Disturbances of the CD95 (APO-1/Fas) system in disorders of lymphohaematopoietic cells

Control of tissue homeostasis is maintained through programs that balance proliferation and cell death. Physiologic cell death is primarily mediated through apoptosis. Deregulations of the cellular programs and genes that determine apoptosis have recently been considered to be involved in a variety of human diseases. One of the central regulatory systems for apoptosis is the CD95 (APO-1/Fas) system. Defects in the CD95 cell surface receptor and deregulated expression of CD95 and the CD95 ligand have been shown to be involved in diseases such as lymphoproliferation, AIDS and haematopoietic failure. This review summarizes our current knowledge on the implication of the CD95 system especially in lymphohaematopoietic diseases in humans.     

Identification of deficient mitochondrial signaling in apoptosis resistant leukemia cells by flow cytometric analysis of intracellular cytochrome c, caspase-3 and apoptosis

Deficient activation of apoptosis signaling pathways may be responsible for treatment failure of malignant diseases. In primary leukemia samples the detection of deficient mitochondrial apoptosis signaling would enable identification of chemo-resistant cells. To investigate the key events of apoptosis at the mitochondrial level, we developed a flow cytometric method for simultaneous detection of mitochondrial cytochrome c release and caspase-3 processing using conformation sensitive monoclonal antibodies. This method proved to identify deficient mitochondrial apoptosis signaling in leukemia cells overexpressing Bcl-2 by a pattern of apoptosis resistance, deficient cytochrome c reduction and partial processing of caspase-3. In primary leukemia cells, reduction of cytochrome c and caspase-3 activation was induced by treatment with anticancer drugs in vitro. In leukemia cells of a patient with resistant disease, a pattern of deficient apoptosis signaling as in Bcl-2 transfected cells was observed, suggesting that deficient mitochondrial signaling contributed to the clinical phenotype of drug resistance in this patient. Flow cytometric analysis of mitochondrial apoptosis signaling may provide a useful tool for the prediction of drug resistance and treatment failure in primary leukemia.     

Role of apoptosis in congenital hematologic disorders and bone marrow failure

Apoptosis, the cell's intrinsic death program, plays a critical role in the regulation of tissue homeostasis, especially in cell systems with a high turnover rate such as hematopoiesis. Imbalances between survival, proliferation and death of precursor cells or mature cells may result in accelerated loss or impaired output or uncontrolled polyclonal or monoclonal expansion and may pave the way to the development of leukemia. Congenital hematologic disorders are characterized by disturbed growth control of hematopoietic cells. In the previous years, it has become clear that deregulated apoptosis contributes or is even a key determinator of the pathophysiology of diseases such as lymphoproliferation, aplastic anemia or chronic neutropenia. Hematopoietic growth factors have been shown not only to stimulate proliferation of hematopoietic stem cells and committed precursor cells, but also to act as survival factors protecting developing precursor cells from apoptotic signals. The molecular delineation of pathways of apoptosis signaling or survival in hematopoietic cells is expected to provide tools for molecular understanding of the pathophysiology of congenital and acquired hematopoietic disorders and to identify targets for therapeutic intervention strategies.     

Disproportionately elevated fasting proinsulin levels in normoglycemic patients with thalassemia major are correlated to the degree of iron overload

OBJECTIVE: To analyze the secretion of the insulin precursor proinsulin in patients with beta-thalassemia and its possible relation to iron overload. METHODS: We assessed fasting proinsulin, insulin, C-peptide and glucose levels from 34 patients with beta-thalassemia and 33 healthy controls. The correlation to age, body mass index, hepatic iron concentration, serum ferritin and serum AST was analyzed. RESULTS: Fasting proinsulin (p < 0.002) and proinsulin-to-insulin ratio (p < 0.02) were significantly increased in patients with thalassemia irrespective of the degree of glucose tolerance. They correlated positively to serum ferritin, liver iron, patient age and serum AST (all p < 0.05). CONCLUSIONS: Disproportionately elevated proinsulin levels in thalassemic patients indicate early beta-cell dysfunction due to siderosis. An additional biological significance of hyperproinsulinemia and its possible ability to predict long-term iron toxicity in these patients remain to be clarified.     

Chronic lymphocytic leukemia: keeping cell death at bay

Chronic lymphocytic leukemia (CLL) is a common adult leukemia caused by abnormal accumulation of B cells. Raval et al. (2007) now implicate dowregulation of the expression of the kinase DAPK1 both genetically and epigenetically in familial and sporadic CLL.     

Satellite tracking of two Montagu’s Harriers (Circus pygargus): dual pathways during autumn migration

Autumn migration routes of two Dutch female Montagu’s Harriers (Circus pygargus) were documented for the first time using satellite telemetry. Both migrated to their African wintering area—one via the Straits of Gibraltar through the Mediterranean and the other via Italy/Tunisia. The rate of travel was comparable to values reported for larger raptor species.     

A high proportion of mutations in the BRCA1 gene in German breast/ovarian cancer families with clustering of mutations in the 3′ third of the gene

We have analyzed 61 German breast and breast/ovarian cancer families for BRCA1 mutations using single-strand conformation polymorphism analysis (SSCP) followed by sequencing. Forty-seven of the families had at least three cases (at least two under 60 years) and 14 families had only two cases of breast/ovarian cancer (at least one under 50 years). Twenty-eight families were breast/ovarian and 33 were breast cancer-only families. Eighteen mutations in BRCA1 were detected in 11/28 breast/ovarian cancer families and 7/33 breast cancer families and none in the families with only two cases. We identified 17 truncation mutations (8 frameshift, 7 nonsense and 2 splice variants) and one missense mutation. Seven of these are novel and two, the 5382insC and 5622C→T mutations, occurred in two apparently unrelated families. The genotype of the two families with the 5382insC mutation is compatible with the rare haplotype segregating with the 5382insC mutation in different populations, further supporting its European origin. One unclassified missense alteration, R841W, was found in one family but did not segregate with the disease, suggesting that it is more likely a polymorphism. We also report and discuss the sequence of several new unclassified single-nucleotide changes first identified by SSCP. Of the 18 mutations, 13 occurred in the 3′ third of the gene (end of exon 11–24) and ovarian cancers were found in eight of these families. Received: 5 February 1998 / Accepted: 7 April 1998     

Source- and product-oriented strategies in L2 acquisition of plural marking in German

This article deals with the acquisition of the German plural system. It raises the question how morphologically complex words are represented in the mental grammar and in the lexicon of children and how this representation emerges.There are several theoretical accounts dealing with this question. These accounts are basically of two kinds. One approach models the German number system as rule-based; i.e. source-oriented rules are postulated that operate on the singular form of the noun. The second approach is schema-based. Essential to this approach is the idea that speakers form the plural of a given noun according to prototypical plural shapes. Empirical evidence can be found for both approaches, but neither of them seems to be able to fully explain acquisitional paths on its own.On the basis of the analysis of acquisitional data, this article argues for an expanded schema account that embraces both source- and product-oriented mechanisms. We propose an acquisition model according to which learners start out with storing plural forms holistically in an associative network; then they abstract product-oriented schemas from these stored forms that focus on the typical gestalts of German plural forms. In a last step, they establish source-oriented schemas that relate singular schemas with plural schemas.The data for this study were gathered in a nonce word elicitation experiment from children aged 6 to 10 learning German either as their native or second language. In the latter case, the children’s L1 was either Russian or Turkish.     

Suppression of growth hormone by oral glucose in the evaluation of tall stature

Excess secretion of growth hormone is a rare diagnosis in children or adolescents with tall stature. An oral glucose tolerance test (OGT) with determination of growth hormone is generally recommended to exclude this disorder. In order to test the validity of this approach in pediatric subjects, OGT tests were performed in 126 tall subjects (age: 12.4 +/- 1.8 years; height: 3.1 +/- 0.8 SDS). Nonsuppression was present in 39 subjects, however, anthropometric analysis and follow-up excluded the diagnosis of eosinophilic pituitary adenoma in all patients. The lowest GH concentration was reached 90 min after ingestion of oral glucose, GH rose above baseline at 180 min. Plasma concentrations of glucose and insulin did not differ between suppressors and nonsuppressors. In conclusion, absent suppression of growth hormone by oral glucose is common in tall children and adolescents. The test is therefore not recommended as a general screening for excess growth hormone. Prolonging the test beyond 120 min does not increase the diagnostic value.