Background and Purpose-The importance of bioactive lipid signaling under physiological and pathophysiological conditions is progressively becoming recognized. The disparate distribution of sphingosine kinase (SphK) isoform activity in normal and ischemic brain, particularly the large excess of SphK2 in cerebral microvascular endothelial cells, suggests potentially unique cell-and region-specific signaling by its product sphingosine-1-phosphate. The present study sought to test the isoform-specific role of SphK as a trigger of hypoxic preconditioning (HPC)-induced ischemic tolerance. Methods-Temporal changes in microvascular SphK activity and expression were measured after HPC. The SphK inhibitor dimethylsphingosine or sphingosine analog FTY720 was administered to adult male Swiss-Webster ND4 mice before HPC. Two days later, mice underwent a 60-minute transient middle cerebral artery occlusion and at 24 hours of reperfusion, infarct volume, neurological deficit, and hemispheric edema were measured. Results-HPC rapidly increased microvascular SphK2 protein expression (1.7Ϯ0.2-fold) and activity (2.5Ϯ0.6-fold), peaking at 2 hours, whereas SphK1 was unchanged. SphK inhibition during HPC abrogated reductions in infarct volume, neurological deficit, and ipsilateral edema in HPC-treated mice. FTY720 given 48 hours before stroke also promoted ischemic tolerance; when combined with HPC, even greater (and dimethylsphingosine-reversible) protection was noted. Conclusions-These findings indicate hypoxia-sensitive increases in SphK2 activity may serve as a proximal trigger that ultimately leads to sphingosine-1-phosphate-mediated alterations in gene expression that promote the ischemia-tolerant phenotype. Thus, components of this bioactive lipid signaling pathway may be suitable therapeutic targets for protecting the neurovascular unit in stroke. (Stroke. 2009;40:3342-3348.)
Mean platelet volume (MPV) has been actively investigated in liver disease such as steatosis, cirrhosis and hepatitis. Recently, MPV/platelet count (PC) ratio has been proposed as a predictor of long-term mortality after myocardial infarction. As PC is known to be decreased in various liver diseases such as cirrhosis, hepatosplenomegaly and malignancy, we planned to evaluate MPV/PC ratio in patients with hepatocellular carcinoma (HCC) in this study. Mean of MPV levels showed significant difference, which were 8.69 fl (range 6.7-12.2 fl) in patients group and 8.02 fl in control group (range 6.7-11.0 fl). In receiver operating characteristic (ROC) curve analysis, the MPV/PC ratio (fl/(10(9)/l)) presented 74.5% of sensitivity and 96.5% of specificity at the criterion > 0.0491 (area under the curve (AUC) = 0.884), while MPV alone showed 57.4% of sensitivity and 81.4% of specificity at the criterion > 8.4 fl. Further studies should evaluate underlying pathogenic mechanisms of MPV/PC ratio difference and various possibilities of this ratio as an indicator of presence of a tumor in HCC.
Purpose: Mothers against decapentaplegic homologue 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study is to more precisely characterize its role in the development and progression of human gastric carcinoma. Experimental Design: The expression of SMAD4 was investigated in 283 gastric adenocarcinomas and related lesions, as well as in 9 gastric carcinoma cell lines. We also analyzed the methylation status of SMAD4 gene by using methylation-specific PCR, examined loss of heterozygosity (LOH) of this gene locus by using a vicinal marker, and detected exon mutation of SMAD4 through exon-by-exon amplification. Moreover, we assessed whether MG132, a proteasome inhibitor, affected the SMAD4 protein level. Results: We found loss of SMAD4 protein expression in the cytoplasm (36 of 114, 32%) and in the nucleus (46 of 114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis.We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. In addition, we found that LOH (20 of 70, 29%) and promoter hypermethylation (4 of 73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels were also affected in certain gastric carcinoma cell lines following incubation with MG132. Conclusion: Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas was due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.
Placement of subdural grid and strip electrodes for invasive video electroencephalographic monitoring is generally well tolerated in the pediatric population. The authors found that aggressive initial electrode coverage was not associated with higher rates of blood transfusion or perioperative complications, and reduced the frequency of repeated operations for placement of supplemental electrodes.
Although patients in both groups with CP were weaker than those in the ND group, they did have strength gains. Gait speed in the SDR-PT group was slower than that in the ND group preoperatively but not at 20 months postoperatively. Gait speed in the PT group remained slower than that in the ND group. The pre- to postoperative change in the Gross Motor Abilities Estimate score was significantly greater in the SDR-PT group than in the PT-only group. An effective treatment for children with CP, SDR offers gains in strength, gait speed, and overall gross motor function.
Forty-five infants with myelomeningocele in whom hydrocephalus was absent or adequately controlled developed signs and symptoms of the Arnold-Chiari malformation before the age of 3 months. All of them underwent laminectomy and opening of the dura mater for hindbrain decompression. The clinical presentation included swallowing difficulty, apneic episodes, stridor, bronchial aspiration, arm weakness, and opisthotonos. Within 2 weeks of the initial clinical presentation, the neurological status of 14 patients (31%) deteriorated dramatically and culminated in irreversible neurological deficits. In all patients, compression of the brain stem occurred in the spinal canal. A transverse dural band constricting the dural sac at the C-1 level was noted in 41% of the patients, and a mild degree of arachnoidal adhesion was noted in 23%. The lowermost level of the cerebellar tongue or medullary kink was located at C-1 to C-4 in 28 cases and at C-5 to T-1 in 17 cases. Twenty-eight (62%) of the patients were alive and 17 (38%) had died at the last follow-up assessment. All survivors showed improvement of their overall neurological function. Twenty-four made a complete recovery. The majority of deaths were attributed to respiratory failure. Early recognition of symptoms and prompt decompressive laminectomy are essential for successful management of the Arnold-Chiari malformation in infants.
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