Effects of chronic uridine treatment on regional neuropeptide and tyrosine hydroxylase-like immunoreactivities in the brain of 12 month-old male rats

Uridine was administered in the drinking water (0.5 mg/ml) in adult 6 month-old rats for 6 months. The mean daily dose of uridine was 12.5 mg/rat. The effects of this treatment on tyrosine hydroxylase, galanin, somatostatin, neuropeptide Y and cholecystokinin-like immunoreactivities were studied by means of semiquantitative immunocytochemistry using the peroxidase-antiperoxidase procedure in combination with image analysis. A decrease of somatostatin, cholecystokinin and galanin-like immunoreactivities in nerve terminals was observed in various brain areas of 12 month-old animals compared with 3 month-old animals, while the levels of tyrosine hydroxylase-like immunoreactivity were unchanged. Uridine-treated animals showed a decrease of galanin, neuropeptide Y and cholecystokinin-like immunoreactivities in nerve terminals of some diencephalic areas and an increase of cholecystokinin-like immunoreactivity in nerve terminals of most of the telencephalic brain areas in comparison with vehicle treated animals of the same age. It is suggested that the pyrimidine nucleoside uridine can affect the synthesis and/or degradation of mRNAs involved in the synthesis of neuropeptides via direct nuclear actions and/or indirect actions involving effects on receptor activated phosphoinositide metabolism. Uridine offers a new way to modulate central peptide synapses.     

A new stage 3 millennial climatic variability record from a SW France speleothem

We present a new high resolution speleothem stable isotope record from the Villars Cave (SW-France) that covers part of marine isotope stage (MIS) 3. The Vil14 stalagmite grew between ~ 52 and 29 ka. The δ¹³C profile is used as a palaeoclimate proxy and clearly shows the interstadial substages 13, 12 and 11. The new results complement and corroborate previously published stalagmite records Vil9 and Vil27 from the same site. The Vil14 stalagmite chronology is based on 12 Th-U dating by MC-ICP-MS and 3 by TIMS. A correction for detrital contamination was done using the ²³⁰Th/²³²Th activity ratio measured on clay collected in Villars Cave. The Vil14 results reveal that the onset of Dansgaard–Oeschger (DO) events 13 and 12 occurred at ~ 49.8 ka and ~ 47.8 ka, respectively. Within uncertainties, this is coherent with the latest NorthGRIP time scale (GICC05-60 ka) and with speleothem records from Central Alps. Our data show an abrupt δ¹³C increase at the end of DO events 14 to 12 which coincides with a petrographical discontinuity probably due to a rapid cooling. As observed for Vil9 and Vil27, Vil14 growth significantly slowed down after ~ 42 ka and finally stopped ~ 29 ka ago where the δ¹³C increase suggests a strong climate deterioration that coincides with both North Atlantic sea level and sea surface temperature drop.     

Multiple Marker Detection in Peripheral Blood for NSCLC Diagnosis

Background

Non-invasive early detection of lung cancer could reduce the number of patients diagnosed with advanced disease, which is associated with a poor prognosis. We analyzed the diagnostic accuracy of a panel of peripheral blood markers in detecting non small cell lung cancer (NSCLC).

Methods

100 healthy donors and 100 patients with NSCLC were enrolled onto this study. Free circulating DNA, circulating mRNA expression of peptidylarginine deiminase type 4 (PAD4/PADI4), pro-platelet basic protein (PPBP) and haptoglobin were evaluated using a Real-Time PCR-based method.

Results

Free circulating DNA, PADI4, PPBP and haptoglobin levels were significantly higher in NSCLC patients than in healthy donors (p<0.0001, p<0.0001, p = 0.0002 and p = 0.0001, respectively). The fitted logistic regression model demonstrated a significant direct association between marker expression and lung cancer risk. The odds ratios of individual markers were 6.93 (95% CI 4.15–11.58; p<0.0001) for free DNA, 6.99 (95% CI 3.75–13.03; p<0.0001) for PADI4, 2.85 (95% CI 1.71–4.75; p<0.0001) for PPBP and 1.16 (95% CI 1.01–1.33; p = 0.031) for haptoglobin. Free DNA in combination with PPBP and PADI4 gave an area under the ROC curve of 0.93, 95% CI = 0.90–0.97, with sensitivity and specificity over 90%.

Conclusions

Free circulating DNA analysis combined with PPBP and PADI4 expression determination appears to accurately discriminate between healthy donors and NSCLC patients. This non-invasive multimarker approach warrants further research to assess its potential role in the diagnostic or screening workup of subjects with suspected lung cancer.     

Functional striatal hypodopaminergic activity in mice lacking adenosine A(2A) receptors.

Adenosine and caffeine modulate locomotor activity and striatal gene expression, partially through the activation and blockade of striatal A(2A) receptors, respectively. The elucidation of the roles of these receptors benefits from the construction of A(2A) receptor-deficient mice (A(2A)-R(-/-)). These mice presented alterations in locomotor behaviour and striatal expression of genes studied so far, which are unexpected regarding the specific expression of A(2A) receptor by striatopallidal neurones. To clarify the functions of A(2A) receptors in the striatum and to identify the mechanisms leading to these unexpected modifications, we studied the basal expression of immediate early and constitutive genes as well as dopamine and glutamate neurotransmission in the striatum. Basal zif268 and arc mRNAs expression was reduced in mutant mice by 60-80%, not only in the striatum but also widespread in the cerebral cortex and hippocampus. Striatal expression of substance P and enkephalin mRNAs was reduced by about 50% and 30%, respectively, whereas the expression of GAD67 and GAD65 mRNAs was slightly increased and unaltered, respectively. In vivo microdialysis in the striatum revealed a 45% decrease in the extracellular dopamine concentration and three-fold increase in extracellular glutamate concentration. This was associated with an up-regulation of D(1) and D(2) dopamine receptors expression but not with changes in ionotropic glutamate receptors. The levels of tyrosine hydroxylase and of striatal and cortical glial glutamate transporters as well as adenosine A(1) receptors expression were indistinguishable between A(2A)-R(-/-) and wild-type mice. Altogether these results pointed out that the lack of A(2A) receptors leads to a functional hypodopaminergic state and demonstrated that A(2A) receptors are necessary to maintain a basal level in immediate early and constitutive genes expression in the striatum and cerebral cortex, possibly via their control of dopamine pathways.     

Circulating ceramides are inversely associated with cardiorespiratory fitness in participants aged 54–96 years from the Baltimore Longitudinal Study of Aging

Cardiorespiratory fitness (VO₂ peak) declines with age and is an independent risk factor for morbidity and mortality in older adults. Identifying biomarkers of low fitness may provide insight for why some individuals experience an accelerated decline of aerobic capacity and may serve as clinically valuable prognostic indicators of cardiovascular health. We investigated the relationship between circulating ceramides and VO₂ peak in 443 men and women (mean age of 69) enrolled in the Baltimore Longitudinal Study of Aging (BLSA). Individual species of ceramide were quantified by HPLC–tandem mass spectrometry. VO₂ peak was measured by a graded treadmill test. We applied multiple regression models to test the associations between ceramide species and VO₂ peak, while adjusting for age, sex, blood pressure, serum LDL, HDL, triglycerides, and other covariates. We found that higher levels of circulating C18:0, C20:0, C24:1 ceramides and C20:0 dihydroceramides were strongly associated with lower aerobic capacity (P < 0.001, P < 0.001, P = 0.018, and P < 0.001, respectively). The associations held true for both sexes (with men having a stronger association than women, P value for sex interaction <0.05) and were unchanged after adjusting for confounders and multiple comparison correction. Interestingly, no significant association was found for C16:0, C22:0, C24:0, C26:0, and C22:1 ceramide species, C24:0 dihydroceramide, or total ceramides. Our analysis reveals that specific long‐chain ceramides strongly associate with low cardiovascular fitness in older adults and may be implicated in the pathogenesis of low fitness with aging. Longitudinal studies are needed to further validate these associations and investigate the relationship between ceramides and health outcomes.     

Increased levels of free circulating DNA in patients with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is difficult to diagnose because of numerous interstitial lung diseases with similar symptoms. As serum DNA has proven useful for early lung cancer detection, we aimed to define the relevance of this marker in discriminating IPF from other fibrotic and nonfibrotic/nonmalignant lung diseases. DNA was quantified in 191 subjects: 64 healthy individuals, 58 patients with IPF, 17 patients with nonspecific pulmonary fibrosis (13 idiopathic nonspecific interstitial pneumonia, 4 chronic hypersensitivity pneumonitis), and 52 patients with other diffuse/nonmalignant lung diseases. The median value of free DNA in IPF patients was 61.1 ng/mL (range 7.1-405), which was significantly higher than that of healthy donors (median 6.8, range 2.2-184) (p<0.001) and that of patients with other diffuse/nonmalignant lung diseases (median 28.0, range 4.2-281) (p=0.004). The area under the ROC curve was 0.926 (95% CI 0.879-0.973) when IPF patients were compared with healthy donors, and 0.702 (95% CI 0.609-0.796) when a comparison was made with non-IPF pulmonary diseases. In conclusion, we observed significantly higher levels of free circulating DNA in patients with IPF than in those with other fibrotic or diffuse/nonmalignant lung diseases.