Painful constipation: a neglected entity?

Functional chronic constipation is a common symptom in daily clinical practice. Although the definition of constipation may be variable, there is usually agreement that (at least for research purposes) the definition given by the Rome Committee are useful. However, some blind spots or hidden angles remain, even in the more thorough classifications; among these, there is painful constipation, a poorly defined yet clinically encountered entity. The present article reviews the current knowledge about painful constipation, trying to put together the scarce data available, and to frame it in the more general context of chronic constipation

Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity

Multiple myeloma (MM) cells induce relevant angiogenic effects within the human bone marrow milieu (huBMM) by the aberrant expression of angiogenic factors. Hypoxia triggers angiogenic events within the huBMM and the transcription factor hypoxia-inducible factor-1α (HIF-1α) is over-expressed by MM cells. Since synthetic miR-199a-5p mimics negatively regulates HIF-1α, we here investigated a miRNA-based therapeutic strategy against hypoxic MM cells. We indeed found that enforced expression of miR-199a-5p led to down-modulated expression of HIF-1α as well as of other pro-angiogenic factors such as VEGF-A, IL-8, and FGFb in hypoxic MM cells in vitro. Moreover, miR-199a-5p negatively affected MM cells migration, while it increased the adhesion of MM cells to bone marrow stromal cells (BMSCs) in hypoxic conditions. Furthermore, transfection of MM cells with miR-199a-5p significantly impaired also endothelial cells migration and down-regulated the expression of endothelial adhesion molecules such as VCAM-1 and ICAM-1. Finally, we identified a hypoxia\AKT/miR-199a-5p loop as a potential molecular mechanism responsible of miR-199a-5p down-regulation in hypoxic MM cells. Taken together our results indicate that miR-199a-5p has an important role for the pathogenesis of MM and support the hypothesis that targeting angiogenesis via a miRNA/HIF-1α pathway may represent a novel potential therapeutical approach for this still lethal diseas

miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1

MicroRNAs (miRNAs) with tumor-suppressor potential might have therapeutic applications in multiple myeloma (MM) through the modulation of still undiscovered molecular pathways. Here, we investigated the effects of enforced expression of miR-29b on the apoptotic occurrence in MM and highlighted its role in the context of a new transcriptional loop that is finely tuned by the proteasome inhibitor bortezomib. In details, in vitro growth inhibition and apoptosis of MM cells was induced by either transient expression of synthetic miR-29b or its stable lentivirus-enforced expression. We identified Sp1, a transcription factor endowed with oncogenic activity, as a negative regulator of miR-29b expression in MM cells. Since Sp1 expression and functions are regulated via the 26S proteasome, we investigated the effects of bortezomib on miR-29b-Sp1 loop, showing that miR-29b levels were indeed upregulated by the drug. At the same time, the bortezomib/miR-29b combination produced significant pro-apoptotic effects. We also demonstrated that the PI3K/AKT pathway plays a major role in the regulation of miR-29b-Sp1 loop and induction of apoptosis in MM cells. Finally, MM xenografts constitutively expressing miR-29b showed significant reduction of their tumorigenic potential. Our findings indicate that miR-29b is involved in a regulatory loop amenable of pharmacologic intervention and modulates the anti-MM activity of bortezomib in MM cells

Effect of weathering on the compressibility and shear strength of a natural clay

In situ, seasonal changes expose soils to frequent wetting–drying–freezing–thawing cycles. Such processes can favour and trigger shallow instabilities controlled by the weathering process. This paper presents an experimental study carried out to investigate the effects of the weathering process, caused by the wetting–drying–freezing–thawing cycles, on the compressibility and shear strength of a natural clay. Several specimens were trimmed from block samples of overconsolidated clays taken from a slope in south Calabria, Italy. Specimens were subjected to wetting– drying–freezing–thawing cycles of different durations and then tested with standard equipment (oedometer and direct shear). Test results show that the wetting–drying–freezing–thawing cycles caused a change in the initial microstructure that produced a decrease in the compression index and an increase in the swelling index. Moreover, the direct shear test results show a decrease in the peak shear strength and demonstrate that a larger reduction occurs in the first month of weathering cycles. The intense cycles performed in the laboratory produced a decay of compressibility and a shear strength approaching reconstituted values. The conclusions are important when choosing the shear strength parameters required when studying shallow landsliding in clay slopes

Influence of degradation cycles on the mechanical characteristics of natural clays.

On low depths, soils are exposed seasonally to frequent wetting-drying and freezing-thawing cycles; the degradation effects of these cycles are more pronounced in clayey soils. The number of cycles is due to periods of rainfall and variations in air temperature. Such processes can trigger shallow instability essentially controlled by the physical weathering of soils. An experimental study was carried out to investigate how the physical weathering, reproduced by laboratory wetting-drying and freezing-thawing cycles, affects the mechanical behaviour of natural clays in the superficial layers. For this purpose block samples of Pliocene clays were taken from a slope in Southern Calabria (Italy). They are overconsolidated stiff clays which can be classified as to high plasticity clays (CH). Different specimens were trimmed from the block samples and they were subjected to different numbers of wetting-drying-freezing-thawing cycles and then tested in oedometer and direct shear tests. Results of oedometer and direct shear tests seem to show that the physical weathering has caused a degradation of the bonding due to an insufficient ability to resist this cyclic process. The variations of peak shear strength are pronounced in the first month then they may be regarded as essentially constant. The wetting-drying-freezing-thawing cycles also cause a decrease in compression index and an increase of swelling inde