Osteoarthritis (OA) also known as degenerative arthritis or degenerative joint disease, is a group of mechanical abnormalities involving degradation of joints, including articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, locking, and sometimes an effusion. A variety of causes—hereditary, developmental, metabolic, and mechanical—may initiate processes leading to loss of cartilage. When bone surfaces become less well protected by cartilage, bone may be exposed and damaged. As a result of decreased movement secondary to pain, regional muscles may atrophy, and ligaments may become more lax.

Treatment generally involves a combination of exercise, lifestyle modification, and analgesics. If pain becomes debilitating, joint replacement surgery may be used to improve the quality of life. OA is the most common form of arthritis, and the leading cause of chronic disability in the United States. It affects about 8 million people in the United Kingdom and nearly 27 million people in the United States.

Osteoarthritis can be classified into either primary or secondary depending on whether or not there is an identifiable underlying cause.

The main symptom is pain, causing loss of ability and often stiffness. "Pain" is generally described as a sharp ache, or a burning sensation in the associate muscles and tendons. OA can cause a crackling noise (called "crepitus") when the affected joint is moved or touched, and patients may experience muscle spasm and contractions in the tendons. Occasionally, the joints may also be filled with fluid. Humid and cold weather increases the pain in many patients.

OA commonly affects the hands, feet, spine, and the large weight bearing joints, such as the hips and knees, although in theory, any joint in the body can be affected. As OA progresses, the affected joints appear larger, are stiff and painful, and usually feel better with gentle use but worse with excessive or prolonged use, thus distinguishing it from rheumatoid arthritis.

In smaller joints, such as at the fingers, hard bony enlargements, called Heberden's nodes (on the distal interphalangeal joints) and/or Bouchard's nodes (on the proximal interphalangeal joints), may form, and though they are not necessarily painful, they do limit the movement of the fingers significantly. OA at the toes leads to the formation of bunions, rendering them red or swollen. Some people notice these physical changes before they experience any pain.

OA is the most common cause of joint effusion, sometimes called water on the knee in lay terms, an accumulation of excess fluid in or around the knee joint.

Exercise, including running in the absence of injury, has not been found to increase one's risk of developing osteoarthritis. Cracking ones knuckles also does not appear to play a role. Some investigators believe that mechanical stress on joints underlies all osteoarthritis, with many and varied sources of mechanical stress, including misalignments of bones caused by congenital or pathogenic causes; mechanical injury; overweight; loss of strength in muscles supporting joints; and impairment of peripheral nerves, leading to sudden or uncoordinated movements that overstress joints.

Primary osteoarthritis is a chronic degenerative disorder related to but not caused by aging, as there are people well into their nineties who have no clinical or functional signs of the disease. As a person ages, the water content of the cartilage decreases as a result of a reduced proteoglycan content, thus causing the cartilage to be less resilient. Without the protective effects of the proteoglycans, the collagen fibers of the cartilage can become susceptible to degradation and thus exacerbate the degeneration. Inflammation of the surrounding joint capsule can also occur, though often mild (compared to that which occurs in rheumatoid arthritis). This can happen as breakdown products from the cartilage are released into the synovial space, and the cells lining the joint attempt to remove them. New bone outgrowths, called "spurs" or osteophytes, can form on the margins of the joints, possibly in an attempt to improve the congruence of the articular cartilage surfaces. These bone changes, together with the inflammation, can be both painful and debilitating.

A number of studies have shown that there is a greater prevalence of the disease among siblings and especially identical twins, indicating a hereditary basis. Up to 60% of OA cases are thought to result from genetic factors.

Both primary generalized nodal OA and erosive OA (EOA. also called inflammatory OA) are sub-sets of primary OA. EOA is a much less common, and more aggressive inflammatory form of OA which often affects the DIPs and has characteristic changes on X-Ray.

Diagnosis is made with reasonable certainty based on history and clinical examination. X-rays may confirm the diagnosis. The typical changes seen on X-ray include: joint space narrowing, subchondral sclerosis (increased bony formation around the joint), subchondral cyst formation, and osteophytes. Plain films may not correlate with the findings on physical examination or with the degree of pain. Usually other imaging techniques are not necessary to clinically diagnose osteoarthritis.

In 1990, the American College of Rheumatology, using data from a multi-center study, developed a set of criteria for the diagnosis of hand osteoarthritis based on hard tissue enlargement and swelling of certain joints. These criteria were found to be 92% sensitive and 98% specific for hand osteoarthritis versus other entities such as rheumatoid arthritis and spondyloarthropathies.

Related pathologies whose names may be confused with osteoarthritis include pseudo-arthrosis. This is derived from the Greek words pseudo, meaning "false", and arthrosis, meaning "joint." Radiographic diagnosis results in diagnosis of a fracture within a joint, which is not to be confused with osteoarthritis which is a degenerative pathology affecting a high incidence of distal phalangeal joints of female patients.

Lifestyle modification (such as weight loss and exercise) and analgesics are the mainstay of treatment. Acetaminophen / paracetamol is used first line and NSAIDS are only recommended as add on therapy if pain relief is not sufficient. This is due to the relative greater safety of acetaminophen.

Physical therapy has been shown to significantly improve function, decrease pain, and delay need for surgical intervention in advanced cases. Exercise prescribed by a physical therapist has been shown to be more effective than medications in treating osteoarthritis of the knee. Functional, gait, and balance training has been recommended to address impairments of proprioception, balance, and strength in individuals with lower extremity arthritis as these can contribute to higher falls in older individuals. Splinting of the thumb for OA of the base of the thumb leads to improvements after one year.

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Sarcoidosis also called sarcoid, Besnier-Boeck disease or Besnier-Boeck-Schaumann disease, is a disease in which abnormal collections of chronic inflammatory cells (granulomas) form as nodules in multiple organs. The cause of sarcoidosis is unknown. Granulomas most often appear in the lungs or the lymph nodes, but virtually any organ can be affected. Normally the onset is gradual. Sarcoidosis may be asymptomatic or chronic. It commonly improves or clears up spontaneously. More than 2/3 of people with lung sarcoidosis have no symptoms after 9 years. About 50% have relapses. About 10% develop serious disability. Lung scarring or infection may lead to respiratory failure and death.

Sarcoidosis is a systemic disease that can affect any organ. Common symptoms are vague, such as fatigue unchanged by sleep, lack of energy, weight loss, aches and pains, arthritis, dry eyes, swelling of the knees, blurry vision, shortness of breath, a dry hacking cough or skin lesions. Sarcoidosis and cancer may mimic one another, making the distinction difficult. The cutaneous symptoms vary, and range from rashes and noduli (small bumps) to erythema nodosum or lupus pernio. It is often asymptomatic.

The combination of erythema nodosum, bilateral hilar lymphadenopathy and arthralgia is called Löfgren syndrome. This syndrome has a relatively good prognosis.

Renal, liver (including portal hypertension), heart or brain involvement may cause further symptoms and altered functioning. Sarcoidosis affecting the brain or nerves is known as neurosarcoidosis.

Although cardiac involvement is present in 20% to 30% of patients with sarcoidosis, only about 5% of patients with systemic sarcoidosis are symptomatic.

The presentation of cardiac sarcoidosis can range from asymptomatic conduction abnormalities to fatal ventricular arrhythmia. Myocardial sarcoidosis can be a rare cause of sudden cardiac death.

Manifestations in the eye include uveitis, uveoparotitis, and retinal inflammation, which may result in loss of visual acuity or blindness. The combination of anterior uveitis, parotitis, VII cranial nerve paralysis and fever is called uveoparotid fever, and is associated with Heerfordt-Waldenstrom syndrome.

The central nervous system is involved in fewer than 1% of patients with sarcoidosis. There is usually granulomatous involvement of the basal meninges that subsequently affects the cranial nerves. Myelopathy may be the initial clinical presentation of intramedullary neurosarcoidosis.

Diagnosis of sarcoidosis is often a matter of exclusion. To exclude sarcoidosis in a case presenting with pulmonary symptoms might involve chest X-ray, CT scan of chest, PET scan, CT-guided biopsy, mediastinoscopy, open lung biopsy, bronchoscopy with biopsy, endobronchial ultrasound and endoscopic ultrasound with FNA of mediastinal lymph nodes(EBUS FNA). Tissue from biopsy of lymph nodes is subjected to both flow cytometry to rule out cancer and special stains (acid fast bacilli stain and Gömöri methenamine silver stain) to rule out microorganisms and fungi. Angiotensin-converting enzyme blood levels are used in diagnosis and monitoring of sarcoidosis.

Differential diagnosis includes metastatic disease, lymphoma, septic emboli, rheumatoid nodules, Wegener's granulomatosis, varicella infection, and atypical infections such as mycobacterium avium complex, cytomegalovirus, and cryptococcus.

Because of the wide range of possible manifestations the investigations to confirm diagnosis may involve many organs and methods depending on initial presentation.

Very often, Sarcoidosis presents as a restrictive disease of the lungs, causing a decrease in lung volume and decreased compliance (the ability to stretch) - hence chest X-ray and other methods are used to assess the severity or rule out pulmonary disease.

The disease typically limits the amount of air drawn into the lungs, but produces higher than normal expiratory flow ratios. The vital capacity (full breath in, to full breath out) is decreased, and most of this air can be blown out in the first second. This means the FEV1/FVC ratio is increased from the normal of about 80%, to 90%. Obstructive lung changes, causing a decrease in the amount of air that can be exhaled, may occur when enlarged lymph nodes in the chest compress airways or when internal inflammation or nodules impede airflow.

Chest X-ray changes are divided into four stages

1. Stage 1 bihilar lymphadenopathy
2. Stage 2 bihilar lymphadenopathy and reticulonodular infiltrates
3. Stage 3 bilateral pulmonary infiltrates
4. Stage 4 fibrocystic sarcoidosis typically with upward hilar retraction, cystic & bullous changes

Investigations to assess involvement of other organs frequently involve electrocardiogram, ocular examination by an ophthalmologist, liver function tests, renal function tests, serum calcium and 24-hour urine calcium.

In female patients, sarcoidosis is significantly associated with hypothyroidism, hyperthyroidism and other thyroid diseases, hence close surveillance of thyroid function is recommended.

The exact cause of sarcoidosis is not known. The current working hypothesis is that in genetically susceptible individuals sarcoidosis is caused through alteration in immune response after exposure to an environmental, occupational, or infectious agent.

Granulomatous inflammation is characterized primarily by accumulation of monocytes, macrophages and activated T-lymphocytes, with increased production of key inflammatory mediators, TNF-alpha, IFN-gamma, IL-2 and IL-12, characteristic of a Th1-polarized response (T-helper lymphocyte-1 response). Sarcoidosis has paradoxical effects on inflammatory processes; it is characterized by increased macrophage and CD4 helper T-cell activation resulting in accelerated inflammation, however, immune response to antigen challenges such as tuberculin is suppressed. This paradoxic state of simultaneous hyper- and hypo- activity is suggestive of a state of anergy. The anergy may also be responsible for the increased risk of infections and cancer. It appears that regulatory T-lymphocytes in the periphery of sarcoid granulomas suppress IL-2 secretion which is hypothesized to cause the state of anergy by preventing antigen-specific memory responses.

While it is widely believed that TNF-alpha plays an important role in the formation of granulomas, it was observed that sarcoidosis can be triggered by treatment with the TNF-alpha antagonist etanercept.

Investigations of genetic susceptibility yielded many candidate genes but only few were confirmed by further investigations and no reliable genetic markers are known. Currently, the most interesting candidate gene is BTNL2; several HLA-DR risk alleles are also being investigated. In persistent sarcoidosis the HLA haplotype HLA-B7-DR15 are either cooperating in disease or another gene between these two loci is associated. In non-persistent disease there is a strong genetic association with HLA DR3-DQ2. Siblings have only a modestly increased risk (hazard ratio 5-6) of developing the disease, indicating that genetic susceptibility plays only a small role. The alternate hypothesis that family members share similar exposures to environmental pathogens is quite plausible to explain the apparent hereditary factor.

Several infectious agents appear to be significantly associated with sarcoidosis but none of the known associations is specific enough to suggest a direct causative role. Propionibacterium acnes can be found in bronchoalveolar lavage of approximately 70% patients and is associated with disease activity, however it can be also found in 23% of controls. A recent meta-analysis investigating the role of mycobacteria in sarcoidosis found it was present in 26.4% of cases, however the meta-analysis also detected a possible publication bias, so the results need further confirmation.

There have also been reports of transmission of sarcoidosis via organ transplants.

Sarcoidosis frequently causes an increase in vitamin D production outside the kidney. Macrophages inside the granulomas convert vitamin D to its active form, resulting in elevated levels of the hormone 1,25-dihydroxyvitamin D and symptoms of hypervitaminosis D that may include fatigue, lack of strength or energy, irritability, metallic taste, temporary memory loss or cognitive problems. Physiological compensatory responses (e.g., suppression of the parathyroid hormone levels) may mean the patient does not develop frank hypercalcemia. This condition may be aggravated by high levels of estradiol and prolactin such as in pregnancy, leading to hypercalciuria and/or compensatory hypoparathyroidism. High levels of Vitamin D are also implicated in immune-system dysfunctions which tie into the sarcoid condition.

Prolactin is frequently increased in sarcoidosis, between 3–32% cases have hyperprolactinemia, this frequently leads to amenorrhea, galactorrhea or nonpuerperal mastitis in women. Prolactin also has a broad spectrum of effects on the immune system and increased prolactin levels are associated with disease activity or may exacerbate symptoms in many autoimmune diseases and treatment with prolactin lowering medication has been shown effective in some cases. However it is unknown if this relation holds in sarcoidosis and the gender predilection in sarcoidosis is less pronounced than in some other autoimmune diseases where such relation has been established. In pregnancy, the effects of prolactin and estrogen counteract each other to some degree, with a slight trend to improve pulmonary manifestations of sarcoidosis while lupus, uveitis and arthralgia might slightly worsen. Lupus, uveitis and arthralgia are known to be in some cases associated with increased prolactin levels and respond to bromocriptin treatment but so far this has not been investigated specifically for sarcoidosis. The reasons for increased prolactin levels in sarcoidosis are uncertain. It has been observed that prolactin is produced by T-lymphocytes in some autoimmune disorders in amounts high enough to affect the feedback by the hypothalamic dopaminergic system.

The extrapituitary prolactin is believed to play a role as a cytokine like proinflammatory factor. Prolactin antibodies are believed to play a role in hyperprolactinemia in other autoimmune disorders and high prevalence endocrine autoimmunity has been observed in patients with sarcoidosis. It may also be a consequence of renal disease or treatment with steroids. Neurosarcoidosis may occasionally cause hypopituiarism but has not been reported to cause hyperprolactinemia.

In women, a substantial association of thyroid disease and sarcoidosis has been reported. The association is less marked but still significant for male patients. Female patients have a significantly elevated risk for hypothyroidism, hyperthyroidism and thyroid autoimmunity and it appears that autoimmunity is very important in the pathogenesis of thyroid disease in this population. Thyroid granulomatosis on the other hand is uncommon.

Association of autoimmune disorders has been frequently observed. The exact mechanism of this relation is not known but some evidence supports the hypothesis that this is a consequence of Th1 lymphokine prevalence.

Sarcoidosis has been associated with celiac disease. Celiac disease is a condition in which there is a chronic reaction to certain protein chains, commonly referred to as glutens, found in some cereal grains. This reaction causes destruction of the villi in the small intestine, with resulting malabsorption of nutrients.

An association with type IV hypersensitivity has been described. Tests of delayed cutaneous hypersensitivity have been used to measure progression.

Between 30 and 70% of patients do not require therapy. Corticosteroids, most commonly prednisolone, have been the standard treatment for many years. In some patients, this treatment can slow or reverse the course of the disease, but other patients do not respond to steroid therapy. The use of corticosteroids in mild disease is controversial because in many cases the disease remits spontaneously. Additionally, corticosteroids have many recognized dose- and duration-related side effects, and their use is generally limited to severe, progressive, or organ-threatening disease. The influence of corticosteroids or other immunosuppressants on the natural history is unclear.

Severe symptoms are generally treated with steroids, and steroid-sparing agents such as azathioprine and methotrexate are often used. Rarely, cyclophosphamide has also been used. As the granulomas are caused by collections of immune system cells, particularly T cells, there has been some early indications of success using immunosuppressants, interleukin-2 inhibitors or anti-tumor necrosis factor-alpha treatment (such as infliximab). Unfortunately, none of these has provided reliable treatment, and there can be significant side effects such as an increased risk of reactivating latent tuberculosis. Anti-tumor necrosis factor-alpha treatment with etanercept in rheumatoid arthritis has been observed to cause sarcoidosis.

Because sarcoidosis can affect multiple organ systems, follow-up on a patient with sarcoidosis should always include an electrocardiogram, ocular examination by an ophthalmologist, liver function tests, serum calcium and 24-hour urine calcium. In female patients sarcoidosis is significantly associated with hypothyroidism, hyperthyroidism and other thyroid diseases, hence close surveillance of thyroid function is recommended.

The disease can remit spontaneously or become chronic, with exacerbations and remissions. In some patients, it can progress to pulmonary fibrosis and death. Approximately half of the cases resolve without treatment or can be cured within 12–36 months and most within 5 years. Some cases persist several decades. Where the heart is involved, the prognosis is poor. Patients with sarcoidosis appear to be at significantly increased risk for cancer, in particular lung cancer, malignant lymphomas, and cancer in other organs known to be affected in sarcoidosis. In sarcoidosis-lymphoma syndrome, sarcoidosis is followed by the development of a lymphoproliferative disorder such as non-Hodgkin lymphoma. This may be attributed to the underlying immunological abnormalities that occur during the sarcoidosis disease process. Sarcoidosis can also follow cancer or occur concurrently with cancer. There have been reports of hairy cell leukemia, acute myeloid leukemia, and acute myeloblastic leukemia associated with sarcoidosis.

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Keratoconus is a degenerative disorder of the eye in which structural changes within the cornea cause it to thin and change to a more conical shape than its normal gradual curve.

Keratoconus can cause substantial distortion of vision, with multiple images, streaking and sensitivity to light all often reported by the patient. It is typically diagnosed in the patient's adolescent years and attains its most severe state in the twenties and thirties. If afflicting both eyes, the deterioration in vision can affect the patient's ability to drive a car or read normal print. In most cases, corrective lenses are effective enough to allow the patient to continue to drive legally and likewise function normally. Further progression of the disease may require surgery including intrastromal corneal ring segments, corneal collagen cross-linking, or corneal transplantation. However, despite the disease's unpredictable course, keratoconus can often be successfully managed with little or no impairment to the patient's quality of life.

Keratoconus affects around one person in a thousand. It seems to occur in populations throughout the world, although it occurs more frequently in certain ethnic groups such as South Asians. The exact cause of keratoconus is uncertain, but has been associated with detrimental enzyme activity within the cornea. Environmental and genetic factors are considered possible causes, but the findings are still yet inconclusive. The progression of keratoconus is rapid in patients having Down syndrome.

People with early keratoconus typically notice a minor blurring of their vision and come to their clinician seeking corrective lenses for reading or driving. At early stages, the symptoms of keratoconus may be no different from those of any other refractive defect of the eye. As the disease progresses, vision deteriorates, sometimes rapidly. Visual acuity becomes impaired at all distances, and night vision is often quite poor. Some individuals have vision in one eye that is markedly worse than that in the other eye. The disease is often bilateral, though asymmetrical in many patients. Some develop photophobia (sensitivity to bright light), eye strain from squinting in order to read, or itching in the eye, but there is normally little or no sensation of pain.

The classic symptom of keratoconus is the perception of multiple 'ghost' images, known as monocular polyopia. This effect is most clearly seen with a high contrast field, such as a point of light on a dark background. Instead of seeing just one point, a person with keratoconus sees many images of the point, spread out in a chaotic pattern. This pattern does not typically change from day to day, but over time it often takes on new forms. Patients also commonly notice streaking and flaring distortion around light sources. Some even notice the images moving relative to one another in time with their heart beat.

The predominant optical aberration of the eye as an optical system in keratoconus is the so-called coma.

Prior to any physical examination, the diagnosis of keratoconus frequently begins with an ophthalmologist's or optometrist's assessment of the patient's medical history, particularly the chief complaint and other visual symptoms, the presence of any history of ocular disease or injury which might affect vision, and the presence of any family history of ocular disease. An eye chart, such as a standard Snellen chart of progressively smaller letters, is then used to determine the patient's visual acuity. The eye examination may proceed to measurement of the localised curvature of the cornea with a manual keratometer, with detection of irregular astigmatism suggesting a possibility of keratoconus. Severe cases can exceed the instrument's measuring ability. A further indication can be provided by retinoscopy, in which a light beam is focused on the patient's retina and the reflection, or reflex, observed as the examiner tilts the light source back and forth. Keratoconus is amongst the ophthalmic conditions that exhibit a scissor reflex action of two bands moving toward and away from each other like the blades of a pair of scissors.

If keratoconus is suspected, the ophthalmologist or optometrist will search for other characteristic findings of the disease by means of slit lamp examination of the cornea. An advanced case is usually readily apparent to the examiner, and can provide for an unambiguous diagnosis prior to more specialised testing. Under close examination, a ring of yellow-brown to olive-green pigmentation known as a Fleischer ring can be observed in around half of keratoconic eyes. The Fleischer ring, caused by deposition of the iron oxide hemosiderin within the corneal epithelium, is subtle and may not be readily detectable in all cases, but becomes more evident when viewed under a cobalt blue filter. Similarly, around 50% of subjects exhibit Vogt's striae, fine stress lines within the cornea caused by stretching and thinning. The striae temporarily disappear while slight pressure is applied to the eyeball. A highly pronounced cone can create a V-shaped indentation in the lower eyelid when the patient's gaze is directed downwards, known as Munson's sign. Other clinical signs of keratoconus will normally have presented themselves long before Munson's sign becomes apparent, and so this finding, though a classic sign of the disease, tends not to be of primary diagnostic importance.

A handheld keratoscope, sometimes known as Placido's disk, can provide a simple non-invasive visualization of the surface of the cornea by projecting a series of concentric rings of light onto the cornea. A more definitive diagnosis can be obtained using corneal topography, in which an automated instrument projects the illuminated pattern onto the cornea and determines its topology from analysis of the digital image. The topographical map indicates any distortions or scarring in the cornea, with keratoconus revealed by a characteristic steepening of curvature which is usually below the centreline of the eye. The technique can record a snapshot of the degree and extent of the deformation as a benchmark for assessing its rate of progression. It is of particular value in detecting the disorder in its early stages when other signs have not yet presented.

Once keratoconus has been diagnosed, its degree may be classified by several metrics:

* The steepness of greatest curvature from mild (< 45 D), advanced (up to 52 D) or severe (> 52 D);

* The morphology of the cone: nipple (small: 5 mm and near-central), oval (larger, below-center and often sagging), or globus (more than 75% of cornea affected);

* The corneal thickness from mild (> 506 μm) to advanced (< 446 μm).

Increasing use of corneal topography has led to a decline in use of these terms.

Despite considerable research, the etiology of keratoconus remains somewhat of a mystery. A number of sources suggest that keratoconus likely arises from a number of different factors: genetic, environmental or cellular, any of which may form the trigger for the onset of the disease.

A genetic predisposition to keratoconus has been observed, with the disease running in certain families, and incidences reported of concordance in identical twins. The frequency of occurrence in close family members is not clearly defined, though it is known to be considerably higher than that in the general population, and studies have obtained estimates ranging between 6% and 19%. A responsible gene has not been identified: two studies involving isolated, largely homogenetic communities have contrarily mapped putative gene locations to chromosomes 16q and 20q. However, most genetic studies agree on an autosomal dominant model of inheritance. Keratoconus is also diagnosed more often in people with Down syndrome, though the reasons for this link have not yet been determined. Keratoconus has been associated with atopic diseases, which include asthma, allergies, and eczema, and it is not uncommon for several or all of these diseases to affect one person. A number of studies suggest that vigorous eye rubbing contributes to the progression of keratoconus, and that patients should be discouraged from the practice.

Iatrogenic keratoconus has also been observed following LASIK surgery, caused by removal of excessive stromal bed tissue.

Once initiated, the disease normally develops by progressive dissolution of Bowman's layer, which lies between the corneal epithelium and stroma. As the two come into contact, cellular and structural changes in the cornea adversely affect its integrity and lead to the bulging and scarring that are characteristic of the disorder. Within any individual keratoconic cornea, there may be found regions of degenerative thinning coexisting with regions undergoing wound healing.

The visual distortion experienced by the patient comes from two sources, one being the irregular deformation of the surface of the cornea; the other being scarring that occurs on its exposed highpoints. These factors act to form regions on the cornea that map an image to different locations on the retina and give rise to the symptom of monocular polyopia. The effect can worsen in low light conditions as the dark-adapted pupil dilates to expose more of the irregular surface of the cornea. Scarring appears to be an aspect of the corneal degradation; however, a recent, large, multi-center study suggests that abrasion by contact lenses may increase the likelihood of this finding by a factor of over two. A number of patients complain of chronic eye rubbing and also think it as a possible cause to the disease but it is not so; however, it has been observed that keratoconus progresses faster due to eye-rubbing.

A number of studies have indicated that keratoconic corneas show signs of increased activity by proteases, a class of enzymes that break some of the collagen cross-linkages in the stroma, with a simultaneous reduced expression of protease inhibitors. Other studies have suggested that reduced activity by the enzyme aldehyde dehydrogenase may be responsible for a build-up of free radicals and oxidising species in the cornea. It seems likely that, whatever the pathogenetical process, the damage caused by activity within the cornea results in a reduction in its thickness and biomechanical strength. While keratoconus is considered a non-inflammatory disorder, one study shows that wearing rigid contact lenses by patients leads to overexpression of pro-inflammatory cytokines, such as IL-6, TNF-alpha, ICAM-1, and VCAM-1 in the tear fluid.

Patients with keratoconus typically present initially with mild astigmatism, commonly at the onset of puberty, and are diagnosed by the late teenage years or early 20s. The disease can however present or progress at any age: in rare cases keratoconus can present in children or not until later adulthood. A diagnosis of the disease at an early age may indicate a greater risk of severity in later life. Patients' vision will seem to fluctuate over a period of months, driving them to change lens prescriptions frequently, but as the condition worsens, contact lenses are required in the majority of cases. The course of the disorder can be quite variable, with some patients remaining stable for years or indefinitely, while others progress rapidly or experience occasional exacerbations over a long and otherwise steady course. It tends to progress more rapidly in patients when the first presentation is in second decade of life. Most commonly, keratoconus progresses for a period of ten to twenty years before the course of the disease generally ceases in the third and fourth decades of life.

In advanced cases, bulging of the cornea can result in a localized rupture of Descemet's membrane, an inner layer of the cornea. Aqueous humor from the eye's anterior chamber seeps into the cornea before Descemet's membrane reseals. The patient experiences pain and a sudden severe clouding of vision, with the cornea taking on a translucent milky-white appearance known as a corneal hydrops. Although disconcerting to the patient, the effect is normally temporary and after a period of six to eight weeks the cornea usually returns to its former transparency. The recovery can be aided non-surgically by bandaging with an osmotic saline solution. Although a hydrops usually causes increased scarring of the cornea, occasionally it will benefit a patient by creating a flatter cone, aiding the fitting of contact lenses. Occasionally, in extreme cases, the cornea thins to the point that a partial rupture occurs, resulting in a small, bead-like swelling on the cornea that has been filled with fluid. When this occurs, a corneal transplant can become urgently necessary to avoid complete rupture and resulting loss of the eye.

The National Eye Institute reports that keratoconus is the most common corneal dystrophy in the United States, affecting approximately 1 in 2,000 Americans, but some reports place the figure as high as 1 in 500. The inconsistency may be due to variations in diagnostic criteria, with some cases of severe astigmatism interpreted as those of keratoconus, and vice versa. A long-term study found a mean incidence rate of 2.0 new cases per 100,000 population per year. It is suggested that males and females, and all ethnicities appear equally susceptible, though some recent studies have cast doubt upon this, suggesting a higher prevalence amongst females; the literature, however, varying as to its extent. Also, a study carried out in the UK suggests that people of a South Asian heritage are 4.4 times as likely to suffer from keratoconus as Caucasians, and are also more likely to be affected with the condition earlier.

Keratoconus is normally bilateral (affecting both eyes) although the distortion is usually asymmetric and is rarely completely identical in both corneas. Unilateral cases tend to be uncommon, and may in fact be very rare if a very mild condition in the better eye is simply below the limit of clinical detection. It is common for keratoconus to be diagnosed first in one eye and not until later in the other. As the condition then progresses in both eyes, the vision in the earlier-diagnosed eye will often persist to be poorer than that in its fellow.

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Glaucoma is an eye disorder in which the optic nerve suffers damage, permanently damaging vision in the affected eye(s) and progressing to complete blindness if untreated. It is often, but not always, associated with increased pressure of the fluid in the eye (aqueous humour). The term 'ocular hypertension' is used for cases having constantly raised intraocular pressure (IOP) without any associated optic nerve damage. Conversely, the term 'normal' or 'low tension glaucoma' is suggested for the typical visual field defects when associated with a normal or low IOP.

The nerve damage involves loss of retinal ganglion cells in a characteristic pattern. There are many different sub-types of glaucoma but they can all be considered a type of optic neuropathy. Raised intraocular pressure is a significant risk factor for developing glaucoma (above 21 mmHg or 2.8 kPa). One person may develop nerve damage at a relatively low pressure, while another person may have high eye pressure for years and yet never develop damage. Untreated glaucoma leads to permanent damage of the optic nerve and resultant visual field loss, which can progress to blindness.

Glaucoma can be divided roughly into two main categories, "open angle" and "closed angle" glaucoma. Closed angle glaucoma can appear suddenly and is often painful; visual loss can progress quickly but the discomfort often leads patients to seek medical attention before permanent damage occurs. Open angle, chronic glaucoma tends to progress at a slower rate and the patient may not notice that they have lost vision until the disease has progressed significantly.

Glaucoma has been nicknamed the "silent thief of sight" because the loss of vision normally occurs gradually over a long period of time and is often only recognized when the disease is quite advanced. Once lost, this damaged visual field cannot be recovered. Worldwide, it is the second leading cause of blindness. It is also the leading cause of blindness among African Americans. Glaucoma affects 1 in 200 people aged fifty and younger, and 1 in 10 over the age of eighty. If the condition is detected early enough it is possible to arrest the development or slow the progression with medical and surgical means.

The word glaucoma comes from the Greek γλαύκωμα, "opacity of the crystalline lens". (Cataracts and glaucoma were not distinguished until c.1705).

There are two main types of glaucoma: open-angle glaucoma and closed-angle glaucoma.

Open-angle glaucoma accounts for 90% of glaucoma cases in the United States. It is painless and does not have acute attacks. The only signs are gradually progressive visual field loss, and optic nerve changes (increased cup-to-disc ratio on fundoscopic examination).

Closed-angle glaucoma accounts for less than 10% of glaucoma cases in the United States, but as much as half of glaucoma cases in other nations (particularly Asian countries). About 10% of patients with closed angles present with acute angle closure crises characterized by sudden ocular pain, seeing halos around lights, red eye, very high intraocular pressure (>30 mmHg), nausea and vomiting, sudden decreased vision, and a fixed, mid-dilated pupil. Acute angle closure is an ocular emergency.

The major risk factor for most glaucomas and focus of treatment is increased intraocular pressure. Intraocular pressure is a function of production of liquid aqueous humor by the ciliary processes of the eye and its drainage through the trabecular meshwork. Aqueous humor flows from the ciliary processes into the posterior chamber, bounded posteriorly by the lens and the zonules of Zinn and anteriorly by the iris. It then flows through the pupil of the iris into the anterior chamber, bounded posteriorly by the iris and anteriorly by the cornea. From here the trabecular meshwork drains aqueous humor via Schlemm's canal into scleral plexuses and general blood circulation.

In open angle glaucoma there is reduced flow through the trabecular meshwork; in angle closure glaucoma, the iridocorneal angle is completely closed because of forward displacement of the final roll and root of the iris against the cornea resulting in the inability of the aqueous fluid to flow from the posterior to the anterior chamber and then out of the trebecular network.

The inconsistent relationship of glaucomatous optic neuropathy with ocular hypertension has provoked hypotheses and studies on anatomic structure, eye development, nerve compression trauma, optic nerve blood flow, excitatory neurotransmitter, trophic factor, retinal ganglion cell/axon degeneration, glial support cell, immune, and aging mechanisms of neuron loss.

There are several causes for glaucoma. Those at risk are advised to have a dilated eye examination at least once a year.

Ocular hypertension (increased pressure within the eye) is the largest risk factor in most glaucomas, but in some populations only 50% of patients with primary open angle glaucoma actually have elevated ocular pressure.

Those of African descent are three times more likely to develop primary open angle glaucoma.

Elderly people have thinner corneal thickness and often suffer from hypermetropia. They are also at higher risk for primary open angle glaucoma.

People with a family history of glaucoma have about six percent chance of developing glaucoma.

Many East Asian groups are prone to developing angle closure glaucoma due to their shallower anterior chamber depth, with the majority of cases of glaucoma in this population consisting of some form of angle closure. Inuit also have a twenty to forty times higher risk than Caucasians of developing primary angle closure glaucoma. Women are three times more likely than men to develop acute angle-closure glaucoma due to their shallower anterior chambers.

Other factors can cause glaucoma, known as "secondary glaucomas," including prolonged use of steroids (steroid-induced glaucoma); conditions that severely restrict blood flow to the eye, such as severe diabetic retinopathy and central retinal vein occlusion (neovascular glaucoma); ocular trauma (angle recession glaucoma); and uveitis (uveitic glaucoma).

Primary open angle glaucoma (POAG) has been found to be associated with mutations in genes at several loci. Normal tension glaucoma, which comprises one third of POAG, is associated with genetic mutations.

There is increasing evidence that ocular blood flow is involved in the pathogenesis of glaucoma. Current data indicate that fluctuations in blood flow are more harmful in glaucomatous optic neuropathy than steady reductions. Unstable blood pressure and dips are linked to optic nerve head damage and correlate with visual field deterioration.

A number of studies also suggest a possible correlation between hypertension and the development of glaucoma. In normal tension glaucoma, nocturnal hypotension may play a significant role.

There is no clear evidence that vitamin deficiencies cause glaucoma in humans. It follows then that oral vitamin supplementation is not a recommended treatment for glaucoma.

Various rare congenital/genetic eye malformations are associated with glaucoma. Occasionally, failure of the normal third trimester gestational atrophy of the hyaloid canal and the tunica vasculosa lentis is associated with other anomalies. Angle closure induced ocular hypertension and glaucomatous optic neuropathy may also occur with these anomalies and modelled in mice.

Screening for glaucoma is usually performed as part of a standard eye examination performed by ophthalmologists, orthoptists and optometrists. Testing for glaucoma should include measurements of the intraocular pressure via tonometry, changes in size or shape of the eye, anterior chamber angle examination or gonioscopy, and examination of the optic nerve to look for any visible damage to it, or change in the cup-to-disc ratio and also rim appearance and vascular change. A formal visual field test should be performed. The retinal nerve fiber layer can be assessed with imaging techniques such as optical coherence tomography (OCT), scanning laser polarimetry (GDx), and/or scanning laser ophthalmoscopy also known as Heidelberg Retina Tomography (HRT3).

Owing to the sensitivity of all methods of tonometry to corneal thickness, methods such as Goldmann tonometry should be augmented with pachymetry to measure central corneal thickness (CCT). A thicker-than-average cornea can result in a pressure reading higher than the 'true' pressure, whereas a thinner-than-average cornea can produce a pressure reading lower than the 'true' pressure.

Because pressure measurement error can be caused by more than just CCT (i.e., corneal hydration, elastic properties, etc.), it is impossible to 'adjust' pressure measurements based only on CCT measurements. The Frequency Doubling Illusion can also be used to detect glaucoma with the use of a Frequency Doubling Technology (FDT) perimeter.

Examination for glaucoma also could be assessed with more attention given to sex, race, history of drug use, refraction, inheritance and family history.

The modern goals of glaucoma management are to avoid glaucomatous damage, nerve damage, preserve visual field and total quality of life for patients with minimal side effects. This requires appropriate diagnostic techniques and follow up examinations and judicious selection of treatments for the individual patient. Although intraocular pressure is only one of the major risk factors for glaucoma, lowering it via various pharmaceuticals and/or surgical techniques is currently the mainstay of glaucoma treatment.

Vascular flow and neurodegenerative theories of glaucomatous optic neuropathy have prompted studies on various neuroprotective therapeutic strategies including nutritional compounds some of which may be regarded by clinicians as safe for use now, while others are on trial.

Intraocular pressure can be lowered with medication, usually eye drops. There are several different classes of medications to treat glaucoma with several different medications in each class.

Each of these medicines may have local and systemic side effects. Adherence to medication protocol can be confusing and expensive; if side effects occur, the patient must be willing either to tolerate these, or to communicate with the treating physician to improve the drug regimen. Initially, glaucoma drops may reasonably be started in either one or in both eyes.

Poor compliance with medications and follow-up visits is a major reason for vision loss in glaucoma patients. A 2003 study of patients in an HMO found that half failed to fill their prescription the first time and one in four failed to refill their prescriptions a second time. Patient education and communication must be ongoing to sustain successful treatment plans for this lifelong disease with no early symptoms.

The possible neuroprotective effects of various topical and systemic medications are also being investigated.

1. Prostaglandin analogs like latanoprost (Xalatan), bimatoprost (Lumigan) and travoprost (Travatan) increase uveoscleral outflow of aqueous humor. Bimatoprost also increases trabecular outflow
2. Topical beta-adrenergic receptor antagonists such as timolol, levobunolol (Betagan), and betaxolol decrease aqueous humor production by the ciliary body.
3. Alpha2-adrenergic agonists such as brimonidine (Alphagan) and apraclonidine work by a dual mechanism, decreasing aqueous humor production and increasing trabecular outflow.
4. Less-selective sympathomimetics such as epinephrine decrease aqueous humor production through vasoconstriction of ciliary body blood vessels. Epinephrine's mydriatic effect, however, renders it unsuitable for closed-angle glaucoma.
5. Miotic agents (parasympathomimetics) like pilocarpine work by contraction of the ciliary muscle, tightening the trabecular meshwork and allowing increased outflow of the aqueous humour. Ecothiopate is used in chronic glaucoma.
6. Carbonic anhydrase inhibitors like dorzolamide (Trusopt), brinzolamide (Azopt), acetazolamide (Diamox) lower secretion of aqueous humor by inhibiting carbonic anhydrase in the ciliary body.
7. Physostigmine is also used to treat glaucoma and delayed gastric emptying.
8. Marijuana (cannabis), when smoked or eaten, reduced interocular pressure by about 25% in several studies, a reduction as good as that obtained by most other medicines. The effect lasts 3-4 hours.

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In medicine (cardiology), myocarditis is inflammation of heart muscle (myocardium). It resembles a heart attack but coronary arteries are not blocked.

Myocarditis is most often due to infection by common viruses, such as parvovirus B19, less commonly non-viral pathogens such as Borrelia burgdorferi (Lyme disease) or Trypanosoma cruzi, or as a hypersensitivity response to drugs.

The definition of myocarditis varies, but the central feature is an infection of the heart, with an inflammatory infiltrate, and damage to the heart muscle, without the blockage of coronary arteries that define a heart attack (myocardial infarction) or other common non-infectious causes. Myocarditis may or may not include death (necrosis) of heart tissue. It may include dilated cardiomyopathy.

Myocarditis is often an autoimmune reaction. Streptococcal M protein and coxsackievirus B have regions (epitopes) that are immunologically similar to cardiac myosin. After the virus is gone, the immune system may attack cardiac myosin.

Because a definitive diagnosis requires a heart biopsy, which doctors are reluctant to do because they are invasive, statistics on the incidence of myocarditis vary widely.

The consequences of myocarditis thus also vary widely. It can cause a mild disease without any symptoms that resolves itself, or it may cause chest pain, heart failure, or sudden death. An acute myocardial infarction-like syndrome with normal coronary arteries has a good prognosis. Heart failure, even with dilated left ventricle, may have a good prognosis. Ventricular arrhythmias and high-degree heart block have a poor prognosis. Loss of right ventricular function is a strong predictor of death.

The signs and symptoms associated with myocarditis are varied, and relate either to the actual inflammation of the myocardium, or the weakness of the heart muscle that is secondary to the inflammation. Signs and symptoms of myocarditis include:

• Chest pain (often described as "stabbing" in character)
• Congestive heart failure (leading to edema, breathlessness and hepatic congestion)
• Palpitations (due to arrhythmias)
• Sudden death (in young adults, myocarditis causes up to 20% of all cases of sudden death)
• Fever (especially when infectious, e.g. in rheumatic fever)
• Symptoms in infants and toddlers tend to be more non-specific with generalized malaise, poor appetite, abdominal pain, chronic cough. Later stages of the illness will present with respiratory symptoms with increased work of breathing and is often mistaken for asthma.

Since myocarditis is often due to a viral illness, many patients give a history of symptoms consistent with a recent viral infection, including fever, rash, diarrhea, joint pains, and easy fatigueability.

Myocarditis is often associated with pericarditis, and many patients present with signs and symptoms that suggest concurrent myocarditis and pericarditis.

A large number of causes of myocarditis have been identified, but often a cause cannot be found. In Europe and North America, viruses are common culprits. Worldwide, however, the most common cause is Chagas' disease, an illness endemic to Central and South America that is due to infection by the protozoan Trypanosoma cruzi.

Myocarditis refers to an underlying process that causes inflammation and injury of the heart. It does not refer to inflammation of the heart as a consequence of some other insult. Many secondary causes, such as a heart attack, can lead to inflammation of the myocardium and therefore the diagnosis of myocarditis can not be made by evidence of inflammation of the myocardium alone.

Myocardial inflammation can be suspected on the basis of electrocardiographic results (ECG), elevated C-reactive protein (CRP) and/or Erythrocyte sedimentation rate (ESR) and increased IgM (serology) against viruses known to affect the myocardium. Markers of myocardial damage (troponin or creatine kinase cardiac isoenzymes) are elevated.

The electrocardiogram (ECG) findings most commonly seen in myocarditis are diffuse T wave inversions; saddle-shaped ST-segment elevations may be present (these are also seen in pericarditis).

The gold standard is still biopsy of the myocardium, generally done in the setting of angiography. A small tissue sample of the endocardium and myocardium is taken, and investigated by a pathologist by light microscopy and—if necessary—immunochemistry and special staining methods. Histopathological features are: myocardial interstitium with abundant edema and inflammatory infiltrate, rich in lymphocytes and macrophages. Focal destruction of myocytes explains the myocardial pump failure.

Cardiac magnetic resonance imaging (cMRI or CMR) has been shown to be very useful in diagnosing myocarditis by visualizing markers for inflammation of the myocardium. Recently, consensus criteria for the diagnosis of myocarditis by CMR have been published

As most viral infections cannot be treated with directed therapy, symptomatic treatment is the only form of therapy for those forms of myocarditis. In the acute phase, supportive therapy including bed rest is indicated. For symptomatic patients, digoxin and diuretics provide clinical improvement. For patients with moderate to severe dysfunction, cardiac function can be supported by use of inotropes such as Milrinone in acute phase followed by oral therapy with ACE inhibitors (Captopril, Lisinopril) when tolerated. People who do not respond to conventional therapy are candidates for bridge therapy with left ventricular assist devices (LVADs). Heart transplantation is reserved for patients who fail to improve with conventional therapy.

In several small case series and randomized control trials, systemic corticosteroids have shown to have beneficial effects in patients with proven myocarditis. However, data on the usefulness of corticosteroids should be interpreted with caution since 58% of adults recover spontaneously while most studies on children and infants lack control groups.

The exact incidence of myocarditis is unknown. However, in series of routine autopsies, 1–9% of all patients had evidence of myocardial inflammation. In young adults, up to 20% of all cases of sudden death are due to myocarditis.

Among patients with HIV, myocarditis is the most common cardiac pathological finding at autopsy, with prevalence of 50% or more.

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Gastritis is an inflammation of the lining of the stomach, and has many possible causes. The main acute causes are excessive alcohol consumption or prolonged use of nonsteroidal anti-inflammatory drugs (also known as NSAIDs) such as aspirin or ibuprofen. Sometimes gastritis develops after major surgery, traumatic injury, burns, or severe infections. Gastritis may also occur in those who have had weight loss surgery resulting in the banding or reconstruction of the digestive tract. Chronic causes are infection with bacteria, primarily Helicobacter pylori, chronic bile reflux, stress and certain autoimmune disorders can cause gastritis as well. The most common symptom is abdominal upset or pain. Other symptoms are indigestion, abdominal bloating, nausea, and vomiting and pernicious anemia. Some may have a feeling of fullness or burning in the upper abdomen. A gastroscopy, blood test, complete blood count test, or a stool test may be used to diagnose gastritis. Treatment includes taking antacids or other medicines, such as proton pump inhibitors or antibiotics, and avoiding hot or spicy foods. For those with pernicious anemia, B12 injections are given.

Many people with gastritis experience no symptoms at all. However, upper central abdominal pain is the most common symptom; the pain may be dull, vague, burning, aching, gnawing, sore, or sharp. Pain is usually located in the upper central portion of the abdomen, but it may occur anywhere from the upper left portion of the abdomen around to the back.

Other signs and symptoms may include:

1. Nausea
2. Vomiting (if present, may be clear, green or yellow, blood-streaked, or completely bloody, depending on the severity of the stomach inflammation)
3. Belching (if present, usually does not relieve the pain much)
4. Bloating
5. Feeling full after only a few bites of food
6. Loss of appetite
7. Unexplained weight loss

Erosive gastritis is a gastric mucosal erosion caused by damage to mucosal defenses. Alcohol consumption does not cause chronic gastritis. It does, however, erode the mucosal lining of the stomach; low doses of alcohol stimulate hydrochloric acid secretion. High doses of alcohol do not stimulate secretion of acid. NSAIDs inhibit cyclooxygenase-1, or COX-1, an enzyme responsible for the biosynthesis of eicosanoids in the stomach, which increases the possibility of peptic ulcers forming. Also, NSAIDs, such as aspirin, reduce a substance that protects the stomach called prostaglandin. These drugs used in a short period of time are not typically dangerous. However, regular use can lead to gastritis.

Chronic gastritis refers to a wide range of problems of the gastric tissues that are the result of H. pylori infection. The immune system makes proteins and antibodies that fight infections in the body to maintain a homeostatic condition. In some disorders the body targets the stomach as if it were a foreign protein or pathogen; it makes antibodies against, severely damages, and may even destroy the stomach or its lining. In some cases bile, normally used to aid digestion in the small intestine, will enter through the pyloric valve of the stomach if it has been removed during surgery or does not work properly, also leading to gastritis. Gastritis may also be caused by other medical conditions, including HIV/AIDS, Crohn's disease, certain connective tissue disorders, and liver or kidney failure.

Mucous gland metaplasia, the reversible replacement of differentiated cells, occurs in the setting of severe damage of the gastric glands, which then waste away (atrophic gastritis), which are progressively replaced by mucous glands. Gastric ulcers may develop; it is unclear if they are the causes or the consequences. Intestinal metaplasia typically begins in response to chronic mucosal injury in the antrum, and may extend to the body. Gastric mucosa cells change to resemble intestinal mucosa and may even assume absorptive characteristics. Intestinal metaplasia is classified histologically as complete or incomplete. With complete metaplasia, gastric mucosa is completely transformed into small-bowel mucosa, both histologically and functionally, with the ability to absorb nutrients and secrete peptides. In incomplete metaplasia, the epithelium assumes a histologic appearance closer to that of the large intestine and frequently exhibits dysplasia.

Helicobacter pylori colonizes the stomach of more than half of the world's population, and the infection continues to play a key role in the pathogenesis of a number of gastroduodenal diseases. Colonization of the gastric mucosa with Helicobacter pylori results in the development of chronic gastritis in infected individuals and in a subset of patients chronic gastritis progresses to complications (i.e. ulcer disease, gastric neoplasias, some distinct extra gastric disorders). However, gastritis has no adverse consequences for most hosts and emerging evidence suggests that H. pylori prevalence is inversely related to gastroesophageal reflux disease and allergic disorders. These observations indicate that eradication may not be appropriate for certain populations due to the potentially beneficial effects conferred by persistent gastric inflammation.

Often, a diagnosis can be made based on the patient's description of his or her symptoms, but other methods which may be used to verify gastritis include:

* Blood tests:

o Blood cell count

o Presence of H. pylori

o Pregnancy

o Liver, kidney, gallbladder, or pancreas functions

* Urinalysis

* Stool sample, to look for blood in the stool

* X-rays

* ECGs

* Endoscopy, to check for stomach lining inflammation and mucous erosion

* Stomach biopsy, to test for gastritis and other conditions

Over-the-counter antacids in liquid or tablet form are a common treatment for mild gastritis. Antacids neutralize stomach acid and can provide fast pain relief. When antacids don't provide enough relief, medications such as cimetidine, ranitidine, nizatidine or famotidine that help reduce the amount of acid the stomach produces are often prescribed. An even more effective way to limit stomach acid production is to shut down the acid "pumps" within acid-secreting stomach cells. Proton pump inhibitors reduce acid by blocking the action of these small pumps. This class of medications includes omeprazole, lansoprazole, rabeprazole, and esomeprazole. Proton pump inhibitors also appear to inhibit H. pylori activity. Cytoprotective agents are designed to help protect the tissues that line the stomach and small intestine. They include the medications sucralfate and misoprostol. If NSAIDs are being taken regularly, one of these medications to protect the stomach may also be taken. Another cytoprotective agent is bismuth subsalicylate. In addition to protecting the lining of stomach and intestines, bismuth preparations appear to inhibit H. pylori activity as well. Several regimens are used to treat H. pylori infection. Most use a combination of two antibiotics and a proton pump inhibitor. Sometimes bismuth is also added to the regimen. The antibiotic aids in destroying the bacteria, and the acid blocker or proton pump inhibitor relieves pain and nausea, heals inflammation, and may increase the antibiotic's effectiveness.

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Septic shock is a medical emergency caused by decreased tissue perfusion and oxygen delivery as a result of severe infection and sepsis, though the microbe may be systemic or localized to a particular site. It can cause multiple organ dysfunction syndrome (formerly known as multiple organ failure) and death. Its most common victims are children, immunocompromised individuals, and the elderly, as their immune systems cannot deal with the infection as effectively as those of healthy adults. Frequently, patients suffering from septic shock are cared for in intensive care units. The mortality rate from septic shock is approximately 25%-50%.

In humans, septic shock has a specific definition requiring several criteria for diagnosis:

* First, SIRS (systemic inflammatory response syndrome) must be met by finding at least any two of the following:

Tachypnea (high respiratory rate) > 20 breaths per minute, or on blood gas, a PCO2 less than 32 mmHg signifying hyperventilation.

White blood cell count either significantly low, < 4000 cells/mm³ or elevated > 12000 cells/mm³.

Heart rate > 90 beats per minute

Temperature: Fever > 38.0 °C (100.4 °F) or hypothermia < 36.0 °C (96.8 °F)

* Second, there must be sepsis and not an alternative form cause of SIRS. Sepsis requires evidence of infection, which may include positive blood culture, signs of pneumonia on chest x-ray, or other radiologic or laboratory evidence of infection

* Third, signs of end-organ dysfunction are required such as renal failure, liver dysfunction, changes in mental status, or elevated serum lactate.

* Finally, septic shock is diagnosed if there is refractory hypotension (low blood pressure that does not respond to treatment). This signifies that intravenous fluid administration alone is insufficient to maintain a patient's blood pressure from becoming hypotensive.

A subclass of distributive shock, shock refers specifically to decreased tissue perfusion resulting in ischemia and organ dysfunction. Cytokines released in a large scale inflammatory response results in massive vasodilation, increased capillary permeability, decreased systemic vascular resistance, and hypotension. Hypotension reduces tissue perfusion pressure causing tissue hypoxia. Finally, in an attempt to offset decreased blood pressure, ventricular dilatation and myocardial dysfunction will occur.

When bacteria or viruses are present in the bloodstream, the condition is known as bacteremia or viremia. If the organisms are particularly virulent, or the host is immunocompromised, then the host organism may develop a condition known as systemic inflammatory response syndrome (or SIRS). Sepsis is by definition bacteremia, combined with SIRS. If sepsis worsens to the point of end-organ dysfunction (renal failure, liver dysfunction, altered mental status, or heart damage), then the condition is called severe sepsis. Once severe sepsis worsens to the point where blood pressure can no longer be maintained with intravenous fluids alone, then the criteria have been met for septic shock. The precipitating infections which may lead to septic shock if severe enough include pneumonia, bacteremia, diverticulitis, pyelonephritis, meningitis, pancreatitis, and necrotizing fasciitis.

Most cases of septic shock (approximately 70%) are caused by endotoxin-producing Gram-negative bacilli. Endotoxins are bacterial wall lipopolysaccharides (LPS) consisting of a toxic fatty acid (lipid A) core common to all Gram-negative bacteria, and a complex polysaccharide coat (including O antigen) unique for each species. Analogous molecules in the walls of Gram-positive bacteria and fungi can also elicit septic shock. Free LPS attaches to a circulating LPS-binding protein, and the complex then binds to a specific receptor (CD14) on monocytes, macrophages, and neutrophils. Engagement of CD14 (even at doses as minute as 10 pg/mL) results in intracellular signaling via an associated "Toll-like receptor" protein 4 (TLR-4), resulting in profound activation of mononuclear cells and production of potent effector cytokines such as IL-1 and TNF-α. These cytokines act on endothelial cells and have a variety of effects including reduced synthesis of anticoagulation factors such as tissue factor pathway inhibitor and thrombomodulin. The effects of the cytokines may be amplified by TLR-4 engagement on endothelial cells. TLR-mediated activation helps to trigger the innate immune system to efficiently eradicate invading microbes. At high levels of LPS, the syndrome of septic shock supervenes; the same cytokine and secondary mediators, now at high levels, result in systemic vasodilation (hypotension), diminished myocardial contractility, widespread endothelial injury and activation, causing systemic leukocyte adhesion and diffuse alveolar capillary damage in the lung activation of the coagulation system, culminating in disseminated intravascular coagulation (DIC). The hypoperfusion resulting from the combined effects of widespread vasodilation, myocardial pump failure, and DIC causes multiorgan system failure that affects the liver, kidneys, and central nervous system, among others. Unless the underlying infection (and LPS overload) is rapidly brought under control, the patient usually dies.

Treatment primarily consists of the following.

1. Volume resuscitation

2. Early antibiotic administration

3. Early goal directed therapy

4. Rapid source identification and control.

5. Support of major organ dysfunction.

Among the choices for vasopressors, norepinephrine is superior to dopamine in septic shock. Both however are still listed as first line in guidelines.

Antimediator agents may be of some limited use in severe clinical situations however are controversial:

* Low dose steroids (hydrocortisone) for 5 – 7 days led to improved outcomes.

* Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease.

According to the US CDC, septic shock is the 13th leading cause of death in the United States, and the #1 cause of deaths in intensive care units. There has been an increase in the rate of septic shock deaths in recent decades, which is attributed to an increases in invasive medical devices and procedures, increases in immunocompromised patients, and an overall increase in elderly patients. Tertiary care centers (such as hospice care facilities) have 2-4 times the rate of bacteremia than primary care centers, 75% of which are nosocomial infections.

The process of infection by bacteria or fungi can result in systemic signs and symptoms that are variously described. Approximately 70% of septic shock cases were once traceable to Gram staining gram-negative bacilli that produce endotoxins; however, with the emergence of MRSA and the increased use of arterial and venous catheters, Gram-positive cocci are implicated approximately as commonly as bacilli. In rough order of increasing severity, these are bacteremia or fungemic; septicemia; sepsis, severe sepsis or sepsis syndrome; septic shock; refractory septic shock; multiple organ dysfunction syndrome, and death.

35% of septic shock cases derive from urinary tract infections, 15% from the respiratory tract, 15% from skin catheters (such as IVs); over 30% of all cases are idiopathic in origin.

The mortality rate from sepsis is approximately 40% in adults, and 25% in children, and is significantly greater when left untreated for more than 7 days.

Sepsis has a worldwide incidence of more than 20 million cases a year, with mortality due to septic shock reaching up to 70 percent even in industrialized countries.

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Sepsis is a potentially deadly medical condition that is characterized by a whole-body inflammatory state (called a systemic inflammatory response syndrome or SIRS) and the presence of a known or suspected infection. The body may develop this inflammatory response by the immune system to microbes in the blood, urine, lungs, skin, or other tissues. A lay term for sepsis is blood poisoning, more aptly applied to septicemia, below. Severe sepsis is the systemic inflammatory response, plus infection, plus the presence of organ dysfunction.

Septicemia (also septicaemia or septicæmia ) is a related medical term referring to the presence of pathogenic organisms in the bloodstream, leading to sepsis. The term has not been sharply defined. It has been inconsistently used in the past by medical professionals, for example as a synonym of bacteremia, causing some confusion.

Severe sepsis is usually treated in the intensive care unit with intravenous fluids and antibiotics. If fluid replacement is insufficient to maintain blood pressure, specific vasopressor medications can be used. Mechanical ventilation and dialysis may be needed to support the function of the lungs and kidneys, respectively. To guide therapy, a central venous catheter and an arterial catheter may be placed; measurement of other hemodynamic variables (such as cardiac output, or mixed venous oxygen saturation) may also be used. Sepsis patients require preventive measures for deep vein thrombosis, stress ulcers and pressure ulcers, unless other conditions prevent this. Some patients might benefit from tight control of blood sugar levels with insulin (targeting stress hyperglycemia), low-dose corticosteroids or activated drotrecogin alfa (recombinant protein C).

Systemic Inflammatory Response Syndrome or SIRS is evidence of the body's ongoing inflammatory response. When SIRS is suspected or known to be caused by an infection, this is sepsis. Severe sepsis occurs when sepsis leads to organ dysfunction, such as trouble breathing, coagulation or other blood abnormalities, decreased urine production, or altered mental status. If the organ dysfunction of severe sepsis is low blood pressure (hypotension), or insufficient blood flow (hypoperfusion) to one or more organs (causing, for example, lactic acidosis), this is septic shock.

Sepsis can lead to multiple organ dysfunction syndrome (MODS) (formerly known as multiple organ failure), and death. Organ dysfunction results from local changes in blood flow, from sepsis-induced hypotension (< 90 mmHg or a reduction of ≥ 40 mmHg from baseline) and from diffuse intravascular coagulation, among other things.

Sepsis can be defined as the body's response to an infection. An infection is caused by microorganisms or bacteria invading the body and can be limited to a particular body region or can be widespread in the bloodstream. Sepsis is acquired quickest with infections developed in surgery and physical contact with someone with sepsis.

Bacteremia is the presence of viable bacteria in the bloodstream. Likewise, the terms viremia and fungemia simply refer to viruses and fungi in the bloodstream. These terms say nothing about the consequences this has on the body. For example, bacteria can be introduced into the bloodstream during toothbrushing. This form of bacteremia almost never causes problems in normal individuals. However, bacteremia associated with certain dental procedures can cause bacterial infection of the heart valves (known as endocarditis) in high-risk patients. Conversely, a systemic inflammatory response syndrome can occur in patients without the presence of infection, for example in those with burns, polytrauma, or the initial state in pancreatitis and chemical pneumonitis.

In addition to symptoms related to the provoking infection, sepsis is characterized by presence of acute inflammation present throughout the entire body, and is, therefore, frequently associated with fever and elevated white blood cell count (leukocytosis) or low white blood cell count and lower-than-average temperature, and vomiting. The modern concept of sepsis is that the host's immune response to the infection causes most of the symptoms of sepsis, resulting in hemodynamic consequences and damage to organs. This host response has been termed systemic inflammatory response syndrome (SIRS) and is characterized by an elevated heart rate (above 90 beats per minute), high respiratory rate (above 20 breaths per minute or a partial pressure of carbon dioxide in the blood of less than 32), abnormal white blood cell count (above 12,000, lower than 4,000, or greater than 10% band forms) and elevated or lowered body temperature, i.e. under 36 °C (97 °F) or over 38 °C (100 °F). Sepsis is differentiated from SIRS by the presence of a known or suspected pathogen. For example SIRS and a positive blood culture for a pathogen indicates the presence of sepsis. However, in many cases of sepsis no specific pathogen is identified.

This immunological response causes widespread activation of acute-phase proteins, affecting the complement system and the coagulation pathways, which then cause damage to the vasculature as well as to the organs. Various neuroendocrine counter-regulatory systems are then activated as well, often compounding the problem. Even with immediate and aggressive treatment, this may progress to multiple organ dysfunction syndrome and eventually death.

In common clinical usage, sepsis specifically refers to the presence of a bacterial blood stream infection (BSI), such as meningitis, pneumonia, pyelonephritis, or gastroenteritis. in the setting of fever. Criteria with regards to hemodynamic compromise or respiratory failure are not useful clinically because these symptoms often do not arise in neonates until death is imminent and unpreventable.

The therapy of sepsis rests on antibiotics, surgical drainage of infected fluid collections, fluid replacement and appropriate support for organ dysfunction. This may include hemodialysis in kidney failure, mechanical ventilation in pulmonary dysfunction, transfusion of blood products, and drug and fluid therapy for circulatory failure. Ensuring adequate nutrition—preferably by enteral feeding, but if necessary by parenteral nutrition—is important during prolonged illness.

A problem in the adequate management of septic patients has been the delay in administering therapy after sepsis has been recognized. Published studies have demonstrated that for every hour delay in the administration of appropriate antibiotic therapy there is an associated 7% rise in mortality. A large international collaboration was established to educate people about sepsis and to improve patient outcomes with sepsis, entitled the "Surviving Sepsis Campaign". The Campaign has published an evidence-based review of management strategies for severe sepsis, with the aim to publish a complete set of guidelines in subsequent years.

Early goal directed therapy (EGDT), developed at Henry Ford Hospital by Emaneul Rivers, MD, is a systematic approach to resuscitation that has been validated in the treatment of severe sepsis and septic shock. It is meant to be started in the Emergency Department. The theory is that a step-wise approach should be used, having the patient meet physiologic goals, to optimize cardiac preload, afterload, and contractility, thus optimizing oxygen delivery to the tissues. A recent meta-analysis showed that EGDT provides a benefit on mortality in patients with sepsis. As of December 2008 some controversy around its uses remained, and a number of trials were in progress in an attempt to resolve this.

In EGDT, fluids are administered until the central venous pressure (CVP), as measured by a central venous catheter, reaches 8–12 cm of water (or 10–15 cm of water in mechanically ventilated patients). Rapid administration of several liters of isotonic crystalloid solution is usually required to achieve this. If the mean arterial pressure is less than 65 mmHg or greater than 90 mmHg, vasopressors or vasodilators are given as needed to reach the goal. Once these goals are met, the mixed venous oxygen saturation (SvO2), i.e., the oxygen saturation of venous blood as it returns to the heart as measured at the vena cava, is optimized. If the SvO2 is less than 70%, blood is given to reach a hemoglobin of 10 g/dl and then inotropes are added until the SvO2 is optimized. Elective intubation may be performed to reduce oxygen demand if the SvO2 remains low despite optimization of hemodynamics. Urine output is also monitored, with a minimum goal of 0.5 ml/kg/h. In the original trial, mortality was cut from 46.5% in the control group to 30.5% in the intervention group. The Surviving Sepsis Campaign guidelines recommend EGDT for the initial resuscitation of the septic patient with a level B strength of evidence (single randomized control trial).

During critical illness, a state of adrenal insufficiency and tissue resistance (the word 'relative' resistance should be avoided) to corticosteroids may occur. This has been termed critical illness–related corticosteroid insufficiency. Treatment with corticosteroids might be most beneficial in those with septic shock and early severe acute respiratory distress syndrome (ARDS), whereas its role in other patients such as those with pancreatitis or severe pneumonia is unclear. These recommendations stem from studies showing benefits from low dose hydrocortisone treatment for septic shock patients and methylprednisolone in ARDS patients. However, the exact way of determining corticosteroid insufficiency remains problematic. It should be suspected in those poorly responding to resuscitation with fluids and vasopressors. ACTH stimulation testing is not recommended to confirm the diagnosis. The method of cessation of glucocorticoid drugs is variable, and it is unclear whether they should be weaned or simply stopped abruptly.

Recombinant activated protein C (drotrecogin alpha) in a 2011 Cochrane review was found not to decrease mortality and thus was not recommended for use. Other reviews however comment that it may be effective in those with very severe disease.

Note that, in neonates, sepsis is difficult to diagnose clinically. They may be relatively asymptomatic until hemodynamic and respiratory collapse is imminent, so, if there is even a remote suspicion of sepsis, they are frequently treated with antibiotics empirically until cultures are sufficiently proven to be negative.

Prognosis can be estimated with the Mortality in Emergency Department Sepsis (MEDS) score. Approximately 20–35% of patients with severe sepsis and 40–60% of patients with septic shock die within 30 days. Others die within the ensuing 6 months. Late deaths often result from poorly controlled infection, immunosuppression, complications of intensive care, failure of multiple organs, or the patient's underlying disease.

Prognostic stratification systems such as APACHE II indicate that factoring in the patient's age, underlying condition, and various physiologic variables can yield estimates of the risk of dying of severe sepsis. Of the individual covariates, the severity of underlying disease most strongly influences the risk of death. Septic shock is also a strong predictor of short- and long-term mortality. Case-fatality rates are similar for culture-positive and culture-negative severe sepsis.

Some patients may experience severe long-term cognitive decline following an episode of severe sepsis, but the absence of baseline neuropsychological data in most sepsis patients makes the incidence of this difficult to quantify or to study. A preliminary study of nine patients with septic shock showed abnormalities in seven patients by MRI.

PD-1 was found to be up-regulated on monocytes/macrophages during sepsis in human and mice. This up-regulation was related to the up-regulation of IL-10 levels in the blood. Interestingly, Said et al. showed that activated monocytes, which is the case in sepsis, express high levels of PD-1 and that triggering monocytes-expressed PD-1 by its ligand PD-L1 induces IL-10 production which inhibits CD4 T-cell function.

A study reported in Science (journal) showed that SphK1 is highly elevated in inflammatory cells from patients with sepsis and inhibition of the molecular pathway reduced the proinflammatory response triggered by bacterial products in the human cells. Moreover, the study also showed the mortality rate of mice with experimental sepsis was reduced when treated with a SphK1 blocker. Similarly, inhibition of the p38 MAPK signaling transduction pathway may help to block enhanced procoagulatory activities during septicemia.

Medical research is focused on combating nitric oxide. Attempts to inhibit its production paradoxically led to a worsening of the organ damage and in an increased lethality, both in animal models and in a clinical trial in sepsis patients. In a study published in the Journal of Experimental Medicine, nitrite treatment, in sharp contrast with the worsening effect of inhibiting NO-synthesis, significantly attenuates hypothermia, mitochondrial damage, oxidative stress and dysfunction, tissue infarction, and mortality in mice

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