Autoplex versus proplex: a controlled, double-blind study of effectiveness in acute hemarthroses in hemophiliacs with inhibitors to factor VIII

In view of uncontrolled observations and anecdotal reports suggesting that the activated PCC, Autoplex, was much more effective than standard (non-activated) PCC in controlling bleeding in hemophiliacs with inhibitors, a controlled double-blind study was designed to compare the effectiveness of Autoplex and Proplex. Acute hemarthrosis was chosen for study as this common but non-life-threatening lesion lends itself well to controlled study. A single dose of "unknown" product (Autoplex 75 FECU/kg; Autoplex 50 FECU/kg; or Proplex 75 FIX U/kg) was given, and effectiveness was judged at 6 hr. By all criteria of efficacy, there were no significant differences between the products. It is noteworthy that a single dose of PCC was judged effective in 50% of episodes, a figure that is consistent with other published clinical trials. In this model, no additional benefit was derived from using the activated PCC, Autoplex, in either dosage.     

Immune status of human immunodeficiency virus seropositive and seronegative hemophiliacs infused for 3.5 years with recombinant factor VIII. The Kogenate Study Group

Recent studies suggest that treatment of hemophiliacs with highly purified factor VIII concentrates may preserve immune function. To test this hypothesis, we prospectively studied 51 hemophilic patients (21 human immunodeficiency virus [HIV] seropositive and 30 seronegative) who were on home therapy exclusively with recombinant factor VIII (Kogenate, Miles Laboratory, Berkeley, CA) for 3.5 years. Patients, all of whom had been previously treated with plasma-derived factor VIII concentrates, were monitored every 6 months with T-lymphocyte subsets and beta 2-microglobulin levels. Mean rate of change in absolute CD4 cell counts, calculated from regression slopes for individual patients, showed a small but statistically significant decrease over the 3.5-year study period for HIV seropositive hemophiliacs. No decrease in CD4 cell counts was seen in HIV seronegative hemophiliacs when the data for children under age 6 years were excluded from the analysis. beta 2- microglobulin levels and CD8 cell counts remained unchanged. These data show stability of immunologic parameters in HIV seronegative hemophiliacs, and a small decrease in CD4 cell counts in HIV seropositive hemophiliacs treated with recombinant factor VIII.     

Intensive leukapheresis as initial therapy for chronic granulocytic leukemia

Intensive leukapheresis has been used as the initial treatment of chronic granulocytic leukemia (CGL) in six patients. The number of leukaphereses ranged from 3 in 7 days to 13 in 39 days (mean, 8 in 22 days). The procedures were well tolerated, and in all patients there was improvement in hematologic values, in most cases with considerable reduction in the peripheral leukocytosis and thrombocytosis and in the proportion of immature granulocytic cells in the circulation. Splenomegaly decreased considerably in the four patients who had more than four leukaphereses. Symptoms of sweating, malaise, and pain due to splenomegaly were rapidly relieved. Problems due to hyperuricemia did not occur, but four patients required blood transfusions for correction of anemia. This method of initial treatment of CGL appears to give more rapid relief of symptoms than does conventional chemotherapy; it incurs no risk of hyperuricemia and lessens that associated with thrombocytosis. In addition, large quantities of granulocyte-rich plasma are made available for the treatment of infections in neutropenic patients. Intensive leukapheresis deserves more widespread evaluation as the initial treatment of CGL.     

NEW INVESTIGATOR AWARD FINALISTSNIA0001Induction of differentiation in human preadipocytes may contribute to adipogenic effect of human adenovirus Ad-36

Human adenovirus Ad-36 causes adiposity in animal models and shows association with human obesity. The mechanism involved is unknown. We previously reported that Ad-36 enhances differentiation of 3T3-L1 preadipocytes and E4orf-1 gene of the virus is responsible for the adipogenic effect in the rodent cell line. We undertook a three-step approach to investigate the role of preadipocyte differentiation in adipogenic effect of Ad-36. First, we showed that the viral mRNA is expressed in adipose-derived stem cells (ASC) of animals experimentally infected with Ad-36. Infection of rats with Ad-36 resulted in increased epididymal fat pad weight and the expression of Ad-36 E4orf-1 mRNA was detected in ASC isolated from the fat pads. Next, we determined if humans naturally infected with Ad-36 will show greater preadipocyte differentiation. Subcutaneous adipose-tissue samples from 33 Pima Indian subjects were screened by nested-PCR specific for Ad-36 DNA. Nine subjects (27%) had Ad-36 DNA. A blinded comparison of their ASC showed greater differentiation to adipocytes for the Ad-36 DNA positive subjects ( P =  0.06) compared to the Ad-36 DNA negative group. Finally, we used a direct approach. Human-ASC when infected with Ad-36 showed spontaneous replication, differentiation, and lipid accumulation, which was significantly greater than the uninfected controls ( P  < 0.01). Ad-36 induced lipid accumulation in human-ASC increased in response to the viral load and the lipogenic response was observed regardless of the donor gender and over an age range of 22–57 years. These results suggest that ability of Ad-36 to induce preadipocyte differentiation may play a role in human adiposity.     

In vivo neutrophil and lymphocyte function studies in a patient with leukocyte adhesion deficiency type II

We investigated in vivo neutrophil and lymphocyte function in a patient who lacks Sialyl-Lewis-X, a ligand for the selectin family of leukocyte adhesion molecules (leukocyte adhesion deficiency II, LAD II). As assessed by skin chamber and skin window techniques, in vivo chemotaxis of neutrophils was markedly impaired (less than 6% of normal values). A marginal pool was present as determined by an increase in circulating neutrophils after epinephrine injection and calculated recovery of infused radiolabeled autologous neutrophils. Kinetic studies showed a reduced half-life of 3.2 hours (normal 7 hours) and markedly increased turnover rate (cells/kg/d) of approximately eight times the normal value. A normal antibody response to the T-cell-dependent antigen bacteriophage phi X174 showed that T/B-cell interaction is not affected in LAD II. These findings provide direct evidence that the selectin family and its ligands play an important role in neutrophil function.     

Adjuvant immunotoxin therapy with anti-B4-blocked ricin after autologous bone marrow transplantation for patients with B-cell non- Hodgkin's lymphoma

Anti-B-blocked ricin (anti-B4-bR) combines the specificity of the anti- B4 (CD19) monoclonal antibody with the protein toxin "blocked ricin." In blocked ricin, affinity ligands are attached to the ricin B-chain to attenuate its lectin binding capacity. In a phase I trial, Anti-B4-bR was administered by 7-day continuous infusion to 12 patients in complete remission after autologous bone marrow transplantation (ABMT) for relapsed B-cell non-Hodgkin's lymphoma (NHL). Patients were treated at 20, 40, and 50 micrograms/kg/d for 7 days. Potentially therapeutic serum levels could be sustained for 3 to 4 days. The maximum tolerated dose was 40 micrograms/kg/d for 7 days (total 280 micrograms/kg). The dose-limiting toxicities were reversible grade IV thrombocytopenia and elevation of hepatic transaminases. Mild capillary leak syndrome was manifested by hypoalbuminemia, peripheral edema (4 patients), and dyspnea (1 patient). Anti-immunotoxin antibodies developed in 7 patients. Eleven patients remain in complete remission between 13 and 26 months post-ABMT (median 17 months). These results show that Anti-B4- bR can be administered with tolerable, reversible toxicities to patients with B-cell NHL in complete remission following ABMT.     

De novo subgaleal abscess

The authors report a case of spontaneous subgaleal abscess formation in a 62-year-old woman without antecedent trauma or injury. She presented with occipital scalp pain and swelling which rapidly became generalized two days following recovery from an upper respiratory infection. Diagnosis was based on radiological examination and aspiration of the subgaleal space, which yielded a purulent exudate with a pure growth of Streptococcus pyogenes. Initial management with incision, drainage and parenteral antimicrobial therapy was not successful. Operative exploration of the subgaleal space revealed extensive necrosis of the galea aponeurotica, and bone curettings revealed microscopic evidence compatible with osteomyelitis. Management with debridement and excision of all necrotic tissue plus prolonged parenteral antimicrobials was successful. Subgaleal abscess formation without an overlying wound or previous trauma has not been reported previously.