<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 Interrupted aortic arch and can you explain it in depth? [/INST] Interrupted aortic arch is a very rare heart defect (affecting 3 per million live births) in which the aorta is not completely developed. There is a gap between the ascending and descending thoracic aorta. In a sense it is the complete form of a coarctation of the aorta. Almost all patients also have other cardiac anomalies, including a ventricular septal defect (VSD), aorto-pulmonary window, and truncus arteriosus. There are three types of interrupted aortic arch, with type B being the most common. Interrupted aortic arch (especially Type B) is often associated with DiGeorge syndrome.

Signs and symptoms
Patients with an interrupted aortic arch usually have symptoms from birth, with nearly all presenting symptoms within two weeks (when the ductus arteriosus is usually closed).

Causes
It is thought that an interrupted aortic arch occurs through excessive apoptosis in the developing, embryonic aorta. Around 50% of patients have DiGeorge syndrome.

Diagnosis
It can be diagnosed with a standard echocardiogram. An echocardiogram can also aid in classifying the type of defect. The diagnosis can also be made prior to birth via ultrasound. Patients will have a loss of appetite, appear tired and weak, and exhibit rapid breathing and a rapid heart rate. If the condition progresses, the infant may turn pale, feel cold in the lower half of the body, and have a weak pulse due to insufficient blood flow. The pattern of pulse abnormalities is dependent upon the classification; e.g., for type B interrupted aortic arch, the right brachial pulse will be palpable and the left brachial and femoral pulses will be impalpable due to closure of the ductus arteriosus. Rarely, an interrupted aortic arch can be associated with an intracranial aneurysm. Signs of ischemia due to interrupted aortic arch can be separated by the organ system involved:
Liver injury: elevated serum glutamic oxaloacetic transaminase (SGOT) (also known as aspartate transaminase, AST) and lactic acid dehydrogenase (LDH)
Kidney injury: elevated serum creatinine
Intestinal injury: signs of necrotizing enterocolitis, such as bloody stoolsCHARGE syndrome, a specific, rare pattern of genetic abnormalities, commonly features conotruncal and aortic arch heart defects, which can include an interrupted aortic arch.

Classification
There are three primary classifications for an interrupted aortic arch, on the basis of the specific, anatomic anomaly. They are:

Type A: The aortic arch is interrupted after the left subclavian artery.
Type B: The aortic arch is interrupted between the left common carotid artery and the left subclavian artery. This is the most common form of the condition, and is the classification most often associated with DiGeorge syndrome.
Type C: The aortic arch is interrupted between the innominate artery and the left common carotid artery. This is the least common form of the condition.Each class can be divided into two subgroups, based upon whether the right subclavian artery originated in a normal, anatomical position (subgroup 1) or if it originated distal to the left subclavian artery and continues behind the esophagus (subgroup 2). However, these subgroups do not affect how the disease is diagnosed or treated.

Treatment
Prostaglandins
If the diagnosis is made prenatally, prostaglandin E1 (PGE1) is started after birth to avoid closure of the ductus arteriosus. Prostaglandin therapy is performed via a continuous infusion, due to how quickly prostaglandins are metabolized in the body. However, the diagnosis may go undetected, delaying treatment until closure of the ductus arteriosus produces symptoms.

Surgery
Curative treatment consists of open heart surgery soon after birth, preferably immediately after diagnosis. Often, a synthetic patch is used to recreate the lost section of aorta. Recent research has revealed that an initial single-stage repair using direct anastomoses and repair of any existing cardiac defects is the preferred surgical technique, as opposed to a two-stage surgical repair.Awaiting surgery, prostaglandin can be administered to keep the ductus arteriosus open, thereby allowing blood flow to the lower body. After successful treatment, the patient is monitored for the rest of their life by a specialist to ensure that problems do not occur.

Prognosis
Failure to treat the condition yields a mortality rate of 90% at a median age of 4 days. Death occurs due to increased blood flow from the left side of the heart (oxygenated blood) to the right side (deoxygenated blood), inducing heart failure; pulmonary edema; and eventual closing of the ductus arteriosus. For an infant with an interrupted aortic arch, a patent (open) ductus arteriosus allows for blood to bypass the "interruption," without which blood will be unable to reach the lower half of the body. As a result, the kidneys fail and the blood becomes acidic, resulting in death.With modern surgical techniques, 81% of children with an interrupted aortic arch survive to be 15 years-old. The fate of survivors in the long-term is still unclear.

Surgical complications
The most common, early complication of surgery is bleeding, the risk of which can be increased by prematurity, prolonged acidosis prior to surgery, and excessive tension on the anastamosis due to inadequate mobilization of the ascending and descending aorta. Other early complications include damage to the left recurrent laryngeal nerve and the phrenic nerve. Late complications include obstruction of the graft and obstruction of the left main bronchus (which passes underneath the aortic arch).

Epidemiology
The incidence of an interrupted aortic arch is extremely rare, occurring between three and twenty times per 1,000,000 births. In the context of other congenital cardiac abnormalities, interrupted aortic arch represents about 1.5% of cases.

History
The condition was first identified by Dr. Raphael Steidele, Professor of Obstetrics at the University of Vienna, in 1778. In the case Steidele described, the infant had a type A interrupted aortic arch, and survived only for "a few hours." In homage to the discoverer, the terminology of "Steideles complex" has been used to describe an interrupted aortic arch </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 Pendular nystagmus and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Intraocular lens and can you explain it in depth? [/INST] Intraocular lens (IOL) is a lens implanted in the eye as part of a treatment for cataracts or myopia. If the natural lens is left in the eye, the IOL is known as phakic, otherwise it is a pseudophakic, or false lens. Such a lens is typically implanted during cataract surgery, after the eyes cloudy natural lens (cataract) has been removed. The pseudophakic IOL provides the same light-focusing function as the natural crystalline lens. The phakic type of IOL is placed over the existing natural lens and is used in refractive surgery to change the eyes optical power as a treatment for myopia (nearsightedness). This is an alternative to LASIK.
IOLs usually consist of a small plastic lens with plastic side struts, called haptics, to hold the lens in place in the capsular bag inside the eye. IOLs were conventionally made of an inflexible material (PMMA), although this has largely been superseded by the use of flexible materials, such as silicone. Most IOLs fitted today are fixed monofocal lenses matched to distance vision. However, other types are available, such as a multifocal intraocular lens that provide multiple-focused vision at far and reading distance, and adaptive IOLs that provide limited visual accommodation.  Multifocal IOLs can further be, Trifocal IOLs or extended depth of focus (EDOF) lenses.
More than six million lenses are implanted annually. The procedure can be done under local or topical anesthesia with the patient awake throughout the operation. The use of a flexible IOL enables the lens to be rolled for insertion into the capsular bag through a very small incision, thus avoiding the need for stitches. This procedure usually takes less than 30 minutes in the hands of an experienced ophthalmologist, and the recovery period is about 2–3 weeks. After surgery, patients should avoid strenuous exercise or anything else that significantly increases blood pressure. They should visit their ophthalmologists regularly for 3 weeks to monitor the implants.
IOL implantation carries several risks associated with eye surgeries, such as infection, loosening of the lens, lens rotation, inflammation and nighttime halos, but a systematic review of studies has determined that the procedure is safer than conventional laser eye treatment. Though IOLs enable many patients to have reduced dependence on glasses, most patients still rely on glasses for certain activities, such as reading. These reading glasses may be avoided if Multifocal IOLs, Trifocal IOLs or EDOF lenses are used.

Medical uses
Intraocular lenses have been used since 1999 for correcting larger errors in near-sighted, far-sighted, and astigmatic eyes. This type of IOL is also called phakic intraocular lens (PIOL), as it is implanted without removing the patients natural crystalline lens.Phakic IOL appear to be less dangerous than excimer laser surgery (LASIK) in those with significant nearsightedness.More commonly IOLs are implanted via Clear Lens Extraction And Replacement (CLEAR) surgery. During CLEAR, the crystalline lens is extracted and an IOL replaces it in a process that is very similar to cataract surgery: both involve lens replacement, local anesthesia, last approximately 30 minutes, and require making a small incision in the eye for lens insertion. People recover from CLEAR surgery 1–7 days after the operation. During this time, they should avoid strenuous exercise or anything else that significantly raises blood pressure. They should visit their ophthalmologists regularly for several weeks to monitor the IOL implants.
CLEAR has a 90% success rate (risks include wound leakage, infection, inflammation, and astigmatism). CLEAR can be performed only on patients ages 40 and older. This is to ensure that eye growth, which disrupts IOL lenses, will not occur post-surgery.
Once implanted, IOL lenses have three major benefits. First, they are an alternative to the excimer laser procedure (LASIK), a form of eye surgery that does not work for people with serious vision problems. Effective IOL implants also eliminate the need for glasses or contact lenses post-surgery for most patients. The cataract will not return, as the lens has been removed. The disadvantage is that the eyes ability to change focus (accommodate) has generally been reduced or eliminated, depending on the kind of lens implanted.
Some of the risks that FDA have been found so far during a three-year study of the Artisan are:

a yearly loss of 1.8% of the endothelial cells,
0.6% risk of retinal detachment,
0.6% risk of cataract (other studies have shown a risk of 0.5–1.0%), and
0.4% risk of corneal swelling.Other risks include:

0.03–0.05% eye infection risk, which in worst case can lead to blindness. (This risk exists in all eye surgery procedures and is not unique to IOLs.)
glaucoma,
astigmatism,
remaining near or far sightedness,
rotation of the lens inside the eye one or two days after surgery.One of the causes of the risks above is that the lens can rotate inside the eye if the PIOL is too short, if the eye was incorrectly measured, or because the sulcus has a slightly oval shape (the height is slightly smaller than the width). Toric IOLs must be powered and aligned inside the eye on a meridian that corrects the patients preexisting astigmatism. Again, these lenses can rotate inside the eye postoperatively or be placed incorrectly by the operating surgeon. Either way, the patients preexisting astigmatism may not be corrected completely or may even increase.
When standard IOLs are implanted with a CLEAR procedure, in substitution of the patients crystalline, astigmatism is typically not corrected, as astigmatism is mainly attributable to a deformation of the cornea. Toric IOLs may be used during the CLEAR procedure to correct astigmatism.
The surgeon can ascertain the astigmatic, or steepest, meridian in a number of ways, including manifest refraction or corneal topography. Manifest refraction is the familiar test where the eye doctor rotates lenses in front of the eye, asking the patient, "Which is better (or clearer), this one or this one?" Corneal topography is considered a more quantitative test, and for purposes of aligning a toric IOL, most surgeons use a measurement called simulated keratometry (SimK), which is calculated by the internal programming of the corneal topography machine, to determine the astigmatic meridian on the surface of the cornea. The astigmatic meridian can also be identified using corneal wavefront technology or paraxial curvature matching.

Type of surgery
Implants with or without removal of natural crystalline
Phakia is the presence of the natural crystalline lenses. Phakic IOL (PIOL) refers to an intraocular lens implanted without removal of the patients original crystalline lens, and this is performed solely to correct refractive error in the presence of a clear crystalline lens.
Aphakia is the absence of the natural crystalline lens. The aphakic state is usually due to surgery to remove a cataractous lens, but post-surgical aphakia is rare nowadays because of the ubiquity of intraocular lenses. Rarely, aphakia can be post-traumatic or congenital in nature. Aphakic IOL refers to a lens implanted secondarily in an eye already aphakic from previous surgery or trauma some time ago.
Pseudophakia is the substitution of the natural crystalline lens with an IOL, as is often done after cataract extraction or to correct refractive error.  Pseudophakic IOL refers to a lens implanted during cataract surgery, immediately after removal of the patients crystalline lens.Many aphakic and pseudophakic IOLs such as anterior chamber IOLs or 3 piece posterior chamber IOLs can be used interchangeably. The exception are one piece IOLs, which must be placed within the capsular bag at the time of cataract surgery and hence cannot be used as secondary implants.

Location of implant
Posterior chamber IOL (PCIOL). This is by far the most common type of implanted lens after cataract surgery in the United States.
Anterior chamber IOL (ACIOL). A less-common type of intraocular lens, which is sometimes used if a PCIOL is not an option for a patient or if the situation requires a phakic IOL (PIOL).

Pseudophakic IOLs
Pseudophakic IOLs are lenses implanted during cataract surgery, immediately after removal of the patients crystalline lens.

Monofocal
Monofocal IOLs are standard lenses used in cataract surgery. One of the major disadvantages of these conventional IOLs is that they can only be focused for one particular distance - either optical infinity (rendering the eye emmetropic) or a fixed finite distance (rendering the eye myopic). Patients who undergo a standard IOL implantation no longer experience clouding from cataracts, but they are unable to accommodate (change focus from near to far, far to near, and to distances in between). This is not a concern for most cataract surgeries, as they are primarily performed on elderly people that are already completely presbyopic.  However, it can be a problem for patients that are not yet presbyopic (or are in the early stages of presbyopia) undergoing refractive lens exchange for the sake of correcting refractive errors.  Monovision, in which one eye is made emmetropic and the other myopic, can partially compensate for the loss of accommodation and enable clear vision at multiple distances.  More versatile types of lenses (multifocal and accommodating IOLs) were introduced in 2003 in the United States, with the approval by the Food and Drug Administration. These come at an additional cost to the recipient beyond what Medicare will pay and each has advantages and disadvantages.

Multifocal
Multifocal IOLs attempt to provide simultaneous viewing of distance vision and near vision. Trifocal IOLs can provide intermediate vision. Many multifocal IOL designs attempt to achieve this simultaneous viewing focus using a concentric ring design, which alternates distance and near focal points. However, many concentric ring multifocal lenses used today are prone to glare and mildly compromised focus at all ranges of vision.
People who have a multifocal IOL after their cataract is removed may be less likely to need additional glasses compared with people who have standard monofocal lenses. However, people receiving multifocal lenses may experience more visual problems than with monofocal lenses.
The most common adverse visual effects from multifocal IOLs include glare, halos (rings around lights), and a loss of contrast sensitivity in low-light conditions.

Adjustable Lens
An adjustable IOL is unlike any other lens as its prescription power can be adjusted after surgery once all healing is complete. All other IOLs require surgeons to use pre-surgery measurements to determine a patients post-surgery lens power. The drawback of this is that pre-surgery measurements are taken while a patient still has cataracts, and they cant account for minuscule shifts that occur during healing. An adjustable IOL allows surgeons to implant it and then, once healing is complete, use an Ultra Violet light delivery device to fine tune it until it suits the patient. An early example being the (RxSight) Light Adjustable Lens (LAL).

Accommodating
Some newer lens designs attempt to allow the eye to regain some partial focusing ability in order to change focus from distance to near (accommodation).  However, many accommodating IOLs used today only achieve a very limited improvements in near vision which reduced over time. Accommodative intraocular lenses may also have a slightly higher risk of developing posterior capsule opacification (PCO), though there is some uncertainty around this finding. PCO is a common side-effect of many cataract surgeries and is easily treatable with a one-time laser capsulotomy procedure (see below).
Accommodating IOLs interact with ciliary muscles and zonules, using hinges at both ends to "latch on" and move forward and backward inside the eye using the same mechanism as normal accommodation. These IOLs have a 4.5-mm square-edged optic and a long hinged plate design with polyimide loops at the end of the haptics. The hinges are made of an advanced silicone called BioSil that was thoroughly tested to make sure it was capable of unlimited flexing in the eye.

Toric
A toric IOL is a type of toric lens used to correct preexisting corneal astigmatism at the time of cataract surgery. Astigmatism can also be treated with limbal relaxing incisions or an excimer laser procedure. About 40% of Americans have significant astigmatism and thus may be candidates for a toric IOL. Cataract surgery with implantation of a toric IOL is essentially the same as cataract surgery with a conventional IOL. Like toric contact lenses, toric IOLs have different powers in different meridians of the lens, and they must be positioned on the correct meridian to reverse the preexisting astigmatism. If the toric IOL is not on the correct meridian, it may need to be repositioned in a second procedure.

Multifocal toric
Standard toric IOLs are monofocal, permanently focused on distant objects. Multifocal toric IOLs are also available. These lenses provide the patient not only with correction of preexisting astigmatism, but also with multiple-focused vision at far and reading distance

Phakic IOLs
Phakic IOLs (PIOLs) are intraocular lenses which are placed in an eye that still contains a natural human crystalline lens. PIOLs are sometimes referred to as an implantable contact lenses (ICLs). As with other IOLs, PIOLs can be either spheric or toric. Toric PIOLs have to be aligned with the meridian of astigmatism; toric IOL misalignment or rotation can lead to residual or even greater astigmatism postoperatively.Depending on their attachment site to the eye, PIOLs can be divided into three categories:
Angle-supported PIOLs, placed in the anterior chamber. They are notorious for their negative impact on the corneal endothelial lining, which is vital for maintaining a healthy clear cornea.
Iris-fixated PIOLs, attached by claws to the mid-peripheral iris by a technique called enclavation. It is believed to have a lesser effect on corneal endothelium. The main complication with this type is their tendency to cause endothelial cell reduction.
Sulcus-supported PIOLs, placed in the posterior chamber in front of the natural crystalline lens. This type of PIOLs is gaining more and more popularity. They have special vaulting so as not to be in contact with the normal lens. The main complication with older versions was a small possibility of cataract formation.

Blue-light filtering IOLs
Blue light filtering IOLs filter the UV and high-energy blue light present in natural and artificial light, both of which can cause vision problems; however too much filtering of blue light can increase depression, especially in the winter months (SAD).  The trademarked "Natural Yellow" material is available in three hydrophilic IOLs. Dr. Patrick H. Benz of Benz Research and Development created the first IOL material to incorporate the same UV-A blocking and violet light filtering chromophore thats present in the human crystalline lens in order to attempt to protect the retina after cataract extraction of the natural crystalline lens.
A Cochrane Review found little evidence of important differences between blue‐light filtering and non‐blue‐light filtering lenses for protecting the macula (back of the eye) after cataract surgery. This was due to studies being too small and too short‐term to provide reliable results.

Posterior capsule opacification
Posterior capsule opacification (PCO), often referred to as "after cataract", is the most common complication of cataract surgery.In a small percentage of patients, posterior chamber intraocular lenses may form PCOs a few months after implantation. They are easily treatable, and typically only require a one-time capsulotomy procedure (using a Nd:YAG laser) to clarify.

Materials
The materials that have been used to manufacture intraocular lens implants include polymethylmethacrylate (PMMA), silicone, hydrophobic acrylate, hydrophilic acrylate and collamer </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 Glucose-6-phosphate dehydrogenase deficiency and can you explain it in depth? [/INST] Glucose-6-phosphate dehydrogenase deficiency (G6PDD), which is the most common enzyme deficiency worldwide, is an inborn error of metabolism that predisposes to red blood cell breakdown. Most of the time, those who are affected have no symptoms. Following a specific trigger, symptoms such as yellowish skin, dark urine, shortness of breath, and feeling tired may develop. Complications can include anemia and newborn jaundice. Some people never have symptoms.It is an X-linked recessive disorder that results in defective glucose-6-phosphate dehydrogenase enzyme. Glucose-6-phosphate dehydrogenase is an enzyme which protects red blood cells, which carry oxygen from the lungs to tissues throughout the body. A defect of the enzyme results in the premature breakdown of red blood cells. This destruction of red blood cells is called hemolysis. Red blood cell breakdown may be triggered by infections, certain medication, stress, or foods such as fava beans. Depending on the specific mutation the severity of the condition may vary. Diagnosis is based on symptoms and supported by blood tests and genetic testing.Affected persons must avoid dietary triggers, notably fava beans. This can be difficult, as fava beans may be called "broad beans" and are used in many foods, whole or as flour. Falafel is probably the best known, but fava beans are also often used as filler in meatballs and other foods. Since G6PD deficiency is not an allergy, food regulations in most countries do not require that fava beans be highlighted as an allergen on the label.Treatment of acute episodes may include medications for infection, stopping the offending medication, or blood transfusions. Jaundice in newborns may be treated with bili lights. It is recommended that people be tested for G6PDD before certain medications, such as primaquine, are taken.About 400 million people have the condition globally. It is particularly common in certain parts of Africa, Asia, the Mediterranean, and the Middle East. Males are affected more often than females. In 2015 it is believed to have resulted in 33,000 deaths.

Signs and symptoms
Most individuals with G6PD deficiency are asymptomatic.Most people who develop symptoms are male, due to the X-linked pattern of inheritance, but female carriers can be affected due to unfavorable lyonization or skewed X-inactivation, where random inactivation of an X-chromosome in certain cells creates a population of G6PD-deficient red blood cells coexisting with unaffected red blood cells. A female with one affected X chromosome will show the deficiency in approximately half of her red blood cells. However, in some cases, including double X-deficiency, the ratio can be much more than half, making the individual almost as sensitive as males.Red blood cell breakdown (also known as hemolysis) in G6PD deficiency can manifest in a number of ways, including the following:
Prolonged neonatal jaundice, possibly leading to kernicterus (arguably the most serious complication of G6PD deficiency)
Hemolytic crises in response to:
Illness (especially infections)
Certain drugs (see below)
Certain foods, most notably broad beans, from which the word favism derives
Certain chemicals
Diabetic ketoacidosis
Hemoglobinuria (red or brown urine)
Very severe crisis can cause acute kidney injuryFavism is a hemolytic response to the consumption of fava beans, also known as broad beans. Though all individuals with favism show G6PD deficiency, not all individuals with G6PD deficiency show favism. The condition is known to be more prevalent in infants and children, and G6PD genetic variant can influence chemical sensitivity. Other than this, the specifics of the chemical relationship between favism and G6PD are not well understood.

Cause
G6PD deficiency results from mutations in the G6PD gene. G6PD gene contributes to the production of glucose-6-phosphate dehydrogenase. Chemical reactions involving glucose-6-phosphate dehydrogenase produce compounds that prevent reactive oxygen species from building up to toxic levels within red blood cells. If reduction in the amount of glucose-6-phosphate dehydrogenase or alteration of structure occurs due to the mutations of G6PD gene, the enzyme loses it protective role and leads to the accumulation of reactive oxygen species and thus damage of red blood cells.

Triggers
Carriers of the underlying mutation do not show any symptoms unless their red blood cells are exposed to certain triggers, which can be of four main types:

Foods (fava beans is the hallmark trigger for G6PD mutation carriers),
Certain medicines including aspirin, quinine and other antimalarials derived from quinine.
Moth balls (naphthalene)
Stress from a bacterial or viral infection.

Drugs
Many substances are potentially harmful to people with G6PD deficiency. Variation in response to these substances makes individual predictions difficult. Antimalarial drugs that can cause acute hemolysis in people with G6PD deficiency include primaquine, pamaquine, chloroquine, and hydroxychloroquine. There is evidence that other antimalarials may also exacerbate G6PD deficiency, but only at higher doses. Sulfonamides (such as sulfanilamide, sulfamethoxazole, and mafenide), thiazolesulfone, methylene blue, and naphthalene should also be avoided by people with G6PD deficiency as they antagonize folate synthesis, as should certain analgesics (such as phenazopyridine and acetanilide) and a few non-sulfa antibiotics (nalidixic acid, nitrofurantoin, isoniazid, dapsone, and furazolidone). Henna has been known to cause hemolytic crisis in G6PD-deficient infants. Rasburicase is also contraindicated in G6PD deficiency. High dose intravenous vitamin C has also been known to cause haemolysis in G6PD deficiency carriers; therefore, G6PD deficiency testing is routine before infusion of doses of 25 g or more.

Genetics
Two variants (G6PD A− and G6PD Mediterranean) are the most common in human populations. G6PD A− has an occurrence of 10% of Africans and African-Americans while G6PD Mediterranean is prevalent in the Middle East. The known distribution of the mutated allele is largely limited to people of Mediterranean origins (Spaniards, Italians, Greeks, Armenians, Sephardi Jews and other Semitic peoples). Both variants are believed to stem from a strongly protective effect against Plasmodium falciparum and Plasmodium vivax malaria. It is particularly frequent in the Kurdish Jewish population, wherein approximately 1 in 2 males have the condition and the same rate of females are carriers. It is also common in African American, Saudi Arabian, Sardinian males, some African populations, and Asian groups.All mutations that cause G6PD deficiency are found on the long arm of the X chromosome, on band Xq28. The G6PD gene spans some 18.5 kilobases. The following variants and mutations are well-known and described:

Pathophysiology
Glucose-6-phosphate dehydrogenase (G6PD) is an enzyme in the pentose phosphate pathway (see image, also known as the HMP shunt pathway). G6PD converts glucose-6-phosphate into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of this metabolic pathway that supplies reducing energy to cells by maintaining the level of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the supply of reduced glutathione in the cells that is used to mop up free radicals that cause oxidative damage.The G6PD / NADPH pathway is the only source of reduced glutathione in red blood cells (erythrocytes). The role of red cells as oxygen carriers puts them at substantial risk of damage from oxidizing free radicals except for the protective effect of G6PD/NADPH/glutathione.People with G6PD deficiency are therefore at risk of hemolytic anemia in states of oxidative stress. Oxidative stress can result from infection and from chemical exposure to medication and certain foods. Broad beans, e.g., fava beans, contain high levels of vicine, divicine, convicine and isouramil, all of which create oxidants.When all remaining reduced glutathione is consumed, enzymes and other proteins (including hemoglobin) are subsequently damaged by the oxidants, leading to cross-bonding and protein deposition in the red cell membranes. Damaged red cells are phagocytosed and sequestered (taken out of circulation) in the spleen. The hemoglobin is metabolized to bilirubin (causing jaundice at high concentrations). The red cells rarely disintegrate in the circulation, so hemoglobin is rarely excreted directly by the kidney, but this can occur in severe cases, causing acute kidney injury.Deficiency of G6PD in the alternative pathway causes the buildup of glucose and thus there is an increase of advanced glycation endproducts (AGE). The deficiency also reduces the amount of NADPH, which is required for the formation of nitric oxide (NO). The high prevalence of diabetes mellitus type 2 and hypertension in Afro-Caribbeans in the West could be directly related to the incidence of G6PD deficiency in those populations.Although female carriers can have a mild form of G6PD deficiency (dependent on the degree of inactivation of the unaffected X chromosome – see lyonization), homozygous females have been described; in these females there is co-incidence of a rare immune disorder termed chronic granulomatous disease (CGD).

Diagnosis
The diagnosis is generally suspected when patients from certain ethnic groups (see epidemiology) develop anemia, jaundice and symptoms of hemolysis after challenges from any of the above causes, especially when there is a positive family history.Generally, tests will include:
Complete blood count and reticulocyte count; in active G6PD deficiency, Heinz bodies can be seen in red blood cells on a blood film;
Liver enzymes (to exclude other causes of jaundice);
Lactate dehydrogenase (elevated in hemolysis and a marker of hemolytic severity)
Haptoglobin (decreased in hemolysis);
A "direct antiglobulin test" (Coombs test) – this should be negative, as hemolysis in G6PD is not immune-mediated;When there are sufficient grounds to suspect G6PD, a direct test for G6PD is the "Beutler fluorescent spot test", which has largely replaced an older test (the Motulsky dye-decolouration test). Other possibilities are direct DNA testing and/or sequencing of the G6PD gene.The Beutler fluorescent spot test is a rapid and inexpensive test that visually identifies NADPH produced by G6PD under ultraviolet light. When the blood spot does not fluoresce, the test is positive; it can be falsely negative in patients who are actively hemolysing. It can therefore only be done 2–3 weeks after a hemolytic episode.When a macrophage in the spleen identifies a RBC with a Heinz body, it removes the precipitate and a small piece of the membrane, leading to characteristic "bite cells". However, if a large number of Heinz bodies are produced, as in the case of G6PD deficiency, some Heinz bodies will nonetheless be visible when viewing RBCs that have been stained with crystal violet. This easy and inexpensive test can lead to an initial presumption of G6PD deficiency, which can be confirmed with the other tests.Testing during and for many weeks after a haemolytic episode will lead to false negative results as the G6PD deficient RBC will have been excreted and the young RBC (reticulocytes)will not yet be G6PD deficient. False negative results will also be likely following any blood transfusions.  For this reason, many hospitals wait for 3 months after a haemolytic episode before testing for G6PD deficiency.  Females should have their G6PD activity measured by quantitative assay to avoid being misclassified by screening tests.

Classification
The World Health Organization classifies G6PD genetic variants into five classes, the first three of which are deficiency states.
Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia
Class II: Severe deficiency (<10% activity), with intermittent hemolysis
Class III: Moderate deficiency (10-60% activity), hemolysis with stressors only
Class IV: Non-deficient variant, no clinical sequelae
Class V: Increased enzyme activity, no clinical sequelae

Differential diagnosis
6-phosphogluconate dehydrogenase (6PGD) deficiency has similar symptoms and is often mistaken for G6PD deficiency, as the affected enzyme is within the same pathway, however these diseases are not linked and can be found within the same person.

Treatment
The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks.In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute kidney failure. Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipients circulation. Those affected should avoid drugs such as aspirin.Some patients may benefit from removal of the spleen (splenectomy), as this is an important site of red cell destruction. Folic acid should be used in any disorder featuring a high red cell turnover. Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.

Prognosis
G6PD-deficient individuals do not appear to acquire any illnesses more frequently than other people, and may have less risk than other people for acquiring ischemic heart disease and cerebrovascular disease.
However, a recent study revealed that G6PD deficiency increases the cardiovascular risk up to 70%. The risk conferred by G6PD deficiency is moderate compared with the impact of primary cardiovascular risk factors.
Besides, a published review hypothesized that G6PD deficiency  could reduce the antiplatelet efficacy of clopidogrel (clopidogrel resistance).

Epidemiology
G6PD deficiency is the second most common human enzyme defect after ALDH2 deficiency, being present in more than 400 million people worldwide. G6PD deficiency resulted in 4,100 deaths in 2013 and 3,400 deaths in 1990. African, Middle Eastern and South Asian people are affected the most, including those who have these ancestries. A side effect of this disease is that it confers protection against malaria, in particular the form of malaria caused by Plasmodium falciparum, the most deadly form of malaria </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 Megaesophagus and can you explain it in depth? [/INST] Megaesophagus, also known as esophageal dilatation, is a disorder of the esophagus in humans and other mammals, whereby the esophagus becomes abnormally enlarged. Megaesophagus may be caused by any disease which causes the muscles of the esophagus to fail to properly propel food and liquid from the mouth into the stomach (that is, a failure of peristalsis). Food can become lodged in the flaccid esophagus, where it may decay, be regurgitated, or maybe inhaled into the lungs (leading to aspiration pneumonia).

Humans
Megaesophagus may occur secondary to diseases such as achalasia or Chagas disease. Achalasia is caused by a loss of ganglion cells in the myenteric plexus. There is a marked lack of contraction within the muscles involved in peristalsis with a constant contraction of the lower esophageal sphincter.  Dilation of the esophagus results in difficulty swallowing.  Retention of food bolus is also noted.

Other animals
Dogs
Megaesophagus can also be a symptom of the disease myasthenia gravis.  Myasthenia gravis is a neuromuscular disease where the primary symptom is weakness in various body parts of the dog.  However, when myasthenia gravis occurs in older dogs it is thought of as an immune-mediated disease.  Often when myasthenia gravis is diagnosed in older dogs the first symptom the dog may manifest is megaesophagus. Myasthenia gravis occurs when acetylcholine receptors (nicotinic acetylcholine receptors) fail to function properly, so that the muscle is not stimulated to contract. There is an invention known as the "bailey chair" that uses the force of gravity to push down liquids and food into the dogs stomach. Usually dogs are known to understand when its time to eat in their bailey chair, and this helps prevent issues </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 Subdural hygroma and can you explain it in depth? [/INST] A subdural hygroma (SDG) is a collection of cerebrospinal fluid (CSF), without blood, located under the dural membrane of the brain. Most subdural hygromas are believed to be derived from chronic subdural hematomas. They are commonly seen in elderly people after minor trauma but can also be seen in children following infection or trauma. One of the common causes of subdural hygroma is a sudden decrease in pressure as a result of placing a ventricular shunt. This can lead to leakage of CSF into the subdural space especially in cases with moderate to severe brain atrophy. In these cases the symptoms such as mild fever, headache, drowsiness and confusion can be seen, which are relieved by draining this subdural fluid.

Etiology and Pathophysiology
Subdural hygromas require two conditions in order to occur. First, there must be a separation in the layers of dura mater of the brain. Second, the resulting subdural space that occurs from the separation of layers must remain uncompressed in order for CSF to accumulate in the subdural space resulting in the hygroma. The arachnoid mater is torn and cerebrospinal fluid (CSF) from the subarachnoid space accumulates in the subdural space. Hygromas also push the subarachnoid vessels away from the inner table of the skull. Subdural hygroma can appear in the first day, but the mean time of appearance is 9 days on CT scan. Subdural hygroma does not have internal membranes that can easily rupture like subdural haematoma, but hygroma can sometimes occur together with hemorrhage to become hematohygroma.Subdural hygromas most commonly occur when events such as head trauma, infections, or cranial surgeries happen in tandem with brain atrophy, severe dehydration, prolonged spinal drainage, or any other event that causes a decrease in intracranial pressure. This provides the basis for why subdural hygromas more commonly occur in infants and elderly; infants have compressible brains while elderly patients have a greater amount of space for fluid to accumulate due to brain atrophy from age.

Signs and symptoms
Most subdural hygromas are small and clinically insignificant. A majority of patients with SDG will not experience symptoms. However, some commonly reported, but nonspecific, symptoms of SDG that have been reported include headache and  nausea. Focal neurologic deficits and seizures have also been reported but are nonspecific to SDG.  Larger hygromas may cause secondary localized mass effects on the adjacent brain parenchyma, enough to cause a neurologic deficit or other symptoms. Acute subdural hygromas can be a potential neurosurgical emergency, requiring decompression. Acute hygromas are typically a result of head trauma—they are a relatively common posttraumatic lesion—but can also develop following neurosurgical procedures, and have also been associated with a variety of conditions, including dehydration in the elderly, lymphoma and connective tissue diseases.

Diagnosis
In CT scan, subdural hygroma will have same density as the normal CSF. Meanwhile, in MRI, subdural hygroma will have same intensity with CSF. If iodinated contrast is administered during CT scan, the hygroma will produce high density because of the contrast at 120 kVp. However, at 190 kVp, hygroma with contrast will have intermediate density.In the majority of cases, if there has not been any acute trauma or severe neurologic symptoms, a small subdural hygroma on the head CT scan will be an incidental finding. If there is an associated localized mass effect that may explain the clinical symptoms, or concern for a potential chronic SDH that could rebleed, then an MRI, with or without neurologic consultation, may be useful.
It is not uncommon for chronic subdural hematomas (SDHs) on CT reports for scans of the head to be misinterpreted as subdural hygromas, and vice versa. Magnetic resonance imaging (MRI) should be done to differentiate a chronic SDH from a subdural hygroma, when clinically warranted. Elderly patients with marked cerebral atrophy, and secondary widened subarachnoid CSF spaces, can also cause confusion on CT. To distinguish chronic subdural hygromas from simple brain atrophy and CSF space expansion, a gadolinium-enhanced MRI can be performed. Visualization of cortical veins traversing the collection favors a widened subarachnoid space as seen in brain atrophy, whereas subdural hygromas will displace the cortex and cortical veins.

Treatment
Most subdural hygromas that are asymptomatic do not require any treatment. Some might opt to perform a simple burr-holes to alleviate intracranial pressure (ICP) </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 Pseudolymphoma and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Early pregnancy bleeding and can you explain it in depth? [/INST] Early pregnancy bleeding (also called first trimester bleeding) refers to vaginal bleeding before 14 weeks of gestational age. If the bleeding is significant, hemorrhagic shock may occur. Concern for shock is increased in those who have loss of consciousness, chest pain, shortness of breath, or shoulder pain.Common causes of early pregnancy bleeding include ectopic pregnancy, threatened miscarriage, and pregnancy loss. Most miscarriages occur before 12 weeks gestation age. Other causes include implantation bleeding, gestational trophoblastic disease, polyps, and cervical cancer. Tests to determine the underlying cause usually include a speculum examination, ultrasound, and hCG.Treatment depends on the underlying cause. If tissue is seen at the cervical opening it should be removed. For those in whom the pregnancy is intrauterine and who have fetal heart sounds, watchful waiting is generally appropriate. Anti-D immune globulin is usually recommended in those who are Rh-negative. Occasionally, surgery is required.About 30% of pregnant people have bleeding in the first trimester (0 to 14 weeks gestational age). Bleeding in the second trimester (12 to 24 weeks gestational age) is less common. About 15% of those who realize they are pregnant have a miscarriage. Ectopic pregnancy occurs in under 2% of pregnancies.

Differential diagnosis
The differential diagnosis depends on whether the bleeding occurs in the first trimester or in the second or third trimesters.
Obstetric causes of first trimester bleeding include the following:

Early pregnancy loss is a term often used interchangeably with spontaneous abortion and miscarriage and refers to pregnancy loss during the first trimester. It is the most common cause of early pregnancy bleeding and is associated only with heavy (versus light) bleeding. However, patients typically remain hemodynamically stable.
Threatened early pregnancy loss, often considered a type of early pregnancy loss, refers vaginal bleeding in the presence of an intrauterine pregnancy and a closed cervix. The presence of fetal heart rate largely determines whether the pregnancy will progress to a viable outcome.
Ectopic pregnancy refers to a pregnancy outside the uterus, commonly in the fallopian tube. It is a less common but more serious cause of early pregnancy bleeding. Ectopic pregnancies can rupture, leading to internal bleeding that can be fatal if untreated.
Implantation bleeding involves a small amount of bleeding that may occur 10 to 14 days after implantation of the fertilized egg. However, there is little evidence to support the existence of such bleeding.
Chorionic hematoma is the pooling of blood (hematoma) between the chorion, a membrane surrounding the embryo, and the uterine wall. It occurs in about 3.1% of all pregnancies and is the most common cause of first trimester bleeding.
Gestational trophoblastic neoplasia, which refers to pregnancy-related tumors that be either cancerous or non-cancerous. This cause is extremely rare with non-cancerous gestational trophoblastic neoplasia found in 23 to 1,299 cases per 100,000 pregnancies and cancerous forms with a 10-fold lower incidence.Obstetric causes of second/third trimester bleeding include the following:

Bloody show refers to the passage of a small amount of blood or blood-tinged mucus resulting from labor or cervical weakness.
Pregnancy loss refers to death of the fetus at any time during pregnancy. Pregnancy loss most commonly occurs during the first trimester, when it is referred to as early pregnancy loss.
Placenta praevia or vasa praevia refers to the placenta or fetal blood vessels, respectively, covering or being located close to the opening of the uterus. More than half of patients affected by placenta praevia (51.6)% have bleeding before delivery. Vasa praevia occurs in about 0.6 per 1000 pregnancies.
Placental abruption involves the separation of the placental lining from the uterus of the mother. It occurs most commonly around 25 weeks of pregnancy.
Uterine rupture is when the muscular wall of the uterus tears during childbirth or, less commonly, during pregnancy.
Nontubal ectopic pregnancy refers to an ectopic pregnancy that occurs in the ovary, cervix, or intra-abdominal cavity.Other causes of early pregnancy bleeding include the following:

Postcoital bleeding, which is vaginal bleeding after sexual intercourse that can be normal with pregnancy.
Iatrogenic causes, or bleeding due to medical treatment or intervention, such as sex steroids, anticoagulants, or intrauterine contraceptive devices.
Vaginal or cervical bleeding, which may arise from many causes including fibroids, polyps, warts, tumors, vaginitis, or trauma. Importantly, these causes may co-occur with other causes of early pregnancy bleeding.
Lower genitourinary tract bleeding, which may result from a urinary tract infection (UTI), strenuous exercise, or bladder cancer.

Pathophysiology
Early pregnancy bleeding is usually from a parental source rather than a fetal one. The parental source may be a disruption in the vessels of the decidua or a lesion in the cervix or vagina. In the earlier stages of pregnancy, the cervix can be vulnerable to bleeding as new blood vessels are being grown. Vasa praevia is a rare condition that can result in bleeding from the fetoplacental circulation. Vasa praevia happens most often when the umbilical cord grows in a way that it directly enters the membrane, and therefore blood vessels that are unprotected by the umbilical cord or placental tissue can rupture and lead to bleeding. Another common source of bleeding can be due to abnormal development of the embryo. The most common early fetal abnormality is abnormal number of chromosomes causing loss of the pregnancy and bleeding.

Diagnostic approach
The initial assessment of vaginal bleeding in early pregnancy must first consider hemodynamic stability and the degree of pain or bleeding.  A hemodynamically unstable patient would necessitate an immediate transfer to the emergency department . It is important to recognize that patients may suffer significant blood loss before any signs of hemodynamic instability are evident.The initial evaluation of early pregnancy bleeding involves a history and physical examination. The relevant history includes determining the gestational age of fetus and characterizing the bleeding. Bleeding that is at least as heavy as menstrual bleeding or associated with clots, tissue, lightheadedness, or pelvic discomfort is associated with increased risks of ectopic pregnancy and spontaneous abortion. Discomfort in the middle of the abdomen is more closely associated with spontaneous abortion; discomfort on a side of the abdomen is more closely associated with ectopic pregnancy. Risk factors for ectopic pregnancy or spontaneous abortion should also be considered.The physical examination includes assessing vital signs and performing an abdominal and pelvic examination. Signs of hemodynamic instability or peritonitis require emergent intervention. A pelvic examination may reveal non-obstetric causes of bleeding such as bleeding from the vagina or cervix. It may also show visible products of conception suggestive of an incomplete abortion.If the person is stable and a pelvic exam is unrevealing, transvaginal ultrasonography and/or serial measurement of hCG is generally recommended to assess fetal location and viability. Reviewed data from observational studies determined that ultrasound examination and hCG concentration could replace pelvic examination in the initial evaluation of early pregnancy bleeding. Transvaginal ultrasound is frequently used in the evaluation of bleeding in early pregnancy.Before 10 weeks gestation, a slower than normal increase in hCG suggests early pregnancy loss or ectopic pregnancy. By approximately 10 weeks, hCG plateaus and ultrasound is preferred to determine the location of the pregnancy (i.e., intrauterine or ectopic). In the presence of prior pelvic imaging, fetal heart tracing with Doppler sonography is sufficient to assess fetal viability beginning at 10–12 weeks of gestation. Bleeding associated with an intrauterine, viable pregnancy suggests threatened early pregnancy loss. Bleeding associated with an intrauterine, nonviable pregnancy suggests early pregnancy loss. If the viability of an intrauterine pregnancy is uncertain, repeat ultrasonography coupled with laboratory measurement of progesterone and/or serial hCG can be helpful. The absence of either intrauterine or ectopic pregnancy on imaging is suggestive of a complete early pregnancy loss (if the pregnancy was previously seen on imaging) or a pregnancy of unknown location (if the pregnancy was not previously seen on imaging).

Management
The management of early pregnancy bleeding depends on its severity and cause.Patients with significant first-trimester bleeding (more than spotting) should have a red blood cell antibody screen. Patients who are Rh-negative are usually given anti-D immune globulin to prevent RhD isoimmunization </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 Hemimegalencephaly and can you explain it in depth? [/INST] Hemimegalencephaly (HME), or unilateral megalencephaly, is a rare congenital disorder affecting all or a part of a cerebral hemisphere. It causes severe seizures, which are often frequent and hard to control. A minority might have seizure control with medicines, but most will need removal or disconnection of the affected hemisphere as the best chance. Uncontrolled, they often cause progressive intellectual disability and brain damage and stop development.

Symptoms and signs
Seizures are the main symptom </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 Polysyndactyly and can you explain it in depth? [/INST]  </s>


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Peripheral artery disease and can you explain it in depth? [/INST] Peripheral artery disease (PAD) is an abnormal narrowing of arteries other than those that supply the heart or brain. When narrowing occurs in the heart, it is called coronary artery disease, and in the brain, it is called cerebrovascular disease. Peripheral artery disease most commonly affects the legs, but other arteries may also be involved – such as those of the arms, neck, or kidneys. The classic symptom is leg pain when walking which resolves with rest, known as intermittent claudication. Other symptoms include skin ulcers, bluish skin, cold skin, or abnormal nail and hair growth in the affected leg. Complications may include an infection or tissue death which may require amputation; coronary artery disease, or stroke. Up to 50% of people with PAD do not have symptoms.The greatest risk factor for PAD is cigarette smoking. Other risk factors include diabetes, high blood pressure, kidney problems, and high blood cholesterol. The most common underlying mechanism of peripheral artery disease is atherosclerosis, especially in individuals over 40 years old. Other mechanisms include artery spasm, blood clots, trauma, fibromuscular dysplasia, and vasculitis. PAD is typically diagnosed by finding an ankle-brachial index (ABI) less than 0.90, which is the systolic blood pressure at the ankle divided by the systolic blood pressure of the arm. Duplex ultrasonography and angiography may also be used. Angiography is more accurate and allows for treatment at the same time; however, it is associated with greater risks.It is unclear if screening for peripheral artery disease in people without symptoms is useful as it has not been properly studied. In those with intermittent claudication from PAD, stopping smoking and supervised exercise therapy improve outcomes. Medications, including statins, ACE inhibitors, and cilostazol may also help. Aspirin does not appear to help those with mild disease but is usually recommended in those with more significant disease due to the increased risk of heart attacks. Anticoagulants such as warfarin are not typically of benefit. Procedures used to treat the disease include bypass grafting, angioplasty, and atherectomy.In 2015, about 155 million people had PAD worldwide. It becomes more common with age. In the developed world, it affects about 5.3% of 45- to 50-year-olds and 18.6% of 85- to 90-year-olds. In the developing world, it affects 4.6% of people between the ages of 45 and 50 and 15% of people between the ages of 85 and 90. PAD in the developed world is equally common among men and women, though in the developing world, women are more commonly affected. In 2015 PAD resulted in about 52,500 deaths, which is an increase from the 16,000 deaths in 1990.

Signs and symptoms
The signs and symptoms of peripheral artery disease are based on the part of the body that is affected. About 66% of patients affected by PAD either do not have symptoms or have atypical symptoms. The most common presenting symptom is intermittent claudication, which causes pain and severe cramping when walking or exercising. The pain is usually located in the calf muscles of the affected leg and relieved by rest. This occurs because during exercise the muscles of the leg need more oxygen. Normally, the arteries would be able to increase the amount of blood flow and therefore increase the amount of oxygen going to the exercised leg. However, in PAD, the artery is unable to respond appropriately to the increased demand for oxygen by the muscles, as a result, the leg muscles are overly saturated with lactic acid, resulting in pain of the muscle that only goes away with rest.Other symptoms may include
Pain, aches, and/or cramps in the buttocks, hip, or thigh
Muscle atrophy (muscle loss) of the affected limb
Hair loss of the affected limb
Skin that is smooth, shiny, or cool to the touch in the affected area
Decreased or absent pulse in feet
Cold and/or numbness in the toes
Sores/ulcers on the affected limb that do not healIn individuals with severe PAD, complications may arise, including critical limb ischemia and gangrene. Critical limb ischemia occurs when the obstruction to blood flow in the artery is compromised to the point where the blood is unable to maintain oxygenation of tissue at rest. This can lead to pain at rest, feeling of cold, or numbness in the affected foot and toes. Other complications of severe PAD include lower limb tissue loss, arterial insufficiency ulcers, erectile dysfunction, and gangrene. People with diabetes are affected by gangrene of the feet at a rate that is 30 times higher than the unaffected population. Many of these severe complications are irreversible.

Causes
Risk factor
Factors contributing to increased risk of PAD are the same as those for atherosclerosis. These include age, sex, and ethnicity. PAD is two times as common in males as females. In terms of ethnicity, PAD is more common in people of color compared to the white population in a 2:1 ratio. The factors with the greatest risk association are hyperlipidemia, hypertension, diabetes mellitus, chronic kidney disease, and smoking. Presenting three of these factors or more increases the risk of developing PAD ten-fold.
Smoking – tobacco use in any form is the single greatest risk factor of peripheral artery disease internationally.  Smokers have up to a 10-fold increase in risk of PAD in a dose-response relationship. Exposure to second-hand smoke has also been shown to promote changes in the lining of blood vessels (endothelium), which can lead to atherosclerosis. Smokers are 2–3 times more likely to have lower extremity PAD than coronary artery disease. Greater than 80%-90% of patients with lower extremity peripheral arterial disease are current or former smokers. The risk of PAD increases with the number of cigarettes smoked per day and the number of years smoked.
High blood sugar – Diabetes mellitus is shown to increase risk of PAD by 2–4 fold. It does this by causing endothelial and smooth-muscle cell dysfunction in peripheral arteries. The risk of developing lower extremity peripheral arterial disease is proportional to the severity and duration of diabetes.
High blood cholesterol – Dyslipidemia, which is an abnormally high level of cholesterol or fat in the blood. Dyslipidemia is caused by a high level of a protein called low-density lipoprotein (LDL cholesterol), low levels of high-density lipoprotein (HDL cholesterol), elevation of total cholesterol, and/or high triglyceride levels. This abnormality in blood cholesterol levels have been correlated with accelerated peripheral artery disease. Management of Dyslipidemia by diet, exercise, and/or medication is associated with a major reduction in rates of heart attack and stroke.
High blood pressure – Hypertension or elevated blood pressure can increase a persons risk of developing PAD. Similarly to PAD, there is a known association between high blood pressure and heart attacks, strokes and abdominal aortic aneurysms. High blood pressure increases the risk of intermittent claudication, the most common symptom of PAD, by 2.5- to 4-fold in men and women, respectively.
Other risk factors which are being studied include levels of various inflammatory mediators such as C-reactive protein, fibrinogen, homocysteine, and lipoprotein A. Individuals with increased levels of homocysteine in their blood have a 2-fold risk of peripheral artery disease. While there are genetics leading to risk factors for peripheral artery disease, including diabetes and high blood pressure; there have been no specific genes or gene mutations directly associated with the development of peripheral artery disease.

High risk populations
Peripheral arterial disease is more common in these populations:
All people who have leg symptoms with exertion (suggestive of claudication) or ischemic rest pain
All people aged 65 years and over regardless of risk factor status
All people between 50 and 69 and who have a cardiovascular risk factor (particularly diabetes or smoking)
Age less than 50 years, with diabetes and one other atherosclerosis risk factor (smoking, dyslipidemia, hypertension, or hyperhomocysteinemia)
Individuals with an abnormal lower extremity pulse examination
Those with known atherosclerotic coronary, carotid, or renal artery disease
All people with a Framingham risk score of 10%–20%
All people who have previously experienced chest pain

Mechanism
As previously mentioned, the most common cause of peripheral artery disease, especially in patients over 40 years old, is atherosclerosis. Atherosclerosis is a narrowing of the arteries caused by lipid or fat build up and calcium deposition in the wall of the affected arteries. The most commonly affected site occurs at arterial branch points, because there is an increase in turbulence and stress on the artery at these areas where the artery branches to supply distant structures. Disease of distant structures, including feet and toes, are usually caused by diabetes and seen in the elderly population.Additional mechanisms of peripheral artery disease including arterial spasm, thrombosis, and fibromuscular dysplasia. The mechanism of arterial spasm is still being studied, but it can occur secondary to trauma. The symptoms of claudication ensue when the artery spasms, or clamps down on itself, creating an obstruction. Similar to atherosclerosis, this leads to decreased blood flow to the tissue downstream of the obstruction. Thrombosis, or the formation of a blood clot, occurs usually due stasis or trauma. Damage to the lining of the blood vessel begins the process of clot formation. The blood clot ultimately creates a narrowing in the artery preventing adequate blood flow and oxygen to the tissue further down.

Diagnosis
Diagnosing or identifying peripheral artery disease requires history of symptoms and a physical exam followed by confirmatory testing. These tests could include CT scans (Computed Tomagraphic Angiography), MRA scans (Magnetic Resonance Angiography), or ultrasounds for imaging.In the setting of symptoms consistent with peripheral artery disease a physician will then examine an individual for specific exam findings. Abnormal physical exam findings can lead a health care provider to consider a specific diagnosis. However, in order to confirm a diagnosis, confirmatory testing is required.These findings are associated with peripheral artery disease:
Decreased or absent pulses
Muscle atrophy or wasting
Noticeable blueness of the affected limb
Decreased temperature (coolness) in affected limb when compared to the other
Thickened nails
Smooth or shiny skin and hair loss
Buergers test can check for pallor when the affected limb is in an elevated position. The limb is then moved from elevated to sitting position and is checked for redness, which is called reactive hyperemia. Buergers test is an assessment of arterial sufficiency, which is the ability of the artery to supply oxygenated blood to the tissue that it goes to.
Nonhealing lower extremity woundIf peripheral artery disease is suspected, the initial study is the ankle–brachial index (ABI). The ABI is a simple, non-invasive test, which measures the ratio of systolic blood pressure in the ankle to the systolic blood pressure in the upper arm. This is based on the idea that if blood pressure readings in the ankle are lower than those in the arm, a blockage in the arteries that provide blood from the heart to the ankle is suspected.An ABI range of 0.90 to 1.40 is considered normal. A person is considered to have PAD when the ABI is ≤ 0.90. However, PAD can be further graded as mild to moderate if the ABI is between 0.41 and 0.90, and severe if an ABI is less than 0.40. These categories can provide insight into the disease course.  Furthermore, ABI values of 0.91 to 0.99 are considered borderline and values >1.40 indicate noncompressible arteries. If an ABI >1.40 is calculated, this could indicate vessel wall stiffness caused by calcification, which can occur in people with uncontrolled diabetes. Abnormally high ABIs (>1.40) are usually considered false negatives and thus, such results merit further investigation and higher-level studies. Individuals with noncompressible arteries have an increased risk of cardiovascular mortality within a two-year period.In individuals with suspected PAD with normal ABIs can undergo exercise testing of ABI. A baseline ABI is obtained prior to exercise. The patient is then asked to exercise (usually patients are made to walk on a treadmill at a constant speed) until claudication pain occurs (for a maximum of 5 minutes), after which the ankle pressure is again measured. A decrease in ABI of 15%–20% would be diagnostic of PAD.If ABIs are abnormal, the next step is generally a lower limb Doppler ultrasound to look at the site of obstruction and extent of atherosclerosis. Other imaging can be performed by angiography, where a catheter is inserted into the common femoral artery and selectively guided to the artery in question. While injecting a radio-dense contrast agent, an X-ray is taken. Any blood flow-limiting blockage found in the X-ray can be identified and treated by procedures including atherectomy, angioplasty, or stenting. Contrast angiography is the most readily available and widely used imaging technique. Modern computerized tomography (CT) scanners provide direct imaging of the arterial system as an alternative to angiography.Magnetic resonance angiography (MRA) is a noninvasive diagnostic procedure that uses a combination of a large magnet, radio frequencies, and a computer to produce detailed images of blood vessels inside the body. The advantages of MRA include its safety and ability to provide high-resolution, three-dimensional imaging of the entire abdomen, pelvis and lower extremities in one sitting.

Classification
The two most commonly used methods to classify peripheral artery disease are the Fontaine and the Rutherford systems of classification. The Fontaine stages, were introduced by René Fontaine in 1954 to define severity of chronic limb ischemia:
Stage I: asymptomatic
Stage IIa: intermittent claudication after walking a distance of more than 200 meters
Stage IIb: intermittent claudication after walking a distance of less than 200 meters
Stage III: rest pain
Stage IV: ulcers or gangrene of the limbThe Rutherford classification was created by the Society for Vascular Surgery and International Society of Cardiovascular Surgery, introduced in 1986 and revised in 1997 (and known as the Rutherford classification after the lead author, Robert B. Rutherford). This classification system consists of four grades and seven categories (categories 0–6):
Grade 0, Category 0: asymptomatic
Grade I, Category 1: mild claudication
Grade I, Category 2: moderate claudication
Grade I, Category 3: severe claudication
Grade II, Category 4: rest pain
Grade III, Category 5: minor tissue loss; ischemic ulceration not exceeding ulcer of the digits of the foot
Grade IV, Category 6: major tissue loss; severe ischemic ulcers or frank gangreneModerate to severe PAD classified by Fontaines stages III to IV or Rutherfords categories 4 to 5, presents limb threat (risk of limb loss) in the form of critical limb ischemia.Recently, the Society for Vascular Surgery came out with a classification system based on "wound, ischemia and foot Infection" (WIfI). This classification system, published in 2013 was created to account for the demographic changes that have occurred over the past forty years including increased incidence of high blood sugar and evolving techniques and ability for revascularization. This system was created on the basis of ischemia and angiographic disease patterns not being the sole determinants of amputation risk. The WIfI classification system is broken up into two parts: wounds and ischemia. Wounds are graded 0 through 3 on the presence of ulceration and/or gangrene and ischemia.
Grade 0: no ulcer, no gangrene
Grade 1: small, shallow ulcer; no gangrene
Grade 2: deep ulcer with exposed tendon or bone, gangrene limited to toes
Grade 3: extensive, full-thickness ulcer; gangrene extending to forefoot or midfootIschemia is graded 0 through 3 based on ABI, ankle systolic pressure, and toe pressure.
Grade 0: ABI 0.8 or higher, ankle
Grade 1: arterial brachial index 0.6 to 0.79, ankle pressure 70 to 100 mm Hg, toe pressure 40 to 59 mm Hg
Grade 2: ABI 0.4–0.59, ankle pressure 50 to 70 mm Hg, toe pressure 30 to 39 mm HgThe TASC (and TASC II) classification suggested PAD treatment is based on the severity of disease seen on angiogram.

Screening
It is not clear if screening for disease in the general population is useful as it has not been properly studied. This includes screening with the ankle-brachial index.Testing for coronary artery disease or carotid artery disease is of unclear benefit. While PAD is a risk factor for abdominal aortic aneurysms (AAA), there is no data on screening individuals with asymptomatic PAD for abdominal aortic aneurysms. In people with symptomatic PAD screening by ultrasound for AAA is not unreasonable.

Treatment
Depending on the severity of the disease, these steps can be taken, according to these guidelines:

Lifestyle
Stopping smoking (cigarettes promote PAD and are a risk factor for cardiovascular disease)
Regular exercise for those with claudication helps open up alternative small vessels (collateral flow) and the limitation in walking often improves.  Treadmill exercise (35 to 50 minutes, three or four times per week) has been reviewed as another treatment with a number of positive outcomes, including reduction in cardiovascular events and improved quality of life. Supervised exercise programs increase pain-free walking time and the maximum walking distance in people with PAD.

Medication
Management of diabetes
Management of hypertension
Management of high cholesterol, and antiplatelet drugs such as aspirin and clopidogrel. Statins reduce clot formation and cholesterol levels, respectively, can help with disease progression, and address the other cardiovascular risks that the affected person is likely to have.According to guidelines, taking aspirin or clopidogrel is recommended to reduce AMI ("heart attack"), stroke, and other causes of vascular death in people with symptomatic peripheral artery disease. It is recommended that aspirin and clopidogrel be taken alone and not in conjunction with one another (i.e., not as dual antiplatelet therapy). The recommended daily dosage of aspirin for treating PAD is between 75 and 325 mg, while the recommended daily dosage for clopidogrel is 75 mg. The effectiveness of both aspirin and clopidogrel to reduce risk of cardiovascular ischemic events in people with symptomatic PAD is not well established. Research also suggests that low-dose rivaroxaban plus aspirin is effective as a new anti-thrombotic regimen for PAD.Cilostazol can improve symptoms in some. Pentoxifylline is of unclear benefit. Cilostazol may improve walking distance for people who experience claudication due to peripheral artery disease, but no strong evidence  suggests that it improves the quality of life, decreases mortality, or decreases the risk of cardiovascular events.Treatment with other drugs or vitamins are unsupported by clinical evidence, "but trials evaluating the effect of folate and vitamin B12 on hyperhomocysteinemia, a putative vascular risk factor, are near completion".

Revascularization
After a trial of the best medical treatment outline above, if symptoms persist, patients may be referred to a vascular or endovascular surgeon. The benefit of revascularization is thought to correspond to the severity of ischemia and the presence of other risk factors for limb loss such as wound and infection severity.
 Angioplasty (or percutaneous transluminal angioplasty) can be done on solitary lesions in large arteries, such as the femoral artery, but may not have sustained benefits. Patency rates following angioplasty are highest for iliac arteries, and decrease with arteries towards the toes. Other criteria that affect outcome following revascularization are length of lesion and number of lesions. There does not appear to be long term advantages or sustained benefit to placing a stent following angioplasty in order to hold the narrowing of the subsartorial artery open.
Atherectomy, in which the plaque is scraped off of the inside of the vessel wall (albeit with no better results than angioplasty).
Vascular bypass grafting can be performed to circumvent a diseased area of the arterial vasculature. The great saphenous vein is used as a conduit if available, although artificial (Gore-Tex or PTFE) material is often used for long grafts when adequate venous conduit is unavailable.
When gangrene has set in, amputation may be required to prevent infected tissues from causing sepsis, a life-threatening illness.
Thrombolysis and thrombectomy are used in cases of arterial thrombosis or embolism.

Guidelines
A guideline from the American College of Cardiology and American Heart Association for the diagnosis and treatment of lower extremity, renal, mesenteric, and abdominal aortic PAD was compiled in 2013, combining the 2005 and 2011 guidelines. For chronic limb threatening ischemia the ACCF/AHA guidelines recommend balloon angioplasty only for people with a life expectancy of 2 years or less or those who do not have an autogenous vein available. For those with a life expectancy greater than 2 years, or who have an autogenous vein, bypass surgery is recommended.

Prognosis
Individuals with PAD have an "exceptionally elevated risk for cardiovascular events and the majority will eventually die of a cardiac or cerebrovascular etiology"; prognosis is correlated with the severity of the PAD as measured by an ABI. Large-vessel PAD increases mortality from cardiovascular disease significantly.  PAD carries a greater than "20% risk of a coronary event in 10 years".The risk is low that an individual with claudication will develop severe ischemia and require amputation, but the risk of death from coronary events is three to four times higher than matched controls without claudication. Of patients with intermittent claudication, only "7% will undergo lower-extremity bypass surgery, 4% major amputations, and 16% worsening claudication", but stroke and heart attack events are elevated, and the "5-year mortality rate is estimated to be 30% (versus 10% in controls)".

Epidemiology
The prevalence of PAD in the general population is 3–7%, affecting up to 20% of those over 70; 70%–80% of affected individuals are asymptomatic; only a minority ever require revascularisation or amputation. Peripheral artery disease affects one in three diabetics over the age of 50. In the US, it affects 12–20 percent of Americans age 65 and older. Around 10 million Americans have PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.In people aged 40 years and older in the United States in 2000, rates of PAD was 4.3%. Rates were 14.5% people aged 70 years or over. Within age groups, rates were generally higher in women than men. Non-Hispanic blacks had a rates of 7.9% compared to 4.4% in Non-Hispanic whites and 3.0% (1.4%–4.6%) in Mexican Americans.The incidence of symptomatic PAD increases with age, from about 0.3% per year for men aged 40–55 years to about 1% per year for men aged over 75 years. The prevalence of PAD varies considerably depending on how PAD is defined, and the age of the population being studied. Diagnosis is critical, as people with PAD have a four- to five-fold higher risk of heart attack or stroke.The Diabetes Control and Complications Trial, and the U.K. Prospective Diabetes Study trials, in people with type 1 and type 2 diabetes, respectively, demonstrated that glycemic control is more strongly associated with microvascular disease than macrovascular disease. Pathologic changes occurring in small vessels may be more sensitive to chronically elevated glucose levels than is atherosclerosis occurring in larger arteries.

Research
Research is being done on therapies to prevent progression of PAD </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 Bloom syndrome and can you explain it in depth? [/INST] Bloom syndrome (often abbreviated as BS in literature) is a rare autosomal recessive genetic disorder characterized by short stature, predisposition to the development of cancer, and genomic instability. BS is caused by mutations in the BLM gene which is a member of the RecQ DNA helicase family. Mutations in other members of this family, namely WRN and RECQL4, are associated with the clinical entities Werner syndrome and Rothmund–Thomson syndrome, respectively. More broadly, Bloom syndrome is a member of a class of clinical entities that are characterized by chromosomal instability, genomic instability, or both and by cancer predisposition.
Cells from a person with Bloom syndrome exhibit a striking genomic instability that includes excessive crossovers between homologous chromosomes and sister chromatid exchanges (SCEs). The condition was discovered and first described by New York dermatologist Dr. David Bloom in 1954.Bloom syndrome has also appeared in the older literature as Bloom–Torre–Machacek syndrome.

Presentation
The most prominent feature of Bloom syndrome is proportional small size. The small size is apparent in utero. At birth, neonates exhibit rostral to caudal lengths, head circumferences, and birth weights that are typically below the third percentile.The second most commonly noted feature is a rash on the face that develops early in life as a result of sun exposure. The facial rash appears most prominently on the cheeks, nose, and around the lips. It is described as erythematous, that is red and inflamed, and telangiectatic, that is characterized by dilated blood vessels at the skins surface. The rash commonly also affects the backs of the hands and neck, and it can develop on any other sun-exposed areas of the skin. The rash is variably expressed, being present in a majority but not all persons with Bloom syndrome, and it is on average less severe in females than in males. Moreover, the sun sensitivity can resolve in adulthood. There are other dermatologic changes, including hypo-pigmented and hyper-pigmented areas, cafe-au-lait spots, and telangiectasias, which can appear on the face and on the ocular surface.There is a characteristic facial appearance that includes a long, narrow face; prominent nose, cheeks, and ears; and micrognathism or undersized jaw. The voice is high-pitched and squeaky.

There are a variety of other features that are commonly associated with Bloom syndrome. There is a moderate immune deficiency, characterized by deficiency in certain immunoglobulin classes and a generalized proliferative defect of B and T cells. The immune deficiency is thought to be the cause of recurrent pneumonia and middle ear infections in persons with the syndrome. Infants can exhibit frequent gastrointestinal upsets, with reflux, vomiting, and diarrhea, and there is a remarkable lack in interest in food. There are endocrine disturbances, particularly abnormalities of carbohydrate metabolism, insulin resistance and susceptibility to type 2 diabetes, dyslipidemia, and compensated hypothyroidism. Persons with Bloom syndrome exhibit a paucity of subcutaneous fat. There is reduced fertility, characterized by a failure in males to produce sperm (azoospermia) and premature cessation of menses (premature menopause) in females. Despite these reductions, several women with Bloom syndrome have had children, and there is a single report of a male with Bloom syndrome bearing children.Although some persons with Bloom syndrome can struggle in school with subjects that require abstract thought, there is no evidence that intellectual disability is more common in Bloom syndrome than in other people.The most serious and frequent complication of Bloom syndrome is cancer. In the 281 persons followed by the Bloom Syndrome Registry, 145 persons (51.6%) have been diagnosed with a malignant neoplasm, and there have been 227 malignancies. The types of cancer and the anatomic sites at which they develop resemble the cancers that affect persons in the general population. The age of diagnosis for these cancers is earlier than for the same cancer in normal persons. And many persons with Bloom syndrome have been diagnosed with multiple cancers. The average life span is approximately 27 years. The most common cause of death in Bloom syndrome is from cancer. Other complications of the disorder include chronic obstructive lung disease and type 2 diabetes.There are a variety of excellent sources for more detailed clinical information about Bloom syndrome.There is a closely related entity that is now referred to as Bloom-syndrome-like disorder (BSLD) which is caused by mutations in components of the same protein complex to which the BLM gene product belongs, including TOP3A, which encodes the type I topoisomerase, topoisomerase 3 alpha, RMI1, and RMI2. The features of BSLD include small size and dermatologic findings, such as cafe-au-lait spots, and the presence of the once pathognomonic elevated SCEs is reported for persons with mutations in TOP3A and RMI1.Bloom syndrome shares some features with Fanconi anemia possibly because there is overlap in the function of the proteins mutated in this related disorder.

Genetics
Bloom syndrome is an autosomal recessive disorder, caused by mutations in the maternally- and paternally-derived copies of the gene BLM. As in other autosomal recessive conditions, the parents of an individual with Bloom syndrome do not necessarily exhibit any features of the syndrome. The mutations in BLM associated with Bloom syndrome are nulls and missense mutations that are catalytically inactive. The cells from persons with Bloom syndrome exhibit a striking genomic instability that is characterized by hyper-recombination and hyper-mutation. Human BLM cells are sensitive to DNA damaging agents such as UV and methyl methanesulfonate, indicating deficient repair capability.  At the level of the chromosomes, the rate of sister chromatid exchange in Blooms syndrome is approximately 10 fold higher than normal and quadriradial figures, which are the cytologic manifestations of crossing-over between homologous chromosome, are highly elevated. Other chromosome manifestations include chromatid breaks and gaps, telomere associations, and fragmented chromosomes. The hyper-recombination can also be detected by molecular assays  The BLM gene is a member of the protein family referred to as RecQ helicases. The diffusion of BLM has been measured to 1.34

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    at nucleoli  DNA helicases are enzymes that attach to DNA and temporarily unravel the double helix of the DNA molecule. DNA helicases function in DNA replication and DNA repair. BLM very likely functions in DNA replication, as cells from persons with Bloom syndrome exhibit multiple defects in DNA replication, and they are sensitive to agents that obstruct DNA replication.The BLM helicase is a member of a protein complex with topoisomerase III alpha, RMI1 and RMI2, also known as BTRR, Bloom Syndrome complex or the dissolvasome. Disruption of the proper assembly of the Bloom Syndrome complex leads to genome stability, genetic dependence on cellular nucleases GEN1 and MUS81, and loss of normal cell growth. Bloom-like phenotypes have been associated with mutations in topoisomerase III alpha, RMI1 and RMI2 genes.

Relationship to cancer and aging
As noted above, there is greatly elevated rate of mutation in Bloom syndrome and the genomic instability is associated with a high risk of cancer in affected individuals. The cancer predisposition is characterized by 1) broad spectrum, including leukemias, lymphomas, and carcinomas, 2) early age of onset relative to the same cancer in the general population, and 3) multiplicity, that is, synchronous or metachronous cancers. There is at least one person with Bloom syndrome who had five independent primary cancers. Persons with Bloom syndrome may develop cancer at any age. The average age of cancer diagnoses in the cohort is approximately 26 years old.

Pathophysiology
When a cell prepares to divide to form two cells, the chromosomes are duplicated so that each new cell will get a complete set of chromosomes. The duplication process is called DNA replication. Errors made during DNA replication can lead to mutations. The BLM protein is important in maintaining the stability of the DNA during the replication process. Lack of BLM protein or protein activity leads to an increase in mutations; however, the molecular mechanism(s) by which BLM maintains stability of the chromosomes is still a very active area of research.Persons with Bloom syndrome have an enormous increase in exchange events between homologous chromosomes or sister chromatids (the two DNA molecules that are produced by the DNA replication process); and there are increases in chromosome breakage and rearrangements compared to persons who do not have Blooms syndrome. Direct connections between the molecular processes in which BLM operates and the chromosomes themselves are under investigation. The relationships between molecular defects in Bloom syndrome cells, the chromosome mutations that accumulate in somatic cells (the cells of the body), and the many clinical features seen in Bloom syndrome are also areas of intense research.

Diagnosis
Bloom syndrome is diagnosed using any of three tests - the presence of quadriradial (Qr, a four-armed chromatid interchange) in cultured blood lymphocytes, and/or the elevated levels of sister chromatid exchange in cells of any type, and/or the mutation in the BLM gene. The US Food and Drug Administration (FDA) announced on February 19, 2015, that they have authorized marketing of a direct-to-consumer genetic test from 23andMe. The test is designed to identify healthy individuals who carry a gene that could cause Bloom Syndrome in their offspring.

Treatment
Bloom syndrome has no specific treatment; however, avoiding sun exposure and using sunscreens can help prevent some of the cutaneous changes associated with photo-sensitivity. Efforts to minimize exposure to other known environmental mutagens are also advisable.

Epidemiology
Bloom syndrome is an extremely rare disorder in most populations and the frequency of the disease has not been measured in most populations. However, the disorder is relatively more common amongst people of Central and Eastern European Ashkenazi Jewish background. Approximately 1 in 48,000 Ashkenazi Jews are affected by Bloom syndrome, who account for about one-third of affected individuals worldwide.

Blooms Syndrome Registry
The Blooms Syndrome Registry lists 265 individuals reported to have this rare disorder (as of 2009), collected from the time it was first recognized in 1954. The registry was developed as a surveillance mechanism to observe the effects of cancer in the patients, which has shown 122 individuals have been diagnosed with cancer. It also acts as a report to show current findings and data on all aspects of the disorder.

See also
Accelerated aging disease
Bloom syndrome (gene)
DNA repair
Progeria
Tumor M2-PK

References
Flanagan M, Cunniff CM (February 14, 2019) [March 22, 2006].  Adam MP, Ardinger HH, Pagon RA,  et al. (eds.). "Bloom syndrome". GeneReviews. Seattle (WA): University of Washington. PMID 20301572. Retrieved July 14, 2019.

Further reading
Adam, M. P.; Mirzaa, G. M.; Pagon, R </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 Mirizzis syndrome and can you explain it in depth? [/INST] Mirizzis syndrome is a rare complication in which a gallstone becomes impacted in the cystic duct or neck of the gallbladder causing compression of the common hepatic duct, resulting in obstruction and jaundice. The obstructive jaundice can be caused by direct extrinsic compression by the stone or from fibrosis caused by chronic cholecystitis (inflammation). A cholecystocholedochal fistula can occur.

Presentation
Mirizzis syndrome has no consistent or unique clinical features that distinguish it from other more common forms of obstructive jaundice. Symptoms of recurrent cholangitis, jaundice, right upper quadrant pain, and elevated bilirubin and alkaline phosphatase may or may not be present. Acute presentations of the syndrome include symptoms consistent with cholecystitis.
Surgery is extremely difficult as Calots triangle is often obliterated and the risks of causing injury to the CBD are high.

Pathophysiology
Multiple and large gallstones can become impacted in the Hartmanns pouch of the gallbladder, leading to chronic inflammation—which leads to compression of the common bile duct (CBD), necrosis, fibrosis, and ultimately fistula formation into the adjacent common hepatic duct (CHD) or common bile duct (CBD) </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 Keratosis pilaris atrophicans and can you explain it in depth? [/INST]  </s>


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


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Hot tub folliculitis and can you explain it in depth? [/INST] Hot tub folliculitis (pseudomonal folliculitis) is a common type of folliculitis, a condition which causes inflammation of hair follicles.: 272 This condition is caused by an infection of hair follicles by a non-pathogenic strain of the bacterium Pseudomonas aeruginosa </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 Vocal cord hemorrhage and can you explain it in depth? [/INST]  </s>


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


<s> [INST] <<SYS>> You are a responsible assistant committed to providing accurate and helpful responses. Avoid sharing harmful or biased content. Clarify any unclear or incorrect questions rather than providing false or misleading information. <</SYS>> What is Early onset dementia and can you explain it in depth? [/INST] Early onset dementia is dementia in which symptoms first appear before the age of 65. The term favored until about 2000 was presenile dementia; young onset dementia is also used.Early onset dementia may be caused by degenerative or vascular disease, or it may be due to other causes, such as alcohol-related dementia and other inflammatory or infectious processes. Early-onset Alzheimers disease, vascular dementia and frontotemporal lobar degeneration are the most common forms of early onset dementia, with Alzheimers accounting for between 30 and 40%. Early onset dementia may also occur, less frequently, in the Lewy body dementias (dementia with Lewy bodies and Parkinsons disease dementia), multiple sclerosis, Huntingtons disease and other conditions.

References
Further reading
Collins JD, Henley SM, Suárez-González A (July 2020). "A systematic review of the prevalence of depression, anxiety, and apathy in frontotemporal dementia, atypical and young-onset Alzheimers disease, and inherited dementia". Int Psychogeriatr (Review): 1–20. doi:10.1017/S1041610220001118. PMID 32684177. S2CID 220653830.
Ducharme S, Dols A, Laforce R,  et al. (June 2020). "Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders". Brain (Review). 143 (6): 1632–1650. doi:10.1093/brain/awaa018. PMC 7849953. PMID 32129844.
Nwadiugwu M (September 2021). "Early-onset dementia: key issues using a relationship-centred care approach". Postgrad Med J (Review) </s>