Resting Rates of Blood Flow and Glucose Use per Neuron Are Proportional to Number of Endothelial Cells Available per Neuron Across Sites in the Rat Brain.

We report in a companion paper that in the mouse brain, in contrast to the 1,000-fold variation in local neuronal densities across sites, capillary density (measured both as capillary volume fraction and as density of endothelial cells) show very little variation, of the order of only fourfold. Here we confirm that finding in the rat brain and, using published rates of local blood flow and glucose use at rest, proceed to show that what small variation exists in capillary density across sites in the rat brain is strongly and linearly correlated to variations in local rates of brain metabolism at rest. Crucially, we show that such variations in local capillary density and brain metabolism are not correlated with local variations in neuronal density, which contradicts expectations that use-dependent self-organization would cause brain sites with more neurons to have higher capillary densities due to higher energetic demands. In fact, we show that the ratio of endothelial cells per neuron serves as a linear indicator of average blood flow and glucose use per neuron at rest, and both increase as neuronal density decreases across sites. In other words, because of the relatively tiny variation in capillary densities compared to the large variation in neuronal densities, the anatomical infrastructure of the brain is such that those sites with fewer neurons have more energy supplied per neuron, which matches a higher average rate of energy use per neuron, compared to sites with more neurons. Taken together, our data support the interpretation that resting brain metabolism is not demand-based, but rather limited by its capillary supply, and raise multiple implications for the differential vulnerability of diverse brain areas to disease and aging.

Slip-Ups in the Diagnosis of Cardiac Amyloidosis: A Case Fatality in Point.

This case report illustrates a tragic example of a "missed diagnosis" of amyloid light-chain (AL) amyloidosis with cardiac involvement that led to progressive heart failure and the ultimate death of the patient. It had a rather atypical presentation in terms of cardiac imaging, although there were certain highly suspicious clinical features, cardiac and otherwise. It also illustrates the importance of selecting the most appropriate assays to establish (or rule out) the presence of monoclonal immunoglobulin consistent with AL amyloidosis, which has a poor clinical prognosis, as unfortunately demonstrated in this case.

Post Heart Transplantation Outcomes of Patients Supported on Biventricular Mechanical Support.

With the implementation of the new heart transplant (HT) allocation system, patients requiring biventricular support systems have the highest priority, a shorter waitlist time, and a higher frequency of HT. However, the short-term and long-term outcomes of such patients are often disputed. Hence, we examined the outcomes of these patients who underwent HT before change in allocation scheme. Additionally, we compared post-HT outcomes of extracorporeal membrane oxygenation (ECMO) with other nondischargeable biventricular (BiVAD) supported patients. We identified adult ECMO or BiVAD supported HT recipients between 2000 and 2018 in the Scientific Registry of Transplant Recipients database. We compared survival with the Kaplan-Meier method. Using overlap propensity score weighting, we constructed Cox proportional hazards regression models to determine the risk-adjusted influence of BiVAD versus ECMO on survival. Of the 730 patients HT recipients; 528 (72.3%) and 202 (27.7%) were bridged with BiVAD and ECMO, respectively. For BiVAD versus ECMO patients, the 30-day, 1-year, 3-year, and 5-year mortality rates were 8.0% versus 14.4%, 16.3% versus 21.3%, 22.4% versus 25.3%, and 26.3% versus 25.7%, respectively. Risk-adjusted post-HT survival of BiVAD and ECMO patients at 30-day (HR 1.24 [95% CI, 0.68-2.27]; P = 0.4863), 1-year (HR 1.29 [95% CI, 0.80-2.09]; P = 0.3009), 3-year (HR 1.27 [95% CI, 0.83-1.94]; P = 0.2801), and 5-year (HR 1.35, 95% CI, 0.90-2.05; P = 0.1501) were similar. Around three-fourth of the ECMO or BiVAD supported patients were alive at 5-years post-HT. The short-term and long-term post-HT survivals of groups were comparable.

Cell-intrinsic sphingosine kinase 2 promotes macrophage polarization and renal inflammation in response to unilateral ureteral obstruction.

Sphingosine Kinase-2 (Sphk2) is responsible for the production of the bioactive lipid Sphingosine-1 Phosphate, a key regulator of tissue repair. Here we address the in vivo significance of Sphingosine Kinase -2 in renal inflammation/fibrosis in response to unilateral ureteral obstruction using both genetic and pharmacological strategies. Obstructed kidneys of Sphk2-/- mice showed reduced renal damage and diminished levels of the renal injury markers TGFß1 and αSMA when compared to wild type controls. We found a consistently significant increase in anti-inflammatory (M2) macrophages in obstructed Sphk2-/- kidneys by flow cytometry and a decrease in mRNA levels of the inflammatory cytokines, MCP1, TNFα, CXCL1 and ILß1, suggesting an anti-inflammatory bias in the absence of Sphk2. Indeed, metabolic profiling showed that the pro-inflammatory glycolytic pathway is largely inactive in Sphk2-/- bone marrow-derived macrophages. Furthermore, treatment with the M2-promoting cytokines IL-4 or IL-13 demonstrated that macrophages lacking Sphk2 polarized more efficiently to the M2 phenotype than wild type cells. Bone marrow transplant studies indicated that expression of Sphk2-/- on either the hematopoietic or parenchymal cells did not fully rescue the pro-healing phenotype, confirming that both infiltrating M2-macrophages and the kidney microenvironment contribute to the damaging Sphk2 effects. Importantly, obstructed kidneys from mice treated with an Sphk2 inhibitor recapitulated findings in the genetic model. These results demonstrate that reducing Sphk2 activity by genetic or pharmacological manipulation markedly decreases inflammatory and fibrotic responses to obstruction, resulting in diminished renal injury and supporting Sphk2 as a novel driver of the pro-inflammatory macrophage phenotype.