<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 Tetralogy of Fallot and can you explain it in depth? [/INST] Tetralogy of Fallot (TOF), formerly known as Steno-Fallot tetralogy, is a congenital heart defect characterized by four specific cardiac defects. Classically, the four defects are:
pulmonary stenosis, which is narrowing of the exit from the right ventricle;
a ventricular septal defect, which is a hole allowing blood to flow between the two ventricles;
right ventricular hypertrophy, which is thickening of the right ventricular muscle; and
an overriding aorta, which is where the aorta expands to allow blood from both ventricles to enter.At birth, children may be asymptomatic or present with many severe symptoms. Later in infancy, there are typically episodes of bluish colour to the skin due to a lack of sufficient oxygenation, known as cyanosis. When affected babies cry or have a bowel movement, they may undergo a "tet spell" where they turn cyanotic, have difficulty breathing, become limp, and occasionally lose consciousness. Other symptoms may include a heart murmur, finger clubbing, and easy tiring upon breastfeeding.The cause of tetralogy of Fallot is typically not known. Risk factors include a mother who uses alcohol, has diabetes, is over the age of 40, or gets rubella during pregnancy.: 62  It may also be associated with Down syndrome and other chromosomal defects that cause congenital heart defects.TOF is typically treated by open heart surgery in the first year of life. The timing of surgery depends on the babys symptoms and size. The procedure involves increasing the size of the pulmonary valve and pulmonary arteries and repairing the ventricular septal defect. In babies who are too small, a temporary surgery may be done with plans for a second surgery when the baby is bigger. With proper care, most people who are affected live to be adults. Long-term problems may include an irregular heart rate and pulmonary regurgitation.The prevalence of TOF is estimated to be anywhere from 0.02 to 0.04%. Though males and females were initially thought to be affected equally, more recent studies have found males to be affected more than females. It is the most common complex congenital heart defect, accounting for about 10 percent of cases. It was initially described in 1671 by Niels Steensen. A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it is named. The first total surgical repair was carried out in 1954.

Signs and symptoms
Tetralogy of Fallot results in low oxygenation of blood. This is due to a mixing of oxygenated and deoxygenated blood in the left ventricle via the ventricular septal defect (VSD) and preferential flow of the mixed blood from both ventricles through the aorta because of the obstruction to flow through the pulmonary valve. The latter is known as a right-to-left shunt.Infants with TOF – a cyanotic heart disease – have low blood oxygen saturation. Blood oxygenation varies greatly from one patient to another depending on the severity of the anatomic defects. Typical ranges vary from 60% to around 90%. Depending on the degree of obstruction, symptoms vary from no cyanosis or mild cyanosis to profound cyanosis at birth. If the baby is not cyanotic, then it is sometimes referred to as a "pink tet". Other symptoms include a heart murmur which may range from almost imperceptible to very loud, difficulty in feeding, failure to gain weight, retarded growth and physical development, labored breathing (dyspnea) on exertion, clubbing of the fingers and toes, and polycythemia. The baby may turn blue with breastfeeding or crying.Those born with tetralogy of Fallot are more likely to experience psychiatric disorders such as attention deficit hyperactivity disorder (ADHD) in later life, potentially due to underlying genetic changes that predispose to both conditions.

Tet spells
Infants and children with unrepaired tetralogy of Fallot may develop "tet spells". These are acute hypoxia spells, characterized by shortness of breath, cyanosis, agitation, and loss of consciousness.: 200  This may be initiated by any event – such as anxiety, pain, dehydration, or fever – leading to decreased oxygen saturation or that causes decreased systemic vascular resistance, which in turn leads to increased shunting through the ventricular septal defect. Typically, these spells decrease in frequency after the first four years of life.Clinically, tet spells are characterized by a sudden, marked increase in cyanosis followed by syncope.: 200 Older children will often squat instinctively during a tet spell. This increases systemic vascular resistance and allows for a temporary reversal of the shunt. It increases pressure on the left side of the heart, decreasing the right to left shunt, thus decreasing the amount of deoxygenated blood entering the systemic circulation.

Cause
While the specific causes of TOF have not been fully identified, there are various environmental or genetic factors that have been associated with TOF. So far, around 20% of overall CHD cases have been due to known causes such as genetic defects and teratogens which are various factors causing embryo development abnormalities or birth defects. However, the other 80% of cases have little known about their cause.Genetic factors linked to TOF include various gene mutations or deletions. Gene deletions associated with TOF include chromosome 22 deletion as well as DiGeorge syndrome.Specific genes associations with TOF include:

JAG1 codes for ligands within the Notch family of proteins and is highly expressed in the developing heart. Mutations of the JAG1 gene can lead to abnormal heart development associated with TOF.
NKX2-5 codes for cardiac morphogenesis regulators to allow for proper heart development. Defects in this gene typically causes septal defects and has been associated with around 4% of all TOF cases.
ZFPM2 is another cardiac regulator involved in regulation of GATA4. Mutations of the ZFPM2 gene lead to reduced GATA production and have been seen in some TOF cases.
VEGF a well-known endothelial growth factor involved in the vascularization of the heart. Decreased VEGF expression has been shown to be a modifier of TOF.
NOTCH1 is involved in the vascularization of tissues and is the most common site of genetic variations involved with TOF, accounting for 7% of all TOF cases.
TBX1 expresses progenitors involved with the development of the right ventricle. Chromosome 22q11 deletions also deleting TBX1 gene have been seen in 17% TOF cases.
FLT4 gene expression leads to Vascular endothelial growth factor receptor 3 (VEGFR-3) which helps vascularization. Mutations of this gene have been associated with TOF, accounting for 2.4% of all cases.
FOXC2 is another gene involved in embryonic development of the cardiac system. Mutations of this gene have been shown to result in dysfunctional lymphatic syndrome and TOF.
GATA4 aids in cardiac development by helping increase the production of cardiomyocytes. Mutations of this gene have been seen in various familial TOF cases often lasting 2-3 generations.
FLNA is a protein coded by the gene of the same name that crosslinks actin filaments into networks in cytoplasm and helps anchor membrane proteins for the actin cytoskeleton. Mutations of this gene were seen to cause TOF in some patients.The Environmental Factors that have been studied to potentially be associated TOF include:

Maternal Alcohol consumption: During embryonic development, many of the body’s processing and filtration systems are not fully developed. Fetal body is unable to process alcohol as well as adults which can lead to improper development, including cardiogenesis. While no conclusive evidence has been found between effects of alcohol consumption and TOF, maternal alcohol consumption has been seen in various patients with TOF.
Maternal smoking: Maternal smoking has been associated with various fetal complications such as premature delivery and low birth weight which can lead to TOF. In the famous Baltimore-Washington Study, it was reported that smoking more than one pack per day while pregnant was associated with two specific cardiac deflects, both part of TOF: pulmonary stenosis and transposition with VSD.
Maternal diabetes: Maternal diabetes, diabetes Mellitus, and gestational diabetes are well-known risk factors of fetal CHD, including TOF. Maternal diabetes has been shown to increase the risk of cardiovascular deformations, namely the transposition of great arteries, one of the four deformations in TOF. Studies have also looked at whether diabetes increases the risk of malformation or poor sugar regulation and have found that sugar regulation does not significantly affect cardiac malformations. Retrospective studies have shown that diabetic mothers with good glucose control still retained the elevated CHD risk.
Rubella: Rubella is characterized as mild, contagious viral disease with often unnoticed consequences. Infection with rubella during the first trimester has been seen to cause various fetal malformations, including TOF.
Maternal Age: Older maternal age, especially after 35 can have various pregnancy risks due to existing co-morbidities such as hypertension, diabetes, hypothyroidism, and consanguinity. These risk factors can effect fetal development and lead to various fetal conditions such as CHD (including TOF), Down Syndrome and Autism.Embryology studies show that anterior malalignment of the aorticopulmonary septum results in the clinical combination of a ventricular septal defect (VSD), pulmonary stenosis, and an overriding aorta.: 200  Right ventricular hypertrophy develops progressively from resistance to blood flow through the right ventricular outflow tract.

Pathophysiology
In healthy individuals, the human heart develops around the 20th day of gestation, when the outer endocardial tubes merge into a single cardiac tube. Thereafter, the cardiac tube begins to fold, developing into the atrium and ventricle. The right ventricle is dominant prior to birth, receiving 65% of the venous return to the heart, and is the main contributor of blood flow to the lower part of the body, the placenta, and the lungs. Though the exact cause of TOF is unknown, an association that has been observed is an anterior deviation of the infundibular septum that results in a misaligned VSD, with an overriding aorta causing a subsequent right ventricular obstruction.Different factors such as pulmonary stenosis can also contribute with the right ventricular outflow obstruction. During tet spells, a decrease in systemic vascular resistance or an increase in pulmonary resistance would be physiologically observed.
The main anatomic defect in TOF is the anterior deviation of the pulmonary outflow septum. This defect results in narrowing of the right ventricular outflow tract (RVOT), override of the aorta, and a VSD.

Four malformations
"Tetralogy" denotes four parts, here implying the syndromes four anatomic defects. This is not to be confused with the similarly named teratology, a field of medicine concerned with abnormal development and congenital malformations (including tetralogy of Fallot). Below are the four heart malformations that present together in tetralogy of Fallot:

There is anatomic variation between the hearts of individuals with tetralogy of Fallot. Primarily, the degree of right ventricular outflow tract obstruction varies between patients and generally determines clinical symptoms and disease progression.Presumably, this arises from an unequal growth of the aorticopulmonary septum (aka pulmonary outflow septum).: 199  The aorta is too large, thus "overriding," and this "steals" from the pulmonary artery, which is therefore stenosed. This then prevents ventricular wall closure, therefore VSD, and this increases the pressures on the right side, and so the R ventricle becomes bigger to handle the work.: 199

Additional anomalies
In addition, tetralogy of Fallot may present with other anatomical anomalies, including:: 66–8
stenosis of the left pulmonary artery, in 40%
a bicuspid pulmonary valve, in 60%
right-sided aortic arch, in 25%
coronary artery anomalies, in 10%
a patent foramen ovale or atrial septal defect, in which case the syndrome is sometimes called a pentalogy of Fallot
an atrioventricular septal defect
partially or totally anomalous pulmonary venous returnTetralogy of Fallot with pulmonary atresia (pseudotruncus arteriosus) is a severe variant in which there is complete obstruction (atresia) of the right ventricular outflow tract, causing an absence of the pulmonary trunk during embryonic development.: 67–8  In these individuals, blood shunts completely from the right ventricle to the left where it is pumped only through the aorta. The lungs are perfused via extensive collaterals from the systemic arteries, and sometimes also via the ductus arteriosus.: 67–8

Diagnosis
There are three different useful diagnostic tests used for the diagnosis of tetralogy of Fallot. These include a chest radiograph, electrocardiogram, and echocardiogram. The echocardiography determines the final diagnosis and typically offers enough information for surgical treatment planning. About half of all patients are now diagnosed before they are born. Differential diagnosis is when physicians diagnose between two or more conditions for a persons symptoms and this can include primary pulmonary causes of cyanosis, cyanotic heart lesions, pulmonary stenosis and transposed arterial trunks.

Chest radiograph
Before more sophisticated techniques became available, chest X-ray was the definitive method of diagnosis. The abnormal "coeur-en-sabot" (boot-like) appearance of a heart with tetralogy of Fallot is classically visible via chest X-ray, although most infants with tetralogy may not show this finding. The boot like shape is due to the right ventricular hypertrophy present in TOF. Lung fields are often dark (absence of interstitial lung markings) due to decreased pulmonary blood flow.: 171–72

Electrocardiogram
An electrocardiogram (ECG) is one of the most basic procedures for assessing the heart. Tiny electrodes are applied to specific areas on the body, near the chest, arm, and neck. Lead cables connect the electrodes to an ECG machine. The hearts electrical activity is then measured. Natural electrical impulses help maintain blood flowing properly by coordinating contractions in different areas of the heart. These impulses are recorded by an ECG, which shows how fast, the rhythm, intensity and timing of the electrical impulses as they travel through the heart.Electrocardiography shows right ventricular hypertrophy (RVH), along with right axis deviation. RVH is noted on EKG as tall R-waves in lead V1 and deep S-waves in lead V5-V6.

Echocardiogram
Congenital heart defects are now diagnosed with echocardiography, which is quick, involves no radiation, is very specific, and can be done prenatally.Echocardiography establishes the presence of TOF by demonstrating a VSD, RVH, and aortic override. Many patients are diagnosed prenatally. Color Doppler (type of echocardiography) measures the degree of pulmonary stenosis. Additionally, close monitoring of the ductus arteriosus is done in the neonatal period to ensure that there is adequate blood flow through the pulmonary valve.: 171–72 In certain cases, coronary artery anatomy cannot be clearly viewed using echocardiogram. In this case, cardiac catheterization can be done.: 37, 201

Genetics
From a genetics perspective, it is important to screen for DiGeorge in all babies with TOF.: 37, 201

Treatment
Tet spells
Tet spells are defined as cyanotic spells occurring due to the obstruction right ventricular outflow. Tet spells can be triggered by various factors such as crying, progressive tachypnea, and deep breathing, with symptoms including but not limited to blue skin, nails and lips, profound crying and difficulty breathing.Tet spells may be treated with beta-blockers such as propranolol, but acute episodes require rapid intervention with morphine or intranasal fentanyl to reduce ventilatory drive, a vasopressor such as phenylephrine, or norepinephrine to increase systemic vascular resistance, and IV fluids for volume expansion.: 18, 201 Oxygen (100%) may be effective in treating spells because it is a potent pulmonary vasodilator and systemic vasoconstrictor. This allows more blood flow to the lungs by decreasing shunting of deoxygenated blood from the right to left ventricle through the VSD. There are also simple procedures such as squatting and the knee chest position which increase systemic vascular resistance and decrease right-to-left shunting of deoxygenated blood into the systemic circulation.: 18, 201 If the spells are refractory to the above treatments, people are usually intubated and sedated. The treatment of last resort for tet spells is extracorporeal membrane oxygenation (ECMO) along with consideration of Blalock Taussig shunt (BT shunt).: 18, 201

Total surgical repair
Total surgical repair of TOF is a curative surgery. Different techniques can be used in performing TOF repair. However, a transatrial, transpulmonary artery approach is used for most cases.: 153  The repair consists of two main steps: closure of the VSD with a patch and reconstruction of the right ventricular outflow tract.This open-heart surgery is designed to relieve the right ventricular outflow tract stenosis by careful resection of muscle and to repair the VSD.: 154 The right ventricle outflow tract can be reconstructed using mainly 2 procedures: a transannular patch (TAP) or a pulmonary valve-sparing procedure (PVS). The decision on the type of the procedure depends on individual anatomy (especially the size of the pulmonary valve). PVS showed better overall survival, event-free survival and less pulmonary regurgitation at 10, 20 and 30 years after the operation.  PVS  can be performed with or without ventriculotomy. A study found similar overall and event-free survival and pulmonary regurgitation rate between patients who underwent PVS with ventriculotomy and the ones who did not.Additional reparative or reconstructive surgery may be done on patients as required by their particular cardiac anatomy.: 153 Timing of surgery in asymptomatic patients is usually between the ages of two months to one year.: 201–2  However, in symptomatic patients showing worsening blood oxygen levels, severe tet-spells (cyanotic spells), or dependence on prostaglandins from early neonatal period (to keep the ductus arteriosus open) need to be planned fairly urgently: 201–2 Potential surgical repair complications include residual ventricular septal defect, residual outflow tract obstruction, complete atrioventricular block, arrhythmias, aneurysm of right ventricular outflow patch, and pulmonary valve insufficiency.: 59  Long-term complications most commonly include pulmonary valve regurgitation, and arrhythmias.Total repair of tetralogy of Fallot initially carried a high mortality risk, but this risk has gone down steadily over the years. Surgery is now often carried out in infants one year of age or younger with less than 5% perioperative mortality.: 205  Post surgery, most patients enjoy an active life free of symptoms.: 205  Currently, long-term survival is close to 90%.: 167  Today the adult TOF population continues to grow and is one of the most common congenital heart defects seen in adult outpatient clinics.: 100–101

Palliative surgery
Initially surgery involved forming a side to end anastomosis between the subclavian artery and the pulmonary artery -i.e. a systemic to pulmonary arterial shunt.: 57  This redirected a large portion of the partially oxygenated blood leaving the heart for the body into the lungs, increasing flow through the pulmonary circuit, and relieving symptoms. The first Blalock-Thomas-Taussig shunt surgery was performed on 15-month-old Eileen Saxon on November 29, 1944 with dramatic results.The Potts shunt and the Waterston-Cooley shunt are other shunt procedures which were developed for the same purpose. These are no longer used.
Currently, palliative surgery is not normally performed on infants with TOF except for extreme cases.: 173  For example, in symptomatic infants, a two-stage repair (initial systemic to arterial shunt placement followed by total surgical repair) may be done. Potential complications include inadequate pulmonary blood flow, pulmonary artery distortion, inadequate growth of the pulmonary arteries, and acquired pulmonary atresia.: 59

Approaches to surgical repair
After years of tetralogy of Fallot surgical repair expertise, the attention shifted to the emerging evidence that long-term pulmonary insufficiency is detrimental to right ventricular function and clinical prognosis. As a result, the hunt for surgical procedures to relieve right ventricular outflow tract obstruction while minimizing pulmonary regurgitation has intensified.A constrained right ventricular outflow tract reconstruction with a Dacron patch matched to a nominal pulmonary annulus expansion or an annulus-sparing approach yielded primary complete repair outcomes in 94 TOF infants. The pulmonary annulus size was larger in babies treated with the latter technique, as predicted. After an average follow-up of around eight years, the first group had a higher than moderate PR, yet there was no significant difference in independence from severe PR after ten years.Furthermore, there was no significant difference in right ventricular dilation between the two techniques. Finally, they found that reconstructing the pulmonary annulus in TOF with only a tiny transannular incision and a stiff Dacron patch to inhibit pulmonary annulus extension throughout the normal growing phase produces the same long-term benefits as preserving the full pulmonary annulus integrity.

Complications
Short-term
Residual ventricular septal defects and persistent right ventricular outflow blockage are common problems in the immediate postoperative period. Arrhythmias such as ventricular tachycardia, atrial fibrillation/flutter, and intra-atrial re-entrant tachycardia can occur after tetralogy repair. With broad complex tachycardia, the ECG will likely show a right bundle branch block or left bundle branch block patterns. Patients who have had their hearts repaired may experience sudden cardiac death. Risk factors for abnormal heart rhythms include:

Age (at repair)
Male gender
Transient complete heart block beyond post operative day three
QRS duration greater than 180 milliseconds

Long-term
Adult patients with congenital cardiac disease are on the rise at a rate of about 5% per year, outpacing the pediatric population. Right ventricular volume overload form pulmonary insufficiency, right ventricular aneurysm from outflow patch or ventriculotomy, distal pulmonary artery obstruction, ventricular hypertrophy, chamber enlargement, biventricular dysfunction, and aortic root dilation and insufficient are all long-term complications seen in these patients. Arrhythmia, heart failure, and complications from reoperations are the three primary causes of death in individuals with corrected tetralogy of Fallot. QRS duration greater than 180 milliseconds, older age at repair (greater than three years), significant pulmonary valve or tricuspid valve regurgitation, history of syncope, multifocal premature ventricular contractions, and ventricular tachycardia are some of the factors associated with sudden death after 30 years of procedure. Pulmonary insufficiency is the most common reason for reoperation, and pulmonary valve replacement criteria have traditionally been based on the severity of the regurgitant fraction on a magnetic resonance or CT scan. Right and left ventricular end-systolic and end-diastolic volume indices, ejection fractions, and the existence of aneurysm generating obstructive outflow are all parameters seen in this research. Exercise intolerance, heart failure signs and symptoms, syncope, and prolonged ventricular tachycardia are all possible symptoms. A transcatheter pulmonary valve method can also be used to replace a pulmonary valve.

Pregnancy
In comparison to the general obstetric population, women who had their tetralogy of Fallot repaired completely have similar outcomes. The degree of pulmonary regurgitation with right or left ventricular dysfunction, as well as the level of pulmonary hypertension, are linked to an increased risk of pregnancy complications. Fetal death is more likely in women who have moderate right ventricular hypertension or who have undergone a palliative shunt. In comparison to 0.8% of the general population, offspring of women with tetralogy have a 3–5% chance of developing congenital cardiac disease. If the 22q11 deletion is present, there is a 50% chance of transferring the damaged chromosome, with a high risk of a congenital cardiac abnormality.

Prognosis
Untreated, tetralogy of Fallot rapidly results in progressive right ventricular hypertrophy due to the increased resistance caused by narrowing of the pulmonary trunk.: 199  This progresses to heart failure which begins in the right ventricle and often leads to left heart failure and dilated cardiomyopathy. Mortality rate depends on the severity of the tetralogy of Fallot. If left untreated, TOF carries a 35% mortality rate in the first year of life, and a 50% mortality rate in the first three years of life. Patients with untreated TOF rarely progress to adulthood.Patients who have undergone total surgical repair of tetralogy of Fallot have improved hemodynamics and often have good to excellent cardiac function after the operation with some to no exercise intolerance (New York Heart Association Class I-II). Long-term outcome is usually excellent for most patients, however residual post-surgical defects such as pulmonary regurgitation, pulmonary artery stenosis, residual VSD, right ventricular dysfunction, right ventricular outflow tract obstruction may affect life expectancy and increase the need for reoperation.: 205 Cardiovascular and cerebrovascular complications in patients with repaired CHD such as TOF occur earlier in life compared to healthy subjects. Chronic pulmonary regurgitation and right ventricular dilation and dysfunction is also common.Within 30 years after correction, 50% of patients will require reoperation. The most common cause of reoperation is a leaky pulmonary valve (pulmonary valve insufficiency). This is usually corrected with a procedure called pulmonary valve replacement.: 136 One common prognostic factor with TOF is the development of ischemia reperfusion injury. Insufficient myocardial protection is considered one of the main causes of death in the correction of TOF.

Comorbidities
There are many comorbid conditions that can occur with TOF that may exacerbate the condition. Often, TOF can present with low birth weight and prematurity. In both of these cases, mortality and morbidity were both seen to increase. Differences in right atrial and ventricular mechanics and liver stiffness was also observed in adults with repaired TOF, as well as pulmonary atresia and persistent pulmonary stenosis. In patients with pulmonary atresia, there is complete failure of forward flow from the right ventricle to the pulmonary arterial vasculature. As such, pulmonary blood flow is entirely dependent on shunting from the systemic circulation, typically through a patent ductus arteriosus. The pathophysiology of TOF together with pulmonary arteriosus is uniquely attributable to defects of the pulmonary arteries. Even after operative care, these patients remain at higher risk for pulmonary arterial stenoses and pulmonary hypertension.Danon disease, which is a rare genetic disorder, was also observed to complicate TOF. In particular, elongation of the QRS complex and a shortened PR interval. Genetic abnormalities found in TOF may lead to the earlier diagnosis of Danon disease, helping to improve prognostic outcomes.

Epidemiology
The prevalence of tetralogy of Fallot is estimated to be 0.02–0.04%, which corresponds to approximately 200 to 400 cases per million live births. It accounts for 7–10% of all congenital heart abnormalities, making it the most common cyanotic heart defect.: 100–101  Although males and females were initially believed to be affected equally, more recent studies have shown TOF affects males more than females. About 1 in 100 newborns is diagnosed with a congential heart defect, of which 10% are diagnosed with TOF. Genetically, it is most commonly associated with Down syndrome and DiGeorge syndrome. Down syndrome and other chromosomal disorders are known to occur alongside congential heart defects such as TOF.

History
Tetralogy of Fallot was initially described in 1671 by the Danish researcher Niels Steensen. Also referenced as Nicolaus Steno in Latin, Stensen was a pioneer in anatomy and geology. His work made significant contributions to the field of cardiac anatomy and pathology, which led to the condition initially being titled Steno-Fallot tetralogy. A further description was published in 1888 by the French physician Étienne-Louis Arthur Fallot, after whom it was ultimately named. In 1924, Maude Elizabeth Seymour Abbott, a pediatric cardiologist from Montreal, Canada, named it tetralogy of Fallot.The short paper "Dissection of a Monstrous Foetus in Paris" in 1671 first described the conditions that would later together be known as TOF. In particular, it highlighted the unusual formation of arteries, the stenosing of the pulmonary artery, the absence of the ductus arteriosus, an overriding aorta, and fetal cardiac circulation where blood was redirected to the aorta from the pulmonary artery. Over a hundred years later in 1777, Dutch physician Eduard Sandifort reported what he referred to as "the blue boy" patient. This patient, who was 16 months old, was initially thought to have asthma, though an autopsy postmortem revealed a cardiac malformation with no ductus arteriosus or ligamentum arteriosum, indicating that the child may have died from TOF. Another 13-year-old patient was reported by Scottish physician William Hunter in 1782. Hunter described the patient, along with three others, as suffering from cyanosis after a posthumous examination in 1774.Other cases, such as those presented by Pulteney (1785), Abernethy (1793), Bell (1797), Dorsey (1812), and Farre (1814) also contributed to modern understandings of TOF. The first reported case of TOF was in America at the University of Pennsylvania in 1816, with more cases being reported by Peacock (1858 and 1869), Widman (1881), and finally Fallot (1888), after whom the condition is named. Fallot was the first to elegantly describe the four key features that differentiate it from other cyanotic cardiac conditions, and was prominent in the disqualification of a patent foramen ovale as a fifth feature. Fallot initially referred to it as "La maladie bleue", which is French for "the blue disease" or "cyanose cardiaque", translating to "cardiac cyanosis".The first surgical repair was carried out in 1944 at Johns Hopkins. The procedure was conducted by surgeon Alfred Blalock and cardiologist Helen B. Taussig, with Vivien Thomas also providing substantial contributions and listed as an assistant. This first surgery was depicted in the film Something the Lord Made. It was actually Helen Taussig who convinced Alfred Blalock that the shunt was going to work. 15-month-old Eileen Saxon was the first person to receive a Blalock–Thomas–Taussig shunt. Furthermore, the Blalock-Thomas-Taussig procedure, initially the only surgical treatment available for tetralogy of Fallot, was palliative but not curative. The first total repair of tetralogy of Fallot was done by a team led by C. Walton Lillehei at the University of Minnesota in 1954 on an 11-year-old boy. Total repair on infants has had success from 1981, with research indicating that it has a comparatively low mortality rate. Today the adult TOF population continues to grow and is one of the most common congenital heart defect seen in adult outpatient clinics.: 100–101

Related disorders
The following illnesses have symptoms that are comparable to tetralogy of Fallot. For a differential diagnosis, comparisons between these disorders provides valuable knowledge.

Atrial septal defects
Atrial septal defects (ASDs) are a kind of congenital heart abnormality in which a tiny opening exists between the two atria of the heart. The burden on the right side of the heart is increased as a result of these abnormalities, as is the blood flow to the lungs. This leads to excessive blood flow to the lungs and an increased workload on the right side of the heart. Another common finding associated with ASDs is right ventricular hypertrophy, also known as enlargement of the right ventricle.

Ventricular septal defects
Ventricular septal defects (VSDs) are a kind of congenital heart abnormality in which one of the ventricles is missing </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 Chronic granulomatous disease and can you explain it in depth? [/INST] Chronic granulomatous disease (CGD), also known as Bridges–Good syndrome, chronic granulomatous disorder, and Quie syndrome, is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly the superoxide radical due to defective phagocyte NADPH oxidase) used to kill certain ingested pathogens. This leads to the formation of granulomas in many organs. CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.This condition was first discovered in 1950 in a series of 4 boys from Minnesota, and in 1957 it was named "a fatal granulomatosus of childhood" in a publication describing their disease. The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease. Bernard Babior made key contributions in linking the defect of superoxide production of white blood cells, to the cause of the disease. In 1986, the X-linked form of CGD was the first disease for which positional cloning was used to identify the underlying genetic mutation.

Symptoms and signs
Classically, patients with chronic granulomatous disease will have recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency:
pneumonia
abscesses of the skin, tissues, and organs
septic arthritis
osteomyelitis
bacteremia/fungemia
superficial skin infections such as cellulitis or impetigoMost people with CGD are diagnosed in childhood, usually, before age 5. Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur. Small groups of CGD patients may also be affected by McLeod syndrome because of the proximity of the two genes on the same X-chromosome.

Atypical infections
People with CGD are sometimes infected with organisms that usually do not cause disease in people with normal immune systems. Among the most common organisms that cause disease in CGD patients are:

Bacteria (particularly those that are catalase-positive)Staphylococcus aureus.
Serratia marcescens.
Listeria species.
E. coli.
Klebsiella species.
Pseudomonas cepacia, a.k.a. Burkholderia cepacia.
Nocardia.
Fungi
Aspergillus species. Aspergillus has a propensity to cause infection in people with CGD and of the Aspergillus species, Aspergillus fumigatus seems to be most common in CGD.
Candida species.Patients with CGD can usually resist infections of catalase-negative bacteria but are susceptible to catalase-positive bacteria. Catalase is an enzyme that catalyzes the breakdown of hydrogen peroxide in many organisms. In infections caused by organisms that lack catalase (catalase-negative), the host with CGD is successfully able to "borrow" hydrogen peroxide being made by the organism and use it to fight off the infection. In infections by organisms that have catalase (catalase-positive), this "borrowing mechanism" is unsuccessful because the enzyme catalase first breaks down any hydrogen peroxide that would be borrowed from the organism. Therefore in the CGD patient, hydrogen peroxide cannot be used to make oxygen radicals to fight infection, leaving the patient vulnerable to infection by catalase-positive bacteria.

Genetics
Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait". The affected gene on the X chromosome codes for the gp91 protein p91-PHOX (91 is the weight of the protein in kDa; the gp means glycoprotein). CGD can also be transmitted in an autosomal recessive fashion (via CYBA, NCF1, NCF2 and NCF4) which affect other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are homozygous for the genetic defect causing glucose-6-phosphate dehydrogenase deficiency (G6PD), which is characterised by reduced NADPH levels.

Pathophysiology
Phagocytes (i.e. neutrophils and macrophages) require an enzyme to produce reactive oxygen species to destroy bacteria after they are ingested (phagocytosis), a process known as the respiratory burst. This enzyme is termed "phagocyte NADPH oxidase" (PHOX). This enzyme oxidizes NADPH and reduces molecular oxygen to produce superoxide anions, a reactive oxygen species. Superoxide is then disproportionated into peroxide and molecular oxygen by superoxide dismutase. Finally, peroxide is used by myeloperoxidase to oxidize chloride ions into hypochlorite (the active component of bleach), which is toxic to bacteria. Thus, NADPH oxidase is critical for phagocyte killing of bacteria through reactive oxygen species.(Two other mechanisms are used by phagocytes to kill bacteria: nitric oxide and proteases, but the loss of ROS-mediated killing alone is sufficient to cause chronic granulomatous disease.)Defects in one of the four essential subunits of phagocyte NADPH oxidase (PHOX) can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease.

Diagnosis
When chronic granulomatous disease (CGD) is suspected, neutrophil-function testing should be carried out, and positive findings should be confirmed by genotyping. The p47phox mutation is due to a pseudogene conversion, hence it may not be detectable by standard sequencing; in these cases, an immunoblot or gene dose determination may be needed to confirm p47phox deficiency.Infections caused by the pathogens commonly associated with CGD should prompt functional or genetic screening; neonatal or early postnatal screening of potentially affected children is essential with a family history of CGD.Neutrophil function tests: These include nitroblue tetrazolium (NBT) reduction test, dihydrorhodamine (DHR) 123 test, direct measurement of superoxide production, cytochrome c reduction assay, and chemiluminescence. DHR test is usually preferred because it is easy to use, objective, and it is able to distinguish between X-linked and autosomal forms of CGD; furthermore, it allows to detect gp91phox carriers.
The nitroblue-tetrazolium (NBT) test is the original and most widely known test for chronic granulomatous disease. It is negative in CGD, meaning that it does not turn blue. The higher the blue score, the better the cell is at producing reactive oxygen species. This test depends upon the direct reduction of NBT to the insoluble blue compound formazan by superoxide which is produced by normal peripheral blood neutrophils stimulated in vitro; NADPH oxidase catalyzes the aforementioned reaction and NADPH is oxidized in the same reaction. This test is simple to perform and gives rapid results but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected.
Dihydrorhodamine (DHR) 123 test: In this test the respiratory burst of the neutrophils is stimulated with phorbol myristate acetate (PMA), resulting in oxidation of dihydrorhodamine 123 (nonfluorescent derivative of rhodamine) to rhodamine 123 (green fluorescent compound), which can be measured by flow cytometry. This test is abnormal in patients with chronic granulomatous disease (i.e., there is no shift in fluorescence with stimulation). Moreover, its quantitative nature allows to differentiate oxidase-positive from oxidase-negative phagocyte subpopulations in CGD carriers and identify deficiencies in gp91phox and p47phox. Modest residual production of reactive oxygen intermediates (ROI) as assessed by DHR 123 test, is associated with significantly less severe illness and a greater likelihood of long-term survival than patients with little residual ROI production. On the other hand, in the case of complete myeloperoxidase deficiency, DHR test gives abnormal results (false positive for CGD) because the DHR signal yielded by flow cytometry depends on intact NADPH oxidase activity as well as the presence of a myeloperoxidase (MPO); however, NBT test demonstrates normal production of superoxide.Genetic testing: Once CGD has been diagnosed based on abnormal neutrophil function tests, genetic testing should go next. As mentioned above, p47phox defect is usually difficult to identify genetically because it is caused by pseudogene conversion and may be missed in typical sequencing studies; in this case, immunoblotting or flow cytometry can show absence of protein.Prenatal testing: It is particularly useful when a family member has already been diagnosed with CGD. This test may be performed by analysis of NADPH oxidase activity of neutrophils from fetal blood. Samples from amniotic fluid or chorionic villi provides an earlier and more reliable diagnosis for families at risk.

Classification
Chronic granulomatous disease is the name for a genetically heterogeneous group of immunodeficiencies. The core defect is a failure of phagocytic cells to kill organisms that they have engulfed because of defects in a system of enzymes that produce free radicals and other toxic small molecules. There are several types, including:
X-linked chronic granulomatous disease (CGD)
autosomal recessive cytochrome b-negative CGD
autosomal recessive cytochrome b-positive CGD type I
autosomal recessive cytochrome b-positive CGD type II
atypical granulomatous disease

Treatment
Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that antibiotic prophylaxis can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs.

Antibiotics
Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections. This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole, although a newer drug of the same type called voriconazole may be more effective. The use of this drug for this purpose is still under scientific investigation.

Immunomodulation
Interferon, in the form of interferon gamma-1b (Actimmune) is approved by the Food and Drug Administration for the prevention of infection in CGD. It has been shown to reduce infections in CGD patients by 70% and to decrease their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been the standard treatment for CGD for several years.

Hematopoietic stem cell transplantation (HSCT)
Hematopoietic stem cell transplantation from a matched donor is curative although not without significant risk.

Prognosis
There are currently no studies detailing the long term outcome of chronic granulomatous disease with modern treatment. Without treatment, children often die in the first decade of life </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 Laryngomalacia and can you explain it in depth? [/INST] Laryngomalacia (literally, "soft larynx") is the most common cause of chronic stridor in infancy, in which the soft, immature cartilage of the upper larynx collapses inward during inhalation, causing airway obstruction.  It can also be seen in older patients, especially those with neuromuscular conditions resulting in weakness of the muscles of the throat. However, the infantile form is much more common. Laryngomalacia is one of the most common laryngeal congenital disease in infancy and public education about the signs and symptoms of the disease is lacking.

Signs and symptoms
In infantile laryngomalacia, the supraglottic larynx (the part above the vocal cords) is tightly curled, with a short band holding the cartilage shield in the front (the epiglottis) tightly to the mobile cartilage in the back of the larynx (the arytenoids).  These bands are known as the aryepiglottic folds.   The shortened aryepiglottic folds cause the epiglottis to be curled on itself.  This is the well known "omega shaped" epiglottis in laryngomalacia.  Another common finding of laryngomalacia involves the posterior or back part of the larynx, where the arytenoid cartilages or the mucosa/tissue over the arytenoid cartilages can collapse into the airway and cause airway obstruction.Laryngomalacia results in partial airway obstruction, most commonly causing a characteristic high-pitched squeaking noise on inhalation (inspiratory stridor).  Some infants have feeding difficulties related to this problem.  Rarely, children will have significant life-threatening airway obstruction.  The vast majority, however, will only have stridor without other more serious symptoms such as dyspnea (difficulty breathing).

Causes
Although laryngomalacia is not associated with a specific gene, there is evidence that some cases may be inherited.  Relaxation or a lack of muscle tone in the upper airway may be a factor. It is often worse when the infant is on his or her back, because the floppy tissues can fall over the airway opening more easily in this position.

Diagnosis
The physician will ask some questions about the babys health problems and may recommend a flexible laryngoscopy to further evaluate the infants condition </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 Reactive arthritis and can you explain it in depth? [/INST] Reactive arthritis, also known as Reiters syndrome, is a form of inflammatory arthritis that develops in response to an infection in another part of the body (cross-reactivity). Coming into contact with bacteria and developing an infection can trigger the disease. By the time the patient presents with symptoms, often the "trigger" infection has been cured or is in remission in chronic cases, thus making determination of the initial cause difficult.
The arthritis often is coupled with other characteristic symptoms; this has been called Reiters syndrome, Reiters disease or Reiters arthritis.  The term "reactive arthritis" is increasingly used as a substitute for this designation because of Hans Reiters war crimes with the Nazi Party.
The manifestations of reactive arthritis include the following triad of symptoms: an inflammatory arthritis of large joints, inflammation of the eyes in the form of conjunctivitis or uveitis, and urethritis in men or cervicitis in women. Arthritis occurring alone following sexual exposure or enteric infection is also known as reactive arthritis. Patients can also present with mucocutaneous lesions, as well as psoriasis-like skin lesions such as circinate balanitis, and keratoderma blennorrhagicum. Enthesitis can involve the Achilles tendon resulting in heel pain. Not all affected persons have all the manifestations.
The clinical pattern of reactive arthritis commonly consists of an inflammation of fewer than five joints which often includes the knee or sacroiliac joint. The arthritis may be "additive" (more joints become inflamed in addition to the primarily affected one) or "migratory" (new joints become inflamed after the initially inflamed site has already improved).Reactive arthritis is an RF-seronegative, HLA-B27-linked arthritis often precipitated by genitourinary or gastrointestinal infections. The most common triggers are intestinal infections (with Salmonella, Shigella or Campylobacter) and sexually transmitted infections (with Chlamydia trachomatis); however, it also can happen after group A streptococcal infections.It most commonly strikes individuals aged 20–40 years of age, is more common in men than in women, and more common in white than in black people. This is owing to the high frequency of the HLA-B27 gene in the white population. It can occur in epidemic form. Patients with HIV have an increased risk of developing reactive arthritis as well.
Numerous cases during World Wars I and II focused attention on the triad of arthritis, urethritis, and conjunctivitis (often with additional mucocutaneous lesions), which at that time was also referred to as Fiessenger-Leroy-Reiter syndrome.

Signs and symptoms
Because common systems involved include the eye, the urinary system, and the hands and feet, one clinical mnemonic in reactive arthritis is "Cant see, cant pee, cant climb a tree."
The classic triad consists of:
Conjunctivitis
Nongonococcal urethritis
Asymmetric oligoarthritis
Symptoms generally appear within 1–3 weeks but can range from 4 to 35 days from the onset of the inciting episode of the disease.
The classical presentation of the syndrome starts with urinary symptoms such as burning pain on urination (dysuria) or an increased frequency of urination. Other urogenital problems may arise such as prostatitis in men and cervicitis, salpingitis and/or vulvovaginitis in women.
It presents with monoarthritis affecting the large joints such as the knees and sacroiliac spine causing pain and swelling. An asymmetrical inflammatory arthritis of interphalangeal joints may be present but with relative sparing of small joints such as the wrist and hand.
Patient can have enthesitis presenting as heel pain, Achilles tendinitis or plantar fasciitis, along with balanitis circinata (circinate balanitis), which involves penile lesions present in roughly 20 to 40 percent of the men with the disease.
A small percentage of men and women develop small hard nodules called keratoderma blennorrhagicum on the soles of the feet and, less commonly, on the palms of the hands or elsewhere. The presence of keratoderma blennorrhagica is diagnostic of reactive arthritis in the absence of the classical triad. Subcutaneous nodules are also a feature of this disease.
Ocular involvement (mild bilateral conjunctivitis) occurs in about 50% of men with urogenital reactive arthritis syndrome and about 75% of men with enteric reactive arthritis syndrome. Conjunctivitis and uveitis can include redness of the eyes, eye pain and irritation, or blurred vision. Eye involvement typically occurs early in the course of reactive arthritis, and symptoms may come and go.
Dactylitis, or "sausage digit", a diffuse swelling of a solitary finger or toe, is a distinctive feature of reactive arthritis and other peripheral spondylarthritides but can also be seen in polyarticular gout and sarcoidosis.
Mucocutaneous lesions can be present. Common findings include oral ulcers that come and go. In some cases, these ulcers are painless and go unnoticed. In the oral cavity, the patients may experience recurrent aphthous stomatitis, geographic tongue and migratory stomatitis in higher prevalence than the general population.
Some patients experience serious gastrointestinal problems similar to those of Crohns disease.
About 10 percent of people with reactive arthritis, especially those with a prolonged course of the disease, will develop cardiac manifestations, including aortic regurgitation and pericarditis. Reactive arthritis has been described as a precursor of other joint conditions, including ankylosing spondylitis.

Causes
Reactive arthritis is associated with the HLA-B27 gene on chromosome 6 and by the presence of enthesitis as the basic pathologic lesion and is triggered by a preceding infection. The most common triggering infection in the US is a genital infection with Chlamydia trachomatis. Other bacteria known to cause reactive arthritis which are more common worldwide are Ureaplasma urealyticum, Salmonella spp., Shigella spp., Yersinia spp., and Campylobacter spp. A bout of food poisoning or a gastrointestinal infection may also precede the disease (the last four genera of bacteria mentioned above are enteric bacteria). Shigella is the most common organism causing reactive arthritis following diarrhea. Chlamydia trachomatis is the most common cause of reactive arthritis following urethritis. Ureaplasma and mycoplasma are rare causes. There is some circumstantial evidence for other organisms causing the disease, but the details are unclear.Reactive arthritis usually manifests about 1–3 weeks after a known infection. The mechanism of interaction between the infecting organism and the host is unknown. Synovial fluid cultures are negative, suggesting that reactive arthritis is caused either by an autoimmune response involving cross-reactivity of bacterial antigens with joint tissues or by bacterial antigens that have somehow become deposited in the joints.

Diagnosis
There are few clinical symptoms, but the clinical picture is dominated by arthritis in one or more joints, resulting in pain, swelling, redness, and heat sensation in the affected areas.
The urethra, cervix and the throat may be swabbed in an attempt to culture the causative organisms. Cultures may also be carried out on urine and stool samples or on fluid obtained by arthrocentesis.
Tests for C-reactive protein and erythrocyte sedimentation rate are non-specific tests that can be done to corroborate the diagnosis of the syndrome.
A blood test for the genetic marker HLA-B27 may also be performed. About 75 percent of all the patients with reactive arthritis have this gene.

Diagnostic criteria
Although there are no definitive criteria to diagnose the existence of reactive arthritis, the American College of Rheumatology has published sensitivity and specificity guidelines.

Treatment
The main goal of treatment is to identify and eradicate the underlying infectious source with the appropriate antibiotics if still present. Otherwise, treatment is symptomatic for each problem. Nonspecific urethritis may be treated with a short course of tetracycline. Analgesics, particularly NSAIDs, are used. Steroids, sulfasalazine and immunosuppressants may be needed for patients with severe reactive symptoms that do not respond to any other treatment. Local corticosteroids are useful in the case of iritis.

Prognosis
Reactive arthritis may be self-limiting, frequently recurring, chronic or progressive. Most patients have severe symptoms lasting a few weeks to six months. 15 to 50 percent of cases involve recurrent bouts of arthritis. Chronic arthritis or sacroiliitis occurs in 15–30 percent of cases </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 Minimal change disease and can you explain it in depth? [/INST] Minimal change disease (also known as MCD, minimal change glomerulopathy, and nil disease, among others) is a disease affecting the kidneys which causes a nephrotic syndrome. Nephrotic syndrome leads to the loss of significant amounts of protein in the urine, which causes the widespread edema (soft tissue swelling) and impaired kidney function commonly experienced by those affected by the disease. It is most common in children and has a peak incidence at 2 to 6 years of age. MCD is responsible for 10–25% of nephrotic syndrome cases in adults. It is also the most common cause of nephrotic syndrome of unclear cause (idiopathic) in children.

Signs and symptoms
The clinical signs of minimal change disease are proteinuria (abnormal excretion of proteins, mainly albumin, into the urine), edema (swelling of soft tissues as a consequence of water retention),  weight gain, and hypoalbuminaemia (low serum albumin). These signs are referred to collectively as nephrotic syndrome.

The first clinical sign of minimal change disease is usually edema with an associated increase in weight.  The swelling may be mild but patients can present with edema in the lower half of the body, periorbital edema, swelling in the scrotal/labial area and anasarca in more severe cases. In older adults, patients may also present with acute kidney injury (20–25% of affected adults) and high blood pressure. Due to the disease process, patients with minimal change disease are also at risk of blood clots and infections.

Pathology
For years, pathologists found no changes when viewing kidney biopsy specimens under light microscopy, hence the name "minimal change disease." Sometimes, the mesangium may have expanded, but otherwise there is no injury to kidney tissue itself.Under immunofluorescence, there are no immunoglobulins or complement deposits bound to kidney tissue.With the advent of electron microscopy, the changes now known as the hallmarks of the disease were discovered. These are diffuse loss of visceral epithelial cells foot processes (i.e., podocyte effacement), vacuolation, and growth of microvilli on the visceral epithelial cells, allowing for excess protein loss in the urine.

Pathophysiology
Proteinuria
The cause and pathogenesis of the pathology is unclear and it is currently considered idiopathic. However, it does not appear to involve complement or immune complex deposition. Rather, an altered T cell-mediated immunologic response with abnormal secretion of lymphokines by T cells is thought to modify the glomerular basement membrane, specifically the podocytes, increasing permeability. This allows the leakage of albumin and other serum proteins into the urine. Also, the exact cytokine responsible has yet to be elucidated, with IL-12, IL-18 and IL-13 having been most studied in this regard, yet never conclusively implicated. Data from a longitudinal study (Nephrotic Syndrome Study Network – NEPTUNE) published in 2022 suggested that up to 29% of biopsy-confirmed,  mixed pediatric and adult minimal change disease cases exhibited serum autoantibodies against nephrin, a structural protein located in the podocyte slit diaphragm.There has been discussion of B cell involvement in nephrotic syndrome, especially minimal change disease due to the success of immunotherapy that target both B and T cells, increased markers for B cell activation during a relapse of minimal change disease, and alterations in B cell sub-classes during minimal change disease remission. This hypothesis is supported by recent findings of anti-nephrin antibodies isolated in minimal change disease.

Edema
When albumin is excreted in the urine, its serum (blood) concentration decreases. Consequently, the plasma oncotic pressure reduces relative to the interstitial tissue. The subsequent movement of fluid from the vascular compartment to the interstitial compartment manifests as the soft tissue swelling referred to as edema. This fluid collects most commonly in the feet and legs, in response to gravity, particularly in those with poorly functioning valves. In severe cases, fluid can shift into the peritoneal cavity (abdomen) and cause ascites. As a result of the excess fluid, individuals with minimal change disease often gain weight, as they are excreting less water in the urine, and experience fatigue.

Diagnosis
As minimal change disease is a subset of nephrotic syndrome, diagnosis involves looking for a combination of edema, high amounts of protein in urine, low albumin and high serum cholesterol. Initial workup can include a urinalysis, kidney function tests, serum albumin level and a lipid panel. Microscopic amounts of blood are present in the urine of 10-30% adults with MCD.As MCD is the most common type of nephrotic syndrome in children, renal biopsy is not usually done in children under the age of 10 unless there are concerning features that are unusual for the disease (high blood pressure, bloody urine, renal dysfunction) and if they fail to respond to corticosteroid therapy. These would suggest that it may not be minimal change disease. In adults, a renal biopsy is required as there is a much wider differential for nephrotic syndrome. As the name suggests, the renal biopsy of a patient with minimal change disease would show minimal or no evidence of disease in light microscopy, which is unique among the causes of nephrotic syndrome.

Treatment
Children
The first line therapy to minimal change disease is corticosteroids T.Prednisolone 60mg/sq.m/day or 2mg/kg/day. For those are who are unable to tolerate corticosteroid treatment, cyclosporine is an alternative; other immunosuppressants have also been used such as calcineurin inhibitor, mycophenolate mofetil, rituximab though studies on their effectiveness is fairly limited. There is no common consensus on how long the corticosteroid therapy should be, with treatment length ranging from 4–12 weeks. Along with corticosteroid therapy, acute symptomatic management involves salt and fluid restriction to control the swelling.For children who do not respond to corticosteroids (usually after a trial of 8 weeks), cyclosporine can be tried.

Adults
Treatment guidelines for adults are fairly limited, and are largely based on studies done on children. The mainline therapy is also corticosteroid therapy T.Prednisolone 1mg/kg/day with other immunosuppressants as possible alternatives, though there is very little data on these alternatives efficacy. Other medications such as ACE inhibitors to reduce the amount of protein in the urine or statins to decrease high levels of cholesterol seen with nephrotic syndrome are generally unnecessary. ACE inhibitors may be considered in people with MCD who also have high blood pressure.

Prognosis
Children
Minimal change disease usually responds well to initial treatment with the first-line therapy: corticosteroids, with 95% responding. Younger children, who are more likely to develop minimal change disease, usually respond faster than adults with 50% of children having complete remission with 8 days of corticosteroid therapy and most other patients responding by the 4th week. Few do not respond to corticosteroids and have to rely on an alternative therapy.  However, despite positive response to corticosteroids, relapses are common, requiring repeat treatment with corticosteroids. About 25% never relapse, another 25% relapse infrequently (one relapse within 6 months of initial response or 1–3 relapses in 12 months), and 50% relapse frequently (>2 relapses within 6 months of initial response or >4 relapses in 12 months). The relapse rate is the reason behind a discussion on continuing prednisone treatment to even beyond 12 weeks to possibly decrease relapse rate; several studies trying this have failed to show significant improvement. A majority of relapses seem to be triggered by respiratory infections </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 Placenta praevia and can you explain it in depth? [/INST] Placenta praevia is when the placenta attaches inside the uterus but in a position near or over the cervical opening. Symptoms include vaginal bleeding in the second half of pregnancy. The bleeding is bright red and tends not to be associated with pain. Complications may include placenta accreta, dangerously low blood pressure, or bleeding after delivery. Complications for the baby may include fetal growth restriction.Risk factors include pregnancy at an older age and smoking as well as prior cesarean section, labor induction, or termination of pregnancy. Diagnosis is by ultrasound. It is classified as a complication of pregnancy.For those who are less than 36 weeks pregnant with only a small amount of bleeding recommendations may include bed rest and avoiding sexual intercourse. For those after 36 weeks of pregnancy or with a significant amount of bleeding, cesarean section is generally recommended. In those less than 36 weeks pregnant, corticosteroids may be given to speed development of the babys lungs. Cases that occur in early pregnancy may resolve on their own.It affects approximately 0.5% of pregnancies.  After four cesarean sections, however, it affects 10% of pregnancies. Rates of disease have increased over the late 20th century and early 21st century. The condition was first described in 1685 by Paul Portal.

Signs and symptoms
Women with placenta previa often present with painless, bright red vaginal bleeding. This commonly occurs around 32 weeks of gestation, but can be as early as late mid-trimester. More than half of women affected by placenta praevia (51.6%) have bleeding before delivery. This bleeding often starts mildly and may increase as the area of placental separation increases. Placenta praevia should be suspected if there is bleeding after 24 weeks of gestation. Bleeding after delivery occurs in about 22% of those affected.Women may also present as a case of failure of engagement of fetal head.

Cause
The exact cause of placenta previa is unknown. It is hypothesized to be related to abnormal vascularisation of the endometrium caused by scarring or atrophy from previous trauma, surgery, or infection. These factors may reduce differential growth of lower segment, resulting in less upward shift in placental position as pregnancy advances.

Risk factors
The following have been identified as risk factors for placenta previa:

Previous placenta previa (recurrence rate 4–8%), caesarean delivery, myomectomy or endometrium damage caused by D&C.
Women who are younger than 20 are at higher risk and women older than 35 are at increasing risk as they get older.
Women who have had previous pregnancies (multiparity), especially a large number of closely spaced pregnancies, are at higher risk due to uterine damage.
Smoking during pregnancy; cocaine use during pregnancy
Women with a large placentae from twins or erythroblastosis are at higher risk.
Race is a controversial risk factor, with some studies finding that people from Asia and Africa are at higher risk and others finding no difference.
Placental pathology (velamentous insertion, succenturiate lobes, bipartite i.e. bilobed placenta etc.)
Baby is in an unusual position: breech (buttocks first) or transverse (lying horizontally across the womb).Placenta previa is itself a risk factor of placenta accreta. Alcohol use during pregnancy was previously listed as a risk factor, but is discredited by this article.

Classification
Traditionally, four grades of placenta previa were used, but it is now more common to simply differentiate between "major" and "minor cases.
Other than that placenta previa can be also classified as:
Complete: When the placenta completely covers the cervix
Partial: When the placenta partially covers the cervix
Marginal: When the placenta ends near the edge of the cervix, about 2 cm from the internal cervical os

Diagnosis
History may reveal antepartum hemorrhage. Abdominal examination usually finds the uterus non-tender, soft and relaxed. Leopolds maneuvers may find the fetus in an oblique or breech position or lying transverse as a result of the abnormal position of the placenta. Malpresentation is found in about 35% cases. Vaginal examination is avoided in known cases of placenta previa.

Confirmatory
Previa can be confirmed with an ultrasound. Transvaginal ultrasound has superior accuracy as compared to transabdominal one, thus allowing measurement of distance between placenta and cervical os. This has rendered traditional classification of placenta previa obsolete.False positives may be due to following reasons:
Overfilled bladder compressing lower uterine segment
Myometrial contraction simulating placental tissue in abnormally low location
Early pregnancy low position, which in third trimester may be entirely normal due to differential growth of the uterus.In such cases, repeat scanning is done after an interval of 15–30 minutes.
In parts of the world where ultrasound is unavailable, it is not uncommon to confirm the diagnosis with an examination in the surgical theatre. The proper timing of an examination in theatre is important. If the woman is not bleeding severely she can be managed non-operatively until the 36th week. By this time the babys chance of survival is as good as at full term.

Management
An initial assessment to determine the status of the mother and fetus is required. Although mothers used to be treated in the hospital from the first bleeding episode until birth, it is now considered safe to treat placenta previa on an outpatient basis if the fetus is at less than 30 weeks of gestation, and neither the mother nor the fetus are in distress. Immediate delivery of the fetus may be indicated if the fetus is mature or if the fetus or mother are in distress. Blood volume replacement (to maintain blood pressure) and blood plasma replacement (to maintain fibrinogen levels) may be necessary.
Corticosteroids are indicated at 24–34 weeks gestation, given the higher risk of premature birth.

Delivery
The method of delivery is determined by clinical state of the mother, fetus and ultrasound findings. In minor degrees (traditional grade I and II), vaginal delivery is possible. RCOG recommends that the placenta should be at least 2 cm away from internal os for an attempted vaginal delivery. When a vaginal delivery is attempted, consultant obstetrician and anesthetists are present in delivery suite. In cases of fetal distress and major degrees (traditional grade III and IV) a caesarean section is indicated. Caesarian section is contraindicated in cases of disseminated intravascular coagulation. An obstetrician may need to divide the anterior lying placenta. In such cases, blood loss is expected to be high and thus blood and blood products are always kept ready. In rare cases, hysterectomy may be required.

Complications
Maternal
Antepartum hemorrhage
Malpresentation
Abnormal placentation
Postpartum hemorrhage
Placenta previa increases the risk of puerperal sepsis and postpartum hemorrhage because the lower segment to which the placenta was attached contracts less well post-delivery.

Fetal
IUGR (15% incidence)
Hypoxia
Premature delivery
Death

Epidemiology
Placenta previa occurs approximately one of every 200 births globally. It has been suggested that rates of placenta previa are increasing due to increased rate of Caesarian section. Reasons for regional variation may include ethnicity and diet.

Africa
Rates of placenta praevia in sub-Saharan Africa are the lowest in the world, averaging 2.7 per 1000 pregnancies. Despite a low prevalence, this disease has had a profound impact in Africa as it is linked with negative outcomes for both the mother and infant. The most common maternal outcome of placenta praevia is extreme blood loss before or after birth (antepartum hemorrhage and postpartum hemorrhage), which is a major cause of maternal and infant mortality in countries like Tanzania. Risk factors for placenta praevia among African women include prior pregnancies, prenatal alcohol consumption, and insufficient gynecologic care. In North Africa placenta praevia rates occur in 6.4 per 1000 pregnancies.

Asia
Mainland China has the highest prevalence of placenta praevia in the world, measuring at an average of 12.2 per 1000 pregnancies. Specifically, placenta praevia is most common in Southeast Asia, though the reason for this has not yet been investigated. There are many risk factors for placenta praevia in Asian women, of which include pregnancies occurring in women ages 35 and older (advanced maternal age) or in women who have had a prior Caesarean section, having multiple pregnancies, and experiencing either miscarriage or abortion in the past </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 Allergic bronchopulmonary aspergillosis and can you explain it in depth? [/INST] Allergic bronchopulmonary aspergillosis (ABPA) is a condition characterised by an exaggerated response of the immune system (a hypersensitivity response) to the fungus Aspergillus (most commonly Aspergillus fumigatus). It occurs most often in people with asthma or cystic fibrosis. Aspergillus spores are ubiquitous in soil and are commonly found in the sputum of healthy individuals. A. fumigatus is responsible for a spectrum of lung diseases known as aspergilloses.
ABPA causes airway inflammation, leading to bronchiectasis—a condition marked by abnormal dilation of the airways. Left untreated, the immune system and fungal spores can damage sensitive lung tissues and lead to scarring.
The exact criteria for the diagnosis of ABPA are not agreed upon. Chest X-rays and CT scans, raised blood levels of IgE and eosinophils, immunological tests for Aspergillus together with sputum staining and sputum cultures can be useful. Treatment consists of corticosteroids and antifungal medications.

Signs and symptoms
Almost all patients have clinically diagnosed asthma, and present with wheezing (usually episodic in nature), coughing, shortness of breath and exercise intolerance (especially in patients with cystic fibrosis). Moderate and severe cases have symptoms suggestive of bronchiectasis, in particular thick sputum production (often containing brown mucus plugs), as well as symptoms mirroring recurrent infection such as pleuritic chest pain and fever. Patients with asthma and symptoms of ongoing infection, who do not respond to antibiotic treatment, should be suspected of ABPA.

Pathophysiology
Aspergillus spores are small (2–3 μm in diameter) and can penetrate deep into the respiratory system to the alveolar level. In healthy people, innate and adaptive immune responses are triggered by various immune cells (notably neutrophils, resident alveolar macrophages and dendritic cells) drawn to the site of infection by numerous inflammatory cytokines and neutrophilic attractants (such as CXCR2 receptor ligands). In this situation, mucociliary clearance is initiated and spores are successfully phagocytosed, clearing the infection from the host.In people with predisposing lung diseases—such as persistent asthma or cystic fibrosis (or rarer diseases such as chronic granulomatous disease or Hyper-IgE syndrome)—several factors lead to an increased risk of ABPA. These include immune factors (such as atopy or immunogenic HLA-restricted phenotypes), as well as genetic factors (such as CFTR gene mutations in both asthmatics and cystic fibrosis patients and a ZNF77 mutation resulting in a premature stop codon in asthmatics and ABPA patients). By allowing Aspergillus spores to persist in pulmonary tissues, it permits successful germination which leads to hyphae growing in mucus plugs.
There are hypersensitivity responses, both a type I response (atopic, with formation of immunoglobulin E, or IgE) and a type III hypersensitivity response (with formation of immunoglobulin G, or IgG). The reaction of IgE with Aspergillus antigens results in mast cell degranulation with bronchoconstriction and increased capillary permeability. Immune complexes (a type III reaction) and inflammatory cells are deposited within the mucous membranes of the airways, leading to necrosis (tissue death) and eosinophilic infiltration. Type 2 T helper cells appear to play an important role in ABPA due to an increased sensitivity to interleukin (IL) 4 and IL-5. These cytokines up-regulate mast cell degranulation, exacerbating respiratory decline.Aspergillus also utilises a number of factors to continue evading host responses, notably the use of proteolytic enzymes that interrupt IgG antibodies aimed towards it. Another important feature is its ability to interact and integrate with epithelial surfaces, which results in massive pro-inflammatory counter-response by the immune system involving IL-6, IL-8 and MCP-1 (a CCL2 receptor ligand). Proteases released by both the fungus and neutrophils induce further injury to the respiratory epithelium, leading to initiation of repair mechanisms (such as an influx of serum and extracellular matrix (ECM) proteins) at the site of infection. Aspergillus spores and hyphae can interact with ECM proteins, and it is hypothesised that this process facilitates the binding of spores to damaged respiratory sites.As concentrations of Aspergillus proteases increase, the immunological effect switches from pro-inflammatory to inhibitory, and further reduces phagocytic ability to clear Aspergillus. Ultimately, repeated acute episodes lead to wider scale damage of pulmonary structures (parenchyma) and function via irreversible lung remodelling. Left untreated, this manifests as progressive bronchiectasis and pulmonary fibrosis that is often seen in the upper lobes, and can give rise to a similar radiological appearance to that produced by tuberculosis.

Diagnosis
The exact criteria for the diagnosis of ABPA are not yet universally agreed upon, though working groups have proposed specific guidelines. Minimal criteria include five factors:  the presence of asthma and/or cystic fibrosis, a positive skin test to Aspergillus sp., total serum IgE > 416 IU/mL (or kU/L), an increased Aspergillus species–specific IgE and IgG antibodies, and the presence of infiltrates on a chest X-ray.ABPA should be suspected in patients with a predisposing lung disease—most commonly asthma or cystic fibrosis— and is often associated with chronic airway limitation (CAL). Patients generally present with symptoms of recurrent infection such as fever, but do not respond to conventional antibiotic therapy. Poorly-controlled asthma is a common finding, with a case series only finding 19% of ABPA patients with well-controlled asthma. Wheezing and hemoptysis (coughing up blood) are common features, and mucus plugging is seen in 31–69% of patients.

Blood tests and serology
The first stage involves exposing the skin to Aspergillus fumigatus antigens; an immediate reaction is hallmark of ABPA. The test should be performed first by skin prick testing, and if negative followed with an intradermal injection. The overall sensitivity of the procedure is around 90%, though up to 40% of asthmatic patients without ABPA can still show some sensitivity to Aspergillus antigens (a phenomenon likely linked to a less severe form of ABPA termed severe asthma with fungal sensitization (SAFS)).Serum blood tests are an important marker of disease severity and are also useful for the primary diagnosis of ABPA. When serum IgE is normal (and patients are not being treated by glucocorticoid medications), ABPA is excluded as the cause of symptoms. A raised IgE increases suspicion, though there is no universally accepted cut-off value. Values can be stated in international units (IU/mL) or ng/mL, where 1 IU is equal to 2.4 ng/mL. Since studies began documenting IgE levels in ABPA during the 1970s, various cut-offs between 833 and 1000 IU/mL have been employed to both exclude ABPA and to warrant further serological testing. The current consensus is that a cut-off of 1000 IU/mL should be employed, as lower values are encountered in SAFS and asthmatic sensitization.IgG antibody precipitin testing from serum is useful, as positive results are found in between 69 and 90% of patients, though also in 10% of asthmatics with and without SAFS. Therefore, it must be used in conjunction with other tests. Various forms exist, including enzyme-linked immunosorbent assay (ELISA) and fluorescent enzyme immunoassay (FEIA). Both are more sensitive than conventional counterimmunoelectrophoresis. IgG may not be entirely specific for ABPA, as high levels are also found in chronic pulmonary aspergillosis (CPA) alongside more severe radiological findings.Until recently, peripheral eosinophilia (high eosinophil counts) was considered partly indicative of ABPA. More recent studies show that only 40% of people with ABPA  present with eosinophilia, and hence a low eosinophil count does not necessarily exclude ABPA; for example patients undergoing steroid therapy have lower eosinophil counts.

Radiological investigation
Consolidation and mucoid impaction are the most commonly described radiological features described in ABPA literature, though much of the evidence for consolidation comes from before the development of computed tomography (CT) scans. Tramline shadowing, finger-in-glove opacities and toothpaste shadows are also prevalent findings.When utilising high-resolution CT scans, there can be a better assessment of the distribution and pattern of bronchiectasis within the lungs, and hence this is the tool of choice in the radiological diagnosis of ABPA. Central (confined to medial two-thirds of the medial half of the lung) bronchiectasis that peripherally tapers bronchi is considered a requirement for ABPA pathophysiology, though in up to 43% of cases there is a considerable extension to the periphery of the lung.Mucoid impaction of the upper and lower airways is a common finding. Plugs are hypodense but appear on CT with high attenuation (over 70 Hounsfield units) in up to 20% of patients. Where present it is a strong diagnostic factor of ABPA and distinguishes symptoms from other causes of bronchiectasis.CT scans may more rarely reveal mosaic-appearance attenuation, centrilobular lung nodules, tree-in-bud opacities and pleuropulmonary fibrosis (a finding consistent with CPA, a disease with ABPA as a known precursor). Rarely other manifestations can be seen on CT scans, including military nodular opacities, perihilar opacities (that mimic hilar lymphadenopathy), pleural effusions and pulmonary masses. Cavitation and aspergilloma are rarer findings, not exceeding 20% of patients, and likely represent a shift from ABPA to CPA if accompanied by pleural thickening or fibrocavitary disease.

Culture
Culturing fungi from sputum is a supportive test in the diagnosis of ABPA, but is not 100% specific for ABPA as A. fumigatus is ubiquitous and commonly isolated from lung expectorant in other diseases. Nevertheless, between 40 and 60% of patients do have positive cultures depending on the number of samples taken.

Staging
New criteria by the ABPA Complicated Asthma ISHAM Working Group suggests a 6-stage criteria for the diagnosis of ABPA, though this is yet to be formalised into official guidelines. This would replace the current gold standard staging protocol devised by Patterson and colleagues. Stage 0 would represent an asymptomatic form of ABPA, with controlled asthma but still fulfilling the fundamental diagnostic requirements of a positive skin test with elevated total IgE (>1000 IU/mL). Stage 6 is an advanced ABPA, with the presence of type II respiratory failure or pulmonary heart disease, with radiological evidence of severe fibrosis consistent with ABPA on a high-resolution CT scan. It must be diagnosed after excluding the other, reversible causes of acute respiratory failure.

Treatment
Underlying disease must be controlled to prevent exacerbation and worsening of ABPA, and in most patients this consists of managing their asthma or CF. Any other co-morbidities, such as sinusitis or rhinitis, should also be addressed.Hypersensitivity mechanisms, as described above, contribute to progression of the disease over time and, when left untreated, result in extensive fibrosis of lung tissue. In order to reduce this, corticosteroid therapy is the mainstay of treatment (for example with prednisone); however, studies involving corticosteroids in ABPA are limited by small cohorts and are often not double-blinded. Despite this, there is evidence that acute-onset ABPA is improved by corticosteroid treatment as it reduces episodes of consolidation. There are challenges involved in long-term therapy with corticosteroids—which can induce severe immune dysfunction when used chronically, as well as metabolic disorders—and approaches have been developed to manage ABPA alongside potential adverse effects from corticosteroids.The most commonly described technique, known as sparing, involves using an antifungal agent to clear spores from airways adjacent to corticosteroid therapy. The antifungal aspect aims to reduce fungal causes of bronchial inflammation, whilst also minimising the dose of corticosteroid required to reduce the immune systems input to disease progression. The strongest evidence (double-blinded, randomized, placebo-controlled trials) is for itraconazole twice daily for four months, which resulted in significant clinical improvement compared to placebo, and was mirrored in CF patients. Using itraconazole appears to outweigh the risk from long-term and high-dose prednisone. Newer triazole drugs—such as posaconazole or voriconazole—have not yet been studied in-depth through clinical trials in this context.Whilst the benefits of using corticosteroids in the short term are notable, and improve quality of life scores, there are cases of ABPA converting to invasive aspergillosis whilst undergoing corticosteroid treatment. Furthermore, in concurrent use with itraconazole, there is potential for drug interaction and the induction of Cushing syndrome in rare instances. Metabolic disorders, such as diabetes mellitus and osteoporosis, can also be induced.In order to mitigate these risks, corticosteroid doses are decreased biweekly assuming no further progression of disease after each reduction.  When no exacerbations from the disease are seen within three months after discontinuing corticosteroids, the patient is considered to be in complete remission </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 Polymorphous light eruption and can you explain it in depth? [/INST] Polymorphous light eruption (PLE), sometimes also called polymorphic light eruption (PMLE), is a non-life-threatening and potentially distressing skin condition that is triggered by sunlight and artificial UV exposure in a genetically susceptible person, particularly in temperate climates during the spring and early summer. Due to its many clinical appearances, it is named polymorphic or polymorphous and the terms are used interchangeably. The resulting itch can cause significant suffering.PLE is also defined as an idiopathic primary photodermatosis, in which the photosensitizer is unknown.Treatments include prevention with sun avoidance and supervised light therapy, and symptom control with topical steroids.

Signs and symptoms
Typically, the first episode develops in the spring following the first exposure to intense sun. Further episodes of the irritable rash occur several hours to days following subsequent sun exposure.PLE appears on areas of the skin newly exposed to sunlight such as the visible part of the neckline, backs of hands, arms and legs, and feet, but less commonly the face. At these areas, there may be feelings of burning and severe itching. Smooth red-topped small papules which merge into plaques, small fluid-filled blisters (papulovesicles) and less commonly target-shaped lesions which look like erythema multiforme may be visible. In addition, it may occur in other parts of the body in some people treated for inflammatory skin diseases with phototherapy.The rash is usually quite symmetrical and characteristic for each individual, appearing similar with each recurrence, but can look dissimilar in different people.Fever, fatigue and headaches have been previously associated with the eruption, but are rare.The rash may persist for many days to a couple of weeks, resolving spontaneously without scarring as long as further sunlight exposure is avoided.Recurring yearly, the eruption can sometimes last longer than a few days if persistent and repeated sun exposure occurs. However, the "hardening" effect, with respite during the later summer, frequently occurs with gradual exposure of sunlight, eventually leading to significant improvement.

Causes
The cause of PLE is not yet understood, but several factors may be involved. It is thought to be due to a type IV delayed-type hypersensitivity to an allergen produced in the body following sunlight exposure, in a genetically susceptible person. It is also thought that skin microbiome or microbial elements could be involved in pathogenesis of the disease

UV exposure
PLE can be provoked by UVA or UVB (chief cause of sunburn) rays, meaning it can be triggered even by sunlight through glass. UV-A is a major constituent of sunlight, can pass through glass, is relatively resistant to sunscreen and can cause light eruption without sunburn.Artificial UV light sources from tanning units and phototherapy treatment units can also trigger PLE. About three-quarters of patients acquire PLE after UV-A exposure only, one-tenth after UV-B exposure only, and the rest after a combination of UV-A and UV-B exposure.People vary in the amount of sun exposure needed to trigger the rash.

Oxidative stress
Oxidative stress and the modification of the redox status of the skin has been implicated in the expression of PLE.

Photosensitizer
It has been suggested that an undefined endogenous or exogenous photo-allergen may trigger a delayed immune reaction resulting in PLE.

Genetics
Half of patients have a family history of PLE, demonstrating a clear genetic influence.

Oestrogen effect
The preponderance in women with a decline in severity following menopause has been thought to be associated with oestrogen effects, A natural fall in oestrogens may account for the tendency to remit after the menopause.

Diagnosis
The diagnosis of PLE is typically made by assessing the history and clinical observations. Any investigations are usually to exclude other conditions, particularly lupus and porphyria.Blood tests are usually normal. However, positive antinuclear antibody and extractable nuclear antigen (anti-Ro/La) in low titre may be found, even in the absence of other criteria to suggest a diagnosis of lupus erythematosus. If clinical findings suggest a possibility of porphyria, urinary and red cell porphyrin screening may be performed and are negative in PLE.Photoprovocation tests are usually not required but may be undertaken by specialised centres in winter. When a decision to undertake this is made, a small area of the frequently affected skin is exposed to varying doses of UVA and minimal erythema dose (MED) (amount of UV radiation that will produce minimal redness of skin within a few hours following exposure) of broadband UVB for three consecutive days. An examination of the skin to detect the rash is made, however, up to 40% have false negative responses.

Biopsy findings
Depending on the clinical signs, histology of a skin biopsy may vary. There may be oedema in the epidermis with a dense superficial and deep lymphocytic infiltrate without vasculitis. Recently appearing lesions may show neutrophils. Spongiosis and vesicle formation may also be present. Direct immunofluorescence testing is negative.

Differential diagnosis
The photosensitivity connected with lupus erythematosus is the main condition that may appear like PLE. However, the rash of lupus is inclined to be more persistent. PLE does not increase the risk of lupus.Other similar appearing conditions are solar urticaria, which has a shorter duration, the eczema-like condition, photosensitive dermatitis, and photosensitivity drug reaction.Prickly heat, which is caused by warm weather or heat is not the same as PLE.Photosensitivity is also found in some of the porphyrias. Nearly all cases of porphyria cutanea tarda exhibit blister formation on the skin within 2–4 days of light exposure </s>