Recent advances in diagnosis and treatment of chronic myeloproliferative neoplasms

The Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPNs) have recently been the focus of tremendous advances in basic knowledge of disease pathophysiology following the recognition of mutations in JAK2 and MPL. These discoveries also led to refinement of the criteria employed for diagnosis. The prognostic roles of the JAK2 V617F mutation and of leukocytosis as independent risk factors for thrombosis, which represents the leading cause of death in patients with polycythemia vera and essential thrombocythemia, are supported by retrospective studies. A new risk stratification approach to the patient with primary myelofibrosis allows clinicians to distinguish categories of patients with significantly different expected survival. Finally, new drugs are currently being tested for MPNs, and molecular discoveries could ultimately lead to the development of a specific targeted therapy. Overall, significant advances in diagnosis, prognostication, and treatment have taken place in the last couple of years in the field of MPNs

Chronic Myeloproliferative Neoplasms: a Collaborative Approach

The classic chronic myeloproliferative neoplasms (MPN) include different entities that pose significant challenges for their optimal diagnosis, treatment and overall management. Polycythemia Vera and Essential Thrombocythemia are the most common among chronic myeloproliferative neoplasms (MPNs); major causes of morbidity and mortality are represented by arterial and venous thrombosis, as well as evolution to myelofibrosis or transformation to acute leukemia. However, survival is only minimally affected. Therapy aims at reducing the rate of thrombosis without increasing the risk of hematologic transformation which could be caused by exposure to cytotoxic drugs. On the other hand, survival is significantly reduced in primary myelofibrosis, and the clinical manifestations may be disabling. In the absence of therapies with the potential of curing the disease, a careful risk-oriented approach is employed for stratifying patients to the most appropriate, currently available, therapeutic options. In this brief review, we will discuss some of the key issues that can arise along the clinical course of MPNs and require an integrated, strictly patient-oriented, approach

Role of cholinergic neurons in the motor effects of glucagon-like peptide-2 in mouse colon.

Glucagon-like peptide-2 (GLP-2) reduces mouse gastric tone and small intestine transit, but its action on large intestine motility is still unknown. The purposes of the present study were 1) to examine the influence of GLP-2 on spontaneous mechanical activity and on neurally evoked responses, by recording intraluminal pressure from mouse isolated colonic segments; 2) to characterize GLP-2 mechanism of action; and 3) to determine the distribution of GLP-2 receptor (GLP-2R) in the mouse colonic muscle coat by immunohistochemistry. Exogenous GLP-2 (0.1\u2013 300 nM) induced a concentration-dependent reduction of the spontaneous mechanical activity, which was abolished by the desensitization of GLP-2 receptor or by tetrodotoxin, a voltage-dependent Na+-channel blocker. GLP-2 inhibitory effect was not affected by Nomega-nitro-L-arginine methyl ester (a nitric oxide synthase inhibitor), apamin (a blocker of small conductance Ca2+-dependent K+ channels), or [Lys1,Pro2,5,Arg3,4,Tyr6]VIP7\u201328 (a VIP receptor antagonist), but it was prevented by atropine or pertussis toxin (PTX), a Gi/o protein inhibitor. Proximal colon responses to electrical field stimulation were characterized by nitrergic relaxation, which was followed by cholinergic contraction. GLP-2 reduced only the cholinergic evoked contractions. This effect was almost abolished by GLP-2 receptor desensitization or PTX. GLP-2 failed to affect the contractile responses to exogenous carbachol. GLP-2R immunoreactivity (IR) was detected only in the neuronal cells of both plexuses of the colonic muscle coat. More than 50% of myenteric GLP-2R-IR neurons shared the choline acetyltransferase IR. In conclusion, the activation of GLP-2R located on cholinergic neurons may modulate negatively the colonic spontaneous and electrically evoked contractions through inhibition of acetylcholine release. The effect is mediated by Gi protein

Shared and Distinctive Ultrastructural Abnormalities Expressed by Megakaryocytes in Bone Marrow and Spleen From Patients With Myelofibrosis

Numerous studies have documented ultrastructural abnormalities in malignant megakaryocytes from bone marrow (BM) of myelofibrosis patients but the morphology of these cells in spleen, an important extramedullary site in this disease, was not investigated as yet. By transmission-electron microscopy, we compared the ultrastructural features of megakaryocytes from BM and spleen of myelofibrosis patients and healthy controls. The number of megakaryocytes was markedly increased in both BM and spleen. However, while most of BM megakaryocytes are immature, those from spleen appear mature with well-developed demarcation membrane systems (DMS) and platelet territories and are surrounded by platelets. In BM megakaryocytes, paucity of DMS is associated with plasma (thick with protrusions) and nuclear (dilated with large pores) membrane abnormalities and presence of numerous glycosomes, suggesting a skewed metabolism toward insoluble polyglucosan accumulation. By contrast, the membranes of the megakaryocytes from the spleen were normal but these cells show mitochondria with reduced crests, suggesting deficient aerobic energy-metabolism. These distinctive morphological features suggest that malignant megakaryocytes from BM and spleen express distinctive metabolic impairments that may play different roles in the pathogenesis of myelofibrosis

Symbolic verification of event–condition–action rules in intelligent environments

In this paper we show how state-of-the art SMT-based techniques for software verification can be employed in the verification of event–condition–action rules in intelligent environments. Moreover, we exploit the specific features of intelligent environments to optimise the verification process. We compare our approach with previous work in a detailed evaluation section, showing how it improves both performance and expressivity of the language for event–condition–action rules

Late Cenozoic tephrostratigraphy offshore the southern Central American Volcanic Arc: 2. Implications for magma production rates and subduction erosion

Pacific drill sites offshore Central America provide the unique opportunity to study the evolution of large explosive volcanism and the geotectonic evolution of the continental margin back into the Neogene. The temporal distribution of tephra layers established by tephrochonostratigraphy in Part 1 indicates a nearly continuous highly explosive eruption record for the Costa Rican and the Nicaraguan volcanic arc within the last 8 M.y. The widely distributed marine tephra layers comprise the major fraction of the respective erupted tephra volumes and masses thus providing insights into regional and temporal variations of large-magnitude explosive eruptions along the southern Central American Volcanic Arc (CAVA). We observe three pulses of enhanced explosive magmatism between 0-1 Ma at the Cordillera Central, between 1-2 Ma at the Guanacaste and at >3 Ma at the Western Nicaragua segments. Averaged over the long-term the minimum erupted magma flux (per unit arc length) is ∼0.017 g/ms. Tephra ages, constrained by Ar-Ar dating and by correlation with dated terrestrial tephras, yield time-variable accumulation rates of the intercalated pelagic sediments with four prominent phases of peak sedimentation rates that relate to tectonic processes of subduction erosion. The peak rate at >2.3 Ma near Osa particularly relates to initial Cocos Ridge subduction which began at 2.91±0.23 Ma as inferred by the 1.5 M.y. delayed appearance of the OIB geochemical signal in tephras from Barva volcano at 1.42 Ma. Subsequent tectonic re-arrangements probably involved crustal extension on the Guanacaste segment that favored the 2-1 Ma period of unusually massive rhyolite production

Ophiolites from the Grammos-Arrenes area, northern Greece:geological, paleontological and geochemical data

The Grammos-Arrenes ophiolites between the Pindos Flysch to the east and the Mesohellenic basin to the west represent the northernmost outcrop of the Pindos Ophiolite belt in Greece. The analyses on key outcrops of the Sub-ophiolitic Mélange allow adding new data on the age of the oceanization and on the geochemistry of the effusive products. Basalts samples show a N-MOR affinity and are associated with late Bajocian-early Bathonian radiolarian cherts. The emplacement of the ophiolites onto the sequences of the continental margin is preceded by mass flow deposition of ophiolitic material in the basins facing the advancing ophiolitic nappe. Ophiolite-bearing debris flow deposits and slide blocks are recognized in the Lower Cretaceous deep water sediments of the Beotian Unit and in the upper portion of the Tertiary Pindos Flysch. The intercalations of ophiolitic material in the Beotian flysch before, and in the Pindos Flysch later, are interpreted as the forerunners of the Ophiolitic Nappe which, coming from the Vardar Ocean located to the east, emplaced westward onto the continental margin of Adria. The collected data allow consolidating the constraints for the timing and mechanism of ophiolite emplacement in the Pindos-Grammos area. In addition, taking in consideration the geometry of tectonic stack in the Grammos-Arrenes and the ages of the involved sedimentary deposits it is possible to reconstruct a geodynamic history comparable to the other zones studied along the Dinaric-Hellenic chain