Some questions on the significance of chromosome alterations in leukemias and lymphomas: a review

Recent improvement in the methods of chromosome analysis has allowed recognition of consistent chromosome alterations in several human cancers, especially leukemias and lymphomas. At the same time, newly discovered human cellular oncogenes have been mapped to individual chromosomes, with precise band assignment. Some of the assignments are coincident with the breakpoints of translocations observed in particular tumors. In fact, a relocation of the corresponding oncogenes has been observed in the cells of some of these tumors. Two notable examples are that of the t(9;22) translocation of chronic myelogenous leukemia (CML), causing the transfer of the oncogene c-abl from chromosome 9 to chromosome 22, and that of the t(8;14) translocation of Burkitt lymphoma, causing the transfer of the oncogene c-myc from chromosome 8 to chromosome 14. These findings can be taken as indicative of a critical role of chromosome alterations in the origin of cancer, through the activation of one or more cellular oncogenes, although there is no firm evidence that such an activation actually occurs. In addition, some concern exists over the validity of accepting in vitro transformation of a cell line by oncogenes as a model of carcinogenesis in man. For these reasons the question on the significance of chromosome alterations in leukemias and lymphomas should not be considered entirely settled yet. Useful models, whose study may lead to the clarification of this important point, are represented by premalignant conditions, such as the myeloproliferative disorders, where chromosome abnormalities are present before the development of a bona fide neoplasm, and by the aneuploidy syndromes, in which there exists an association between a constitutional chromosome anomaly and an increased risk of cancer.     

A case of progression from type II cryoglobulinaemia to Waldenstrom’s macroglobulinaemia in a patient with chronic hepatitis C

In recent years, much interest has been generated over the potential of human embryonic stem cells in transplantation medicine. The ground-breaking study of Fraidenraich and colleagues conclusively demonstrated that rescue of lethal cardiac defects in Id knockout mutant mouse embryos was not due to transplanted embryonic stem cells giving rise to functional new tissues within the defective embryonic heart. Instead, there is indirect evidence that the observed therapeutic effect was due to various secreted factors emanating from the transplanted cells. This therefore introduces the exciting prospect of utilizing human embryonic stem cells as "catalysts" to promote biological repair and regeneration in transplantation therapy. Nevertheless, the immunological barrier against allogenic transplantation, as well as the teratogenic potential of human embryonic stem cells poses major technical challenges. A possible strategy to overcome the immunological barrier may be to impose a temporary regimen of immunosuppressive drugs followed by their gradual withdrawal, once adequate tissue regeneration has been achieved. Other more novel alternatives include the use of microencapsulation to block interaction with the transplant recipient's immune system, and co-transplantation with bone marrow-derived mesenchymal stem cells, which have been demonstrated to possess immuno-suppressive properties. The teratogenic potential of human embryonic stem cells could possibly be alleviated by directing the differentiation of these cells to specific lineages prior to transplantation, or through mitotic inactivation. Co-transplantation with autologous adult stem cells may represent a novel strategy to further enhance the "catalytic" effects of human embryonic stem cells. The various factors secreted by human embryonic stem cells could then have a concentrated localized effect on relatively large numbers of co-transplanted autologous adult stem cells, which may in turn lead to enhanced repair and regeneration of the damaged tissue or organ. This new therapeutic strategy needs to rigorously investigated, in view of its potentially important clinical applications.     

Buffering action of endogenous nitric oxide on the adrenocortical secretagogue effect of endothelins in the rat

The secretagogue effect of endothelins (ETs) on the rat adrenal cortex is mediated by the ETB receptor. ETB receptors are coupled with nitric oxide (NO) synthase (NOS), and NO is known to inhibit steroid-hormone secretion from adrenal cortex. We investigated whether ETB-mediated NO production interferes with the stimulatory action of ETs on rat adrenal cortex. The selective agonist of ETB receptor BQ-3020 concentration-dependently increased aldosterone secretion from dispersed zona glomerulosa (ZG) cells and corticosterone secretion from dispersed zona fasciculata-reticularis (ZF/R) cells, and the NOS inhibitor NG-nitro-L-arginine methylester (L-NAME) potentiated the effect of BQ-3020 in a concentration-dependent manner. The guanylate cyclase inhibitor Ly-83583, at a concentration suppressing guanylin- and L-arginine-induced cyclic-GMP release from dispersed adrenocortical cells, did not affect the secretory response of ZG and ZF/R cells to BQ-3020. ET-1, an agonist of both ETA and ETB receptors, stimulated the release of both aldosterone and corticosterone by in situ perfused rat adrenal gland. This effect was potentiated by L-NAME and unaffected by Ly-83583. Collectively, our findings allow us to suggest that endogenous NO exerts in vivo and in vitro a cyclic-GMP-independent buffering action on the ETB receptor-mediated adrenocortical secretagogue action of ETs.     

XLMR genes: update 1992.

Up to now, we have identified 77 X-linked conditions in which mental retardation is the primary or a major component manifestation. These conditions were subdivided into 2 categories, designated respectively "X-linked mental retardation syndromes" and "Non-specific X-linked mental retardation". Forty genes have been regionally mapped onto the X chromosome. However, in several instances the data were derived from a single family and most lod scores were less than 3.0.     

Economic analysis of two structured treatment and teaching programs on asthma

The aims of the present study were as follows:

• 1). to evaluate the medical outcomes of two treatment and educational asthma programs
• 2). to determine by cost-analysis both cost and economic outcome of the programs
• 3). to perform a cost-benefit analysis (determining the net cost-benefit) and a cost-effectiveness analysis (determining the cost per unit of effect and the incremental cost-effectiveness ratio) from the perspective of health program policy makers (HPP; indirect costs, i.e., loss of productivity, excluded) and of society as a whole (Saw; all costs included).

Patients were randomly assigned to a complete (CP; n = 32) or reduced (RP; n = 33) program: the RP group received a reduced education (self-reading of an educational booklet on asthma), while the CP group attended an “asthma school”, consisting of six lessons based on the same booklet and including educational videotapes. Both programs included peak-flow monitoring and treatment according to international guidelines, and follow-up. The outcome variables (asthma attacks, urgent medical examinations, admission days, working days lost) did not differ significantly between CP and RP. Morbidity savings were $1894.70 (CP) and $1697.80 (RP) according to Saw, and $1349.50 and $1301.80, respectively, according to HPP. The net cost-benefit was $1181.50 for CP and $1028.00 for RP, and the cost-benefit ratio per dollar spent was 1:2.6 for CP and 1:2.5 for RP, according to Saw. One day of admission prevented had a cost of $110.20 (CP) and $94.10 (RP). CP gave slightly better results and was slightly more cost-effective than RP in improving patients' welfare. It cannot be excluded that the retrospective analysis used to determine baseline costs might have inflated differences for both groups. Sensitivity analysis was slightly in favor of RP when the outcome variables were tested at their upper and lower 95% CI.     

Investigations on the turnover of adrenocortical mitochondria. X. A correlated biochemical and stereological study of the effects of Chronic treatment with chloramphenicol on the mitochondria of the rat zona fasciculata

The effects of chloramphenicol (CAP) on rat adrenocortical cells were investigated by biochemical and stereological methods. It was found that administering 50 mg/kg of CAP every 12 hours provoked a persistent inhibition of the incorporation of ³H-leucine into mitochondrial proteins. Chronic treatment (up to 15 consecutive days) with this dose of CAP induced a significant decrease in the volume of the mitochondrial compartment, in the surface area of the outer and inner mitochondrial membranes and in the number of mitochondria per cell. These results confirm the hypothesis that the ACTH-induced maintenance of adrenocortical mitochondrial growth requires continuous mitochondrial DNA-dependent protein synthesis.     

Heterogeneous pattern of chromosomal breakpoints involving the MYC locus in multiple myeloma

Chromosomal rearrangements of the MYC locus, which often involve the IG loci, are recurrent events in multiple myeloma (MM) and plasma cell leukemia (PCL). We used dual-color fluorescence in situ hybridization (FISH) to characterize the breakpoint locations of chromosomal translocations/rearrangements involving the MYC locus at 8q24 found in a panel of 14 MM cell lines and 70 primary tumors (66 MM and 4 PCL). MYC locus alterations were observed in 21 cases: MYC/IG (mainly IGH@) fusions in 11 cell lines and three patients (2 MM and 1 PCL), and extra signals and/or abnormal MYC localizations in seven patients (5 MM and 2 PCL). Fourteen of these cases were investigated by FISH analyses by use of a panel of BAC clones covering about 6 Mb encompassing the MYC locus. The breakpoints were localized in a region 100-250 kb centromeric to MYC in four cases, a region 500-800 kb telomeric to the gene in four cases, and regions > or = 2 Mb centromeric or telomeric to MYC in five cases. Two different breakpoints were detected in the KMS-18 cell line, whereas the insertion of a MYC allele was found in a complex t(16;22) chromosomal translocation in the RPMI8226 cell line. Our data document a relatively high dispersion of 8q24 breakpoints in MM.