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Study Design: Multiple center study to evaluate cerebrospinal fluid (CSF) concentrations of nitric oxide metabolites [NOx] in relation to neurologic severity and prognosis in spinal cord injury (SCI)., Objective: To examine whether CSF [NOx] correlates with neurologic severity and recovery in SCI., Summary of Background Data: Inducible nitric oxide synthase is expressed in rat spinal cord immediately after SCI. Excessive nitric oxide production is cytotoxic, causing neuronal apoptosis with subsequent neurodysfunction in the spinal cord. We previously reported a significant correlation between initial [NOx] after incomplete cervical cord injury (CCI) and neurologic recovery at the final follow-up in 25 cases., Methods: Ninety-six cases (SCI group), including 76 patients with CCI and 20 patients with thoracic cord injury were examined. Mean follow-up period was 11 months. The control group comprised 40 cases (3 healthy volunteers and 37 patients with neither pain nor neurologic disorders). CSF [NOx] were measured using the Griess method. Severity of neurologic impairment was assessed using Frankel's classification and the American Spinal Injury Association motor score (ASIA MS). Degree of neurologic recovery was assessed using Frankel's classification and the ASIA motor recovery percentage., Results: CSF [NOx] did not differ significantly among the control, CCI, and thoracic cord injury groups at the initial examination. In the CCI group, [NOx] in the Frankel A and B classes were significantly higher than [NOx] in the control group at 5 to 14 days, in the Frankel A and B classes at 0 to 4 days, and in the Frankel C and D classes at 5 to 14 days. Also, in the CCI group at 5 to 14 days, [NOx] correlated significantly with ASIA MS and motor recovery percentage., Conclusion: There was a significant correlation between CSF [NOx] at the pathologic early subacute stage (approximately 5-14 days) and neurologic severity and recovery in SCI.

Background: The prevalence of HIV-associated neurocognitive disorders is increasing as HIV-infected individuals are living longer. The clinical manifestations of the syndrome also continue to evolve under the influence of antiretroviral drugs and comorbidities such as drugs of abuse. However, there are no surrogate markers for the disease, either to identify it de novo or to track its progression, and there is no proven treatment with the exception of antiretroviral drugs., Methods: Levels of nitric oxide, nitrate, and 3-nitrotyrosine (3-NT)-modified proteins were measured in the CSF of 46 patients with HIV infection stratified according to their neurocognitive status and history of IV drug use (IVD). The 3-NT-modified proteins were isolated and identified by tandem mass spectrometry, and the functional consequence of 3-NT modification of L-prostaglandin D synthase (L-PGDS), the most abundant protein, was determined., Results: 3-NT-modified proteins were significantly elevated in patients with HIV infection who had progressive neurocognitive decline over the next 6 months and in patients with a history of IVD. Thirteen different proteins with 3-NT modification were identified in the CSF of these patients. L-PGDS was the most abundant. 3-NT modification of this protein resulted in loss of its enzymatic activity., Conclusions: There is increased nitrosative stress in CSF of HIV-infected patients with active dementia and in patients with a history of IV drug use, measurement of which may serve as a surrogate marker for these patients. Nitrosative stress may also have important functional consequences and may impact the pathogenesis of HIV-associated neurocognitive disorders.

We investigated the time course of changes in nitric oxide metabolite (NO2- plus NO3-: NOx) levels in the cerebrospinal fluid and the expression of local inducible nitric oxide synthase following cauda equina compression in rats. Cerebrospinal fluid NOx levels were significantly increased from 12 h to 3 days after compression, and decreased thereafter. Histologically, inducible nitric oxide synthase immunoreactivity was observed in macrophages that infiltrated the dura mater on days 1 and 3 after compression, but not in foamy macrophages in the parenchyma of the cauda equina observed afterwards. The pattern of NOx levels coincided with the appearance of inducible nitric oxide synthase labeled macrophages, indicating a critical role of these cells as the main synthesizers of NOx in the acute stage of cauda equina compression.

Unlabelled: In this study, we investigated the effects of 1.0 and 2.0 minimum alveolar anesthetic concentration (MAC) sevoflurane on cerebral blood flow (CBF) autoregulation before and after nonselective inhibition of nitric oxide (NO) synthase in rats. Rats were randomly assigned as follows: Group 1 (n = 8): 1.0 MAC sevoflurane; Groups 2 and 3 (n = 8 per group): 2.0 MAC sevoflurane. Assessment of autoregulation within a mean arterial blood pressure range of 140-60 mm Hg was performed by graded hemorrhage before and after administration of l-arginine methyl ester (l-NAME, 30 mg/kg IV, Groups 1 and 2) or during hypocapnia (Group 3). In 10 additional animals, brain tissue NO(2)(-) concentrations were measured at 1.0 and 2.0 MAC sevoflurane. CBF autoregulation was maintained with 1.0 MAC sevoflurane (Group 1) regardless of NO synthase status indicating that CBF autoregulation might not be related to NO availability. Sevoflurane dose-dependently increased brain tissue NO(2)(-) and impaired CBF autoregulation. Administration of l-NAME (Group 2) but not hypocapnia (Group 3) restored CBF autoregulation. This suggests that sevoflurane impairs the autoregulatory capacity secondary to an increase of the perivascular NO availability and questions the importance of basal cerebrovascular tone in terms of vasodilatory capacity during hypotensive challenges., Implications: The present study suggests that the volatile anesthetic sevoflurane dose-dependently impairs cerebrovascular autoregulation by mechanisms secondary to increase of perivascular nitric oxide availability.

Unlabelled: It is still unclear which neurotransmitters are involved in labor pain. We measured the concentrations of excitatory amino acids, nitric oxide, and prostaglandin E2 in the cerebrospinal fluid (CSF) of pregnant women, particularly in those with labor pain. The patients included in the study consisted of women who underwent cesarean delivery either with labor pain (Labor Pain group, n = 40) or without labor pain (Nonlabor Pain group, n = 58). All patients received spinal anesthesia (intrathecal injection of 10-12 mg of bupivacaine) for the operation, and 2 mL of CSF was collected before bupivacaine injection. Concentrations of aspartate and glutamate (0.50 +/- 0.06 microM and 0.79 +/- 0.10 microM, respectively) were significantly larger in the Labor Pain group than in the Nonlabor Pain group (0.35 +/- 0.03 microM and 0.54 +/- 0.04 microM, P < 0.05). There were no significant differences in the concentrations of nitric oxide and prostaglandin E2 between the groups. A positive correlation was found between CSF concentrations of excitatory amino acids and labor pain., Implications: The excitatory amino acids, aspartate and glutamate, play a role in labor pain. N-methyl-D-aspartate receptor antagonists may be useful for labor pain and postlabor uterine contraction pain relief.

Because nitric oxide (NO) is a putative mediator of oligodendrocyte damage in the primary progressive form of MS (PPMS), the authors analyzed the levels of NO oxidation products in CSF and plasma from 25 patients with PPMS and 15 controls. The levels of nitrite + nitrate (NOx) in CSF were fourfold higher in patients with PPMS than in controls (p < 0.001), whereas the concentrations in plasma were similar. These data suggests involvement of NO in nervous tissue damage in PPMS.

This study was undertaken to determine whether or not nitric oxide metabolites (NO(2)(-) plus NO(3)(-): NOx levels) in cerebrospinal fluid (CSF) would be predictors of treatment outcome in patients with degenerative lumbar diseases (DLD) including lumbar disc herniation (LDH) and lumbar spinal canal stenosis (LCS). The NOx levels in CSF were measured using an NO analyzer based on the Griess method. Six healthy volunteers and 18 patients with painless diseases were included in the control group. The pre- and postoperative NOx levels in 25 DLD patients, who underwent herniotomy for LDH (17 patients) or selective decompression for LCS (eight patients), were analyzed. The postoperative follow-up periods were approximately 8 months. Nineteen of 25 DLD patients, whose preoperative NOx levels were two standard deviations higher than the mean NOx levels of an age-matched control group, were included in an NO elevated (NOE) group. Among the 25 DLD patients, the preoperative NOx levels in six patients (young LDH group) were within the normal range. The pain-related Japanese Orthopaedic Association score and the Hirabayashi recovery rate were respectively used to evaluate the pain severity and the degree of pain relief. The preoperative and changes of postoperative NOx levels in the NOE group were negatively correlated with the Hirabayashi recovery rate. Normal postoperative NOx levels and excellent pain relief were achieved in young DLD patients. In conclusion, the preoperative and changes in postoperative NOx levels are quantitative predictors of postoperative pain relief in DLD patients.

Objective: To measure cerebrospinal fluid and plasma concentrations of nitrate and nitrite as indicators of nitric oxide production in adults after subarachnoid hemorrhage (SAH)., Design: A prospective, clinical study., Setting: Multidisciplinary intensive care unit., Patients: Nine patients (three males and six females, aged 29-64 yrs) with aneurysm-induced SAH were studied. Glasgow Coma Scale score on admission ranged from 9 to 15. Ruptured aneurysms were clipped within 72 hrs of ictus, and then conventional hypervolemic, hemodilution, and induced hypertension methods were applied., Interventions: None., Measurements and Main Results: Nitrate and nitrite concentrations of patients were examined sequentially by a capillary zone electrophoresis every day for 13 days. As a control group, cerebrospinal fluid was sampled from patients (n = 9, six males and three females, aged 30-60 yrs) without neurologic disorders who underwent spinal taps for spinal anesthesia, and plasma from healthy human volunteers (n = 43, 21 males and 22 females, aged 23-49 yrs). There were no significant differences over time in cerebrospinal fluid nitrate concentrations after SAH. Concentrations of cerebrospinal fluid nitrate after SAH were increased compared with control values. Plasma nitrate concentration was decreased compared with control values, but the value on day 14 was increased significantly (p < .05) compared with those during days 2-11. Plasma and cerebrospinal fluid nitrite concentrations after SAH were similar to those in control subjects. Similar concentrations of nitric oxide metabolite in plasma and cerebrospinal fluid were observed between the patients with and without symptomatic vasospasm., Conclusion: The increase of cerebrospinal fluid nitrate after SAH may attribute to the endogenous nitric oxide production in the injured brain.

Background: Increasing evidence has suggested the possibility that the activation of N-methyl-D-aspartate (NMDA) receptors modulates spinal nociceptive transmission via a nitric oxide (NO)/cyclic guanosine 3',5'-monophosphate (cGMP) pathway. However, the existence and the role of an NO/cGMP pathway in the modulation of spinal nociceptive transmission has been unclear. The authors hypothesized that the activation of NMDA receptors stimulates an NO/cGMP pathway, and this pathway evokes glutamate release within the spinal cord, modulating spinal nociceptive transmission., Methods: The authors have examined the effects of an NO synthase inhibitor and a soluble guanylate cyclase inhibitor on the concentrations of NO metabolites (NO2-/NO3-) and glutamate in the cerebrospinal fluid after intrathecal perfusion of NMDA, concomitantly observing pain-related behavior (scratching, biting, and vocalization) in unanesthetized, free-moving rats using an intrathecal microdialysis method. The contents of cGMP in the dorsal horn were also measured using enzyme immunoassay method., Results: Intrathecal perfusion of NMDA produced pain-related behavior and increased glutamate and NO2-/NO3-concentrations in a dose-dependent manner. A competitive NMDA receptor antagonist, D,L-2-amino-5-phosphonovaleric acid, completely blocked the NMDA-induced responses. An NO synthase inhibitor, N(G)-monomethyl-L-arginine acetate, at a dose that completely blocked the increase in NO2-/NO3-, inhibited both the NMDA-induced pain-related behavior and the increase in glutamate concentration. In addition, a soluble guanylate cyclase inhibitor, 1H-[1,2,4]oxadiazole[4,3-a]quinoxaline-1-one, also inhibited significantly NMDA-induced pain-related behavior and the increase in glutamate concentration. NMDA induced an increase in cGMP in the dorsal half of the spinal cord, which was blocked by N(G)-monomethyl-L-arginine acetate., Conclusions: The results of this study support the hypothesis that the activation of NMDA receptors modulated pain-related behavior via an NO/cGMP/glutamate release cascade within the spinal cord.

The aim of the present study was to investigate some putative neurotransmitters involved in nociception and pain in parturients during active labour experiencing intense visceral pain. The concentration of the excitatory amino acid aspartate was significantly increased, and there was a tendency for an increase in glutamate, in lumbar cerebrospinal fluid (CSF) of parturients in active vaginal labour compared with control patients without pain subjected to elective caesarean section. The CSF concentration of the nitric oxide breakdown product nitrate was significantly decreased in parturients compared with control patients and healthy volunteers. No significant differences in the concentrations of substance P, substance P-endopeptidase or met-enkephalin were detected between parturients and controls. Our data suggest a paradoxical negative relationship between CSF concentrations of excitatory amino acids and nitric oxide in labour pain. The mechanisms behind this finding is unclear at present.