Proliferation kinetics of plasma cells and of normal haemopoietic cells in multiple myeloma

Abstract. DNA synthesis time ( T _s) and ³H thymidine (TdR) labelling index (LI) of bone marrow (BM) myelomatous plasma cells (PC) and of the residual haemopoietic cell population (RHCP) were measured by in vitro quantitative ¹⁴C-TdR autoradiography in five patients with multiple myeloma (MM) in different phases of disease (three at presentation and two at relapse) and in one patient with solitary extra-osseous myeloma. One other patient with plasma cell leukaemia (PCL) was studied during an initial relapse phase and later during the leukaemic terminal phase. PC T _s was 18.8 ± 3.7 (from 13.3 to 25.0) hr and PC LI was 2.5 ± 1.8%; (from 1.0 to 6.3%). In the case of PCL, circulating PC had a T _s of 14.4 hr and a LI of 3.1. From these experimental measurements, the fractional turnover rate (FTR—percentage of cells produced per unit time) and the potential doubling time ( T _d) of BMPC were calculated assuming that all BMPC were in a steady-state at the time of the study. BMPC FTR was 3.53 ± 2.3% cells per day (from 1.2 to 6.72) and BMPC T _d was 46.8 ± 27.5 days (from 15.0 to 75.4). Comparison with results obtained in BM blasts of children with acute lymphoblastic leukaemia (ALL) indicated that BMPC had a lower proliferative activity ( P < 0.001), although BMPC T _s was not significantly different. In two patients a tumour doubling time of 6 and 13 months was determined by clinical follow up. Comparison of this parameter with T _d showed a cell loss factor of more than 90% in both patients.
Kinetic data relative to RHCP showed slight variations with respect to those found in normal subjects, with a general tendency towards a prolongation of T _s and a reduction of LI.     

Fetal Calcium Regulates Branching Morphogenesis in the Developing Human and Mouse Lung: Involvement of Voltage-Gated Calcium Channels

Airway branching morphogenesis in utero is essential for optimal postnatal lung function. In the fetus, branching morphogenesis occurs during the pseudoglandular stage (weeks 9–17 of human gestation, embryonic days (E)11.5–16.5 in mouse) in a hypercalcaemic environment (∼1.7 in the fetus vs. ∼1.1–1.3 mM for an adult). Previously we have shown that fetal hypercalcemia exerts an inhibitory brake on branching morphogenesis via the calcium-sensing receptor. In addition, earlier studies have shown that nifedipine, a selective blocker of L-type voltage-gated Ca²⁺ channels (VGCC), inhibits fetal lung growth, suggesting a role for VGCC in lung development. The aim of this work was to investigate the expression of VGCC in the pseudoglandular human and mouse lung, and their role in branching morphogenesis. Expression of L-type (Ca_V1.2 and Ca_V1.3), P/Q type (Ca_V2.1), N-type (Ca_V2.2), R-type (Ca_V2.3), and T-type (Ca_V3.2 and Ca_V3.3) VGCC was investigated in paraffin sections from week 9 human fetal lungs and E12.5 mouse embryos. Here we show, for the first time, that Ca_v1.2 and Ca_v1.3 are expressed in both the smooth muscle and epithelium of the developing human and mouse lung. Additionally, Ca_v2.3 was expressed in the lung epithelium of both species. Incubating E12.5 mouse lung rudiments in the presence of nifedipine doubled the amount of branching, an effect which was partly mimicked by the Ca_v2.3 inhibitor, SNX-482. Direct measurements of changes in epithelial cell membrane potential, using the voltage-sensitive fluorescent dye DiSBAC₂(3), demonstrated that cyclic depolarisations occur within the developing epithelium and coincide with rhythmic occlusions of the lumen, driven by the naturally occurring airway peristalsis. We conclude that VGCC are expressed and functional in the fetal human and mouse lung, where they play a role in branching morphogenesis. Furthermore, rhythmic epithelial depolarisations evoked by airway peristalsis would allow for branching to match growth and distension within the developing lung.     

Relationship between histology,development and tumorigenesis of mammary gland in female rat

The mammary gland is a dynamic organ that undergoes structural and functional changes associated with growth, reproduction, and post-menopausal regression. The postnatal transformations of the epithelium and stromal cells of the mammary gland may contribute to its susceptibility to carcinogenesis. The increased cancer incidence in mammary glands of humans and similarly of rodents in association with their development is believed to be partly explained by proliferative activity together with lesser degree of differentiation, but it is not completely understood how the virgin gland retains its higher susceptibility to carcinogenesis. During its developmental cycle, the mammary gland displays many of the properties associated with breast cancer. An early first full-term pregnancy may have a protective effect. Rodent models are useful for investigating potential breast carcinogens. The purpose of this review is to help recognizing histological appearance of the epithelium and the stroma of the normal mammary gland in rats, and throughout its development in relation to tumorigenic potential.     

Early Plasma Cell Recruitment In Multiple Myeloma Following Chemotherapy

Abstract. Therapy-induced modifications of bone marrow plasma cell kinetics were studied in three patients with myelomatosis. the investigation was performed prior to and 15 d after termination of a course of aggressive chemotherapy. an increase in the labelling index (40-212% of pretreatment values) with a corresponding reduction of T _s (5-34%) was observed in all cases. As a consequence of this combined variation, the fractional turnover rate (which represents the percentage of cells produced per unit time) was the parameter with the highest increment (54-276%). These results indicate that plasma cell recruitment occurs soon after chemotherapy and is characterized by a shorter S phase and a higher number of DNA-synthesizing cells.     

Phenotypic and Genotypic Characterisation of Burkholderia cenocepacia J2315 Mutants Affected in Homoserine Lactone and Diffusible Signal Factor-Based Quorum Sensing Systems Suggests Interplay between Both Types of Systems

Many putative virulence factors of Burkholderia cenocepacia are controlled by various quorum sensing (QS) circuits. These QS systems either use N-acyl homoserine lactones (AHL) or cis-2-dodecenoic acid (“Burkholderia diffusible signal factor”, BDSF) as signalling molecules. Previous work suggested that there is little cross-talk between both types of systems. We constructed mutants in B. cenocepacia strain J2315, in which genes encoding CepI (BCAM1870), CciI (BCAM0239a) and the BDSF synthase (BCAM0581) were inactivated, and also constructed double (ΔcepIΔBCAM0581, ΔcciIΔBCAM0581 and ΔcepIΔcciI) mutants and a triple (ΔcepIΔcciIΔBCAM0581) mutant. Subsequently we investigated phenotypic properties (antibiotic susceptibility, biofilm formation, production of AHL and BDSF, protease activity and virulence in Caenorhabditis elegans) and measured gene expression in these mutants, and this in the presence and absence of added BDSF, AHL or both. The triple mutant was significantly more affected in biofilm formation, antimicrobial susceptibility, virulence in C. elegans, and protease production than either the single or double mutants. The ΔBCAM0581 mutant and the ΔcepIΔBCAM0581 and ΔcciIΔBCAM0581 double mutants produced significantly less AHL compared to the WT strain and the ΔcepI and ΔcciI single mutant, respectively. The expression of cepI and cciI in ΔBCAM0581, was approximately 3-fold and 7-fold (p<0.05) lower than in the WT, respectively. The observed differences in AHL production, expression of cepI and cciI and QS-controlled phenotypes in the ΔBCAM0581 mutant could (at least partially) be restored by addition of BDSF. Our data suggest that, in B. cenocepacia J2315, AHL and BDSF-based QS systems co-regulate the same set of genes, regulate different sets of genes that are involved in the same phenotypes and/or that the BDSF system controls the AHL-based QS system. As the expression of the gene encoding the C6-HSL synthase CciI (and to a lesser extent the C8-HSL synthase CepI) is partially controlled by BDSF, it seems likely that the BDSF QS systems controls AHL production through this system.     

Lower Rate of Cardiovascular Complications in Patients on Bolus Insulin Analogues: A Retrospective Population-Based Cohort Study

Background

Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.

Methods

A population-based cohort study was conducted using administrative data from four local health authorities in the Abruzzo Region (900,000 inhabitants). Diabetic patients free of macrovascular disease at baseline and treated either with human regular insulin or rapid-acting insulin analogues were followed for a maximum of 3 years. The incidence of diabetic complications was ascertained by hospital discharge claims. Hazard ratios (HRs) and 95% CIs of any diabetic complication and macrovascular, microvascular and metabolic complications were estimated separately using Cox proportional hazard models adjusted for patients’ characteristics and anti-diabetic drug use. Propensity score matching was also used to adjust for significant difference in the baseline characteristics between the two treatment groups.

Results

A total of 2,286 patients were included: 914 receiving human regular insulin and 1,372 rapid-acting insulin analogues. During the follow-up, 286 (31.3%) incident events occurred in the human regular insulin group and 235 (17.1%) in the rapid-acting insulin analogue group. After propensity score-based matched-pair analyses, rapid-acting insulin analogues users had a HR of 0.73 (0.58–0.92) for any diabetes-related complication and HRs of 0.73 (0.55–0.93) and 0.55 (0.32–0.96) for macrovascular and metabolic complications respectively, as compared with human regular insulin users. No difference between the two groups was found for microvascular complications.

Conclusions

Our findings suggest that the use of rapid-acting insulin analogues is associated with a lower risk of cardiovascular and metabolic complications compared with human regular insulin use.     

Genetic diversity patterns in Curcuma reflect differences in genome size

The relationships between genome size and the systematic and evolutionary patterns in vascular plants are equivocal, although a close relationship between genome size and evolutionary patterns has been previously reported. However, several studies have also revealed the dynamic nature of genome size evolution and its considerable ‘ups’ and ‘downs’. Thus, in this study, the phylogenetic relationships among three previously revealed genome size groups and among species of the highly polyploid genus Curcuma were evaluated using AFLP. Our results suggest two main lineages within Indian Curcuma reflecting evolution of genome size. The first one includes hexaploids and higher polyploids of the previously recognized genome size group I, and the second one includes mainly hexaploids of genome size groups II and III. Within genome size group I, relationships among species seem to be influenced by reticulate evolution and higher polyploids are likely to be of allopolyploid origin. Reproductive systems in Indian Curcuma vary considerably among ploidy levels and these differences considerably affect morphological and genetic variation. In general, clonally reproducing species are expected to exhibit low genotypic diversity, but, at the same time, species of allopolyploid origin are expected to maintain higher levels of heterozygosity compared with their progenitors. We investigated intra‐populational genetic variability in Curcuma spp. to evaluate whether mode of reproduction or ploidy represent the main factor influencing the degree of genetic diversity. We found that hexaploid species exhibited significantly higher genetic diversity than higher polyploids (9x, 15x). Our results suggest that this genetic diversity pattern is largely influenced by the mode of reproduction, as higher polyploids reproduce exclusively vegetatively, whereas hexaploids reproduce mainly sexually. © 2011 The Linnean Society of London, Botanical Journal of the Linnean Society, 2011, 165 , 388–401.