<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 Phakomatosis and can you explain it in depth? [/INST] Phakomatoses, also known neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.Many phakomatoses are caused by mutations which alter functioning of the RAS–mitogen-activated protein kinase (MAPK) pathway that regulates cellular growth, differentiation, proliferation and death. This results in a tendency for individuals with these mutations to develop various types of benign or malignant tumors depending on the particular mutation. The presence of these tumors may result in functional and/or cosmetic problems depending on their type and location.

History
The term phakomatosis originated in 1923, when the Dutch ophthalmologist van der Hoeve used the term phakoma to refer to a "mother spot" or birthmark, a physical characteristic common to patients with tuberous sclerosis and neurofibromatosis that he examined. The term phakomatoses was derived from phakos, the Greek term for birthmark. He originally used the phrase to describe two diseases: neurofibromatosis and tuberous sclerosis. This term later became imprecise when van der Hoeve also used it to include those with Sturge-Weber syndrome as they do not have similar lesions on the skin. In addition, the term phakomatosis makes no reference to the central nervous system involvement. The term neurocutaneous syndrome was subsequently defined by the Russian-American neurologist Paul Ivan Yakovlev and psychiatrist Riley H. Guthrie and it is currently more commonly used.The first clinical description was made in “Monstrorum Historia” by an Italian physician and naturalist named Ulisse Aldrovandi who described a patient with probable neurofibromatosis type I in 1592. He described a short man with a large tumor which was likely a plexiform neurofibroma. However, there are artistic or descriptive representations which have been speculated to depict individuals with phakomatoses as far back as the Hellenistic period and ancient Egypt.Over time, the number of neurocutaneous syndromes have increased and there are several dozen that have been characterized.

Types
There are a large number of neurocutaneous syndromes that exceed the scope of this article. Therefore, characteristics of a few of the more common types are summarized.

Neurofibromatosis Type I (von Recklinghausen disease)
Neurofibromatosis type 1 is the most common phakomatosis and it affects approximately 1 in 2500-3000 live births. It is a genetic disorder due to a germline mutation in the NF1 gene. This gene encodes a protein called neurofibromin that is involved in controlling cellular growth. Malfunction of the gene results in multisystem manifestations involving the skin, central nervous system, peripheral nervous system, eyes and musculoskeletal system. The condition is inherited in an autosomal dominant manner. However, approximately one-half of patients with this condition have no family history and the mutation occurs spontaneously. In most instances, neurofibromatosis type 1 can be diagnosed clinically according to consensus criteria and genetic testing is only used in atypical presentations or for family planning decisions.Café au lait spots are one of the most characteristic features of neurofibromatosis type 1. They are hyperpigmented lesions of the skin that increase in number and size during the first years of life. They are present in almost all patients but do not have malignant potential. Freckling in the axillary and inguinal regions are another common presenting feature seen in as many as 90% of patients during childhood. Lisch nodules (benign hamartomas of the iris) are seen in almost all patients but they do not cause any visual or ocular impairment.
Neurofibromas are benign nerve sheath tumors that occur in peripheral nerves. These typically develop during the teenage years. Neurofibromas do not become malignant but can cause cosmetic concerns as well as local pruritus. When present in the spine they can affect nerve roots and result in both motor and sensory defects. Surgery may be required in some cases. On the contrary, plexiform neurofibromas arise from multiple nerve fascicles and malignant transformation occurs in approximately 10% of cases. They may result in significant morbidity as they may cause organ compression, vascular occlusions, bone destruction, pain and cosmetic issues. Plexiform neurofibromas are seen in 30-50% of patients.Optic pathway gliomas are seen in 15-20% of patients with neurofibromatosis type 1. They most often arise during childhood. They often do not cause additional morbidity but may in up to one-half of patients. Neurocognitive impairment, attention-deficit hyperactivity disorder,  autism spectrum disorder and behavioral disorders are also commonly seen in patients with neurofibromatosis type 1. Epilepsy is seen in 4-7% of patients.Musculoskeletal system manifestations can develop in patients with neurofibromatosis type 1. Common findings include sphenoid wing dysplasia, osteopenia, osteoporosis, anterior chest wall deformities as well as scoliosis. Patients are at a much greater risk for fractures than the general population.Vascular abnormalities are also frequently encountered in patients with neurofibromatosis type 1. These may include renal artery stenosis, pulmonary artery stenosis, cerebral artery stenosis and aneurysms. Complications may include myocardial infarction and stroke.
Relative to the general population the risk for certain types of cancer is increased significantly. For instance, the risk for brain tumors and breast cancer is increased by 5 times.

Neurofibromatosis Type II
Neurofibromatosis type 2 is an autosomal dominant condition that affects approximately 1 in 35,000-40,000 people. It is caused by mutations in the NF2 gene on chromosome 22 which has a high penetrance though most patients do not present with symptoms until adulthood. Approximately half of patients have de novo mutations and as many as 59.7% are mosaic. Patients who present in childhood tend to have a more severe phenotype.Bilateral vestibular schwannomas are the most characteristic finding and in the vast majority of cases are benign. However, they are responsible for significant morbidity and are responsible for the most common presenting symptom of hearing loss in adults. They can also less commonly present with dizziness or balance impairment. It is estimated that schwannomas occur in over 90% of patients.Meningiomas are the second most common tumor in NF2. Approximately half of patients have an intracranial meningioma and extramedullary spinal meningiomas occur in one-fifth of patients. Relative to the general population, meningiomas in NF2 tend to occur at a younger age, are more likely to be multiple and are associated with increased mortality.Spinal cord ependymomas occur in 20-50% of patients but they are asymptomatic in the majority of cases. In cases that they are symptomatic the specific presentation will depend upon where they are located. Potential symptoms include back pain, weakness and sensory changes.
Peripheral neuropathy eventually occurs in most patients with NF2. In some cases, a mononeuropathy affecting the facial nerve can occur as the first presenting symptom of NF2. Other potential manifestations include focal amyotrophy, mononeuropathy multiplex or a severe generalized polyneuropathy in 3-5% of patients.Ophthalmologic manifestations are also common with 60-80% of patients developing cataracts. Optic nerve meningiomas and retinal hamartomas can result in vision loss.
Approximately, 70% of patients will have cutaneous manifestations but only 10% have more than 10 lesions. The majority of skin lesions are schwannomas but neurofibromas can also occur.

Tuberous sclerosis (Bourneville syndrome)
Tuberous sclerosis complex (TSC) is a multisystemic disorder due to autosomal dominant mutations in either TSC1 or TSC2 which results in the impaired inhibition of the mechanistic target of rapamycin (mTOR) signaling pathway. This leads to impaired regulation of cellular proliferation, survival, homeostasis, migration and other critical functions. The most typically affected organs include the brain, skin, kidney, heart and lung. The incidence of TSC is approximately 1 in 6,000 live births. Similar to other neurocutaneous disorders there is variable penetrance and expressivity. TSC1 mutations tend to have a less severe phenotype and are more likely to be familial. A major development in the treatment of this condition occurred in 2010s when the FDA approved mTOR inhibitors for the treatment of several manifestations of TSC.
Epilepsy is among the most common manifestations of TSC and it occurs 80-90% of patients. It usually presents during the first few years of life and is medically refractory in two-thirds of patients. Approximately, one-third of patients have infantile spasms. There are several types of brain lesions that can be found in TSC including subependymal nodules (SENs), cortical tubers and subependymal giant cell astrocytomas (SEGAs). SENs and cortical tubers occur in approximately 80% and 90% of patients, respectively. SEGAs occur in 10-15% of patients and are a major potential cause of morbidity and potentially mortality. They tend to present during the first 20 years of life. TSC-Associated Neuropsychiatric Disorder (TAND) refers to the behavioral, intellectual and psychiatric manifestations of TSC including autism spectrum disorder, attention deficit hyperactivity disorder, intellectual disability, depression and anxiety. Approximately 90% of patients will have at least 1 symptom of TAND.Lymphangioleiomyomatosis (LAM) occurs in the lung and may result in pneumothorax, cystic lung destruction and pleural effusions. Symptoms which occur as a result may include fatigue, chest pain and shortness of breath. It occurs in approximately 30-40% of women with TSC, up to 80% by the age of 40, and it is much less common in men.Renal angiomyolipomas and cysts are the most common manifestations of TSC involving the kidney. Renal disease is among the most common causes of early death in TSC. One study found that renal lesions were present in 80% of patients by a mean age of 10.5 years. Renal cell carcinoma occurs in 2-5% of patients with TSC at a mean age of 28–30 years.Cardiac rhabdomyomas are benign hamartomas and are the most common cardiac manifestations of TSC. It is found in approximately two-third of newborns with TSC. Most of the time they do not cause symptoms and spontaneously regress. In a minority of cases, they may result in heart failure, arrhythmias, and murmurs.Dermatological manifestations occur in almost all patients and may include facial angiofibromas, confetti skin lesions, ungual fibromas, shagreen patches, hypomelanotic macules and fibrous cephalic plaques.[13] None of these tend to result in significant complications however facial angiofibromas may cause significant cosmetic concerns.

Sturge–Weber Syndrome
Sturge-Weber syndrome occurs in approximately 1 in 20,000-50,000 live births and is caused by a somatic activating mutation in GNAQ. Normally, GNAQ is involved in cell growth signal transmission. It is classically characterized by a facial port-wine stain in the ophthalmic division of the trigeminal nerve, glaucoma and leptomeningeal angioma. However, the clinical presentation can vary significantly depending on the timing of the somatic mutation ranging from an isolated port-wine stain to complete Sturge-Weber syndrome.The characteristic port-wine stain, also called nevus flammeus, is caused by a capillary or venular malformation. It is present from birth while the extent and size of it is associated with the risk of leptomeningeal and ophthalmologic involvement. The greatest risk is associated with port-wine stains that appear to involve the entire V1 distribution followed by partial V1 involvement. There is ontroversy as to whether or not the distribution of port-wine stains truly follows trigeminal nerve branches per se. Port-wine stains are most often unilateral but can be bilateral. Typically, brain and eye involvement occur on the same side as the port-wine stain. Over time, port-wine stains can develop soft tissue or bone hypertrophy, proliferative nodules, and progressive ectasia which can lead to significant disfigurement.The two most common ocular manifestations include glaucoma and choroidal hemagioma. Glaucoma is estimated to occur in 30-70% with a bimodal peak occurring at the time of birth in 60% and between childhood and adolescence in 40%. The most frequent form of glaucoma is open-angle however closed-angle glaucoma may also occur. Congenital onset glaucoma is associated with other changes of the eye including megalocornea and buphthalmos. The choroidal hemangioma occurs in 40-50% of patients. They are usually asymptomatic but they may become thickened overtime and may be associated with an increased risk for glaucoma.Seizures typically develop within the first two years of life and occur in 75-100% of patients. Onset of seizures occur in 95% by the age of 5 years. Status epilepticus occurs in approximately 50% of patients. Approximately 25% of patients develop drug-resistant epilepsy. In these cases, surgery may be pursued with the two main approaches being lesionectomy and hemispherectomy.Neurological impairment can accrue gradually over time and may occur in the context of stroke-like episodes which may be triggered by seizures or head injuries. Intellectual disability occurs in approximately one-half of patients. In addition, patients with Sturge-Weber syndrome have an increased prevalence of depression, endocrinological abnormalities, headaches with migraine-like features, ADHD and behavioral problems. Cortically mediated visual field defects and hemiparesis occur in approximately one-third and one-half of patients, respectively.

Von Hippel–Lindau syndrome (hemangiomatosis)
Von Hippel-Lindau (VHL) disease is an autosomal dominant condition caused by mutations of the VHL gene. Approximately one-in-five cases are de novo rather than familial and it has nearly complete penetrance. VHL occurs in an estimated 1 in 36,000-45,000 live births. VHL normally functions as a tumor suppressor gene and thus when not functioning normally results in the development of benign and malignant tumors as well as cysts. Some of the most common manifestations include hemangioblastomas in the retina and central nervous system, clear cell renal cell carcinomas, pheochromocytomas, endolymphatic sac tumors and pancreatic neuroendocrine tumors. Life expectancy is reduced for individuals with this condition and one study found a median age of death at 52 years.CNS hemangioblastomas are the cardinal feature of VHL and occur in as many as 80% of cases. The most common locations include the cerebellum, spinal cord and brainstem. These tumors are benign however they may cause significant morbidity as well as mortality due to mass effect. Tumor growth rates can be highly variable. Treatment options include resection and radiation.Retinal hemangioblastomas occur in approximately half of patients and are often the first presenting manifestation of VHL. One longitudinal study that followed patients for a mean period of 7.3 years found that in individuals with unilateral disease 100% had bilateral involvement by the age of 56 years. Blindness or severe visual impairment occurs in less than 10% of patients. Laser photocoagulation and cryotherapy are the most common surgical treatments.Renal cell carcinoma is a major cause of death in patients with VHL and it occurs in 70% of patients. Lesions larger than 3 cm are associated with a risk of metastasis and thus present a recommended threshold for resection. Nephron sparing surgery allows for preservation of kidney function and 10-year survival rates up to 81%.Additional manifestations of VHL may include pheochromocytomas in as many as 16% of patients with VHL. They are most often unilateral but can be bilateral or multifocal. Approximately 5% are malignant.Pancreatic involvement occurs in 77% of patients with VHL. Asymptomatic cysts consist of the majority of cases. Neuroendocrine tumors occur in approximately 15% of cases. Less than 10% with neuroendocrine tumors will develop metastases.

Genetics
The majority of neurocutaneous syndromes are single-gene disorders however they are caused by different genes and have different inheritance patterns. For instance, neurofibromatosis 1 and 2, Tuberous sclerosis complex, Von Hippel-Lindau syndrome and Legius syndrome are inherited in an autosomal dominant manner. Incontinentia pigmenti is X-linked dominant and Sturge-Weber syndrome is sporadic. Some neurocutaneous disorders are found exclusively as mosaics such as Sturge-Weber syndrome and Proteus syndrome. Others such as neurofibromatosis type 1 and 2 as well as tuberous sclerosis complex can potentially be mosaics but may not be. Mosaicism may be suspected in cases with either a mild or incomplete presentation of a neurocutaneous disorder. A definitive diagnosis is most likely to be obtained if testing of affected tissues is possible.Patients and families of those affected by neurocutaneous disorders often benefit from genetic counseling. It may provide an opportunity to provide a better understanding of the potential risk to future offspring as well as to improve coping with the various implications of the condition. If desired, a prenatal diagnosis can be obtained by either amniocentesis or chorionic villus sampling. Another potential option is preimplantation genetic diagnosis where an embryo that does not have the mutation can be selectively implanted into the mother.

Diagnosis
Many neurocutaneous syndromes have established diagnostic criteria which may facilitate a diagnosis without necessarily requiring genetic testing. For instance, neurofibromatosis types 1 and 2, tuberous sclerosis complex and incontinentia pigmenti have formal diagnostic criteria. Whereas other syndromes such as Noonan syndrome with multiple lentigines, for instance, do not. In cases where conditions that do not have diagnostic criteria are suspected, genetic testing is more likely to be necessary. Diagnostic criteria are not perfect as sensitivity and specificity is not 100%. Similarly, genetic testing can produce false negatives. For example, genetic testing is positive in only 75-90% of cases of tuberous sclerosis complex. Thus, clinicians must apply clinical judgement when evaluating an individual suspected to have a neurocutaneous syndrome.

Treatment
The treatment of each neurocutaneous syndrome is unique </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 Autosomal dominant nocturnal frontal lobe epilepsy and can you explain it in depth? [/INST] Autosomal dominant nocturnal frontal lobe epilepsy is an epileptic disorder that causes frequent violent seizures during sleep. These seizures often involve complex motor movements, such as hand clenching, arm raising/lowering, and knee bending. Vocalizations such as shouting, moaning, or crying are also common. ADNFLE is often misdiagnosed as nightmares. Attacks often occur in clusters and typically first manifest in childhood. There are four known loci for ADNFLE, three with known causative genes. These genes, CHRNA4, CHRNB2, and CHRNA2, encode various nicotinic acetylcholine receptor α and β subunits.

Signs and symptoms
ADNFLE is a partial epilepsy disorder characterized by brief violent seizures during sleep. Seizures are complex, consisting of arm and leg movements, fist clenching, and vocalizations such as yelling and moaning. These seizures often occur in clusters and can first manifest in childhood. Diagnosis is often initially incorrectly made as nightmares, night terrors, parasomnias and various psychiatric disorders.

Causes
While not well understood, it is believed that malfunction in thalamocortical loops plays a vital role in ADNFLE. The reasons for this belief are threefold. Firstly, thalamocortical loops are important in sleep and the frontal cortex is the origin of ADNFLE seizures. Secondly, both the thalamus and cortex receive cholinergic inputs and acetylcholine receptor subunits comprise the three known causative genes for ADNFLE. Thirdly, K-complex are almost invariably present at the start of seizures.
It is thought that epilepsy is caused because these receptor subunits are expressed presynaptically by neurons that release the inhibitory transmitter GABA. Therefore, the mutation in the α4 subunit could lead to reduced GABA release, causing hyperexcitability.

Pathophysiology
CHRNA4
The first mutation associated with ADNFLE is a serine to phenylalanine transition at position 248 (S248F), located in the second transmembrane spanning region of the gene encoding a nicotinic acetylcholine receptor α4 subunit. Using the numbering based on the human CHRNA4 protein, this mutation is called S280F. Receptors containing this mutant subunit are functional, but desensitize at a much faster pace compared to wild-type only receptors. These mutant containing receptors also recover from desensitization at a much slower rate than wild-type only receptors. These mutant receptors also have a decreased single channel conductance than wild-type and have a lower affinity for acetylcholine.  Also importantly, this mutation along with the others in CHRNA4 produce receptors less sensitive to calcium.The second discovered ADNFLE mutation was also in CHRNA4. This mutation, L259_I260insL, is caused by the insertion of three nucleotides (GCT) between a stretch of leucine amino acids and an isoleucine. As with the S248F mutation, the L259_I260insL mutation is located in the second transmembrane spanning region. Electrophysiological experiments have shown that this mutant is tenfold more sensitive to acetylcholine than wild-type. Calcium permeability, however is notably decreased in mutant compared to wild-type containing receptors. Furthermore, this mutant shows slowed desensitization compared to both wild-type and S248F mutant receptors.Also located in the second transmembrane spanning region, the S252L mutation has also been associated with ADNFLE. This mutant displays increased affinity for acetylcholine faster desensitization compared to wild-type receptors.The most recently discovered mutation in CHRNA4 associated with ADNFLE is T265M, again located in the second transmembrane spanning segment </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 Cephalic presentation and can you explain it in depth? [/INST] A cephalic presentation or head presentation or head-first presentation is a situation at childbirth where the fetus is in a longitudinal lie and  the  head enters the pelvis first;  the most common form of cephalic presentation is the vertex presentation, where the occiput is the leading part (the part that first enters the birth canal). All other presentations are abnormal (malpresentations) and are either more difficult to deliver or not deliverable by natural means.

Engagement
The movement of the fetus to cephalic presentation is called head engagement. It occurs in the third trimester. In head engagement, the fetal head descends into the pelvic cavity so that only a small part (or none) of it can be felt abdominally. The perineum and cervix are further flattened and the head may be felt vaginally. Head engagement is known colloquially as the baby drop, and in natural medicine as the lightening because of the release of pressure on the upper abdomen and renewed ease in breathing. However, it severely reduces bladder capacity resulting in a need to void more frequently.

Classification
In the vertex presentation the head is flexed and the occiput leads the way. This is the most common configuration and seen at term in 95% of singletons. If the head is extended, the face becomes the leading part. Face presentations account for less than 1% of presentations at term. In the sinicipital presentation the large fontanelle is the presenting part; with further labor the head will either flex or extend more so that in the end this presentation leads to a vertex or face presentation. In the brow presentation the head is slightly extended, but less than in the face presentation. The chin presentation is a variant of the face presentation with maximum extension of the head.
Non-cephalic presentations are the breech presentation (3.5%) and the shoulder presentation (0.5%).

Vertex presentation
The vertex is the area of the vault bounded anteriorly by the anterior fontanelle and the coronal suture, posteriorly by the posterior fontanelle and the lambdoid suture and laterally by 2 lines passing through the parietal eminences.
In the vertex presentation the occiput typically is anterior and thus in an optimal position to negotiate the pelvic curve by extending the head. In an occiput posterior position, labor becomes prolonged, and more operative interventions are deemed necessary. The prevalence of the persistent occiput posterior is given as 4.7%.The vertex presentations are further classified according to the position of the occiput, both right, left, or transverse and anterior or posterior:

Left Occipito-Anterior (LOA), Left Occipito-Posterior (LOP), Left Occipito-Transverse (LOT)
Right Occipito-Anterior (ROA), Right Occipito-Posterior (ROP), Right Occipito-Transverse (ROT)The Occipito-Anterior position is ideal for birth; it means that the baby is lined up so as to fit through the pelvis as easily as possible. The baby is head down, facing the spine, with its back anterior. In this position, the babys chin is tucked onto its chest, so that the smallest part of its head will be applied to the cervix first. The position is usually "Left Occiput Anterior", or LOA. Occasionally, the baby may be "Right Occiput Anterior", or ROA.

Face presentation
Factors that predispose to face presentation are prematurity, macrosomia, anencephaly and other malformations, cephalopelvic disproportion, and polyhydramnios. In an uncomplicated face presentation duration of labor is not altered. Perinatal losses with face presentation occur with traumatic version and extraction and midforceps procedures Duff indicates that the prevalence of face presentations is about 1/500–600., while Benedetti et al. found it to be 1/1,250 term deliveries.Face presentations are classified according to the position of the chin (mentum):

Left Mento-Anterior (LMA), Left Mento-Posterior (LMP), Left Mento-Transverse (LMT)
Right Mento-Anterior (RMA), Right Mento-Posterior (RMP), Right Mento-Transverse (RMT)

Brow presentation
While some consider the brow presentation as an intermediate stage towards the face presentation, others disagree. Thus Bhal et al. indicated that both conditions are about equally common (1/994 face and 1/755 brow positions), and that prematurity was more common with face while postmaturity was more common with brow positions.

Oskie presentation
The Oskie presentation is similar to the Occipito-Anterior position, where the baby is head down, facing the spine, with back on the ventral side of the uterus; however, in this position, while the torso is aligned with the mothers longitudinal axis, the legs of the fetus are extended straight along the frontal axis of the mother, as if the baby is creating a right angle with its body. For the Oskie position to occur the babys head must be far down the pelvis in order to allow room for leg extension, typically the arms are bent, tucked against the babys body </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 Purtschers retinopathy and can you explain it in depth? [/INST] Purtschers retinopathy is a disease where part of the eye (retina) is damaged.  Usually associated with severe head injuries, it may also occur with other types of trauma, such as long bone fractures, or with several non-traumatic systemic diseases.  However, the exact cause of the disease is not well understood </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 Megalopapilla 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 Atrophic vaginitis and can you explain it in depth? [/INST] Atrophic vaginitis is inflammation of the vagina as a result of tissue thinning due to not enough estrogen. Symptoms may include pain with sex, vaginal itchiness or dryness, and an urge to urinate or burning with urination. It generally does not resolve without ongoing treatment. Complications may include urinary tract infections.The lack of estrogen typically occurs following menopause. Other causes may include when breastfeeding or as a result of specific medications. Risk factors include smoking. Diagnosis is typically based on symptoms.Treatment is generally with estrogen cream applied to the vagina. Other measures that may help include vaginal lubricants. It is recommended that soaps and other irritants are avoided. About half of postmenopausal women are affected. Many however are not being treated. Women often report reduced enjoyment in sex as well as life generally.

Signs and symptoms
After menopause the vaginal epithelium changes and becomes a few layers thick. Many of the signs and symptoms that accompany menopause occur in atrophic vaginitis. Genitourinary symptoms include

dryness
pain
itching
burning
soreness
pressure
white discharge
malodorous discharge due to infection
painful sexual intercourse
bleeding after intercourse
painful urination
blood in the urine
increased urinary frequency
incontinence
increased susceptibility to infections
decreased vaginal lubrication
urinary tract infections
painful urination
difficulty sitting
difficulty wiping

Diagnosis
Since women can have signs and symptoms that could be attributed to other causes, diagnosis is based upon the symptoms that cannot be better accounted for by another diagnosis. Lab tests usually do not provide information that will aid in diagnosing. A visual exam is useful. The observations of the following may indicate lower estrogen levels: little pubic hair, loss of the labial fat pad, thinning and resorption of the labia minora, and the narrowing of the vaginal opening. An internal exam will reveal the presence of low vaginal muscle tone, the lining of the vagina appears smooth, shiny, pale with loss of folds. The cervical fornices may have disappeared and the cervix can appear flush with the top of the vagina. Inflammation is apparent when the vaginal lining bleeds easily and appears swollen. The vaginal pH will be measured at 4.5 and higher.

Treatment
Symptoms of genitourinary syndrome of menopause (GSM) will unlikely be resolved without treatment. Women may have many or a few symptoms so treatment is provided that best suits each woman. If other health problems are also present, these can be taken into account when determining the best course of treatment. For those who have symptoms related to sexual activities, a lubricant may be sufficient. If both urinary and genital symptoms exist, local, low-dose estrogen therapy can be effective. Those women who are survivors of hormone-sensitive cancer may need to be treated more cautiously. Some women can have symptoms that are widespread and may be at risk for osteoporosis. Estrogen and adjuvants may be best.Topical treatment with estrogen is effective when the symptoms are severe and relieves the disruption in pH to restore the microbiome of the vagina. When symptoms include those related to the urinary system, systematic treatment can be used. Recommendations for the use of the lowest effective dose for the shortest duration  help to prevent adverse endometrial effects.Some treatments have been developed more recently. These include selective estrogen receptor modulators, vaginal dehydroepiandrosterone, and laser therapy. Other treatments are available without a prescription such as vaginal lubricants and moisturizers. Vaginal dilators may be helpful. Since GSM may also cause urinary problems related to pelvic floor dysfunction, a woman may benefit from pelvic floor strengthening exercises. Women and their partners have reported that estrogen therapy resulted in less painful sex, more satisfaction with sex, and an improvement in their sex life.

Epidemiology
Up to 50% of postmenopausal women have at least some degree of vaginal atrophy. It is likely to be underdiagnosed and undertreated.

Terminology
Vulvovaginal atrophy, and atrophic vaginitis have been the preferred terms for this condition and cluster of symptoms until recently. These terms are now regarded as inaccurate in describing changes to the entire genitourinary system occurring after menopause </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 Cystitis glandularis and can you explain it in depth? [/INST] Cystitis glandularis is the transformation of mucosal cells lining the urinary bladder.  They undergo glandular metaplasia, a process in which irritated tissues take on a different form, in this case that of a gland. The main importance is in the findings of test results, in this case histopathology.  They must distinguish a benign metaplastic change from the cancerous condition urothelial cell carcinoma </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 Leukocoria 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 Annular pancreas 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 IgG4-related disease and can you explain it in depth? [/INST] IgG4-related disease (IgG4-RD), formerly known as IgG4-related systemic disease, is a chronic inflammatory condition characterized by tissue infiltration with lymphocytes and IgG4-secreting plasma cells, various degrees of fibrosis (scarring) and a usually prompt response to oral steroids. In approximately 51–70% of people with this disease, serum IgG4 concentrations are elevated during an acute phase.It is a relapsing-remitting disease associated with a tendency to mass forming, tissue-destructive lesions in multiple sites, with a characteristic histopathological appearance in whichever site is involved. Inflammation and the deposition of connective tissue in affected anatomical sites can lead to organ dysfunction, organ failure, or even death if not treated.Early detection is important to avoid organ damage and potentially serious complications. Treatment is recommended in all symptomatic cases of IgG4-RD and also in asymptomatic IgG4-RD involving certain anatomical sites.

Signs and symptoms
IgG4-related disease has been described as an indolent condition. Although possibly based on opinion rather than on objective assessments, symptoms, if any, are commonly described as mild in the medical literature.
This can be in spite of considerable underlying organ destruction. People are often described as being generally well at the time of diagnosis, although some may give a history of weight loss.
Pain is generally not a feature of inflammation. However, it may occur as a secondary effect, for example, due to either obstruction or compression.
Often diagnosis is made due to the presence of painless swellings or mass lesions, or due to complications of masses, e.g. jaundice due to involvement of the pancreas, biliary tree or liver. Symptoms are commonly attributed to other conditions and other diagnoses may have been made years before diagnosis, e.g. urinary symptoms in men attributed to common prostate conditions. Lesions may also be detected incidentally on radiological images, but can be easily misdiagnosed as malignancies.Reported cases do include some significant symptoms or findings however:

Individual organ manifestations
IgG4-RD can involve one or multiple sites in the body. With multiorgan involvement, the sites involved can be affected at the same time (synchronously) or at different unrelated periods (metachronously).
Several different diseases that have been known for many years are now considered to be manifestations of IgG4-RD. These include: type 1 autoimmune pancreatitis, interstitial nephritis, Riedels thyroiditis, Mikuliczs disease, Küttners tumor, inflammatory pseudotumors (in various sites of the body), mediastinal fibrosis and some cases of retroperitoneal fibrosis.
This is not a complete list, as IgG4-RD can involve any site in the body.
Other affected sites, confirmed on histology to be manifestations of IgG4-RD, include:
heart; hard palate, esophagus, stomach, small intestine, rectum, adrenal gland, ovary, uterus, ureter, bladder, urachus, and synovium. Approximately 1/3 of cases exhibit increases in blood eosinophil counts, either eosinophilia or hypereosinophilia.Radiologic evidence suggestive of involvement of the superior vena cava and seminal vesicle has been reported in confirmed cases of IgG4-RD.

Histology
Whatever area of the body is involved, the hallmark histopathological features of IgG4-RD are:
A dense lymphoplasmacytic (lymphocytes and plasma cells) infiltrate rich in IgG4-positive plasma cells.
IgG4 immunostaining needs to be specifically requested and performed in order to detect IgG4-positive plasma cells.
Fibrosis, arranged at least focally in a "storiform" pattern.
"Storiform" is commonly referred to as meaning having a cartwheel pattern, but its literal meaning is the appearance of a woven mat [Latin: storea] (of rush or straw).
Obliterative phlebitis.
The venous channels are obliterated by a dense lymphoplasmacytic infiltrate, within both the venous walls and the lumen.Other histopathological features associated with IgG4-RD are:

Phlebitis without obliteration of the lumen.
Tissue has increased numbers of eosinophils.

Submandibular gland research
In an article from 1977, histological research into 349 cases of Küttners tumor (now known as IgG4-related sialadenitis) identified four distinct stages of the fibroinflammatory process:
Stage 1: Focal periductal (around the salivary ducts) infiltration of lymphocytes
Stage 2: Diffuse infiltration of lymphocytes and severe periductal fibrosis (scarring around the salivary ducts)
Stage 3: Prominent infiltration of lymphocytes, atrophy of parenchyma (i.e. loss of functional areas due to shrinkage), and periductal sclerosis (scarring resulting in hardening around the salivary ducts)
Stage 4: Marked loss of and sclerosis (hardening) of the parenchyma (functional area) - similar to the process involved in cirrhosis where there is shrinkage and loss of functional areas of the liverThis may reflect the inflammatory process and development of fibrosis that occurs in other organs involved in IgG4-RD.

Diagnosis
Diagnosis requires tissue biopsy of an affected organ with characteristic histological findings. Serum immunoglobulin G4 is often elevated but this is not always the case.

Treatment
The goal of treatment is the induction and maintenance of remission so as to prevent progression of fibrosis and organ destruction in affected organ(s).
An international panel of experts have developed recommendations for the management of IgG4-RD. They concluded that in all cases of symptomatic, active IgG4-RD that treatment is required. Some cases with asymptomatic IgG4-RD also require treatment, as some organs tend to not cause symptoms until the late stages of disease. Urgent treatment is advised with certain organ manifestations, such as aortitis, retroperitoneal fibrosis, proximal biliary strictures, tubulointerstitial nephritis, pachymeningitis, pancreatic enlargement and pericarditis.

Induction of remission
In untreated patients with active disease, the recommended first-line agent for induction of remission is glucocorticoids unless contraindications exist. Glucocorticoids characteristically result in a rapid and often dramatic improvement in clinical features and often a resolution of radiographic features. However, where advanced fibrotic lesions have resulted in irreversible damage, the response to glucocorticoids and other current treatment options may be poor or even absent.
Although not validated yet in clinical trials, the common induction regime is prednisolone 30–40 mg per day for 2–4 weeks, then gradually tapered over 3 to 6 months. Recurrences during or after tapering of glucocorticoids are frequent, however. Steroid-sparing immunosuppressive agents might be considered, depending on local availability of these drugs, for use in combination with glucocorticoids from the start of treatment in order to reduce the side-effects of prolonged glucocorticoid usage </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 Metabolic bone disease 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 Chloroquine retinopathy 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 Placentitis and can you explain it in depth? [/INST] Placentitis is an inflammation of the placenta. The main forms of placentitis are:

Villitis, inflammation of chorionic villi.
Intervillositis, inflammation of the intervillous space.It may be caused by vertically transmitted infections.
Because of the close proximity, placentitis often occurs simultaneously as funisitis (inflammation of the umbilical cord) and chorioamnionitis (inflammation of the fetal membranes).
Chronic lymphocytic placental inflammation occurs in 5% to 15% of pregnancies, and are generally not associated with documented infection.

Villitis of unknown etiology
Villitis of unknown etiology (VUE), also known as chronic villitis, is a placental injury </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 Scrub typhus and can you explain it in depth? [/INST] Scrub typhus or bush typhus  is a form of typhus caused by the intracellular parasite Orientia tsutsugamushi, a Gram-negative α-proteobacterium of family Rickettsiaceae first isolated and identified in 1930 in Japan.Although the disease is similar in presentation to other forms of typhus, its pathogen is no longer included in genus Rickettsia with the typhus bacteria proper, but in Orientia. The disease is thus frequently classified separately from the other typhi.

Signs and symptoms
Signs and symptoms include fever, headache, muscle pain, cough, and gastrointestinal symptoms. More virulent strains of O. tsutsugamushi can cause hemorrhaging and intravascular coagulation. Morbilliform rash, eschar, splenomegaly, and lymphadenopathies are typical signs. Leukopenia and abnormal liver function tests are commonly seen in the early phase of the illness. Pneumonitis, encephalitis, and myocarditis occur in the late phase of illness. It has particularly been shown to be the most common cause of acute encephalitis syndrome in Bihar, India.

Causes
Scrub typhus is transmitted by some species of trombiculid mites ("chiggers", particularly Leptotrombidium deliense), which are found in areas of heavy scrub vegetation. The mites feed on infected rodent hosts and subsequently transmit the parasite to other rodents and humans. The bite of this mite leaves a characteristic black eschar that is useful to the doctor for making the diagnosis.Scrub typhus is endemic to a part of the world known as the tsutsugamushi triangle (after O. tsutsugamushi). This extends from northern Japan and far-eastern Russia in the north, to the territories around the Solomon Sea into northern Australia in the south, and to Pakistan and Afghanistan in the west. It may also be endemic in parts of South America.The precise incidence of the disease is unknown, as diagnostic facilities are not available in much of its large native range, which spans vast regions of equatorial jungle to the subtropics.  In rural Thailand and Laos, murine and scrub typhus account for around a quarter of all adults presenting to hospital with fever and negative blood cultures.  The incidence in Japan has fallen over the past few decades, probably due to land development driving decreasing exposure, and many prefectures report fewer than 50 cases per year.It affects females more than males in Korea, but not in Japan, which may be because sex-differentiated cultural roles have women tending garden plots more often, thus being exposed to vegetation inhabited by chiggers.
The incidence is increasing in the southern part of the Indian subcontinent and in northern areas around Darjeeling.

Diagnosis
In endemic areas, diagnosis is generally made on clinical grounds alone.  However, overshadowing of the diagnosis is quite often as the clinical symptoms overlap with other infectious diseases such as dengue fever, paratyphoid, and pyrexia of unknown origin (PUO). If the eschar can be identified, it is quite diagnostic of scrub typhus, but this can be unreliable on dark skin, and moreover, the site of eschar which is usually where the mite bites is often located in covered areas. Unless it is actively searched for, the eschar can easily be missed. History of mite bite is often absent since the bite does not inflict pain and the mites are almost too small to be seen by the naked eye. Usually, scrub typhus is often labelled as PUO in remote endemic areas, since blood culture is often negative, yet it can be treated effectively with chloramphenicol. Where doubt exists, the diagnosis may be confirmed by a laboratory test such as serology. Again, this is often unavailable in most endemic areas, since the serological test involved is not included in the routine screening tests for PUO, especially in Burma (Myanmar).The choice of laboratory test is not straightforward, and all currently available tests have their limitations. The cheapest and most easily available serological test is the Weil-Felix test, but this is notoriously unreliable.  The gold standard is indirect immunofluorescence, but the main limitation of this method is the availability of fluorescent microscopes, which are not often available in resource-poor settings where scrub typhus is endemic.  Indirect immunoperoxidase, a modification of the standard IFA method, can be used with a light microscope, and the results of these tests are comparable to those from IFA.  Rapid bedside kits have been described that produce a result within one hour, but the availability of these tests is severely limited by their cost.  Serological methods are most reliable when a four-fold rise in antibody titre is found.  If the patient is from a nonendemic area, then diagnosis can be made from a single acute serum sample.  In patients from endemic areas, this is not possible because antibodies may be found in up to 18% of healthy individuals.Other methods include culture and polymerase chain reaction, but these are not routinely available and the results do not always correlate with serological testing, and are affected by prior antibiotic treatment. The currently available diagnostic methods  have been summarised.

Treatment
Without treatment, the disease is often fatal. Since the use of antibiotics, case fatalities have decreased from 4–40% to less than 2%.The drug most commonly used is doxycycline or tetracycline, but chloramphenicol is an alternative.  Strains that are resistant to doxycycline and chloramphenicol have been reported in northern Thailand.  Rifampicin and azithromycin are alternatives. Azithromycin is an alternative in children and pregnant women with scrub typhus, and when doxycycline resistance is suspected. Ciprofloxacin cannot be used safely in pregnancy and is associated with stillbirths and miscarriage.
Combination therapy with doxycycline and rifampicin is not recommended due to possible antagonism.

Vaccine
No licensed vaccines are available.An early attempt to create a scrub typhus vaccine occurred in the United Kingdom in 1937 (with the Wellcome Foundation infecting around 300,000 cotton rats  in a classified project called "Operation Tyburn"), but the vaccine was not used.  The first known batch of scrub typhus vaccine actually used to inoculate human subjects was dispatched to India for use by Allied Land Forces, South-East Asia Command in June 1945.  By December 1945, 268,000 cc had been dispatched.  The vaccine was produced at Wellcomes laboratory at Ely Grange, Frant, Sussex.  An attempt to verify the efficacy of the vaccine by using a placebo group for comparison was vetoed by the military commanders, who objected to the experiment.Enormous antigenic variation in Orientia tsutsugamushi strains is now recognized, and immunity to one strain does not confer immunity to another </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 Ganglioglioma and can you explain it in depth? [/INST] Ganglioglioma is a rare, slow-growing primary central nervous system (CNS) tumor which most frequently occurs in the temporal lobes of children and young adults

Classification
Gangliogliomas are generally benign WHO grade I tumors; the presence of anaplastic changes in the glial component is considered to represent WHO grade III (anaplastic ganglioglioma). Criteria for WHO grade II have been suggested, but are not established. Malignant transformation of spinal ganglioglioma has been seen in only a select few cases.  Poor prognostic factors for adults with gangliogliomas include older age at diagnosis, male sex, and malignant histologic features.

Histopathology
Histologically, ganglioglioma is composed of both neoplastic glial and ganglion cells which are disorganized, variably cellular, and non-infiltrative. Occasionally, it may be challenging to differentiate ganglion cell tumors from an infiltrating glioma with entrapped neurons. The presence of neoplastic ganglion cells forming abnormal clusters, the presence of binucleation and dysmorphic neurons are helpful clues favoring ganglioglioma over glioma. The glial component of ganglioglioma includes fibrillary astrocytes with varying degrees of cellular atypia. The neoplastic neuronal components are often clustered or irregularly oriented. Fibrovascular stroma confined to the neuronal component, perivascular lymphocytic infiltrates, and small foci of calcification are common, as is immunopositivity for synaptophysin, neuron-specific enolase, and chromogranin A. Elevated Ki-67 and p53 labeling index is associated with more aggressive tumor behavior in both children and adults with gangliogliomas. The rare occurrence of malignant transformation is confined to the glial cell population, and is characterized by increased cellularity and mitotic activity, endothelial proliferation, and necrosis.

Diagnosis
Computed Tomography (CT) is generally not a recommended modality for diagnosis and evaluation of spinal cord tumors. Evaluation with Magnetic Resonance (MR) most commonly demonstrates a circumscribed solid or mixed solid and cystic mass spanning a long segment of the cord with hypointense T1 signal and hyperintense T2 signal in the solid component. Enhancement patterns are highly variable, ranging from minimal to marked, and may be solid, rim, or nodular </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 Situs ambiguus and can you explain it in depth? [/INST] Situs ambiguus is a rare congenital defect in which the major visceral organs are distributed abnormally within the chest and abdomen. Clinically heterotaxy spectrum generally refers to any defect of Left-right asymmetry and arrangement of the visceral organs; however, classical heterotaxy requires multiple organs to be affected. This does not include the congenital defect situs inversus, which results when arrangement of all the organs in the abdomen and chest are mirrored, so the positions are opposite the normal placement. Situs inversus is the mirror image of situs solitus, which is normal asymmetric distribution of the abdominothoracic visceral organs. Situs ambiguus can also be subdivided into left-isomerism and right isomerism based on the defects observed in the spleen, lungs and atria of the heart.
Individuals with situs inversus or situs solitus do not experience fatal dysfunction of their organ systems, as general anatomy and morphology of the abdominothoracic organ-vessel systems are conserved. Due to abnormal arrangement of organs in situs ambiguus, orientation across the left-right axis of the body is disrupted early in fetal development, resulting in severely flawed cardiac development and function in 50–80% of cases. They also experience complications with systemic and pulmonary blood vessels, significant morbidity, and sometimes death. All patients with situs ambiguus lack lateralization and symmetry of organs in the abdominal and thoracic cavities and are clinically considered to have a form of heterotaxy syndrome.
Heterotaxy syndrome with atrial isomerism occurs in 1 out of every 10,000 live births and is associated with approximately 3% of congenital heart disease cases. Additional estimation of incidence and prevalence of isomerism proves difficult due to failure to diagnose and underestimation of the disease by clinicians. Furthermore, right isomerism is much more easily recognized than left isomerism, contributing to the failure to diagnose.Situs ambiguus is a growing field of research with findings dating back to 1973.

Signs and symptoms
There are a variety of clinical manifestations of situs ambiguus. Acute symptoms can be due to both cardiac and non-cardiac defects. Cyanosis or blue skin coloration, primarily affecting the lips and fingernails, can indicate a systemic or circulatory issue. Poor feeding, failure to thrive, and rapid shallow breathing may also be observed due to poor circulation. Upon examination, arrhythmia and heart murmur may raise further suspicion of a cardiac abnormality. Non-cardiac symptoms include impairments of the liver and gastrointestinal tract. Biliary atresia, or inflammation and destruction of the bile ducts, may lead to jaundice. Vomiting and swelling of the abdominal region are features that suggest improper positioning of the intestines. Poor positioning of the intestine also makes it more prone to blockage, which can result in numerous chronic health issues. Asplenia and polysplenia are also possible features of heterotaxy syndrome.Due to abnormal cardiac development, patients with situs ambiguus usually develop right atrial isomerism consisting of two bilaterally paired right atria, or left atrial isomerism consisting of two bilaterally paired left atria. Clinical features and symptoms can vary dependent upon assignment of left versus right atrial isomerism. In either instance, the apex of the heart will be poorly positioned, which should alert a clinician of the likelihood of atrial isomerism. It is estimated that 5–10% of isomeric patients have mesocardia, in which the heart is positioned at the center of the thorax, 25–50% have dextrocardia, in which the apex of the heart is pointed toward the right side of the thorax, and 50–70% have levocardia, in which the apex of the heart is pointed toward the left side of the thorax.

Right atrial appendage isomerism
Right atrial appendage isomerism, also called right atrial isomerism, is a cardiac development defect in which the heart has bilateral right atria and atrial attachments in the muscle wall, as opposed to the normal right atrium and left atrium. In right atrial isomerism, the pulmonary blood oxygen tract is damaged due to right-left shunting of blood. In addition, the atrial septum which distinguishes the 2 atria is absent. These impairments, in addition to congestion in the pulmonary tract, allows deoxygenated blood to mix with oxygenated blood, contributing to cyanosis and possible respiratory distress. Poor systemic circulation also results due to improper positioning of the aorta.

Left atrial appendage isomerism
Left atrial appendage isomerism, also called left atrial isomerism, is a cardiac development defect in which the heart has two bilateral left atria and atrial appendages in the muscle wall. Left atrial isomerism can have varied clinical manifestations, including a later onset of symptoms. Heart failure is often a concern because the inferior vena cava is disrupted due to the inappropriate morphology of the left ventricle to support the vena cava.

Conductive nodes and tissues
Abnormal development of the heart results in impaired doubles of conductive nodes, as well as faulty electrical fibers throughout the ventricles. Individuals with right atrial isomerism develop two sinoatrial nodes, as they have 2 mirrored right atria, whereas those with left atrial isomerism fail to develop a sinus node at all. Thus, patients with left atrial isomerism are more likely to experience atrial fibrillation, or irregular rapid heart beat, and abnormal heart rhythm, known as atrial flutter. Development of the atrioventricular node and bundle of His largely depends on physiological looping of the ventricles. Abnormal looping of the ventricles contributes to arrhythmia and heart block in fetuses.

Bronchial tree and lungs
Isomerism of the bronchial tree is not typically damaging and presents no significant clinical complications. Pulmonary valve stenosis results in issues of blood flow to the lungs.

Abdominal organs
Abdominal organs, including the liver, stomach, intestinal tract, and spleen may be randomly arranged throughout the left-right axis of the body. Distribution of these organs largely dictates treatment, clinical outcomes, and further evaluation.
The liver is typically symmetrical across the left-right axis in patients with situs ambiguus, which is abnormal. A majority of left atrial isomeric patients have defects throughout the biliary tree, which is responsible for bile production, even when the gall bladder is functional and morphologically normal. This biliary atresia can lead to acute problems such as nutrient malabsorption, pale stools, dark urine, and abdominal swelling. If this condition continues without proper treatment, cirrhosis and liver failure become a major concern. Biliary atresia is not usually observed in patients with right atrial isomerism.Random positioning of the stomach is often one of the first signals of situs ambiguus upon examination. Malrotation of the entire intestinal tract, or improper folding and bulging of the stomach and intestines, results in bowel obstruction. This impairment leads to vomiting, abdominal distension, mucus and blood in the stool. Patients may also experience abdominal pain. Intestinal malrotation is more commonly identified in patients with right atrial isomerism than in those with left atrial isomerism.Isomeric patients often experience disruptions to splenic development during embryogenesis, resulting in an overall lack a spleen (asplenia) or development of many spleens (polysplenia). Asplenia is most often observed in patients with right atrial isomerism. Polysplenia results in 90% of patients with left atrial isomerism. Although they have many spleens, each is usually ineffective resulting in functional asplenia. Rarely, left atrial isomeric patients have a single, normal, functional spleen. Patients lacking a functional spleen are in danger of sepsis and must be monitored.

Causes
Situs ambiguus has been linked to family history of malformations  and maternal cocaine use, suggesting both genetic and environmental factors play a role. Several genes in the TGF-beta pathway, which controls left-right patterning of visceral organs across the body axis, have been indicated in sporadic and familial cases of atrial isomerism. There is also overlap between genes associated with situs ambiguus and primary ciliary dyskinesia, likely due to the important role of cilia is establishing left-right asymmetry. The planar cell polarity has an important role in positioning these cilia, and thus genes within this pathway are increasingly associated with situs ambiguus.Disrupted mitochondria function has also been recently linked to heterotaxy.

Pathophysiology
Molecular and cellular mechanism
Several genes have been identified in normal development of the right-left axis. These genes have been extensively researched. Gene mutations that lead to atrial isomerism is a growing area of research. Mutations in genes that encode proteins in the TGF-beta pathway, including NODAL, NKX2-5, and ZIC3, have been linked to tetralogy of Fallot and hypoplastic left heart syndrome. Mutations in the ZIC3 gene, which encodes a zinc finger family transcription factor, is linked to a 50% risk of atrial isomerism in families. It is also an X-linked disorder, so testing for ZIC3 mutations is highly encouraged in male births.The most prevalent and best characterized genetic associations of heterotaxy include:

Classical pathology
Cardiac looping malformations:
Fallots tetralogy
transposition of the great vessels
Ventricular and atrial septal defects.
Deranged abdominal organ asymmetry:
The stomach and spleen are prone to isolated reversal
The stomach, liver, and a single adrenal gland are occasionally found in the midline.
Organ malformations:
asplenia and polysplenia often lead to sepsis
More rarely, the head of the pancreas fails to form
Horseshoe kidneys develop, which can lead to cancer, kidney stones, and/or infection.
Malrotation errors cause volvulus and/or faulty peritoneal attachments, which completely obstruct the bowel.
Vascular abnormalities:
Interrupted inferior vena cava,
Bilateral superior or inferior venae cavae
Intrahepatic interruption of the inferior vena cava with connection to the azygos or hemiazygos veins
Aberrant portal veins.

Bronchial tree and lungs
Pathophysiology in the bronchial tree can be observed by radiography. Under normal development, the bronchial tree consists of two main bronchi that are anatomically different:

Hyparterial bronchus (below the pulmonary artery): supplies blood to the bi-lobed left lung
Eparterial bronchus (adjacent to the artery): supplies blood to the tri-lobed right lungIn situs ambiguus, there is a duplication of either the hyparterial or eparterial bronchus. These features are not associated with any significant clinical complications. Mechanisms leading to bronchial duplication are not thoroughly understood.
In pulmonary valve stenosis, there is a reduction in blood flow to the lungs due to an obstruction of the heart at the pulmonic valve. This contributes to cyanosis and pulmonary hypertension.

Diagnosis
For proper diagnosis of situs ambiguus, cardiac and non-cardiac features must be evaluated. Diagnostic criteria for atrial isomerism includes observation of symmetry of thoracic visceral organs upon echocardiogram, arrhythmia upon electrocardiogram, and chest x-ray for confirmation of the hearts location across the left-right axis. Additional radiographic and cross-sectional imaging may be obtained to evaluate both cardiac and non-cardiac manifestations of situs ambiguus. In addition, a series of gastrointestinal tests can be conducted for observation of intestinal malrotation, as well as a scan of the liver and spleen for biliary function.

Diagnostic techniques for cardiac causes
Echocardiography
Electrocardiography
Computed tomography
Magnetic resonance imaging
Cardiac catheterization and angiography
Chest x-ray

Diagnostic techniques for non-cardiac causes
Computed tomography
Magnetic resonance imaging
Splenic function analysis
Evaluation of biliary anatomy and cholangiogram
Evaluation of intestinal malrotation
Pulse oximeter

Other diagnostic features
Assessment of family history
Genetic testing

Management
Each of the symptoms of situs ambiguus must be managed with appropriate treatment dependent upon the organ system involved. Intestinal malrotation is treated surgically using the Ladd procedure. This procedure widens a fold in the peritoneum so that the intestines can be placed in non-rotated formation. It is not possible to return the bowel to a normal morphology However, 89% of patients that undergo the Ladd surgery experience a complete resolution of symptoms.
Following cholangiogram, a Kasai procedure is usually performed in cases of biliary atresia. In this surgery, a Y-shaped shunt is used to passage bile from the liver directly to the intestine. If this is unsuccessful, liver transplantation can be considered based on the overall health of the patient. The Kasai procedure is successful in approximately 80% of patients. Following the operation, patients are advised to take fat-soluble vitamins, choleretics, and anti-inflammatory medications.
Functionally asplenic patients have an elevated lifetime risk of sepsis, as they have no functional spleen for fighting infection. For this reason, asplenic patients are under constant observation for any signs of fever or infection. In the case of infection, patients are placed on controlled empiric antibiotic therapy to avoid development of antibiotic resistance. This therapy battles infection by both gram-positive and gram-negative bacteria.
Right-atrial and left-atrial isomerism and associated pulmonary issues are treated in a series of steps based on the severity of symptoms. Isomeric patients are first treated by inserting a shunt that will move incoming blood through the pulmonary circuit. The Fontan procedure routes blood through the patients single ventricle, to the lungs, and into systemic circulation. This process is favorable in patients aged 2 to 5 years old. About 20–30% of patients will require a heart transplant. Left-atrial isomeric patients have less severe complications, as they typically have 2 functional ventricles. In this case, they can undergo biventricular repair to form 2 separate ventricles and functional associated valves.

Prognosis
Prognosis for patients with situs ambiguus is quite varied, owed to the spectrum of clinical manifestations. Infants who experience severe cyanosis at birth may die within hours of delivery if medical intervention is not immediate </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 Opsismodysplasia and can you explain it in depth? [/INST] Opsismodysplasia is a type of skeletal dysplasia (a bone disease that interferes with bone development) first described by Zonana and associates in 1977, and designated under its current name by Maroteaux (1984). Derived from the Greek opsismos ("late"), the name "opsismodysplasia" describes a delay in bone maturation. In addition to this delay, the disorder is characterized by micromelia (short or undersized bones), particularly of the hands and feet, delay of ossification (bone cell formation), platyspondyly (flattened vertebrae), irregular metaphyses, an array of facial aberrations and respiratory distress related to chronic infection. Opsismodysplasia is congenital, being apparent at birth. It has a variable mortality, with some affected individuals living to adulthood. The disorder is rare, with an incidence of less than 1 per 1,000,000 worldwide. It is inherited in an autosomal recessive pattern, which means the defective (mutated) gene that causes the disorder is located on an autosome, and the disorder occurs when two copies of this defective gene are inherited. No specific gene has been found to be associated with the disorder. It is similar to spondylometaphyseal dysplasia, Sedaghatian type.

Presentation
Opsismodysplasia can be characterized by a delay in bone maturation, which refers to "bone aging", an expected sequence of developmental changes in the skeleton corresponding to the chronological age of a person. Factors such as gender and ethnicity also play a role in bone age assessment. The only indicator of physical development that can be applied from birth through mature adulthood is bone age. Specifically, the age and maturity of bone can be determined by its state of ossification, the age-related process whereby certain cartilaginous and soft tissue structures are transformed into bone. The condition of epiphyseal plates (growth plates) at the ends of the long bones (which includes those of the arms, hands, legs and feet) is another measurement of bone age </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 Vulvar intraepithelial neoplasia and can you explain it in depth? [/INST] Vulvar intraepithelial neoplasia (VIN) refers to particular changes that can occur in the skin that covers the vulva. VIN is an intraepithelial neoplasia, and can disappear without treatment. VINs are benign but if the changes become more severe, there is a chance of cancer developing after many years, and so it is referred to as a precancerous condition.

Classification
Medically speaking, the term denotes a squamous intraepithelial lesion of the vulva that shows dysplasia with varying degrees of atypia </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 Crouzon syndrome and can you explain it in depth? [/INST] Crouzon syndrome is an autosomal dominant genetic disorder known as a branchial arch syndrome. Specifically, this syndrome affects the first branchial (or pharyngeal) arch, which is the precursor of the maxilla and mandible. Since the branchial arches are important developmental features in a growing embryo, disturbances in their development create lasting and widespread effects.
This syndrome is named after Octave Crouzon, a French physician who first described this disorder. First called "craniofacial dysostosis" ("craniofacial" refers to the skull and face, and "dysostosis" refers to malformation of bone), the disorder was characterized by a number of clinical features which can be described by the rudimentary meanings of its former name. This syndrome is caused by a mutation in the fibroblast growth factor receptor 2 (FGFR2), located on chromosome 10. The developing fetuss skull and facial bones fuse early or are unable to expand. Thus, normal bone growth cannot occur. Fusion of different sutures leads to abnormal patterns of growth of the skull.

Signs and symptoms
A defining characteristic of Crouzon syndrome is craniosynostosis, which results in an abnormal head shape. This is present in combinations of: frontal bossing, trigonocephaly (fusion of the metopic suture), brachycephaly (fusion of the coronal suture), dolichocephaly (fusion of the sagittal suture), plagiocephaly (unilateral premature closure of lambdoid and coronal sutures), oxycephaly (fusion of coronal and lambdoidal sutures), and complex craniosynostosis (premature closure of some or all sutures).Exophthalmos (bulging eyes due to shallow eye sockets after early fusion of surrounding bones), hypertelorism (greater than normal distance between the eyes), and psittichorhina (beak-like nose) are also very common features. Other facial characteristics that are present in many cases include external strabismus and hypoplastic maxilla (insufficient growth of the midface), which results in relative mandibular prognathism (protruding chin) and gives the effect of the patient having a concave face.Most symptoms are secondary to the abnormal skull structure. Approximately 30% of people with Crouzon syndrome develop hydrocephalus. Sensorineural hearing loss is present in some cases. The abnormalities in the manner in which the eyes fit in the eye sockets can cause vision problems, the most common of which is corneal exposure that can lead to visual impairment. Some people with the condition have a restricted airway and can experience severe problems breathing.Common features are a narrow/high-arched palate, posterior bilateral crossbite, hypodontia (missing some teeth), and crowding of teeth. Due to maxillary hypoplasia, people with Crouzon syndrome generally have a considerable permanent underbite.

Causes
The current research indicates fibroblast growth factor receptors (FGFR) FGFR2 and FGFR3 as the leading factors in causing the autosomal dominant Crouzon syndrome. These two transmembrane proteins are two of four fibroblast growth factor receptors involved in osteoblast differentiation during embryonic development; mutations amongst these receptors are involved in several genetic disorders.There are 40 known mutations, most of which are caused by a missense mutation. FGFR2 is the most commonly mutated gene, a missense at cysteine 342 in exon 9, which creates a gain-of-function. The FGFR2lllc isoform, created via alternative splicing of exon 3 of the FGFR2 gene, uses exon 9 and is used in mesenchymal stem cells to control ossification. However, the mutation constitutively activates the transmembrane protein via a disulfide bond formed incorrectly due to the loss of cysteine 342 </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 Pelvic organ prolapse and can you explain it in depth? [/INST] Pelvic organ prolapse (POP) is characterized by descent of pelvic organs from their normal positions. In women, the condition usually occurs when the pelvic floor collapses after gynecological cancer treatment, childbirth or heavy lifting.In men, it may occur after the prostate gland is removed. The injury occurs to fascia membranes and other connective structures that can result in cystocele, rectocele or both. Treatment can involve dietary and lifestyle changes, physical therapy, or surgery.

Types
Anterior vaginal wall prolapse
Cystocele (bladder into vagina)
Urethrocele (urethra into vagina)
Cystourethrocele (both bladder and urethra)
Posterior vaginal wall prolapse
Enterocele (small intestine into vagina)
Rectocele (rectum into vagina)
Sigmoidocele
Apical vaginal prolapse
Uterine prolapse (uterus into vagina)
Vaginal vault prolapse (roof of vagina) – after hysterectomy

Grading
Pelvic organ prolapses are graded either via the Baden–Walker System, Shaws System, or the Pelvic Organ Prolapse Quantification (POP-Q) System.

Shaws System
Anterior wall

Upper 2/3 cystocele
Lower 1/3 urethrocelePosterior wall

Upper 1/3 enterocele
Middle 1/3 rectocele
Lower 1/3 deficient perineumUterine prolapse

Grade 0 Normal position
Grade 1 descent into vagina not reaching introitus
Grade 2 descent up to the introitus
Grade 3 descent outside the introitus
Grade 4 Procidentia

Baden–Walker
POP-Q
Management
Vaginal prolapses are treated according to the severity of symptoms.

Non-surgical
With conservative measures, such as changes in diet and fitness, Kegel exercises, and pelvic floor physical therapy.With a pessary, a rubber or silicone rubber device fitted to the patient which is inserted into the vagina and may be retained for up to several months. Pessaries are a good choice of treatment for women who wish to maintain fertility, are poor surgical candidates, or who may not be able to attend physical therapy. Pessaries require a provider to fit the device, but most can be removed, cleaned, and replaced by the woman herself </s>