<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 Laminitis and can you explain it in depth? [/INST] Laminitis is a disease that affects the feet of ungulates and is found mostly in horses and cattle. Clinical signs include foot tenderness progressing to inability to walk, increased digital pulses, and increased temperature in the hooves. Severe cases with outwardly visible clinical signs are known by the colloquial term founder, and progression of the disease will lead to perforation of the coffin bone through the sole of the hoof or being unable to stand up, requiring euthanasia.

Laminae
The bones of the hoof are suspended within the axial hooves of ungulates by layers of modified skin cells, known as laminae or lamellae, which act as shock absorbers during locomotion. In horses, there are about 550–600 pairs of primary epidermal laminae, each with 150–200 secondary laminae projection from their surface. These interdigitate with equivalent structures on the surface of the coffin bone (PIII, P3, the third phalanx, pedal bone, or distal phalanx), known as dermal laminae. The secondary laminae contain basal cells which attach via hemidesmosomes to the basement membrane. The basement membrane is then attached to the coffin bone via the connective tissue of the dermis.

Pathophysiology
Laminitis literally means inflammation of the laminae, and while it remains controversial whether this is the primary mechanism of disease, evidence of inflammation occurs very early in some instances of the disease. A severe inflammatory event is thought to damage the basal epithelial cells, resulting in dysfunction of the hemidesmosomes and subsequent reduction in adherence between the epithelial cells and the basement membrane. Normal forces placed on the hoof are then strong enough to tear the remaining laminae, resulting in a failure of the interdigitation of the epidermal and dermal laminae between the hoof wall and the coffin bone. When severe enough, this results in displacement of the coffin bone within the hoof capsule. Most cases of laminitis occur in both front feet, but laminitis may be seen in all four feet, both hind feet, or in cases of support limb laminitis, in a single foot.

Mechanism
The mechanism remains unclear and is the subject of much research. Three conditions are thought to cause secondary laminitis:

Sepsis/endotoxemia or generalized inflammation
Endocrinopathy
Trauma: concussion or excessive weight-bearingInflammationInflammatory events that are associated with laminitis include sepsis, endotoxemia, retained placenta, carbohydrate overload (excessive grain or pasture), enterocolitis, pleuropneumonia, and contact with black walnut shavings. In these cases, there is an increase in blood flow to the hoof, bringing in damaging substances and inflammatory cells into the hoof.

EndocrinopathyEndocrinopathy is usually the result of improper insulin regulation, and is most commonly seen with pituitary pars intermedia dysfunction (also called equine Cushings syndrome) and equine metabolic syndrome (EMS), as well as obesity and glucocorticoid administration. In cases of EMS, most episodes occur in the spring when the grass is lush.
TraumaMechanical laminitis starts when the hoof wall is pulled away from the bone or lost, as a result of external influences. Mechanical laminitis can occur when a horse habitually paws, is ridden or driven on hard surfaces ("road founder"), or in cases of excessive weight-bearing due to compensation for the opposing limb, a process called support limb laminitis. Support limb laminitis is most common in horses suffering from severe injury to one limb, such as fracture, resulting in a non-weight bearing state that forces them to take excessive load on the opposing limb. This causes decreased blood flow to the cells, decreasing oxygen and nutrient delivery, and thus altering their metabolism which results in laminitis.

Theories of pathophysiology
Matrix metalloproteinasesOne of the newest theories for the molecular basis of laminitis involves matrix metalloproteinases (MMPs). Metalloproteinases are enzymes that can degrade collagen, growth factors, and cytokines to remodel the extracellular matrix of tissues. To prevent tissue damage, they are regulated by tissue inhibitors of metalloproteinases (TIMPs). In cases of laminitis, an underlying cause is thought to cause an imbalance of MMPs and TIMPs, favoring MMPs, so that they may cleave substances within the extracellular matrix and therefore break down the basement membrane. Since the basement membrane is the main link between the hoof wall and the connective tissue of P3, it is thought that its destruction results in their separation. MMP-2 and MMP-9 are the primary enzymes thought to be linked to laminitis.
Theories for developmentThere are multiple theories as to how laminitis develops. These include:

Enzymatic and inflammatory theories: The enzymatic theory postulates that increased blood flow to the foot brings in inflammatory cytokines or other substances to the hoof, where they increase production of MMPs, which subsequently break down the basement membrane. The inflammatory theory states that inflammatory mediators produce inflammation, but recognizes that MMP production occurs later. Therefore, this is possibly a 2-step process, beginning with inflammation and leading to MMP production and subsequent laminitis.
Vascular theory: Postulates that increases in capillary pressure, constriction of veins, and shunting of blood through anastomoses to bypass the capillaries, causes decreased blood and therefore decreased oxygen and nutrient delivery to lamellae. The end-result would be ischemia, leading to cellular death and breakdown between the lamellae. Subsequently, increased vascular permeability leads to edema within the hoof, compression of small vessels, and ischemia. Vasoactive amines may be partially to blame for changes in hoof blood flow.
Metabolic theory: Insulin affects multiple processes within the body, including inflammation, blood flow, and tissue remodeling. Change in insulin regulation may lead to laminitis. Hyperinsulinemia has been shown to cause increased length of the secondary lamellae and epidermal cell proliferation.
Traumatic theory: Concussion is thought to directly damage lamellae, and increased weight-bearing is thought to decrease blood supply to the foot.

Rotation, sinking, and founder
Normally, the front of the third phalanx is parallel to the hoof wall and its lower surface should be roughly parallel to the ground surface.  A single severe laminitic episode or repeated, less severe episodes can, depending upon the degree of separation of dermal and epidermal laminae, lead to either rotation or sinking of the pedal bone, both of which result in anatomical changes in the position of the coffin bone with visible separation of the laminae, colloquially known as founder.  Rotation and distal displacement may occur in the same horse.  Both forms of displacement may lead to the coffin bone penetrating the sole.  Penetration of the sole is not inherently fatal; many horses have been returned to service by aggressive treatment by a veterinarian and farrier, but the treatment is time-consuming, difficult and expensive.
Rotation is the most common form of displacement, and, in this case, the tip of the coffin bone rotates downward.  The degree of rotation may be influenced by the severity of the initial attack and the time of initiation and aggressiveness of treatment.  A combination of forces (e.g. the tension of the deep digital flexor tendon and the weight of the horse) result in the deep digital flexor tendon literally pulling the dorsal face of the coffin bone away from the inside of the hoof wall, which allows the coffin bone to rotate.  Also, ligaments attaching the collateral cartilages to the digit, primarily in the palmar portion of the foot, possibly contribute to a difference in support from front to back.  The body weight of the animal probably contributes to rotation of the coffin bone.  Rotation results in an obvious misalignment between PII (the short pastern bone) and PIII (the coffin bone).  If rotation of the third phalanx continues, its tip can eventually penetrate the sole of the foot.
Sinking is less common and much more severe.  It results when a significant failure of the interdigitation between the sensitive and insensitive laminae around a significant portion of the hoof occurs.  The destruction of the sensitive laminae results in the hoof wall becoming separated from the rest of the hoof, so that it drops within the hoof capsule.  Sinking may be symmetrical, i.e., the entire bone moves distally, or asymmetric, where the lateral or medial aspect of the bone displaces distally.  Pus may leak out at the white line or at the coronary band.  In extreme cases, this event allows the tip to eventually penetrate the sole of the foot.  A severe "sinker" usually warrants the gravest prognosis and may, depending upon many factors, including the quality of aftercare, age of the horse, diet and nutrition, skill, and knowledge and ability of the attending veterinarian and farrier(s), lead to euthanasia of the patient.

Phases of laminitis
Treatment and prognosis depend on the phase of the disease, with horses treated in earlier stages often having a better prognosis.

Developmental phaseThe developmental phase is defined as the time between the initial exposure to the causative agent or incident, until the onset of clinical signs. It generally lasts 24–60 hours, and is the best time to treat a laminitis episode. Clinical laminitis may be prevented if cryotherapy (icing) is initiated during the developmental phase.
Acute phaseThe acute phase is the first 72 hours following the initiation of clinical signs. Treatment response during this time determines if the horse will go into the subacute phase or chronic phase. Clinical signs at this time include bounding digital pulses, lameness, heat, and possibly response to hoof testing.
Subacute phaseThe subacute phase occurs if there is minimal damage to the lamellae. Clinical signs seen in the acute phase resolve, and the horse becomes sound. The horse never shows radiographic changes, and there is no injury to the coffin bone.
Chronic phase
The chronic phase occurs if damage to the lamellae is not controlled early in the process, so that the coffin bone displaces. Changes that may occur include separation of the dermal and epidermal lamellae, lengthening of the dermal lamellae, and compression of the coronary and solar dermis. If laminitis is allowed to continue, long-term changes such as remodeling of the apex and distal border of the coffin bone (so that a "lip" develops) and osteolysis of the coffin bone can occur.The chronic phase may be compensated or uncompensated. Compensated cases will have altered hoof structure, including founder rings, wide white lines, and decreased concavity to the sole. Horses will be relatively sound. On radiographs, remodeling of the coffin bone and in cases of rotational displacement, the distal hoof wall will be thicker than that proximally. Venograms will have relatively normal contrast distribution, including to the apex and distal border of the coffin bone, and the coronary band, but "feathering" may be present at the lamellar "scar."Uncompensated cases will develop a lamellar wedge (pathologic horn), leading to a poor bridge between P3 and the hoof capsule. This will lead to irregular horn growth and chronic lameness, and horses will suffer from laminitis "flares." Inappropriate hoof growth will occur: the dorsal horn will have a tendency to grow outward rather than down, the heels will grow faster than the toe, and the white line will widen, leading to a potential space for packing of debris. The solar dermis is often compressed enough to inhibit growth, leading to a soft, thin sole (<10 mm) that may develop seromas. In severe cases where collapse of the suspensory apparatus of P3 has occurred, the solar dermis or the tip of P3 may penetrate the sole. The horse will also be prone to recurrent abscessation within the hoof capsule. Venogram will show "feathering" into the vascular bed beneath the lamellae, and there will be decreased or absent contrast material in the area distal to the apex of the coffin bone.

Causes
Laminitis has various causes, some of which commonly occur together.  These include:

Vasoactive amines
The inflammatory molecule histamine has also been hypothesized as a causative agent of laminitis.  However, contradictory evidence indicates the role of histamine in laminitis has not been conclusively established.

Mechanical separation
Commonly known as road founder, mechanical separation occurs when horses with long toes are worked extensively on hard ground.  The long toes and hard ground together contribute to delayed breakover, hence mechanical separation of the laminae at the toe.  Historically, this was seen in carriage horses bred for heavy bodies and long, slim legs with relatively small hooves; their hooves were trimmed for long toes (to make them lift their feet higher, enhancing their stylish "action"), and they were worked at speed on hard roads. Road founder is also seen in overweight animals, particularly when hooves are allowed to grow long; classic examples are ponies on pasture board in spring, and pregnant mares.

Poor blood circulation
Normal blood circulation in the lower limbs of a horse depends in part on the horse moving about.  Lack of sufficient movement, alone or in combination with other factors, can cause stagnant anoxia, which in turn can cause laminitis.A horse favoring an injured leg will both severely limit its movement and place greater weight on the other legs.  This sometimes leads to static laminitis, particularly if the animal is confined in a stall.  A notable example is the 2006 Kentucky Derby winner Barbaro.Transport laminitis sometimes occurs in horses confined in a trailer or other  transportation for long periods of time.  Historically, the most extreme instances were of horses shipped overseas on sailing ships.  However, the continual shifting of weight required to balance in a moving vehicle may enhance blood circulation, so some horsemen recommend trailering as an initial step in rehabilitation of a horse after long confinement.Laminitis has been observed following an equine standing in extreme conditions of cold, especially in deep snow. Laminitis has also followed prolonged heating such as may be experienced from prolonged contact with extremely hot soil or from incorrectly applied hot-shoeing.

Complex causes
Pituitary pars intermedia dysfunction, or Cushings disease, is common in older horses and ponies and causes an increased predisposition to laminitis.
Equine metabolic syndrome is a subject of much new research and is increasingly believed to have a major role in laminitis. It involves many factors such as cortisol metabolism and insulin resistance. It has some similarities to type II diabetes in humans. In this syndrome, peripheral fat cells synthesise adipokines which are analogous to cortisol, resulting in Cushings-like symptoms.
A retained placenta, if not passed completely after the birth of a foal, can cause mares to founder, whether through toxicity, bacterial fever, or both.
Anecdotal reports of laminitis following the administration of drugs have been made, especially in the case of corticosteroids.  The reaction may be an expression of idiosyncrasy in a particular patient, as many horses receive high dose glucocorticoid into their joints without showing any evidence of clinical laminitis.
Even horses not considered to be susceptible to laminitis can become laminitic when exposed to certain agrichemicals. The most commonly experienced examples are certain herbicides and synthetic nitrate fertilizer.

Risk factors
Whilst diet has long been known to be linked to laminitis, there is emerging evidence that breed and body condition also play a role. Levels of hormones, particularly adiponectin, and serum insulin are also implicated, opening up new possibilities for developing early prognostic tests and risk assessments.

Diagnosis
Early diagnosis is essential to effective treatment.  However, early outward signs may be fairly nonspecific.  Careful physical examination typically is diagnostic, but radiographs are also very useful.

Clinical signs
Increased temperature of the wall, sole and/or coronary band of the foot
A pounding pulse in the digital palmar artery
Anxiety and visible trembling
Increased vital signs and body temperature
Sweating
Flared nostrils
Walking very tenderly, as if walking on egg shells
Repeated "easing" of affected feet, i.e. constant shifting of weight
Lameness with a positive response to hoof testers at the toe
The horse stands in a "founder stance" in attempt to decrease the load on the affected feet. If it has laminitis in the front hooves, it will bring its hind legs underneath its body and put its fore legs out in front. In cases of sinking, the horse stands with all four feet close together, like a circus elephant.
Tendency to lie down whenever possible, and recumbency in extreme cases
Change in the outward appearance of the hoof in cases of chronic laminitis: dished (concave) dorsal hoof wall, "founder rings" (growth rings that are wider at the heel than the toe), a sole that is either flat or convex just dorsal to the apex of the frog which indicates P3 has displaced or penetrated, widening of the white line at the toe with or without bruising, "clubbing" of the foot.
Change in the appearance of the coronary band: hair that does not lie in a normal position (not against the hoof wall), indentation or rim just above the hoof capsule allowing palpation behind the coronary band.
In cases of sinking, it may be possible to palpate a groove between the coronary band and the skin of the pastern.

Lameness evaluation
Hoof testingLaminitic horses are generally sore to pressure from hoof testers applied over the toe area. However, there is risk of a false negative if the horse naturally has a thick sole, or if the hoof capsule is about to slough.
Obel grading systemThe severity of lameness is qualified using the Obel grading system:
Obel grade 1: Horse shifts weight between affected feet or continuously lifts feet up. It is sound at the walk but displays a shortened stride at the trot.
Obel grade 2: Horse displays a stilted, stiff gait, although is willing to walk. It is possible to easily lift a front foot and have the horse take all of its weight on the contralateral limb.
Obel grade 3: Horse displays a stilted, stiff gait, but is reluctant to walk and is difficult when asked to lift a front foot.
Obel grade 4: Horse is very reluctant to move, or is recumbent.Nerve blocksHorses suffering from the disease usually require an abaxial sesamoid block to relieve them of pain, since the majority of pain comes from the hoof wall. However, chronic cases may respond to a palmar digital block since they usually have primarily sole pain. Severe cases may not respond fully to nerve blocks.

Radiographs
Radiographs are an important part of evaluating the laminitic horse. They not only allow the practitioner to determine the severity of the episode, which does not always correlate with degree of pain,  but also to gauge improvement and response to treatment. Several measurements are made to predict severity. Additionally, radiographs also allow the visualization and evaluation of the hoof capsule, and can help detect the presence of a lamellar wedge or seromas. The lateral view provides the majority of the information regarding degree of rotation, sole depth, dorsal hoof wall thickness, and vertical deviation.  A 65-degree dorsopalmar view is useful in the case of chronic laminitis to evaluate the rim of the coffin bone for pathology.
Radiographic measurements
Several radiographic measurements, made on the lateral view, allow for objective evaluation of the episode.

Coronary extensor distance (CE): the vertical distance from the level of the proximal coronary band to the extensor process of P3. It is often used to compare progression of the disease over time, rather than as a stand-alone value. A rapidly increasing CE value can indicate distal displacement (sinking) of the coffin bone, while a more gradual increase in CE can occur with foot collapse. Normal values range from 0–30 mm, with most horses >12–15 mm.
Sole depth (SD): the distance from the tip of P3 to the ground.
Digital breakover (DB): distance from the tip of P3 to the breakover of the hoof (dorsal toe).
Palmar angle (PA): the angle between a line perpendicular to the ground, and a line at the angle of the palmar surface of P3.
Horn:lamellar distance (HL): the measurement from the most superficial aspect of the dorsal hoof wall to the face of P3. 2 distances are compared: a proximal measurement made just distal to the extensor process of P3, and a distal measurement made toward the tip of P3. These two values should be similar. In cases of rotation, the distal measurement will be higher than the proximal. In cases of distal displacement, both values will increase, but may remain equal. Therefore, it is ideal to have baseline radiographs for horses, especially for those at high-risk for laminitis, to compare to should laminitis ever be suspected. Normal HL values vary by breed and age:Weanlings will have a greater proximal HL compared to distal HL
Yearlings will have approximately equal proximal and distal HL
Thoroughbreds are usually 17mm proximally, and 19mm distally
Standardbreds have been shown to have a similar proximal and distal HL, around 16 mm at 2 years old, and 20 mm at 4 years old
Warmbloods have similar proximal and distal values, up to 20 mm each
HL tends to increase with age, up to 17 mm in most light breeds, or higher, especially in very old animalsVenogramsVenograms can help determine the prognosis for the animal, particularly in horses where the degree of pain does not match the radiographic changes. In venography, a contrast agent, visible on radiographs, is injected into the palmar digital vein to delineate the vasculature of the foot. The venogram can assess the severity and location of tissue compromise and monitor effectiveness of the current therapy. Compression of veins within the hoof will be seen as sections that do not contain contrast material. Poor or improper blood flow to different regions of the hoof help determine the severity of the laminitic episode. Venography is especially useful for early detection of support limb laminitis, as changes will be seen on venograph (and MRI) within 1–2 weeks, whereas clinical signs and radiographic changes do not manifest until 4–6 weeks.Horses undergoing venography have plain radiographs taken beforehand to allow for comparison. The feet are blocked to allow the sedated horse to stand comfortably during the procedure. Prior to injection, a tourniquet is placed around the fetlock to help keep the contrast material within the foot during radiography. Diffusion of contrast may make some areas appear hypoperfused, falsely increasing the apparent severity of the laminitic episode. After injection of the contrast material, films are taken within 45 seconds to avoid artifact caused by diffusion. Evaluation of blood supply to several areas of the foot allows the practitioner to distinguish mild, moderate, and severe compromise of the hoof, chronic laminitis, and sinking.

Other diagnostics
Other imaging tools have been used to show mechanical deviations in laminitis cases include computed tomography, as well as MRI, which also provides some physiologic information.  Nuclear scintigraphy may also be useful in certain situations. Ultrasonography has been explored as a way to quantify changes in bloodflow to the foot.

Prognosis
The sooner the diagnosis is made, the faster the treatment and the recovery process can begin. Rapid diagnosis of laminitis is often difficult, since the general problem often starts somewhere else in the horses body. With modern therapies, most laminitics will be able to bear a rider or completely recover, if treated quickly, and if the laminitis was not severe or complicated (e.g. by equine metabolic syndrome or Cushings disease). Even in these cases, a clinical cure can often be achieved. Endotoxic laminitis (e.g. after foaling) tends to be more difficult to treat. Successful treatment requires a competent farrier and veterinarian, and success is not guaranteed. A horse can live with laminitis for many years, and although a single episode of laminitis predisposes to further episodes, with good management and prompt treatment it is by no means the catastrophe sometimes supposed: most horses suffering an acute episode without pedal bone displacement make a complete functional recovery. Some countermeasures can be adopted for pasture based animals. Discovery of laminitis, either active or relatively stabilized, on an equine prepurchase exam typically downgrades the horses value, as the possibility of recurrence is a significant risk factor for the future performance of the horse.
Several radiographic abnormalities can be judged to correlate with a worsened prognosis:

Increased degree of rotation of P3 relative to the dorsal hoof wall (rotation greater than 11.5 degrees has a poorer prognosis)
Increased founder distance, the vertical distance from the coronary band (seen with a radio-opaque marker) to the dorsoproximal aspect of P3 (distance greater than 15.2mm has a poorer prognosis)
Decreased sole depth
Sole penetration by P3

Treatment
In laminitis cases, a clear distinction must be made between the acute onset of a laminitis attack and a chronic situation. A chronic situation can be either stable or unstable. The difference between acute, chronic, stable, and unstable is of vital importance when choosing a treatment protocol. There is no cure for a laminitic episode and many go undetected. Initial treatment with cryotherapy and anti-inflammatory drugs may prevent mechanical breakdown if instituted immediately, but many cases are only detected after the initial microscopic damage has been done. In cases of sepsis or endotoxemia, the underlying cause should be addressed concurrently with laminitis treatment. There are various methods for treating laminitis, and opinions vary on which are most useful. Additionally, each horse and affected hoof should be evaluated individually to determine the best treatment plan, which may change with time. Ideally, affected hooves are re-evaluated on a regular basis once treatment commences to track progress.

Management
Initial management usually includes stall rest to minimize movement, and deeply bedding the stall with shavings, straw, or sand. Exercise is slowly increased once the horse has improved, ideally in an area with good (soft) footing, beginning with hand-walking, then turn-out, and finally riding under saddle. This process may take months to complete.

Cryotherapy
Cooling of the hoof in the developmental stages of laminitis has been shown to have a protective effect when horses are experimentally exposed to carbohydrate overload. Feet placed in ice slurries were less likely to experience laminitis than "uniced" feet. Cryotherapy reduces inflammatory events in the lamellae. Ideally, limbs should be placed in an ice bath up to the level of the knee or hock. Hooves need to be maintained at a temperature less than 10 degrees Celsius at the hoof wall, for 24–72 hours.In the case of a full-blown case of laminitis, use of a cold water spa proved effective in the treatment of Bal a Bali. For the first three days, Bal a Bali was kept in the spa for eight hours at a time. Once his condition stabilized, he continued to be put in the spa twice a day over the next few months.

Drug therapies
Anti-inflammatories and analgesicsAnti-inflammatories are always used when treating acute case of laminitis, and include Nonsteroidal anti-inflammatory medications (NSAIDS), DMSO, pentoxpfylline, and cryotherapy. For analgesia, NSAIDs are often the first line of defense. Phenylbutazone is commonly used for its strong effect and relatively low cost. Flunixin (Banamine), ketofen, and others are also used.  Nonspecific NSAIDs such as suxibuzone, or COX-2-specific drugs, such as firocoxib and diclofenac, may be somewhat safer than phenylbutazone in preventing NSAID toxicity such as right dorsal colitis, gastric ulcers, and kidney damage. However, firocoxib provides less pain relief than phenylbutazone or flunixin. Care must be taken that pain is not totally eliminated, since this will encourage the horse to stand and move around, which increases mechanical separation of the laminae.Pentafusion, or the administration of ketamine, lidocaine, morphine, detomidine, and acepromazine at a constant rate of infusion, may be of particular benefit to horses suffering from laminitis. Epidurals may also be used in hind-limb laminitis.
VasodilatorsVasodilators are often used with the goal of improving laminar blood flow. However, during the developmental phases of laminitis, vasodilation is contraindicated, either through hot water or vasodilatory drugs.  Systemic acepromazine as a vasodilator with the fringe benefit of mild sedation which reduces the horse/ponys movements and thus reduces concussion on the hooves, may be beneficial after lamellar damage has occurred, although no effects on laminar blood flow with this medication have been shown. Nitroglycerine has also been applied topically in an attempt to increase blood flow, but this treatment does not appear to be an effective way to increase blood flow in the equine digit.

Trimming and shoeing
Besides pain management and control of any predisposing factors, mechanical stabilization is a primary treatment goal once the initial inflammatory and metabolic issues have resolved. No approach has been shown to be effective in all situations, and debate is ongoing about the merits and faults of the numerous techniques. Once the distal phalanx rotates, it is essential to derotate and re-establish its proper spatial orientation within the hoof capsule, to ensure the best long-term prospects for the horse. With correct trimming and, as necessary, the application of orthotics, one can effect this reorientation. However, this is not always completely effective.

TrimmingSuccessful treatment for any type of founder must necessarily involve stabilization of the bony column by some means. Correct trimming can help improve stabilization. This usually includes bringing the "break over" back to decrease the fulcrum-effect that stresses the laminae. Trimming the heels helps to ensure frog pressure and increases surface area for weight-bearing on the back half of the hoof. While horses may stabilize if left barefooted, some veterinarians believe the most successful methods of treating founder involve positive stabilisation of the distal phalanx, by mechanical means, e.g., shoes, pads, polymeric support, etc. Pour-in pads or putty is sometimes placed on the sole to increase surface area for weight-bearing, so that the sole in the area of the quarters, and the bars, will take some of the weight.
Altering the palmar angleThe deep digital flexor tendon places a constant pull on the back of the coffin bone. This is sometimes counteracted by decreasing the palmar angle of the hoof by raising the heels, often with the use of special shoes which have a wedge in the heel of approximately 20 degrees. Shoes are usually glued or cast onto the foot so painful nailing does not have to take place. The position of P3 within the hoof is monitored with radiographs. Once the horse has improved, the wedge of the shoe must be slowly reduced back to normal.
Use of orthoticsThe application of external orthotic devices to the foot in a horse with undisplaced laminitis and once displacement has occurred is widespread.  Most approaches attempt to shift weight away from the laminae and onto secondary weight-bearing structures, while sparing the sole.

Corrective hoof trimmingCorrective hoof trimming will restore proper hoof form and function. Corrective trimming will allow the hooves to be healthy again.

Realigning trimmingRealigning trimming trims back the toe so that it is in line with the coffin bone. Realigning trimming pushes the coffin bone back into the correct position. The process of a new hoof capsule totally growing out to replace the old one takes up to a year.

Alternative horseshoeing methods
New non-invasive horseshoeing methods are available for farriers to take advantage of. They encapsulate the damaged hoof, protecting and supporting the sensitive internal structures. This prevents further deterioration, whilst also immediately reducing pain and improving the horse’s ability to move. The resulting comfort also reduces overall stress levels, leading to a faster recovery as the horse can quickly return to a regular routine.

Aggressive therapies
Dorsal hoof wall resectionA dorsal hoof wall resection may help in certain conditions after consultation with an experienced veterinarian and farrier team. If decreased bloodflow distal to the coronary plexus is seen on a venogram, or when a laminar wedge forms between P3 and the hoof wall, preventing the proper reattachment (interdigitation) of the laminae, this procedure may be beneficial. When the coffin bone is pulled away from the hoof wall, the remaining laminae will tear. This may lead to abscesses within the hoof capsule that can be severe and very painful, as well as a mass of disorganized tissue called a laminar (or lamellar) wedge.
Coronary groovingCoronary grooving involves removing a groove of hoof wall just distal to the coronary band. It is thought to encourage dorsal hoof wall growth and improve alignment of the wall.
Deep digital flexor tenotomy
Because the rotation of P3 is exacerbated by continued pull on the deep digital flexor tendon, one approach to therapy has been to cut this tendon, either in the cannon region (mid-metacarpus) or in the pastern region </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 Diabetic bulla 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 Glucagonoma and can you explain it in depth? [/INST] Glucagonoma is a very rare tumor of the pancreatic alpha cells that results in the overproduction of the hormone, glucagon. Typically associated with a rash called necrolytic migratory erythema, weight loss, and mild diabetes mellitus, most people with glucagonoma contract it spontaneously. However, about 10% of cases are associated with multiple endocrine neoplasia type 1 (MEN-1) syndrome.

Causes
Although the cause of glucagonoma is unknown, some genetic factors may lead to the condition. A family history of multiple endocrine neoplasia type 1 (MEN1) is a risk factor. Additionally, those with Mahvash disease have an increased risk for glucagonoma, as glucagon receptor gene (GCGR) is mutated.

Mechanism
Glucagonoma results from the overproduction of glucagon, a peptide hormone located in the pancreatic alpha cells. Classic symptoms include, but are not limited to, necrolytic migratory erythema (NME), diabetes mellitus, and weight loss. NME presents in about 70% of cases of glucagonoma, and is characterized by erythematous lesions over the distal extremities and the groin area. NME has occasionally been observed in people who do not have glucagonoma. People who develop glucagonoma from Mahvash disease also do not develop NME, implying that working glucagon receptors are needed in order for NME to be present in a person. Weight loss, the most commonly associated effect with glucagonoma, results from the glucagon hormone, which prevents the uptake of glucose by somatic cells. Diabetes is not present in all cases of glucagonoma, but does frequently result from the insulin and glucagon imbalance.

Diagnosis
The presence of glucagonoma syndrome, the symptoms that accompany the pancreatic tumor, as well as elevated levels of glucagon in the blood, are what is used to diagnose glucagonoma </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 Non-specific interstitial pneumonia 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 Ghons complex and can you explain it in depth? [/INST] Ghons complex is a lesion seen in the lung that is caused by tuberculosis </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 African trypanosomiasis and can you explain it in depth? [/INST] African trypanosomiasis, also known as African sleeping sickness or simply sleeping sickness, is an insect-borne parasitic infection of humans and other animals. It is caused by the species Trypanosoma brucei. Humans are infected by two types, Trypanosoma brucei gambiense (TbG) and Trypanosoma brucei rhodesiense (TbR). TbG causes over 98% of reported cases. Both are usually transmitted by the bite of an infected tsetse fly and are most common in rural areas.Initially, the first stage of the disease is characterized by fevers, headaches, itchiness, and joint pains, beginning one to three weeks after the bite. Weeks to months later, the second stage begins with confusion, poor coordination, numbness, and trouble sleeping. Diagnosis is by finding the parasite in a blood smear or in the fluid of a lymph node. A lumbar puncture is often needed to tell the difference between first- and second-stage disease. If the disease is not treated quickly it can lead to death.
Prevention of severe disease involves screening the at-risk population with blood tests for TbG. Treatment is easier when the disease is detected early and before neurological symptoms occur. Treatment of the first stage has been with the medications pentamidine or suramin. Treatment of the second stage has involved eflornithine or a combination of nifurtimox and eflornithine for TbG. Fexinidazole is a more recent treatment that can be taken by mouth, for either  stages of TbG. While melarsoprol works for both types, it is typically only used for TbR, due to serious side effects. Without treatment, sleeping sickness typically results in death.The disease occurs regularly in some regions of sub-Saharan Africa with the population at risk being about 70 million in 36 countries. An estimated 11,000 people are currently infected with 2,800 new infections in 2015. In 2018 there were 977 new cases. In 2015 it caused around 3,500 deaths, down from 34,000 in 1990. More than 80% of these cases are in the Democratic Republic of the Congo. Three major outbreaks have occurred in recent history: one from 1896 to 1906 primarily in Uganda and the Congo Basin and two in 1920 and 1970 in several African countries. It is classified as a neglected tropical disease. Other animals, such as cows, may carry the disease and become infected in which case it is known as Nagana or animal trypanosomiasis.

Signs and symptoms
African trypanosomiasis symptoms occur in two stages: the hemolymphatic stage and the neurological stage (the latter being characterised by parasitic invasion of the central nervous system). Neurological symptoms occur in addition to the initial features, however, and the two stages may be difficult to distinguish based on clinical features alone.The disease has been reported to present with atypical symptoms in infected individuals who originate from non-endemic areas (e.g. travelers). The reasons for this are unclear and may be genetic. The low number of such cases may also have skewed findings. In such persons, the infection is said to present mainly as fever with gastrointestinal symptoms (e.g. diarrhoea and jaundice) with lymphadenopathy developing only rarely.Trypanosomal chancre
Systemic disease is sometimes presaged by a trypanosomal chancre developing at the site of the infectious fly bite within 2 days of infection. The chancre is most commonly observed in T. b. rhodesiense infection, and only rarely in T. b. gambiense (however, in T. b. gambiense infection, chancres are more common in persons from non-endemic areas).

Hemolymphatic phase
Incubation period is 1–3 weeks for T. b. rhodesiense, and longer (but less precisely characterised) in T. b. gambiense infection. The first/initial stage, known as the hemolymphatic phase, is characterized by non-specific, generalised symptoms like: fever (intermittent), headaches (severe), joint pains, itching, weakness, malaise, fatigue, weight loss, lymphadenopathy, and hepatosplenomegaly.Diagnosis may be delayed due to the vagueness of initial symptoms. The disease may also be mistaken for malaria (which may in fact occur as a co-infection).Intermittent fever
Fever is intermittent, with attacks lasting from a day to a week, separated by intervals of a few days to a month or longer. Episodes of fever become less frequent over the course of the disease.Lymphadenopathy
Invasion of the circulatory and lymphatic systems by the parasite is associated with severe swelling of lymph nodes, often to tremendous sizes. Posterior cervical lymph nodes are most commonly affected, however, axillary, inguinal, and epitrochlear lymph node involvement may also occur. Winterbottoms sign, the tell-tale swollen lymph nodes along the back of the neck, may appear. Winterbottoms sign is common in T. b. gambiense infection.Other features
Those affected may additionally present with: skin rash, haemolytic anaemia, hepatomegaly and abnormal liver function, splenomegaly, endocrine disturbance, cardiac involvement (e.g. pericarditis, and congestive heart failure), and ophthalmic involvement.

Neurological phase
The second phase of the disease, the neurological phase (also called the meningoencephalic stage), begins when the parasite invades the central nervous system by passing through the blood–brain barrier. Progression to the neurological phase occurs after an estimated 21–60 days in case of T. b. rhodesiense infection, and 300–500 days in case of T. b. gambiense infection.In actuality, the two phases overlap and are difficult to distinguish based on clinical features alone; determining the actual stage of the disease is achieved by examining the cerebrospinal fluid for the presence of the parasite.Sleep disorders
Sleep-wake disturbances are a leading feature of neurological stage and gave the disease its common name African sleeping sickness. Infected individuals experience a disorganized and fragmented sleep-wake cycle. Those affected experience sleep inversion resulting in daytime sleep and somnolence, and nighttime periods of wakefulness and insomnia. Additionally, those affected also experience episodes of sudden sleepiness.Neurological/neurocognitive symptoms
Neurological symptoms include: tremor, general muscle weakness, hemiparesis, paralysis of a limb, abnormal muscle tone, gait disturbance, ataxia, speech disturbances, paraesthesia, hyperaesthesia, anaesthesia, visual disturbance, abnormal reflexes, seizures, and coma. Parkinson-like movements might arise due to non-specific movement disorders and speech disorders.Psychiatric/behavioural symptoms
Individuals may exhibit psychiatric symptoms which may sometimes dominate the clinical diagnosis and may include aggressiveness, apathy, irritability, psychotic reactions and hallucinations, anxiety, emotional lability, confusion, mania, attention deficit, and delirium.

Advanced/late disease and outcomes
Without treatment, the disease is invariably fatal, with progressive mental deterioration leading to coma, systemic organ failure, and death. An untreated infection with T. b. rhodesiense will cause death within months whereas an untreated infection with T. b. gambiense will cause death after several years. Damage caused in the neurological phase is irreversible.

Cause
Trypanosoma brucei gambiense accounts for the majority of African trypanosomiasis cases, with humans as the main reservoir needed for the transmission, while Trypanosoma brucei rhodesiense is mainly zoonotic, with the occasional human infection. African trypanosomiasis is dependent on the interaction of the parasite (trypanosome) with the tsetse flies (vector), as well as the host (human for Trypanosoma brucei gambiense, and animals for Trypanosoma brucei rhodesiense). The risk of contracting African trypanosomiasis is dependent on coming in contact with an infected tsetse fly.

Trypanosoma brucei
There are two subspecies of the parasite that are responsible for starting the disease in humans. Trypanosoma brucei gambiense causes the diseases in west and central Africa, whereas Trypanosoma brucei rhodesiense has a limited geographical range and is responsible for causing the disease in east and southern Africa. In addition, a third subspecies of the parasite known as Trypanosoma brucei brucei is responsible for affecting animals but not humans.Humans are the main reservoir for T. b. gambiense but this species can also be found in pigs and other animals. Wild game animals and cattle are the main reservoir of T. b. rhodesiense. These parasites primarily infect individuals in sub-Saharan Africa because that is where the vector (tsetse fly) is located. The two human forms of the disease also vary greatly in intensity. T. b. gambiense causes a chronic condition that can remain in a passive phase for months or years before symptoms emerge and the infection can last about three years before death occurs.T. b. rhodesiense is the acute form of the disease, and death can occur within months since the symptoms emerge within weeks and it is more virulent and faster developing than T. b. gambiense. Furthermore, trypanosomes are surrounded by a coat that is composed of variant surface glycoproteins (VSG). These proteins act to protect the parasite from any lytic factors that are present in human plasma. The hosts immune system recognizes the glycoproteins present on the coat of the parasite leading to the production of different antibodies (IgM and IgG).These antibodies will then act to destroy the parasites that circulate around the blood. However, from the several parasites present in the plasma, a small number of them will experience changes in their surface coats resulting in the formation of new VSGs. Thus, the antibodies produced by the immune system will no longer recognize the parasite leading to proliferation until new antibodies are created to combat the novel VSGs. Eventually, the immune system will no longer be able to fight off the parasite due to the constant changes in VSGs and infection will arise.

Vector
The tsetse fly (genus Glossina) is a large, brown, biting fly that serves as both a host and vector for the trypanosome parasites. While taking blood from a mammalian host, an infected tsetse fly injects metacyclic trypomastigotes into skin tissue. From the bite, parasites first enter the lymphatic system and then pass into the bloodstream. Inside the mammalian host, they transform into bloodstream trypomastigotes, and are carried to other sites throughout the body, reach other body fluids (e.g., lymph, spinal fluid), and continue to replicate by binary fission.The entire life cycle of African trypanosomes is represented by extracellular stages. A tsetse fly becomes infected with bloodstream trypomastigotes when taking a blood meal on an infected mammalian host. In the flys midgut, the parasites transform into procyclic trypomastigotes, multiply by binary fission, leave the midgut, and transform into epimastigotes. The epimastigotes reach the flys salivary glands and continue multiplication by binary fission.The entire life cycle of the fly takes about three weeks. In addition to the bite of the tsetse fly, the disease can be transmitted by:

Mother-to-child infection: the trypanosome can sometimes cross the placenta and infect the fetus.
Laboratories: accidental infections, for example, through the handling of blood of an infected person and organ transplantation, although this is uncommon.
Blood transfusion
Sexual contactHorse-flies (Tabanidae) and stable flies (Muscidae) possibly play a role in transmission of nagana (the animal form of sleeping sickness) and the human disease form.

Pathophysiology
Tryptophol is a chemical compound produced by the trypanosomal parasite in sleeping sickness which induces sleep in humans.

Diagnosis
The gold standard for diagnosis is identification of trypanosomes in a sample by microscopic examination. Samples that can be used for diagnosis include chancre fluid, lymph node aspirates, blood, bone marrow, and, during the neurological stage, cerebrospinal fluid. Detection of trypanosome-specific antibodies can be used for diagnosis, but the sensitivity and specificity of these methods are too variable to be used alone for clinical diagnosis. Further, seroconversion occurs after the onset of clinical symptoms during a T. b. rhodesiense infection, so is of limited diagnostic use.Trypanosomes can be detected from samples using two different preparations. A wet preparation can be used to look for the motile trypanosomes. Alternatively, a fixed (dried) smear can be stained using Giemsas or Fields technique and examined under a microscope. Often, the parasite is in relatively low abundance in the sample, so techniques to concentrate the parasites can be used prior to microscopic examination. For blood samples, these include centrifugation followed by examination of the buffy coat; mini anion-exchange/centrifugation; and the quantitative buffy coat (QBC) technique. For other samples, such as spinal fluid, concentration techniques include centrifugation followed by examination of the sediment.Three serological tests are also available for detection of the parasite: the micro-CATT (card agglutination test for trypanosomiasis), wb-CATT, and wb-LATEX. The first uses dried blood, while the other two use whole blood samples. A 2002 study found the wb-CATT to be the most efficient for diagnosis, while the wb-LATEX is a better exam for situations where greater sensitivity is required.

Prevention
Currently there are few medically related prevention options for African trypanosomiasis (i.e. no vaccine exists for immunity). Although the risk of infection from a tsetse fly bite is minor (estimated at less than 0.1%), the use of insect repellants, wearing long-sleeved clothing, avoiding tsetse-dense areas, implementing bush clearance methods and wild game culling are the best options to avoid infection available for local residents of affected areas.In July 2000, a resolution was passed to form the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC). The campaign works to eradicate the tsetse vector population levels and subsequently the protozoan disease, by use of insecticide-impregnated targets, fly traps, insecticide-treated cattle, ultra-low dose aerial/ground spraying (SAT) of tsetse resting sites and the sterile insect technique (SIT). The use of SIT in Zanzibar proved effective in eliminating the entire population of tsetse flies but was expensive and is relatively impractical to use in many of the endemic countries afflicted with African trypanosomiasis.A pilot program in Senegal has reduced the tsetse fly population by as much as 99% by introducing male flies which have been sterilized by exposure to gamma rays.Regular active surveillance, involving detection and prompt treatment of new infections, and tsetse fly control is the backbone of the strategy used to control sleeping sickness. Systematic screening of at-risk communities is the best approach, because case-by-case screening is not practical in endemic regions. Systematic screening may be in the form of mobile clinics or fixed screening centres where teams travel daily to areas of high infection rates. Such screening efforts are important because early symptoms are not evident or serious enough to warrant people with gambiense disease to seek medical attention, particularly in very remote areas. Also, diagnosis of the disease is difficult and health workers may not associate such general symptoms with trypanosomiasis. Systematic screening allows early-stage disease to be detected and treated before the disease progresses, and removes the potential human reservoir. A single case of sexual transmission of West African sleeping sickness has been reported.

Treatment
First stage
The treatment for first-stage disease is fexinidazole by mouth or pentamidine by injection for T. b. gambiense. Suramin by injection is used for T. b. rhodesiense.

Second stage
Fexinidazole may be used for the second stage of TbG, if the disease is not severe. Otherwise a regimen involving the combination of nifurtimox and eflornithine, nifurtimox-eflornithine combination treatment (NECT), or eflornithine alone appear to be more effective and result in fewer side effects. These treatments may replace melarsoprol when available. NECT has the benefit of requiring less injections of eflornithine.Intravenous melarsoprol was previously the standard treatment for second-stage (neurological phase) disease and is effective for both types. Melarsoprol is the only treatment for second stage T. b. rhodesiense; however, it causes death in 5% of people who take it. Resistance to melarsoprol can occur.

Prognosis
If untreated, T. b. gambiense almost always results in death, with only a few individuals shown in a long-term 15 year follow-up to have survived after refusing treatment. T. b. rhodesiense, being a more acute and severe form of the disease, is consistently fatal if not treated. Disease progression greatly varies depending on disease form. For individuals which are infected by T. b. gambiense, which accounts for 98% of all of the reported cases, a person can be infected for months or even years without signs or symptoms until the advanced disease stage, where it is too late to be treated successfully. For individuals affected by T. b. rhodesiense, which accounts for 2% of all reported cases, symptoms appear within weeks or months of the infection. Disease progression is rapid and invades the central nervous system, causing death within a short amount of time.

Epidemiology
In 2010, it caused around 9,000 deaths, down from 34,000 in 1990. As of 2000, the disability-adjusted life-years (9 to 10 years) lost due to sleeping sickness are 2.0 million. From 2010 to 2014, there was an estimated 55 million people at risk for gambiense African Trypanosomiasis and over 6 million people at risk for rhodesiense African trypanosomiasis. In 2014, the World Health Organization reported 3,797 cases of Human African Trypanosomiasis when the predicted number of cases were to be 5,000. The number of total reported cases in 2014 is an 86% reduction to the total number of cases reported in 2000.The disease has been recorded as occurring in 37 countries, all in sub-Saharan Africa. It occurs regularly in southeast Uganda and western Kenya, and killed more than 48,000 Africans in 2008. The Democratic Republic of the Congo is the most affected country in the world, accounting for 75% of the Trypanosoma brucei gambiense cases. The population at risk being about 69 million with one third of this number being at a very high to moderate risk and the remaining two thirds at a low to very low risk. The number of people being affected by the disease has declined. At this rate, sleeping sickness elimination is a possibility. The World Health Organization plans to eradicate sleeping sickness by 2030.

History
The condition has been present in Africa for thousands of years. Because of a lack of travel between indigenous people, sleeping sickness in humans had been limited to isolated pockets. This changed after Arab slave traders entered central Africa from the east, following the Congo River, bringing parasites along. Gambian sleeping sickness travelled up the Congo River, and then further east.An Arab writer of the 14th century left the following description in the case of a sultan of the Mali Kingdom: "His end was to be overtaken by the sleeping sickness (illat an-nawm) which is a disease that frequently befalls the inhabitants of these countries especially their chieftains. Sleep overtakes one of them in such a manner that it is hardly possible to awake him."The British naval surgeon John Atkins described the disease on his return from West Africa in 1734:
The Sleepy Distemper (common among the Negroes) gives no other previous Notice, than a want of Appetite 2 or 3 days before; their sleeps are sound, and Sense and Feeling very little; for pulling, drubbing or whipping will scarce stir up Sense and Power enough to move; and the Moment you cease beating the smart is forgot, and down they fall again into a state of Insensibility, drivling constantly from the Mouth as in deep salivation; breathe slowly, but not unequally nor snort. Young people are more subject to it than the old; and the Judgement generally pronounced is Death, the Prognostik seldom failing. If now and then one of them recovers, he certainly loses the little Reason he had, and turns Ideot...
French naval surgeon Marie-Théophile Griffon du Bellay treated and described cases while stationed aboard the hospital ship Caravane in Gabon in the late 1860s.In 1901, a devastating epidemic erupted in Uganda, killing more than 250,000 people, including about two-thirds of the population in the affected lakeshore areas. According to The Cambridge History of Africa, "It has been estimated that up to half the people died of sleeping-sickness and smallpox in the lands on either bank of the lower river Congo."The causative agent and vector were identified in 1903 by David Bruce, and the subspecies of the protozoa were differentiated in 1910. Bruce had earlier shown that T. brucei was the cause of a similar disease in horses and cattle that was transmitted by the tsetse fly (Glossina morsitans).The first effective treatment, atoxyl, an arsenic-based drug developed by Paul Ehrlich and Kiyoshi Shiga, was introduced in 1910, but blindness was a serious side effect.
Suramin was first synthesized by Oskar Dressel and Richard Kothe in 1916 for Bayer. It was introduced in 1920 to treat the first stage of the disease. By 1922, Suramin was generally combined with tryparsamide (another pentavalent organoarsenic drug), the first drug to enter the nervous system and be useful in the treatment of the second stage of the gambiense form. Tryparsamide was announced in the Journal of Experimental Medicine in 1919 and tested in the Belgian Congo by Louise Pearce of the Rockefeller Institute in 1920. It was used during the grand epidemic in West and Central Africa on millions of people and was the mainstay of therapy until the 1960s. American medical missionary Arthur Lewis Piper was active in using tryparsamide to treat sleeping sickness in the Belgian Congo in 1925.Pentamidine, a highly effective drug for the first stage of the disease, has been used since 1937. During the 1950s, it was widely used as a prophylactic agent in western Africa, leading to a sharp decline in infection rates. At the time, eradication of the disease was thought to be at hand.The organoarsenical melarsoprol (Arsobal) developed in the 1940s is effective for people with second-stage sleeping sickness. However, 3–10% of those injected have reactive encephalopathy (convulsions, progressive coma, or psychotic reactions), and 10–70% of such cases result in death; it can cause brain damage in those who survive the encephalopathy. However, due to its effectiveness, melarsoprol is still used today. Resistance to melarsoprol is increasing, and combination therapy with nifurtimox is currently under research.Eflornithine (difluoromethylornithine or DFMO), the most modern treatment, was developed in the 1970s by Albert Sjoerdsma and underwent clinical trials in the 1980s. The drug was approved by the United States Food and Drug Administration in 1990. Aventis, the company responsible for its manufacture, halted production in 1999. In 2001, Aventis, in association with Médecins Sans Frontières and the World Health Organization, signed a long-term agreement to manufacture and donate the drug.In addition to sleeping sickness, previous names have included negro lethargy, maladie du sommeil (Fr), Schlafkrankheit (Ger), African lethargy, and Congo trypanosomiasis.
The British-led Sleeping Sickness Commission collecting tsetse flies, Uganda and Nyasaland, 1908-1913

Research
The genome of the parasite has been sequenced and several proteins have been identified as potential targets for drug treatment. Analysis of the genome also revealed the reason why generating a vaccine for this disease has been so difficult. T. brucei has over 800 genes that make proteins the parasite "mixes and matches" to evade immune system detection.Using a genetically modified form of a bacterium that occurs naturally in the gut of the vectors is being studied as a method of controlling the disease.Recent findings indicate that the parasite is unable to survive in the bloodstream without its flagellum. This insight gives researchers a new angle with which to attack the parasite.Trypanosomiasis vaccines are undergoing research.
Additionally, the Drugs for Neglected Diseases Initiative has contributed to the African sleeping sickness research by developing a compound called fexinidazole. This project was originally started in April 2007 and enrolled 749 people in the DRC and Central African Republic. The results showed efficacy and safety in both stages of the disease, both in adults and children ≥ 6 years old and weighing ≥ 20 kg. The European Medicines Agency approved it for first and second stage disease outside of Europe in November 2018. The treatment was approved in the DRC in December 2018.

Funding
For current funding statistics, human African trypanosomiasis is grouped with kinetoplastid infections. Kinetoplastids refer to a group of flagellate protozoa. Kinetoplastid infections include African sleeping sickness, Chagas disease, and Leishmaniasis. All together, these three diseases accounted for 4.4 million disability adjusted life years (DALYs) and an additional 70,075 recorded deaths yearly. For kinetoplastid infections, the total global research and development funding was approximately $136.3 million in 2012. Each of the three diseases, African sleeping sickness, Chagas disease, and Leishmaniasis each received approximately a third of the funding, which was about $36.8 million US dollars, $38.7 million US dollars, and $31.7 million US dollars, respectively.For sleeping sickness, funding was split into basic research, drug discovery, vaccines, and diagnostics. The greatest amount of funding was directed towards basic research of the disease; approximately $21.6 million US dollars was directed towards that effort. As for therapeutic development, approximately $10.9 million was invested.The top funder for kinetoplastid infection research and development are public sources. About 62% of the funding comes from high-income countries while 9% comes from low- and middle-income countries. High-income countries public funding is the largest contributor to the neglected disease research effort. However, in recent years, funding from high-income countries has been steadily decreasing; in 2007, high-income countries provided 67.5% of the total funding whereas, in 2012, high-income countries public funds only provided 60% of the total funding for kinetoplastid infections. This downwards trend leaves a gap for other funders, such as philanthropic foundations and private pharmaceutical companies to fill.Much of the progress that has been made in African sleeping sickness and neglected disease research as a whole is a result of the other non-public funders. One of these major sources of funding has come from foundations, which have increasingly become more committed to neglected disease drug discovery in the 21st century. In 2012, philanthropic sources provided 15.9% of the total funding. The Bill and Melinda Gates Foundation has been a leader in providing funding for neglected disease drug development. They have provided $444.1 million US dollars towards neglected disease research in 2012. To date, they have donated over $1.02 billion US dollars towards the neglected disease discovery efforts.For kinetoplastid infections specifically, they have donated an average of $28.15 million US dollars annually between the years 2007 to 2011. They have labeled human African trypanosomiasis a high-opportunity target meaning it is a disease that presents the greatest opportunity for control, elimination, and eradication, through the development of new drugs, vaccines, public-health programs, and diagnostics. They are the second-highest funding source for neglected diseases, immediately behind the US National Institutes of Health. At a time where public funding is decreasing and government grants for scientific research are harder to obtain, the philanthropic world has stepped in to push the research forward.
Another important component of increased interest and funding has come from industry. In 2012, they contributed 13.1% total to the kinetoplastid research and development effort, and have additionally played an important role by contributing to public-private partnerships (PPP) as well as product-development partnerships (PDP). A public-private partnership is an arrangement between one or more public entities and one or more private entities that exists to achieve a specific health outcome or to produce a health product. The partnership can exist in numerous ways; they may share and exchange funds, property, equipment, human resources, and intellectual property. These public-private partnerships and product-development partnerships have been established to address challenges in pharmaceutical industry, especially related to neglected disease research. These partnerships can help increase the scale of the effort towards therapeutic development by using different knowledge, skills, and expertise from different sources </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 Congenital stromal corneal dystrophy 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 Vici syndrome and can you explain it in depth? [/INST] Vici syndrome, also called immunodeficiency with cleft lip/palate, cataract, hypopigmentation and absent corpus callosum (or absent corpus callosum cataract immunodeficiency), is a rare autosomal recessive congenital disorder characterized by albinism, agenesis of the corpus callosum, cataracts, cardiomyopathy, severe psychomotor retardation, seizures, immunodeficiency and recurrent severe infections. To date, about 50 cases have been reported.

Presentation
This syndrome consists of a number of typical features. These include
Agenesis of the corpus callosum (80–99% patients)
Hypopigmentation of the eyes and hair (80–99% patients)
Cardiomyopathy (80–99% patients)
Combined immunodeficiency (80–99% patients)
Muscular hypotonia (80–99% patients)
Abnormality of retinal pigmentation (80–99% patients)
Recurrent chest infections (80–99% patients)
Abnormal EEG (80–99% patients)
Intellectual disability (80–99% patients)
Cataracts (75%)
Seizures (65%)
Renal abnormalities (15%)Infections of the gastrointestinal and urinary tracts are common. Swallowing and feeding difficulties early on may result in a failure to thrive. Optic nerve hypoplasia, nystagmus and photophobia may occur. Facial dysmorphism (cleft lip/palate and micrognathia) and syndactyly may be present. Sensorineural hearing loss may also be present.Death in infancy is not uncommon and is usually due to cardiac complications or severe infections.

Genetics
Inheritance
Vici syndrome is inherited in an autosomal recessive manner. This means the defective gene responsible for the disorder is located on an autosome, and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both carry one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder.
The hypothesis of autosomal recessive inheritance of Vici syndrome was strengthened in 2002 with the clinical description of two new cases, one brother and one sister, by Chiyonobu et al.

Gene
Vici syndrome is caused by mutations in the gene EPG5 (OMIM # 615068), which encodes an important regulator of the autophagy pathway, the ectopic P-granules autophagy protein 5, involved in the formation of lysosomes.
EPG5 is the human homolog of the C.elegans epg5 gene. The gene EPG5 has been cloned for the first time by Nagase et al. by sequencing clones obtained from a size-fractionated fetal brain cDNA library, and was initially named KIAA1632.The EPG5 human gene is located on chromosome 18q12.3, has a length of 119,67Kb (NC_000018.10), consists of 44 exons and is transcriptionally driven from the centromere toward the telomere. The messenger RNA (mRNA) is 12633bp long (NM_020964.2) and contains a CDS of 7740 bp translated into a protein sequence of 2579 amino acids (NP_066015.2) with a molecular weight of 280kDa, presumed. The protein EPG5 is expressed primarily in the central nervous system (CNS), skeletal muscle, heart, thymus, cells of the immune system, lungs and kidneys.Mutations in the EPG5 gene interfere with the autophagy </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 cystica 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 Accommodative insufficiency and can you explain it in depth? [/INST] Accommodative insufficiency (AI) involves the inability of the eye to focus properly on an object. Accommodation is the adjustment of the curvature of the lens to focus on objects near and far.
In this condition, amplitude of accommodation of a person is lesser compared to physiological limits for his age. AI is generally considered separate from presbyopia, but mechanically both conditions represent a difficulty engaging the near vision system (accommodation) to see near objects clearly </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 Myoclonic astatic epilepsy and can you explain it in depth? [/INST] Myoclonic astatic epilepsy (MAE), also known as myoclonic atonic epilepsy or Doose syndrome, is a generalized idiopathic epilepsy. It is characterized by the development of myoclonic seizures and/or myoclonic astatic seizures. Some of the common monogenic causes include mutations in the genes SLC6A1 (3p25.3),CHD2 (15q26.1), AP2M1 (10q23.2).

Signs and symptoms
Tonic-clonic seizures: seizures with repetitive sequences of stiffening and jerking of the extremities.
Myoclonic seizures: seizures with rapid, brief contractions of muscles.
Atonic seizures: seizures with a sudden loss of muscle tone, often resulting in sudden collapse. These are also called drop seizures or astatic seizures.
Absence seizures: a generalized seizure characterized by staring off and occasionally some orofacial automatisms.
Myoclonic astatic seizures: seizures that involve a myoclonic seizure followed immediately by an atonic seizure. This type of seizure is exclusive to MAE and is one of the defining characteristics of this syndrome.
Tonic seizures: muscle stiffening or rigidity. This seizure is rare in this syndrome.

Onset
The onset of seizures is between the ages of 2 and 5 years of age. EEG shows regular and irregular bilaterally synchronous 2- to 3-Hz spike-waves and polyspike patterns with a 4- to 7-Hz background. 84% of affected children show normal development prior to seizures; the remainder show moderate psychomotor retardation mainly affecting speech. Boys (74%) are more often affected than girls (Doose and Baier 1987a).

Diagnosis
Treatments
The treatment for seizures may include antiepileptic medications, diet and vagus nerve stimulator.

Medication
Any number of medications may be used to both prevent and treat seizures.
Generally after three medications are tried, different treatment should be considered. Some medications are harmful to those with this syndrome and can increase seizures.

Diet
The ketogenic diet mimics some of the effects of starvation, in which the body first uses up glucose and glycogen before burning stored body fat. In the absence of glucose, the body produces ketones, a chemical by-product of fat metabolism that has been known to inhibit seizures.
A modified version of a popular low-carbohydrate, high-fat diet which is less restrictive than the ketogenic diet.
The low glycemic index treatment (LGIT) is a new dietary therapy currently being studied to treat epilepsy. LGIT attempts to reproduce the positive effects of the ketogenic diet. The treatment allows a more generous intake of carbohydrates than the ketogenic diet, but is restricted to foods that have a low glycemic index, meaning foods that have a relatively low impact on blood-glucose levels. These foods include meats, cheeses, and most vegetables because these foods have a relatively low glycemic index. Foods do not have to be weighed, but instead careful attention must be paid to portion size and balancing the intake of carbohydrates throughout the day with adequate amounts of fats and proteins.

Prognosis
Epilepsy with myoclonic-astatic seizures has a variable course and outcome </s>