IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms

Myeloproliferative neoplasms (MPNs) are characterized by the clonal expansion of one or more myeloid cell lineage. In most cases, proliferation of the malignant clone is ascribed to defined genetic alterations. MPNs are also associated with aberrant expression and activity of multiple cytokines; however, the mechanisms by which these cytokines contribute to disease pathogenesis are poorly understood. Here, we reveal a non-redundant role for steady-state IL-33 in supporting dysregulated myelopoiesis in a murine model of MPN. Genetic ablation of the IL-33 signaling pathway was sufficient and necessary to restore normal hematopoiesis and abrogate MPN-like disease in animals lacking the inositol phosphatase SHIP. Stromal cell–derived IL-33 stimulated the secretion of cytokines and growth factors by myeloid and non-hematopoietic cells of the BM, resulting in myeloproliferation in SHIP-deficient animals. Additionally, in the transgenic JAK2^V617F model, the onset of MPN was delayed in animals lacking IL-33 in radio-resistant cells. In human BM, we detected increased numbers of IL-33–expressing cells, specifically in biopsies from MPN patients. Exogenous IL-33 promoted cytokine production and colony formation by primary CD34⁺ MPN stem/progenitor cells from patients. Moreover, IL-33 improved the survival of JAK2^V617F-positive cell lines. Together, these data indicate a central role for IL-33 signaling in the pathogenesis of MPNs.     

Lipid-dependent control of hepatic glycogen stores in healthy humans

Aims/hypothesis. Non-esterified fatty acids and glycerol could stimulate gluconeogenesis and also contribute to regulating hepatic glycogen stores. We examined their effect on liver glycogen breakdown in humans.¶Methods. After an overnight fast healthy subjects participated in three protocols with lipid/heparin (plasma non-esterified fatty acids: 2.2 ± 0.1 mol/l; plasma glycerol: 0.5 ± 0.03 mol/l; n = 7), glycerol (0.4 ± 0.1 mol/l; 1.5 ± 0.2 mol/l; n = 5) and saline infusion (control; 0.5 ± 0.1 mol/l; 0.2 ± 0.02 mol/l; n = 7). Net rates of glycogen breakdown were calculated from the decrease of liver glycogen within 9 h using ¹³C nuclear magnetic resonance spectroscopy. Endogenous glucose production was measured with infusion of D-[6,6-²H₂]glucose.¶Results. Endogenous glucose production decreased by about 25 % during lipid and saline infusion (p < 0.005) but not during glycerol infusion (p < 0.001 vs lipid, saline). An increase of plasma non-esterified fatty acids or glycerol reduced the net glycogen breakdown by about 84 % to 0.6 ± 0.3 μmol · kg^–1· min^–1 (p < 0.001 vs saline: 3.7 ± 0.5 μmol · kg^–1· min^–1) and by about 46 % to 2.0 ± 0.4 μmol · kg^–1· min^–1 (p < 0.01 vs saline and lipid), respectively. Rates of gluconeogenesis increased to 11.5 ± 0.8 μmol · kg^–1· min^–1 (p < 0.01) and 12.8 ± 1.0 μmol · kg^–1· min^–1 (p < 0.01 vs saline: 8.2 ± 0.7 μmol · l^–1· min^–1), respectively.¶Conclusion/interpretation: An increase of non-esterified fatty acid leads to a pronounced inhibition of net hepatic glycogen breakdown and increases gluconeogenesis whereas glucose production does not differ from the control condition. We suggest that this effect is not due to increased availability of glycerol alone but rather to lipid-dependent control of hepatic glycogen stores. [Diabetologia (2001) 44: 48–54]     

Expression of a human T-cell protein-tyrosine-phosphatase in baby hamster kidney cells.

A human T-cell cDNA encoding a 48-kDa protein-tyrosine-phosphatase (PTPase; protein-tyrosine-phosphate phosphohydrolase, EC 3.1.3.48) was cloned into a mammalian expression vector and introduced into baby hamster kidney cells, and stable colonies were isolated. The expressed PTPase was found to be associated with the particulate fraction of the cells, where it was essentially inactive in an in vitro assay unless first subjected to limited trypsinization; trypsin treatment generated an active fragment of 33 kDa by the removal of a carboxyl-terminal segment of the full-length enzyme. Gel filtration indicated that the expressed enzyme was associated with a complex of greater than 600 kDa. Introduction of a premature stop codon into the T-cell cDNA at position 1012 resulted in the production of a fully active 37-kDa species that distributed between both the particulate and soluble fractions. The truncated form of the enzyme was readily solubilized by detergents and was eluted within its predicted molecular mass range. These results suggest that the carboxyl-terminal segment is important in determining the localization and regulation of the PTPase. The level of protein-tyrosine phosphorylation observed after 5 min of platelet-derived growth factor stimulation was reduced in cells overexpressing either form of the phosphatase, indicating that both are active in vivo. Overexpressing the truncated enzyme resulted in a growth rate that was approximately 50% of that observed in cells transfected with either the full-length PTPase cDNA or the vector alone.     

Visual attention and the acquisition of information in human crowds

Pedestrian crowds can form the substrate of important socially contagious behaviors, including propagation of visual attention, violence, opinions, and emotional state. However, relating individual to collective behavior is often difficult, and quantitative studies have largely used laboratory experimentation. We present two studies in which we tracked the motion and head direction of 3,325 pedestrians in natural crowds to quantify the extent, influence, and context dependence of socially transmitted visual attention. In our first study, we instructed stimulus groups of confederates within a crowd to gaze up to a single point atop of a building. Analysis of passersby shows that visual attention spreads unevenly in space and that the probability of pedestrians adopting this behavior increases as a function of stimulus group size before saturating for larger groups. We develop a model that predicts that this gaze response will lead to the transfer of visual attention between crowd members, but it is not sufficiently strong to produce a tipping point or critical mass of gaze-following that has previously been predicted for crowd dynamics. A second experiment, in which passersby were presented with two stimulus confederates performing suspicious/irregular activity, supports the predictions of our model. This experiment reveals that visual interactions between pedestrians occur primarily within a 2-m range and that gaze-copying, although relatively weak, can facilitate response to relevant stimuli. Although the above aspects of gaze-following response are reproduced robustly between experimental setups, the overall tendency to respond to a stimulus is dependent on spatial features, social context, and sex of the passerby.     

The Torg-Pavlov ratio for the prediction of acute spinal cord injury after a minor trauma to the cervical spine

Background contextAcute cervical spinal cord injury (SCI) has been observed in some patients after a minor trauma to the cervical spine. The discrepancy between the severity of the trauma and the clinical symptoms has been attributed to spinal canal stenosis. However, to date, there is no universally established radiological parameter for identifying critical spinal stenosis in these patients. The spinal canal–to–vertebral body ratio (Torg-Pavlov ratio) has been proposed for assessing developmental spinal canal stenosis. The relevance of the Torg-Pavlov ratio for predicting the occurrence and severity of acute cervical SCI after a minor trauma to the cervical spine has not yet been established.PurposeTo investigate the Torg-Pavlov ratio values of the cervical spine in patients suffering from acute cervical SCI after a minor trauma to the cervical spine and the use of the Torg-Pavlov ratio for identifying patients at risk of cervical SCI and predicting the severity and course of symptoms.Study design/settingRetrospective radiological study of consecutive patients.Patient sampleForty-five patients suffering from acute cervical SCI and 68 patients showing no neurologic symptoms after a minor trauma to the cervical spine.Outcome measuresMidvertebral sagittal cervical spinal canal diameter and the sagittal vertebral body diameter. Calculation of the Torg-Pavlov ratio values.MethodsConventional lateral radiographs of the cervical spine (C3–C7) were analyzed to determine the Torg-Pavlov ratio values. Receiver operating characteristic curves were calculated for evaluating the classification accuracy of the Torg-Pavlov ratio for predicting SCI.ResultsThe Torg-Pavlov ratio values in the SCI group were significantly (p<.04) smaller compared with that in the control group. A Torg-Pavlov ratio cutoff value of 0.7 yielded the greatest positive likelihood ratio for predicting the occurrence of SCI. However, there were no significant differences in the Torg-Pavlov ratio values between the different American Spinal Injury Association Impairment Score groups and between patients with complete, partial, and no recovery of symptoms.ConclusionsDevelopmental cervical spinal canal stenosis assessed by the Torg-Pavlov ratio was characteristic for patients suffering from acute cervical SCI after a minor trauma to the cervical spine. Patients at risk of SCI after a minor trauma to the cervical spine can be identified by applying a Torg-Pavlov ratio cutoff value of 0.7. Other factors in addition to the spinal canal–to–vertebral body ratio affect the severity and course of symptoms as a result of cervical SCI.