5'  Nucleotidase  (5NT) is a  glycoprotein  found throughout the body, in the cytoplasmic membrane, catalyzing the conversion to inorganic phosphates from nucleoside-5-phosphate. Its level is raised in conditions such as obstructive jaundice, parenchymal liver disease, liver metastases, and bone disease. [ 6 ]


Serum NT levels are higher during 2nd and 3rd trimesters in pregnancy. [ 6 ]


Ceruloplasmin is an  acute phase protein  synthesized in the liver. It is the carrier of the copper ion. Its level is increased in infections,  rheumatoid arthritis , pregnancy, non-Wilson liver disease and obstructive jaundice. In Wilson disease, the ceruloplasmin level is depressed which lead to copper accumulation in body tissues. [ 6 ]


Alpha-fetoprotein (AFP) is significantly expressed in foetal liver. However, the mechanism that led to the suppression of AFP synthesis in adults is not fully known. Exposure of the liver to cancer-causing agents and arrest of liver maturation in childhood can lead to the rise in AFP. AFP can reach until 400–500 μg/L in  hepatocellular carcinoma . AFP concentration of more than 400 μg/L is associated with greater tumour size, involvement of both lobes of liver, portal vein invasion and a lower median survival rate. [ 6 ]


The liver is responsible for the production of the vast majority of  coagulation  factors. In patients with liver disease,  international normalized ratio  (INR) can be used as a marker of liver synthetic function as it includes  factor VII , which has the shortest half life (2–6 hours) of all coagulation factors measured in INR. An elevated INR in patients with liver disease, however, does not necessarily mean the patient has a tendency to bleed, as it only measures procoagulants and not anticoagulants. In liver disease the synthesis of both are decreased and some patients are even found to be hypercoagulable (increased tendency to clot) despite an elevated INR. In liver patients, coagulation is better determined by more modern tests such as  thromboelastogram  (TEG) or thomboelastrometry (ROTEM). [ citation needed ]


Prothrombin time (PT) and its derived measures of prothrombin ratio (PR) and INR are measures of the  extrinsic pathway  of  coagulation . This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of  warfarin  dosage, liver damage, and  vitamin K  status. [ 16 ]


The serum glucose test, abbreviated as "BG" or "Glu", measures the liver's ability to produce glucose ( gluconeogenesis ); it is usually the last function to be lost in the setting of  fulminant liver failure . [ 17 ]


Lactate dehydrogenase  (LDH) is found in many body tissues, including the liver. Elevated levels of LDH may indicate liver damage. [ 18 ]  LDH isotype-1 (or cardiac) is used for estimating damage to cardiac tissue, although troponin and creatine kinase tests are preferred. [ 19 ]


A  low-FODMAP diet  is a person's global restriction of consumption of all  fermentable   carbohydrates  ( FODMAPs ), [ 1 ]  recommended only for a short time. A low-FODMAP diet is recommended for managing patients with  irritable bowel syndrome  (IBS) and can reduce digestive symptoms of IBS including  bloating  and  flatulence . [ 2 ]


If the problem lies with indigestible  fiber  instead, the patient may be directed to a  low-residue diet .


A low-FODMAP diet might help to improve short-term digestive symptoms in adults with functional abdominal  bloating [ 3 ]  and  irritable bowel syndrome , [ 4 ] [ 5 ] [ 6 ] [ 7 ]  but its long-term use can have negative effects because it causes a detrimental impact on the  gut microbiota  and  metabolome . [ 8 ] [ 5 ] [ 7 ] [ 9 ]  It should only be used for short periods of time and under the advice of a specialist. [ 10 ]  More studies are needed to evaluate its effectiveness in children with irritable bowel syndrome. [ 4 ]
There is only a little evidence of its effectiveness in treating functional symptoms in  inflammatory bowel disease  from small studies that are susceptible to bias. [ 11 ] [ 12 ]  More studies are needed to assess the true impact of this diet on health. [ 5 ] [ 7 ]


In addition, the use of a low-FODMAP diet without medical advice can lead to serious health risks, including nutritional deficiencies and misdiagnosis, so it is advisable to conduct a complete medical evaluation before starting a low-FODMAP diet to ensure a correct diagnosis and that the appropriate therapy may be undertaken. [ 13 ]


Since the consumption of  gluten  is suppressed or reduced with a low-FODMAP diet, the improvement of the digestive symptoms with this diet may not be related to the withdrawal of the FODMAPs, but of gluten, indicating the presence of an unrecognized  celiac disease , avoiding its diagnosis and correct treatment, with the consequent risk of several serious health complications, including various types of cancer. [ 13 ] [ 14 ]


A low-FODMAP diet is highly restrictive in various groups of nutrients, can be impractical to follow in the long-term and may add an unnecessary financial burden. [ 12 ]


Below are low-FODMAP foods categorized by group according to the  Monash University  "Low-FODMAP Diet". [ 15 ] [ 16 ]


Other sources confirm the suitability of these and suggest some additional foods. [ 17 ]


The basis of many  functional gastrointestinal disorders  (FGIDs) is distension of the  intestinal lumen . Such luminal distension may induce pain, a sensation of  bloating ,  abdominal distension  and  motility  disorders. Therapeutic approaches seek to reduce factors that lead to distension, particularly of the distal  small  and proximal  large intestine . Food substances that can induce distension are those that are poorly absorbed in the proximal small intestine,  osmotically  active, and fermented by intestinal bacteria with  hydrogen  (as opposed to  methane ) production. The small molecule FODMAPs exhibit these characteristics. [ 1 ]


Over many years, there have been multiple observations that ingestion of certain short-chain carbohydrates, including lactose, fructose and sorbitol, fructans and  galactooligosaccharides , can induce gastrointestinal discomfort similar to that of people with irritable bowel syndrome. These studies also showed that dietary restriction of short-chain carbohydrates was associated with symptoms improvement. [ 18 ]


These short-chain carbohydrates (lactose, fructose and sorbitol, fructans and GOS) behave similarly in the intestine. Firstly, being small molecules and either poorly absorbed or not absorbed at all, they drag water into the intestine via osmosis. [ 19 ]  Secondly, these molecules are readily fermented by colonic bacteria, so upon malabsorption in the small intestine they enter the large intestine where they generate gases (hydrogen, carbon dioxide and methane). [ 1 ]  The dual actions of these carbohydrates cause an expansion in volume of intestinal contents, which stretches the intestinal wall and stimulates nerves in the gut.  It is this 'stretching' that triggers the sensations of pain and discomfort that are commonly experienced by people with IBS. [ 8 ]


The FODMAP concept was first published in 2005 as part of a hypothesis paper. [ 20 ]  In this paper, it was proposed that a collective reduction in the dietary intake of all indigestible or slowly absorbed, short-chain carbohydrates would minimise stretching of the intestinal wall. This was proposed to reduce stimulation of the gut's nervous system and provide the best chance of reducing symptom generation in people with IBS (see below). At the time, there was no collective term for indigestible or slowly absorbed, short-chain carbohydrates, so the term 'FODMAP' was created to improve understanding and facilitate communication of the concept. [ 20 ]


The low FODMAP diet was originally developed by a research team at  Monash University  in Melbourne, Australia. [ 15 ]  The Monash team undertook the first research to investigate whether a low FODMAP diet improved symptom control in patients with IBS and established the mechanism by which the diet exerted its effect. [ 8 ] [ 21 ]  Monash University also established a rigorous food analysis program to measure the FODMAP content of a wide selection of Australian and international foods. [ 22 ] [ 23 ] [ 24 ]  The FODMAP composition data generated by Monash University updated previous data that was based on limited literature, with guesses (sometimes wrong) made where there was little information. [ 25 ]


The  Manning criteria  are a  diagnostic algorithm  used in the diagnosis of  irritable bowel syndrome  (IBS).  The criteria consist of a list of questions the physician can ask the patient. [ 1 ]  The answers are used in a process to produce a diagnostic decision regarding whether the patient can be considered to have IBS.


The Manning criteria have been compared with other diagnostic algorithms for IBS, such as the  Rome I criteria , the  Rome II process , and the Kruis criteria. [ 2 ]   A 2013 validation study found the Manning criteria to have less sensitivity but more specificity than the Rome criteria. [ 3 ]


The threshold for a positive diagnosis varies from two to four of the Manning criteria below. [ 4 ]


Mesalazine , also known as  mesalamine  or  5-aminosalicylic acid  ( 5-ASA ), is a medication used to treat  inflammatory bowel disease , including  ulcerative colitis  and  Crohn's disease . [ 1 ]  It is generally used for mildly to moderately severe disease. [ 1 ]  It is taken by mouth or  rectally . [ 1 ]  The formulations which are taken by mouth appear to be similarly-effective. [ 12 ]


Common side-effects include headache, nausea, abdominal pain, and fever. [ 1 ]  Serious side-effects may include  pericarditis ,  liver problems , and  kidney problems . [ 1 ] [ 12 ]  Use in  pregnancy  and  breastfeeding  appears safe. [ 12 ]  In people with a  sulfa allergy  certain formulations may result in problems. [ 1 ]  Mesalazine is an  aminosalicylate  and  anti-inflammatory . [ 1 ] [ 12 ]  It works by direct contact with the  intestines . [ 1 ]


Mesalazine was approved for medical use in the United States in 1987. [ 1 ] [ 8 ]  It is on the  World Health Organization's List of Essential Medicines . [ 13 ]  It is available as a  generic medication . [ 1 ] [ 14 ] [ 15 ] [ 16 ]  In 2021, it was the 239th most commonly prescribed medication in the United States, with more than 1   million prescriptions. [ 17 ] [ 18 ]


It is used to treat  inflammatory bowel disease , including  ulcerative colitis  and  Crohn's disease  (effective only in colonic diseases). [ 1 ]


In 2022 Germany introduced guidance to use mesalamine to treat acute uncomplicated  diverticulitis . [ 19 ]


Most often reported side-effects are gastrointestinal (GI) (but may also include headache), including: nausea, diarrhea, and abdominal pain. [ 7 ]


Very rarely, use of mesalazine has been associated with an exacerbation of the symptoms of  colitis ,  Stevens Johnson syndrome , and  erythema multiforme . [ 7 ]


There is no data on use in pregnant women, but the drug does cross the placenta and is excreted in  breast milk . The drug should not be used in children under two years of age, [ 7 ]  people with  kidney disease , [ 7 ]  or people who are allergic to  aspirin . [ 7 ]


Mesalazine is the active  moiety  of  sulfasalazine , which is metabolized to  sulfapyridine  and mesalazine. [ 20 ]  It is also the active component of the prodrug  balsalazide  along with the inert carrier molecule 4-aminobenzoyl-beta-alanine. [ 21 ]  It is in the category of  disease-modifying antirheumatic drugs  (DMARDs) family of medications. [ 22 ]  It is unclear exactly how it works. [ 22 ]  Mesalazine is claimed to be a  PPAR-γ agonist . [ 23 ]


Exact mechanism of mesalazine is unknown, but is speculated that mesalazine decreases synthesis of  prostaglandin  and  leukotriene , modulating the inflammatory response derived from the  cyclooxygenase  and  lipooxygenase  pathways. [ 24 ]  It appears to act locally on colonic mucosa. [ 25 ]


Mesalazine is sold under various names including Apriso, Asacol, Asacol HD, Canasa, Delzicol, Fivasa, Lialda, Salofalk, Pentasa, Rowasa, Octasa, and Sfrowasa. In Europe, it is sold under the name Salofalk (rectal suppository).  [ 26 ] [ 27 ]


Misoprostol  is a synthetic  prostaglandin  medication used to prevent and treat  stomach and duodenal ulcers ,  induce labor , cause an  abortion , and treat  postpartum bleeding  due to poor contraction of the  uterus . [ 10 ] [ 11 ]  It is taken  by mouth  when used to prevent gastric ulcers in people taking  nonsteroidal anti-inflammatory drugs  (NSAID). [ 11 ]  For abortions it is used by itself or in conjunction with  mifepristone  or  methotrexate . [ 12 ]  By itself, effectiveness for abortion is between 66% and 90%. [ 13 ] [ 14 ]  For labor induction or abortion, it is taken by mouth, dissolved in the mouth, or  placed in the vagina . [ 12 ] [ 15 ] [ 16 ] [ 17 ] [ 18 ]  For postpartum bleeding it may also be  used rectally . [ 19 ]


Common side effects include  diarrhea  and abdominal pain. [ 11 ]  It is in  pregnancy category  X, meaning that it is known to result in negative outcomes for the fetus if taken during  pregnancy . [ 11 ]  In rare cases,  uterine rupture  may occur. [ 11 ]  It is a  prostaglandin analogue —specifically, a synthetic  prostaglandin E 1  (PGE 1 ). [ 11 ]


Misoprostol was developed in 1973. [ 20 ]  It is on the  World Health Organization's List of Essential Medicines . [ 21 ]  It is available as a  generic medication . [ 11 ]


Misoprostol is used for the prevention of  NSAID -induced gastric ulcers. It acts upon gastric  parietal cells , inhibiting the secretion of  gastric acid  by  G-protein coupled receptor -mediated inhibition of  adenylate cyclase , which leads to decreased intracellular  cyclic AMP  levels and decreased  proton pump  activity at the  apical  surface of the parietal cell. Misoprostol is sometimes coprescribed with NSAIDs to prevent their common adverse effect of  gastric ulceration  (e.g., with  diclofenac  in  Arthrotec ). [ citation needed ]


However, even in the treatment of NSAID-induced ulcers,  omeprazole  proved to be at least as effective as misoprostol, [ 22 ]  but was significantly better tolerated, so misoprostol should not be considered a first-line treatment. Misoprostol-induced diarrhea and the need for multiple daily doses (typically four) are the main issues impairing compliance with therapy. [ medical citation needed ]


Misoprostol is commonly used for  labor induction . It causes  uterine  contractions and the ripening ( effacement  or thinning) of the  cervix . [ 23 ]  It can be less expensive than the other commonly used ripening agent,  dinoprostone . [ 24 ]


Oxytocin  has long been used as the standard agent for labor induction, but does not work well when the cervix is not yet ripe. Misoprostol also may be used in conjunction with oxytocin. [ 24 ]


Between 2002 and 2012, a misoprostol vaginal insert was studied, and was approved in the EU. [ 25 ] [ 26 ] [ 27 ]  It was not approved for use in the United States, and the US FDA still considers cervical ripening and labor induction to be outside of the approved uses for misoprostol. [ 28 ] [ 29 ]


When administered prior to  myomectomy  in women with uterine fibroids, misoprostol reduces operative blood loss and requirement of blood transfusion. [ 30 ]


Misoprostol is used either alone or in conjunction with another medication ( mifepristone  or  methotrexate ) for  medical abortions  as an alternative to  surgical abortion . [ 31 ]  Medical abortion has the advantage of being less invasive, and more autonomous, self-directed, and discreet. It is preferred by some women because it feels more natural, as the drugs induce a miscarriage. [ 32 ]  It is also more easily accessible in places where abortion is illegal. [ 33 ]  The  World Health Organization  (WHO) provides clear guidelines on the use, benefits and risks of misoprostol for abortions. [ 34 ]


Misoprostol is most effective when it is used in combination with methotrexate or mifepristone (RU-486). [ 35 ]  Mifepristone blocks signaling by  progesterone , causing the uterine lining to degrade, the blood vessels of the  cervix  and  uterus  to dilate and causing uterine contraction, similar to a  menstrual period , which causes the embryo to detach from the uterine walls. [ 36 ]  Misoprostol then dilates the cervix and induces muscle contractions which clear the uterus. [ citation needed ]  Misoprostol alone is less effective (typically 88% up to eight-weeks gestation). It is not inherently unsafe if medically supervised, but 1% of women will have heavy bleeding requiring medical attention, some women may have  ectopic pregnancy , and the 12% of pregnancies that continue after misoprostol failure are more likely to have birth defects and are usually followed up with a more effective method of abortion. [ 37 ]


Most large studies recommend a protocol for the use of misoprostol in combination with mifepristone. [ 38 ] [ 39 ]  Together they are effective in around 95% for early pregnancies. [ 40 ]  Misoprostol alone may be more effective in earlier gestation. [ 41 ]


Misoprostol can also be used to  dilate the cervix  in preparation for a surgical abortion, particularly in the second trimester (either alone or in combination with  osmotic dilators ). [ citation needed ]


Misoprostol by mouth is the least effective treatment for producing complete abortion in a period of 24 hours due to the liver's  first-pass effect  which reduces the  bioavailability  of the misoprostol. Vaginal and sublingual routes result in greater efficacy and extended duration of action because these routes of administration allow the drug to be directly absorbed into circulation by bypassing the liver first-pass effect. [ 42 ] [ 17 ] [ 18 ]


Hematocrit  or Hb tests and Rh testing are recommended before use for abortion confirmation of pregnancy. [ 43 ]  Following use, it is recommended that people attend a follow-up visit 2 weeks after treatment. If used for treatment of complete abortion, a pregnancy test, physical examination of the uterus, and ultrasound should be performed to ensure success of treatment. Surgical management is possible in the case of failed treatment. [ 42 ]


Misoprostol may be used to complete a  miscarriage  or  missed abortion  when the body does not expel the embryo or fetus on its own. Compared to no medication or placebo, it could decrease the time to complete expulsion. [ 44 ]  Use of a single dose of misoprostol vaginally or buccally is preferred, with additional doses as needed. It also can be used in combination with mifepristone, with a similar regimen to medical abortion. [ 17 ] [ 18 ]


Misoprostol is regularly used in some Canadian hospitals for labour induction for fetal deaths early in pregnancy, and for termination of pregnancy for fetal anomalies. A low dose is used initially, then doubled for the remaining doses until delivery. In the case of a previous Caesarian section, however, lower doses are used.


Misoprostol is also used to prevent and treat  post-partum bleeding . Orally administered misoprostol was marginally less effective than  oxytocin . [ 45 ]  The use of rectally administered misoprostol is optimal in cases of bleeding; it was shown to be associated with lower rates of side effects compared to other routes. Rectally administered misoprostol was reported in a variety of case reports and randomised controlled trials. [ 46 ] [ 47 ]  However, it is inexpensive and thermostable (thus does not require refrigeration like oxytocin), making it a cost-effective and valuable drug to use in the developing world. [ 48 ]  A randomised control trial of misoprostol use found a 38% reduction in maternal deaths due to  post partum  haemorrhage in resource-poor communities. [ 49 ]  Misoprostol is recommended due to its cost, effectiveness, stability, and low rate of side effects. [ 50 ]  Oxytocin must also be given by injection, while misprostol can be given orally or rectally for this use, making it much more useful in areas where nurses and physicians are less available. [ 51 ]


In women with prior caesarean section or prior failure of insertion of an intrauterine contraceptive device, pre-procedure administration of misoprostol reduces the rate of failure of insertion of intrauterine contraceptive device. However, due to a higher rate of adverse effects, routine use of misoprostol for this purpose in other women is not supported by the data. [ 52 ]


For  cervical ripening  in advance of endometrial biopsy to reduce the need for use of a tenaculum or cervical dilator. [ citation needed ]


There is limited evidence supporting the use of misoprostol for the treatment of  trigeminal neuralgia  in patients with  multiple sclerosis . [ 53 ] [ 54 ]


The most commonly reported  adverse effect  of taking misoprostol by mouth for the prevention of stomach ulcers is  diarrhea . In clinical trials, an average 13% of people reported diarrhea, which was dose-related and usually developed early in the course of therapy (after 13 days) and was usually self-limiting (often resolving within 8 days), but sometimes (in 2% of people) required discontinuation of misoprostol. [ 55 ]


The next most commonly reported adverse effects of taking misoprostol by mouth for the prevention of gastric ulcers are:  abdominal pain ,  nausea ,  flatulence ,  headache ,  dyspepsia ,  vomiting , and  constipation , but none of these adverse effects occurred more often than when taking  placebos . [ 55 ]


There are increased side effects with sublingual or oral misoprostol, compared to a low dose (400 μg) vaginal misoprostol. However, low dose vaginal misoprostol was linked with low complete abortion rate. [ 42 ]  The study concluded that sublingually administered misoprostol dosed at 600 μg or 400 μg had greater instances of fever and diarrhea due to its quicker onset of action, higher peak concentration and bioavailability in comparison to vaginal or oral misoprostol. [ 42 ]


For the indication of medical abortion, bleeding and cramping is commonly experienced after administration of misoprostol. Bleeding and cramping is likely to be greater than that experienced with menses, however, emergency care is advised if bleeding is excessive. [ 43 ]


Misoprostol should not be taken by pregnant women with wanted pregnancies to reduce the risk of NSAID-induced gastric ulcers because it increases uterine tone and contractions in pregnancy, which may cause partial or complete abortions, and because its use in pregnancy has been associated with birth defects. [ 55 ] [ 56 ]


All cervical ripening and induction agents can cause  uterine hyperstimulation , which can negatively affect the blood supply to the fetus and increases the risk of complications such as uterine rupture. [ 57 ]  Concern has been raised that uterine hyperstimulation that occurs during a misoprostol-induced labor is more difficult to treat than hyperstimulation during labors induced by other drugs. [ 58 ]  Because the complications are rare, it is difficult to determine if misoprostol causes a higher risk than do other cervical ripening agents. One estimate is that it would require around 61,000 people enrolled in randomized controlled trials to detect a difference in serious fetal complications and about 155,000 people to detect a difference in serious maternal complications. [ 59 ]


It is recommended that medical treatment for  missed abortion  with misoprostol should only be considered in people without the following contraindications: suspected ectopic pregnancy, use of non-steroidal drugs, signs of pelvic infections or sepsis, unstable hemodynamics, known allergy to misoprostol, previous caesarean section, mitral stenosis, hypertension, glaucoma, bronchial asthma, and remote areas without a hospital nearby. [ 42 ]


Misoprostol, a  prostaglandin analogue , binds to myometrial cells to cause strong myometrial contractions leading to expulsion of tissue. This agent also causes cervical ripening with softening and dilation of the cervix. Misoprostol binds to and stimulates  prostaglandin EP 2  receptors ,  prostaglandin EP 3  receptor  and  prostaglandin EP 4  receptor  but not  prostaglandin EP 1  receptor  and therefore is expected to have a more restricted range of physiological and potentially toxic actions than prostaglandin E 2  or other analogs which activate all four prostaglandin receptors. [ 60 ]


In August 2000, a letter from  G.D. Searle, LLC , the inventor of the drug, [ 61 ] [ 62 ]  generated controversy by warning against its use by pregnant women because of its ability to induce abortion, citing reports of maternal and fetal deaths when it was used to induce labor. [ 63 ]  The  American College of Obstetricians and Gynecologists  holds that substantial evidence supports the use of misoprostol for induction of labor, a position it reaffirmed in response to the Searle letter. [ 64 ]  It is on the  World Health Organization's List of Essential Medicines . [ 21 ]


A vaginal form of the medication is sold in the EU under the names Misodel [ 65 ]  and Mysodelle [ 66 ]  for use in labor induction. [ medical citation needed ]


Misoprostol is used for  self-induced abortions  in Brazil, where  black market  prices exceed US$100 per dose. Illegal medically unsupervised misoprostol abortions in Brazil are associated with a lower complication rate than other forms of illegal self-induced abortion, but are still associated with a higher complication rate than legal, medically supervised surgical and medical abortions. Failed misoprostol abortions are associated with birth defects in some cases. [ 67 ] [ 68 ] [ 69 ] [ 70 ] [ 71 ]  Low-income and immigrant populations in  New York City  have also been observed to use self-administered misoprostol to induce abortions, as this method is much cheaper than a surgical abortion (about $2 per dose). [ 72 ]  The drug is readily available in Mexico. [ 73 ]  Use of misoprostol has also increased in Texas in response to increased regulation of abortion providers. [ 74 ]  Following the United States Supreme Court decision of  Dobbs v. Jackson Women's Health Organization , many states restricted access to legal abortion services, including medication abortion using misoprostol. As a result of these restrictions, it was reported that there was an increase in self-managed abortions by women in the United States. Many women purchased the pills from overseas online pharmacies or obtained misoprostol from Mexico. [ 75 ]


Maddrey's discriminant function  (DF) is the traditional model for evaluating the severity and prognosis in alcoholic hepatitis and evaluates the efficacy of using alcoholic hepatitis steroid treatment.  The Maddrey DF score is a predictive statistical model compares the subject's DF score with mortality prognosis within 30-day or 90-day scores. [ clarification needed ]   The subject's Maddrey DF score is determined by blood analysis.


The  modified Maddrey's discriminant function  was originally described by Maddrey and Boitnott [ 1 ]  to predict  prognosis  in  alcoholic hepatitis .  It is calculated by a simple formula using  prothrombin time  and serum  bilirubin  concentration: [ citation needed ]


(

 4.6
 ×

 (

 prothrombin time

 −

 control time

 )

 )

 +

 serum bilirubin in mg/dl

 {\displaystyle \left(4.6\times \left({\hbox{prothrombin time}}-{\hbox{control time}}\right)\right)+{\hbox{serum bilirubin in mg/dl}}}

 [ 2 ]


Prospective studies  have shown that it is useful in predicting short term prognosis, especially mortality within 30 days. [ 3 ]   A value more than 32 implies poor outcome with one month mortality ranging between 35% and 45%. [ 4 ]   Corticosteroid therapy or pentoxifylline have been used with mixed results for patients whose increased mortality is indicated with a value greater than 32. [ 5 ]


To calculate Maddrey discriminant function using SI units, such as  micromoles  per litre, divide bilirubin value by 17.


A  Murphy drip  is a  rectal infusion  apparatus to administer the medical procedure of  proctoclysis , also known as rectoclysis. [ 2 ] [ 3 ]  During the procedure, an end of the Murphy drip is inserted into the  rectum  and large quantities of liquid are infused into the rectum drop by drop. [ 4 ]  Prior to fluids or medicines being given  intravenously , the Murphy drip and  hypodermoclysis  were the prime routes to administer fluids such as for  replacement  when patients could not be fed by mouth. [ 5 ]  American surgeon  John Benjamin Murphy  introduced the drip method of  saline  infusion per rectum in the treatment of  peritonitis . [ 6 ]


The Murphy drip was invented by  Wisconsin  surgeon  John Benjamin Murphy , for the purpose of administering a proctoclysis for  hydration  and replenishment of  electrolytes , via a  sodium  and  calcium chloride  solution. This would be used when administration by mouth was not possible because of the condition of the patient. [ 7 ]  The Murphy drip was described in the April 1909 issue of the  Journal of the American Medical Association . [ 8 ]  By as early as July 1928, the Murphy drip was considered an auxiliary method of injection behind  intravenous therapy  and  subcutaneous injection , the two principal methods of  injection  at that time. [ 9 ]


The Murphy drip can be used for administering drugs by this route and the apparatus is also used in conjunction with a  catheter  for  bladder  irrigation.
The term can even be applied to apparatus used to administer fluids intravenously. [ 10 ]


A curious anecdote involving the Murphy drip is related by  Walter Lord  in his book on the  Battle of Midway . On 4 June 1942 Pharmacist's Mate Edwin Miller was stationed on Sand Island (part of the  Midway Atoll ) and was making ready for the expected Japanese attack. Miller prepared undrinkably strong coffee which, he claimed, was to be used in an "old fashioned" treatment for  shock  – administration of  strong coffee through the rectum  via a Murphy drip. When the attack got underway, Miller was joined by his commanding officer and doctor in charge, Lieutenant Commander A. E. Ady, who did not appear to know the medical purpose of the coffee and asked for some to be poured. Miller thought that it would be amusing to let his commander drink it, but made the mistake of also drinking some himself. Dr. Ady continued to tell jokes throughout the attack. Miller, however, paid for his practical joke and was sick. [ 11 ]


A description of a Murphy drip set-up is contained in the 1932  Kansas Supreme Court  legal case  Ratliffe v. Wesley Hospital and Nurses' Training School: [ 12 ]


On February 14, 1929, "Dr. Horn directed the nurse to use the proctoclysis, known as the “Murphy drip.” While the operation was in progress a student nurse in the employ of the hospital prepared the room for the return of the appellant. The proctoclysis set was a part of the equipment of the hospital and was assembled and placed at or near the foot of the bed by the student nurse. The proctoclysis set consists of a standard which is an iron pole setting on a tripod containing hooks at intervals, and on these hooks by means of a chain, tape, string, or piece of gauze is hung a can containing hot water and soda solution. From this can a tube extends which is inserted in the rectum of the patient to whom the proctoclysis is administered. It was necessary to keep the solution hot in order that it would have a body temperature after dropping through the tube and entering the body. ... It was not unusual for the vessel holding the water to be fastened to the standard by gauze, string, or other bandage, although a part of the vessels were equipped with chains." [ 12 ]


Olsalazine  is an anti-inflammatory medication used in the treatment of  ulcerative colitis . [ 2 ] [ 3 ]  It is sold under the brand name  Dipentum . [ 4 ]


Olsalazine itself is a pro-drug of  mesalazine  (5-aminosalicyclic acid or 5-ASA) and is not absorbed in the small intestine. Instead it continues through to the colon where it is cleaved into two molecules of 5-ASA by  azoreductases  produced by colonic bacteria. Olsalazine thus exerts its anti-inflammatory effect by its colonic breakdown into 5-ASA which inhibits cyclooxygenase and lipoxygenase thereby reducing prostaglandin and leukotriene production. [ 4 ]


Olsalazine gained  Food and Drug Administration  (FDA) approval in 1990.


The drug is supplied by  UCB Pharma .


In 2006 the Australian biotech company  Giaconda  received a European patent for a combination therapy for treating constipation-predominant  irritable bowel syndrome  that uses olsalazine and the anti- gout  drug  colchicine , for trials the following year. [ 5 ]


Oral rehydration therapy  ( ORT ) is a type of  fluid replacement  used to prevent and treat  dehydration , especially due to  diarrhea . [ 1 ]  It involves drinking water with modest amounts of sugar and salts, specifically  sodium  and  potassium . [ 1 ]  Oral rehydration therapy can also be given by a  nasogastric tube . [ 1 ]  Therapy can include the use of  zinc supplements  to reduce the duration of diarrhea in infants and children under the age of 5. [ 1 ]  Use of oral rehydration therapy has been estimated to decrease the risk of death from diarrhea by up to 93%. [ 2 ]


Side effects may include  vomiting ,  high blood sodium , or  high blood potassium . [ 1 ]  If vomiting occurs, it is recommended that use be paused for 10 minutes and then gradually restarted. [ 1 ]  The recommended formulation includes  sodium chloride ,  sodium citrate ,  potassium chloride , and  glucose . [ 1 ]  Glucose may be replaced by  sucrose  and sodium citrate may be replaced by  sodium bicarbonate , if not available, although the resulting mixture is not shelf stable in high-humidity environments. [ 1 ] [ 3 ]  It works as glucose increases the uptake of sodium and thus water by the  intestines , and the potassium chloride and sodium citrate help prevent  hypokalemia  and  acidosis , respectively, which are both common side effects of diarrhea. [ 4 ] [ 3 ] [ 5 ]  A number of other formulations are also available including versions that can be made at home. [ 4 ] [ 2 ]  However, the use of homemade solutions has not been well studied. [ 2 ]


Oral rehydration therapy was developed in the 1940s using electrolyte solutions with or without glucose on an empirical basis chiefly for mild or convalescent patients, but did not come into common use for rehydration and maintenance therapy until after the discovery that glucose promoted sodium and water absorption during cholera in the 1960s. [ 6 ]  It is on the  World Health Organization's List of Essential Medicines . [ 7 ]  Globally, as of 2015 [update] , oral rehydration therapy is used by 41% of children with diarrhea. [ 8 ]  This use has played an important role in reducing the  number of deaths in children under the age of five . [ 8 ]


ORT is less invasive than the other strategies for fluid replacement, specifically  intravenous  (IV) fluid replacement. Mild to moderate dehydration in children seen in an  emergency department  is best treated with ORT. Persons taking ORT should eat within six hours and return to their full diet within 24–48 hours. [ 9 ]


Oral rehydration therapy may also be used as a treatment for the symptoms of  dehydration  and rehydration in  burns  in resource-limited settings. [ 10 ]


ORT may lower the mortality rate of diarrhea by as much as 93%. [ 2 ]  Case studies in four developing countries also have demonstrated an association between increased use of ORS and reduction in mortality. [ 11 ]
ORT using the original ORS formula has no effect on the duration of the diarrheic episode or the volume of fluid loss, [ 12 ]  although reduced osmolarity solutions have been shown to reduce stool volume. [ 13 ]


The degree of dehydration should be assessed before initiating ORT. ORT is suitable for people who are not dehydrated and those who show signs and symptoms of mild to moderate dehydration. People who have severe dehydration should seek professional medical help immediately and receive intravenous rehydration as soon as possible to rapidly replenish fluid volume in the body. [ 14 ]


ORT should be discontinued and fluids replaced intravenously when vomiting is protracted despite proper administration of ORT; or signs of dehydration worsen despite giving ORT; or the person is unable to drink due to a decreased level of consciousness; or there is evidence of intestinal blockage or  ileus . ORT might also be contraindicated in people who are in hemodynamic shock due to impaired airway protective reflexes. [ 15 ]  Short-term vomiting is not a contraindication to receiving oral rehydration therapy. In persons who are vomiting, drinking oral rehydration solution at a slow and continuous pace will help resolve vomiting. [ 9 ]


WHO  and  UNICEF  have jointly developed official guidelines for the manufacture of oral rehydration solution and the oral rehydration salts used to make it (both often abbreviated  ORS ). They also describe other acceptable solutions, depending on material availability. Commercial preparations are available as prepared fluids and as packets of powder ready to mix with water. [ 16 ] [ 17 ]


A basic oral rehydration therapy solution can also be prepared when packets of oral rehydration salts are not available. [ 18 ] [ 19 ]  The  molar   ratio  of sugar to salt should be 1:1 and the solution should not be  hyperosmolar . [ 20 ]  The Rehydration Project states, "Making the mixture a little diluted (with more than 1 litre of clean water) is not harmful." [ 21 ]


The optimal fluid for preparing oral rehydration solution is clean water. However, if this is not available, the usually available water should be used. Oral rehydration solution should  not   be withheld simply because the available water is potentially unsafe; rehydration takes precedence. [ 22 ]


When oral rehydration salts packets and suitable teaspoons for measuring sugar and salt are not available, the WHO has recommended that homemade gruels, soups, etc., may be considered to help maintain hydration. [ 23 ]  A Lancet review in 2013 emphasized the need for more research on appropriate home made fluids to prevent dehydration. [ 24 ]   Sports drinks  are not optimal oral rehydration solutions, but they can be used if optimal choices are not available. They should not be withheld for lack of better options; again, rehydration takes precedence. But they are not replacements for oral rehydration solutions in nonemergency situations. [ 25 ]


In 2003, WHO and UNICEF recommended that the  osmolarity  of oral rehydration solution be reduced from 311 to 245 mOsm/L. [ 26 ] [ 27 ]  These guidelines were also updated in 2006. This recommendation was based on multiple clinical trials showing that the reduced osmolarity solution reduces stool volume in children with diarrhea by about twenty-five percent and the need for IV therapy by about thirty percent when compared to standard oral rehydration solution. The incidence of vomiting is also reduced. The reduced osmolarity oral rehydration solution has lower concentrations of glucose and sodium chloride than the original solution, but the concentrations of potassium and  citrate  are unchanged. [ 28 ] [ 13 ] [ 29 ] [ 30 ]


The reduced osmolarity solution has been criticized by some for not providing enough sodium for adults with cholera. [ 31 ]  Clinical trials have, however, shown reduced osmolarity solution to be effective for adults and children with cholera. [ 30 ]  They seem to be safe but some caution is warranted according to the  Cochrane review . [ 30 ]


ORT is based on evidence that water continues to be absorbed from the  gastrointestinal tract  even while fluid is lost through diarrhea or vomiting. The  World Health Organization  specify indications, preparations and procedures for ORT. [ 22 ]


WHO/UNICEF guidelines suggest ORT should begin at the first sign of diarrhea in order to prevent dehydration. [ 28 ] [ 33 ]  Babies may be given ORS with a dropper or a syringe. Infants under two may be given a teaspoon of ORS fluid every one to two minutes. Older children and adults should take frequent sips from a cup, with a recommended intake of 200–400 mL of solution after every loose movement. [ 1 ]  The WHO recommends giving children under two a quarter- to a half-cup of fluid following each loose  bowel movement  and older children a half- to a full cup. If the person vomits, the caregiver should wait 5–10 minutes and then resume giving ORS. [ 22 ] : Section 4.2   ORS may be given by  aid workers  or health care workers in  refugee  camps, health clinics and hospital settings. [ 34 ]  Mothers should remain with their children and be taught how to give ORS. This will help to prepare them to give ORT at home in the future. Breastfeeding should be continued throughout ORT. [ 22 ]


As part of oral rehydration therapy, the WHO recommends supplemental zinc (10 to 20 mg daily) for ten to fourteen days, to reduce the severity and duration of the illness and make recurrent illness in the following two to three months less likely. Preparations are available as a  zinc sulfate  solution for adults, a modified solution for children and in tablet form. [ 35 ]


After severe dehydration is corrected and appetite returns, feeding the person speeds the recovery of normal intestinal function, minimizes weight loss and supports continued growth in children. Small frequent meals are best tolerated (offering the child food every three to four hours). Mothers should continue to  breastfeed . [ 22 ] [ 11 ] [ 36 ]  A child with watery diarrhea typically regains their appetite as soon as dehydration is corrected, whereas a child with bloody diarrhea often eats poorly until the illness resolves. Such children should be encouraged to resume normal feeding as soon as possible. Once diarrhea is corrected, the WHO recommends giving the child an extra meal each day for two weeks, and longer if the child is malnourished. [ 22 ]


Dehydration may be overestimated in  wasted  children and underestimated in  edematous  children. [ 37 ]  Care of these children must also include careful management of their  malnutrition  and treatment of other infections. Useful signs of dehydration include an eagerness to drink, lethargy, cool and moist extremities, weak or absent  radial pulse  (wrist), and reduced or absent  urine  flow.  In children with severe malnutrition, it is often impossible to reliably distinguish between moderate and severe dehydration. A severely malnourished child who has signs of severe dehydration but who does not have a history of watery diarrhea should be treated for  septic shock . [ 22 ]


The original ORS (90 mmol sodium/L) and the current standard reduced-osmolarity ORS (75 mmol sodium/L) both contain too much sodium and too little potassium for severely malnourished children with dehydration due to diarrhea. ReSoMal ( Re hydration  So lution for  Mal nutrition) is recommended for such children. It contains less sodium (45 mmol/L) and more potassium (40 mmol/L) than reduced osmolarity ORS. [ 38 ]  It can be obtained in packets produced by UNICEF or other manufacturers. [ citation needed ]


An exception is if the severely malnourished child also has severe diarrhea (in which case ReSoMal may not provide enough sodium), in which case standard reduced-osmolarity ORS (75 mmol sodium/L) is recommended. [ 22 ]  Malnourished children should be rehydrated slowly. The WHO recommends 10 milliliters of ReSoMal per kilogram body weight for each of the first two hours (for example, a 9-kilogram child should be given 90 mL of ReSoMal over the course of the first hour, and another 90 mL for the second hour) and then continuing at this same rate or slower based on the child's thirst and ongoing stool losses, keeping in mind that a severely dehydrated child may be lethargic.  If the child drinks poorly, a nasogastric tube should be used. The IV route should not be used for rehydration except in cases of shock and then only with care, infusing slowly to avoid flooding the circulation and overloading the heart. [ 22 ]


Feeding should usually resume within 2–3 hours after starting rehydration and should continue every 2–3 hours, day and night. For an initial cereal diet before a child regains his or her full appetite, the WHO recommends combining 25 grams skimmed milk powder, 20 grams vegetable oil, 60 grams sugar, and 60 grams rice powder or other cereal into 1,000 milliliters water and boiling gently for five minutes. Give 130 mL per kilogram of body weight during per 24 hours. A child who cannot or will not eat this minimum amount should be given the diet by nasogastric tube divided into six equal feedings. Later on, the child should be given cereal made with a greater amount of skimmed milk product and vegetable oil and slightly less sugar. As appetite fully returns, the child should be eating 200 mL per kilogram of body weight per day. Zinc, potassium, vitamin A, and other vitamins and minerals should be added to both recommended cereal products, or to the oral rehydration solution itself. Children who are breastfed should continue breastfeeding. [ 22 ]


The WHO recommends that all severely malnourished children admitted to hospital should receive  broad-spectrum antibiotics  (for example,  gentamicin  and  ampicillin ). In addition, hospitalized children should be checked daily for other specific infections. [ 22 ]


If cholera is suspected give an antibiotic to which  V. cholera e are susceptible. This reduces the volume loss due to diarrhea by 50% and shortens the duration of diarrhea to about 48 hours. [ 39 ]


Fluid from the body enters the  intestinal   lumen  during  digestion . This fluid is  isosmotic  with the blood and contains a high quantity, about 142 mEq/L, of  sodium . A healthy individual secretes 2000–3000 milligrams of sodium per day into the intestinal lumen. Nearly all of this is reabsorbed so that sodium levels in the body  remain constant . In a diarrheal illness, sodium-rich intestinal secretions are lost before they can be reabsorbed. This can lead to life-threatening  dehydration  or  electrolyte imbalances  within hours when fluid loss is severe. The objective of therapy is the replenishment of sodium and water losses by ORT or intravenous infusion. [ 40 ]


Sodium absorption occurs in two stages. The first is via intestinal  epithelial  cells ( enterocytes ). Sodium passes into these cells by  co-transport  with glucose, via the  SGLT1  protein. From the intestinal epithelial cells, sodium is pumped by  active transport  via the  sodium-potassium pump  through the  basolateral cell membrane  into the  extracellular space . [ 41 ] [ 42 ]


The  sodium–potassium ATPase pump  at the basolateral  cell membrane  moves three sodium ions into the extracellular space, while pulling into the enterocyte two  potassium  ions. This creates a "downhill" sodium  gradient  within the cell.  SGLT proteins  use energy from this downhill sodium gradient to transport  glucose  across the  apical membrane  of the cell against the glucose gradient. The co-transporters are examples of  secondary active transport . The GLUT  uniporters  then transport glucose across the basolateral membrane. Both SGLT1 and SGLT2 are known as  symporters , since both sodium and glucose are transported in the same direction across the membrane. [ citation needed ]


The co-transport of glucose into epithelial cells via the  SGLT1  protein requires sodium. Two sodium ions and one molecule of glucose (or  galactose ) are transported together across the  cell membrane  via the SGLT1 protein. Without glucose, intestinal sodium is not absorbed. This is why oral rehydration salts include both sodium and glucose. For each cycle of the transport, hundreds of water molecules move into the epithelial cell to maintain osmotic equilibrium. The resultant absorption of sodium and water can achieve rehydration even while diarrhea continues. [ 40 ]


In the early 1980s, "oral rehydration therapy" meant only the preparation prescribed by the  World Health Organization  (WHO) and  UNICEF . In 1988, the definition was changed to include recommended home-made solutions, because the official preparation was not always available. The definition was also amended in 1988, to include continued feeding as associated therapy. In 1991, the definition became "an increase in administered  hydrational fluids "; in 1993, "an increase in administered fluids and continued feeding". [ 34 ]


Dehydration was a major cause of death during the 1829  cholera  pandemic in Russia and Western Europe. In 1831,  William Brooke O'Shaughnessy  noted the changes in blood composition and loss of water and salt in the stool of people with cholera and prescribed  intravenous fluid therapy  (IV fluids). The prescribing of  hypertonic  IV therapy decreased the mortality rate of cholera to 40%, from 70%. In the West, IV therapy became the "gold standard" for the treatment of moderate and severe dehydration. [ 43 ]


In 1953,  Hemendra Nath Chatterjee  published in  The Lancet  the results of using ORT to treat people with mild cholera. [ 44 ]  He gave the solution orally and rectally, along with Coleus extract, antihistamines, and antiemetics, without controls. The formula of the fluid replacement solution was 4 g of  sodium chloride , 25 g of  glucose , and 1000 mL of  water . [ 44 ] [ 45 ]  He did not publish any balance data, and his exclusion of patients with severe dehydration did not lead to any confirming study; his report remained anecdotal. [ citation needed ]


Robert Allan Phillips  tried to make an effective ORT solution based on his discovery that, in the presence of glucose, sodium, and chloride could be absorbed in patients with cholera; but he failed because his solution was too hypertonic and he used it to try to stop the diarrhea rather than to rehydrate patients. [ citation needed ]


In the early 1960s,  Robert K. Crane  described the  sodium-glucose co-transport mechanism  and its role in intestinal glucose absorption. [ 46 ]  This, along with evidence that the intestinal  mucosa  appears undamaged in cholera, suggested that intestinal absorption of glucose and sodium might continue during the illness. This supported the notion that oral rehydration might be possible even during severe diarrhea due to cholera. In 1967–1968,  Norbert Hirschhorn  and Nathaniel F. Pierce showed that people with severe cholera can absorb glucose, salt, and water and that this can occur in sufficient amounts to maintain hydration. [ 47 ] [ 48 ]  In 1968,  David R. Nalin  and  Richard A. Cash , helped by  Rafiqul Islam  and Majid Molla, reported that giving adults with cholera an oral glucose-electrolyte solution in volumes equal to those of the diarrhea losses reduced the need for IV fluid therapy by eighty percent. [ 49 ] [46]


In 1971, fighting during the  Bangladesh Liberation War  displaced millions and an epidemic of cholera ensued among the refugees. When IV fluid ran out in the  refugee camps ,  Dilip Mahalanabis , a physician working with the Johns Hopkins International Center for Medical Research and Training in Calcutta, issued instructions to prepare an oral rehydration solution and to distribute it to family members and caregivers. Over 3,000 people with cholera received ORT in this way. The  mortality rate  was 3.6% among those given ORT, compared with 30% in those given IV fluid therapy. [ 43 ] [ 45 ]  After Bangladesh won independence, there was a wide campaign to promote the use of saline in the treatment of diarrhea.  In 1980, the World Health Organization recognized ORT and began a global program for its dissemination. [ citation needed ]


In the 1970s,  Norbert Hirschhorn  used oral rehydration therapy on the  White River Apache Indian Reservation  with a grant from the National Institute of Allergy and Infectious Diseases. [ 50 ] [ 51 ] [ 52 ]  He observed that children voluntarily drank as much of the solution as needed to restore hydration, and that rehydration and early re-feeding would protect their nutrition. This led to increased use of ORT for children with diarrhea, especially in developing countries. [ citation needed ]


In 1980, the Bangladeshi nonprofit BRAC created a door-to-door and person-to-person sales force to teach ORT for use by mothers at home. A  task force  of fourteen women, one cook, and one male supervisor traveled from village to village. After visiting with women in several villages, they hit upon the idea of encouraging the women in the village to make their own oral rehydration fluid. They used available household equipment, starting with a "half a seer" (half a quart) of water and adding a fistful of sugar and a three-finger pinch of salt. Later on, the approach was broadcast over television and radio, and a market for oral rehydration salts packets developed. Three decades later, national surveys have found that almost 90% of children with severe diarrhea in Bangladesh are given oral rehydration fluids at home or in a health facility. [ 53 ]  ORT is known in Bangladesh as Orosaline or Orsaline. [ citation needed ]


From 2006 to 2011, UNICEF estimated that worldwide about a third of children under 5 who had diarrhea received an oral rehydration solution, with estimates ranging from 30% to 41% depending on the region. [ 54 ] [ 55 ]


ORT is one of the principal elements of the UNICEF "GOBI FFF" program (growth monitoring; ORT; breast feeding; immunization; female education; family spacing and  food supplementation ). The program aims to increase child survival in developing nations through proven low-cost interventions. [ 56 ]


An  ostomy pouching system [ 1 ]  is a  prosthetic   medical device  that provides a means for the collection of waste from a surgically diverted biological system ( colon ,  ileum ,  bladder ) and the creation of a  stoma . Pouching systems are most commonly associated with  colostomies ,  ileostomies , and  urostomies . [ 2 ]


Pouching systems usually consist of a collection pouch, a barrier on the skin, and connect with the stoma itself, which is the part of the body that has been diverted to the skin. The system may be a one-piece system consisting only of a bag or, in some instances involve a device placed on the skin with a collection pouch that is attached mechanically or with an  adhesive  in an  airtight  seal, known as a two-piece system.


The system used varies between individuals and is often based on the medical reason, personal preference and lifestyle.


Ostomy pouching systems collect  waste  that is output from a stoma. The pouching system allows the stoma to drain into a sealed collection pouch, while protecting the surrounding  skin  from  contamination . [ 3 ]  They are used to maintain independence, so that a wearer can continue to lead an active lifestyle that can include all forms of sports and recreation. [ citation needed ]


Ostomy barriers sit on the skin and separate the ostomy pouch from the internal conduit. They are not always present. These barriers, also called flanges, wafers, or baseplates are manufactured using  pectin  or similar organic material and are available in a wide variety of sizes to accommodate a person's particular anatomy.


The internal opening must be the correct size to accommodate the individual's  stoma  while protecting the skin from contact with waste. The methods for sizing this opening vary depending on the type of wafer/baseplate; some pre-cut sizes are available, some users customize the opening using  scissors . Manufacturers have recently [ when? ]  introduced moldable wafers that can be shaped by hand without the need for scissors. [ 2 ]


Skin adhesion for modern wafers/baseplates/flanges are optimized on all the five parameters required in an adhesive:


In addition, barriers with adhesive border can provide additional security that the system stays in place. Using a barrier film spray before applying a new flange will improve adhesion, soothe irritated skin and protect the skin from irritation.


A barrier may last between one and many days before it needs to be replaced; this is highly dependent on the individual's lifestyle, ostomy type, and anatomy.


The method of attachment to the barrier varies between manufactures and includes permanent (one-piece), press-on/click (" Tupperware " type), turning locking rings and "sticky" adhesive mounts. The two-piece arrangement allows pouches to be exchanged without removing the wafer; for example, some people prefer to temporarily switch to a "mini-pouch" for swimming, intimate and other short-term activities. Mini-pouches are suitable for minimum usage only.


Pouches can be divided into two basic types: open-end (drainable) and closed-end (disposable).


The use of open-end vs. closed-end pouches is dependent on the frequency in which an individual needs to empty the contents, as well as  economics . [ 3 ]


Gas  is created during  digestion , and an airtight pouch will collect this and inflate. To prevent this some pouches are available with special  charcoal filtered  vents that will allow the gas to escape, and prevent ballooning at night. Some odor can be expelled through the charcoal filter especially if  sufficient deodorant is not used in the pouch.


Pouch covers are helpful to disguise the plastic pouch when it is exposed when reaching or other physical activity. These are usually made of cloth and can be decorative or plain to blend in with clothing. Various sources stock sizes for most manufacturers pouches. There are flexible elastic pouch belts available for extreme physical activity but some of these require the pouch to be worn sideways so it does not fill properly and the tight fit causes pancaking of the effluent.


People with colostomies must wear an ostomy pouching system to collect intestinal waste.  Ordinarily the pouch must be emptied or changed a couple of times a day depending on the frequency of activity; in general the further from the  anus  (i.e., the further 'up' the intestinal tract) the ostomy is located the greater the output and more frequent the need to empty or change the pouch. [ 4 ]


People with colostomies who have ostomies of the  sigmoid colon  or  descending colon  may have the option of irrigation, which allows for the person to not wear a pouch, but rather just a gauze cap over the stoma, and to schedule irrigation for times that are convenient. [ 5 ]  To irrigate, a  catheter  is placed inside the stoma, and flushed with water, which allows the feces to come out of the body into an irrigation sleeve. [ 6 ]  Most colostomates irrigate once a day or every other day, though this depends on the person, their food intake, and their health.


Ostomy systems often take some time for a person to adjust to, including requiring time to learn how to use them and change the pouch, as well as psychologically adjust. [ 7 ]  The time taken to adjust may last for more than a year. [ 7 ]


Because of embarrassment or stigma associated with an ostomy system, a person who has an ostomy system can experience  social isolation ,  depression , and change in  sexual function  as well as physical complications such as weight change. In various online ostomy groups and ostomy societies, ostomates share their experiences and help each other. One of the largest is MeetAnOstoMate, a community where people with similar experiences share information, ask questions, and receive support.  [ 7 ]


Pancreatic elastase  is a form of  elastase  that is produced in the  acinar  cells of the  pancreas , initially produced as an inactive  zymogen  and later activated in the duodenum by  trypsin . Elastases form a subfamily of  serine proteases , characterized by a distinctive structure consisting of two  beta barrel  domains converging at the active site that hydrolyze amides and esters amongst many proteins in addition to  elastin , a type of connective tissue that holds organs together. Pancreatic elastase 1 is a serine endopeptidase, a specific type of protease that has the amino acid  serine  at its active site. Although the recommended name is pancreatic elastase, it can also be referred to as elastase-1, pancreatopeptidase, PE, or serine elastase.


The first  isozyme , pancreatic elastase 1, was initially thought to be expressed in the pancreas. However it was later discovered that it was the only  chymotrypsin -like elastase that was not expressed in the pancreas. In fact, pancreatic elastase is expressed in basal layers of  epidermis  (at protein level). Hence pancreatic elastase 1 has been renamed  elastase 1  (ELA1) or  chymotrypsin-like elastase family, member 1  ( CELA1 ). [ 1 ]  For a period of time, it was thought that ELA1 / CELA1 was not  transcribed  into a protein. [ 2 ]   However it was later discovered that it was expressed in skin  keratinocytes . [ 3 ]


Clinical literature that describes human elastase 1 activity in the pancreas or fecal material is actually referring to chymotrypsin-like elastase family, member 3B ( CELA3B ). [ 1 ]


Pancreatic elastase is a compact globular protein with a  hydrophobic  core. This enzyme is formed by three subunits. Each subunit binds one calcium ion ( cofactor ). There are three important metal-binding sites in  amino acids  77, 82, 87. [ 4 ]  The  catalytic triad , located in the active site is formed by three hydrogen-bonded amino acid residues (H71, D119, S214), and plays an essential role in the cleaving ability of all proteases. It is composed of a single  peptide  chain of 240 amino acids and contains 4 disulfide bridges. It has a high degree of sequence identity with pancreatic elastases that correspond to other species, such as the rat's, with whom it shares 86% of its sequence. [ 5 ]  Its enzymatic activity is a result of the specific three-dimensional conformation which its single polypeptide chain adopts, and therefore, activity is lost by  denaturation  and/or conformational changes. [ citation needed ]


Elafin, the skin-derived elastase inhibitor, has been shown to be a potent and specific inhibitor of both the porcine homolog of ELA1 and human leukocyte elastase in vitro. Elafin is expressed by epidermal keratinocytes under hyperproliferative conditions such as psoriasis and wound healing. It has also been reported to be present in many other adult epithelia that are exposed to environmental stimuli: tongue, plate, lingual tonsils, gingiva, pharynx, epiglottis, vocal fold, esophagus, uterine cervix, vagina, and hair follicles. In all these tissues, the presence of inflammatory cells is physiologic and elafin expression is believed to protect against leukocyte proteases, thereby helping to maintain epithelial integrity. [ citation needed ]


Elafin on the contrary has never been found in the basal layer in any type of epithelial tissue. Indeed, elafin is virtually absent in normal human epidermis. The other known elastase inhibitor,  SLPI , however, has been reported to be expressed in the basal keratinocytes suggesting that this may be the major elastase inhibitor in normal epidermis. [ citation needed ]


Alpha 1-antitrypsin  and  alpha-2-macroglobulin  are human serum protease inhibitors that completely inhibit the general proteolytic activity of pancreatic elastase 1 and 2. It has been observed that a protease must be active in order to bind to these two inhibitors. Studies proved that the activity of elastase 2 was enhanced in 25-250 mM NaCl. The activity of elastase 2 in NaCl approached approximately twice the activity without NaCl.
Elastase 1 is slightly inhibited above 150 mM NaCl [ 6 ]


Mutations of the CELA1 gene were suspected to be associated with  diffuse nonepidermolytic palmoplantar keratoderma  (diffuse NEPPK). [ 3 ]  However the suspected sequence variant was fully functional and did not strongly associate with the disease.  More recently, a specific mutation in the  KRT6C  gene has been linked to some cases of diffuse NEPPK. [ 7 ]


A possible  polymorphism  of the CELA1 gene coding this protein was found. On a secondary structure level, this polymorphism manifests itself in an excision of a short sequence of CELA1. The disappeared sequence carries the key amino acid residues Val-227 and Thr-239, which contribute to the  substrate specificity  of elastase I (highlighted in Figure 3), as well as five of the eight amino acids involved in the primary contact of the  elafin (inhibitor)/elastase complex formation. These observations imply that the sequence variant might modify the substrate specificity of the enzyme and abolish the  inhibitor  binding capability. Though there were no obvious pathogenic epidermal abnormalities associated with the truncated ELA1 variant, it is possible that carriers of the polymorphism may be at greater risk of developing the common skin diseases such as psoriasis and eczema (genetic and histologic studies will be required to investigate the role of ELA1 in these common epidermal disorders.). [ 3 ]


Pancreatic elastase is formed by activation of  proelastase  from mammalian pancreas by  trypsin . After processing to proelastase, it is stored in the zymogen granules and then activated to elastase in the  duodenum  by the tryptic cleavage of a peptide bond in the inactive form of the precursor molecule. [ 8 ]  This process results in the removal of an activation peptide from the N-terminal, that enables the  enzyme  to adopt its native conformation. [ citation needed ]


Humans have five chymotrypsin-like elastase genes which encode the structurally similar proteins:


Glycosylation  at Asn79 and Asn233. [ 9 ]


The gene that codes for pancreatic elastase 1 is  CELA1  (synonym: ELA1)
Pancreatic elastase 1 is encoded by a single genetic locus on chromosome 12. Studies of human pancreatic elastase 1 have shown that this serine protease maps to the chromosomal region 12q13 [ 10 ]  and it is close to a locus for an autosomal dominant skin disease,  Diffuse nonepidermolytic palmoplantar keratoderma . [ 3 ]


The hydrolysis that elastases bring about occur in several steps, starting with the formation of a complex between elastase and its substrate, with the carbonyl carbon positioned near the nucleophilic serine, followed by a nucleophillic attack that forms an acyl-enzyme intermediate (a pair of electrons from the double bond of the carbonyl oxygen moves to the oxygen) while the first product is released. The intermediate is then hydrolyzed in a deacylation step, regenerating the active enzyme and resulting in the release of the second product ( the electron-deficient carbonyl carbon re-forms the double bond with the oxygen and the  C-terminus  of the peptide is released.  It preferentially cleaves peptide bonds at the carbonyl end of amino acid residues with small hydrophobic side chains such as  glycine ,  valine ,  leucine ,  isoleucine  and  alanine . The wide specificity of elastases for non-aromatic uncharged side chains can explain its ability to break down native elastin. [ 11 ]


Human pancreatic elastase 1 (E1) is not degraded in intestinal transit, so that its concentration in feces reflects exocrine pancreatic function. In inflammation of the pancreas, E1 is released into the bloodstream. Thus the quantification of pancreatic elastase 1 in serum allows diagnosis or exclusion of acute pancreatitis. [ 12 ]


Main indications:


Method of detection:


Reference concentration to interpret Pancreatic Elastase results:
For adults and children after the first month of life


This article incorporates text from the  United States National Library of Medicine , which is in the  public domain .


Paneth cells  are cells in the small intestine  epithelium , alongside  goblet cells ,  enterocytes , and  enteroendocrine cells . [ 1 ]  Some can also be found in the  cecum  and  appendix . They are located below the intestinal stem cells in the  intestinal glands  (also called crypts of  Lieberkühn ) and the large  eosinophilic   refractile granules  that occupy most of their  cytoplasm .


When exposed to  bacteria  or bacterial  antigens , Paneth cells secrete several anti-microbial compounds (notably  defensins  and  lysozyme ) that are known to be important in immunity and host-defense into the  lumen  of the intestinal gland, thereby contributing to maintenance of the gastrointestinal barrier by controlling the enteric bacteria. Therefore, Paneth cells play a role in the  innate immune system .


Paneth cells are named after 19th-century pathologist  Joseph Paneth .


Paneth cells are found throughout the  small intestine  and the appendix at the base of the  intestinal glands . [ 2 ]  There is an increase in Paneth cell numbers towards the end of the small intestine. [ 3 ]  Like the other epithelial cell lineages in the small intestine, Paneth cells originate at the stem cell region near the bottom of the gland. [ 4 ]  There are on average 5–12 Paneth cells in each small intestinal crypt. [ 5 ]


Unlike the other epithelial cell types, Paneth cells migrate downward from the stem cell region and settle just adjacent to it. [ 4 ]  This close relationship to the stem cell region suggests that Paneth cells are important in defending the gland stem cells from microbial damage, [ 4 ]  although their function is not entirely known. [ 2 ]  Furthermore, among the four aforementioned intestinal cell lineages, Paneth cells live the longest (approximately 57 days). [ 6 ]


Paneth cells secrete antimicrobial peptides and proteins, which are "key mediators of host-microbe interactions, including homeostatic balance with colonizing microbiota and innate immune protection from enteric pathogens." [ 7 ]


Small intestinal crypts house  stem cells  that serve to constantly replenish  epithelial cells  that die and are lost from the  villi . [ 7 ]  Paneth cells support the physical barrier of the epithelium by providing essential niche signals to their neighboring  intestinal stem cells . Protection and stimulation of these  stem cells  is essential for long-term maintenance of the intestinal  epithelium , in which Paneth cells play a critical role. [ 8 ]


Paneth cells display  merocrine  secretion, that is, secretion via  exocytosis . [ 9 ]


Paneth cells are stimulated to secrete  defensins  when exposed to bacteria (both  Gram positive  and  Gram-negative  types), or such bacterial products as  lipopolysaccharide ,  lipoteichoic acid ,  muramyl dipeptide  and  lipid A . [ 10 ]  They are also stimulated by  cholinergic signaling  normally preceding the arrival of food which potentially may contain a new bacterial load. [ 10 ]


Paneth cells sense bacteria via  MyD88 -dependent  toll-like receptor  (TLR) activation which then triggers antimicrobial action. [ 11 ]  For example, research showed that in the secretory granules, murine and human Paneth cells express high levels of  TLR9 . TLR9 react to  CpG-ODN  and unmethylated oligonucleotides,  pathogen-associated molecular patterns (PAMPs)  typical for bacterial DNA. Internalizing these PAMPs and activating TLR9 leads to  degranulation  and release of antimicrobial peptides and other secretions. [ 12 ]  Surprisingly, murine Paneth cells do not express mRNA transcripts for  TLR4 . [ 5 ]


The principal defense molecules secreted by Paneth cells are  alpha-defensins , which are known as  cryptdins  in mice. [ 13 ]  These  peptides  have  hydrophobic  and positively charged domains that can interact with  phospholipids  in  cell membranes . This structure allows defensins to insert into membranes, where they interact with one another to form pores that disrupt membrane function, leading to cell lysis. Due to the higher concentration of negatively charged  phospholipids  in bacterial than vertebrate  cell membranes , defensins preferentially bind to and disrupt bacterial cells, sparing the cells they are functioning to protect. [ 14 ]


Human Paneth cells produce two α-defensins known as  human α-defensin HD-5 (DEFA5)  and  HD-6 (DEFA6) . [ 15 ]  HD-5 has a wide spectrum of killing activity against both Gram positive and Gram negative bacteria as well as fungi ( Listeria monocytogenes ,  Escherichia coli ,  Salmonella typhimurium , and C andida albicans ). [ 5 ]  The antimicrobial activity of HD-6 consists of self-assembling into extracellular nets that entrap bacteria in the intestine and thereby preventing their translocation across the epithelial barrier. [ 16 ]


Human Paneth cells also produce other AMPs including  lysozyme , secretory  phospholipase A2 , and  regenerating islet-derived protein IIIA . [ 17 ]  Lysozyme is an  antimicrobial  enzyme that dissolves the cell walls of many bacteria, and phospholipase A2 is an enzyme specialized in the lysis of bacterial  phospholipids  . [ 10 ]  This battery of secretory molecules gives Paneth cells a potent arsenal against a broad spectrum of agents, including bacteria,  fungi  and even some enveloped  viruses . [ 18 ]


During conventional protein secretion, proteins are transported through the  ER-Golgi complex  packaged in secretory granules and released to the extracellular space. Should invasive pathogens disrupt the  Golgi apparatus , causing an impairment in the Paneth cell secretion of antimicrobial proteins, an alternative secretion pathway exists: it has been shown that  lysozyme  can be rerouted through secretory  autophagy . In secretory autophagy, cargo is transported in an LC3+ vesicle and discharged at the  plasma membrane , thus bypassing the  ER-Golgi complex.  Not all bacteria prompts secretory autophagy: commensal bacteria, for example, does not cause Golgi breakdown and therefore does not trigger the secretory autophagy of  lysozyme . A dysfunction in secretory autophagy is thought to be a possible contriburing factor to Crohn's disease. [ 19 ]


Paneth cells maintain the health of the intestine by acting as  macrophages ; it has been shown that Paneth cells clear dying cells via apoptotic cell uptake. The phagocytic function of Paneth cells was discovered using a series of experiments, one of which made use of mice that were radiated with a low dose Cesium-137 (137Cs), mimicking chemotherapy undergone by cancer patients. [ 20 ]  These findings may be significant for addressing the side effects suffered by cancer patient whose intestinal health is damaged by chemotherapy: approximately 40% of all cancer therapy patients experience gastrointestinal (GI)  mucositis  during their treatment, with the number jumping to 80% in patients receiving abdominal or pelvic  irradiation . [ 21 ]


Paneth cells participate in the  Wnt signaling pathway  and  Notch signalling pathway , which regulate proliferation of intestinal stem cells and  enterocytes  necessary for epithelium cell renewal. They express the canonical Wnt ligands:  Wnt3a ,  Wnt9b , and  Wnt11 , which bind to  Frizzled  receptors on intestinal stem cells to drive  β-catenin / Tcf  signaling. Paneth cells are also a major source of Notch ligands  DLL1  and  DLL4 , binding to Notch receptors  Notch1  and  Notch2  on intestinal stem cells and  enterocyte  progenitors. [ 8 ]


Recently, however, it has been discovered that the regenerative potential of intestinal epithelial cells declines over time as a result of aged Paneth cells secreting the protein  Notum , which is an extracellular inhibitor of Wnt signaling. If Notum secretion is inhibited, the regenerative potential of the intestinal epithelium could increase. [ 22 ]


It has been established that  zinc  is essential for the function of Paneth cells. A defect in the Zn transporter (ZnT)2 impairs Paneth cell function by causing uncoordinated granule secretion. Mice lacking the (ZnT)2 transporter not only exhibit impaired granule secretion, they also suffer from increased inflammatory response to lipopolysaccharide and are less capable of bactericidal activity. [ 23 ]  Normally,  zinc  is stored in the secretory granules and, upon degranulation, is released in the lumen. It has been speculated that the storage of heavy metals contributes to direct antimicrobial toxicity, as Zn is released upon cholinergic PC stimulation. [ 24 ]


Zinc  deficiency is also implicated in alcohol‐induced Paneth cell α‐defensin dysfunction, which contributes to alcohol-related  steatohepatitis . Zinc can stabilize human α‐defensin 5 (HD5), which is responsible for microbiome homeostasis. In line with this, the administration of HD5 can effectively alter the microbiome (especially by increasing  Akkermansia muciniphila) , and reverse the damage inflicted on the microbiome by excessive alcohol consumption. Dietary zinc deficiency on the other hand exacerbates the deleterious effect of alcohol on the bactericidal activity of Paneth cells. [ 25 ]


Abnormal Paneth cells with reduced expression or secretion of defensins HD-5 and HD-6 (in human) and antimicrobial peptides are associated with  inflammatory bowel disease . [ 26 ] [ 17 ]  In addition to that, several of the  Crohn's disease -risk alleles are associated with Paneth cell dysfunction are involved in processes such as  autophagy , the  unfolded protein response , and the regulation of  mitochondrial  function. [ 17 ]


It is believed that the dysfunction of Paneth cells compromises antimicrobial peptides leading to a  microbiota  composition shift, and even dysbiosis. [ 27 ]   Crohn's disease  patients with a higher percentage of abnormal Paneth cells showed significantly reduced bacterial diversity compared with patients with a lower percentage of abnormal Paneth cells, reflecting a reduced abundance of anti-inflammatory microbes. [ 28 ]  Collectively, these findings support the theory that Paneth cell dysfunction may lead to a dysbiotic microbiota that, in turn, could predispose an individual to the development of Crohn's disease. [ 17 ]  However, it is yet to be established whether Paneth cell dysfunction is the cause of dysbiosis, or its concomitant effect. [ 27 ]


Paneth cells develop gradually during gestation and therefore preterm babies might not have them in sufficient numbers. This leaves preterm babies vulnerable to  necrotizing enterocolitis . About mid-way though the development of the small intestine,  cathelicidin  secretion is replaced by α-defensin secretion. [ 29 ]  The small intestine of the premature baby is at this transition stage when the baby is born, making preterm babies susceptible to intestinal injury and, subsequently, to  necrotizing enterocolitis . [ 18 ]  It should furthermore be noted that early Paneth cells do not possess fully functional, mature granules. [ 30 ]


The mechanism that links Paneth cells to  necrotizing enterocolitis  remains unclear, but it has been theorized that a bloom of  Proteobacteria  and, more specifically,  Enterobacteriaceae  species precedes the development of the condition. [ 31 ]  When an inflammation then subsequently occurs, nitrates can be fermented by  Enterobacteriaceae  sp. but not by obligate anaerobes, which cannot use nitrates as a growth substrate. Thus,  Proteobacteria  are able to use this selective pressure to out-compete the obligate anaerobic  Firmicutes  and  Bacteroidetes , resulting in their overgrowth and consequent dysbiosis. [ 18 ]


The process is thought to begin when the premature infant is exposed to foreign antigens via formula feeding. Inflammatory cytokines are subsequently released, creating a more aerobic state leading to a competitive advantage for  Proteobacteria . As the microbiome becomes more dysbiotic, anti-inflammatory mechanisms weaken, which contributes to a cycle of increasing intestinal inflammation. The inflammation leads to a further loss in Paneth cells density and function, resulting in the impairment of AMP secretion and the destruction of the stem cell niche. [ 18 ]


Whereas the role of Paneth cells in irritable bowel syndrome and Crohn's disease has received ample attention, [ 32 ] [ 17 ]  relatively little is known about the effect Panth cell impairment has on the pathogenesis of  non-alcoholic steato-hepatitis  or  non-alcoholic fatty liver disease .


Murine models indicate that obesity may decrease the secretion of  α-defensin  from Paneth cells, leading to  dysbiosis . [ 33 ]  and at least one murine model suggests that when α-defensin levels in the intestinal lumen are restored by intravenous administration of  R-Spondin1  to induce Paneth cell regeneration, liver fibrosis is ameliorated as a result of the dysbiosis resolving. It is hypothesized that selective microbicidal activities, as well as increasing Muribaculaceae and decreasing  Harryflintia , contribute to amelioration in fibrogenesis. [ 34 ]


One study described the injection of  dithizone , which can disrupt cell granulates, into mice that were fed a high-fat diet in order to identify Paneth-cell-oriented microbial alterations. The application of  dithizone  improved high-fat diet glucose intolerance and insulin resistance and was associated with an alleviation in the severity of liver steatosis in HFD mice, possibly through gut microbiome modulation involving the increase in  Bacteroides.  It has therefore been suggested that microbiome-targeted therapies may have a role in the treatment of non-alcoholic fatty liver disease. [ 35 ]


Further research is needed to elucidate the connection between Paneth cells and the gut-liver-axis.


Pediatric gastroenterology  developed as a sub-specialty of  pediatrics  and  gastroenterology . It is concerned with treating the  gastrointestinal tract , liver and  pancreas  of children from infancy until age eighteen. The principal diseases it is concerned with are acute diarrhea, persistent vomiting,  gastritis , and problems with the development of the gastric tract.


Pediatric gastroenterology has grown greatly in North America and Europe. It began with the speciality of pediatrics, which was developed along with children’s hospitals in the 19th century. The concept of specialists concentrating on organ specific specialties started around the same time. A person who contributed to the development of the specialty was Dr.  Samuel Gee  in London with his focus on serious clinical conditions in children such as  celiac disease  and  cyclic vomiting syndrome . The first national gastrointestinal society was created in Germany in 1920 by  Ismar Isidor Boas . He was also the first physician devoted completely to only gastroenterology. Later the  American Gastroenterological Association  was founded in 1897 by Dr. D. Stewart. The combination to make a pediatric gastroenterological a specialty emerged in the 1960s, almost a century after the specialties of pediatrics and gastroenterology started out individually. All pediatric specialties started out with the concept that children with special needs were not receiving the adequate medical attention that they needed. [ 1 ]


Margot Shiner , who in 1956 invented a biopsy tube that could be used to diagnose intestinal disease in children, particularly celiac disease, has been credited with initiating the emergence of pediatric gastroenterology as a distinct clinical specialty. [ 2 ] [ 3 ] [ 4 ]


Centers for gastrointestinal disorders in children began being established in the 1960s in Great Britain, Australia, and continental Europe. The first centers for pediatric gastroenterology were established by Dolf Weijers and the biochemist Van de Kamer. Pediatricians and biochemists were crucial to the development of such specialty since they created the ability to calculate the fat in the feces of celiac patients with or without gluten. A clinical and research program in pediatric gastroenterology and a gastroenterological research were established in the 1960s at the Royal Children’s Hospital in Melbourne by  Charlotte Anderson . Later on an important center focused on nutrition and gut  pathophysiology  was established by Bertil Linquist in  Lund, Sweden . This was the first place in which  glucose-galactose malabsorption  was reported.  Pediatric gastroenterology centers in London contributed greatly to this field and  hepatology  by helping and recognizing multiple doctors with their investigations. An example is Tom Macdonald, who concentrated his immunological research on gastroenterological diseases in children and the use of a fetal intestinal organ culture model. Important pediatric gastroenterology centers were also established in  Helsinki  and  Tampere , Finland. These centers, led by Jamro Visakorpi, primarily focused on celiac disease,  gastroenteritis ¸ and food allergies. Other important centers were established in Switzerland, under the leadership of  Andrea Prader  making  Zürich  one of the first main centers for pediatric gastroenterology. In that same center, David Shmerling started studying gluten elimination and celiac disease. Salvatore Auricchio along with Giorgio Semenza began comprehending and identifying sugar absorption disorders in children. Ettore Rossi in  Bern  founded centers in which Beat Hadorn and Michael Kentze, who later went on to establish German centers in  Munich  and  Bonn , which made great contributions in the research of absorption pathophysiology. After working in Zurich, Salvatore Auricchio went on to establish an important center in  Naples  which focused research on celiac disease, the physiology of absorption, and oral re hydration therapy. In a center located in  Brussels , led by E. Eggermont and Helmuth Loeb, Samy Cadranel started developing the concept of endoscopy in children. [ 1 ]


North America has also been a center for the development of pediatric gastroenterology. A pediatric gastroenterology program focusing on researching  inflammatory bowel disease ,  infectious diarrhea , and motility disorders associated with gastrointestinal complications such as constipation and gastro esophageal reflux was established by Murray Davidson at the Albert Einstein Medical School and the  Bronx-Lebanon Hospital Center  in New York. Harry Shwachman created the center of excellence for pediatric gastroenterology in Boston in the early 1960s.  This center, under the leadership of Richard Grand and Allan Walker, went on to become a major training program for pediatric gastroenterologists. In order to commemorate Dr. Shwaschman and his impact to the field, a Scwaschman Award is given annually since 1984 by the North American Society for Pediatric Gastroenterology and Nutrition to a person with important contributions to the field. In Canada, gastroenterology and hepatology surged independently from nutrition at the  Hospital for Sick Children  (HSC) in  Toronto .  Peter Durie combined the nutrition and gastroenterology research at the HSC in 1985. [ 1 ]


Many more centers have been developed in multiple places including Sydney, Adelaide, Brisbane, Jerusalem, São Paulo, Santiago, Taipei, and Tokyo. [ 1 ]


The specialty of pediatric gastroenterology requires four years of undergraduate courses at a college or university in order to obtain a BS, BA, or other bachelor's degree. During these four years a student studying pediatric gastroenterology can also take a pre-med course. Afterwards, the student needs four years of medical school in order to obtain an MD or DO degree and become a general doctor. Afterwards the student needs to take a specialty in pediatrics consisting in three more years of education called residency. Afterwards pediatrics sub-specialize in a more specific area such as pediatric gastroenterology. The time to sub-specialize is called post-residency training also known as a fellowship. It can take from one to three or more years consisting in a total of fourteen years or more. In the United States, the committees to certify pediatric gastroenterologist were created in the 1980s. This gave rise to sub-specialty boards in pediatric gastroenterology in 1990 under the leadership of American board of Pediatrics and its Pediatric Gastroenterology and Nutrition subspecialty sub-board, led by Bill Kish. A formal training program was created later in 1997 by the sub-specialty advisory committee for pediatric gastroenterology of the royal college of pediatrics and child health in Great Britain. [ 1 ]


The correct function of the gastric tract and the internal health is related to the nutrition that the child or its mother receives. From the prenatal period, correct nutrition can affect the developing of the system,  short bowel syndrome  (the most common one),  necrotizing enterocolitis ,  gastroschisis  or  omphalocele  to the postnatal period with diseases such as diarrhea. [ 5 ] [ 6 ]


One of the principal problems of a newborn is an iron deficiency, which will generate  anemia . This is caused when the only food that the baby receives is maternal milk which does not fulfill the baby’s nutrition. There is no treatment for this in this period because iron will reach normal levels with the weaning process. The weaning process consists in transitioning from feeding the baby low density food such as maternal milk to start feeding it more complex foods such as meat, fish, or chicken. (uniped) If the weaning process is not carried out correctly or if the child rejects the transition of food the iron deficiency will generate an anemia or even create allergies to certain food. In such cases gastric pediatricians, and not regular pediatricians, should be consulted to treat the anemia because they will now how to recover the correct iron levels without causing any secondary effects in the digestive system. [ 7 ]


The most common nutrition problems during the childhood are being overweight or underweight, both caused by an imbalance in the number of calories consumed versus the number burned. Both in children should be treated by a gastric pediatrician and a pediatric nutritionist at the same time to help the child recover his normal weight without secondary effects (hypertension, gastritis, etc.). The nutritionist will regulate the eating habits of the child, however, the pediatric gastroenterologist will be the one checking how the change in food habits affects the correct functionality of the digestive system. [ 5 ]


A pediatrician can provide treatment to many gastric diseases, but chronic diseases, related with the nutrition of the children, the pancreas or the liver needs to be treated by a specialist. The following are two of the most common ones. Acute diarrhea is one of the most common. Globally, each of the 140 million children born annually experience an average of 7-30 episodes of diarrhea in the first 5 years of life.  Some of the causes are infections, lower levels of zinc or problems with some gastric cells. [ 5 ]


Infant regurgitation is caused by a central nervous system reflex involving both autonomic and skeletal muscles in which gastric contents are forcefully expelled through the mouth because of coordinated movements of the small bowel, stomach, esophagus, and diaphragm.  Diagnosis requires that the child be between 1 and 12, the regurgitation must be two or more times per day for three or more weeks, and there is a strong involuntary effort to vomit,  hematemesis , aspiration,  apnea ,  failure to thrive , or abnormal posturing. This is transient problem, possibly cause to the immaturity of gastrointestinal motility. [ 6 ]


In  medicine , a  Phrygian cap  is the folded portion of some  gallbladders  that resembles the  Phrygian cap  (a soft conical cap with the top pulled forward, associated in antiquity with the inhabitants of  Phrygia , a region of central  Anatolia ). It is a normal  anatomical  variant seen in 1-6% of patients. [ 1 ]  It is caused by a fold in the gallbladder where the  gallbladder fundus  joins the gallbladder body. [ 2 ]  Apart from the chance of being mistaken for stones on a  sonogram , it has no other medical implications nor does it predispose one to other diseases. [ citation needed ]
However, due to potential decrease in bile flow, it may warrant a preventive removal of the gallbladder.  [ citation needed ]


Phycomycosis  is an uncommon condition affecting the  gastrointestinal tract  and  skin , most commonly found in  dogs  and  horses .  The condition is caused by various  molds  (a type of  fungi ), with individual forms including  pythiosis ,  zygomycosis , and  lagenidiosis .  Pythiosis, the most common type, is caused by  Pythium , a type of  water mould .  Zygomycosis can be caused by two types of  zygomycetes :  Entomophthorales  (e.g.,  Basidiobolus  and  Conidiobolus ) and  Mucorales  (e.g.,  Mucor ,  Mortierella ,  Absidia ,  Rhizopus ,  Rhizomucor , and  Saksenaea ). [ 1 ]   The latter type of zygomycosis is also referred to as  mucormycosis . Lagenidiosis is caused by a  Lagenidium  species, which like  Pythium  is a water mould.  Since both pythiosis and lagenidiosis are caused by organisms from the  Oomycetes  and not the kingdom fungi, they are sometimes collectively referred to as  oomycosis .


Pythiosis is caused by  Pythium insidiosum  and occurs most commonly in dogs and  horses , but is also found in  cats ,  cattle , and humans.  In the United States, it is most commonly found in states bordering the Gulf of Mexico , especially  Louisiana , but has been found in the Midwest and Eastern states.  It is also found in  Southeast Asia , eastern  Australia ,  New Zealand , and  South America .  Pythiosis occurs in areas with mild winters due to the organism surviving in standing water that does not reach freezing temperatures. [ 2 ]   Pythium  occupies swamps in late summer and infects dogs who drink water containing it.  The disease is typically found in young, large breed dogs. [ 1 ]


It is suspected that pythiosis is caused by invasion of the organism into wounds, either in the skin or in the gastrointestinal tract. [ 2 ]   The disease grows slowly in the  stomach  and  small intestine , eventually forming large lumps of  granulation tissue .  It can also invade surrounding  lymph nodes .    Symptoms include vomiting, diarrhea, weight loss, a mass in the abdomen, and depression.  Pythiosis of the skin in dogs is very rare, and appears as  ulcerated  lumps.  Primary infection can also occur in the bones and lungs.


In horses,  subcutaneous  pythiosis is the most common form and infection occurs through a wound  while standing in water containing the pathogen. [ 3 ]   The disease is also known as  leeches ,  swamp cancer , and  bursatti .  Lesions are most commonly found on the lower limbs, abdomen, chest, and genitals.  They are  granulomatous  and itchy, and may be ulcerated or  fistulated .  The lesions often contain yellow, firm masses of dead tissue known as  kunkers . [ 4 ]   It is possible with chronic infection, the disease can spread to underlying bone. [ 5 ]


In cats, pythioisis is almost always confined to the skin as hairless and edematous lesions.  It is usually found on the limbs,  perineum , and at the base of the tail. [ 6 ]   Lesions may also develop in the  nasopharynx . [ 4 ]


In humans, it can cause  arteritis ,  keratitis , and  periorbital   cellulitis . [ 7 ]


Pythium insidiosum  is different from other members of the genus in that human and horse hair, skin, and decaying animal tissue are  chemoattractants  for its  zoospores , in addition to decaying plant tissue. [ 3 ]


Usually, zygomycosis is a disease of the skin, but can also occur in the sinuses or gastrointestinal tract. In humans, it is most prevalent in immunocompromised patients (human immunodeficiency virus/acquired immunodeficiency syndrome [ HIV/AIDS] , the  elderly , severe combined immunodeficiency [ SCID] , etc.) and patients with acidosis (i.e., diabetes, burns), particularly after barrier injury to the skin or mucous membranes.  Zygomycosis caused by  Mucorales  causes a rapidly progressing disease of sudden onset in sick or  immunocompromised  animals.   Entomophthorales  cause chronic, local infections in otherwise healthy animals.  The important species that causes  entomophthoromycosis  are  Conidiobolus coronatus ,  C. incongruous , and  Basidiobolus ranarum .   Conidiobolus  infections of the upper respiratory system have been reported in humans, sheep, horses, and dogs, and  Basidiobolus  has been reported less commonly in humans and dogs. [ 8 ]   Horses are one of the most common domestic animals to be affected by entomophthoromycosis.   C. coronatus  causes lesions in the nasal and oral  mucosa  of horses that may cause nasal discharge or difficulty breathing.   B. ranarum  causes large circular nodules on the upper body and neck of horses. [ 9 ]   Entomophthorales  is found in soil and decaying plant matter, and specifically,  Basidiobolus  can be contracted from insects and the feces of reptiles or amphibians. [ 7 ]


Zygomycosis of the sinuses can extend from the sinuses into the orbit and the cranial vault, leading to rhinocerebral mucormycosis. [ citation needed ]


The best known species of  Lagenidium  is  Lagenidium giganteum , a parasite of  mosquito  larvae used in the  biological control  of mosquitoes.  Two different species cause disease exclusively in dogs:  L. caninum  and  L. karlingii .   Lagenidium  is found in the Southeastern United States in lakes and ponds.  Lagenidiosis causes progressive skin and subcutaneous lesions in the legs, groin, trunk, and near the tail.  The lesions are firm nodules or ulcerated regions with  draining tracts .  Regional lymph nodes are usually swollen.  Spread of the disease to distant lymph nodes, large blood vessels, and the lungs may occur. [ 7 ]   An  aneurysm  of a  great vessel  can rupture and cause sudden death. [ 4 ]   L. caninum  is the more aggressive species and is more likely to spread to other organs than  L. karlingii . [ 10 ]


Diagnosis is through  biopsy  or  culture , although an enzyme-linked immunosorbent assay ( ELISA ) test has been developed for  Pythium insidiosum  in animals. [ 11 ]   Treatment is very difficult and includes  surgery  when possible.  Postoperative recurrence is common.   Antifungal drugs  show only limited effect on the disease, but  itraconazole  and  terbinafine hydrochloride  are often used for 2 to 3 months following surgery. [ 7 ]   Humans with  Basidiobolus  infections have been treated with  amphotericin B  and  potassium iodide . [ 8 ]   For pythiosis and lagenidiosis, a new drug targeting water moulds called  caspofungin  is available, but it is very expensive. [ 7 ]   Immunotherapy  has been used successfully in humans and horses with pythiosis. [ 11 ]   The  prognosis  for any type of phycomycosis is poor.