Safety and efficacy of high-dose melphalan and auto-SCT in patients with AL amyloidosis and cardiac involvement.

In Ig light chain (AL) amyloidosis, cardiac involvement is associated with worse prognosis and increased treatment-related complications. In this retrospective cohort study, we assessed survival, hematologic and cardiac responses to high-dose melphalan and auto-SCT (HDM/SCT) in patients with AL amyloidosis and cardiac involvement, stratified by cardiac biomarkers brain natriuretic peptide and Troponin I, analogous to the Mayo cardiac staging. Forty-seven patients underwent HDM/SCT based upon functional measures; six patients had modified cardiac stage I disease, seventeen had modified cardiac stage II disease and twenty-four had modified cardiac stage III disease. Treatment-related mortality was 4% for all patients and 8% for patients with stage III disease. Three-year survival was 88% and EFS was 47%; these did not differ by stage. By intention-to-treat analysis, 27% of patients achieved a hematologic complete response and 32% a very good partial response, of whom 70 and 45%, respectively, have not required additional therapy at 36 months. Cardiac response was achieved in 53% of patients. We conclude that with appropriate patient selection and a risk-adapted treatment approach, HDM/SCT is safe and effective in patients with AL amyloidosis and cardiac involvement.

Engagement of human PECAM-1 (CD31) on human endothelial cells increases intracellular calcium ion concentration and stimulates prostacyclin release.

Platelet-endothelial cell adhesion molecule-1 (PECAM-1) is a member of the immunoglobulin superfamily that plays a role in a number of endothelial cell (EC) functions including migration, angiogenesis, and transmigration of leukocytes across endothelium. We postulated that one way PECAM-1 might exert its effects was by regulating intracellular EC levels of calcium. Using single-cell fluorometry, we found that engagement of PECAM-1 by mAbs induced a slow but sustained increase in intracellular calcium, both in EC and in an adherent PECAM-1-transfected cell line that models endothelium. Generation of this signal was specific for certain anti-PECAM-1 antibodies, required the presence of the cytoplasmic domain, depended on extracellular calcium and on tyrosine phosphorylation, but did not require cross-linking; in fact, calcium increases were stimulated by certain Fab fragments. Activation of EC by PECAM-1 also caused a time-dependent increase in prostacyclin release. Given the importance of intracellular calcium and prostacyclin release as signaling molecules, engagement of PECAM-1 during cell-cell interactions may alter a number of EC functions including secretion of vasoactive mediators.

Melatonin regulation in humans with color vision deficiencies.

Light can induce an acute suppression and/or circadian phase shift of plasma melatonin levels in subjects with normal color vision. It is not known whether this photic suppression requires an integrated response from all photoreceptors or from a specialized subset of photoreceptors. To determine whether normal cone photoreceptor systems are necessary for light-induced melatonin suppression, we tested whether color vision-dificient human subjects experience light-induced melatonin suppression. In 1 study, 14 red-green color vision-deficient subjects and 7 normal controls were exposed to a 90-min, 200-lux, white light stimulus from 0200-0330 h. Melatonin suppression was observed in the controls (t = -7.04; P < 0.001), all color vision-deficient subjects (t = -4.76; P < 0.001), protanopic observers (t = -6.23; P < 0.005), and deuteranopic observers (t = -3.48; P < 0.05), with no significant difference in the magnitude of suppression between groups. In a second study, 6 red/green color vision-deficient males and 6 controls were exposed to a broad band green light stimulus (120 nm with lambda max 507 nm; mean +/- SEM, 305 +/- 10 lux) or darkness from 0030-0100 h. Hourly melatonin profiles (2000-1000 h) were not significantly different in onset, offset, or duration between the two groups. Melatonin suppression was also observed after exposure to the green light source at 0100 h (color vision deficient: t = -2.3; df = 5; P < 0.05; controls: t = -3.61; df = 5; P < 0.01) and 0115 h (color vision deficient: t = -2.74; df = 5; P < 0.05; controls: t = -3.57; df = 5; P < 0.01). These findings suggest that a normal trichromatic visual system is not necessary for light-mediated neuroendocrine regulation.