Identification of a new class of proteasome inhibitors based on a naphthyl-azotricyclic-urea-phenyl scaffold.

Proteasomes play an important role in protein degradation and regulation of many cellular pathways by maintaining protein balance. Inhibitors of proteasomes disrupt this balance affecting proteins that are key in malignancies and as such have found applications in the treatment of multiple myeloma and mantle cell lymphoma. However, resistance mechanisms have been reported for these proteasome inhibitors including mutations at the β5 site which necessitates the constant development of new inhibitors.

Argyrin B, a non-competitive inhibitor of the human immunoproteasome exhibiting preference for β1i.

Inhibitors of the proteasome have found broad therapeutic applications; however, they show severe toxicity due to the abundance of proteasomes in healthy cells. In contrast, inhibitors of the immunoproteasome, which is upregulated during disease states, are less toxic and have increased therapeutic potential including against autoimmune disorders. In this project, we report argyrin B, a natural product cyclic peptide to be a reversible, non-competitive inhibitor of the immunoproteasome.

Why relatives do not donate organs for transplants: 'sacrifice' or 'gift of life'?

Aim: This paper is a report of a study to explore the reasons family members declined organ donation from a deceased relative.

Background: In the United Kingdom family members' consent is usually sought before organ donation from their deceased relative can proceed. Knowledge of the concerns that may influence families' decision-making could be helpful to nurses supporting bereaved family members.

Traumatic perforation of duodenal diverticulum.

A fragile 72-year-old female with previous coronary artery disease sustained blunt abdominal trauma in a motor vehicle crash. A ruptured duodenum was identified by computed tomography scanning. Exploratory laparotomy revealed that the duodenal rupture was caused by perforation of a diverticulum in the second portion of the duodenum.

Incidence of necrotizing pancreatitis and factors related to mortality.

Of 348 cases of acute pancreatitis presenting between 1980 and 1985, extensive retroperitoneal necrosis with bacterial or fungal superinfection developed in only 17 (4.8 percent). However, in 14 of the 17 patients (80 percent), multiple surgical interventions and intensive supportive therapy failed to control the process, and they died from complications.

Serial measurement of plasma cholesterol and lecithin:cholesterol acyl transferase activity in adults receiving total parenteral nutrition.

The effect of total parenteral nutrition (TPN) containing approximately 800 ml Nutralipid daily on plasma cholesterol and lecithin:cholesterol acyl transferase (LCAT) activity was studied in 11 adult hospital patients. LCAT was assayed using an endogenous (S/N) and an artificial (ASA) substrate to differentiate between altered plasma substrate composition (which would influence the S/N method) and enzyme quantity (measured by the exogenous ASA method). Total cholesterol levels increased significantly during TPN, but generally remained within normal range.

Management of small bowel fistulas.

Fifty-two patients with fistulas that arose from the small intestine were encountered in the 6 year span between 1975 and 1981. The mortality rate in this group was 38 percent, the average hospital stay was 95 days, and 47 patients were receiving total parenteral nutrition for an average of 56 days. Intraabdominal sepsis and peritonitis forced early reoperation in eight patients in whom exteriorization of the fistula as an ileostomy and mucous fistula and reconstruction after a long interval, was a more successful means of management than were attempts at immediate resection and anastomosis.

Possible biotin deficiency in adults receiving long-term total parenteral nutrition.

Two adult patients receiving total parenteral nutrition on a long-term home basis presented with severe loss of hair. Both patients had extensive gut resection, consumed no biotin orally and received no biotin parenterally. Supplementation with Berroca-C, one ampule containing 200 micrograms biotin per day resulted in gradual regrowth of healthy hair.

Cholestasis caused by lipid emulsions.

Liver function was observed in 35 patients receiving intravenous feeding for more than three weeks. A progressive cholestatic jaundice occurred in ten of 18 patients receiving a lipid emulsion in a dose of 3 grams per kilogram per day. Only one of 17 patients receiving a dose of 1 gram per kilogram per day showed evidence of cholestasis.

Polytetrafluoroethylene grafts for vascular access for hyperalimentation.

A polytetrafluoroethylene (PTFE) graft from the brachial artery to the axillary vein may provide a safe and trouble-free means of vascular access in selected patients requiring long-term intravenous feeding in the hospital setting. This route for the administration of solutions supplying total parenteral nutrition (TPN) should be considered in persons whose requirement for parenteral feeding is likely to extend over many months and in whom there are other sources of bacteremia which can imitate or be confused with infection of a conventional central venous feeding line. In a 52-year-old man an 8-mm PTFE graft was anastomosed end-to-side to the brachial artery and the axillary vein and brought through a subcutaneous tunnel on the medial aspect of the upper arm.

Preoperative parenteral feeding in Crohn's disease: preoperatively, to induce remission, and at home.

Extended courses of preoperative parenteral nutrition were used in eight cases of complicated Crohn's disease. Impressive gains in weight and strength were demonstrated, as well as radiologic improvement in the diseased bowel. It is recommended that preoperative parenteral feeding be carried out for a minimum of 20-30 days, in order that full nutritional benefits be realized, as well as the resolution of inflammatory changes in the bowel and supporting structures.

Symposium on intensive care: 1. Monitoring of the critically ill surgical patient.

The skill and experience of the medical and nursing staff are the factors that have the greatest impact on the quality of monitoring and treatment of the critically ill surgical patient. Basic determinations at the bedside together with periodic evaluation of the whole patient by the medical staff may, in selected cases, be supplemented usefully by more invasive monitoring techniques. The specific complications and technical pitfalls of these techniques should be known, and caution should always be exercised that the values provided are not misinterpreted.

Parenteral solutions for nutritional support in surgical patients. A comparison of nitrogen gains employing 5 per cent and 10 per cent amino acid solutions.

A 10 per cent amino acid solution accompanied by 10 per cent Intralipid and 50 per cent glucose could be infused by peripheral veins. This safe and practical method induced positive nitrogen balance of 7 to 8 gm daily in five of six septic patients.

Pancreatic secretion in response to jejunal feeding of elemental diet.

The instillation of elemental diet into the proximal jejunum of dogs results in a brisk pancreatic secretory response, but the fluid is watery and "enzyme-poor." The administration of the caloric equivalent in a standard blenderized ward diet induces pancreatic enzyme secretion. Although elemental diet does not "rest" the pancreas, the failure of these preparations to stimulate pancreatic enzyme secretion gives them a theoretical advantage as a nutritional source in the convalescent phase of acute pancreatitis.