Somatic mutations in the HLA genes of patients with hematological malignancy.

Somatic mutations and genomic alterations are frequent events in the clonal evolution of hematologic malignancies. Recent studies have reported copy neutral loss of heterozygosity (LOH) for the mismatched human leukocyte antigen (HLA) haplotype in patients relapsed after haploidentical hematopoietic cell transplantation (HCT) for a hematologic malignancy. Herein, we report 15 cases of somatic mutations in the HLA genes of patients with a variety of hematologic diseases, including acute myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and non-Hodgkin's lymphoma, encountered at our institute over the past decade. While two of the cases were identified in patient relapse specimens collected post-HCT, 13 cases were found in peripheral blood specimens submitted for HLA typing prior to transplantation. Ten patients exhibited acquired LOH for all or part of one HLA haplotype. Five other cases involved somatic mutations in the nucleotide sequences of common HLA-A or HLA-B alleles. Since they are not systematically evaluated prior to HCT, acquired mutations in HLA genes are likely under reported. Beyond the implications for accurate HLA typing and donor selection, alternations that result in the loss of HLA expression may allow escape from immune surveillance and adversely impact transplant outcome.

Immunosuppressive activity and alpha interferon concentrations in human embryo culture media as an index of potential for successful implantation.

OBJECTIVE: To evaluate potential correlations between establishment of pregnancy and immunosuppressive activity secreted by the preimplantation embryo. DESIGN: To evaluate immunosuppressive activity, supernatants from preimplantation embryos were assessed for their ability to inhibit lymphocyte proliferation. Additionally, alpha interferon concentrations were also measured in these supernatants. We compared these parameters from embryo culture supernatants of women who did and did not achieve pregnancy after in vitro fertilization (IVF). Immunosuppression was assessed using a lymphocyte proliferation assay with concanavalin A (Con A) and phytohemagglutinin (PHA) as mitogens. SETTING: In vitro fertilization program at the University of Utah Medical Center. PARTICIPANTS: Couples less than 40 years of age, with normal semen quality and bilateral tubal obstruction. RESULTS: Immunosuppression calculated using the stimulation index (mean +/- SEM) in pregnant and nonpregnant women, respectively, were: Con A: 43.9 +/- 3.9 versus 19.1 +/- 10.1, P less than 0.04. PHA: 23.6 +/- 5.6 versus 12.5 +/- 12.8, P less than 0.02. Alpha interferon levels (mean +/- SD) in pregnant and nonpregnant women were not significantly different: 23.98 +/- 9.6 U/mL versus 24.79 +/- 2.5 U/mL. CONCLUSIONS: We conclude that pre-embryos with the capacity for successful implantation secrete greater amounts of immunosuppressive factors than those destined not to implant, as measured by Con A and PHA lymphocyte proliferation assays. Refinement of assay techniques and identification of the substances involved could have significant impact on IVF programs.

Contaminant profiles of two species of shorebirds foraging together at two neighboring sites in South San Francisco Bay, California.

The San Francisco Bay estuary is used by over one million shorebirds during spring migration and is home to several hundred thousand during the winter. Most shorebird use occurs in the southern reach of the estuary (South Bay). The reduced water circulation and discharge from industrial sources in the South Bay are responsible for the highest levels of some trace elements in the estuary. Wintering shorebirds have been found to have strong site fidelity to areas as small as a few kilometers in the South Bay, which may increase their exposure to contaminants near local point sources. In addition, different shorebird species foraging at the same site have been shown to have different contaminant burdens. Thus, our objectives were to test whether contaminant burdens differed by species, or whether contaminant burdens differed in shorebirds collected at adjacent sites. We examined the contaminant profiles of two species of shorebirds, long-billed dowitchers (Limnodromus scolopaceus) and western sandpipers (Calidris mauri) that forage together at two sites, Hayward and Newark, separated by 8 km in the South Bay. We used multivariate analysis of variance tests to compare the composition of 14 elemental analytes in their liver tissues and estimated their molar ratios of Hg and Se. Composite samples were used for contaminant analyses because of the small body size of the shorebirds. Seven elemental analytes (Ag, Ba, Be, Cr, Ni, Pb, V) were below detection limits in a majority of the samples so statistical analyses were precluded. In the measurable analytes (As, Cd, Cu, Hg, Mn, Se, Zn), we found no significant intra-site differences of contaminant profiles for the two species. We pooled the samples to examine inter-site differences and found significant differences in contaminant profiles between shorebirds at the neighboring sites (P = 0.03). Shorebirds at Newark had higher (P < 0.05) concentrations of As, Cd, and Se than those at Hayward. Dowitchers at Newark had concentrations of Hg and Se which were highly correlated (P < 0.003) in a mean molar ratio of 1:19, similar to that reported in other birds. In the larger dowitcher species, we also examined exposure to 20 organochlorine compounds. Organic analyses showed that the dowitchers had been exposed to DDE, PCBs, dieldrin and trans-nonachlor, but with no significant differences in concentrations between Hayward and Newark (P > 0.05).

Intracranial MRA: single volume vs. multiple thin slab 3D time-of-flight acquisition.

Single volume three-dimensional (3D) time-of-flight (TOF) MR angiography is the most commonly used noninvasive method for evaluating the intracranial vasculature. The sensitivity of this technique to signal loss from flow saturation limits its utility. A recently developed multislab 3D TOF technique, MOTSA, is less affected by flow saturation and would therefore be expected to yield improved vessel visualization. To study this hypothesis, intracranial MR angiograms were obtained on 10 volunteers using three techniques: MOTSA, single volume 3D TOF using a standard 4.9 ms TE (3D TOFA), and single volume 3D TOF using a 6.8 ms TE (3D TOFB). All three sets of axial source images and maximum intensity projection (MIP) images were reviewed. Each exam was evaluated for the number of intracranial vessels visualized. A total of 502 vessel segments were studied with each technique. With use of the MIP images, 86% of selected vessels were visualized with MOTSA, 64% with 3D TOFA (TE = 4.9 ms), and 67% with TOFB (TE = 6.8 ms). Similarly, with the axial source images, 91% of selected vessels were visualized with MOTSA, 77% with 3D TOFA (TE = 4.9 ms), and 82% with 3D TOFB (TE = 6.8 ms). There is improved visualization of selected intracranial vessels in normal volunteers with MOTSA as compared with single volume 3D TOF. These improvements are believed to be primarily a result of decreased sensitivity to flow saturation seen with the MOTSA technique. No difference in overall vessel visualization was noted for the two single volume 3D TOF techniques.