Acute effects of insulin-like growth factor-1 and recombinant growth hormone on liporotein(a) levels in baboons

Elevated lipoprotein(a) [Lp(a)] is an established factor for coronary artery disease (CAD) that acts possibly by increasing cholesterol deposition in arterial wall and promoting thrombosis. The only known Lp(a)-lowering agents, niacin and neomycin, often produce intolerable side effects. We observed that administration of growth hormone (GH) increases but insulin-like growth factor-1 (IGF-1) decreases Lp(a) levels in patients with GH deficiency. To explore the mechanisms for the hormonal effects and to search for an effective pharmaceutical agent, we examined the suitability of the baboon as an animal model by investigating the effects of GH and IGF-1 on Lp(a). We selected 5 baboons with high (group 1) and 5 with low (group 2) Lp(a) levels. Group 1 baboons first received a bolus subcutaneous injection of IGF-1 (300 microg/kg body weight). After a period of 7 days, they were given a bolus infusion of recombinant human (rh)GH (300 microg/kg body weight). For group 2 baboons, the order of injection was reversed, and rhGH was given first and followed by IGF-1. Blood samples were collected during the day before and for 3 days following each injection. Levels of plasma Lp(a), insulin, GH, and IGF-1 were measured for each time point. While rhGH appeared not to raise Lp(a) levels among baboons with extremely low levels (6.8 +/- 1.1 mg/dL at baseline v 6.6 +/- 0.9 mg/dL, n = 5), IGF-1 significantly reduced Lp(a) levels among those with high levels within 2 hours of injection (57.0 +/- 6.6 mg/dL v 37.4 +/- 6.2 mg/dL, or a 34% reduction, n = 3, P =.013). Our study for the first time demonstrated that IGF-1 can lower plasma Lp(a) levels by more than 30% within 2 hours in baboons and the effects are sustained for at least 1 week. The effect is likely mediated through increased Lp(a) degradation, but the responsible organs remain to be identified. On the other hand, rhGH appeared to have no effect on those animals with very low Lp(a) levels.     

Platelet survival time and thromboembolism in patients with mitral valve prolapse.

Thromboembolism (TE) occurs in about 20% of patients with rheumatic mitral valve disease, and platelet survival time in these patients has correlated with TE. In patients with mitral valve prolapse, TE appears to occur very infrequently. Platelet survival (autologous labeling with chromium-51) was performed in 26 patients with mitral prolapse. Five patients had a history of stroke, as well as normal cerebrovascular arteriography and shortened platelet survival (average half-time +/- SEM 2.3 +/- 0.18 days; normal half-time 3.7 +/- 0.03 days; n = 26; p less than 0.01). Platelet survival was shortened in seven of 21 patients without TE (33%) (3.3 +/- 0.06 days; p less than 0.01 vs patients with TE). In 138 patients with rheumatic heart disease, platelet survival was shortened in 40 of 41 (98%) with a history of TE (2.3 +/- 0.08 days) and in 76 of 97 (78%) without TE (2.9 +/- 0.07 days; p less than 0.001 vs patients with TE). In patients with mitral prolapse, sulfinpyrazone increased platelet survival (2.4 +/- 0.16 to 2.7 +/- 0.19 days; n = 7; p less than 0.05). Our results suggest that platelet survival time is shortened in patients with mitral prolapse and rheumatic heart disease who have had TE. Of those without TE there is an increased frequency of shortened platelet survival in patients with rheumatic heart disease (78%) compared with those with mitral prolapse (33%), consistent with the infrequency of TE in mitral prolapse.     

Immunosuppression in renal transplantation: Long-term clinical trial of a double versus triple therapy regimen

Summary: Sixty-nine renal allograft recipients were randomized to two immunosuppressive regimens: 35 patients received cyclosporine A and prednisolone (PC) while 34 patients received low dose cyclosporine A, prednisolone and short term azathioprine (PCA). the data of 66 patients (34 in PC and 32 in PCA groups) were analysed. the median follow-up periods were 62 months for the PC group and 60 months for the PCA group. There was no difference in graft survival between the two groups but five patients died in the PC group compared to none in the PCA group (graft survival: 88 vs 90% at 1 year and 82 vs 82% at 5 years, P = not significant at any time point; patient survival: 90 vs 100% at 1 year and 88 vs 100% at 5 years, P = 0.05 at 5 years). There was a trend for patients in the PCA group to develop earlier and more frequent rejections (not significant; P = 0.106 and P = 0.062, respectively). There were also more episodes of acute cyclosporine A nephrotoxicity and cytomegalovirus (CMV) infection in the PC group. the mean serum creatinine at 5 years was significantly higher in the PCA group when compared to the PC group (179.8 ± 76.5 μmol/L vs 154.7 ± 41.0 μmol/L; P =0.05). We found that both therapeutic regimens were effective in preventing renal allograft rejections. However, double therapy was associated with higher patient mortality secondary to infection. Patients on triple therapy, on the other hand, were more prone to develop rejections in the early post-transplant period and were associated with less favourable renal function in the long run.     

Immunochemical characterization and quantitation of lipoprotein (a) in baboons. Development of an assay depending on two antigenically distinct proteins

We have raised specific antibodies against the protein component of baboon lipoprotein (a) (Lp(a]. Apolipoprotein (apo) Lp(a) is a very large protein which separates into two distinct proteins, apo B and apo (a), when 2-mercaptoethanol is included during sample treatment for sodium dodecyl sulfate-electrophoresis. The antibodies were specific for baboon apo (a) and apo B. The presence of the two distinct antigens in the lipoprotein permitted the development of an enzyme-linked immunosorbent assay that was specific for Lp(a) particles in serum. The assay could detect less than 1 ng of Lp(a) protein per well and was useful in the range of 1-9 ng. The assay was specific for Lp(a) and did not respond to other lipoproteins, such as low density lipoprotein. Lp(a) could be accurately quantitated in serum frozen at -80 degrees C in plastic tubing segments. Using the Lp(a) assay, the mean serum level of 80 unrelated baboons was 4.7 mg/dl, with the distribution skewed toward the lower levels. These data further support the value of the baboon as a model of the atherogenic lipoprotein Lp(a).     

Percutaneous cholecystostomy: an alternative to surgical cholecystostomy for acute cholecystitis?

Emergency percutaneous cholecystostomy was successfully performed in 39 of 40 attempted procedures in 37 hospitalized patients with possible acute cholecystitis. All cholecystostomies were performed with ultrasound guidance and preferentially with the transhepatic route, and all but four were performed at the patient's bedside. The patients had been hospitalized an average of 27 days before the procedure. Twenty-two of the 37 patients (59%) eventually died during hospitalization because of other medical or surgical problems. Only minor complications related to percutaneous cholecystostomy placement occurred in this series: catheter dislodgment without sequelae (n = 2) and significant abdominal pain (n = 2). Technical problems included guide-wire buckling during catheter insertion (n = 1) and failed attempted cholecystostomy (n = 1). Percutaneous cholecystostomy is a safe alternative to surgical cholecystostomy in the treatment of patients suspected of having acute cholecystitis.