Lung crackles, either alone or combined with peripheral edema, very poorly reflect interstitial lung edema in patients with ESRD. These findings reinforce the rationale underlying the Lung Water by Ultra-Sound Guided Treatment to Prevent Death and Cardiovascular Complications in High Risk ESRD Patients with Cardiomyopathy Trial, a trial adopting ultrasound B lines as an instrument to guide interventions aimed at mitigating lung congestion in high-risk patients on hemodialysis.

IntroductionNaive B cells are poor antigen-presenting cells (APC) for naive T cells. In many systems, they have been dispensable for CD4 ϩ T-cell priming. 1,2 Yet antigen presentation by naive B cells is not an immunologic null event. Animals can be rendered tolerant toward antigens presented by naive B cells. 3 Indeed, evidence suggests that B cells can take part in antigen presentation via major histocompatibility complex (MHC) II molecules 4-7 and might even be required to reach full T-cell effector potential. 8 We have previously shown that naive B cells, despite low efficiency on a per cell basis, when loaded with specific peptide antigen can induce antigen-specific proliferation in naive T cells. 9 However, the biophysics of the underlying T-B contact was very different from bona fide T-cell activation by dendritic cells (DCs). 10 While T-cell contacts to DCs were dynamic and sequential, contacts to B cells were mostly very stable in vitro and in vivo. 9,11 The functional significance of this discrepancy is not clear.Information transfer between T cell and APC during cell-cell interaction is characterized by the formation of a supramolecular assembly of signaling and adhesion molecules termed immunologic synapse (IS). 12 Its exact function is still debated yet it is generally accepted as a T-cell activating structure. 13,14,14 A mature IS presents with a distinguished central part of the supramolecular activation cluster (c-SMAC) enriched in signaling molecules like T-cell receptor (TCR) and MHC, and a peripheral part (p-SMAC) enriched in adhesion molecules. 15 The formation of a mature IS takes between 30 to 60 minutes. 12 Encounters between DCs and T cells in early and late phases of immune responses, however, last only for several minutes. 16,17 This is too short to form a mature IS. In contrast, antigen-specific contacts to naive B cells invariably last several hours. 9 It is unclear whether a mature synapse can form under these circumstances.Based on these arguments, we reasoned that the molecular organization of the IS between T cells and naive B cells might be different from the one found in T-DC pairs. We also wanted to test the potential consequences for the resulting activated CD4 ϩ T cells. To further evaluate the outcome of antigen-specific CD4 ϩ T-cell stimulation by naive B cells, we investigated the molecular structure of the underlying IS and the phenotype of CD4 ϩ T cells after in vitro contact with specific-antigen loaded naive B cells or DCs.We present evidence that stimulation of naive T cells by naive B cells results in formation of a mature IS which is absent in DC-T-cell pairs. In addition, while DC stimulation generates classical effector T cells, naive B-cell-activated T cells show regulatory capacity in vitro and in vivo. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by gue...

Macrophages adopt different phenotypes in response to microenvironmental changes, which can be principally classified into inflammatory and anti-inflammatory states. Inflammatory activation of macrophages has been linked with metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis. In contrast to mouse macrophages, little information is available on the link between metabolism and inflammation in human macrophages. In the current report it is demonstrated that lipopolysaccharide (LPS)-activated human peripheral blood monocyte-derived macrophages (hMDMs) fail to undergo metabolic reprogramming towards glycolysis, but rely on oxidative phosphorylation for the generation of ATP. By contrast, activation by LPS led to an increased extracellular acidification rate (glycolysis) and decreased oxygen consumption rate (oxidative phosphorylation) in mouse bone marrow-derived macrophages (mBMDMs). Mitochondrial bioenergetics after LPS stimulation in human macrophages was unchanged, but was markedly impaired in mouse macrophages. Furthermore, treatment with 2-deoxyglucose, an inhibitor of glycolysis, led to cell death in mouse, but not in human macrophages. Finally, glycolysis appeared to be critical for LPS-mediated induction of the anti-inflammatory cytokine interleukin-10 in both human and mouse macrophages. In summary, these findings indicate that LPS-induced immunometabolism in human macrophages is different to that observed in mouse macrophages.

Activation of protein kinase C (PKC) isoforms has been implicated in the pathogenesis of diabetic nephropathy. We showed earlier that PKC-␣ is activated in the kidneys of hyperglycemic animals. We now used PKC-␣ ؊/؊ mice to test the hypothesis that this PKC isoform mediates streptozotocin-induced diabetic nephropathy. We observed that renal and glomerular hypertrophy was similar in diabetic wild-type and PKC-␣ ؊/؊ mice. However, the development of albuminuria was almost absent in the diabetic PKC-␣ ؊/؊ mice. The hyperglycemia-induced downregulation of the negatively charged basement membrane heparan sulfate proteoglycan perlecan was completely prevented in the PKC-␣ ؊/؊ mice, compared with controls. We then asked whether transforming growth factor-␤1 (TGF-␤ 1 ) and/or vascular endothelial growth factor (VEGF) is implicated in the PKC-␣-mediated changes in the basement membrane. The hyperglycemia-induced expression of VEGF165 and its receptor VEGF receptor II (flk-1) was ameliorated in PKC-␣ ؊/؊ mice, whereas expression of TGF-␤ 1 was not affected by the lack of PKC-␣. Our findings indicate that two important features of diabetic nephropathy-glomerular hypertrophy and albuminuria-are differentially regulated. The glucose-induced albuminuria seems to be mediated by PKC-␣ via downregulation of proteoglycans in the basement membrane and regulation of VEGF expression. Therefore, PKC-␣ is a possible therapeutic target for the prevention of diabetic albuminuria.

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