiac arrest. A cherry red skin color that darkens may be present as the result of increased venous hemoglobin oxygen saturation. Despite the similar name, cyanide does not directly cause cyanosis. A fatal dose for humans can be as low as 1.5 mg/kg body weight.  Other sources claim a lethal dose is 1–3 mg per kg body weight for vertebrates.

Chronic exposure
Exposure to lower levels of cyanide over a long period (e.g., after use of improperly processed cassava roots, which are a primary food source in tropical Africa) results in increased blood cyanide levels, which can result in weakness and a variety of symptoms, including permanent paralysis, nervous lesions, hypothyroidism, and miscarriages. Other effects include mild liver and kidney damage.

Causes
Cyanide poisoning can result from the ingestion of cyanide salts; imbibing pure liquid prussic acid; skin absorption of prussic acid; intravenous infusion of nitroprusside for hypertensive crisis; or the inhalation of hydrogen cyanide gas. The last typically occurs through one of three mechanisms:

The gas is directly released from canisters (e.g. as part of a pesticide, insecticide, or Zyklon B).
It is generated on site by reacting potassium cyanide or sodium cyanide with sulfuric acid (e.g. in a modern American gas chamber).
Fumes arise during a building fire or any similar scenario involving the burning of polyurethane, vinyl or other polymer products that required nitriles in their production.As potential contributing factors, cyanide is present in:

Tobacco smoke.
Many seeds or kernels such as those of almonds, apricots, apples, oranges, and flaxseed.
Foods including cassava (also known as tapioca, yuca or manioc) and bamboo shoots.As a potential harm-reduction factor, Vitamin B12, in the form of hydroxocobalamin (also spelled hydroxycobalamin), might reduce the negative effects of chronic exposure; whereas, a deficiency might worsen negative health effects following exposure to cyanide.

Mechanism
Cyanide is a potent cytochrome c oxidase (COX, a.k.a Complex IV) inhibitor. As such, cyanide poisoning is a form of histotoxic hypoxia, because it interferes with oxidative phosphorylation.: 1475 Specifically, cyanide binds to the heme a3-CuB binuclear center of COX (and thus is a non-competitive inhibitor of it). This prevents electrons passing through COX from being transferred to O2, which not only blocks the mitochondrial electron transport chain but also interferes with the pumping of a proton out of the mitochondrial matrix which would otherwise occur at this stage. Therefore, cyanide interferes not only with aerobic respiration but also with the ATP synthesis pathway it facilitates, owing to the close relationship between those two processes.: 705 One antidote for cyanide poisoning, nitrite (i.e. via amyl nitrite), works by converting ferrohemoglobin to ferrihemoglobin, which can then compete with COX for free cyanide (as the cyanide will bind to the iron in its heme groups instead). Ferrihemoglobin cannot carry oxygen, but the amount of ferrihemoglobin that can be formed without impairing oxygen transport is much greater than the amount of COX in the body.: 1475 Cyanide is a broad-spectrum poison because the reaction it inhibits is essential to aerobic metabolism; COX is found in many forms of life. However, susceptibility to cyanide is far from uniform across affected species; for instance, plants have an alternative electron transfer pathway available that passes electrons directly from ubiquinone to O2, which confers cyanide resistance by bypassing COX.: 704

Diagnosis
Lactate is produced by anaerobic glycolysis when oxygen concentration becomes too low for the normal aerobic respiration pathway. Cyanide poisoning inhibits aerobic respiration and therefore increases anaerobic glycolysis which causes a rise of lactate in the plasma. A lactate concentration above 10 mmol per liter is an indicator of cyanide poisoning, as defined by the presence of a blood cyanide concentration above 40 µmol per liter. Lactate levels greater than 6 mmol/L after reported or strongly suspected pure cyanide poisoning, such as cyanide-containing smoke exposure, suggests significant cyanide exposure.Methods of detection include colorimetric assays such as the Prussian blue test, the pyridine-barbiturate assay, also known as the "Conway diffusion method" and the taurine fluorescence-HPLC but like all colorimetric assays these are prone to false positives. Lipid peroxidation resulting in "TBARS," an artifact of heart attack produces dialdehydes that cross-react with the pyridine-barbiturate assay.  Meanwhile, the taurine-fluorescence-HPLC assay used for cyanide detection is identical to the assay used to detect glutathione in spinal fluid.
Cyanide and thiocyanate assays have been run with mass spectrometry (LC/MS/MS), which are considered specific tests. Since cyanide has a short half-life, the main metabolite, thiocyanate is typically measured to determine exposure. Other methods of detection include the identification of plasma lactate.

Treatment
Decontamination
Decontamination of people exposed to hydrogen cyanide gas only requires removal of the outer clothing and the washing of their hair. Those exposed to liquids or powders generally require full decontamination.

Antidote
The International Programme on Chemical Safety issued a survey (IPCS/CEC Evaluation of Antidotes Series) that lists the following antidotal agents and their effects: oxygen, sodium thiosulfate, amyl nitrite, sodium nitrite, 4-dimethylaminophenol, hydroxocobalamin, and dicobalt edetate (Kelocyanor), as well as several others. Other commonly-recommended antidotes are solutions A and B (a solution of ferrous sulfate in aqueous citric acid, and aqueous sodium carbonate, respectively) and amyl nitrite.
The United States standard cyanide antidote kit first uses a small inhaled dose of amyl nitrite, followed by intravenous sodium nitrite, followed by intravenous sodium thiosulfate. Hydroxocobalamin was approved for use in the US in late 2006 and is available in Cyanokit antidote kits. Sulfanegen TEA, which could be delivered to the body through an intra-muscular (IM) injection, detoxifies cyanide and converts the cyanide into thiocyanate, a less toxic substance. Alternative methods of treating cyanide intoxication are used in other countries.
The Irish Health and Safety Executive (HSE) has recommended against the use of solutions A and B because of their limited shelf life, potential to cause iron poisoning, and limited applicability (effective only in cases of cyanide ingestion, whereas the main modes of poisoning are inhalation and skin contact). The HSE has also questioned the usefulness of amyl nitrite due to storage/availability problems, risk of abuse, and lack of evidence of significant benefits. It also states that the availability of kelocyanor at the workplace may mislead doctors into treating a patient for cyanide poisoning when this is an erroneous diagnosis. The HSE no longer recommends a particular cyanide antidote.

History
Fires
The República Cromañón nightclub fire broke out in Buenos Aires, Argentina on 30 December 2004, killing 194 people and leaving at least 1,492 injured. Most of the victims died from inhaling poisonous gases, and carbon monoxide. After the fire, the technical institution INTI found that the level of toxicity due to the materials and volume of the building was 225 ppm of cyanide in the air. A lethal dose for rats is between 150 ppm and 220 ppm, meaning the air in the building was highly toxic.
On 5 December 2009, a fire in the night club Lame Horse (Khromaya Loshad) in the Russian city of Perm took the lives of 156 people. Fatalities consisted of 111 people at the site and 45 later in hospitals. One of the main causes of death was poisoning from cyanide and other toxic gases released by the burning of plastic and polyurethane foam used in the construction of club interiors. Taking into account the number of deaths, this was the largest fire in post-Soviet Russia.On 27 January 2013, a fire at the Kiss nightclub in the city of Santa Maria, in the south of Brazil, caused the poisoning of hundreds of young people by cyanide released by the combustion of soundproofing foam made with polyurethane. By March 2013, 245 fatalities were confirmed.

Gas chambers
In early 1942, Zyklon B, which contains hydrogen cyanide, emerged as the preferred killing tool of Nazi Germany for use in extermination camps during the Holocaust. The chemical was used to murder roughly one million people in gas chambers installed in extermination camps at Auschwitz-Birkenau, Majdanek, and elsewhere. Most of the people who were murdered were Jews, and by far the majority of these murders took place at Auschwitz. Zyklon B was supplied to concentration camps at Mauthausen, Dachau, and Buchenwald by the distributor Heli, and to Auschwitz and Majdanek by Testa. Camps also occasionally bought Zyklon B directly from the manufacturers. Of the 729 tonnes of Zyklon B sold in Germany in 1942–44, 56 tonnes (about eight percent of domestic sales) were sold to concentration camps. Auschwitz received 23.8 tonnes, of which six tonnes were used for fumigation. The remainder was used in the gas chambers or lost to spoilage (the product had a stated shelf life of only three months). Testa conducted fumigations for the Wehrmacht and supplied them with Zyklon B. They also offered courses to the SS in the safe handling and use of the material for fumigation purposes. In April 1941, the German agriculture and interior ministries designated the SS as an authorized applier of the chemical, and thus they were able to use it without any further training or governmental oversight.Hydrogen cyanide gas has been used for judicial execution in some states of the United States, where cyanide was generated by reaction between potassium cyanide (or sodium cyanide) dropped into a compartment containing sulfuric acid, directly below the chair in the gas chamber.

Suicide
Cyanide salts are sometimes used as fast-acting suicide devices. Cyanide reacts at a higher level with high stomach acidity.

On 26 January 1904, company promoter and swindler Whitaker Wright committed suicide by ingesting cyanide in a court anteroom immediately after being convicted of fraud.
In February 1937, the Uruguayan short story writer Horacio Quiroga committed suicide by drinking cyanide in a hospital at Buenos Aires.
In 1937, polymer chemist Wallace Carothers committed suicide by cyanide.
In the 1943 Operation Gunnerside to destroy the Vemork Heavy Water Plant in World War II (an attempt to stop or slow German atomic bomb progress), the commandos were given cyanide tablets (cyanide enclosed in rubber) kept in the mouth and were instructed to bite into them in case of German capture. The tablets ensured death within three minutes.
Cyanide, in the form of pure liquid prussic acid (a historical name for hydrogen cyanide), was the favored suicide agent of Nazi Germany. Erwin Rommel (1944), Adolf Hitlers wife, Eva Braun (1945), and Nazi leaders Heinrich Himmler (1945), possibly Martin Bormann (1945), and Hermann Göring (1946) all committed suicide by ingesting it.
It is speculated that, in 1954, Alan Turing used an apple that had been injected with a solution of cyanide to commit suicide after being convicted of having a homosexual relationship, which was illegal at the time in the United Kingdom, and forced to undergo hormonal castration to avoid prison. An inquest determined that Turings death from cyanide poisoning was a suicide, although this has been disputed.
Members of the Sri Lankan LTTE (Liberation Tigers of Tamil Eelam, whose insurgency lasted from 1983 to 2009), used to wear cyanide vials around their necks with the intention of committing suicide if captured by the government forces.
On 22 June 1977, Moscow, Aleksandr Dmitrievich Ogorodnik, a Soviet diplomat accused of spying on behalf of the Colombian Intelligence Agency and the US Central Intelligence Agency, was arrested. During the interrogations, Ogorodnik offered to write a full confession and asked for his pen. Inside the pen cap was a cleverly hidden cyanide pill, which when bitten on, caused Ogorodnik to die before he hit the floor, according to the Soviets.
On 18 November 1978, Jonestown. A total of 909 individuals died in Jonestown, many from apparent cyanide poisoning, in an event termed "revolutionary suicide" by Jones and some members on an audio tape of the event and in prior discussions. The poisonings in Jonestown followed the murder of five others by Temple members at Port Kaituma, including United States Congressman Leo Ryan, an act that Jones ordered. Four other Temple members committed murder-suicide in Georgetown at Jones command.
On 6 June 1985, serial killer Leonard Lake died in custody after having ingested cyanide pills he had sewn into his clothes.
On 28 June 2012, Wall Street trader Michael Marin ingested a cyanide pill seconds after a guilty verdict was read in his arson trial in Phoenix, AZ; he died minutes after.
On 22 June 2015, John B. McLemore, a horologist and the central figure of the podcast S-Town, died after ingesting cyanide.
On 29 November 2017, Slobodan Praljak died from drinking potassium cyanide, after being convicted of war crimes by the International Criminal Tribunal for the former Yugoslavia.

Mining and industrial
In 1993, an illegal spill resulted in the death of seven people in Avellaneda, Argentina. In their memory, the National Environmental Conscious Day (Día Nacional de la Conciencia Ambiental) was established.
In 2000, a spill at Baia Mare, Romania, resulted in the worst environmental disaster in Europe since Chernobyl.
In 2000, Allen Elias, CEO of Evergreen Resources was convicted of knowing endangerment for his role in the cyanide poisoning of employee Scott Dominguez. This was one of the first successful criminal prosecutions of a corporate executive by the Environmental Protection Agency.

Murder
John Tawell, a murderer who in 1845 became the first person to be arrested as the result of telecommunications technology.
Grigori Rasputin (1916; attempted, later killed by gunshot)
The Goebbels children (1945)
Stepan Bandera (1959)
Jonestown, Guyana, was the site of a large mass murder–suicide, in which over 900 members of the Peoples Temple drank potassium cyanide–laced Flavor Aid in 1978.
Chicago Tylenol murders (1982)
Timothy Marc OBryan (1966–1974) died on October 31, 1974 by ingesting potassium cyanide placed into a giant Pixy Stix. His father, Ronald Clark OBryan, was  convicted of Tims murder plus four counts of attempted murder. OBryan put potassium cyanide into five giant Pixy Stix that he gave to his son and daughter along with three other children. Only Timothy ate the poisoned candy and died.
Bruce Nickell (5 June 1986) Murdered by his wife who poisoned a bottle of Excedrin.
Richard Kuklinski (1935–2006)
Janet Overton (1942–1988) Her husband, Richard Overton was convicted of poisoning her, but Janets symptoms did not match those of classic cyanide poisoning, the timeline was inconsistent with cyanide poisoning, and the amount found was just a trace. The diagnostic method used was prone to false positives. Richard Overton died in prison in 2009.
Urooj Khan (1966–2012), won the lottery and was found dead a few days later. A blood diagnostic reported a lethal level of cyanide in his blood, but the body did not display any classic symptoms of cyanide poisoning, and no link to cyanide could be found in Uroojs social circle.  The diagnostic method used was the Conway diffusion method, prone to false positives with artifacts of heart attack and kidney failure.
Autumn Marie Klein (20 April 2013), a prominent 41-year-old neuroscientist and physician, died from cyanide poisoning. Kleins husband, Robert J. Ferrante, also a prominent neuroscientist who used cyanide in his research, was convicted of murder and sentenced to life in prison for her death. Robert Ferrante is appealing his conviction.
Mirna Salihin died in hospital on 6 January 2016, after drinking a Vietnamese iced coffee at a cafe in a shopping mall in Jakarta. Police reports claim that cyanide poisoning was the most likely cause of her death.
Jolly Thomas of Kozhikode, Kerala, India, was arrested in 2019 for the murder of 6 family members. Murders took place over 14-year period and each victim ate a meal prepared by the killer. The murders were allegedly motivated by wanting control of the family finances and property.
Mei Xiang Li of Brooklyn, NY, collapsed and died in April 2017, with cyanide later reported to be in her blood. However, Mei never exhibited symptoms of cyanide poisoning and no link to cyanide could be found in her life.

Warfare or terrorism
In 1988, between 3,200 and 5,000 people died in the Halabja massacre owing to unknown chemical nerve agents. Hydrogen cyanide gas was strongly suspected.
In 1995, a device was discovered in a restroom in the Kayabacho Tokyo subway station, consisting of bags of sodium cyanide and sulfuric acid with a remote controlled motor to rupture them in what was believed to be an attempt by the Aum Shinrikyo cult to produce toxic amounts of hydrogen cyanide gas.
In 2003, Al Qaeda reportedly planned to release cyanide gas into the New York City Subway system. The attack was supposedly aborted because there would not be enough casualties.

Research
Cobinamide is the final compound in the biosynthesis of cobalamin. It has greater affinity for the cyanide than cobalamin itself, which suggests that it could be a better option for emergency treatment.

See also
Anaerobic glycolysis
Lactic acidosis
List of poisonings
Konzo

References
Explanatory notes
Citations
Sources
Longerich, Peter (2010). Holocaust: The Nazi Persecution and Murder of the Jews. Oxford; New York: Oxford University Press. ISBN 978-0-19-280436-5.
Hayes, Peter (2004) </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 Lactation suppression and can you explain it in depth? [/INST] Lactation suppression refers to the act of suppressing lactation by medication or other non pharmaceutical means. The breasts may become painful when engorged with milk if breastfeeding is ceased abruptly, or if never started. This may occur if a woman never initiates breastfeeding, or if she is weaning from breastfeeding abruptly. Historically women who did not plan to breastfeed were given diethylstilbestrol and other medications after birth to suppress lactation. However, its use was discontinued, and there are no medications currently approved for lactation suppression in the US and the UK. Dopamine agonists are routinely prescribed to women following a stillbirth in the UK under the NHS.

Reasons
After birth, some women may desire to stop the production of breast milk, for example when the mother decides to bottle feed from birth, or in the case when the infant dies or is surrendered at birth. Additionally, women who are breastfeeding may need to stop breastfeeding abruptly, for instance if she is taking medication contraindicated for breastfeeding or undergoes surgery. The abrupt weaning process may lead to severe engorgement, extremely painful breasts, and possibly mastitis. Up to one third of women who do not breast-feed and who use a brassiere or binder, ice packs, or analgesics may experience severe breast pain. Specific studies of nonpharmacologic methods of lactation suppression were limited and inconclusive. Available data suggest that many women using currently recommended strategies for treatment of symptoms may nevertheless experience engorgement or pain for most of the first postpartum week.

Methods
Medication
Dopamine agonists are currently the preferred medication for suppressing lactation, which work by suppressing prolactin production. Cabergoline (Dostinex™) is currently most effective option currently available, as it is available as a single dose (as opposed to bromocriptine which must be taken twice daily for 2 weeks.)  It may be prescribed in the case of breast abscess. Although the preferred method of treatment for breast abscess and mastitis is actually to continue breastfeeding, if the decision is made to stop breastfeeding, then chemical lactation suppression is indicated, particularly for severe cases. Carbergoline is not indicated for treatment of discomfort caused by engorgement.  In the UK dopamine agonists are routinely prescribed following a stillbirth. Pre-eclampsia is a contraindication for prescribing dopamine agonists.In the past, hormonal therapies such as diethylstilbestrol were routinely used in the postpartum period, but these are no longer recommended due to side effects such as nausea and vomiting, and severe potential side effects such as thromboembolism, cerebral accident, and myocardial infarction. Estrogen containing birth control pills may have the same side effect, but like diethylstilbestrol is inappropriate for use in the postpartum period due to the risk of side effects </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 Epithelial dysplasia and can you explain it in depth? [/INST] Epithelial dysplasia, a term becoming increasingly referred to as intraepithelial neoplasia, is the sum of various disturbances of epithelial proliferation and differentiation as seen microscopically. Individual cellular features of dysplasia are called epithelial atypia.Examples of epithelial dysplasia include cervical intraepithelial neoplasia – a disorder commonly detected by an abnormal pap smear) consisting of an increased population of immature (basal-like) cells which are restricted to the mucosal surface, and have not invaded through the basement membrane to the deeper soft tissues. Analogous conditions include vaginal intraepithelial neoplasia and vulvar intraepithelial neoplasia. Metanephric dysplastic hematoma of the sacral region is a dysplastic overgrowth observed in infants.

Screening
Some tests which detect cancer could be called "screening for epithelial dysplasia". The principle behind these tests is that physicians expect dysplasia to occur at the same rate in a typical individual as it would in many other people. Because of this, researchers design screening recommendations which assume that if a physician can find no dysplasia at certain time, then doing testing before waiting until new dysplasia could potentially develop would be a waste of medical resources for the patient and the healthcare provider because the chances of detecting anything is extremely low.
Some examples of this in practice are that if a patient whose endoscopy did not detect dysplasia on biopsy during screening for Barretts esophagus, then research shows that there is little chance of any test detecting dysplasia for that patient within three years.Individuals at average-risk for colorectal cancer should have another screening after ten years if they get a normal result and after five years if they have only one or two  adenomatous polyps removed.

Microscopic changes
Dysplasia is characterised by four major pathological microscopic changes:

Anisocytosis (cells of unequal size)
Poikilocytosis (abnormally shaped cells)
Hyperchromatism (excessive pigmentation)
Presence of mitotic figures (an unusual number of cells which are currently dividing).Other changes that occur in epithelial dysplasia include:

Drop-shaped rete processes
Basal cell hyperplasia
Irregular epithelial stratification
Increased nuclear-cytoplasmic ratio
Increased normal and abnormal mitosis
Enlarged nucleoli
Individual cell keratinization
Loss or reduction of cellular cohesion
Cellular pleomorphism
Loss of basal cell polarity
KoilocytosisEpithelial cell dysplasia is divided into three categories of severity: mild, moderate, and severe.
Epithelial dysplasia becomes microinvasive squamous cell carcinoma once the tumor begins to invade nearby tissue.

Dysplasia vs. carcinoma in situ vs. invasive carcinoma
These terms are related since they represent three stages in the progression of many malignant tumors of the epithelium </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Purple glove syndrome and can you explain it in depth? [/INST] Purple glove syndrome (PGS) is a poorly understood skin disease in which the extremities become swollen, discoloured and painful. PGS is potentially serious, and may require amputation </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 Preadolescence and can you explain it in depth? [/INST] Preadolescence is a stage of human development following early childhood and preceding adolescence. It commonly ends with the beginning of puberty but may also be defined as ending with the start of the teenage years. Preadolescence is commonly defined as ages 9-12 ending with the major onset of puberty. It may also be defined as simply the 2-year period before the major onset of puberty.  Preadolescence can bring its own challenges and anxieties.

Terminology
Other slang and terminology used to refer to the preadolescent stage include tween or tweener, as a combination of the words "teen" and "between."While known as preadolescent in psychology, the terms preteen, preteenager, or tween are common in everyday use. A preteen or preteenager is a person 12 and under. Generally, the term is restricted to those close to reaching age 13, especially ages 9 to 12. Tween is an American neologism and marketing term for preteen, which is a blend of between and teen. People within this age range are variously described as tweens, preadolescents, tweenies, preteens, pubescents, junior highschoolers, middle schoolers, or tweenagers.

Prepubescence, puberty, and age range
Being prepubescent is not the same thing as being preadolescent. Instead, prepubescent (and sometimes child) is a term for boys and girls who have not developed secondary sex characteristics, while preadolescent is generally defined as those ranging from age 9 to 12 years.
Preadolescence may also be defined as the period from 10 to 13 years.The point at which a child becomes an adolescent is defined by the onset of puberty or the beginning of the teenage stage. However, in some individuals (particularly females), puberty begins in the preadolescence years. Studies indicate that the onset of puberty has been one year earlier with each generation since the 1950s.One can also distinguish middle childhood and preadolescence – middle childhood from approximately 5–8 years, as opposed to the time children are generally considered to reach preadolescence. There is no exact agreement as to when preadolescence starts and ends.

Hormonal development and the development of secondary sex characteristics
Early puberty begins as the result of the initiation of the pulsatile gonadotropin-releasing hormone (GnRH) secretion by the hypothalamus; the exact mechanism of this initiation is currently unknown and remains under investigation. Pulsatile GnRH secretion results in the pulsatile secretions of gonadotropins Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH), which act on the gonads (ovaries in females or testicles in males) to cause increase secretion of sex steroids. In females, the predominant sex steroid released is estrogen and in individuals with testicles, the predominant sex steroid released is testosterone. These sex hormones then lead to the development of secondary sex characteristics.

The stages of puberty can be described with the Tanner scale, also known as the Sexual Maturity Rating, which incorporates measurements and characteristics of primary and secondary sex characteristics. For example, genital and breast development, as well as pubic hair growth. Pubertal development is regulated by the hypothalamic-pituitary-gonadal (HPG) axis. Tanner staging ranges from 1 through 5 (with 5 being the most developed).With regards to pubic hair development, the scale goes as follows: Stage 1-no hair; 2-downy hair; 3-scant terminal hair; 4-terminal hair overlying the pubic triangle; 5-terminal hair extending to the thigh. With regards to male genitalia development, the scale goes as follows: 1-testes at the same size and proportion of early childhood; 2-enlargement of the scrotum/change in texture of scrotal skin; 3-growth of the penis length-wise; 4-growth of the penis in terms of length and circumference; 5-adult-sized genitalia.
With regards to female breast development, the scale is as follows: 1-no palpable gland tissue; 2-palpable breast bud under areola; 3-breast tissue palpable outside of areola; 4-areola elevated above breast contour; 5-areolar mound recedes into single breast contour. The average age in which both males and females reach Tanner stage 5 of pubertal development is around 15–16.

Neurological development
There are significant neurological changes that are expressed during preadolescence. White matter refers to the region of the nervous system corresponding to neuronal axons, which form fibers that convey information across different regions of the brain. In contrast, grey matter refers to the region of the nervous system corresponding to neuronal cell bodies, which process and relay neuronal signals. White matter volume increases at a relatively linear rate of about 12% from ages 4 through 22, specifically focused in the frontal, parietal, and occipital lobes. Increases in white matter volume may be correlated to improvements of fine motor performance, auditory processing, as well as sensory information transfer between language areas of the brain. In contrast, cortical gray matter increases in early life, peaks in preadolescence, and declines through adulthood, with the exception of occipital lobe gray matter. For example, parietal lobe gray matter peaks at age 10 in girls and 12 in boys, while frontal lobe gray matter peaks at age 11 in girls and 12 in boys. Such changes might reflect overproduction of synapses in the preadolescent years; in subsequent years, there seems to be pruning dependent on environmental context, corresponding to increased synchronicity of neuron firing. A key caveat from these imaging studies, however, is that there exists significant variability in the timing and characteristics of neurological change in preadolescents. Neurological changes, particularly in the prefrontal cortex, appear to be highly dependent on environmental input. Toxins, hormones, and lifestyle factors including stress and nutrition impact neurological maturation, demonstrating the importance of early lifestyle health interventions in preadolescence with regards to neurological and psychological development.

Psychological and social development
Of the two major socializing agents in childrens lives: the family environment...and formal educational institutions, it is the family in its function a primary socializer of the child that predominates in the first five years of life: middle childhood by contrast is characterized by a childs readiness for school...being self-assured and interested; knowing what kind of behavior is expected...being able to wait, to follow directions, and getting along with other children.Preadolescent children have a different view of the world from younger children in many significant ways. Typically, theirs is a more realistic view of life than the intense, fantasy-oriented world of earliest childhood. Preadolescents have more mature, sensible, realistic thoughts and actions: the most "sensible" stage of development...the child is a much less emotional being now. They will often have developed a sense of  intentionality. The wish and capacity to have an impact, and to act upon that with persistence; and will have a more developed sense of looking into the future and seeing effects of their actions (as opposed to early childhood where children often do not worry about their future). This can include more realistic job expectations ("I want to be an engineer when I grow up", as opposed to "I want to be a wizard"). Middle children generally show more investment in control over external reality through the acquisition of knowledge and competence: where they do have worries, these may be more a fear of kidnappings, rapes, and scary media events, as opposed to fantasy things (e.g., witches, monsters, ghosts).
Preadolescents may well view human relationships differently (e.g. they may notice the flawed, human side of authority figures). Alongside that, they may begin to develop a sense of self-identity, and to have increased feelings of independence: may feel an individual, no longer "just one of the family." A different view on morality can emerge; and the middle child will also show more cooperativeness. The ability to balance ones own needs with those of others in group activities. Many preadolescents will often start to question their home life and surroundings around this time and they may also start to form opinions that may differ from their upbringing in regards to issues such as politics, religion, sexuality, and gender roles.
Greater responsibility within the family can also appear, as middle children become responsible for younger siblings and relatives, as with babysitting; while preadolescents may start caring about what they look like and what they are wearing.
Prior to adolescence, children may have a dependence on their family as their main agent of socialization. This helps the child establish their attitudes, viewpoints, social norms, and societal roles.Among these changes is the shift from elementary to middle (or junior high) school. In this unfamiliar environment, the child may find the pressure to rapidly adapt and fit in. Children start to spend less time with family and more time with friends. At this time, socialization by the school and peer environment can become more predominant, as the preadolescent starts to learn more about how they would wish to hold themselves during interpersonal relationships.While children find this need to fit in, preadolescents have a conflicting desire to establish their own individualism. As the child grows into the transitionary period of preadolescence, the child often starts to develop a sense of autonomy as the child is exposed to a larger world around them full of sudden and unfamiliar changes. Compounded with a sense of self-consciousness, the preadolescent starts to explore their own self-identity and their role in society further.

Development of sexual orientation
During preadolescence (early adolescence), individuals may become more preoccupied with body image and privacy, corresponding to physical changes seen during adrenarche and puberty. Early adolescents may become aware of their sexuality for the first time, and experience attraction towards others. Homosexual and heterosexual experimentation is not uncommon, although it is important to note that many teens who eventually identify as LGBT do not always do so during adolescence. On average, gay, lesbian, and bisexual individuals report experiencing same-sex attraction in early adolescence, at age 12. About 4 in 10 gay men, and 2 in 10 lesbian women report experiencing same-sex attraction before age 10. For individuals who begin to experience same-sex attraction, familial support and acceptance consistently predicts positive outcomes. Parents and guardians can support preadolescents, regardless of sexual orientation, by having honest conversations about sex. Specifically, parents can talk and listen in a way that invites preadolescents to have an open discussion about sexual orientation.

Home from home
Where development has been optimal, preadolescents come to school for something to be added to their lives; they want to learn lessons...which can lead to their eventually working in a job like their parents. When earlier developmental stages have gone astray, however, then, on the principle that if you miss a stage, you can always go through it later, some middle children come to school for another purpose...[not] to learn but to find a home from home...a stable emotional situation in which they can exercise their own emotional liability, a group of which they can gradually become a part.

Divorce
Children at the threshold of adolescence in the nine-to-twelve-year-old group would seem to have particular vulnerabilities to parental separation. Among such problems were the very "eagerness of these youngsters to be co-opted into the parental battling; their willingness to take sides...and the intense, compassionate, caretaking relations which led these youngsters to attempt to rescue a distressed parent often to their own detriment".

Media
Preadolescents may well be more exposed to popular culture than younger children and have interests based on internet trends, television shows and movies (no longer just cartoons), fashion, technology, music and social media. Preadolescents generally prefer certain brands, and are a heavily targeted market of many advertisers </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 Dilated cardiomyopathy and can you explain it in depth? [/INST] Dilated cardiomyopathy (DCM) is a condition in which the heart becomes enlarged and cannot pump blood effectively. Symptoms vary from none to feeling tired, leg swelling, and shortness of breath. It may also result in chest pain or fainting. Complications can include heart failure, heart valve disease, or an irregular heartbeat.Causes include genetics, alcohol, cocaine, certain toxins, complications of pregnancy, and certain infections. Coronary artery disease and high blood pressure may play a role, but are not the primary cause. In many cases the cause remains unclear. It is a type of cardiomyopathy, a group of diseases that primarily affects the heart muscle. The diagnosis may be supported by an electrocardiogram, chest X-ray, or echocardiogram.In those with heart failure, treatment may include medications in the ACE inhibitor, beta blocker, and diuretic families. A low salt diet may also be helpful. In those with certain types of irregular heartbeat, blood thinners or an implantable cardioverter defibrillator may be recommended. Cardiac resynchronization therapy (CRT) may be necessary. If other measures are not effective a heart transplant may be an option in some.About 1 per 2,500 people is affected. It occurs more frequently in men than women. Onset is most often in middle age. Five-year survival rate is about 50%. It can also occur in children and is the most common type of cardiomyopathy in this age group.

Signs and symptoms
Dilated cardiomyopathy develops insidiously, and may not initially cause symptoms significant enough to impact on quality of life. Nevertheless, many people experience significant symptoms. These might include:
Shortness of breath
Syncope (fainting)
Angina, but only in the presence of ischemic heart diseaseA person who has dilated cardiomyopathy may have an enlarged heart, with pulmonary edema and an elevated jugular venous pressure and a low pulse pressure. Signs of mitral and tricuspid regurgitation may be present.

Causes
Although in many cases no cause is apparent, dilated cardiomyopathy is probably the result of damage to the myocardium produced by a variety of toxic, metabolic, or infectious agents. In many cases the cause remains unclear. It may be due to fibrous change of the myocardium from a previous myocardial infarction. Or, it may be the late sequelae of acute viral myocarditis, such as with Coxsackie B virus and other enteroviruses possibly mediated through an immunologic mechanism. Specific autoantibodies are detectable in some cases.Other causes include:

Chagas disease, due to Trypanosoma cruzi. This is the most common infectious cause of dilated cardiomyopathy in Latin America
Pregnancy: Dilated cardiomyopathy occurs late in gestation or several weeks to months postpartum as a peripartum cardiomyopathy. It is reversible in half of cases.
Alcohol use disorder (alcoholic cardiomyopathy)
Non-alcoholic toxic insults include administration of certain chemotherapeutic agents, in particular doxorubicin (Adriamycin), and cobalt.
Thyroid disease
Inflammatory diseases such as sarcoidosis and connective tissue diseases
Tachycardia-induced cardiomyopathy
Muscular dystrophy
Tuberculosis: 1 to 2% of TB cases.
Autoimmune mechanisms
Thiamine deficiencyRecent studies have shown that those subjects with an extremely high occurrence (several thousands a day) of premature ventricular contractions (extrasystole) can develop dilated cardiomyopathy. In these cases, if the extrasystole are reduced or removed (for example, via ablation therapy) the cardiomyopathy usually regresses.

Genetics
About 25–35% of affected individuals have familial forms of the disease, with most mutations affecting genes encoding cytoskeletal proteins, while some affect other proteins involved in contraction. The disease is genetically heterogeneous, but the most common form of its transmission is an autosomal dominant pattern.Autosomal recessive (as found, for example, in Alström syndrome), X-linked (as in Duchenne muscular dystrophy), and mitochondrial inheritance of the disease is also found. Some relatives of those affected by dilated cardiomyopathy have preclinical, asymptomatic heart-muscle changes.Other cytoskeletal proteins involved in DCM include α-cardiac actin, desmin, and the nuclear lamins A and C. Mitochondrial deletions and mutations presumably cause DCM by altering myocardial ATP generation.Kayvanpour et al. performed 2016 a meta-analysis with the largest dataset available on genotype-phenotype associations in DCM and mutations in lamin (LMNA), phospholamban (PLN), RNA Binding Motif Protein 20 (RBM20), Cardiac Myosin Binding Protein C (MYBPC3), Myosin Heavy Chain 7 (MYH7), Cardiac Troponin T 2 (TNNT2), and Cardiac Troponin I (TNNI3). They also reviewed recent studies investigating genotype-phenotype associations in DCM patients with titin (TTN) mutations. LMNA and PLN mutation carriers showed a high prevalence of cardiac transplantation and ventricular arrhythmia. Dysrhythmias and sudden cardiac death (SCD) was shown to occur even before the manifestation of DCM and heart failure symptoms in LMNA mutation carriers.

Pathophysiology
The progression of heart failure is associated with left ventricular remodeling, which manifests as gradual increases in left ventricular end-diastolic and end-systolic volumes, wall thinning, and a change in chamber geometry to a more spherical, less elongated shape. This process is usually associated with a continuous decline in ejection fraction. The concept of cardiac remodeling was initially developed to describe changes that occur in the days and months following myocardial infarction.

Compensation effects
As DCM progresses, two compensatory mechanisms are activated in response to impaired myocyte contractility and reduced stroke volume:
Frank-Starling law
Neurohormonal feedback, via activation of the sympathetic nervous system and the renin-angiotensin system.These responses initially compensate for decreased cardiac output and maintain those with DCM as asymptomatic. Eventually, however, these mechanisms become detrimental, intravascular volume becomes too great, and progressive dilatation leads to heart failure symptoms.

Computational models
Cardiac dilatation is a transversely isotropic, irreversible process resulting from excess strains on the myocardium. A computation model of volumetric, isotropic, and cardiac wall growth predicts the relationship between cardiac strains (e.g. volume overload after myocardial infarction) and dilation using the following governing equations:

        F
        =

          F

            e

        ⋅

          F

            g

    {\displaystyle F=F^{e}\cdot F^{g}\,}

where

          F

            e

    {\displaystyle F^{e}}
   is elastic volume stretch that is reversible and

          F

            g

    {\displaystyle F^{g}}
   is irreversible, isotropic volume growth described by:

          F

            g

        =

          I

        +
        [

          λ

            g

        −
        1
        ]

          f

            0

        ⊗

          f

            0

    {\displaystyle F^{g}=\mathbb {I} +[\lambda ^{g}-1]f_{0}\otimes f_{0}\,}

where

          f

            0

    {\displaystyle f_{0}}
   is a vector, which points along a cardiomyocytes long axis and

          λ

            g

    {\displaystyle \lambda ^{g}}
   is the cardiomyocyte stretch due to growth. The total cardiomyocyte growth is given by:

        λ
        =

          λ

            e

        ⋅
        F

          λ

            g

    {\displaystyle \lambda =\lambda ^{e}\cdot F\lambda ^{g}\,}

The above model reveals a gradual dilation of the myocardium, especially the ventricular myocardium, to support the blood volume overload in the chambers. Dilation manifests itself in an increase in total cardiac mass and cardiac diameter. Cardiomyocytes reach their maximum length of 150

        μ

    {\displaystyle \mu }
  m in the endocardium and 130

        μ

    {\displaystyle \mu }
  m in the epicardium by the addition of sarcomeres.  Due to the increase in diameter, the dilated heart appears spherical in shape, as opposed the elliptical shape of a healthy human heart. In addition, the ventricular walls maintain the same thickness, characteristic of pathophysiological cardiac dilation.

Valvular effects
As the ventricles enlarge, both the mitral and tricuspid valves may lose their ability to come together properly. This loss of coaptation may lead to mitral and tricuspid regurgitation. As a result, those with DCM are at increased risk of atrial fibrillation. Furthermore, stroke volume is decreased and a greater volume load is placed on the ventricle, thus increasing heart failure symptoms.

Diagnosis
Generalized enlargement of the heart is seen upon normal chest X-ray. Pleural effusion may also be noticed, which is due to pulmonary venous hypertension.The electrocardiogram often shows sinus tachycardia or atrial fibrillation, ventricular arrhythmias, left atrial enlargement, and sometimes intraventricular conduction defects and low voltage. When left bundle-branch block (LBBB) is accompanied by right axis deviation (RAD), the rare combination is considered to be highly suggestive of dilated or congestive cardiomyopathy. Echocardiogram shows left ventricular dilatation with normal or thinned walls and reduced ejection fraction. Cardiac catheterization and coronary angiography are often performed to exclude ischemic heart disease.Genetic testing can be important, since one study has shown that gene mutations in the TTN gene (which codes for a protein called titin) are responsible for "approximately 25% of familial cases of idiopathic dilated cardiomyopathy and 18% of sporadic cases." The results of the genetic testing can help the doctors and patients understand the underlying cause of the dilated cardiomyopathy. Genetic test results can also help guide decisions on whether a patients relatives should undergo genetic testing (to see if they have the same genetic mutation) and cardiac testing to screen for early findings of dilated cardiomyopathy.Cardiac magnetic resonance imaging (cardiac MRI) may also provide helpful diagnostic information in patients with dilated cardiomyopathy.

Treatment
Medical therapy
Drug therapy can slow down progression and in some cases even improve the heart condition. Standard therapy may include salt restriction, ACE inhibitors, diuretics, and beta blockers. Anticoagulants may also be used for antithrombotic therapy. There is some evidence for the benefits of coenzyme Q10 in treating heart failure.

Electrical treatment
Artificial pacemakers may be used in patients with intraventricular conduction delay, and implantable cardioverter-defibrillators in those at risk of arrhythmia </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 Neutropenic enterocolitis 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 Hypertonia and can you explain it in depth? [/INST] Hypertonia is a term sometimes used synonymously with spasticity and rigidity in the literature surrounding damage to the central nervous system, namely upper motor neuron lesions. Impaired ability of damaged motor neurons to regulate descending pathways gives rise to disordered spinal reflexes, increased excitability of muscle spindles, and decreased synaptic inhibition. These consequences result in abnormally increased muscle tone of symptomatic muscles. Some authors suggest that the current definition for spasticity, the velocity-dependent over-activity of the stretch reflex, is not sufficient as it fails to take into account patients exhibiting increased muscle tone in the absence of stretch reflex over-activity. They instead suggest that "reversible hypertonia" is more appropriate and represents a treatable condition that is responsive to various therapy modalities like drug and/or physical therapy.

Presentation
Symptoms associated with central nervous systems disorders are classified into positive and negative categories. Positive symptoms include those that increase muscle activity through hyper-excitability of the stretch reflex (i.e., rigidity and spasticity) where negative symptoms include those of insufficient muscle activity (i.e. weakness) and reduced motor function. Often the two classifications are thought to be separate entities of a disorder; however, some authors propose that they may be closely related.

Pathophysiology
Hypertonia is caused by upper motor neuron lesions which may result from injury, disease, or conditions that involve damage to the central nervous system.  The lack of or decrease in upper motor neuron function leads to loss of inhibition with resultant hyperactivity of lower motor neurons.  Different patterns of muscle weakness or hyperactivity can occur based on the location of the lesion, causing a multitude of neurological symptoms, including spasticity, rigidity, or dystonia.Spastic hypertonia involves uncontrollable muscle spasms, stiffening or straightening out of muscles, shock-like contractions of all or part of a group of muscles, and abnormal muscle tone. It is seen in disorders such as cerebral palsy, stroke, and spinal cord injury.  Rigidity is a severe state of hypertonia where muscle resistance occurs throughout the entire range of motion of the affected joint independent of velocity. It is frequently associated with lesions of the basal ganglia. Individuals with rigidity present with stiffness, decreased range of motion and loss of motor control.  Dystonic hypertonia refers to muscle resistance to passive stretching (in which a therapist gently stretches the inactive contracted muscle to a comfortable length at very low speeds of movement) and a tendency of a limb to return to a fixed involuntary (and sometimes abnormal) posture following movement.

Management
Therapeutic interventions are best individualized to particular patients.Basic principles of treatment for hypertonia are to avoid noxious stimuli and provide frequent range of motion exercise.

Physical interventions
Physiotherapy has been shown to be effective in controlling hypertonia through the use of stretching aimed to reduce motor neuron excitability. The aim of a physical therapy session could be to inhibit excessive tone as far as possible, give the patient a sensation of normal position and movement, and to facilitate normal movement patterns. While static stretch has been the classical means to increase range of motion, PNF stretching has been used in many clinical settings to effectively reduce muscle spasticity.Icing and other topical anesthetics may decrease the reflexive activity for short period of time in order to facilitate motor function </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 Blister and can you explain it in depth? [/INST] A blister is a small pocket of body fluid (lymph, serum, plasma, blood, or pus) within the upper layers of the skin, usually caused by forceful rubbing (friction), burning, freezing, chemical exposure or infection. Most blisters are filled with a clear fluid, either serum or plasma. However, blisters can be filled with blood (known as "blood blisters") or with pus (for instance, if they become infected).
The word "blister" entered English in the 14th century. It came from the Middle Dutch bluyster and was a modification of the Old French blostre, which meant a leprous nodule—a rise in the skin due to leprosy. In dermatology today, the words vesicle and bulla refer to blisters of smaller or greater size, respectively.
To heal properly, a blister should not be popped unless medically necessary. If popped, the excess skin should not be removed because the skin underneath needs the top layer to heal properly.

Causes
A blister may form when the skin has been damaged by friction or rubbing, heat, cold or chemical exposure. Fluid collects between the upper layers of skin (the epidermis) and the layers below (the dermis). This fluid cushions the tissue underneath, protecting it from further damage and allowing it to heal.

Friction
Intense rubbing can cause a blister, as can any friction on the skin if continued long enough. This kind of blister is most common after walking long distances or by wearing old or poorly fitting shoes. Blisters are most common on the hands and feet, as these extremities are susceptible while walking, running, or performing repetitive motions, such as joystick manipulation whilst playing certain video games, certain sports (e.g., baseball pitching), digging with a shovel, playing guitar or bass, etc. Blisters form more easily on damp skin than on dry or soaked skin, and are more common in warm conditions. Less-aggressive rubbing over long periods of time may cause calluses to form rather than a blister. Both blisters and calluses can lead to more serious complications, such as foot ulceration and infection, particularly when sensation or circulation is impaired, as in the case of diabetes, neuropathy or peripheral artery disease (PAD).

Burning
This type of blistering is one of the tools used to determine the degree of burns sustained. First and second degree burns may result in blistered skin; however, it is characteristic of second degree burns to blister immediately, whereas first degree burns can have blisters after a couple of days. Sunburn can also result in blisters.
Blisters can also form on the hands and feet as a result of tissue damage incurred by frostbite.

Chemical exposure
Sometimes, the skin will blister when it comes into contact with a cosmetic, detergent, solvent, or other chemical such as nickel sulfate, Balsam of Peru, or urushiol (poison ivy, poison oak, poison sumac). This is known as contact dermatitis. Blisters can also develop as a result of an allergic reaction to an insect bite or sting.  Some chemical warfare agents, known as blister agents or vesicants, cause large, painful blisters wherever they contact skin; an example is mustard gas.

Blood blister
A blood blister usually forms when a minute blood vessel close to
the surface of the skin ruptures (breaks), and blood leaks into a tear between the layers of skin. This can happen if the skin is crushed, pinched or aggressively squeezed.

Medical conditions
There are also a number of medical conditions that cause blisters. The most common are chickenpox, herpes, impetigo, and a form of eczema called dyshidrosis. Other, much rarer conditions that cause blisters include:

Bullous pemphigoid: a skin disease that causes large, tightly filled blisters to develop, usually affecting people over the age of 60.
Pemphigus: a serious skin disease in which blisters develop if pressure is applied to the skin; the blisters burst easily, leaving raw areas that can become infected.
Dermatitis herpetiformis: a skin disease that causes intensely itchy blisters, usually on the elbows, knees, back and buttocks. The blisters usually develop in patches of the same shape and size on both sides of the body.
Chronic bullous dermatosis: a disease that causes clusters of blisters on the face, mouth or genitals.
Cutaneous radiation syndrome
Epidermolysis bullosa

Pathophysiology
Friction blisters
Friction blisters are caused by excess shear stress between the bottom and surface of the skin and the body. The strata of skin around the stratum spinosum are most susceptible to shear. As the stratum spinosum tears away from the connecting tissues below, plasma from the cells diffuses out. This plasma solution helps new cells divide and grow into new connective tissues and epidermal layers.
The clear fluid will be reabsorbed as new cells develop and the swollen appearance will subside. Painful blisters located on hands (palmar surface) and feet (plantar surface) are due to tissue shearing deeper in the epidermis, near nerve endings. Lower tissues are more susceptible to infection.

Prevention
Friction blisters
Friction blisters, caused by rubbing against the skin, can be prevented by reducing the friction to a level where blisters will not form. This can be accomplished in a variety of ways.
Blisters on the feet can be prevented by wearing comfortable, well-fitting shoes and clean socks. Inherently ill-fitting or stiffer shoes, such as high heels and dress shoes, present a larger risk of blistering. Blisters are more likely to develop on skin that is moist, so socks that manage moisture or frequent sock changes will aid those with particularly sweaty feet. While exercising or playing sports, special sports socks can help keep feet drier and reduce the chance of blisters. Before going for a long walk, it is also important to ensure that shoes or hiking boots have been properly broken in.
Even before a "hot" or irritated area on the foot is felt, taping a protective layer of padding or a friction-reducing interface between the affected area and the footwear can prevent the formation of a blister. Bandages, moleskin and tapes generally must be applied to the foot daily, and most have a very high coefficient of friction (COF), but a friction-management patch applied to the shoe will remain in place much longer, throughout many changes of socks and insoles. This type of intervention may be used with footwear that is worn daily, with specialty shoes and boots like hockey skates, ice skates, inline skates, ski boots and cleats, or even with orthotic braces and splints </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 Livedoid dermatitis and can you explain it in depth? [/INST] Livedoid dermatitis is a iatrogenic cutaneous reaction that occurs immediately after a drug injection.  It presents as an immediate, extreme pain around the injection site, with overlying skin rapidly becoming erythematous, violaceous, or blanched ("ischemic pallor"): 124  and sometimes with reticular pattern </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 Empyema 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 Irritant diaper dermatitis and can you explain it in depth? [/INST] Irritant diaper dermatitis (IDD, also called a diaper/nappy rash) is a generic term applied to skin rash in the diaper nappy area that are caused by various skin disorders and/or irritants.
Generic irritant diaper/nappy  dermatitis is characterized by joined patches of erythema and scaling mainly seen on the convex surfaces, with the skin folds spared.
Diaper/nappy dermatitis with secondary bacterial or fungal involvement tends to spread to concave surfaces (i.e. skin folds), as well as convex surfaces, and often exhibits a central red, beefy erythema with satellite pustules around the border.
It is usually considered a form of irritant contact dermatitis. The word "diaper" is in the name not because the diaper/nappy itself causes the rash but rather because the rash is associated with diaper use, being caused by the materials trapped by the diaper (usually feces). Allergic contact dermatitis has also been suggested, but there is little evidence for this cause. In adults with incontinence (fecal, urinary, or both), the rash is sometimes called incontinence-associated dermatitis (IAD).The term diaper candidiasis is used when a fungal origin is identified. The distinction is critical because the treatment (antifungals) is completely different.

Causes
Irritant diaper dermatitis develops when skin is exposed to prolonged wetness, increased skin pH caused by the combination, and subsequent reactions, of urine and feces, and resulting breakdown of the stratum corneum, or outermost layer of the skin.  This may be due to diarrhea, frequent stools, tight diapers, overexposure to ammonia, or allergic reactions.  In adults, the stratum corneum is composed of 25 to 30 layers of flattened dead keratinocytes, which are continuously shed and replaced from below. These dead cells are interlaid with lipids secreted by the stratum granulosum just underneath, which help to make this layer of the skin a waterproof barrier. The stratum corneums function is to reduce water loss, repel water, protect deeper layers of the skin from injury, and to repel microbial invasion of the skin. In infants, this layer of the skin is much thinner and more easily disrupted.

Urine
Although wetness alone has the effect of macerating the skin, softening the stratum corneum, and greatly increasing susceptibility to friction injury, urine has an additional impact on skin integrity because of its effect on skin pH. While studies show that ammonia alone is only a mild skin irritant, when urea breaks down in the presence of fecal urease it increases pH because ammonia is released, which in turn promotes the activity of fecal enzymes such as protease and lipase. These fecal enzymes increase the skins hydration and permeability to bile salts which also act as skin irritants.
There is no detectable difference in rates of diaper rash in conventional disposable diaper wearers and reusable cloth diaper wearers. "Babies wearing superabsorbent disposable diapers with a central gelling material have fewer episodes of diaper dermatitis compared with their counterparts wearing cloth diapers. However, keep in mind that superabsorbent diapers contain dyes that were suspected to cause allergic contact dermatitis (ACD)." Whether wearing cloth or disposable diapers they should be changed frequently to prevent diaper rash, even if they dont feel wet. To reduce the incidence of diaper rash, disposable diapers have been engineered to pull moisture away from the babys skin using synthetic non-biodegradable gel.  Today, cloth diapers use newly available superabsorbent microfiber cloth placed in a pocket with a layer of light permeable material that contacts the skin.  This design serves to pull moisture away from the skin in to the microfiber cloth.  This technology is used in most major pocket cloth diapers brands today.

Diet
The interaction between fecal enzyme activity and IDD explains the observation that infant diet and diaper rash are linked because fecal enzymes are in turn affected by diet. Breast-fed babies, for example, have a lower incidence of diaper rash, possibly because their stools have higher pH and lower enzymatic activity. Diaper rash is also most likely to be diagnosed in infants 8–12 months old, perhaps in response to an increase in eating solid foods and dietary changes around that age that affect fecal composition. Any time an infants diet undergoes a significant change (i.e. from breast milk to formula or from milk to solids) there appears to be an increased likelihood of diaper rash.The link between feces and IDD is also apparent in the observation that infants are more susceptible to developing diaper rash after treating with antibiotics, which affect the intestinal microflora. Also, there is an increased incidence of diaper rash in infants who have had diarrhea in the previous 48 hours, which may be because fecal enzymes such as lipase and protease are more active in feces which have passed rapidly through the gastrointestinal tract.

Secondary infections
The significance of secondary infection in IDD remains controversial. There seems to be no link between presence or absence of IDD and microbial counts. Although apparently healthy infants sometimes culture positive for Candida and other organisms without exhibiting any symptoms, there does seem to be a positive correlation between the severity of the diaper rash noted and the likelihood of secondary involvement. A wide variety of infections has been reported, including Staphylococcus aureus, Streptococcus pyogenes, Proteus mirabilis, enterococci and Pseudomonas aeruginosa, but it appears that Candida is the most common opportunistic invader in diaper areas.

Diagnosis
The diagnosis of IDD is made clinically, by observing the limitation of an erythematous eruption to the convex surfaces of the genital area and buttocks. If the diaper dermatitis occurs for greater than 3 days it may be colonized with Candida albicans, giving it the beefy red, sharply marginated, appearance of diaper candidiasis.

Differential diagnosis
Other rashes that  occur in the diaper area include seborrhoeic dermatitis and atopic dermatitis. Both Seborrheic and Atopic dermatitis require individualized treatment; they are not the subject of this article.

Seborrheic dermatitis, typified by oily, thick yellowish scales, is most commonly seen on the scalp (cradle cap) but can also appear in the inguinal folds.
Atopic dermatitis, or eczema, is associated with allergic reaction, often hereditary. This class of rashes may appear anywhere on the body and is characterized by intense itchiness.

Treatments
Possible treatments include minimizing diaper use, barrier creams, mild topical cortisones, and antifungal agents. A variety of other inflammatory and infectious processes can occur in the diaper area and an awareness of these secondary types of diaper dermatitis aids in the accurate diagnosis and treatment of patients.Overall, there is sparse evidence of sufficient quality to be certain of the effectiveness of the various treatments. Washcloths with cleansing, moisturising and protective properties may be better than soap and water, and skin cleansers may also be better than soap and water, but the certainty of evidence with regard other treatments is very low.

Diaper changing
The most effective treatment, although not the most practical one, is to discontinue use of diapers, allowing the affected skin to air out </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 Gait abnormality 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 Eczema herpeticum and can you explain it in depth? [/INST]  </s>