Chromosome 20 deletions in myelodysplastic syndromes and Philadelphia-chromosome-negative myeloproliferative disorders: characterization by molecular cytogenetics of commonly deleted and retained regions

Deletion of the long arm of chromosome 20 is a recurrent abnormality observed in myelodysplastic syndromes (MDS) and in Philadelphia-chromosome-negative myeloproliferative disorders (MPD). Our objective was to characterize the deletion size among 38 MDS and MPD patients using fluorescence in situ hybridization (FISH) with bacterial artificial chromosome (BAC) probes and to define commonly deleted and retained regions on chromosome 20. Patients were distributed in three groups according to the World Health Organization classification: MDS (22 patients), MPD (12 patients) and myelodysplastic/myeloproliferative diseases (four patients). FISH with centromeric, subtelomeric, and unique sequence probes was performed to characterize the deletion whereas its size was delineated using BAC clones. All 38 deletions were found to be interstitial. A commonly deleted region was identified for each of the three groups; it varied from 6.62 to 10.4 Mb and showed considerable overlapping. Two commonly retained regions (CRR), also showing overlapping, were identified in all three groups, one in the centromeric region, the other in the telomeric region. The deletion size is highly variable, with no apparent recurrent breakpoint. The deletion may result in the loss of one or several tumor suppressor genes but the target genes remain unknown. Loss of genes plays an important part in the myeloid leukemic process associated with del(20q). However, genes located in the retained chromosomal regions may also play a role in the oncogenetic mechanisms. Nathalie Douet-Guilbert and Audrey Basinko contributed equally to the study.     

Rabies exposure in international travelers: do we miss the target?

BackgroundLittle data exist about the spatial distribution of the risk for travelers of being injured by a potentially rabid animal.MethodsOver the last 14 years, animal-associated injuries in 424 international travelers presenting to a travel medicine clinic in Marseille, southern France, were investigated.ResultsThe majority of cases were reported from North Africa (41.5%) and Asia (22.2%). Most countries where at-risk injuries occurred (Algeria, Morocco, Tunisia, Thailand, and Turkey) were those for which travelers do not usually seek advice at a specialized travel clinic, because these countries are not at risk for specific travel-associated diseases like malaria or yellow fever. The probability of travelers being attacked by each animal species varied significantly according to the destination country. Dogs were more frequently involved in Algeria, cats in Tunisia and the Middle East, and non-human primates in sub-Saharan Africa, Madagascar, and Asia.ConclusionsWe suggest that rabies pre-exposure vaccination should be offered to individuals traveling regularly to North Africa to visit their relatives and who are at high risk of exposure to potentially rabid animal attacks. Pre-travel advice when addressing rabies prevention should consider the specific epidemiology of animal-related injuries in the traveled country, as well as the traveler's characteristics. Travelers should be advised about which species of animal are potentially aggressive in their destination country so that they can more easily avoid risk-contacts.     

Active Wnt signaling in response to cardiac injury

Although the contribution of Wnt signaling in infarct healing is suggested, its exact role after myocardial infarction (MI) still needs to be unraveled. We evaluated the cardiac presence of active Wnt signaling in vivo following MI, and investigated in which cell types active Wnt signaling was present by determining Axin2 promoter-driven LacZ expression. C57BL/6 Axin2-LacZ reporter mice were sacrificed at days 0, 1, 3, 7, 14, and 21 after LAD ligation. Hearts were snap-frozen for immunohistochemistry (IHC) or enzymatically digested to obtain a single cell suspension for flow cytometric analysis. For both FACS and IHC, samples were stained for β-galactosidase and antibodies against Sca-1, CD31, ckit, and CD45. Active Wnt signaling increased markedly in the myocardium, from 7 days post-MI onwards. Using Sca-1 and CD31, to identify progenitor and endothelial cells, a significant increase in LacZ+ cells was found at 7 and 14 days post-MI. LacZ+ cells also increased in the ckit+ and CD45+ cell population. IHC revealed LacZ+ cells co-expressing Sca, CD31, CD45, vWF, and αSMA in the border zone and the infarcted area. Wnt signaling increased significantly after MI in Sca+- and CD31+-expressing cells, suggesting involvement of Wnt signaling in resident Sca+ progenitor cells, as well as endothelial cells. Moreover, active Wnt signaling was present in ckit+ cells, leukocytes, and fibroblast. Given its broad role during the healing phase after cardiac injury, additional research seems warranted before a therapeutic approach on Wnt to enhance cardiac regeneration can be carried out safely.     

Interleukin-1beta induces phosphodiesterase 4B2 expression in human myometrial cells through a prostaglandin E2- and cyclic adenosine 3',5'-monophosphate-dependent pathway

Intrauterine infections are important etiological factors of preterm labor. They trigger an increase in proinflammatory cytokines, in particular IL-1beta, that induces a cascade of events resulting in the production of potent effectors of myometrial contractility, such as the prostaglandin E(2) (PGE(2)). Within the smooth muscle cells, contractility is under the control of cAMP content, partly regulated by cAMP-phosphodiesterase 4 (PDE4), the predominant family of PDEs expressed in human myometrium. In the present study, using a model of inflammation of human myometrial cells in culture, we demonstrated that exposing the cells to IL-1beta resulted in a significant up-regulation of PDE4 activity through an increase in PDE4B2 mRNA and protein levels. The IL-1beta-induced PDE4 activity occurs after an increase in PGE(2) production and subsequent cAMP augmentation. Pretreatment with indomethacin or NS 398 completely blocked this long-term effect of IL-1beta, revealing a PGE(2)-dependent pathway. Accordingly, our results demonstrated that the PDE4B2 variant can participate in the regulation of the inflammatory reaction that occurs at term or in preterm labor and leads to myometrial contractions. Knowing the myorelaxant effect of PDE4 inhibitors and the implication of the PDE4B2 in the inflammatory process, this isoform may be an appropriate target for discovering antiinflammatory drugs to manage infection-induced preterm deliveries.     

Long-term complete haematological and molecular remission after allogeneic bone marrow transplantation in a patient with a stem cell myeloproliferative disorder associated with t(8;13)(p12;q12)

A rare atypical myeloproliferative disorder (aMPD) associated with chromosomal translocations involving the short arm of chromosome 8, region p11-p12 has been described. In most patients, the cytogenetic abnormality is a t(8;13)(p12;q12) that fuses fibroblast growth factor receptor 1, the 8p12 key gene, to FIM/ZNF198 gene. Prognosis is poor with frequent evolution to acute myeloid leukaemia within 1 year of diagnosis. We report a new patient with aMPD with a t(8;13) translocation. Complete haematological, cytogenetic and molecular remission was demonstrated 39 months after allogeneic bone marrow transplantation. This is the first report to demonstrate a molecular remission in this disorder.     

The Artificial Pancreas on the Threshold of Ambulatory Use: Setting the Stage for a Critical Transition: DiAs Web Monitoring: A Real-Time Remote Monitoring System Designed for Artificial Pancreas Outpatient Trials

Background

Developments in an artificial pancreas (AP) for patients with type 1 diabetes have allowed a move toward performing outpatient clinical trials. “Home-like” environment implies specific protocol and system adaptations among which the introduction of remote monitoring is meaningful. We present a novel tool allowing multiple patients to monitor AP use in home-like settings.

Methods

We investigated existing systems, performed interviews of experienced clinical teams, listed required features, and drew several mockups of the user interface. The resulting application was tested on the bench before it was used in three outpatient studies representing 3480 h of remote monitoring.

Results

Our tool, called DiAs Web Monitoring (DWM), is a web-based application that ensures reception, storage, and display of data sent by AP systems. Continuous glucose monitoring (CGM) and insulin delivery data are presented in a colored chart to facilitate reading and interpretation. Several subjects can be monitored simultaneously on the same screen, and alerts are triggered to help detect events such as hypoglycemia or CGM failures. In the third trial, DWM received approximately 460 data per subject per hour: 77% for log messages, 5% for CGM data. More than 97% of transmissions were achieved in less than 5 min.

Conclusions

Transition from a hospital setting to home-like conditions requires specific AP supervision to which remote monitoring systems can contribute valuably. DiAs Web Monitoring worked properly when tested in our outpatient studies. It could facilitate subject monitoring and even accelerate medical and technical assessment of the AP. It should now be adapted for long-term studies with an enhanced notification feature.J Diabetes Sci Technol 2013;7(6):1427–1435     

Etiopathogenic and clinical aspects of asymmetry

Complex dysmorphies, asymmetries can affect the various elements of the stomatognathic system: cranial base, maxilla, mandible, musculature and dental arches, in the three dimensions of space. Their etiopathogenesis, as well as their clinical forms, vary considerably. Dysembryopathies, growth disorders, TMJ damages, postural or functional disorders and dental anomalies can create, according to their severity and their moment of appearance, severe or minor facial asymmetries, or asymmetries of the arches. An exo- and endobuccal clinical examination endeavors to specify the localization and the severity of the damage, and to evaluate the importance of the possible alveolar compensations. Consolidated by additional examinations, it enables the clinician to differentiate the various forms of asymmetries.