Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
S-nitrosohemoglobin deficiency: a mechanism for loss of physiological activity in banked blood.
RBCs distribute oxygen to tissues, but, paradoxically, blood transfusion does not always improve oxygen delivery and is associated with ischemic events. We hypothesized that storage of blood would result in loss of NO bioactivity, impairing RBC vasodilation and thus compromising blood flow, and that repleting NO bioactivity would restore RBC function. ⋯ In addition, canine coronary blood flow was greater during infusion of renitrosylated RBCs than during infusion of S-nitrosothiol-depleted RBCs, and this difference in coronary flow was accentuated by hypoxemia (P < 0.001). Our findings indicate that NO bioactivity is depleted in banked blood, impairing the vasodilatory response to hypoxia, and they suggest that SNO-Hb repletion may improve transfusion efficacy.
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Recent studies have underscored questions about the balance of risk and benefit of RBC transfusion. A better understanding of the nature and timing of molecular and functional changes in stored RBCs may provide strategies to improve the balance of benefit and risk of RBC transfusion. We analyzed changes occurring during RBC storage focusing on RBC deformability, RBC-dependent vasoregulatory function, and S-nitrosohemoglobin (SNO-Hb), through which hemoglobin (Hb) O(2) desaturation is coupled to regional increases in blood flow in vivo (hypoxic vasodilation). ⋯ RBC deformability assayed at a physiological shear stress decreased gradually over the 42-day period (P < 0.001). Time courses vary for several storage-induced defects that might account for recent observations linking blood transfusion with adverse outcomes. Of clinical concern is that SNO levels, and their physiological correlate, RBC-dependent vasodilation, become depressed soon after collection, suggesting that even "fresh" blood may have developed adverse biological characteristics.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Inhibition of 5-HT neuron activity and induction of depressive-like behavior by high-frequency stimulation of the subthalamic nucleus.
Bilateral, high-frequency stimulation (HFS) of the subthalamic nucleus (STN) is the surgical therapy of choice for movement disability in advanced Parkinson's disease (PD), but this procedure evokes debilitating psychiatric effects, including depressed mood, of unknown neural origin. Here, we report the unexpected finding that HFS of the STN inhibits midbrain 5-hydroxytryptamine (5-HT) neurons to evoke depression-related behavioral changes. We found that bilateral HFS of the STN consistently inhibited (40-50%) the firing rate of 5-HT neurons in the dorsal raphe nucleus of the rat, but not neighboring non-5-HT neurons. ⋯ Importantly, the depressive-like behavior elicited by HFS of the STN was reversed by a selective 5-HT-enhancing antidepressant, thereby linking the behavioral change to decreased 5-HT neuronal activity. Overall, these findings link reduced 5-HT function to the psychiatric effects of HFS of the STN observed in PD patients and provide a rational basis for their clinical management. More generally, the powerful interaction between the STN and 5-HT system uncovered here offers insights into the high level of comorbidity of basal ganglia disease and mood disorder.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Hypertension and dysregulated proinflammatory cytokine production in receptor activity-modifying protein 1-deficient mice.
Calcitonin gene-related peptide (CGRP) is thought to be a prominent neuropeptide in cardiovascular regulation and neuroimmune modulation. There are two isoforms of CGRP (alphaCGRP and betaCGRP), and the main CGRP receptors are probably composed of a calcitonin receptor-like receptor (CLR) and a receptor activity-modifying protein (RAMP)1. However, the physiological functions of CGRP that are mediated through the CLR/RAMP1 receptors remain to be clarified. ⋯ The LPS-induced inflammatory responses of the RAMP1(-/-) mice revealed a transient and significant increase in the serum CGRP levels and high serum levels of proinflammatory cytokines compared with the RAMP1(+/+) mice. alphaCGRP and betaCGRP equally suppressed the production of TNF-alpha and IL-12 in bone marrow-derived dendritic cells stimulated with lipopolysaccharide. Their inhibitory effects were not observed in the bone marrow-derived dendritic cells of the RAMP1(-/-) mice. These results indicate that CGRP signaling through CLR/RAMP1 receptors plays a crucial role in the regulation of both blood pressure by vascular relaxation and proinflammatory cytokine production from dendritic cells.
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Proc. Natl. Acad. Sci. U.S.A. · Oct 2007
Case ReportsImpaired familiarity with preserved recollection after anterior temporal-lobe resection that spares the hippocampus.
It is well established that the medial-temporal lobe (MTL) is critical for recognition memory. The MTL is known to be composed of distinct structures that are organized in a hierarchical manner. At present, it remains controversial whether lower structures in this hierarchy, such as perirhinal cortex, support memory functions that are distinct from those of higher structures, in particular the hippocampus. ⋯ Her resection included a large portion of perirhinal cortex but spared the hippocampus. The results of four experiments based on three different experimental procedures (remember-know paradigm, receiver operating characteristics, and response-deadline procedure) indicate that NB exhibits impaired familiarity with preserved recollection. The present findings thus provide a crucial missing piece of support for functional specialization in the MTL.