<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 Shwachman–Diamond syndrome and can you explain it in depth? [/INST] Shwachman–Diamond syndrome (SDS), or Shwachman–Bodian–Diamond syndrome, is a rare congenital disorder characterized by exocrine pancreatic insufficiency, bone marrow dysfunction, skeletal abnormalities and short stature. After cystic fibrosis (CF), it is the second most common cause of exocrine pancreatic insufficiency in children.

Signs and symptoms
The syndrome shows a wide range of abnormalities and symptoms. The main characteristics of the syndrome are exocrine pancreatic dysfunction, hematologic abnormalities and growth retardation. Only the first two of these are included in the clinical diagnostic criteria.
Hematologic abnormalities: neutropenia may be intermittent or persistent and is the most common hematological finding. Low neutrophil counts leave patients at risk of developing severe recurrent infections that may be life-threatening. Anemia (low red blood cell counts) and thrombocytopenia (low platelet counts) may also occur. Bone marrow is typically hypocellular, with maturation arrest in the myeloid lineages that give rise to neutrophils, macrophages, platelets and red blood cells. Patients may also develop progressive marrow failure or transform to acute myelogenous leukemia.
Exocrine pancreatic dysfunction: Pancreatic exocrine insufficiency arises due to a lack of acinar cells that produce digestive enzymes. These are extensively depleted and replaced by fat. A lack of pancreatic digestive enzymes leaves patients unable to digest and absorb fat. However, pancreatic status may improve with age in some patients.
Growth retardation: More than 50% of patients are below the third percentile for height, and short stature appears to be unrelated to nutritional status. Other skeletal abnormalities include metaphyseal dysostosis (45% of patients), thoracic dystrophy (rib cage abnormalities in 46% of patients) and costochondral thickening (shortened ribs with flared ends in 32% of patients). Skeletal problems are one of the most variable components of SDS, with 50% affected siblings from the same family discordant for clinical presentation or type of abnormality. Despite this, a careful review of radiographs from 15 patients indicated that all of them had at least one skeletal anomaly, though many were subclinical.
Other features include metaphysial dysostosis, mild hepatic dysfunction, increased frequency of infections.

Genetics
Shwachman–Diamond syndrome is characterized by an autosomal recessive mode of inheritance. The gene that is mutated in this syndrome, SBDS, lies on the long arm of chromosome 7 at cytogenetic position 7q11. It is composed of five exons and has an associated mRNA transcript that is 1.6 kilobase pairs in length. The SBDS gene resides in a block of genomic sequence that is locally duplicated on the chromosome. The second copy contains a non-functional version of the SBDS gene that is 97% identical to the original gene, but has accumulated inactivating mutations over time. It is considered to be a pseudogene. In a study of 158 SDS families, 75% of disease-associated mutations appeared to be the result of gene conversion, while 89% of patients harbored at least one such mutation. Gene conversion occurs when the intact SBDS gene and its pseudogene copy aberrantly recombine at meiosis, leading to an incorporation of pseudogene-like sequences into the otherwise functional copy of the SBDS gene, thereby inactivating it.Two gene conversion mutations predominate in SDS patients.  One is a splice site mutation affecting the 5 splice site of intron two, while the second is an exon two nonsense mutation. The marked absence of patients homozygous for the otherwise common nonsense mutation suggested that the SBDS gene is essential.  Consistent with this, knockout of the mouse gene leads to early embryonic lethality. This, in turn, suggests that the common splice site mutation seen in patients may be hypomorphic, i.e. that it results in only a partial loss of function, whereas the complete loss of SBDS function is likely to be lethal.

Mechanisms
The SBDS gene is expressed in all tissues and encodes a protein of 250 amino acid residues.  A great deal of indirect evidence suggested that the SBDS protein may be involved in an aspect of cellular RNA metabolism or ribosome assembly or function. The wide occurrence of the gene in all archaea and eukaryotes supported a role for this protein in a very fundamental and evolutionarily conserved aspect of cellular biology. The homologous genes in archaea also tend to be present in conserved cluster enriched for RNA processing and ribosomal genes.  A specific function for SBDS in RNA metabolism or ribosome assembly or function is further supported by its localization to the nucleolus, the nuclear subdomain where these processes occur. In line with this, the yeast homologue, SdoI, has been shown to be critical for maturation of pre-60S ribosomes, by effecting release and recycling of the nucleolar shuttling factor Tif6. This is required for 60S maturation and translational activation of ribosomes. It has also been shown that the Dictyostelium discoideum homologue catalyzes the removal of eukaryotic initiation factor 6 (eIF6), which is required for the translational activation of ribosomes.  Cells from SDS patients were shown to have a defect in assembly of ribosome subunits.At present, it is not obvious how disruption of the basic cellular process of translation leads to the tissue- and organ-specific manifestations seen in SDS. However, unusual and combinations of tissues and organs are also affected in Diamond–Blackfan anemia, X-linked dyskeratosis congenita, and cartilage–hair hypoplasia—three diseases that may also be linked to defective ribosome function.  Pleiotropic disease features may be the result of cell-specific effects of reduced levels of SBDS activity provided by hypomorphic mutations.

Diagnosis
Initially, the clinical presentation of SDS may appear similar to cystic fibrosis. However, CF can be excluded with a normal chloride in sweat test but faecal elastase as a marker of pancreatic function will be reduced. The variation, intermittent nature, and potential for long-term improvement of some clinical features make this syndrome difficult to diagnose. SDS may present with either malabsorption, or hematological problems. Rarely, SDS may present with skeletal defects, including severe rib cage abnormalities that lead to difficulty in breathing. Diagnosis is generally based on evidence of exocrine pancreatic dysfunction and neutropenia. Skeletal abnormalities and short stature are characteristics that can be used to support the diagnosis. The gene responsible for the disease has been identified and genetic testing is now available.

Management
Pancreatic exocrine insufficiency may be treated through pancreatic enzyme supplementation, while severe skeletal abnormalities may require surgical intervention. Neutropenia may be treated with granulocyte-colony stimulating factor (GCSF) to boost peripheral neutrophil counts. However, there is ongoing and unresolved concern that this drug could contribute to the development of leukemia. Signs of progressive marrow failure may warrant bone marrow transplantation (BMT). This has been used successfully to treat hematological aspects of disease. However, SDS patients have an elevated occurrence of BMT-related adverse events, including graft-versus-host disease (GVHD) and toxicity relating to the pre-transplant conditioning regimen. In the long run, study of the gene that is mutated in SDS should improve understanding of the molecular basis of disease. This, in turn, may lead to novel therapeutic strategies, including gene therapy and other gene- or protein-based approaches.

Research
A major goal of curative therapy for SDS is to reduce the risk of bone marrow failure and halt the progression of malignant transformation toward myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), the most detrimental complications of SDS.  Currently, there is no such therapy.  However, several emerging therapeutic strategies, including gene therapy and antisense oligonucleotides (ASOs), could potentially slow or prevent malignant transformation, at least in theory.  These new therapies have been proven effective for several rare diseases, including metachromatic leukodystrophy and spinal muscular atrophy.  Several SDS patient groups are advocating for better therapies for SDS, and one organization is focused on driving the therapy development efforts.  The challenge is whether the SDS community can come together to support the required research, and whether the organizations can successfully execute a strategy that coordinates the efforts for new therapy development.

Epidemiology
It is thought to have an estimated incidence of 1 in 75,000 people.

History
The disease was first described as a coherent clinical entity in May 1964 by Bodian, Sheldon, and Lightwood. It was subsequently described by Shwachman, Diamond, Oski, and Khaw in November of the same year. In 2001, linkage analysis in SDS families indicated that affected gene mapped to a large region of human chromosome seven. In 2002, this interval was refined to a region on the long arm of the chromosome next to the centromere.In 2003, a team of researchers led by Johanna Rommens at the Hospital of Sick Children (SickKids) in Toronto, Canada, discovered mutations in the SBDS gene (Shwachman–Bodian–Diamond syndrome) were associated with disease.

Eponym
Shwachman–Diamond syndrome, less commonly known as Shwachman–Bodian–Diamond syndrome, is named for Harry Shwachman (1910 – September 12, 1986), an American physician, Martin Bodian (1912 – May 12, 1994), a British ophthalmologist who worked in New York City, and Louis Klein Diamond (May 11, 1902 – June 14, 1999), an American pediatrician.

References
Further reading
Foerster (2014). "Ch 37. Inherited Aplastic Anemia Syndromes" </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 cyst and can you explain it in depth? [/INST] Vocal fold cysts (also known as vocal cord cysts) are benign masses of the membranous vocal folds. These cysts are enclosed, sac-like structures that are typically of a yellow or white colour.  They occur unilaterally on the midpoint of the medial edge of the vocal folds. They can also form on the upper/superior, surface of the vocal folds. There are two types of vocal fold cysts:
Sub-epithelial vocal fold cysts- located in the superficial lamina propria of the vocal folds.
Ligament vocal fold cysts- located within the deeper layers of the lamina propria or on the vocal ligament.The symptoms of vocal fold cysts vary but most commonly include a hoarse voice and problems with the pitch of the voice. Vocal fold cysts are diagnosed based on gathering a case history, perceptual examination, and laryngeal imaging. Practicing good vocal hygiene is recommended to prevent vocal fold cysts. Initial treatment of the cysts involves voice therapy to reduce harmful vocal behaviours. If symptoms remain after voice therapy, patients may require surgery to remove the cyst. Surgery is typically followed by vocal rest and further voice therapy to improve voice function. Cysts may also be treated using vocal fold steroid injection.

Histology
The vocal folds consist of 3 primary layers; the Epithelium, the Lamina Propria (containing superficial, intermediate and deep layers) and the Thyroarytenoid Muscle. Vocal fold cysts commonly appear in the Superficial portion of the Lamina Propria, the cyst size impacts the nature of this layer making it more rigid. The border of vocal fold cysts contains squamous or epithelial cells. In the case of retention cysts, the border consists of glandular epithelium. Epidermoid cysts closely resemble epidermal cysts that can occur anywhere in the body.

Types of Vocal Cord Cysts
Sub-epithelial cysts (also known as mucous retention cysts) are closed lesions that occur from a build-up of tissue on the vocal folds. They are typically found in the middle portion of the upper lamina propria of the vocal folds. Sub-epithelial cysts are small and white in colour. Their presence on the vocal folds usually does not disrupt the vibration of the vocal folds for speech (known as the "mucosal wave").Ligament cysts (also known as epidermoid cysts) are closed lesions that occur near the vocal ligament in the deep layers of the lamina propria. Ligament cysts are usually larger in size than sub-epithelial cysts. They are yellow in colour and unlike sub-epithelial cysts, their presence is usually observed to disrupt the mucosal wave of the vocal folds in the region around the cyst.

Signs and Symptoms
Sub-epithelial vocal fold cysts and ligament vocal fold cysts are characterized by similar symptoms. The presence and severity of symptoms may be influenced by the location and size of the cyst.Common symptoms include:

Hoarse voice
Inability to produce high pitch notes
Fatigue when speaking
Limited pitch range
Pain near the larynx
Variations in pitch when speakingSigns and symptoms of vocal fold cysts may remain stable or increase over time. In rare cases it is also possible for symptoms to improve if the cyst ruptures spontaneously. Symptoms affecting quality of voice tend to worsen after speaking for long periods of time, or when speaking with increased volume. Many individuals who use their voice professionally find even a slight presence of symptoms to be problematic. However, some voice professionals are not impacted by the presence of vocal cysts.

Vocal Dynamics
Vocal fold cysts cause the properties of the vocal folds to change. When a cyst is present on a vocal fold, the cover of the vocal fold becomes more stiff and increases in mass. The increased mass and stiffness tends to result in hyperkinetic muscular movement during phonation. Hyperkinetic movement is characterized by increased rigidity in the affected vocal fold(s). This hyperkinetic movement results in the voice being perceived as hoarse. (see Signs and Symptoms) Specifically, the presence of a vocal fold cyst leads to an asynchronous mucosal wave of the vocal folds during phonation.

Causes
There are several possible causes of vocal fold cysts:

They can be congenital.
They can result from the blockage of a mucous glands excretory duct. In this case, they are sometimes referred to as retention cysts.
They can be the result of phonotrauma. Phonotrauma refers to behaviours that can lead to vocal fold injuries, such as vocal overuse (i.e. too much speaking), vocal misuse (i.e. speaking in an unnaturally high or low pitch), or vocal abuse (i.e. yelling or whispering for prolonged periods). Vocal folds vibrate during phonation resulting in repeated collisions of the right and left vocal folds. Phonotrauma subjects the vocal folds to excessive mechanical forces during these vibratory cycles, which can lead to the development of a wound. It is the healing of these wounds, which leads to tissue re-structuring, that can result in a vocal fold cyst.

Diagnosis
There are generally four components included in the full diagnosis of a vocal cord cyst: a medical and voice history, a head and neck exam, a perceptual assessment of the voice and imaging of the vocal folds. A medical and voice history can help distinguish patterns of misuse and phonotrauma to assist in diagnosis. The primary perceptual sign of vocal fold cysts is hoarseness of the voice. Diagnosis through perceptual means alone is difficult, therefore in the fourth component of diagnosis the patient often undergoes an imaging procedure. Imaging is most commonly done with laryngeal videostroboscopy. A videostroboscopy is an examination of the vocal folds using flashes of light to slow down the image of the vocal fold movement enough to provide a sharp picture of the phases of the movement cycle (mucosal wave.) This procedure provides information about vocal fold vibrations during speech, vocal intensity and vocal frequency. Imaging shows the reduced movement of the vocal folds (mucosal wave) when a vocal fold cyst is present. Further, videostroboscopy tends to show increased submucosal swelling in the affected areas of the vocal fold(s) More recently, other technologies have been introduced to assist with obtaining imaging of the vocal folds, including the use of Narrow-band imaging (NBI.) Narrow-band imaging involves the use of blue and yellow lights to improve the picture quality of an image and accentuate blood vessel visibility. NBI has been found to help improve visual identification of vocal fold cysts in some cases.Vocal fold cysts can be differentiated from other vocal fold growths as they are usually unilateral. The two types of vocal fold cysts (sub-epithelial and ligament cysts) can be differentiated by colour, size and location. (See section on Types of vocal cord cysts for more information.)
If the vocal fold cyst(s) are presumed to be congenital, the patient should have a history of presenting with a hoarse voice.Patients with vocal fold cysts are considered for surgery when presenting with:
Dysphonia
Lack of improvement through voice therapy

Prevention
A key aspect of preventing vocal fold cysts is good vocal hygiene. Good vocal hygiene promotes the healthy use of the vocal apparatus and the avoidance of phonotrauma. Good vocal hygiene practices involve the avoidance of:
Shouting
Whispering loudly or for long periods of time
Frequently of talking over loud background noise
Talking while yawning
Continual clearing of the throat
Speaking in an unnatural voice (i.e. too high or low)
Talking with a cold or laryngitis
Smoking tobacco or marijuana
The consumption of alcohol and coffee
The use of antihistamines, aspirin, steroids, tricyclic antidepressants, or any substance that alters perception (i.e. sleeping pills)
Foul airIn addition, good vocal hygiene involves getting enough rest and drinking sufficient water. It is important to keep the vocal fold tissue healthy and hydrated, and when possible to limit the quantity of speaking in order to avoid damage.

Treatment
Vocal fold cysts are treated using a multidisciplinary approach. Vocal fold cysts are most responsive when surgical intervention is supplemented with voice therapy. Applying vocal therapy techniques in isolation has not yet been proven to remediate and decrease the actual size of the vocal fold cyst.Voice therapy to address harmful vocal behaviours is recommended as the first treatment option. Voice therapy may involve reducing tension in the larynx, reducing loudness, reducing the amount of speech produced, and modifying the environment. If symptoms are significant, treatment usually involves microsurgery to remove the cyst. Although voice therapy is useful for preventing vocal fold cysts caused by phonotrauma and for promoting safe vocal practices, vocal fold cysts tend not to respond to therapy alone and typically require surgery for full repair.During surgery, attempts are made to preserve as much vocal fold tissue as possible, given that glottal insufficiency (a gap in the vocal folds) is a possible consequence of surgery. Vocal fold tissue can be preserved during surgery by raising a micro-flap, removing the cyst, then laying the flap back down. This is intended to lead to minimal scarring and improved voice function. However, if any epithelium from the cyst sac is left behind during surgery, the cyst may regrow. Surgery of the larynx may also be conducted using a CO2 laser, which was reported as early as the 1970s. Congenital ductal cysts (those caused by blockage of a glandular duct) may be treated by marsupialization.Following surgery, patients are recommended to take 2 to 14 days of vocal rest. In absolute vocal rest, activities such as talking, whispering, whistling, straining, coughing, and sneezing are restricted. Once adequate healing has occurred, the patient may be transitioned to relative vocal rest, which typically involves 5 to 10 minutes of breathy voicing per hour. Voice therapy is then required to restore as much function as possible. Post-operative voice therapy may include addressing harmful vocal behaviours, exercises to restrengthen the larynx, and reintegration into normal voice activities.
Professional voice users who do not experience substantial limitations due to their cysts may choose to forego surgery </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 Pemphigoid nodularis 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 Far-sightedness and can you explain it in depth? [/INST] Far-sightedness, also known as long-sightedness, hypermetropia, or hyperopia, is a condition of the eye where distant objects are seen clearly but near objects appear blurred. This blurred effect is due to incoming light being focused behind, instead of on, the retina wall due to insufficient accommodation by the lens. Minor hypermetropia in young patients is usually corrected by their accommodation, without any defects in vision. But, due to this accommodative effort for distant vision, people may complain of asthenopic symptoms during prolonged reading. Some hypermetropes can see clear at distance, but near vision may be blurred due to insufficient accommodation. For this reason, this defect is referred as far-sightedness.  If the hypermetropia is high, there will be defective vision for both distance and near. People may also experience accommodative dysfunction, binocular dysfunction, amblyopia, and strabismus. Newborns are almost invariably hypermetropic, but it gradually decreases as the newborn gets older.There are many causes for this condition. It may occur when the axial length of eyeball is too short or if the lens or cornea is flatter than normal. Changes in refractive index of lens, alterations in position of the lens or absence of lens are the other main causes. Risk factors include a family history of the condition, diabetes, certain medications, and tumors around the eye. It is a type of refractive error. Diagnosis is based on an eye exam.Management can occur with eyeglasses, contact lenses, or refractive corneal surgeries. Glasses are easiest while contact lenses can provide a wider field of vision. Surgery works by changing the shape of the cornea. Far-sightedness primarily affects young children, with rates of 8% at 6 years and 1% at 15 years. It then becomes more common again after the age of 40, known as presbyopia, affecting about half of people. Best treatment option to correct hypermetropia due to aphakia is IOL implantation.Other common types of refractive errors are near-sightedness, astigmatism, and presbyopia.

Signs and symptoms
In young patients, mild hypermetropia may not produce any symptoms. The signs and symptoms of far-sightedness include blurry vision, frontal or fronto temporal headaches, eye strain, tiredness of eyes etc. The common symptom is eye strain. Difficulty seeing with both eyes (binocular vision) may occur, as well as difficulty with depth perception. The asthenopic symptoms and near blur are usually seen after close work, especially in the evening or night.

Complications
Far-sightedness can have rare complications such as strabismus and amblyopia. At a young age, severe far-sightedness can cause the child to have double vision as a result of "over-focusing".Hypermetropic patients with short axial length are at higher risk of developing primary angle closure glaucoma, so, routine gonioscopy and glaucoma evaluation is recommended for all hypermetropic adults.

Causes
Simple hypermetropia, the most common form of hypermetropia, is caused by normal biological variations in the development of eyeball. Aetiologically, causes of hypermetropia can be classified as:

Axial: Axial hypermetropia occur when the axial length of eyeball is too short. About 1 mm decrease in axial length cause 3 diopters of hypermetropia. One condition that cause axial hypermetropia is nanophthalmos.
Curvatural: Curvatural hypermetropia occur when curvature of lens or cornea is flatter than normal. About 1 mm increase in radius of curvature results in 6 diopters of hypermetropia. Cornea is flatter in microcornea and cornea plana.
Index: Age related changes in refractive index (cortical sclerosis) can cause hypermetropia.  Another cause of index hypermetropia is diabetes. Occasionally, mild hypermetropic shift may be seen in association with cortical or subcapsular cataract also.
Positional: Positional hypermetropia occur due to posterior dislocation of Lens or IOL. It may occur due to trauma.
Consecutive: Consecutive hypermetropia occur due to surgical over correction of myopia or surgical under correction in cataract surgery.
Functional: Functional hypermetropia results from paralysis of accommodation as seen in internal ophthalmoplegia, CN III palsy etc.
Absence of lens: Congenital or acquired aphakia cause high degree hypermetropia.Far-sightedness is often present from birth, but children have a very flexible eye lens, which helps to compensate. In rare instances hyperopia can be due to diabetes, and problems with the blood vessels in the retina.

Diagnosis
A diagnosis of far-sightedness is made by utilizing either a retinoscope or an automated refractor-objective refraction; or trial lenses in a trial frame or a phoropter to obtain a subjective examination.
Ancillary tests for abnormal structures and physiology can be made via a slit lamp test, which examines the cornea, conjunctiva, anterior chamber, and iris.In severe cases of hyperopia from birth, the brain has difficulty in merging the images that each individual eye sees. This is because the images the brain receives from each eye are always blurred. A child with severe hyperopia can never see objects in detail. If the brain never learns to see objects in detail, then there is a high chance of one eye becoming dominant. The result is that the brain will block the impulses of the non-dominant eye. In contrast, the child with myopia can see objects close to the eye in detail and does learn at an early age to see objects in detail.

Classification
Hyperopia is typically classified according to clinical appearance, its severity, or how it relates to the eyes accommodative status.

Clinical classification
There are three clinical categories of hyperopia.
Simple hyperopia: Occurs naturally due to biological diversity.
Pathological hyperopia: Caused by disease, trauma, or abnormal development.
Functional hyperopia: Caused by paralysis that interferes eyes ability to accommodate.

Classification according to severity
There are also three categories severity:
Low: Refractive error less than or equal to +2.00 diopters (D).
Moderate: Refractive error greater than +2.00 D up to +5.00 D.
High: Refractive error greater than +5.00 D.

Components of hypermetropia
Accommodation has significant role in hyperopia. Considering accommodative status, hyperopia can be classified as:
Total hypermetropia: It is the total amount of hyperopia which is obtained after complete relaxation of accommodation using cycloplegics like atropine.
Latent hyperopia: It is the amount of hyperopia normally corrected by ciliary tone (approximately 1 diopter).
Manifest hyperopia: It is the amount of hyperopia not corrected by ciliary tone. Manifest hyperopia is further classified into two, facultative and absolute.
Facultative hyperopia: It is the part of hyperopia corrected by patients accommodation.
Absolute hyperopia: It is the residual part of hyperopia which causes blurring of vision for distance.So, Total hyperopia= latent hyperopia + manifest hyperopia (facultative + absolute)

Treatment
Corrective lenses
The simplest form of treatment for far-sightedness is the use of corrective lenses, i.e. eyeglasses or contact lenses. Eyeglasses used to correct far-sightedness have convex lenses.

Surgery
There are also surgical treatments for far-sightedness:
Laser procedures

Photorefractive keratectomy (PRK): This is a refractive technique that is done by removal of a minimal amount of the corneal surface. Hyperopic PRK has many complications like regression effect, astigmatism due to epithelial healing, and corneal haze. Post operative epithelial healing time is also more for PRK.
Laser assisted in situ keratomileusis (LASIK): Laser eye surgery to reshape the cornea, so that glasses or contact lenses are no longer needed </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 Macrodontia 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 Nephrogenic systemic fibrosis and can you explain it in depth? [/INST] Nephrogenic systemic fibrosis is a rare syndrome that involves fibrosis of skin, joints, eyes, and internal organs. NSF is caused by exposure to gadolinium in gadolinium-based MRI contrast agents (GBCAs) in patients with impaired kidney function. Epidemiological studies suggest that the incidence of NSF is unrelated to gender or ethnicity and it is not thought to have a genetic basis. After GBCAs were identified as a cause of the disorder in 2006, and screening and prevention measures put in place, it is now considered rare.

Signs and symptoms
Clinical features of NSF develop within days to months and, in some cases, years following exposure to some GBCAs. The main symptoms are the thickening and hardening of the skin associated with brawny hyperpigmentation, typically presenting in a symmetric fashion. The skin gradually becomes fibrotic and adheres to the underlying fascia. The symptoms initiate distally in the limbs and progress proximally, sometimes involving the trunk. Joint contractures of the fingers, elbows and knees can develop secondary to skin involvement and can severely impair physical function. While skin involvement is on the foreground, the process may involve any organ, e.g., the eye, heart, diaphragm, pleura, pericardium, and kidneys, as well as the lungs and liver.

Causes
NSF is an iatrogenic disease caused by exposure to gadolinium-based contrast agents used in magnetic resonance imaging.

Risk factors
Impaired kidney function reduces the clearance of GBCAs and is the major risk factor for the development of NSF. The etiology or duration of renal failure seems not to be relevant, but NSF risk greatly depends on the residual kidney function. The majority of NSF cases have been identified in patients with stage 5 CKD, but NSF has also developed in patients with stage 4 and 3 CKD, and those with acute kidney injury, even if kidney function subsequently returned to normal following GBCA administration. Thus NSF should be considered as a differential diagnosis in any patient who has been exposed to a GBCA, regardless of the kidney function level.Three GBCAs have been principally implicated in NSF: gadodiamide, gadopentetate dimeglumine, and gadoversetamide, though cases have been reported with majority of GBCAs on the market. High doses in individual GBCA administrations and high cumulative doses of GBCA over the lifetime of patients with renal dysfunction are associated with increased risk of NSF.

Mechanism
De-chelation of Gd(III) is responsible for the toxicity associated with gadolinium complexes such as GBCAs, and the toxicity appears to be a consequence of Zn2+, Cu2+, and Ca2+ transmetallation in vivo. This hypothesis is supported by acute toxicity experiments, which demonstrate that despite a 50-fold range of LDse values for four Gd(III) complexes, all become lethally toxic when they release precisely the same quantity of Gd(III). It is also supported by subchronic rodent toxicity experiments, which demonstrate a set of gross and microscopic findings similar to those known to be caused by Zn2+ deficiency. Under the transmetallation hypothesis, we can expect that subtle changes in formulation can affect the intrinsic safety of gadolinium complexes, which is indeed observed.

Diagnosis
There is no specific imaging finding for NSF, and the diagnosis is a clinicopathological one, based on presentation and histological findings.

Microscopic pathology
At the microscopic level, NSF shows a proliferation of dermal fibroblasts and dendritic cells, thickened collagen bundles, increased elastic fibers, and deposits of mucin. More recent case reports have described the presence of sclerotic bodies (also known as elastocollagenous balls) in skin biopsies from NSF patients. While not universally present, this finding is believed to be unique to patients exposed to gadolinium, although not necessarily limited to areas involved by NSF.

Differential diagnosis
The differential diagnoses for NSF include diffuse cutaneous or limited cutaneous systemic sclerosis, scleromyxedema, lipodermatosclerosis, scleroedema diabeticorum, graft versus host disease, eosinophilic fasciitis; eosinophilia-myalgia syndrome; porphyria cutanea tarda, and other disorders. The nearly universal absence of facial skin involvement in NSF, presence of yellow plaques on the sclera of the eyes, absence of Raynauds phenomenon, and other differences in presentation can aid the proper diagnosis. History of exposure to GBCAs would favor NSF as the differential diagnosis.

Prevention
The only known measure for prevention of NSF is the non-use or cautious use of GBCAs in patients with renal impairment, including preferential use of safer, macrocyclic GBCAs. Performing dialysis immediately after the MRI exam is recommended for patients already in dialysis treatment, but there is no evidence for introducing dialysis in non-dialytic patients for prevention of NSF </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 Bigeminy and can you explain it in depth? [/INST] Bigeminy is a cardiac arrhythmia in which there is a single ectopic beat, or irregular heartbeat, following each regular heartbeat. Most often this is due to ectopic beats occurring so frequently that there is one after each sinus beat, or normal heartbeat. The two beats are figuratively similar to two twins (hence bi- + gemini).  For example, in ventricular bigeminy, a sinus beat is shortly followed by a premature ventricular contraction (PVC), a pause, another normal beat, and then another PVC. In atrial bigeminy, the other "twin" is a premature atrial contraction (PAC).

Cause
After any PVC there is a pause that can lead to the development of bigeminy. A PVC wavefront often encounters a refractory AV node that does not conduct the wavefront retrograde. Thus the atrium is not depolarized and the sinus node is not reset. Since the sinus P wave to PVC interval is less than the normal P–P interval, the interval between the PVC and the next P wave is prolonged to equal the normal time elapsed during two P–P intervals. This is called a "compensatory" pause. The pause after the PVC leads to a longer recovery time, which is associated with a higher likelihood of myocardium being in different stages of repolarization. This then allows for re-entrant circuits and sets up the ventricle for another PVC after the next sinus beat. The constant interval between the sinus beat and PVC suggests a reentrant etiology rather than spontaneous automaticity of the ventricle.Premature atrial contractions by contrast do not have a compensatory pause, since they reset the sinus node, but atrial or supraventricular bigeminy can occur </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 Chondrodysplasia punctata 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 Acidosis and can you explain it in depth? [/INST] Acidosis is a process causing increased acidity in the blood and other body tissues (i.e., an increase in hydrogen ion concentration).  If not further qualified, it usually refers to acidity of the blood plasma.
The term acidemia describes the state of low blood pH, while acidosis is used to describe the processes leading to these states. Nevertheless, the terms are sometimes used interchangeably. The distinction may be relevant where a patient has factors causing both acidosis and alkalosis, wherein the relative severity of both determines whether the result is a high, low, or normal pH.
Acidemia is said to occur when arterial pH falls below 7.35 (except in the fetus – see below), while its counterpart (alkalemia) occurs at a pH over 7.45. Arterial blood gas analysis and other tests are required to separate the main causes.
The rate of cellular metabolic activity affects and, at the same time, is affected by the pH of the body fluids. In mammals, the normal pH of arterial blood lies between 7.35 and 7.50 depending on the species (e.g., healthy human-arterial blood pH varies between 7.35 and 7.45). Blood pH values compatible with life in mammals are limited to a pH range between 6.8 and 7.8. Changes in the pH of arterial blood (and therefore the extracellular fluid) outside this range result in irreversible cell damage.

Signs and symptoms
Nervous system involvement may be seen with acidosis and occurs more often with respiratory acidosis than with metabolic acidosis. Signs and symptoms that may be seen in acidosis include headaches, confusion, feeling tired, tremors, sleepiness, flapping tremor, and dysfunction of the cerebrum of the brain which may progress to coma if there is no intervention.

Metabolic acidosis
Metabolic acidosis may result  from either increased production of metabolic acids, such as lactic acid, or disturbances in the ability to excrete acid via the kidneys, such as either renal tubular acidosis or the acidosis of kidney failure, which is associated with an accumulation of urea and creatinine as well as metabolic acid residues of protein catabolism.
An increase in the production of other acids may also produce metabolic acidosis.  For example, lactic acidosis may occur from:

severe (PaO2 <36mm Hg) hypoxemia causing a fall in the rate of oxygen diffusion from arterial blood to tissues.
hypoperfusion (e.g., hypovolemic shock) causing an inadequate blood delivery of oxygen to tissues.A rise in lactate out of proportion to the level of pyruvate, e.g., in mixed venous blood, is termed "excess lactate", and may also be an indicator of fermentation due to anaerobic metabolism occurring in muscle cells, as seen during strenuous exercise. Once oxygenation is restored, the acidosis clears quickly.  Another example of increased production of acids occurs in starvation and diabetic ketoacidosis.  It is due to the accumulation of ketoacids (via excessive ketosis) and reflects a severe shift from glycolysis to lipolysis for energy needs.
Acid consumption from poisoning such as methanol ingestion, elevated levels of iron in the blood, and chronically decreased production of bicarbonate may also produce metabolic acidosis.
Metabolic acidosis is compensated for in the lungs, as increased exhalation of carbon dioxide promptly shifts the buffering equation to reduce metabolic acid. This is a result of stimulation to chemoreceptors, which increases alveolar ventilation, leading to respiratory compensation, otherwise known as Kussmaul breathing (a specific type of hyperventilation). Should this situation persist, the patient is at risk of exhaustion leading to respiratory failure.
Mutations to the V-ATPase a4 or B1 isoforms result in distal renal tubular acidosis, a condition that leads to metabolic acidosis, in some cases with sensorineural deafness.
Arterial blood gases will indicate low pH, low blood HCO3, and normal or low PaCO2.
In addition to arterial blood gas, an anion gap can also differentiate between possible causes.
The Henderson-Hasselbalch equation is useful for calculating blood pH, because blood is a buffer solution. In the clinical setting, this equation is usually used to calculate HCO3 from measurements of pH and PaCO2 in arterial blood gases. The amount of metabolic acid accumulating can also be quantitated by using buffer base deviation, a derivative estimate of the metabolic as opposed to the respiratory component. In hypovolemic shock for example, approximately 50% of the metabolic acid accumulation is lactic acid, which disappears as blood flow and oxygen debt are corrected.

Treatment
Treatment of uncompensated metabolic acidosis is focused upon correcting the underlying problem </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 Ecthyma gangrenosum and can you explain it in depth? [/INST] Ecthyma gangrenosum is a type of skin lesion characterized by vesicles or blisters which rapidly evolve into pustules and necrotic ulcers with undermined tender erythematous border. "Ecthyma" means a pus forming infection of the skin with an ulcer, "gangrenosum" refers to the accompanying gangrene or necrosis. It is classically associated with Pseudomonas aeruginosa bacteremia, but it is not pathognomonic.  Pseudomonas aeruginosa is a gram negative, aerobic bacillus.This type of skin lesion was first described in association with Pseudomonas aeruginosa by L. Barker in 1897. It was given the name "ecthyma gangrenosum" by Hitschmann and Kreibich.It mostly occurs in patients with underlying immunocompromise (e.g. malignancy or HIV). Although most cases are due to Pseudomonas aeruginosa infection, there are recent reports of this skin lesion in association with other microorganisms, such as Escherichia coli, Citrobacter freundii, Klebsiella pneumoniae, various other Pseudomonas species, and Morganella morganii.

Signs and symptoms
The primary skin lesion usually starts with a macule that is painless, round and erythematous. Then, it develops into a pustule, and then a bulla with central hemorrhagic focus. The bulla progresses into an ulcer which extends laterally. Finally it becomes a gangrenous ulcer with a central black eschar surrounded by an erythematous halo.The lesions may be single or multiple. They are most commonly seen in perineum and under arm pit. However, they can occur in any part of the body.

Mechanism
The organism enters directly through the breakdown of mechanical defense barriers such as mucosa or skin. Conditions which lead to the development of an immunocompromised state make the patient more susceptible to ecthyma gangrenosum and sepsis. In case of sepsis, the bacteria reaches the skin via the bloodstream </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 Pentosuria and can you explain it in depth? [/INST] Pentosuria is a condition where the sugar xylitol, a pentose, presents in the urine in unusually high concentrations. It was characterized as an inborn error of carbohydrate metabolism in 1908. It is associated with a deficiency of L-xylulose reductase, necessary for xylitol metabolism </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 Phantom limb and can you explain it in depth? [/INST] A phantom limb is the sensation that an amputated or missing limb is still attached. Approximately 80 to 100% of individuals with an amputation experience sensations in their amputated limb. However, only a small percentage will experience painful phantom limb sensation. These sensations are relatively common in amputees and usually resolve within two to three years without treatment. Research continues to explore the underlying mechanisms of phantom limb pain (PLP) and effective treatment options.

Signs and symptoms
Most (80% to 100%) amputees experience a phantom limb, with some of them having non-painful sensations. The amputee may feel very strongly that the phantom limb is still part of the body.People will sometimes feel as if they are gesturing, feel itches, twitch, or even try to pick things up. The missing limb often feels shorter and may feel as if it is in a distorted and painful position. Occasionally, the pain can be made worse by stress, anxiety and weather changes. Exposure to extreme weather conditions, especially below freezing temperatures, can cause increased sensitivity to the sensation. Phantom limb pain is usually intermittent, but can be continuous in some cases. The frequency and intensity of attacks usually declines with time.Repressed memories in phantom limbs could potentially explain the reason for existing sensations after amputation. Specifically, there have been several reports from patients of painful clenching spasms in the phantom hand with the feeling of their nails digging into their palms. The motor output is amplified due to the missing limb; therefore, the patient may experience the overflow of information as pain. The patient contains repressed memories from previous motor commands of clenching the hand and sensory information from digging their nails into their palm. These memories remain due to previous neural connections in the brain.

Phantom limb syndrome
The term "phantom limb" was coined by physician Silas Weir Mitchell in 1871. For many years, the dominant hypothesis for the cause of phantom limbs was irritation in the peripheral nervous system at the amputation site (neuroma). By the late 1980s, Ronald Melzack had recognized that the peripheral neuroma account could not be correct, because many people born without limbs also experienced phantom limbs. According to Melzack the experience of the body is created by a wide network of interconnecting neural structures, which he called the "neuromatrix".Pons and colleagues (1991) at the National Institutes of Health (NIH) showed that the primary somatosensory cortex in macaque monkeys undergoes substantial reorganization after the loss of sensory input.Hearing about these results, Vilayanur S. Ramachandran hypothesized that phantom limb sensations in humans could be due to reorganization in the human brains somatosensory cortex. Ramachandran and colleagues illustrated this hypothesis by showing that stroking different parts of the face led to perceptions of being touched on different parts of the missing limb. Later brain scans of amputees showed the same kind of cortical reorganization that Pons had observed in monkeys.Maladaptive changes in the cortex may account for some but not all phantom limb pain. Pain researchers such as Tamar Makin (Oxford) and Marshall Devor (Hebrew University, Jerusalem) argue that phantom limb pain is primarily the result of "junk" inputs from the peripheral nervous system.Despite a great deal of research on the underlying neural mechanisms of phantom limb pain there is still no clear consensus as to its cause. Both the brain and the peripheral nervous system may be involved.Research continues into more precise mechanisms and explanations.

Neural mechanisms
Pain, temperature, touch, and pressure information are carried to the central nervous system via the anterolateral system (spinothalamic tracts, spinoreticular tract, spinomesencefalic tract), with pain and temperature information transferred via lateral spinothalamic tracts to the primary sensory cortex, located in the postcentral gyrus in the parietal lobe, where sensory information is represented somatotropically, forming the sensory homunculus.In phantom limb syndrome, there is sensory input indicating pain from a part of the body that is no longer existent. This phenomenon is still not fully understood, but it is hypothesized that it is caused by activation of the somatosensory cortex.

Treatment
Most approaches to treatment over the past two decades have not shown consistent symptom improvement. Treatment approaches have included medication such as antidepressants, spinal cord stimulation, vibration therapy, acupuncture, hypnosis, and biofeedback. Reliable evidence is lacking on whether any treatment is more effective than the others.

Most treatments are not very effective. Ketamine or morphine may be useful around the time of surgery </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 Langerhans cell sarcoma and can you explain it in depth? [/INST] Langerhans cell sarcoma (LCS) is a rare form of malignant histiocytosis. It should not be confused with Langerhans cell histiocytosis, which is cytologically benign. It can present most commonly in the skin and lymphatic tissue, but may also present in the lung, liver, and bone marrow. Treatment is most commonly with surgery or chemotherapy.

Classification
Dendritic cell neoplasms are classified by the World Health Organization as follows:
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma/tumor
Follicular dendritic cell sarcoma/tumor
Dendritic cell sarcoma

Epidemiology
The exact incidence of LCS is unknown due to the rarity of the condition. The related condition, Langerhans Cell Histiocytosis (LCH) is estimated to have an incidence of around 5 cases per 1 million people per year. In one review of Japanese patients with confirmed LCS, patients were a median age of 41 years. Patients were twice as likely to be female than male. In another systematic review, the median age of presentation was 50 years, but with a slight predilection for males.

Pathophysiology
Throughout the body in locations such as mucous membranes, skin, lymph nodes, thymus, and spleen are cells known as antigen-presenting cells. These cells are surveillance cells that take foreign antigens and present them to antigen-processing cells, such as T-cells, protecting the body from potential harm. Antigen-presenting cells are also termed Dendritic cells, of which Langerhans cells are a subtype. There are four main types that make up the structure and functions of lymphoid tissue, such as lymph nodes and splenic tissue. By definition, Langerhans Cell Sarcoma (LCS) is a cancerous disease caused by the uncontrolled overproliferation of Langerhans cells.Because Langerhans cells are most commonly found in the mucosa and the skin, LCS is thought to usually begin here with further spread to other areas of the body via the lymphatic system.Langerhans cell sarcoma can occur de novo, or can occur as a malignant transformation of Langerhans cell histiocytosis.

Clinical Manifestations
The related condition, LCH, presents with various clinical features depending on the bodily organs involved. LCS shares most of these clinical presentations. Most commonly, these patients will present with generalized signs and symptoms such as fever and weight loss. Blood tests will commonly show pancytopenia, an overall reduction in blood cell counts. Additionally, these patients may display lymphadenopathy, hepatosplenomegaly, skin lesions, bone lesions, and lung lesions. Most common site presentations are the skin and lymphatics. Other common sites of involvement include the lung, liver, and spleen.LCS will present with a varied gross appearance. When involving the skin, LCS will present as a patches of erythema, with nodules and ulceration present as well. Skin lesions will most commonly involve the trunk, scalp, and legs. Tumor size may range from 1-6 cm, but may be larger. Usually the tumor is well circumscribed with a surface covered in small nodules or protuberances. Most are of a solid consistency  and are of a pink, white, or tan color. LCS tumors may present with much larger sizes and aggressive features, even causing some bleeding and necrosis of the surrounding tissue.

Diagnosis
Diagnosis of Langerhans Cell Sarcoma is predominantly a pathologic diagnosis. Cells from these tumor samples will display features characteristic of Langerhans cells, but with additional signs of malignancy, such as increased mitoses, cellular atypia, and pleomorphic nuclei.CD-207 is a cellular marker associated with Birbeck granules than can be used for confirmation of cell type. LCS will also stain positive for CD-68, CD-68R, CD-21, CD-35, S-100, CD1a, lysozyme, HLA-DR, CD4, fascin, Factor XIIIa, and cyclin D1, which are cellular markers typically used in the characterization of various pathology specimens. Positive staining with CD1a and S-100 are required for diagnosis of LCS. Positive staining with CD-207 (Langerin) is an additional confirmation marker of malignancy in LCS. Other cellular markers have been reported to be positive in LCS, but have are not as routinely used.Histologically, Langerhans cells characteristically display Birbeck granules and nuclei with a longitudinal groove. Birbeck granules are currently a poorly understood cellular structure, but are commonly used for cell-type identification. Previously, the presence of Birbeck granules was necessary for diagnosis, but this is no longer considered diagnostic.Currently, there appears to be no relation of LCS with chromosomal abnormalities.The diagnosis of LCS can be difficult, especially due to its rarity. It has previously been mistaken with metastatic melanoma and metastatic large-cell carcinoma.

Treatment
Treatment for this rare disease consists of a variety of approaches, with none displaying any increased efficacy over another. There are currently three broad treatment strategies for LCS: surgery, chemotherapy, and combination with radiation therapy. When the LCS tumor is readily accessible, the best treatment method is usually surgical removal. There is, however, an observed increased risk of tumor relapse following surgical resection. Both chemotherapy and radiation therapy are useful as treatments, either as monotherapy or in conjunction with other treatments. Chemotherapy is currently the most common treatment method, either alone or in combination. The most common chemotherapeutic regimen consisted of cyclophosphamide, doxorubicin, vincristine, and prednisolone (otherwise known as CHOP therapy). Other common chemotherapeutic regimens include MAID (mesna, doxorubicin, ifosfamide, and dacarbazine), ESHAP (etoposide, carboplatin, cytarabine, and methylprednisolone), EPIG (etoposide, cisplatin, ifosfamide, mesna, and gemcitabine), and AIM (doxorubicin, ifosfamide, and mesna). Other regimens have been used with mixed levels of success. In an effort to prevent recurrence, sometimes combination therapy is used. Following surgical resection, additional radiation therapy or chemotherapy may be performed to prevent relapse. Patients receiving combined chemotherapy and radiation therapy has only shown limited benefit.There are a variety of other therapies under research with varying levels of reported success. These include high-dose chemotherapy, bone marrow transplants,  and somatostatin analogues.When there is only one site of LCS involvement, monotherapy may be sufficient treatment </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 Fetal distress and can you explain it in depth? [/INST] Fetal distress, also known as non-reassuring fetal status, is a condition during pregnancy or labor in which the fetus shows signs of inadequate oxygenation. Due to its imprecision, the term "fetal distress" has fallen out of use in American obstetrics. The term "non-reassuring fetal status" has largely replaced it. It is characterized by changes in fetal movement, growth, heart rate, and presence of meconium stained fluid.Risk factors for fetal distress/non-reassuring fetal status include anemia, restriction of fetal growth, maternal hypertension or cardiovascular disease, low amniotic fluid or meconium in the amniotic fluid, or a post-term pregnancy. The condition is detected most often with electronic fetal heart rate (FHR) monitoring through cardiotocography (CTG), which allows clinicians to measure changes in the fetal cardiac response to declining oxygen. Specifically, heart rate decelerations detected on CTG can represent danger to the fetus and to delivery.Treatment primarily consists of intrauterine resuscitation, the goal of which is to restore oxygenation of the fetus. This can involve improving the position, hydration, and oxygenation of the mother, as well as amnioinfusion to restore sufficient amniotic fluid, delaying preterm labor contractions with tocolysis, and correction of fetal acid-base balance. An algorithm is used to treat/resuscitate babies in need of respiratory support post-birth.

Signs and symptoms
Generally it is preferable to describe specific signs in lieu of declaring fetal distress that include:

Decreased movement felt by the mother
Meconium in the amniotic fluid ("meconium stained fluid")
Non-reassuring patterns seen on cardiotocography:
increased or decreased fetal heart rate (tachycardia and bradycardia), especially during and after a contraction
decreased variability in the fetal heart rate
late decelerations
Biochemical signs, assessed by collecting a small sample of babys blood from a scalp prick through the open cervix in labor
fetal metabolic acidosis
elevated fetal blood lactate levels (from fetal scalp blood testing) indicating the baby has a lactic acidosisSome of these signs are more reliable predictors of fetal compromise than others. For example, cardiotocography can give high false positive rates, even when interpreted by highly experienced medical personnel </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 Nijmegen breakage syndrome and can you explain it in depth? [/INST] Nijmegen breakage syndrome (NBS) is a rare autosomal recessive congenital disorder causing chromosomal instability, probably as a result of a defect in the double Holliday junction DNA repair mechanism and/or the synthesis dependent strand annealing mechanism for repairing double strand breaks in DNA (see Homologous recombination).NBS1 codes for a protein (nibrin) that has two major functions: (1) to stop the cell cycle in the S phase, when there are errors in the cell DNA (2) to interact with FANCD2 that can activate the BRCA1/BRCA2 pathway of DNA repair. This explains why mutations in the NBS1 gene lead to higher levels of cancer (see Fanconi anemia, Cockayne syndrome.)
The name derives from the Dutch city Nijmegen, where the condition was first described.Most people with NBS have West Slavic origins. The largest number of them live in Poland.

Presentation
It is characterized by microcephaly, a distinct facial appearance, short stature, immunodeficiency, radiation sensitivity and a strong predisposition to lymphoid malignancy. NBS is caused by a mutation in the NBS1 gene. Unsurprisingly, many of the features are similar to ataxia telangiectasia (AT) and this syndrome was sometimes termed AT-variant 1, as the protein mutated in AT, ATM, interacts with the MRE11/RAD50/NBS1 (MRN) complex </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 Fatal insomnia and can you explain it in depth? [/INST] Fatal familial insomnia is an extremely rare genetic (and even more rarely, sporadic) disorder that results in trouble sleeping as its hallmark symptom. The problems with sleeping typically start out gradually and worsen over time. Other symptoms may include speech problems, coordination problems, and dementia. It results in death within a few months to a few years.Fatal familial insomnia is a prion disease of the brain. It is usually caused by a mutation to the gene encoding protein PrPC. It has two forms: fatal familial insomnia (FFI), which is autosomal dominant, and sporadic fatal insomnia (sFI), which lacks the gene mutation. Diagnosis is suspected based on symptoms and can be supported by a sleep study, a PET scan, and genetic testing if the patients family has a history of the disease. Similar to other prion diseases, the diagnosis can only be confirmed by a brain autopsy at post-mortem.Fatal insomnia has no known cure and involves progressively worsening insomnia, which leads to hallucinations, delirium, and confusional states like that of dementia, until the patient slips into a stupor and eventually dies. The average survival time from onset of symptoms is 18 months. The first recorded case was an Italian man who died in Venice in 1765.

Signs and symptoms
The disease has four stages:
Characterized by worsening insomnia, resulting in panic attacks, paranoia, and phobias. This stage lasts for about four months.
Hallucinations and panic attacks become noticeable, continuing for about five months.
Complete inability to sleep is followed by rapid loss of weight. This lasts for about three months.
Dementia, during which the person becomes unresponsive or mute over the course of six months, is the final stage of the disease, after which death follows.Other symptoms include: profuse sweating, miosis (pinpoint pupils), sudden entrance into menopause or  impotence, neck stiffness, and elevation of blood pressure and heart rate. The sporadic form of the disease often presents with double vision. Constipation is common as well. As the disease progresses, the person becomes stuck in a state of pre-sleep limbo, or hypnagogia, which is the state just before sleep in healthy individuals. During these stages, people commonly and repeatedly move their limbs as if dreaming.The age of onset is variable, ranging from 13 to 60 years, with an average of 50. The disease can be detected prior to onset by genetic testing. Death usually occurs between 6–36 months from onset. The presentation of the disease varies considerably from person to person, even among people within the same family; in the sporadic form, for example, sleep problems are not commonly reported and early symptoms are ataxia, cognitive impairment, and double vision.

Cause
The gene PRNP that provides instructions for making the prion protein PrPC is located on the short (p) arm of chromosome 20 at position p13. Both people with FFI and those with familial Creutzfeldt–Jakob disease (fCJD) carry a mutation at codon 178 of the prion protein gene. FFI is also invariably linked to the presence of the methionine codon at position 129 of the mutant allele, whereas fCJD is linked to the presence of the valine codon at that position. "The disease is where there is a change of amino acid at position 178 when an asparagine (N) is found instead of the normal aspartic acid (D). This has to be accompanied with a methionine at position 129."

Pathophysiology
In itself, the presence of prions causes reduced glucose use by the thalamus and a mild hypo-metabolism of the cingulate cortex. The extent of this symptom varies between two variations of the disease, these being those presenting methionine homozygotes at codon 129 and methionine/valine heterozygotes being the most severe in the latter one. Given the relationship between the involvement of the thalamus in regulating sleep and alertness, a causal relationship can be drawn, and is often mentioned as the cause.

Diagnosis
Diagnosis is suspected based on symptoms. Further work up often include a sleep study and PET scan. Confirmation of the familial form is by genetic testing.

Differential diagnosis
Other diseases involving the mammalian prion protein are known. Some are transmissible (TSEs, including FFI) such as kuru, bovine spongiform encephalopathy (BSE, also known as "mad cow disease") in cattle, and chronic wasting disease in American deer and American elk in some areas of the United States and Canada, as well as Creutzfeldt–Jakob disease (CJD). Until recently, prion diseases were only thought to be transmissible by direct contact with infected tissue, such as from eating infected tissue, transfusion, or transplantation; research suggests that prions can be transmitted by aerosols, but that the general public is not at risk of airborne infection.

Treatments
Treatment involves palliative care. There is conflicting evidence over the use of sleeping pills, including barbiturates, as a treatment for the disease.

Prognosis
Similar to other prion diseases, the disease is invariably fatal. Life expectancy ranges from seven months to six years, with an average of 18 months.

Epidemiology
In 1998, 40 families were known to carry the gene for FFI globally: eight German, five Italian, four American, two French, two Australian, two British, one Japanese, and one Austrian. In the Basque Country, Spain, 16 family cases of the 178N mutation were seen between 1993 and 2005 related to two families with a common ancestor in the 18th century. In 2011, another family was added to the list when researchers found the first man in the Netherlands with FFI. While he had lived in the Netherlands for 19 years, he was of Egyptian descent. Other prion diseases are similar to FFI and could be related, but are missing the D178N gene mutation.As of 2016, 24 cases of sporadic fatal insomnia have been diagnosed. Unlike in FFI, those with sFI do not have the D178N mutation in the PRNP-prion gene; they all have a different mutation in the same gene causing methionine homozygosity at codon 129.
Nonetheless, the methionine presence in lieu of the valine (Val129) is what causes the sporadic form of disease. The targeting of this mutation is another strategy that has been suggested as possible for treatment, or hopefully as cure for the disease.

Silvano, 1983, Bologna, Italy
In late 1983, Italian neurologist/sleep expert Dr. Ignazio Roiter received a patient at the University of Bologna hospitals sleep institute. The man, known only as Silvano, decided in a rare moment of consciousness to be recorded for future studies and to donate his brain for research in hopes of finding a cure for future victims.

Unnamed American patient, 2001
In a 2006 published article, Schenkein and Montagna wrote of a 52-year-old American man who was able to exceed the average survival time by nearly one year with various strategies that included vitamin therapy and meditation, different stimulants and hypnotics, and even complete sensory deprivation in an attempt to induce sleep at night and increase alertness during the day. He managed to write a book and drive hundreds of miles in this time, but nonetheless, over the course of his trials, the man succumbed to the classic four-stage progression of the illness.

Egyptian man, 2011, Netherlands
In 2011, the first reported case in the Netherlands was of a 57-year-old man of Egyptian descent. The man came in with symptoms of double vision and progressive memory loss, and his family also noted he had recently become disoriented, paranoid, and confused </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 Accessory breast and can you explain it in depth? [/INST] Accessory breasts, also known as polymastia, supernumerary breasts, or mammae erraticae, is the condition of having an additional breast. Extra breasts may appear with or without nipples or areolae </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 Youngs syndrome and can you explain it in depth? [/INST] Youngs syndrome, also known as azoospermia sinopulmonary infections, sinusitis-infertility syndrome and Barry-Perkins-Young syndrome, is a rare condition that encompasses a combination of syndromes such as bronchiectasis, rhinosinusitis and reduced male fertility. In individuals with this syndrome the functioning of the lungs is usually normal but the mucus is abnormally viscous. The reduced fertility (obstructive azoospermia) is due to functional obstruction of sperm transport down the genital tract at the epididymis, where the sperm is found in viscous, lipid-rich fluid </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 Ghost sickness and can you explain it in depth? [/INST] Ghost sickness is a cultural belief among some traditional indigenous peoples in North America, notably the Navajo, and some Muscogee and Plains cultures, as well as among Polynesian peoples. People who are preoccupied and/or consumed by the deceased are believed to suffer from ghost sickness. Reported symptoms can include general weakness, loss of appetite, suffocation feelings, recurring nightmares, and a pervasive feeling of terror </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 Osteochondrodysplasia and can you explain it in depth? [/INST] Osteochondrodysplasia is a general term for a disorder of the development (dysplasia) of bone ("osteo") and cartilage ("chondro"). Osteochondrodysplasias are rare diseases. About 1 in 5,000 babies are born with some type of skeletal dysplasia. Nonetheless, if taken collectively, genetic skeletal dysplasias or osteochondrodysplasias comprise a recognizable group of genetically determined disorders with generalized skeletal affection. Osteochondrodysplasias can result in marked functional limitation and even mortality.
Osteochondrodysplasias subtypes can overlap in clinical aspects, therefore plain radiography is absolutely necessary to establish an accurate diagnosis. Magnetic resonance imaging can provide further diagnostic insights and guide treatment strategies especially in cases of spinal involvement. Early diagnosis, and timely management of skeletal dysplasia are important to combat functional deterioration.

Types
Achondroplasia
Achondroplasia is a type of autosomal dominant genetic disorder that is the most common cause of dwarfism. It is also the most common type of non-lethal osteochondrodysplasia or skeletal dysplasia. The prevalence is approximately 1 in 25,000 births. Achondroplastic dwarfs have short stature, with an average adult height of 131 cm (4 feet, 3 inches) for males and 123 cm (4 feet, 0 inches) for females. In achondroplasia the dwarfism is readily apparent at birth. likewise, craniofacial abnormalities in the form of macrocephaly and mid-face hypoplasia are present at birth. The previous clinical findings differentiate between achondroplasia and pseudoachondroplasia in which dwarfism is not recognizable at birth and craniofacial abnormalities are not considered a disease feature. Plain radiography plays an additional and important role in the differential diagnosis of achondroplasia.

Pseudoachondroplasia
Pseudoachondroplasia is an osteochondrodysplasia made distinctive by disproportionate short stature, hip and knee deformities, brachydactyly (short fingers) and ligamentous laxity. It affects at least 1 in 20,000 individuals. Pseudoachondroplasia is inherited in an autosomal dominant manner and is caused solely by mutations in the cartilage oligomeric matrix protein COMP gene. It’s distinguished by a moderate to severe form of disproportionate short-limb short stature. The limb shortening is fundamentally confined to the proximal limb segments i.e. Femurs and humeri. A known presenting feature is a waddling gait, noticed at the onset of walking. A prompt diagnosis of a skeletal dysplasia in general and Pseudoachondroplasia in specific is still based upon a comprehensive clinical and radiographic correlation. A detailed radiographic examination of the axial and appendicular skeleton is invaluable for the differential diagnosis of Pseudoachondroplasia. Coxa vara (reduced neck shaft angle), broad femoral necks, short femurs and humeri, and bullet-shaped vertebrae are noticeable radiographic features. Additionally, the presence of metaphyseal broadening, cupping and dense line of ossification about the knee can simulate rachitic changes. These radiographic features are collectively known as rachitic-like changes. The presence of epiphyseal changes serves as an important differentiating feature from achondroplasia.

Osteogenesis imperfecta
COL1A1/2-related osteogenesis imperfecta is inherited in an autosomal dominant manner. The proportion of cases caused by a De novo COL1A1 or COL1A2 mutations are the cause of osteogenesis imperfecta in the vast majority of perinatally lethal osteogenesis imperfecta, and progressively deforming osteogenesis imperfecta. In classic non-deforming osteogenesis imperfecta with blue sclerae or common variable osteogenesis imperfecta with normal sclerae, nearly 60% of cases are de novo. COL1A1/2-related osteogenesis imperfecta is identified by repeated fractures with trivial trauma, defective dentinogenesis imperfecta (DI), and hearing loss. The clinical features of COL1A1/2-related osteogenesis imperfecta can be highly variable ranging from severe and lethal perinatal fractures to individuals with minimal tendency to repeated fractures and skeletal deformities and with a normal stature and life span. In between the clinical spectrum may include individuals with various degrees of disabling skeletal deformities and short stature. The radiographic findings of osteogenesis imperfecta include; long bone deformations such as bowing of the tibias and femurs, pencil-like deformity and tapering of bones, cortical thinning and rarefaction, pathologic fractures at various degrees of healing, bone shortening and vertebral wedging. Accordingly, COL1A1/2-related osteogenesis imperfecta has been classified into four sub-types (I, II, III, and IV) built upon the diversity of the radioclinical features.
OI type I: classic non-deforming OI with blue sclerae
OI type II: perinatally lethal OI
OI type III: progressively deforming OI
OI type IV: common variable OI with normal sclerae

Muocopolysachariodosis
Mucopolysaccharidoses (MPS) constitute a commonly seen group of osteochondrodysplasias. Mucopolysaccharidosis can cause a wide spectrum of clinical and radiologic manifestations ranging from mild skeletal and systemic involvement to severe life-threatening manifestations. It is caused by a contiguous gene duplication or deletion syndrome in which multiple genes are involved. All forms of MPS are inherited in an autosomal recessive pattern, except fir of MPS II; Hunter syndrome which is X-linked. They are caused by an abnormal function of the lysosomal enzymes, which blocks degradation of mucopolysaccharides and leads to accumulation of harmful byproducts, namely, heparan sulfate, dermatan sulfate, and keratan sulfate. The resulting cellular malfunction can lead to a diverse array of skeletal and visceral manifestations. MPS have been subcategorized according to the type of enzyme inadequacy and glycoprotein accumulated.

Cleidocranial dysostosis
Cleidocranial dysostosis is a general skeletal condition named for the collarbone (cleido-) and cranium deformities which people with it often have. Common features include:
Partly or completely missing collarbones.
A soft spot or larger soft area in the top of the head where the fontanelle failed to close.
Bones and joints are underdeveloped.
The permanent teeth include supernumerary teeth.
Permanent teeth not erupting
Bossing (bulging) of the forehead.
Hypertelorism

Fibrous dysplasia
Fibrous dysplasia causes bone thinning and growths or lesions in one or more bones of the human body.
These lesions are tumor-like growths that consist of replacement of the medullary bone with fibrous tissue, causing the expansion and weakening of the areas of bone involved. Especially when involving the skull or facial bones, the lesions can cause externally visible deformities. The skull is often, but not necessarily, affected, and any other bones can be involved.

Langer–Giedion syndrome
Langer–Giedion syndrome is a very rare genetic disorder caused by a deletion of chromosomal material. Diagnosis is usually made at birth or in early childhood. The features associated with this condition include mild to moderate learning difficulties, short stature, unique facial features, small head and skeletal abnormalities including bony growths projecting from the surfaces of bones.

Maffucci syndrome
Maffucci syndrome is a sporadic disease characterized by the presence of multiple enchondromas associated with multiple simple or cavernous soft tissue hemangiomas. Also lymphangiomas may be apparent.Patients are normal at birth and the syndrome manifests during childhood and puberty. The enchondromas affect the extremities and their distribution is asymmetrical.

Osteosclerosis
Osteosclerosis, an elevation in bone density, is normally detected on an X-ray as an area of whiteness, and is where the bone density has significantly increased </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 Acrofrontofacionasal dysostosis and can you explain it in depth? [/INST] Acrofrontofacionasal dysostosis is an extremely rare disorder, characterized by intellectual disability, short stature, hypertelorism, broad notched nasal tip, cleft lip/palate, postaxial camptobrachypolysyndactyly, fibular hypoplasia, and anomalies of foot structure.An association with mutations in the neuroblastoma amplified sequence gene (NBAS) has been reported </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 Melanonychia 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 Tinea faciei 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 Spinal epidural hematoma 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 Oculocutaneous albinism type I and can you explain it in depth? [/INST] Oculocutaneous albinism type I or type 1A  is an autosomal recessive skin disease. This subtype of oculocutaneous albinism is caused when the gene for tyrosinase (symbol TYR or OCA1) does not function properly.
The location of OCA1 may be written as "11q1.4-q2.1", meaning it is on chromosome 11, long arm, somewhere in the range of band 1, sub-band 4, and band 2, sub-band 1. Since the disorder is autosomal recessive, genetic counseling can be used to determine if both parents are heterozygous for the condition when considering having children. If both parents are heterozygous, their child has a 25% chance of inheriting both recessive copies of OCA1 and having the skin disease.This symptoms in this disease include absence of pigmentation, due to a mutation that affects melanin levels in the eyes, hair, and skin. This rare disease is found in 1 out of 20,000 people around the world, being much more prevalent in Caucasians. There is no known cure for this disease as of present, but there are various ways to manage this disease, including safety around the sun and regular checks for other skin diseases such as skin cancer.

Signs and Symptoms
OCA is characterized by the absence of pigmentation caused by the mutation that effects the production of tyrosinase that causes partial or total absence of melanin in the hair, skin, and eyes. Reduction in melanin production specifically in the peripheral retina during embryonic development can trigger other symptoms such as abnormal nerve fiber projection that causes defects in neuronal migration that interrupts visual pathways and creates reduced visual acuity in the range of 20/60 to 20/400. This vision acuity is dependent upon the amount of pigmentation in the eye.  Acuity is usually better in individuals with greater amounts of pigment. Aside from decreased pigment in the iris and retina, optic changes include decreased visual acuity, misrouting of the optic nerves at the chiasm, and nystagmus.OCA1 is one of the more extreme types of albinism where the iris is translucent and the eye appears pink or red in ambient light and have white skin with slight to no pigmentation when other types may have residual pigmentation.  OCA1 is caused by mutations in the TYR gene, where there is a complete lack of tyrosinase activity.

Genetics
The tyrosinase (TYR) gene is located on chromosome 11q14. This protein coding gene produces tyrosinase, an enzyme which catalyzes a total of three steps in the conversion of tyrosine to the end product, melanin. This enzyme and conversion process takes place within melanocytes, which are specialized cells for melanin production. Melanin is a large group of molecules that give skin, eyes, and hair their respective colors. It is also partially responsible for vision, as it protects the light sensitive portion of the eye, the retina, through absorbing light. OCA Type 1A is an autosomal recessive condition, meaning there is a homozygous or compound heterozygous mutation related to the TYR gene. There are many different types of albinism, differing due to the effects of various mutations. Oculocutaneous albinism type IA is the most severe type of albinism, as it is characterized by no melanin production. Other types of albinism have limited melanin production. Because type IA Albinism has no functioning copies of the gene, it is the most severe type of albinism. The mutations on this gene lead to a complete lack of tyrosinase activity as the inactive enzyme is produced. An inactive enzyme can be caused by a missense or nonsense mutation. Due to the lack of enzymes needed to catalyze the production of melanin, patients do not have melanin protecting them from the sun, resulting in sensitive eyes, skin, and other symptoms mentioned in the signs and symptoms of OCA1A. The different forms of albinism and range of severity is dependent upon the level of melanin production, which depends on the level of tyrosinase activity.

Diagnosis
Because albinism is autosomal recessive, prenatal genetic screening and genetic counseling can be performed to diagnose OCA early on. When pathogenic variants are known to be present in an affected family, carrier testing can also be conducted. The level of expression can be variable depending on the pigmentation background, so phenotypically, OCA can be expressed on a spectrum. OCA is heterogenous, with OCA1 being caused by a mutation in the TYR gene. The separate subdivisions are categorized by the genes that they effect. The seven types are not evenly distributed amongst ethnic groups with OCA1 being the subtype most prominent in Caucasians - "accounting for approximately 50% of cases worldwide."Previously, diagnosis was done from observation of hypopigmentation which is obvious at birth, but this is now insufficient early on to distinguish between the seven major types of OCA.Prenatal testing has been achieved through fetal skin biopsy followed by subsequent histologic and electron microscope examination for melanin levels. Clinical findings have established that molecular genetic testing of TYR, the gene encoding tyrosinase, can distinguish between 1A and 1B because the phenotypes can be identical during the first year of life. OCA1A results in complete loss of tyrosinase enzyme activity. Individuals with 1B will experience increased pigmentation with age because they have a very low level of melanin production that can increase. The histological approach for prenatal diagnosis is useful for all families at risk for OCA1 whereas the molecular genetic test is only helpful when at least one mutation is known.

Management
There is currently no treatment for this disease. The extremely hypopigmented skin that is characteristic in OCA1 particularly leads to risk of skin damage and non-melanotic skin cancers due to increased sensitivity to UV rays. In OCA1B, because there is some presence of melanin, it grows with age and pigmentation can increase; the same cannot be said for OCA1A. Individuals affected by OCA1A should be attentive to the amount of sun exposure they experience and wear proper protection such as clothing that covers the skin </s>