Bridging the gap: from discovery to clinical trials in spinal cord injury.

Recently, the Kent Waldrep National Paralysis Foundation initiated a think tank intended to bridge several gaps and achieve several goals in regard to spinal cord injury (SCI) research and funding. Affiliated with the need to bridge a pathophysiological gap in spinal parenchyma and/or reorganize remaining circuitry after injury is a need to bridge resource gaps for timely funding for translational research, gaps in knowledge between researchers, and between researchers/clinicians and SCI patients. The epistemology of cure was examined and redefined to include transitional recoveries and advances. Modes and mechanisms of funding have been evaluated and where deficits were perceived, suggestions have been made to expedite and increase the number and breadth of funding opportunities. Innovative infrastructure changes are submitted. We discuss the progression of clinical trials as well as offer suggestions to facilitate benchtop-to-bedsite translation of valuable research to the customer. Highlights of recently completed, in progress, and future trials are detailed. Finally, we submit five essential processes required to promote advances to the SCI patient population: discovery, development, clinical trials, evaluation, and rehabilitation. These ideas are intended to facilitate entry of serious dialogue and to ultimately improve the lives of patients living with SCI.

Effects of recombinant interferon-gamma and interleukin-2 on the generation of lymphokine-activated killer cells in vitro.

In order to determine if recombinant interferon-gamma (rIFN-gamma) can augment the effect of recombinant interleukin-2 (rIL-2) in generating lymphokine-activated killer (LAK) cells, we have incubated normal peripheral blood mononuclear cells (PBMC) with these lymphokines for 3 days and then tested their LAK and natural killer (NK) cell activity. We have found that LAK activity in PBMC from 13 out of 13 normal donors was increased by the combined lymphokines above that due to either lymphokine alone, provided that rIL-2 was present at suboptimal concentration: Optimal levels of rIFN-gamma (100 U/ml) were able to enhance the LAK-inducing activity of suboptimal levels (5 U/ml) but not optimal levels (100 U/ml) of rIL-2. NK activity showed a similar response to these concentrations of lymphokines. Activation of LAK/NK cells was accompanied by increases in the percentages of Leu 19+ (CD56) cells and TAC+ (IL-2-receptor) cells, and in the intensity of TAC antigen expression. These results indicate that combination rIFN-gamma and rIL-2 may be more effective in generating LAK/NK cells than rIL-2 alone, particularly with suboptimal concentrations of rIL-2 such as occur during continuous infusion therapy with this agent.

The estimation of total serum lipids by a completely enzymatic 'summation' method.

Expressing serum organic toxicant concentrations per weight of total lipid rather than by volume of serum is often advantageous, but it requires a reliable and convenient method for determining the total serum lipids. We compared a completely enzymatic 'summation' method for estimating serum total lipids with a traditional gravimetric analysis. Serum total cholesterol (TC), nonesterified cholesterol (FC), triglycerides (TG), and phospholipids (PL) were assayed by automated, enzymatic methods and total lipids (TL) were calculated from the expression TL = 1.677 * (TC-FC) + FC + TG + PL. Examining three reference serum pools by both summation and gravimetric methods yielded results that agreed within 1-3%. The evaluation of thirty serum samples resulted in similar mean total lipid values (697 mg/dl gravimetric; 675 mg/dl summation) with excellent correlation between the two methods (r2 = 0.978). We conclude that the enzymatic summation procedure is a useful method for routinely estimating serum total lipid content.

A phase I study of interleukin-2 in children with cancer and evaluation of clinical and immunologic status during therapy. A Pediatric Oncology Group Study.

The authors performed a Phase I study to assess the toxicity and hematologic effect of recombinant human interleukin-2 (rIL-2) in seven children with advanced malignancies. The rIL-2 was given as a bolus injection of 1 or 3 X 10(6) U/m2/dose three times a week (Monday, Wednesday, and Friday) for 3 weeks. No life-threatening toxicity occurred with the dose of 1 X 10(6) U/m2 of rIL-2. At a dose of 3 X 10(6) U/m2, therapy had to be terminated due to cardiovascular toxicity in two patients. Toxic effects at low-dose rIL-2 included fever, nausea, vomiting, and mild hypotension. High-dose rIL-2 toxicity included fluid retention, increased creatinine, oliguria, elevated liver enzymes, and significant hypotension. Immunologic studies showed that rIL-2 caused a drop in the number of circulating peripheral blood mononuclear cells, T-cells, and natural killer cells which returned to pretherapy levels or above by 24 to 48 hours. The rIL-2 exerted no growth or stimulatory activity on the leukemic cell population. To the authors' knowledge, this is the first report of a Phase I study of IL-2 therapy in children.