Awakenings to the pathogenicity of urease and the requirement for continuous long term therapy.

Urease is an enzyme found in plants and bacteria, but not mammals. It catalyzes the conversion of urea to carbon dioxide and ammonia. Ammonia shortens the life span of cells; and higher concentrations cause tissue necrosis and cytolysis. Twenty percent of total body urea is converted to ammonia by bacterial urease in the colon. Small injections of urease immunize animals by producing antiurease, a gamma globulin, which inactivates urease. Immunization eliminates the colonic conversion of urea to ammonia. Injection of urease produces ammonia intoxication making immunization hazardous. Although previously impossible, a non enzymatic urease antigen was synthesized by covalently bonding jack bean urease with glutaraldehyde. This antigen stimulated the production of antiurease that inactivates native urease. Helicobacter pylori, a potent urease producer, has been implicated in peptic ulcer, gastritis and other inflammatory bowel lesions. The pathogenicity of H pylori is dependent on its urease production. Immunization to urease can render H pylori non pathogenic. Cirrhotics develop encephalopathy and hyperammonemia because their livers fail to convert all the ammonia in portal venous blood to urea and collaterals develop by passing the liver. Colonic ammonia increases the turnover rate of colonic mucosa. Ammonia absorbed into the portal venous system is transported to the liver where it is reconverted to urea. Absorbed ammonia adversely influences liver function. Infections with urease producing organisms destroy the renal parenchyma and produce struvite stones. Urease immunization aids colonic healing and prevents uremic colitis. Absorbed ammonia is a noxious influence on the liver. Animals immunized to urease regenerate the liver faster and are less susceptible to hepatotoxins. Immunization to urease ameliorates cirrhosis. Proteus and other urease producers become non toxic and do not damage the renal parenchyma. Urease is responsible for the pathogenicity of infections with urease producing organisms. Immunization to urease renders urease producing organisms non pathogenic.

The mythology of povidone-iodine and the development of self-sterilizing plastics.

The predominance of elemental iodine as a chemical antiseptic has been established during a century. Free iodine is effective for treatment and prevention of infection. Iodophors, such as povidone-iodine, have replaced elemental iodine in clinical use. Toxic absorption of povidone-iodine occurs from all tissues except intact adult skin, to which its use should be restricted. Povidone-iodine binds iodine so firmly that insufficient free iodine is released to be effective for treating or preventing infection. It is a weak antiseptic that is marginally acceptable as a disinfectant for adult skin. The shortcomings of povidone-iodine stimulated a search for iodophors that would liberate therapeutically effective concentrations of free iodine. These investigations led to a new self-sterilizing plastic formed by the complexing of polyurethane and iodine.

The place of the peritoneovenous shunt in the treatment of ascites.

The peritoneovenous shunt (PVS) is a safe procedure; all of its complications have been found to be preventable. Disseminated intravascular coagulopathy (DIC) can be a life threatening complication but has been completely eliminated by draining the ascitic fluid at the time of surgery, as it is caused by the introduction of excessive quantities of peritoneal fluid into the venous system. Peritoneal fluid is rich in tissue plasminogen activator (TPA), which is inhibited by epsilon aminocaproic acid. This substance has been successfully used to treat postshunt coagulopathy. The salt retention associated with ascites is related to a diminished plasma volume, a condition further aggravated by diuretic drugs. A PVS should be inserted if the patient does not respond to a salt restricted diet. Occult peritonitis occurs in 10% of cirrhotic ascites. The shunt does not prevent this, and a high percentage of late shunt failures are caused by fibrinopurulent debris in the valve. The valve system should not contain a pump, which disseminates infection and causes fatal emboli; pumping and flushing are seldom remedial and often dangerous. Because the complications of the shunt are all preventable, the indications for the shunt should be liberalized.

Coagulopathy post peritoneovenous shunt.

In 1942, 53% of medically treated patients with cirrhosis were dead 6 months after the onset of ascites. Only 30% survived 1 year. This dismal outlook has improved only slightly with advances in medicine. Yet, some internists reject the peritoneovenous shunt (PVS) for this fatal condition even if they are aware that a diminished blood volume causes the abnormal sodium retention responsible for ascites. Their objections are based on life-threatening complications of PVS, especially post shunt coagulopathy (PSC). Blood shed into the peritoneal cavity becomes incoagulable. Such blood is immediately coagulated by a protocoagulant (soluble collagen) and concurrently lysed by tissue plasminogen activator (TPA) secreted by the peritoneal serosa. Wide zones of lysis surround peritoneal tissue placed on fibrin plates. Large volumes of ascitic fluid infused into circulating blood simulates the fate of blood shed into the peritoneal cavity with lysis playing the major role. Addition of ascitic fluid to normal platelet-rich plasma in vitro initiates clot lysis on thromboelastogram (TEG). Epsilon-aminocaproic acid (EACA) counteracts this lysis. EACA and clotting factors normalize the TEG and arrest PSC. Disposal of ascitic fluid at surgery prevents or ameliorates PSC. Mild PSC was encountered only twice in 150+ consecutive patients (1.3%) with only one case being clinically significant (0.6%). Severe PSC occurred seven times in 98 early shunt patients whose ascitic fluid was not discarded. Severe PSC requires shunt interruption and control of bleeding with clotting factors and EACA. Peritoneal lavage with saline prevents the recurrence of PSC on reopening the shunt. In four patients, EACA and clotting factors were adequate to arrest coagulopathy. Three earlier patients died of PSC before its cause and treatment were understood. Proper management eliminates this life-threatening complication, and PSC cannot be considered a deterrent to PVS. Disseminated intravascular coagulopathy (DIC) is produced in experimental animals only by the injection of thrombin or thromboplastin. PSC is a distinct entity differing from DIC; EACA and not heparin is the antidote for PSC.

Enhancement of tissue Po2 of strangulated bowel by topical application of sodium nitroprusside.

The Po2 was measured in the tissue of the ileal wall of dogs before, during, and up to one hour after reversible occlusion of segmental arteries. The occlusion was then released and the reoxygenation of the bowel wall was observed. Sodium nitroprusside (50 mg in 100 ml of solution) applied topically to the ischemic segment enhanced reoxygenation as compared to control animals. Nitroprusside absorbed into the portal system did not cause hypotension, as is usual with systemic administration, because nitroprusside is inactivated by passage through the liver. Topically applied sodium nitroprusside alleviates intestinal ischemia by direct local vasodilatation and relaxation of smooth muscle spasm in the ischemic bowel wall. The intraperitoneal use of sodium nitroprusside should be clinically evaluated in situations where visceral perfusion is impaired.

Urease as a contributing factor in ulcerative lesions of the colon.

Urease immunization protects animals against the development of uremic colitis. This indicates that ammonia formed by bacterial urease is the causative factor in the breakdown of the colonic mucosa.