Selective vulnerability of preterm white matter to oxidative damage defined by F2-isoprostanes

Periventricular white matter injury (PWMI) is the leading cause of cerebral palsy and chronic neurological disability in survivors of prematurity. Despite the large number of affected children, the pathogenetic mechanisms related to PWMI remain controversial. Through studies of 33 human autopsy brains, we determined that early PWMI was related to oxidative damage that particularly targeted the oligodendrocyte lineage, whereas other neuronal and glial cell types were markedly more resistant. F(2)-isoprostanes, an arachidinate metabolite/lipid peroxidation marker of oxidative damage, were significantly increased in early PWMI lesions but not in cerebral cortex. That deleterious lipid peroxidation accompanied early PWMI was supported by similar increases in F(2)-isoprostanes levels in the cerebral cortex from term infants with hypoxic-ischemic cortical injury. Detection of F(4)-neuroprostanes, a neuronal-specific oxidative damage marker, confirmed that neuroaxonal elements were resistant to injury in cerebral cortex and white matter. Significant protein nitration was not detected in PWMI lesions by 3-nitrotyrosine staining. Significant cellular degeneration was confirmed in early PWMI lesions by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling and a marked depletion of oligodendrocyte progenitors of 71 +/- 8%. Hence, the predilection of preterm infants for PWMI is related to selective lipid peroxidation-mediated injury of cerebral white matter and targeted death of oligodendrocyte progenitors.     

Systemic ethanol administration elevates deoxycorticosterone levels and chronic ethanol exposure attenuates this response

Systemic ethanol administration is known to elevate levels of the GABAergic neuroactive steroid 3alpha,21-dihydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THDOC). 3alpha,5alpha-THDOC is synthesized from deoxycorticosterone (DOC) by metabolism in adrenals and brain. The present study investigated DOC levels in plasma and brain following ethanol administration to na?ve and ethanol-exposed rats. Rats were administered ethanol (2 g/kg, i.p.) or saline and DOC levels were measured in plasma and brain regions by radioimmunoassay. Chronic ethanol-exposed rats were administered an ethanol challenge (2 g/kg, i.p.) following 15 days of ethanol liquid diet consumption. Ethanol administration markedly increased DOC levels in plasma, cerebral cortex, hippocampus, hypothalamus, cerebellum, and olfactory tubercle of na?ve rats. Ethanol challenge produced an attenuated elevation of DOC in rat plasma and brain following chronic ethanol consumption for 2 weeks. These findings suggest that acute ethanol increases DOC levels in ethanol na?ve rats and chronic ethanol consumption induces tolerance to ethanol-induced increases in DOC levels.     

Angiography and revascularization in patients with heart failure following fibrinolytic therapy for ST-elevation acute myocardial infarction

We evaluated the use of coronary angiography and clinical outcomes among patients who had heart failure and were enrolled in the Intravenous Novel Plasminogen Activator (NPA) for the Treatment of Infarcting Myocardium Early study, a large international trial of fibrinolytic therapy in ST-elevation myocardial infarction.     

gamma-Aminobutyric acid inhibits cholangiocarcinoma growth by cyclic AMP-dependent regulation of the protein kinase A/extracellular signal-regulated kinase 1/2 pathway

We studied the effect of the inhibitory neurotransmitter, gamma-aminobutyric acid (GABA), in the regulation of cholangiocarcinoma growth. We determined the in vitro effect of GABA on the proliferation of the cholangiocarcinoma cell lines (Mz-ChA-1, HuH-28, and TFK-1) and evaluated the intracellular pathways involved. The effect of GABA on migration of Mz-ChA-1 cells was also evaluated. In vivo, Mz-ChA-1 cells were s.c. injected in athymic mice, and the effects of GABA on tumor size, tumor cell proliferation, apoptosis, collagen quantity, and the expression of vascular endothelial growth factor-A (VEGF-A) and VEGF-C (cancer growth regulators) were measured after 82 days. GABA decreased in vitro cholangiocarcinoma growth in a time-dependent and dose-dependent manner, by both cyclic AMP/protein kinase A- and D-myo-inositol-1,4,5-thriphosphate/Ca(2+)-dependent pathways, leading to down-regulation of extracellular signal-regulated kinase 1/2 phosphorylation. Blocking of GABA(A), GABA(B), and GABA(C) receptors prevented GABA inhibition of cholangiocarcinoma proliferation. GABA inhibited Mz-ChA-1 cell migration and, in vivo, significantly decreased tumor volume, tumor cell proliferation, and VEGF-A/C expression whereas increasing apoptosis compared with controls. An increase in collagen was evident in GABA-treated tumors. GABA decreases biliary cancer proliferation and reduces the metastatic potential of cholangiocarcinoma. GABA may represent a therapeutic agent for patients affected by malignancies of the biliary tract.     

Treatment of radiotherapy-induced fatigue through a nonpharmacological approach

BACKGROUND: Cancer-related fatigue (CRF) is a frequently occurring, burdensome side effect of radiation therapy that can result in detrimental effects to health-related quality of life (HRQL). The findings from a pilot study examining the efficacy of the complementary and alternative practice of Polarity Therapy (PT) in reducing CRF and improving HRQL are reported. METHODS: Fifteen women undergoing radiation therapy for breast cancer and experiencing fatigue were randomized to receive 1, 2, or no PT treatments. Treatments were given 1 week apart to the patients receiving 2 treatments. Fatigue and HRQL were assessed at baseline prior to PT, 3 days following the first PT treatment (week 1), and 3 days following the second PT treatment (week 2). RESULTS: There was a statistically significant improvement in both CRF and HRQL in the 10 patients who received a PT treatment compared to the 5 control patients at the week 1 assessment. In addition, there was a statistically significant difference among the 3 treatment groups in improvement in CRF at the week 2 assessment. This finding, coupled with a visual inspection of the means, supports the plausibility of a dose response concerning PT. CONCLUSION: Results from this pilot investigation suggest that PT may have a positive influence on CRF and HRQL in women undergoing radiation treatment for breast cancer. Randomized, controlled clinical trials with larger sample sizes are needed.     

Patterns and correlates of local therapy for women with ductal carcinoma-in-situ.

PURPOSE: Concerns have been raised about the quality of treatment for women with ductal carcinoma-in-situ (DCIS) because persistent high rates of mastectomy suggest overtreatment, whereas lower than expected rates of radiation therapy after breast-conserving surgery (BCS) suggest undertreatment. PATIENTS AND METHODS: All women with DCIS diagnosed in 2002 and who reported to the Detroit and Los Angeles Surveillance, Epidemiology, and End Results (SEER) registries were identified and surveyed shortly after receipt of surgery (response rate, 79.7%; n = 817). Analyses were restricted to patients with DCIS (n = 659) indicated by SEER stage data. RESULTS: Only 14.0% of patients at lowest risk of recurrence (based on tumor size and histologic grade) received a mastectomy compared with 22.8% and 52.6% of patients at intermediate and highest risk (P < .001). Only 13.1% of patients who were not influenced or slightly influenced by concerns about recurrence received mastectomy compared with 48.8% of women who were greatly influenced by this concern (P < .001). A between-geographic site difference in receipt of radiation after BCS was observed for the lowest risk group (38.9% in Los Angeles v 70.5% in Detroit) but not for the highest risk group (80.2% in Los Angeles v 85.9% in Detroit, P = .006 for site and risk group differences). Between-site differences in receipt of radiation after BCS were consistent with patient recall of surgeon discussions about treatment. CONCLUSION: Surgeons are tailoring their recommendations for local therapy options for DCIS based on important clinical factors. Patient attitudes also play an important role in treatment decisions. The substantial influence of both surgeon opinion and patient attitudes should temper concerns about the quality of treatment for women with DCIS.     

Age-related variability in cortical activity during language processing.

PURPOSE: The present study investigated the extent of cortical activity during overt picture naming using functional magnetic resonance imaging (fMRI). METHOD: Participants comprised 20 healthy, adult participants with ages ranging from 20 to 82 years. While undergoing fMRI, participants completed a picture-naming task consisting of 60 high-frequency nouns. RESULTS: Linear regression analysis revealed a positive relationship between age and cortical activation intensity in Broca's and Wernicke's areas as well as the right-hemisphere homologue of Broca's area. In contrast, neural activity in the anterior cingulate gyrus, an area thought to be involved in attentional processing, did not increase as a function of age. CONCLUSIONS: These findings suggest age-related increases in cortical activation during simple language tasks, such as picture naming, in brain areas typically associated with language processing.