<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 Osteochondritis dissecans and can you explain it in depth? [/INST] Osteochondritis dissecans (OCD or OD) is a joint disorder primarily of the subchondral bone in which cracks form in the articular cartilage and the underlying subchondral bone. OCD usually causes pain during and after sports.  In later stages of the disorder there will be swelling of the affected joint which catches and locks during movement. Physical examination in the early stages does only show pain as symptom, in later stages there could be an effusion, tenderness, and a crackling sound with joint movement.
OCD is caused by blood deprivation of the secondary physes around the bone core of the femoral condyle. This happens to the epiphyseal vessels under the influence of repetitive overloading of the joint during running and jumping sports. During growth such chondronecrotic areas grow into the subchondral bone. There it will show as bone defect area under articular cartilage. The bone will then possibly heal to the surrounding condylar bone in 50% of the cases. Or it will develop into a pseudarthrosis between condylar bone core and osteochondritis flake leaving the articular cartilage it supports prone to damage. The damage is executed by ongoing sport overload. The result is fragmentation (dissection) of both cartilage and bone, and the free movement of these bone and cartilage fragments within the joint space, causing pain, blockage and further damage. OCD has a typical anamnesis with pain during and after sports without any history of trauma. Some symptoms of late stages of osteochondritis dissecans are found with other diseases like rheumatoid disease of children and meniscal ruptures. However, the disease can be confirmed by X-rays, computed tomography (CT) or magnetic resonance imaging (MRI) scans.
Non-surgical treatment is successful in 50% of the cases. If in late stages the lesion is unstable and the cartilage is damaged, surgical intervention is an option as the ability for articular cartilage to heal is limited. When possible, non-operative forms of management such as protected reduced or non-weight bearing and immobilization are used. Surgical treatment includes arthroscopic drilling of intact lesions, securing of cartilage flap lesions with pins or screws, drilling and replacement of cartilage plugs, stem cell transplantation, and in very difficult situation in adults joint replacement. After surgery rehabilitation is usually a two-stage process of unloading and physical therapy. Most rehabilitation programs combine efforts to protect the joint with muscle strengthening and range of motion. During an immobilization period, isometric exercises, such as straight leg raises, are commonly used to restore muscle loss without disturbing the cartilage of the affected joint. Once the immobilization period has ended, physical therapy involves continuous passive motion (CPM) and/or low impact activities, such as walking or swimming.
OCD occurs in 15 to 30 people per 100,000 in the general population each year. Although rare, it is an important cause of joint pain in physically active children and adolescents. Because their bones are still growing, adolescents are more likely than adults to recover from OCD; recovery in adolescents can be attributed to the bones ability to repair damaged or dead bone tissue and cartilage in a process called bone remodeling. While OCD may affect any joint, the knee tends to be the most commonly affected, and constitutes 75% of all cases. Franz König coined the term osteochondritis dissecans in 1887, describing it as an inflammation of the bone–cartilage interface. Many other conditions were once confused with OCD when attempting to describe how the disease affected the joint, including osteochondral fracture, osteonecrosis, accessory ossification center, osteochondrosis, and hereditary epiphyseal dysplasia. Some authors have used the terms osteochondrosis dissecans and osteochondral fragments as synonyms for OCD.

Signs and symptoms
In osteochondritis dissecans, fragments of cartilage or bone become loose within a joint, leading to pain and inflammation. These fragments are sometimes referred to as joint mice. OCD is a type of osteochondrosis in which a lesion has formed within the cartilage layer itself, giving rise to secondary inflammation. OCD most commonly affects the knee, although it can affect other joints such as the ankle or the elbow.People with OCD report activity-related pain that develops gradually. Individual complaints usually consist of mechanical symptoms including pain, swelling, catching, locking, popping noises, and buckling / giving way; the primary presenting symptom may be a restriction in the range of movement. Symptoms typically present within the initial weeks of stage I; however, the onset of stage II occurs within months and offers little time for diagnosis. The disease progresses rapidly beyond stage II, as OCD lesions quickly move from stable cysts or fissures to unstable fragments. Non-specific symptoms, caused by similar injuries such as sprains and strains, can delay a definitive diagnosis.Physical examination typically reveals fluid in the joint, tenderness, and crepitus. The tenderness may initially spread, but often reverts to a well-defined focal point as the lesion progresses. Just as OCD shares symptoms with common maladies, acute osteochondral fracture has a similar presentation with tenderness in the affected joint, but is usually associated with a fatty hemarthrosis. Although there is no significant pathologic gait or characteristic alignment abnormality associated with OCD, the patient may walk with the involved leg externally rotated in an attempt to avoid tibial spine impingement on the lateral aspect of the medial condyle of the femur.

Causes
Despite much research, the causes remain unclear but include repetitive physical trauma, ischemia (restriction of blood flow), hereditary and endocrine factors, avascular necrosis (loss of blood flow), rapid growth, deficiencies and imbalances in the ratio of calcium to phosphorus, and problems of bone formation. Although the name "osteochondritis" implies inflammation, the lack of inflammatory cells in histological examination suggests a non-inflammatory cause. It is thought that repetitive microtrauma, which leads to microfractures and sometimes an interruption of blood supply to the subchondral bone, may cause subsequent localized loss of blood supply or alteration of growth.Trauma, rather than avascular necrosis, is thought to cause osteochondritis dissecans in juveniles. In adults, trauma is thought to be the main or perhaps the sole cause, and may be endogenous, exogenous or both. The incidence of repetitive strain injury in young athletes is on the rise and accounts for a significant number of visits to primary care; this reinforces the theory that OCD may be associated with increased participation in sports and subsequent trauma. High-impact sports such as gymnastics, soccer, basketball, lacrosse, football, tennis, squash, baseball and weight lifting may put participants at a higher risk of OCD in stressed joints (knees, ankles and elbows).Recent case reports suggest that some people may be genetically predisposed to OCD. Families with OCD may have mutations in the aggrecan gene. Studies in horses have implicated specific genetic defects.

Pathophysiology
Osteochondritis dissecans differs from "wear and tear" degenerative arthritis, which is primarily an articular surface problem. Instead, OCD is a problem of the bone underlying the cartilage, which may secondarily affect the articular cartilage. Left untreated, OCD can lead to the development of degenerative arthritis secondary to joint incongruity and abnormal wear patterns.OCD occurs when a loose piece of bone or cartilage partially (or fully) separates from the end of the bone, often because of a loss of blood supply (osteonecrosis) and decalcification of the trabecular bone matrix. The loose piece may stay in place or slide around, making the joint stiff and unstable. OCD in humans most commonly affects the knees, ankles, and elbow but can affect any joint.In skeletally immature individuals, the blood supply to the epiphyseal bone is good, supporting both osteogenesis and chondrogenesis. With disruption of the epiphyseal plate vessels, varying degrees and depth of necrosis occur, resulting in a cessation of growth to both osteocytes and chondrocytes. In turn, this pattern leads to disordered ossification of cartilage, resulting in subchondral avascular necrosis and consequently OCD.Four minor stages of OCD have been identified after trauma. These include revascularization and formation of granulation (scar) tissue, absorption of necrotic fragments, intertrabecular osteoid deposition, and remodeling of new bone. With delay in the revascularization stage, an OCD lesion develops. A lesion can lead to articular-surface irregularities, which in turn may cause progressive arthritic deterioration.

Diagnosis
To diagnose osteochondritis dissecans, an X-ray, CT scan or MRI scan can be performed to show necrosis of subchondral bone, formation of loose fragments, or both. Occasionally a nuclear medicine bone scan is used to assess the degree of loosening within the joint.

Physical examination
Physical examination often begins with examination of the patients gait. In OCD of the knee, people may walk with the involved leg externally rotated in an attempt to avoid tibial spine impingement on the lateral aspect of the medial condyle of the femur.Next, the examining physician may check for weakness of the quadriceps. This examination may reveal fluid in the joint, tenderness, and crepitus. The Wilson test is also useful in locating OCD lesions of the femoral condyle. The test is performed by slowly extending the knee from 90 degrees, maintaining internal rotation. Pain at 30 degrees of flexion and relief with tibial external rotation is indicative of OCD.Physical examination of a patient with ankle OCD often returns symptoms of joint effusion, crepitus, and diffuse or localized tenderness. Examination often reveals symptoms of generalized joint pain, swelling, and times with limited range of motion. Some with loose body lesions may report catching, locking, or both. The possibility of microtrauma emphasizes a need for evaluation of biomechanical forces at the knee in a physical examination. As a result, the alignment and rotation of all major joints in the affected extremity is common, as are extrinsic and intrinsic abnormalities concerning the affected joint, including laxity.

Diagnostic imaging
X-rays show lucency of the ossification on the anterior aspect of the knee in juvenile patients. In older people, the lesion typically appears as an area of osteosclerotic bone with a radiolucent line between the osteochondral defect and the epiphysis. The visibility of the lesion depends on its location and on the amount of knee flexion used. Harding described the lateral X-ray as a method to identify the site of an OCD lesion.Magnetic resonance imaging (MRI) is useful for staging OCD lesions, evaluating the integrity of the joint surface, and distinguishing normal variants of bone formation from OCD by showing bone and cartilage edema in the area of the irregularity. MRI provides information regarding features of the articular cartilage and bone under the cartilage, including edema, fractures, fluid interfaces, articular surface integrity, and fragment displacement. A low T1 and high T2 signal at the fragment interface is seen in active lesions. This indicates an unstable lesion or recent microfractures. While MRI and arthroscopy have a close correlation, X-ray films tend to be less inductive of similar MRI results.Computed tomography (CT) scans and Technetium-99m bone scans are also sometimes used to monitor the progress of treatment. Unlike plain radiographs (X-rays), CT scans and MRI scans can show the exact location and extent of the lesion. Technetium bone scans can detect regional blood flow and the amount of osseous uptake. Both of these seem to be closely correlated to the potential for healing in the fragment.

Classification
OCD is classified by the progression of the disease in stages.
There are two main staging classifications used; one is determined by MRI diagnostic imaging while the other is determined arthroscopically. However, both stagings represent the pathological conditions associated with OCDs natural progression.While the arthroscopic classification of bone and cartilage lesions is considered standard, the Anderson MRI staging is the main form of staging used in this article. Stages I and II are stable lesions. Stages III and IV describe unstable lesions in which a lesion of the cartilage has allowed synovial fluid between the fragment and bone.

Treatment
Treatment options include modified activity with or without weight bearing; immobilization; cryotherapy; anti-inflammatory medication; drilling of subchondral bone; microfracture; removal or reattachment of loose bodies; mosaicplasty and osteoarticular transfer system (OATS) procedures. The primary goals of treatment are:
Enhance the healing potential of subchondral bone;
Fix unstable fragments while maintaining joint congruity; and
Replace damaged bone and cartilage with implanted tissues or cells that can grow cartilage.The articular cartilages capacity for repair is limited: partial-thickness defects in the articular cartilage do not heal spontaneously, and injuries of the articular cartilage which fail to penetrate subchondral bone tend to lead to deterioration of the articular surface. As a result, surgery is often required in even moderate cases where the osteochondral fragment has not detached from the bone (Anderson Stage II, III).

Non-surgical
Candidates for non-operative treatment are limited to skeletally immature teenagers with a relatively small, intact lesion and the absence of loose bodies. Non-operative management may include activity modification, protected weight bearing (partial or non-weight bearing), and immobilization. The goal of non-operative intervention is to promote healing in the subchondral bone and prevent potential chondral collapse, subsequent fracture, and crater formation.Once candidates for treatment have been screened, treatment proceeds according to the lesions location. For example, those with OCD of the knee are immobilized for four to six weeks or even up to six months in extension to remove shear stress from the involved area; however, they are permitted to walk with weight bearing as tolerated. X-rays are usually taken three months after the start of non-operative therapy; if they reveal that the lesion has healed, a gradual return to activities is instituted. Those demonstrating healing by increased radiodensity in the subchondral region, or those whose lesions are unchanged, are candidates to repeat the above described three-month protocol until healing is noted.

Surgery
The choice of surgical versus non-surgical treatments for osteochondritis dissecans is controversial. Consequently, the type and extent of surgery necessary varies based on patient age, severity of the lesion, and personal bias of the treating surgeon—entailing an exhaustive list of suggested treatments. A variety of surgical options exist for the treatment of persistently symptomatic, intact, partially detached, and completely detached OCD lesions. Post-surgery reparative cartilage is inferior to healthy hyaline cartilage in glycosaminoglycan concentration, histological, and immunohistochemical appearance. As a result, surgery is often avoided if non-operative treatment is viable.

Intact lesions
If non-surgical measures are unsuccessful, drilling may be considered to stimulate healing of the subchondral bone. Arthroscopic drilling may be performed by using an antegrade (from the front) approach from the joint space through the articular cartilage, or by using a retrograde (from behind) approach through the bone outside of the joint to avoid penetration of the articular cartilage. This has proven successful with positive results at one-year follow-up with antegrade drilling in nine out of eleven teenagers with the juvenile form of OCD, and in 18 of 20 skeletally immature people (follow-up of five years) who had failed prior conservative programs.

Hinged lesions
Pins and screws can be used to secure flap (sometimes referred to as hinged) lesions. Bone pegs, metallic pins and screws, and other bioresorbable screws may be used to secure these types of lesions.

Full thickness lesions
The three methods most commonly used in treating full thickness lesions are arthroscopic drilling, abrasion, and microfracturing.
In 1946, Magnusson established the use of stem cells from bone marrow with the first surgical debridement of an OCD lesion. These cells typically differentiate into fibrocartilage and rarely form hyaline cartilage. While small lesions can be resurfaced using this form of surgery, the repair tissue tends to have less strength than normal hyaline cartilage and must be protected for 6 to 12 months. Results for large lesions tend to diminish over time; this can be attributed to the decreased resilience and poor wear characteristics of the fibrocartilage.In attempts to address the weaker structure of the reparative fibrocartilage, new techniques have been designed to fill the defect with tissue that more closely simulates normal hyaline articular cartilage. One such technique is autologous chondrocyte implantation (ACI), which is useful for large, isolated femoral defects in younger people. In this surgery, chondrocytes are arthroscopically extracted from the intercondylar notch of the articular surface. The chondrocytes are grown and injected into the defect under a periosteal patch. ACI surgery has reported good to excellent results for reduced swelling, pain and locking in clinical follow-up examinations. However, some physicians have preferred to use undifferentiated pluripotential cells, such as periosteal cells and bone marrow stem cells, as opposed to chondrocytes. These too have demonstrated the ability to regenerate both the cartilage and the underlying subchondral bone.Similar to OATS, arthroscopic articular cartilage paste grafting is a surgical procedure offering cost-effective, long-lasting results for stage IV lesions. A bone and cartilage paste derived from crushed plugs of the non-weight-bearing intercondylar notch can achieve pain relief, repair damaged tissue, and restore function.

Unstable lesions
Some methods of fixation for unstable lesions include countersunk compression screws and Herbert screws or pins made of stainless steel or materials that can be absorbed by the body. If loose bodies are found, they are removed. Although each case is unique and treatment is chosen on an individual basis, ACI is generally performed on large defects in skeletally mature people.

Rehabilitation
Continuous passive motion (CPM) has been used to improve healing of the articular surface during the postoperative period for people with full-thickness lesions. It has been shown to promote articular cartilage healing for small (< 3 mm in diameter) lesions in rabbits. Similarly, Rodrigo and Steadman reported that CPM for six hours per day for eight weeks produced an improved clinical outcome in humans.A rehabilitation program often involves protection of the compromised articular surface and underlying subchondral bone combined with maintenance of strength and range of motion. Post-operative analgesics, namely a mix of opioids and NSAIDs, are usually required to control pain, inflammation and swelling. Straight leg raising and other isometric exercises are encouraged during the post-operative or immobilization period. A six to eight-week home or formal physical therapy program is usually instituted once the immobilization period has ended, incorporating range of motion, stretching, progressive strengthening, and functional or sport-specific training. During this time, patients are advised to avoid running and jumping, but are permitted to perform low impact activities, such as walking or swimming. If patients return to activity before the cartilage has become firm, they will typically complain of pain during maneuvers such as squatting or jumping.

Prognosis
The prognosis after different treatments varies and is based on several factors which include the age of the patient, the affected joint, the stage of the lesion and, most importantly, the state of the growth plate. It follows that the two main forms of osteochondritis dissecans are defined by skeletal maturity. The juvenile form of the disease occurs in open growth plates, usually affecting children between the ages of 5 and 15 years. The adult form commonly occurs between ages 16 to 50, although it is unclear whether these adults developed the disease after skeletal maturity or were undiagnosed as children.The prognosis is good for stable lesions (stage I and II) in juveniles with open growth plates; treated conservatively—typically without surgery—50% of cases will heal. Recovery in juveniles can be attributed to the bones ability to repair damaged or dead bone tissue and cartilage in a process called bone remodeling. Open growth plates are characterized by increased numbers of undifferentiated chondrocytes (stem cells) which are precursors to both bone and cartilaginous tissue. As a result, open growth plates allow for more of the stem cells necessary for repair in the affected joint. Unstable, large, full-thickness lesions (stage III and IV) or lesions of any stage found in the skeletally mature are more likely to fail non-operative treatment. These lesions offer a worse prognosis and surgery is required in most cases.

Epidemiology
OCD is a relatively rare disorder, with an estimated incidence of 15 to 30 cases per 100,000 persons per year. Widuchowski W et al. found OCD to be the cause of articular cartilage defects in 2% of cases in a study of 25,124 knee arthroscopies. Although rare, OCD is noted as an important cause of joint pain in active adolescents. The juvenile form of the disease occurs in children with open growth plates, usually between the ages 5 and 15 years and occurs more commonly in males than females, with a ratio between 2:1 and 3:1. However, OCD has become more common among adolescent females as they become more active in sports. The adult form, which occurs in those who have reached skeletal maturity, is most commonly found in people 16 to 50 years old.While OCD may affect any joint, the knee—specifically the medial femoral condyle in 75–85% of knee cases—tends to be the most commonly affected, and constitutes 75% of all cases. The elbow (specifically the capitulum of the humerus) is the second most affected joint with 6% of cases; the talar dome of the ankle represents 4% of cases. Less frequent locations include the patella, vertebrae, the femoral head, and the glenoid of the scapula.The oldest case of OCD was identified on the temporo-mandibular joint of the Qafzeh 9 fossil.

History
The condition was initially described by Alexander Monro (primus) in 1738.
In 1870, James Paget described the disease process for the first time, but it was not until 1887 that Franz König published a paper on the cause of loose bodies in the joint. In his paper, König concluded that:
Trauma had to be very severe to break off parts of the joint surface.
Less severe trauma might contuse the bone to cause an area of necrosis which might then separate.
In some cases, the absence of notable trauma made it likely that there existed some spontaneous cause of separation.König named the disease "osteochondritis dissecans", describing it as a subchondral inflammatory process of the knee, resulting in a loose fragment of cartilage from the femoral condyle. In 1922, Kappis described this process in the ankle joint </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 Superior vena cava syndrome and can you explain it in depth? [/INST] Superior vena cava syndrome (SVCS), is a group of symptoms caused by obstruction of the superior vena cava ("SVC"), a short, wide vessel carrying circulating blood into the heart. The majority of cases are caused by malignant tumors within the mediastinum, most commonly lung cancer and non-Hodgkins lymphoma, directly compressing or invading the SVC wall.  Non-malignant causes are increasing in prevalence due to expanding use of intravascular devices (such as permanent central venous catheters and leads for pacemakers and defibrillators), which can result in thrombosis.  Other non-malignant causes include benign mediastinal tumors, aortic aneurysm, infections, and fibrosing mediastinitis.Characteristic features are edema (swelling due to excess fluid) of the face and arms and development of swollen collateral veins on the front of the chest wall. Shortness of breath and coughing are quite common symptoms; difficulty swallowing is reported  in 11% of cases, headache in 6% and stridor (a high-pitched wheeze) in 4%. The symptoms are rarely life-threatening, though edema of the epiglottis can make breathing difficult, edema of the brain can cause reduced alertness, and in less than 5% of cases of SVCO, severe neurological symptoms or airway compromise are reported. Resolution of superior vena cava syndrome is directly related to the treatment of the underlying compression.

Signs and symptoms
Shortness of breath is the most common symptom, followed by face or arm swelling.Following are frequent symptoms:

Difficulty breathing
Headache
Facial swelling
Venous distention in the neck and distended veins in the upper chest and arms
Migraines (especially if unusual to normal)
Large decrease in lung capacity
Facial swelling after bending/laying down
Upper limb edema
Lightheadedness
Cough
Edema (swelling) of the neck, called the collar of Stokes
Pembertons signSuperior vena cava syndrome usually presents more gradually with an increase in symptoms over time as malignancies increase in size or invasiveness.

Cause
Over 80% of cases are caused by malignant tumors compressing the superior vena cava.  Lung cancer, usually small cell carcinoma, comprises 75–80% of these cases and non-Hodgkin lymphoma, most commonly diffuse large B-cell lymphoma, comprises 10–15%.  Rare malignant causes include  Hodgkins lymphoma, metastatic cancers, leukemia, leiomyosarcoma of the mediastinal vessels, and plasmocytoma. Syphilis and tuberculosis have also been known to cause superior vena cava syndrome. SVCS can be caused by invasion or compression by a pathological process or by a deep vein thrombosis in the vein itself, although this latter is less common (approximately 35% due to the use of intravascular devices).

Diagnosis
The main techniques of diagnosing SVCS are with chest X-rays (CXR), CT scans, transbronchial needle aspiration at bronchoscopy and mediastinoscopy. CXRs often provide the ability to show mediastinal widening and may show the presenting primary cause of SVCS. However, 16% of people with SVC syndrome have a normal chest X-ray. CT scans should be contrast enhanced and be taken on the neck, chest, lower abdomen, and pelvis. They may also show the underlying cause and the extent to which the disease has progressed.

Treatment
Several methods of treatment are available, mainly consisting of careful drug therapy and surgery. Glucocorticoids (such as prednisone or methylprednisolone) decrease the inflammatory response to tumor invasion and edema surrounding the tumor. Glucocorticoids are most helpful if the tumor is steroid-responsive, such as lymphomas.  In addition, diuretics (such as furosemide) are used to reduce venous return to the heart which relieves the increased pressure.In an acute setting, endovascular stenting by an interventional radiologist may provide relief of symptoms in as little as 12–24 hours with minimal risks.Should a patient require assistance with respiration whether it be by bag/valve/mask, bilevel positive airway pressure (BiPAP), continuous positive airway pressure (CPAP) or mechanical ventilation, extreme care should be taken.  Increased airway pressure will tend to further compress an already compromised SVC and reduce venous return and in turn cardiac output and cerebral and coronary blood flow.  Spontaneous respiration should be allowed during endotracheal intubation until sedation allows placement of an ET tube and reduced airway pressures should be employed when possible.

Prognosis
Symptoms are usually relieved with radiation therapy within one month of treatment. However, even with treatment, 99% of patients die within two and a half years. This relates to the cancerous causes of SVC found in 90% of cases. The average age of disease onset is 54 years.

See also
Pembertons sign

References
Further reading
Wilson LD, Detterbeck FC, Yahalom J (May 2007). "Clinical practice </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 Periodic limb movement disorder and can you explain it in depth? [/INST] Periodic limb movement disorder (PLMD) is a sleep disorder where the patient moves limbs involuntarily and periodically during sleep, and has symptoms or problems related to the movement. PLMD should not be confused with restless legs syndrome (RLS). RLS is characterized by a voluntary response to an urge to move legs due to discomfort. PLMD on the other hand is involuntary, and the patient is often unaware of these movements altogether. Periodic limb movements (PLMS) occurring during daytime period can be found but are considered as a symptom of RLS. Only PLMS during sleep can suggest a diagnosis of PLMD.Periodic limb movement disorder is characterized by recurrent episodes of frequent limb movements while sleeping. It mostly happens in the lower parts of the body like the toes, ankles, knees and hips. It can also, in some cases, appear in the upper extremities of the body. These movements can lead the patient to wake up, and if so, sleep interruption can be the origin of excessive daytime sleepiness.PLMD is characterized by increased periodic limb movements during sleep (PLMS), which must coexist with a sleep disturbance or other functional impairment, in an explicit cause-effect relationship. Usually, these involuntary movements come from lower extremities (including toes, ankles, knees, and hips), although they can also be observed in upper extremities, occasionally. PLMS seem to be common features within many people, and identifying whether or not these movements are clinically relevant for a distinct diagnosis of PLMD remains a challenge for clinical and scientific fields. Moreover, diagnosis of PLMD cannot be used when narcolepsy, restless legs syndrome (RLS), REM sleep behaviour disorder (RBD) or untreated obstructive sleep apnea (OSA) is already diagnosed, since abnormal movements during sleep are frequent in these disorders.

Signs and symptoms
People with PLMD often have excessive daytime sleepiness (EDS), falling asleep during the day, trouble falling asleep at night, and difficulty staying asleep throughout the night. Patients also display involuntary limb movements that occur at periodic intervals anywhere from 20 to 40 seconds apart. They often only last the first half of the night during non-REM sleep stages. Movements do not occur during REM because of muscle atonia.
PLMS can be unilateral or bilateral and not really symmetrical or simultaneous. PLMS is often a symptom of RLS but evidence for differences between those two sleep disorders was found in literature. Sleep structure differed, when RLS patients had significantly more REM sleep and less stage 1 sleep compared to PLMD patients. Besides, PLMI was significantly higher in patients with PLMD.

Causes
It is mostly unknown what causes PLMD, but in many cases the patient also has other medical problems such as Parkinsons disease or narcolepsy. Medical agents must be taken into consideration: several psychopharmacological drugs (serotonergic and tricyclic antidepressants, venlafaxine and mirtazapine) heighten the risk of PLMD. For women, the presence of musculoskeletal disease, heart disease, obstructive sleep apnea, cataplexy, doing physical activities close to bedtime and the presence of a mental disorder were significantly associated with having a higher risk of both PLMD and restless legs syndrome.PLMS seems to have an origin in the spinal cord.  In fact, PLMS was suggested to be associated with increased spinal reflexes. Manifestations of PLMS seem to occur mostly in disorders associated with dopaminergic dysfunctions.Hypothesis of low ferritin levels in adult population was raised to explain PLMD where increased RLS severity and increased PLMS were significantly correlated with low ferritin levels. Research evidence suggested iron is possibly contributing to PLMD. Thus, lack of iron may induce inhibition of dopamine formation which might underlie PLMS.

Diagnosis
People with PLMD often do not know the cause of their excessive daytime sleepiness and their limb movements are reported by a spouse or sleep partner. PLMD cannot be diagnosed by polysomnogram (PSG) alone, it is necessary to obtain a full medical history and taking into account all available information.Polysomnography is recognized as the assessment method which brings most precise information on sleep quality, sleep structure and physiological parameters during sleep (respiration, heart rate, movements). Therefore, diagnostic of PLMD can usually be established only in laboratory settings. As people usually ignore the cause of their daytime impairments, PLMS during sleep are mostly found through laboratory examination rather than clinical complaints.Video-Polysomnography may be recommended to distinguish PLMS from other leg movements during sleep time which may be similar to PLMS when it comes to duration and pattern. Measures from PSG allocated to the diagnostic of PLMD are essentially based on electromyography (EMG) measuring muscle activity. EMG electrodes are usually placed on anterior tibialis muscle.Recent studies showed actigraphy may be combined to PSG as a screening tool for PLMD diagnosis. Actigraphs are watch-shaped devices - usually worn by adult population on the wrist - used to record sleep and wake periods for at least a week. Recent actigraphy devices allow more precise recordings which helps evaluating if actual movements meet diagnostic criteria for PLMD. Recent studies showed actigraph records reflect quite accurately PLMI criterion.Crucial for the diagnosis are the inter-movement intervals and the frequency of PLMS - each movement must happen within a 4 to 90 second interval from the previous movement. The periodic limb movement index (PLMI), which corresponds to the number of periodic limb movements per hour, must be more than 15 movements per hour in adults and 5 movements or more per hour in children. The diagnosis of PLMD requires a visible cause-effect relationship between PLMS and an observed sleep disturbance or daytime impairment (both disturbance and impairment have to be clinically significant).Other relevant causes of Insomnia and Hypersomnia have to be ruled out before diagnosing PLMD (most importantly anxiety, obstructive sleep apnea, and narcolepsy). Furthermore, symptoms can not be better explained by any other conditions.For the differential diagnosis it is important to differentiate PLMD from other leg movements during sleep, which are high-frequency:
alternating leg movement activity (ALMA) are very similar events and could be mistaken for PLMS
hypnagogic foot tremor (HFT) events are also very similar to PLMS and could be misdiagnosed
excessive fragmentary myoclonus (EFM) events are shorter than PLMS

Classification
PLMD is classified in the third edition of the International Classification of Sleep Disorders (ICSD-3) which presents current sleep disorders nosology. ICSD-3 is divided in 7 sections and PLMD is classified in the Sleep-Related Movement Disorders section. There are some updates from ICSD-2. The diagnosis is more strict. A simple complaint is no longer enough: a significant clinical impairment is needed. Sleep impairments need to be clearly caused by PLMS and the symptoms also need to be explained solely by the PLMS.

Treatment
PLMD can be effectively treated with dopaminergic agents (pramipexole, ropinirole, cabergoline, and rotigotine) and it has been found that patients with a low ferritin level respond well to oral iron supplements. Adverse effects of these agents have been reported and include the occurrence of restless leg syndrome triggered by the medication, as well as cortical arousals, which are a cause of disturbed sleep. Patients must stay on these medications in order to experience relief, because there is no known cure for this disorder.
PLMs tend to be exacerbated by tricyclic antidepressants, SSRIs, stress, and sleep deprivation. It is also advised not to consume caffeine, alcohol, or antidepressants as these substances could worsen the PLMD symptoms.
Other medications aimed at reducing or eliminating the leg jerks or the arousals can be prescribed. Non-ergot derived dopaminergic medications (pramipexole and ropinirole) are preferred. Other dopaminergic agents such as co-careldopa, co-beneldopa, pergolide, or lisuride may also be used </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 Pyelonephritis and can you explain it in depth? [/INST] Pyelonephritis  is inflammation of the kidney, typically due to a bacterial infection. Symptoms most often include fever and flank tenderness. Other symptoms may include nausea, burning with urination, and frequent urination. Complications may include pus around the kidney, sepsis, or kidney failure.It is typically due to a bacterial infection, most commonly Escherichia coli. Risk factors include sexual intercourse, prior urinary tract infections, diabetes, structural problems of the urinary tract, and spermicide use. The mechanism of infection is usually spread up the urinary tract. Less often infection occurs through the bloodstream. Diagnosis is typically based on symptoms and supported by urinalysis. If there is no improvement with treatment, medical imaging may be recommended.Pyelonephritis may be preventable by urination after sex and drinking sufficient fluids. Once present it is generally treated with antibiotics, such as ciprofloxacin or ceftriaxone. Those with severe disease may require treatment in hospital. In those with certain structural problems of the urinary tract or kidney stones, surgery may be required.Pyelonephritis affects about 1 to 2 per 1,000 women each year and just under 0.5 per 1,000 males. Young adult females are most often affected, followed by the very young and old. With treatment, outcomes are generally good in young adults. Among people over the age of 65 the risk of death is about 40%.

Signs and symptoms
Signs and symptoms of acute pyelonephritis generally develop rapidly over a few hours or a day. It can cause high fever, pain on passing urine, and abdominal pain that radiates along the flank towards the back. There is often associated vomiting.Chronic pyelonephritis causes persistent flank or abdominal pain, signs of infection (fever, unintentional weight loss, malaise, decreased appetite), lower urinary tract symptoms and blood in the urine. Chronic pyelonephritis can in addition cause fever of unknown origin. Furthermore, inflammation-related proteins can accumulate in organs and cause the condition AA amyloidosis.Physical examination may reveal fever and tenderness at the costovertebral angle on the affected side.

Causes
Most cases of community-acquired pyelonephritis are due to bowel organisms that enter the urinary tract. Common organisms are E. coli (70–80%) and Enterococcus faecalis. Hospital-acquired infections may be due to coliform bacteria and enterococci, as well as other organisms uncommon in the community (e.g., Pseudomonas aeruginosa and various species of Klebsiella). Most cases of pyelonephritis start off as lower urinary tract infections, mainly cystitis and prostatitis. E. coli can invade the superficial umbrella cells of the bladder to form intracellular bacterial communities (IBCs), which can mature into biofilms. These biofilm-producing E. coli are resistant to antibiotic therapy and immune system responses, and present a possible explanation for recurrent urinary tract infections, including pyelonephritis. Risk is increased in the following situations:
Mechanical: any structural abnormalities in the urinary tract, vesicoureteral reflux (urine from the bladder flowing back into the ureter), kidney stones, urinary tract catheterization, ureteral stents or drainage procedures (e.g., nephrostomy), pregnancy, neurogenic bladder (e.g., due to spinal cord damage, spina bifida or multiple sclerosis) and prostate disease (e.g., benign prostatic hyperplasia) in men
Constitutional: diabetes mellitus, immunocompromised states
Behavioral: change in sexual partner within the last year, spermicide use
Positive family history (close family members with frequent urinary tract infections)

Diagnosis
Laboratory examination
Analysis of the urine may show signs of urinary tract infection. Specifically, the presence of nitrite and white blood cells on a urine test strip in patients with typical symptoms are sufficient for the diagnosis of pyelonephritis, and are an indication for empirical treatment. Blood tests such as a complete blood count may show neutrophilia. Microbiological culture of the urine, with or without blood cultures and antibiotic sensitivity testing are useful for establishing a formal diagnosis, and are considered mandatory.

Imaging studies
If a kidney stone is suspected (e.g. on the basis of characteristic colicky pain or the presence of a disproportionate amount of blood in the urine), a kidneys, ureters, and bladder x-ray (KUB film) may assist in identifying radioopaque stones. Where available, a noncontrast helical CT scan with 5 millimeter sections is the diagnostic modality of choice in the radiographic evaluation of suspected nephrolithiasis. All stones are detectable on CT scans except very rare stones composed of certain drug residues in the urine. In patients with recurrent ascending urinary tract infections, it may be necessary to exclude an anatomical abnormality, such as vesicoureteral reflux or polycystic kidney disease. Investigations used in this setting include kidney ultrasonography or voiding cystourethrography. CT scan or kidney ultrasonography is useful in the diagnosis of xanthogranulomatous pyelonephritis; serial imaging may be useful for differentiating this condition from kidney cancer.

Ultrasound findings that indicate pyelonephritis are enlargement of the kidney, edema in the renal sinus or parenchyma, bleeding, loss of corticomedullary differentiation, abscess formation, or an areas of poor blood flow on doppler ultrasound. However, ultrasound findings are seen in only 20% to 24% of people with pyelonephritis.A DMSA scan is a radionuclide scan that uses dimercaptosuccinic acid in assessing the kidney morphology. It is now the most reliable test for the diagnosis of acute pyelonephritis.

Classification
Acute pyelonephritis
Acute pyelonephritis is an exudative purulent localized inflammation of the renal pelvis (collecting system) and kidney. The kidney parenchyma presents in the interstitium abscesses (suppurative necrosis), consisting in purulent exudate (pus): neutrophils, fibrin, cell debris and central germ colonies (hematoxylinophils). Tubules are damaged by exudate and may contain neutrophil casts. In the early stages, the glomerulus and vessels are normal. Gross pathology often reveals pathognomonic radiations of bleeding and suppuration through the renal pelvis to the renal cortex.

Chronic pyelonephritis
Chronic pyelonephritis implies recurrent kidney infections and can result in scarring of the renal parenchyma and impaired function, especially in the setting of obstruction. A perinephric abscess (infection around the kidney) and/or pyonephrosis may develop in severe cases of pyelonephritis.

Xanthogranulomatous pyelonephritis
Xanthogranulomatous pyelonephritis is an unusual form of chronic pyelonephritis characterized by granulomatous abscess formation, severe kidney destruction, and a clinical picture that may resemble renal cell carcinoma and other inflammatory kidney parenchymal diseases. Most affected individuals present with recurrent fevers and urosepsis, anemia, and a painful kidney mass. Other common manifestations include kidney stones and loss of function of the affected kidney. Bacterial cultures of kidney tissue are almost always positive. Microscopically, there are granulomas and lipid-laden macrophages (hence the term xantho-, which means yellow in ancient Greek). It is found in roughly 20% of specimens from surgically managed cases of pyelonephritis.

Prevention
In people who experience recurrent urinary tract infections, additional investigations may identify an underlying abnormality. Occasionally, surgical intervention is necessary to reduce the likelihood of recurrence. If no abnormality is identified, some studies suggest long-term preventive treatment with antibiotics, either daily or after sexual activity. In children at risk for recurrent urinary tract infections, not enough studies have been performed to conclude prescription of long-term antibiotics have a net positive benefit. Drinking cranberry juice does not appear to provide much if any benefit in decreasing urinary tract infections.

Management
In people suspected of having pyelonephritis, a urine culture and antibiotic sensitivity test is performed, so therapy can eventually be tailored on the basis of the infecting organism. As most cases of pyelonephritis are due to bacterial infections, antibiotics are the mainstay of treatment. The choice of antibiotic depends on the species and antibiotic sensitivity profile of the infecting organism, and may include fluoroquinolones, cephalosporins, aminoglycosides, or trimethoprim/sulfamethoxazole, either alone or in combination.

Simple
A 2018 systematic review recommended the use of norfloxacin as it has the lowest rate of side effects with a comparable efficacy to commonly used antibiotics.In people who do not require hospitalization and live in an area where there is a low prevalence of antibiotic-resistant bacteria, a fluoroquinolone by mouth such as ciprofloxacin or levofloxacin is an appropriate initial choice for therapy. In areas where there is a higher prevalence of fluoroquinolone resistance, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside, and then continuing treatment with a fluoroquinolone. Oral trimethoprim/sulfamethoxazole is an appropriate choice for therapy if the bacteria is known to be susceptible. If trimethoprim/sulfamethoxazole is used when the susceptibility is not known, it is useful to initiate treatment with a single intravenous dose of a long-acting antibiotic such as ceftriaxone or an aminoglycoside. Oral beta-lactam antibiotics are less effective than other available agents for treatment of pyelonephritis. Improvement is expected in 48 to 72 hours.

Complicated
People with acute pyelonephritis that is accompanied by high fever and leukocytosis are typically admitted to the hospital for intravenous hydration and intravenous antibiotic treatment. Treatment is typically initiated with an intravenous fluoroquinolone, an aminoglycoside, an extended-spectrum penicillin or cephalosporin, or a carbapenem. Combination antibiotic therapy is often used in such situations. The treatment regimen is selected based on local resistance data and the susceptibility profile of the specific infecting organism(s).During the course of antibiotic treatment, serial white blood cell count and temperature are closely monitored. Typically, the intravenous antibiotics are continued until the person has no fever for at least 24 to 48 hours, then equivalent antibiotics by mouth can be given for a total of two–week duration of treatment. Intravenous fluids may be administered to compensate for the reduced oral intake, insensible losses (due to the raised temperature) and vasodilation and to optimize urine output. Percutaneous nephrostomy or ureteral stent placement may be indicated to relieve obstruction caused by a stone. Children with acute pyelonephritis can be treated effectively with oral antibiotics (cefixime, ceftibuten and amoxicillin/clavulanic acid) or with short courses (2 to 4 days) of intravenous therapy followed by oral therapy. If intravenous therapy is chosen, single daily dosing with aminoglycosides is safe and effective.Fosfomycin can be used as an efficacious treatment for both UTIs and complicated UTIs including acute pyelonephritis </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 Abetalipoproteinemia and can you explain it in depth? [/INST] Abetalipoproteinemia (also known as: Bassen-Kornzweig syndrome, microsomal triglyceride transfer protein deficiency disease, MTP deficiency, and betalipoprotein deficiency syndrome) is a disorder that interferes with the normal absorption of fat and fat-soluble vitamins from food. It is caused by a mutation in microsomal triglyceride transfer protein resulting in deficiencies in the apolipoproteins B-48 and B-100, which are used in the synthesis and exportation of chylomicrons and VLDL respectively. It is not to be confused with familial dysbetalipoproteinemia.It is a rare autosomal recessive disorder.

Presentation
Symptoms
Often symptoms will arise that indicate the body is not absorbing or making the lipoproteins that it needs. These symptoms usually appear en masse.These symptoms come as follows:

Failure to thrive (i.e. failure to grow in infancy)
Steatorrhea (i.e. fatty, pale stools)
Frothy stools
Foul smelling stools
Protruding abdomen
Intellectual disability/developmental delay
Developmental coordination disorder, evident by age ten
Ataxia
Muscle weakness
Slurred speech (dysarthria)
Scoliosis (curvature of the spine)
Progressive decreased vision
Balance and coordination problems

Signs
Acanthocytosis
Retinitis pigmentosa
Low blood cholesterol

Features
Abetalipoproteinemia affects the absorption of dietary fats, cholesterol, and certain vitamins. People affected by this disorder are not able to make certain lipoproteins, which are molecules that consist of proteins combined with cholesterol and particular fats called triglycerides. This leads to a multiple vitamin deficiency, affecting the fat-soluble vitamin A, vitamin D, vitamin E, and vitamin K. However, many of the observed effects are due to vitamin E deficiency in particular.

Signs and symptoms vary and present differently from person to person. In general, 80–99% of individuals exhibit malabsorption of fats and fat-soluble vitamins. Approximately 30%-79% of people with the disease display symptoms of abnormality of the retinal pigmentation, ataxia, muscular hypotonia or reduced tendon reflexes.The signs and symptoms of abetalipoproteinemia appear in the first few months of life (because pancreatic lipase is not active in this period). They can include failure to gain weight and grow at the expected rate (failure to thrive); diarrhea; abnormal spiny red blood cells (acanthocytosis); and fatty, foul-smelling stools (steatorrhea). The stool may contain large chunks of fat and/or blood. Infants often present with gastrointestinal problems caused by the poor fat absorption, which also contributes to steatorrhea. Other features of this disorder may develop later in childhood and often impair the function of the nervous system. They can include poor muscle coordination, difficulty with balance and movement (ataxia), and progressive degeneration of the retina (the light-sensitive layer in the posterior eye) that can progress to near-blindness (due to deficiency of vitamin A, retinol). Adults in their thirties or forties may have increasing difficulty with balance and walking. Many of the signs and symptoms of abetalipoproteinemia result from a severe vitamin deficiency, especially vitamin E deficiency, which typically results in eye problems with degeneration of the spinocerebellar and dorsal column tracts.

Genetics
Mutations in the microsomal triglyceride transfer protein (MTTP) gene has been associated with this condition. (apolipoprotein B deficiency, a related condition, is associated with deficiencies of apolipoprotein B.)The MTTP gene provides instructions for making a protein called microsomal triglyceride transfer protein, which is essential for creating beta-lipoproteins. These lipoproteins are both necessary for the absorption of fats, cholesterol, and fat-soluble vitamins from the diet and necessary for the efficient transport of these substances in the bloodstream. Most of the mutations in this gene lead to the production of an abnormally short microsomal triglyceride transfer protein, which prevents the normal creation of beta-lipoproteins in the body. MTTP-associated mutations are inherited in an autosomal recessive pattern, which means both copies of the gene must be faulty to produce the disease.The disease is extremely rare with approximately 100 reported cases worldwide since it was first identified by doctors Bassen and Kornzweig in 1950.

Mechanism
Abetalipoproteinemia effects multiple physiological systems, the two most common being the nervous and the skeletal. Disruption of nervous function includes loss of reflexes, speech impairments, tremors or involuntary motor tics, or peripheral neuropathy (damage to the nerves outside of the brain and spinal cord). Peripheral neuropathy causes loss of sensation, weakness or numbness and pain in the extremities through stabbing, burning, or tingling sensations. Skeletal system developments often include lordosis, kyphoscoliosis, or pes cavus. Individuals often have abnormal bleeding due to the difficulty of forming clots.Additional complications of the diseases if not properly treated include blindness, mental deterioration, ataxia, loss of peripheral nerve function.

Diagnosis
The initial workup of Abetalipoproteinemia typically consists of stool sampling, a blood smear, and a fasting lipid panel, though these tests are not confirmatory. As the disease is rare, though a genetics test is necessary for diagnosis, it is generally not done initially. However, prenatal testing may be available for pregnancies identified to be at an increased risk (if both parents are unaffected carrier or one parent is affected and the other in a carrier).Acanthocytes are seen on blood smear. Since there is no or little assimilation of chylomicrons, their levels in plasma remains low.The inability to absorb fat in the ileum will result in steatorrhea, or fat in the stool.  As a result, this can be clinically diagnosed when foul-smelling stool is encountered.  Low levels of plasma chylomicron are also characteristic.There is an absence of apolipoprotein B. On intestinal biopsy, vacuoles containing lipids are seen in enterocytes. This disorder may also result in fat accumulation in the liver (hepatic steatosis). Because the epithelial cells of the bowel lack the ability to place fats into chylomicrons, lipids accumulate at the surface of the cell, crowding the functions that are necessary for proper absorption.Multiple related disorders present with similar symptoms as abetalipoproteinemia that can provide a useful diagnosis through comparisons. Some of those disorders are:

Treatment
Treatment normally consists of rigorous dieting, involving massive amounts of vitamin E. High-dose Vitamin E therapy helps the body restore and produce lipoproteins, which people with abetalipoproteinemia usually lack. Vitamin E also helps keep skin and eyes healthy; studies show that many affected males will have vision problems later on in life. Common additional supplementation includes medium chain fatty acids and linoleic acid. Treatments also aim to slow the progression of nervous system abnormalities. Developmental coordination disorder and muscle weakness are usually treated with physiotherapy or occupational therapy. Dietary restriction of triglycerides has also been useful. Nutritionists often work with medical professionals to design appropriate dietary treatments for their patients.

Prognosis
Prognosis can vary heavily based on the severity of the neurological dysfunction. If treatment is initiated early in disease the neurologic sequelae may be reversed and further deterioration can be prevented. Long-term outlook is reasonably good for most people when diagnosed and treated early. A case study presented a female patient diagnosed at the age of 11. Despite the relatively late diagnosis, the patient married and at the age of 34, gave birth to a full-term healthy infant. Her medication included vitamin K 10 mg twice a week, beta-carotene 40,000 IU daily, vitamin A 10,000 IU daily, vitamin E 400 IU daily, vitamins B6 and B12, calcium, magnesium and eye drops.Prolonged vitamin deficiencies can further compromise health. Specifically, a prolonged vitamin E deficiency can lead to the development of limiting ataxia and gait disturbances. Some individuals may develop retinal degeneration and blindness </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 Atypical pneumonia and can you explain it in depth? [/INST] Atypical pneumonia, also known as walking pneumonia, is any type of pneumonia not caused by one of the pathogens most commonly associated with the disease. Its clinical presentation contrasts to that of "typical" pneumonia. A variety of microorganisms can cause it. When it develops independently from another disease, it is called primary atypical pneumonia (PAP).
The term was introduced in the 1930s and was contrasted with the bacterial pneumonia caused by Streptococcus pneumoniae, at that time the best known and most commonly occurring form of pneumonia. The distinction was historically considered important, as it differentiated those more likely to present with "typical" respiratory symptoms and lobar pneumonia from those more likely to present with "atypical" generalized symptoms (such as fever, headache, sweating and myalgia) and bronchopneumonia.

Signs and symptoms
Usually the atypical causes also involve atypical symptoms:

No response to common antibiotics such as sulfonamide and beta-lactams like penicillin.
No signs and symptoms of lobar consolidation, meaning that the infection is restricted to small areas, rather than involving a whole lobe. As the disease progresses, however, the look can tend to lobar pneumonia.
Absence of leukocytosis.
Extrapulmonary symptoms, related to the causing organism.
Moderate amount of sputum, or no sputum at all (i.e </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 Paraphimosis and can you explain it in depth? [/INST] Paraphimosis is an uncommon medical condition in which the foreskin of a penis becomes trapped behind the glans penis, and cannot be reduced (pulled back to its normal flaccid position covering the glans). If this condition persists for several hours or there is any sign of a lack of blood flow, paraphimosis should be treated as a medical emergency, as it can result in gangrene.

Causes
Paraphimosis is usually caused by medical professionals (iatrogenic) or parents who handle the foreskin improperly. The foreskin may be retracted during penile examination, penile cleaning, urethral catheterization, or cystoscopy; if the foreskin is left retracted for a long period, some of the foreskin tissue may become edematous (swollen with fluid), which makes subsequent reduction of the foreskin difficult.

Prevention and treatment
Paraphimosis can be avoided by bringing the foreskin back into its normal, forward, non-retracted position after retraction is no longer necessary (for instance, after cleaning the glans penis or placing a Foley catheter) </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 Budd–Chiari syndrome and can you explain it in depth? [/INST] Budd–Chiari syndrome is a very rare condition, affecting one in a million adults. The condition is caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites, and liver enlargement. The formation of a blood clot within the hepatic veins can lead to Budd–Chiari syndrome. The syndrome can be fulminant, acute, chronic, or asymptomatic. Subacute presentation is the most common form.

Signs and symptoms
The acute syndrome presents with rapidly progressive severe upper abdominal pain, yellow discoloration of the skin and whites of the eyes, liver enlargement, enlargement of the spleen, fluid accumulation within the peritoneal cavity, elevated liver enzymes, and eventually encephalopathy. The fulminant syndrome presents early with encephalopathy and ascites. Liver cell death and severe lactic acidosis may be present as well. Caudate lobe enlargement is often present. The majority of patients have a slower-onset form of Budd–Chiari syndrome. This can be painless. A system of venous collaterals may form around the occlusion which may be seen on imaging as a "spiders web". Patients may progress to cirrhosis and show the signs of liver failure.On the other hand, incidental finding of a silent, asymptomatic form may not be a cause for concern.

Causes
The cause can be found in more than 80% of patients.
Primary Budd–Chiari syndrome (75%): thrombosis of the hepatic vein
Hepatic vein thrombosis is associated with the following in decreasing order of frequency:Polycythemia vera
Pregnancy
Postpartum state
Use of oral contraceptives
Paroxysmal nocturnal hemoglobinuria
Hepatocellular carcinoma
Lupus anticoagulantsSecondary Budd–Chiari syndrome (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)Budd–Chiari syndrome is also seen in tuberculosis, congenital venous webs and occasionally in inferior vena caval stenosis.
Often, the patient is known to have a tendency towards thrombosis, although Budd–Chiari syndrome can also be the first symptom of such a tendency. Examples of genetic tendencies include protein C deficiency, protein S deficiency, the Factor V Leiden mutation, hereditary anti-thrombin deficiency and prothrombin mutation G20210A. An important non-genetic risk factor is the use of estrogen-containing (combined) forms of hormonal contraception. Other risk factors include the antiphospholipid syndrome, aspergillosis, Behçets disease, dacarbazine, pregnancy, and trauma.Many patients have Budd–Chiari syndrome as a complication of polycythemia vera (myeloproliferative disease of red blood cells). People who have paroxysmal nocturnal hemoglobinuria (PNH) appear to be especially at risk for Budd–Chiari syndrome, more than other forms of thrombophilia: up to 39% develop venous thromboses, and 12% may acquire Budd-Chiari.A related condition is veno-occlusive disease, which occurs in recipients of bone marrow transplants as a complication of their medication. Although its mechanism is similar, it is not considered a form of Budd–Chiari syndrome.Other toxicologic causes of veno-occlusive disease include plant & herbal sources of pyrrolizidine alkaloids such as Borage, Boneset, Coltsfoot, Tu-san-chi, Comfrey, Heliotrope (sunflower seeds), Gordolobo, Germander, and Chaparral.

Pathophysiology
Any obstruction of the venous vasculature of the liver is referred to as Budd–Chiari syndrome, from the venules to the right atrium. This leads to increased portal vein and hepatic sinusoid pressures as the blood flow stagnates. The increased portal pressure causes increased filtration of vascular fluid with the formation of ascites in the abdomen and collateral venous flow through alternative veins leading to esophageal, gastric and rectal varices. Obstruction also causes centrilobular necrosis and peripheral lobule fatty change due to ischemia. If this condition persists chronically what is known as nutmeg liver will develop. Kidney failure may occur, perhaps due to the body sensing an "underfill" state and subsequent activation of the renin-angiotensin pathways and excess sodium retention.

Diagnosis
When Budd–Chiari syndrome is suspected, measurements are made of liver enzyme levels and other organ markers (creatinine, urea, electrolytes, LDH).Budd–Chiari syndrome is most commonly diagnosed using ultrasound studies of the abdomen and retrograde angiography. Ultrasound may show obliteration of hepatic veins, thrombosis or stenosis, spiderweb vessels, large collateral vessels, or a hyperechoic cord replacing a normal vein. Computed tomography (CT) or magnetic resonance imaging (MRI) is sometimes employed although these methods are generally not as sensitive. Liver biopsy is nonspecific but sometimes necessary to differentiate between Budd–Chiari syndrome and other causes of hepatomegaly and ascites, such as galactosemia or Reyes syndrome. Evaluation for a JAK2 V617F mutation is recommended.

Treatment
A minority of patients can be treated medically with sodium restriction, diuretics to control ascites, anticoagulants such as heparin and warfarin, and general symptomatic management. However, the majority of patients require further intervention. Milder forms of Budd–Chiari may be treated with surgical shunts to divert blood flow around the obstruction or the liver itself. Shunts must be placed early after diagnosis for best results. The TIPS is similar to a surgical shunt: it accomplishes the same goal but has a lower procedure-related mortality, a factor that has led to a growth in its popularity. If all the hepatic veins are blocked, the portal vein can be approached via the intrahepatic part of inferior vena cava, a procedure called DIPS (direct intrahepatic portocaval shunt) </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 Fungal meningitis and can you explain it in depth? [/INST] Fungal meningitis refers to meningitis caused by a fungal infection.

Signs and symptoms
Symptoms of fungal meningitis are generally similar to those of other types of meningitis, and include: a fever, stiff neck, severe headache, photophobia (sensitivity to light), nausea and vomiting, and altered mental status (drowsiness or confusion).

Causes
Fungal meningitis may be caused by the following (and also other) types of fungi:
Candida - C. albicans is the most common Candida species that causes infections of the central nervous system.
Coccidioides - it is endemic to southwestern United States and Mexico. A third of patients presenting with disseminated coccidioidomycosis have developed meningitis.
Histoplasma - occurs in bird and bat droppings and is endemic to parts of the United States, South, and Central America. Involvement of the central nervous system occurs in about 10-20% of cases of disseminated histoplasmosis.
Blastomyces - occurs in soil rich in decaying organic matter in the Midwest United States. Meningitis is an unusual manifestation of blastomycosis and can be very difficult to diagnose.
Cryptococcus (Cryptococcal meningitis) - it is thought to be acquired through inhalation of soil contaminated with bird droppings. C. neoformans is the most common pathogen to cause fungal meningitis.
Aspergillus - Aspergillus infections account for 5% of fungal infections involving the central nervous system.

Risk factors
Individuals with a weak immune system are most at risk </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 Peutz–Jeghers syndrome and can you explain it in depth? [/INST] Peutz–Jeghers syndrome (often abbreviated PJS) is an autosomal dominant genetic disorder characterized by the development of benign hamartomatous polyps in the gastrointestinal tract and hyperpigmented macules on the lips and oral mucosa (melanosis). This syndrome can be classed as one of various hereditary intestinal polyposis syndromes and one of various hamartomatous polyposis syndromes. It has an incidence of approximately 1 in 25,000 to 300,000 births.

Signs and symptoms
The risks associated with this syndrome include a substantial risk of cancer, especially of the breast  and gastrointestinal tracts. Colorectal is the most common malignancy, with a lifetime risk of 39 percent, followed by breast cancer in females with a lifetime risk of 32 to 54 percent.Patients with the syndrome also have an increased risk of developing carcinomas of the liver, lungs, breast, ovaries, uterus, testes, and other organs. Specifically, it is associated with an increased risk of sex-cord stromal tumor with annular tubules in the ovaries.Due to the increased risk of malignancies, direct surveillance is recommended.The average age of first diagnosis is 23. The first presentation is often bowel obstruction or intussuseption from the hamartomatous gastrointestinal polyps. Dark blue, brown, and black pigmented mucocutaneous macules, are present in over 95 percent of individuals with Peutz-Jeghers syndrome. Pigmented lesions are rarely present at birth, but often appear before 5 years of age. The macules may fade during puberty. The mealoncytic macules are not associated with malignant transformation.Complications associated with Peutz-Jeghers syndrome include obstruction and intussusception, which occur in up to 69 percent of patients, typically first between the ages of 6 and 18, though surveillance for them is controversial. Anemia is also common due to gastrointestinal bleeding from the polyps.

Genetics
In 1998, a gene was found to be associated with the mutation. On chromosome 19, the gene known as STK11 (LKB1) is a possible tumor suppressor gene. It is inherited in an autosomal dominant pattern, which means that anyone who has PJS has a 50% chance of passing the disease on to their offspring.Peutz–Jeghers syndrome is rare and studies typically include only a small number of patients.  Even in those few studies that do contain a large number of patients, the quality of the evidence is limited due to pooling patients from many centers, selection bias (only patients with health problems coming from treatment are included), and historical bias (the patients reported are from a time before advances in the diagnosis of treatment of Peutz–Jeghers syndrome were made). Probably due to this limited evidence base, cancer risk estimates for Peutz–Jeghers syndrome vary from study to study. There is an estimated 18–21% risk of ovarian cancer, 9% risk of endometrial cancer, and 10% risk of cervical cancer, specifically adenoma malignum.

Diagnosis
The main criteria for clinical diagnosis are:
Family history
Mucocutaneous lesions causing patches of hyperpigmentation in the mouth and on the hands and feet.  The oral pigmentations are the first on the body to appear, and thus play an important part in early diagnosis.  Intraorally, they are most frequently seen on the gingiva, hard palate and inside of the cheek.  The mucosa of the lower lip is almost invariably involved as well.
Hamartomatous polyps in the gastrointestinal tract.  These are benign polyps with an extraordinarily low potential for malignancy.Having 2 of the 3 listed clinical criteria indicates a positive diagnosis.  The oral findings are consistent with other conditions, such as Addisons disease and McCune–Albright syndrome, and these should be included in the differential diagnosis.  90–100% of patients with a clinical diagnosis of PJS have a mutation in the STK11/LKB1 gene. Molecular genetic testing for this mutation is available clinically.

Management
Resection of the polyps is required only if serious bleeding or intussusception occurs. Enterotomy is performed for removing large, single nodules. Short lengths of heavily involved intestinal segments can be resected. Colonoscopy can be used to snare the polyps if they are within reach.

Prognosis
Most patients will develop flat, brownish spots (melanotic macules) on the skin, especially on the lips and oral mucosa, during the first year of life, and a patients first bowel obstruction due to intussusception usually occurs between the ages of six and 18 years </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 Umbilical hernia and can you explain it in depth? [/INST] An umbilical hernia is a health condition where the abdominal wall behind the navel is damaged. It may cause the navel to bulge outwards—the bulge consisting of abdominal fat from the greater omentum or occasionally parts of the small intestine. The bulge can often be pressed back through the hole in the abdominal wall, and may "pop out" when coughing or otherwise acting to increase intra-abdominal pressure. Treatment is surgical, and surgery may be performed for cosmetic as well as health-related reasons.

Signs and symptoms
A hernia is present at the site of the umbilicus (commonly called a navel or belly button) in newborns; although sometimes quite large, these hernias tend to resolve without any treatment by around the age of 2–3 years. Obstruction and strangulation of the hernia is rare because the underlying defect in the abdominal wall is larger than in an inguinal hernia of the newborn.  The size of the base of the herniated tissue is inversely correlated with risk of strangulation (i.e., a narrow base is more likely to strangulate).
Babies are prone to this malformation because of the process during fetal development by which the abdominal organs form outside the abdominal cavity, later returning into it through an opening which will become the umbilicus.Hernias may be asymptomatic and present only as a bulge of the umbilicus. Symptoms may develop when the contracting abdominal wall causes pressure on the hernia contents. This results in abdominal pain or discomfort. These symptoms may be worsened by the patient lifting or straining.

Causes
The causes of umbilical hernia are congenital and acquired malformation, but an apparent third cause is really a cause of a different type, a paraumbilical hernia.

Congenital
Congenital umbilical hernia is a congenital malformation of the navel (umbilicus).  Among adults, it is three times more common in women than in men; among children, the ratio is roughly equal.  It is also found to be more common in children of African descent.

Acquired
An acquired umbilical hernia directly results from increased intra-abdominal pressure caused by obesity, heavy lifting, a long history of coughing, or multiple pregnancies. Another type of acquired umbilical hernias are incisional hernias, which are hernia developing in a scar following abdominal surgery, e.g. after insertion of laparoscopy trocars through the umbilicus.

Paraumbilical
Importantly, an umbilical hernia must be distinguished from a paraumbilical hernia, which occurs in adults and involves a defect in the midline near to  the umbilicus, and from omphalocele.

Diagnosis
Navels with the umbilical tip protruding past the umbilical skin ("outies") are often mistaken for umbilical hernias, which are a completely different shape. Treatment for cosmetic purposes is not necessary, unless there are health concerns such as pain, discomfort or incarceration of the hernia content. Incarceration refers to the inability to reduce the hernia back into the abdominal cavity. Prolonged incarceration can lead to tissue ischemia (strangulation) and shock when untreated.
Umbilical hernias are common. With a study involving Africans, 92% of children had protrusions, 49% of adults, and 90% of pregnant women. However, a much smaller number actually had hernias: only 23% of children, 8% of adults, and 15% of pregnant women.When the orifice is small (< 1 or 2 cm), 90% close within 3 years (some sources state 85% of all umbilical hernias, regardless of size), and if these hernias are asymptomatic, reducible, and dont enlarge, no surgery is needed (and in other cases it must be considered).

Treatment
Children
In some communities mothers routinely push the small bulge back in and tape a coin over the palpable hernia hole until closure occurs. This practice is not medically recommended as there is a small risk of trapping a loop of bowel under part of the coin resulting in a small area of ischemic bowel. This "fix" does not help and germs may accumulate under the tape, causing infection. The use of bandages or other articles to continuously reduce the hernia is not evidence-based.An umbilical hernia can be fixed in two different ways.  The surgeon can opt to stitch the walls of the abdomen or he/she can place mesh over the opening and stitch it to the abdominal walls.  The latter is of a stronger hold and is commonly used for larger defects in the abdominal wall. Most surgeons will not repair the hernia until 5–6 years after the baby is born. Most umbilical hernias in infants and children close spontaneously and rarely have complications of gastrointestinal-content incarcerations.How far the projection of the swelling extends from the surface of the abdomen (the belly) varies from child to child. In some, it may be just a small protrusion; in others it may be a large rounded swelling that bulges out when the baby cries. It may hardly be visible when the child is quiet and or sleeping.Normally, the abdominal muscles converge and fuse at the umbilicus during the formation stage, however, in some cases, there remains a gap where the muscles do not close and through this gap the inner intestines come up and bulge under the skin, giving rise to an umbilical hernia. The bulge and its contents can easily be pushed back and reduced into the abdominal cavity.In contrast to an inguinal hernia, the complication incidence is very low, and in addition, the gap in the muscles usually closes with time and the hernia disappears on its own. The treatment of this condition is essentially conservative: observation allowing the child to grow up and see if it disappears. Operation and closure of the defect is required only if the hernia persists after the age of 3 years or if the child has an episode of complication during the period of observation like irreducibility, intestinal obstruction, abdominal distension with vomiting, or red shiny painful skin over the swelling. Surgery is always done under anesthesia. The defect in the muscles is defined and the edges of the muscles are brought together with sutures to close the defect. In general, the child needs to stay in the hospital for 1 day and the healing is complete within 8 days.At times, there may be a fleshy red swelling seen in the hollow of the umbilicus that persists after the cord has fallen off. It may bleed on touch, or may stain the clothes that come in contact with it. This needs to be shown to a pediatric surgeon. This is most likely to be an umbilical polyp and the therapy is to tie it at the base with a stitch so that it falls off and there is no bleeding. Alternatively, it may be an umbilical granuloma that responds well to local application of dry salt or silver nitrate but may take a few weeks to heal and dry.

Adults
Many hernias never cause any problems, and do not require any treatment at all </s>