Engineering human immunodeficiency virus 1 protease heterodimers as macromolecular inhibitors of viral maturation.

Dimerization of human immunodeficiency virus type 1 protease (HIV-1 PR) monomers is an essential prerequisite for viral proteolytic activity and the subsequent generation of infectious virus particles. Disruption of the dimer interface inhibits this activity as does formation of heterodimers between wild-type and defective monomers. A structure-based approach was used to identify amino acid substitutions at the dimer interface of HIV-1 PR that facilitate preferential association of heterodimers and inhibit self-association of the defective monomers. Expression of the designed PR monomers inhibits activity of wild-type HIV-1 PR and viral infectivity when assayed in an ex vivo model system. These results show that it is possible to design PR monomers as macromolecular inhibitors that may provide an alternative to small molecule inhibitors for the treatment of HIV infection.     

Solitary plasmacytoma of the spine. Long-term clinical course

The data for 19 patients with solitary plasmacytoma of the spine were reviewed with regard to clinical course and prognosis (median follow-up, 96 months). Eight patients presented with spinal cord compression. A monoclonal immunoglobulin was initially detected in seven of 15 evaluable patients. Treatment included radiotherapy (18 of 19) and/or surgery (11 of 19) and chemotherapy (eight of 19). Spinal cord compression was reversed in every patient. The expected survival rate was 85% at 10 years after diagnosis. Local recurrence or dissemination was observed in 13 patients. It occurred within 5 years of diagnosis in 11 patients and was localized (that is, local recurrence or single bone metastasis) in eight patients. It was always associated with the appearance or an increase of the M component. Dissemination frequently had a "metastatic" pattern with no diffuse bone marrow plasmacytosis. The incidence of local recurrence (five patients) and leukemia (four patients) was high. Local recurrence and/or dissemination were significantly more frequent in patients with the M component at diagnosis than in those without it (P less than 0.05; relative risk, R = 4). The effectiveness of surgery and chemotherapy combined with radiotherapy is also discussed.     

Haemostyptic preparations on the basis of collagen alone and as fixed combination with fibrin glue

Preparations containing collagen play a prominent role among local haemostyptic agents in surgery. Sheets of collagen are used as degradable haemostyptic tampons. Various investigations have shown better haemostasis with collagen compared to other degradable materials, although the haemostyptic effect of these collagen preparations is limited. Concerning the mechanism of haemostasis, not all the reactions stimulated, e.g. by the collagen of an injured vessel wall, may be activated by a haemostyptic tampon from collagen. This depends very much on the kind of preparation. The combined application of a sheet of collagen with fibrin glue improved local haemostasis to a great extent. Large areas of capillary bleeding can be treated successfully with this method. Despite the very good results, this method has not been applied on a broad scale. This is due to the necessary skill and experience and the relatively cumbersome preparation required at the operation site. These drawbacks have been overcome with the latest development in this field--a sheet of collagen covered with a fixed layer of the solid components of a fibrin glue (fibrinogen, thrombin and aprotinin). The performance of this new local haemostyptic agent is described with special emphasis on the results of clinical trials. Haemostasis of large areas of capillary bleeding was very efficient and safe with the new material. Moreover, bile leakage and liquor, pancreatic and aerial fistulae could be sealed without problems.