The scavenger receptor MARCO mediates cytoskeleton rearrangements in dendritic cells and microglia

Macrophage receptor with collagenous structure (MARCO) is a scavenger receptor expressed in peritoneal macrophages and in a subpopulation of macrophages in the marginal zone of the spleen and in the medullary cord of lymph nodes. By global gene expression analysis, it has been found that the MARCO mRNA was one of the most up-regulated in splenic dendritic cells (DCs) following lipopolysaccharide or bacterial activation and in granulocyte-macrophage colony-stimulating factor (GM-CSF)-treated microglial cells. Here we show that MARCO is expressed on splenic DCs at late time points after activation and that its expression correlates with profound changes in actin cytoskeleton organization in DCs and microglia. During maturation, DCs undergo profound rearrangements of actin cytoskeleton. Immature DCs are adherent with visible actin cables, while fully mature, MARCO-expressing, splenic DCs are nonadherent, round in shape, and have an actin cytoskeleton with a punctate distribution. The simple expression of MARCO was sufficient to induce these cytoskeleton modifications in DCs. MARCO-transfected immature DCs acquired a typical morphology of mature DCs and did not rearrange the actin cytoskeleton following activation. Moreover, DCs in which MARCO was knocked down did not reach the mature phenotype and maintained the typical morphology of transitional DCs. MARCO expression in DCs and microglial cells was also associated with a decrease of antigen internalization capacity. Thus, the MARCO receptor is important for actin cytoskeleton rearrangements and the down-regulation of antigen uptake function during DC and microglial cell maturation.     

Decreased differentiation of erythroid cells exacerbates ineffective erythropoiesis in beta-thalassemia

In β-thalassemia, the mechanism driving ineffective erythropoiesis (IE) is insufficiently understood. We analyzed mice affected by β-thalassemia and observed, unexpectedly, a relatively small increase in apoptosis of their erythroid cells compared with healthy mice. Therefore, we sought to determine whether IE could also be characterized by limited erythroid cell differentiation. In thalassemic mice, we observed that a greater than normal percentage of erythroid cells was in S-phase, exhibiting an erythroblast-like morphology. Thalassemic cells were associated with expression of cell cycle–promoting genes such as EpoR, Jak2, Cyclin-A, Cdk2, and Ki-67 and the antiapoptotic protein Bcl-X_L. The cells also differentiated less than normal erythroid ones in vitro. To investigate whether Jak2 could be responsible for the limited cell differentiation, we administered a Jak2 inhibitor, TG101209, to healthy and thalassemic mice. Exposure to TG101209 dramatically decreased the spleen size but also affected anemia. Although our data do not exclude a role for apoptosis in IE, we propose that expansion of the erythroid pool followed by limited cell differentiation exacerbates IE in thalassemia. In addition, these results suggest that use of Jak2 inhibitors has the potential to profoundly change the management of this disorder.     

Dopamine-induced migrating myoelectrical complex-like activity in human duodenum

The effect of dopamine on human gastric and small intestinal interdigestive motility was investigated in 12 subjects. Intestinal motility was recorded by means of a four-lumen polyvinyl probe with four open tips located 15 cm apart, continuously perfused with distilled water. In each subject during the same study, after recording two consecutive spontaneous phase III of migrating myoelectrical complexes and when a phase II appeared, dopamine was infused intravenously twice in a dose of 5 g/kg/min for 15 min with an interval of 20 min between each infusion. In six subjects, the second dopamine infusion was preceded by a treatment with sulpiride (10 mg, intravenously, as bolus) or domperidone (10 mg, intravenously, as bolus), each considered a highly selective dopamine antagonist. The results show that dopamine stimulates duodenal motility producing a pattern similar to that observed in phase III of spontaneously occurring migrating myoelectrical complexes. The second dopamine infusion reproduced in all cases the same pattern of motility as observed during the first infusion. Sulpiride and domperidone prevented the effect of dopamine in all cases. It is therefore suggested that dopamine-induced duodenal motility may involve specific dopaminergic receptors.     

Interventricular delay interval optimization in cardiac resynchronization therapy guided by echocardiography versus guided by electrocardiographic QRS interval width

Present devices for cardiac resynchronization therapy offer the possibility of tailoring the hemodynamic effect of biventricular pacing by optimization of the interventricular delay (VV) beyond atrioventricular (AV)-interval optimization. It was not yet defined whether a QRS width-based strategy may be a helpful tool for echocardiography for device programming. The aim of the study was to investigate the relation between VV-interval optimization guided by echocardiography and guided by QRS interval width. One hundred six patients with a cardiac resynchronization therapy device for > or =3 months were enrolled. All patients underwent echocardiographic AV and VV delay optimization. The AV interval was optimized according to the E wave-A wave (EA) interval and left ventricular filling time. At the optimal AV delay, VV optimization was performed by measuring the aortic velocity time integral at 5 different settings: simultaneous right and left ventricle output, left ventricle pre-excitation (left ventricle + 40 and 80 ms, respectively), and right ventricle pre-excitation (right ventricle + 40 and 80 ms, respectively). A 12-lead electrocardiogram was recorded and QRS duration was measured in the lead with the greatest QRS width. The electrocardiographic (ECG)-optimized VV interval was defined according to the narrowest achievable QRS interval among 5 VV intervals. The echocardiographic-optimized VV interval was left ventricle + 40 ms in 28 patients, left ventricle + 80 ms in 15 patients, simultaneous in 46 patients, right ventricle + 40 ms in 14 patients, and right ventricle + 80 ms in 3 patients. Significant concordance (kappa = 0.69, p <0.001) was found between the echocardiographic- and ECG-optimized VV interval. In conclusion, significant concordance appeared to exist during biventricular pacing between VV programming based on the shortest QRS interval at 12-lead ECG pacing and echocardiographic-guided VV-interval optimization. A combined ECG- and echocardiographic approach could be a less time-consuming solution in performing this operation.     

Clinical impact of direct referral to primary percutaneous coronary intervention following pre-hospital diagnosis of ST-elevation myocardial infarction.

AIMS: Treatment delay is a powerful predictor of survival in ST-elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI). We investigated effectiveness of pre-hospital diagnosis of STEMI with direct referral to PCI, alongside more conventional referral strategies. METHODS AND RESULTS: From January 2003 to December 2004, 658 STEMI patients were referred for primary PCI at our intervention laboratory. Three predefined referral routes were compared: (1) for patients within 90 min drive of the PCI centre, pre-hospital diagnosis and direct transportation (n=166), (2) diagnosis at the interventional hospital emergency department (n=316), (3) diagnosis at local hospitals before transportation (n = 176). Pre-hospital diagnosis was associated with more than 45 min reduction in treatment delay (P = 0.001). No significant difference in in-hospital mortality was apparent in the overall study population. In the cardiogenic shock subgroup (n = 80), pre-hospital diagnosis was associated with a two-thirds reduction in in-hospital mortality (P = 0.019); mortality was only 6.2% in shock patients who underwent PCI in < 2 h. CONCLUSION: This study shows that pre-hospital diagnosis can provide a reduction in primary PCI treatment delay, and suggests the hypothesis that this referral strategy might provide survival benefits to patients with cardiogenic shock.     

Mesenteric Cyst with GI Symptoms: A Fluid Approach to Treatment—Case Report and Literature Review

Digestive Diseases and Sciences - Mesenteric cysts are defined as a heterogeneous group of intra-abdominal cystic lesions of the mesentery or omentum that may be found in any portion of the...     

Expanding the mutational spectrum of LZTR1 in schwannomatosis

Schwannomatosis is characterized by the development of multiple non-vestibular, non-intradermal schwannomas. Constitutional inactivating variants in two genes, SMARCB1 and, very recently, LZTR1, have been reported. We performed exome sequencing of 13 schwannomatosis patients from 11 families without SMARCB1 deleterious variants. We identified four individuals with heterozygous loss-of-function variants in LZTR1. Sequencing of the germline of 60 additional patients identified 18 additional heterozygous variants in LZTR1. We identified LZTR1 variants in 43% and 30% of familial (three of the seven families) and sporadic patients, respectively. In addition, we tested LZTR1 protein immunostaining in 22 tumors from nine unrelated patients with and without LZTR1 deleterious variants. Tumors from individuals with LZTR1 variants lost the protein expression in at least a subset of tumor cells, consistent with a tumor suppressor mechanism. In conclusion, our study demonstrates that molecular analysis of LZTR1 may contribute to the molecular characterization of schwannomatosis patients, in addition to NF2 mutational analysis and the detection of chromosome 22 losses in tumor tissue. It will be especially useful in differentiating schwannomatosis from mosaic Neurofibromatosis type 2 (NF2). However, the role of LZTR1 in the pathogenesis of schwannomatosis needs further elucidation.