Nociceptive neuropeptide increases and periorbital allodynia in a model of traumatic brain injury.

OBJECTIVE: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury. METHODS: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization. RESULTS: Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P \u3c .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P \u3c .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P \u3c .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P \u3c .0001. There was a significant correlation between CGRP and periorbital allodynia (P \u3c .0001, r = -0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P \u3c .001. GFAP(+) immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P \u3c .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy. CONCLUSION: Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex

Acute effects of a selective cannabinoid-2 receptor agonist on neuroinflammation in a model of traumatic brain injury.

Proposed therapeutic strategies for attenuating secondary traumatic brain injury (TBI) include modulation of acute neuroimmune responses. The goal of this study was to examine the acute effects of cannabinoid-2 receptor (CB(2)R) modulation on behavioral deficits, cerebral edema, perivascular substance P, and macrophage/microglial activation in a murine model of TBI. Thirty male C57BL/6 mice underwent sham surgery, or cortical contusion impact injury (CCI). CCI mice received vehicle or the CB(2)R agonist 0-1966 at 1 and 24 h after injury. Performance on the rotarod, forelimb cylinder, and open-field tests were evaluated before and at 48 h after sham or CCI surgery. Cerebral edema was evaluated using the wet-dry weight technique. Immunohistochemical analysis was used to examine changes in substance P and macrophage/microglia-specific Iba1 protein immunoreactivity. Locomotor performance and exploratory behavior were significantly improved in mice receiving 0-1966 (CB(2)R agonist) compared to vehicle-treated mice. Significant reductions were found for cerebral edema, number of perivascular areas of substance P immunoreactivity, and number of activated macrophages/microglial cells in the injured brains of 0-1966-treated mice compared to vehicle-treated mice. The findings show that the effects of the CB(2)R agonist 0-1966 on edema, substance P immunoreactivity, and macrophage/microglial activation, were associated with recovery of acute motor and exploratory deficits. This study provides evidence of acute neuroprotective effects derived from selective CB(2)R activation that may represent an avenue for further development of novel therapeutic agents in the treatment of TBI

Cervical spondylotic myelopathy in the young adult: A review of the literature and clinical diagnostic criteria in an uncommon demographic

Background: Cervical spondylotic myelopathy (CSM) is typically encountered in the elderly population. Significant inconsistencies currently exist regarding the definition of the disorder, the true incidence of CSM in younger populations, and the established diagnostic criteria. Objective: To highlight the lack of standardization in the definition and diagnosis of CSM. Methods: A PubMed literature search was conducted spanning the years 2001 to 2011. The search was limited by the following terms: 1) English language, 2) Adults (19-44 years old), and 3) “cervical spondylotic myelopathy.” Each article was reviewed to determine if the presence of the definition of CSM existed in the article. The clinical characteristics used to make the diagnosis of CSM were recorded for each article. Cochran’s Q statistic was used to determine whether some clinical characteristics were more frequently used than others. Results: 93 papers were reviewed in detail and 16 case reports, reviews, and articles concerning less than three patients were excluded, resulting in 77 articles in the final analysis. The most common clinical definitions were gait disturbance (22/77 articles (28.6%)), upper limb paresthesias or sensory disturbance (21/77 (27.3%)), and clumsy hands (15/77 (19.5%)). Hyperreflexia, spasticity, and pathologically increased reflexes were identified as diagnostic criteria in a minority of patients. Conclusion: The literature employs a wide range of neurologic signs and symptoms to make the diagnosis of CSM, with a majority of studies failing to rely on strict diagnostic criteria. The clinician should not discount CSM as an explanation for the aforementioned findings, as it is well-reported in the literature among the ages 18-44

Prevention and Management of Bleeding During Endoscopic Approaches to Skull Base Pathologies

The rate of serious permanent morbidity and mortality with endonasal approaches has declined secondary to increased knowledge of the pertinent anatomy, advanced neuroimaging and navigation techniques, better surgical instruments, and improved exposure and reconstruction strategies.1-3 Although rare, vascular injury remains a potentially serious complication. However, with limited systematically-collected and reported data, the exact incidence rate of vascular injuries is difficult to determine. In terms of arterial injuries, the incidence based on reported series likely ranges from 0.3%-9% (Table 1),4-11 with higher rates most commonly associated with chordomas and chondrosarcomas involving the clivus. Venous injury is comparatively less severe and easier to manage. As a result, there is a comparatively lower impetus to publish epidemiological data and management strategies for these injuries. The consequences of arterial injury include fatal hemorrhage, vessel occlusion or thromboembolism causing infarction, development of a pseudoaneurysm (PA), carotid-cavernous fistula (CCF), subarachnoid hemorrhage (SAH), and vasospasm.6,7,9 Surgical expertise and detailed knowledge of the neurovascular anatomy is critical to the avoidance and management of vascular injuries. Pages: 20-2

Pyruvate kinase M2 activation may protect against the progression of diabetic glomerular pathology and mitochondrial dysfunction

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (≥ 50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function

Rankum Sari Histologi Dan Embriologi

332 hal;21 c