Ubiquitin Regulation of Trk Receptor Trafficking and Degradation.

The regulation of Trk receptors is critical for orchestrating multiple signalling pathways required for developing and maintaining neuronal networks. Activation of Trk receptors results in signalling, internalisation and subsequent degradation of the protein. Although ubiquitination of TrkA by Nedd4-2 has been identified as an important degradation pathway, much less is known about the pathways regulating the degradation of TrkB and TrkC. Critical to the interaction between TrkA and Nedd4-2 is a PPxY motif present within TrkA but absent in TrkB and TrkC. Given the absence of this interaction motif, it remains to be determined how TrkB and TrkC are ubiquitinated. Here we report that the adaptor protein Ndfip1 can interact with all three Trk receptors and show for TrkB the recruitment of Nedd4-2 through PPxY motifs present in Ndfip1. Ndfip1 mediates the ubiquitination of TrkB, resulting in receptor trafficking predominantly on Rab7 containing late endosomes, highlighting a pathway for TrkB degradation at the lysosome. In vitro, overexpression of Ndfip1 increased TrkB ubiquitination and decreased viability of BDNF-dependent primary neurons. In vivo, conditional genetic deletion of Ndfip1 increased TrkB in the brain and resulted in enlargement of the granular cell layer of the dentate gyrus.

Case-control comparison of profundaplasty and femoropopliteal supragenicular bypass for peripheral arterial disease.

BACKGROUND: The aim of this study was to compare preoperative and postoperative findings, and clinical progress in patients with peripheral arterial occlusive disease undergoing femoropopliteal supragenicular bypass or profundaplasty in a case-control study. METHODS: Between January 2001 and June 2004, 171 patients with occlusion of the superficial femoral artery underwent surgery. A retrospective analysis of 28 matched patient pairs was performed. Endpoints were bypass occlusion, surgical revision, amputation and death. Mean length of follow-up was 36 months. RESULTS: At 3 years after surgery there was no statistically significant difference in outcome between femoropopliteal bypass surgery and profundaplasty. There was a trend towards improved results in patients who had bypass surgery for critical leg ischaemia. Preoperative patency of the crural outflow arteries was an independent prognostic factor in multivariable analysis. CONCLUSION: There were no significant outcome differences between supragenicular bypass surgery or profundaplasty in patients who had surgery for intermittent claudication or ischaemic rest pain. Patients with a single patent tibial artery and gangrene or ulceration appeared to benefit more from bypass surgery.

[Recurring, severe upper abdominal pain in a 45 year old patient]. / Rezidivierende, stärkste Oberbauchschmerzen bei einem 45-jährigen Patienten.

A 45-year-old patient presented with a history of recurrent abdominal pain of unknown origin. The CT scan of the abdomen demonstrated a thickened mesenteric root and a segmental ileus of the jejunum. Laparotomy revealed a neuroendocrine tumour of the small bowel. Such tumours are rare causes of recurrent abdominal pain. Especially when the CT scan of the abdomen reveals mesenteric abnormalities (desmoplastic reaction) and/or a segmental ileus, a neuroendocrine tumour of the small bowel should be considered. The therapy of choice is resection of the tumour followed by systemic therapy including somatostain analogues and chemotherapy in the case of a hormone secreting tumour or metastases.

Evidence for persistence of parvovirus B19 DNA in livers of adults.

Recent studies have suggested a pathogenic role of human parvovirus B19 (B19) in the development of acute fulminant liver failure in children. The hypothesis was based on the detection of B19 DNA in 8 of 10 explanted livers of children requiring liver transplantation. In the present study, explanted livers from 43 adults selected at random undergoing orthotopic liver transplantation for various reasons were examined. Pre-transplant sera were available from 40 patients of whom 35 (88%) were anti-B19 IgG-seropositive. All but one serum were negative for anti-B19 IgM antibody. By polymerase chain reaction, B19 DNA was detected in the livers of 15/35 (43%) anti-B19 IgG-positive patients, in 2/3 livers of patients with unknown anti-B19 antibody status, and in the initial transplant of an anti-B19 IgG-positive patient who underwent liver retransplantation, and whose own liver was negative for B19 DNA. In a second study group, liver and bone marrow samples from 23 autopsied adults selected at random were tested. Serum specimens were available from 22 individuals, of whom 17 (77%) were anti-B19 IgG-seropositive. All sera were negative for anti-B19 IgM antibody. B19 DNA was detected in the livers of 4/17 (24%) anti-B19 IgG-positive individuals, three of whom had also B19 DNA in their bone marrow. This is the first report demonstrating that B19 DNA is frequently present in livers of anti-B19 seropositive adults suggesting persistence of B19 in the liver. Further studies are needed to address whether B19 is an innocent bystander in the liver or whether the presence of B19 in liver is of biological and clinical significance.

Demonstration of direct glycosylation of nondegradable glucosylceramide analogs in cultured cells.

After uptake by various cells (human skin fibroblasts, rat neuroblastoma B 104, human neuroblastoma SHSY5Y, murine cerebellar cells), a radioactive and a fluorescent analog of a nondegradable glucosylceramide with sulfur in the glycosidic link were glycosylated to a cell-specific pattern of glycolipid analogs. These results, for the first time, show that a glucosylceramide analog can be conveyed from the plasma membrane of cultured cells to those Golgi compartments that function in the early glycosylation steps of glycolipids. This observation is further confirmed by the fact that the cationic ionophore monensin, known to impede membrane flow from proximal to distal Golgi cisternae, inhibited the formation of complex ganglioside analogs but not those of lactosylceramide, sialyl lactosylceramide (GM3), and disialyl lactosylceramide (GD3).