The development of Fournier's gangrene following rubber band ligation of haemorrhoids.

The development of Fournier's gangrene in an 80-year-old male patient with diabetes after a routine outpatient haemorrhoid banding procedure is described. Four days following the procedure, the patient noticed an increasing amount of pain and swelling of the perianal region. When the patient presented to the emergency department 18 days later, immediate radical debridement of ischiorectal necrotic tissue was performed. A defunctioning loop sigmoid colostomy was also formed. Subsequent operations required excision of the scrotum and abdominoperineal excision of the rectum. Histology studies later confirmed the presence of necrotising fasciitis. The case acts as a reminder that clinicians should maintain a high index of suspicion for high-risk patients still suffering from problems following the procedure.

Intussusception in the elderly.

We present the case of an 82-year-old Caucasian lady with a 16-day history of colicky lower abdominal pain and reduced appetite. When presenting to hospital she was haemodynamically stable with no fever. Examination revealed a soft but tender abdomen with normal bowel sounds. No masses or hernias were present. Per-rectal examination revealed an empty rectum. Investigations showed raised inflammatory markers, white cell count 11.9 and C reactive protein 24, in addition to which she had dilated loops of small and large bowel on the abdominal radiograph. The patient underwent an emergency laparotomy where a mass in the descending colon was found to be intussuscepting into the proximal sigmoid colon for which a Hartmanns procedure was performed. Histopathology confirmed a Dukes B T3 N0 Mx adenocarcinoma.

A specific inhibitor of cholesterol biosynthesis, BM15.766, reduces the expression of beta-secretase and the production of amyloid-beta in vitro.

We have previously shown that statins reduce the production of amyloid-beta (Abeta) by both isoprenoid- and cholesterol-dependent mechanisms. These pathways contribute to the regulation of the dimerisation of BACE into its physiologically active form. Statins reduce cellular cholesterol levels by 20-40%; therefore, it is possible that the remaining cholesterol within the cell may play a significant role in the production of Abeta. Incubation of cells with the specific cholesterol biosynthesis inhibitor BM15.766 together with 50 micromol/L simvastatin and 400 micromol/L mevalonate reduced cellular cholesterol levels in a dose-dependent manner with increasing BM15.766 concentration (r = -0.9736, p = 0.0264). Furthermore, decreases in cellular cholesterol levels correlated with reductions in total Abeta production (r = 0.9683, p = 0.0317). A total of 2.5 micromol/L BM15.766 inhibited the dimerisation of BACE, whilst the expression of BACE monomer was reduced by 5 micromol/L BM15.766. BM15.766 treatment localised BACE predominantly within the Golgi, and reduced total BACE expression per cell. Similar changes were observed in the expression of the Golgi marker golgin-97, suggesting that reduced BACE expression may arise from a decrease in protein trafficking and an increase in degradation. By targeting cholesterol synthesis using specific cholesterol biosynthesis inhibitors, it is possible to reduce Abeta production without reducing protein isoprenylation.

Statins inhibit the dimerization of beta-secretase via both isoprenoid- and cholesterol-mediated mechanisms.

We have previously reported that protein lipidation in the form of palmitoylation and farnesylation is critical for the production of Abeta (amyloid beta-peptide), the dimerization of beta-secretase and its trafficking into cholesterol-rich microdomains. As statins influence these lipid modifications in addition to their effects on cholesterol biosynthesis, we have investigated the effects of lovastatin and SIMVA (simvastatin) at a range of concentrations chosen to distinguish different cellular effects on Abeta production and beta-secretase structure and its localization in bHEK cells [HEK-293 cells (human embryonic kidney cells) transfected with the Asp-2 gene plus a polyhistidine coding tag] cells. We have compared the changes brought about by statins with those brought about by the palmitoylation inhibitor cerulenin and the farnesyltransferase inhibitor CVFM (Cys-Val-Phe-Met). The statin-mediated reduction in Abeta production correlated with an inhibition of beta-secretase dimerization into its more active form at all concentrations of statin investigated. These effects were reversed by the administration of mevalonate, showing that these effects were mediated via 3-hydroxy-3-methylglutaryl-CoA-dependent pathways. At low (1 microM) statin concentrations, reduction in Abeta production and inhibition of beta-secretase dimerization were mediated by inhibition of isoprenoid synthesis. At high (>10 microM) concentrations of statins, inhibition of beta-secretase palmitoylation occurred, which we demonstrated to be regulated by intracellular cholesterol levels. There was also a concomitant concentration-dependent change in beta-secretase subcellular trafficking. Significantly, Abeta release from cells was markedly higher at 50 microM SIMVA than at 1 microM, whereas these concentrations resulted in similar reductions in total Abeta production, suggesting that low-dose statins may be more beneficial than high doses for the therapeutic treatment of Alzheimer's disease.