Molecular definition of a narrow interval at 7q22.1 associated with myelodysplasia

Chromosome 7 translocations, deletions, or monosomy are associated with myelodysplasia (MDS) and acute myeloid leukemia both in children and adults. These chromosomal anomalies represent one of the most common cytogenetic abnormalities associated with these diseases and usually herald a poor prognosis. In this study two cosmid DNA probes that mapped to 7q22.1 and were known to be separated by approximately 500 kb were identified to flank the proximal inversion breakpoint in a patient carrying a constitutional inversion (7q22.1-34) associated with MDS. A yeast artificial chromosome (YAC) clone that encompassed the two cosmids was identified and shown to span the breakpoint. Fluorescence in situ hybridization was then used to analyze six additional patients with myelodysplasia and chromosomal rearrangements of the 7q22 region (three patients had translocations and three carried deletions). The breakpoint in one of the patients was found to be contained within the same YAC clone that spanned the inversion breakpoint. Moreover, this same interval was determined to be absent in all three patients with chromosomal deletions. These results suggest that this segment of DNA on chromosome 7q22.1 may contain specific gene(s) that have a significant role in myeloid malignancies.     

Expression of murine CD38 defines a population of long-term reconstituting hematopoietic stem cells

Using a monoclonal antibody to murine CD38, we showed that a population of adult bone marrow cells that expressed the markers Sca-1 and c-kit but lacked the lineage markers Mac-1, GR-1, B220, IgM, CD3, CD4, CD8 and CD5 could be subdivided by the expression of CD38. We showed that CD38high c-kit+ Sca-1+, linlow/-cells sorted from adult bone marrow cultured with interleukin-3 (IL-3), IL-6, and kit-L produced much larger colonies in liquid culture at a greater frequency than their CD38low/- counterparts. In addition, we found that CD36low/ - cells contained most of the day-12 colony-forming units-spleen (CFU-S) but were not long-term reconstituting cells, whereas the population that expressed higher levels of CD38 contained few, but significant, day-12 CFU-S and virtually all the long-term reconstituting stem cells. Interestingly, the CD38high Sca-1+ c-kit+ linlow/- cells isolated from day-E14.5 fetal liver were also found to be long-term reconstituting stem cells. This is in striking contrast to human hematopoietic progenitors in which the most primitive hematopoietic cells from fetal tissues lack the expression of CD38. Furthermore, because antibodies to CD38 could functionally replace antibodies to Thy-1.1 in a stem cell purification procedure, the use of anti-CD38 may be more generally applicable to the purification of hematopoietic stem cells from mouse strains that do not express the Thy-1.1 allele.     

Report: workshop on mediastinal grey zone lymphoma

Abstract:  There are several indications that classical Hodgkin lymphoma (cHL) and at least a proportion of cases of Primary Mediastinal B cell Lymphoma (PMBL) are derived from B cells at similar stages of differentiation and share common pathogenic mechanisms. The first indication was the existence of mediastinal grey zone lymphomas as identified in the 4th International Symposium on HL, with clinical, histological and immunohistochemical features intermediate between cHL and PMBL. Second, both tumor types resemble a cell that is developmentally situated in-between the germinal center reaction and a plasma cell. Third, cHL and PMBL were found to have similar gene expression profiles, including the lack of immunoglobulin expression and low levels of B cell receptor signalling molecules, and the secretion of molecules like the chemokine TARC and the prominent expression of IL-13 receptors. Fourth, both entities were found to have common genomic aberrancies, notably in 2p15 and 9p24, the sites of the REL oncogene and the tyrosine kinase gene JAK2, respectively. Further comparison of both lymphoma types may provide further insight in the pathogenic mechanisms and allow the design of diagnostic algorithms to sort out the small number of so-called mediastinal grey zone lymphomas, that appear to be intermediate between PMBL and cHL.     

Predictive markers of chronic liver disease in hemophilia

In an attempt to predict progressive liver damage in hemophiliac patients by noninvasive means, we conducted a retrospective analysis of clinical and laboratory data from 44 liver biopsies taken from 35 hemophiliac patients. This showed that serum IgG was normal in patients with chronic persistent hepatitis (CPH) but significantly elevated in those with chronic active hepatitis (CAH) or cirrhosis (CIR) (P less than .001). Relationships were less significant between liver histology and IgM (P less than .01), IgA (P less than .05), and globulin (P less than .05). This was unaffected by human immunodeficiency virus (HIV) antibody status in asymptomatic individuals. Although patients with progressive liver disease were also older than those with CPH (P less than .001), the immunoglobulin abnormalities were independent of this. Neither clinical examination nor liver biochemistry at the time of biopsy were of significant diagnostic value. Our results indicate that in the absence of AIDS an elevated IgG level is a reliable indicator of progressive hemophilic liver disease.     

Serologic evidence that Scianna null (Sc:-1,-2) red cells lack multiple high-frequency antigens

Sera from three unrelated persons whose red cells (RBC) had the common Scianna phenotype (Sc:1,-2) contained IgG alloantibodies directed against high-frequency RBC antigens. In each case, sera or eluates or both failed to react only with Scianna null (Sc:-1,-2) cells, although an eluate from one person was compatible with a sibling's Sc:1,-2 cells. Cross-testing cells with sera or eluates, or both, from the three persons revealed no mutual compatibility. These studies show the existence of three additional RBC antigens phenotypically related to the Scianna blood group system. Sc:-1,-2 cells lack these antigens, which indicates that Scianna null cells lack multiple high-frequency antigens.     

Endothelium modulates vasoconstrictor response to prostaglandin I2 in rat mesenteric resistance arteries: interaction between EP1 and TP receptors

Background and purpose:

Prostacyclin (PGI₂) is usually described as an endothelium-derived vasodilator, but it can also induce vasoconstriction. We studied the vasomotor responses to PGI₂ in resistance arteries and the role of thromboxane (TP) and prostaglandin E₂ (EP) receptors in this effect.

Experimental approach:

Mesenteric resistance arteries were obtained from Sprague-Dawley rats. Vasomotion to PGI₂ was studied in segments of these arteries with and without endothelium and in presence of the nitric oxide (NO) synthase inhibitor N^G-nitro-L-arginine methyl ester (L-NAME), the potassium channel blockers apamin plus charybdotoxin, the non-selective EP receptor antagonist AH6809, the selective TP receptor antagonist SQ29548 or the EP₁ receptor antagonist SC19220. PGI₂-induced NO release was analysed in the absence or presence of SQ29548, AH6809 or SC19220.

Key results:

PGI₂ caused contractions in arterial segments that were increased by endothelium removal, L-NAME or L-NAME plus apamin plus charybdotoxin and abolished by SQ29548. In segments with endothelium, AH6809 or SC19220 almost abolished the contractions to PGI₂; this effect was prevented by L-NAME, L-NAME plus apamin plus charybdotoxin or by endothelium removal. PGI₂ induced NO release that was inhibited by the prostacyclin receptor (IP receptor) antagonist, RO1138452, and increased by SQ29548, SC19220 and AH6809. The increase in NO release induced by these separate drugs was inhibited by RO1138452.

Conclusions and implications:

PGI₂ activated the TP receptor in mesenteric resistance arteries and produced vasoconstriction, which the endothelium modulated through TP and EP₁ receptors. PGI₂ also released endothelium-derived hyperpolarizing factor and, through IP receptor activation, induced NO release, which in turn, was antagonized by TP and EP₁ receptor activation.     

蛇床子素对豚鼠离体回肠和结肠带的作用

以豚鼠离体回肠和结肠带为标本,观察蛇床子素(Ost)的作用与Ca~(2+)的关系。结果表明:Ost和钙拮抗剂Ver产生剂量依赖性抑制乙酰胆碱(ACh)、组胺及KCl所致回肠条或结肠带的收缩;非竞争性拮抗CaCl_2累积量—效曲线,pD_2分别为4.41±0.15,7.0±0.2。Ost 100μmol/L和Ver 1μmol/L均能对抗小剂量Ca~(2+)所致结肠带收缩,但被加入较大量Ca~(2+)所取消。Ost和Ver均能抑制ACh诱导的依内钙性收缩,不影响依外钙性收缩。结果提示Ost具有钙拮抗作用,其作用方式与Ver类似。