Validity of the Central Sensitization Inventory (CSI) through Rasch analysis in patients with knee osteoarthritis

Clinical Rheumatology - Central sensitization (CS) is a known contributor to chronic pain in people with knee osteoarthritis (KOA) and is commonly measured by psychophysical testing or...     

ICOS is required for the generation of both central and effector CD4+ memory T‐cell populations following acute bacterial infection

Interactions between ICOS and ICOS ligand (ICOSL) are essential for the development of T follicular helper (Tfh) cells and thus the formation and maintenance of GC reactions. Given the conflicting reports on the requirement of other CD4⁺ T‐cell populations for ICOS signals, we have employed a range of in vivo approaches to dissect requirements for ICOS signals in mice during an endogenous CD4⁺ T‐cell response and contrasted this with CD28 signals. Genetic absence of ICOSL only modestly reduced the total number of antigen‐specific CD4⁺ T cells at the peak of the primary response, but resulted in a severely diminished number of both T central memory and T effector memory cells. Treatment with blocking anti‐ICOS mAb during the primary response recapitulated these effects and caused a more substantial reduction than blocking CD28 signals with CTLA4Ig. During the memory phase of the response further signals through ICOS or CD28 were not required for survival. However, upon secondary challenge only Tfh cell expansion remained heavily ICOS‐dependent, while CD28 signals were required for optimal expansion of all subsets. These data demonstrate the importance of ICOS signals specifically for memory CD4⁺ T‐cell formation, while highlighting the potential of therapeutically targeting this pathway.     

Supporting hemodynamics: what should we target? What treatments should we use?

Assessment and monitoring of hemodynamics is a cornerstone in critically ill patients as hemodynamic alteration may become life-threatening in a few minutes. Defining normal values in critically ill patients is not easy, because 'normality' is usually referred to healthy subjects at rest. Defining 'adequate' hemodynamics is easier, which embeds whatever pressure and flow set is sufficient to maintain the aerobic metabolism. We will refer to the unifying hypothesis proposed by Schrier several years ago. Accordingly, the alteration of three independent variables - heart (contractility and rate), vascular tone and intravascular volume - may lead to underfilling of the arterial tree, associated with reduced (as during myocardial infarction or hemorrhage) or expanded (sepsis or cirrhosis) plasma volume. The underfilling is sensed by the arterial baroreceptors, which activate primarily the sympathetic nervous system and renin-angiotensin-aldosterone system, as well as vasopressin, to restore the arterial filling by increasing the vascular tone and retaining sodium and water. Under 'normal' conditions, therefore, the homeostatic system is not activated and water/sodium excretion, heart rate and oxygen extraction are in the range found in normal subjects. When arterial underfilling occurs, the mechanisms are activated (sodium and water retention) - associated with low central venous oxygen saturation (ScvO₂) if underfilling is caused by low flow/hypovolemia, or with normal/high ScvO₂ if associated with high flow/hypervolemia. Although the correction of hemodynamics should be towards the correction of the independent determinants, the usual therapy performed is volume infusion. An accepted target is ScvO₂ >70%, although this ignores the arterial underfilling associated with volume expansion/high flow. For large-volume resuscitation the worst solution is normal saline solution (chloride load, strong ion difference = 0, acidosis). To avoid changes in acid-base equilibrium the strong ion difference of the infused solution should be equal to the baseline bicarbonate concentration.     

S6K1 regulates hematopoietic stem cell self-renewal and leukemia maintenance

Hyperactivation of the mTOR pathway impairs hematopoietic stem cell (HSC) functions and promotes leukemogenesis. mTORC1 and mTORC2 differentially control normal and leukemic stem cell functions. mTORC1 regulates p70 ribosomal protein S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E–binding (eIF4E-binding) protein 1 (4E-BP1), and mTORC2 modulates AKT activation. Given the extensive crosstalk that occurs between mTORC1 and mTORC2 signaling pathways, we assessed the role of the mTORC1 substrate S6K1 in the regulation of both normal HSC functions and in leukemogenesis driven by the mixed lineage leukemia (MLL) fusion oncogene MLL-AF9. We demonstrated that S6K1 deficiency impairs self-renewal of murine HSCs by reducing p21 expression. Loss of S6K1 also improved survival in mice transplanted with MLL-AF9–positive leukemic stem cells by modulating AKT and 4E-BP1 phosphorylation. Taken together, these results suggest that S6K1 acts through multiple targets of the mTOR pathway to promote self-renewal and leukemia progression. Given the recent interest in S6K1 as a potential therapeutic target in cancer, our results further support targeting this molecule as a potential strategy for treatment of myeloid malignancies.