Kozaburo Akiyoshi

Regulatory B Cells Limit CNS Inflammation and Neurologic Deficits in Murine Experimental Stroke

Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion (MCAO) strongly implicates a mixture of both pathogenic and regulatory immune cell subsets in stroke pathogenesis and recovery. Our goal was to evaluate the contribution of B cells to the development of MCAO by comparing infarct volumes and functional outcomes in wild-type (WT) versus B-cell-deficient μMT−/− mice. The results clearly demonstrate larger infarct volumes, higher mortality, more severe functional deficits, and increased numbers of activated T cells, macrophages, microglial cells, and neutrophils in the affected brain hemisphere of MCAO-treated μMT−/− versus WT mice. These MCAO-induced changes were completely prevented in B-cell-restored μMT−/− mice after transfer of highly purified WT GFP+ B cells that were detected in the periphery, but not the CNS. In contrast, transfer of B cells from IL-10−/− mice had no effect on infarct volume when transferred into μMT−/− mice. These findings strongly support a previously unrecognized activity of IL-10-secreting WT B cells to limit infarct volume, mortality rate, recruitment of inflammatory cells, and functional neurological deficits 48 h after MCAO. Our novel observations are the first to implicate IL-10-secreting B cells as a major regulatory cell type in stroke and suggest that enhancement of regulatory B cells might have application as a novel therapy for this devastating neurologic condition.

CD4+FoxP3+ regulatory T-cells in cerebral ischemic stroke.

Experimental cerebral ischemic stroke is exacerbated by inflammatory T-cells and is accompanied by systemic increases in CD4+CD25+Foxp3+ regulatory T-cells (Treg). To determine their effect on ischemic brain injury, Treg were depleted in Foxp3DTR mice prior to stroke induction. In contrast to a recent Nature Medicine report, our results demonstrate unequivocally that Treg depletion did not affect stroke infarct volume, thus failing to implicate this regulatory pathway in limiting stroke damage.

Estradiol and G1 Reduce Infarct Size and Improve Immunosuppression after Experimental Stroke

Reduced risk and severity of stroke in adult females is thought to depend on normal endogenous levels of estrogen, a well-known neuroprotectant and immunomodulator. In male mice, experimental stroke induces immunosuppression of the peripheral immune system, characterized by a reduction in spleen size and cell numbers and decreased cytokine and chemokine expression. However, stroke-induced immunosuppression has not been evaluated in female mice. To test the hypothesis that estradiol (E2) deficiency exacerbates immunosuppression after focal stroke in females, we evaluated the effect of middle cerebral artery occlusion on infarct size and peripheral and CNS immune responses in ovariectomized mice with or without sustained, controlled levels of 17-β–E2 administered by s.c. implant or the putative membrane estrogen receptor agonist, G1. Both E2- and G1-replacement decreased infarct volume and partially restored splenocyte numbers. Moreover, E2-replacement increased splenocyte proliferation in response to stimulation with anti-CD3/CD28 Abs and normalized aberrant mRNA expression for cytokines, chemokines, and chemokine receptors and percentage of CD4+CD25+FoxP3+ T regulatory cells observed in E2-deficient animals. These beneficial changes in peripheral immunity after E2 replacement were accompanied by a profound reduction in expression of the chemokine, MIP-2, and a 40-fold increased expression of CCR7 in the lesioned brain hemisphere. These results demonstrate for the first time that E2 replacement in ovariectomized female mice improves stroke-induced peripheral immunosuppression.

Programmed Death-1 Pathway Limits Central Nervous System Inflammation and Neurologic Deficits in Murine Experimental Stroke

Background and Purpose— Evaluation of infarct volumes and infiltrating immune cell populations in mice after middle cerebral artery occlusion strongly implicates a mixture of both pathogenic and regulatory immune cell subsets that affect stroke outcome. Our goal was to evaluate the contribution of the well-described coinhibitory pathway, programmed death (PD)-1, to the development of middle cerebral artery occlusion. Methods— Infarct volumes, functional outcomes, and effects on infiltrating immune cell populations were compared in wild-type C57BL/6 versus PD-1-deficient mice after 60 minutes middle cerebral artery occlusion and 96 hours reperfusion. Results— The results clearly demonstrate a previously unrecognized activity of the PD-1 pathway to limit infarct volume, recruitment of inflammatory cells from the periphery, activation of macrophages and central nervous system microglia, and functional neurological deficits. These regulatory functions were associated with increased percentages of circulating PD-ligand-1 and PD-ligand-2 expressing CD19+ B-cells in blood, the spleen, and central nervous system with the capacity to inhibit activation of inflammatory T-cells and central nervous system macrophages and microglial cells through upregulated PD-1. Conclusions— Our novel observations are the first to implicate PD-1 signaling as a major protective pathway for limiting central nervous system inflammation in middle cerebral artery occlusion. This inhibitory circuit would likely be pivotal in reducing stroke-associated Toll-like receptor-2- and Toll like receptor-4-mediated release of neurotoxic factors by activated central nervous system microglia.

Performance evaluation of a new pulse oximeter during mild hypothermic cardiopulmonary bypass.

UNLABELLED Newly developed pulse oximeters (POs) are designed to display accurate SpO(2) during motion and hypoperfusion. We compared the performance of a new PO, the Masimo SET Radical (M), with a conventional PO, the Nihon Kohden AY-900P (N), during hypothermic cardiopulmonary bypass. Eighteen patients were studied prospectively. PO failure was defined as failure to show no SpO(2) value or show incorrect SpO(2) values for longer than 3 min continuously. PO failure occurred in 4 and 14 patients with M and N, respectively (P = 0.0022). All 4 patients in whom PO failure developed with M were among the 14 patients with N. No SpO(2) was provided for 4% +/- 12% of the duration of aorta cross-clamping with M and 36% +/- 39% with N (P = 0.002). Skin temperature and mean arterial blood pressure when PO failure started to occur and ended were similar between M and N. PO failure easily developed in patients with preoperative diuretic therapy or with intraoperative hyperlactatemia in N, but not in M. M was able to display accurate SpO(2) values significantly more frequently and longer than N during mild hypothermic cardiopulmonary bypass with nonpulsatile flow, suggesting that M is more useful for monitoring SpO(2) during hypoperfusion. IMPLICATIONS We compared the performance of a new pulse oximeter with that of a conventional pulse oximeter during hypothermic cardiopulmonary bypass with nonpulsatile flow. The newly developed device displayed accurate SpO(2) significantly more frequently and longer than a conventional oximeter. Newly developed pulse oximeters seem to be more useful for monitoring SpO(2) during hypoperfusion.

Effects of olprinone, a new phosphodiesterase inhibitor, on gastric intramucosal acidosis and systemic inflammatory responses following hypothermic cardiopulmonary bypass

Background: Phosphodiesterase (PDE) III inhibitors have both an inotropic and a peripheral vasodilatory effect, and also inhibit the activation of macrophages. Thus a newly developed PDE III inhibitor, olprinone, could modify gastric intramucosal pH (pHi), systemic oxygen consumption, and systemic inflammatory responses in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB).

Role of dihydrotestosterone in post-stroke peripheral immunosuppression after cerebral ischemia

Stroke is a sexually dimorphic disease with male gender considered a disadvantage in terms of risk and disease outcome. In intact males, stroke induces peripheral immunosuppression, characterized by decreased splenocyte numbers and proliferation and altered percentages of viable T, B, and CD11b+ cells. To investigate whether the potent androgen and known immunomodulator, dihydrotestosterone (DHT), exacerbates post-stroke immunosuppression in castrated male mice after focal stroke, we evaluated the effect of middle cerebral artery occlusion (MCAO) on peripheral and central nervous system (CNS) immune responses in castrated mice with or without controlled levels of DHT. MCAO reduced spleen cell numbers in both groups, but altered T cell and B cell percentages in remaining splenocytes and concomitantly increased the percentage of CD11b+ blood cells solely in DHT-replaced animals at 24 h. Furthermore, DHT-replacement reduced splenocyte proliferation which was accompanied by an increased percentage of immunosuppressive regulatory T cells relative to castrates 96 h post-MCAO. In brain, the percentages of immune cell populations in the ischemic hemisphere relative to the non-ischemic hemisphere were similar between castrated and DHT-replaced mice after MCAO. These data suggest DHT modulates peripheral immunosuppression after MCAO but with relatively little effect on early immune response of the recovering CNS.

Changes in left ventricular end-diastolic area, end-systolic wall stress, and fractional area change during anesthetic induction with propofol or thiamylal

AbstractPurpose. To elucidate the mechanisms of the more profound hypotensive effects of propofol relative to thiamylal, we monitored changes in left ventricular (LV) preload, afterload, and contractility during the course of anesthetic induction with propofol and thiamylal. Methods. Thirty-two patients (ASA I) were randomly assigned into two groups and injected with propofol (2 mg·kg−1) or thiamylal (4 mg·kg−1) as anesthetic induction agents. Transthoracic echocardiography (TTE) was used to assess LV performance before and during induction by the two anesthetics. The LV end-diastolic area (EDA) and LV end-systolic wall stress (ESWS) were used as indices of LV preload and LV afterload, respectively, while LV contractility was assessed by the fractional area change (FAC). Results. Both propofol and thiamylal significantly reduced EDA and ESWS without significant change in FAC. Propofol-induced reductions in EDA and ESWS were significantly greater than those of thiamylal. Conclusion. The more profound hypotension observed during induction of anesthesia with propofol is due to the greater decrease in preload and afterload than with thiamylal, but not to a decrease in LV contractility.

Esophageal Submucosal Hematoma Possibly Caused by Gastric Tube Insertion Under General Anesthesia

We present a case of an esophageal submucosal hematoma that developed after endovascular treatment for coil embolization for an unruptured cerebral aneurysm. The patient had received antiplatelet therapy before surgery and anticoagulation therapy during surgery. The orogastric tube was removed at case end with sustained negative pressure. After surgery, the patient reported chest and back pain and was diagnosed with an esophageal submucosal hematoma. The hematoma might have been related to the gastric tube insertion or removal. Providers should keep in mind the possibility of this complication when a patient who was given antithrombotic therapy reports chest or back pain after surgery.