Impact of single-nucleotide polymorphisms in DNA repair pathway genes on response to chemoradiotherapy in rectal cancer patients: Results from ACCORD-12/PRODIGE-2 phase III trial

We examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (p_interaction = 0.05) and XPA rs3176683 (p_interaction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40–38.23], p_interaction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32–0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34–0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease-free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT.     

Unilateral vestibular deafferentation impairs embodied spatial cognition

A growing number of studies indicate that cognitive complaints are common in patients with peripheral vestibular disorders. A better understanding of how vestibular disorders influence cognition in these patients requires a clear delineation of the cognitive domains affected by vestibular disorders. Here, we compared the consequences of left and right vestibular neurectomy on third-person perspective taking—a visuo-spatial task requiring mainly own-body mental imagery, and on 3D objects mental rotation imagery—requiring object-based mental imagery, but no perspective taking. Patients tested 1 week after a unilateral vestibular neurectomy and a group of age- and gender-matched healthy participants played a virtual ball-tossing game from their own first-person perspective (1PP) and from the perspective of a distant avatar (third-person perspective, 3PP). Results showed larger response times in the patients with respect to their controls for the 3PP taking task, but not for the 1PP task and the 3D objects mental imagery. In addition, we found that only patients with left vestibular neurectomy presented altered 3PP taking abilities when compared to their controls. This study suggests that unilateral vestibular loss affects mainly own-body mental transformation and that only left vestibular loss seems to impair this cognitive process. Our study also brings further evidence that vestibular signals contribute to the sensorimotor bases of social cognition and strengthens the connections between the so far distinct fields of social neuroscience and human vestibular physiology.

     

Food,water, energy,and macronutrient intake of non-breastfed infants and young children (0–3 years)

European Journal of Nutrition - The French Nutri-Bébé 2013 study aimed to assess the nutritional intake of infants and young children in comparison with the recommendations of the 2013...     

Glutamate transporter 1-expressing glia in the rat substantia nigra—Morphometric analysis and relationships to synapses

Glial cells have a major role in protecting neurons against various forms of stress. Especially, astrocytes mediate the bulk of glutamate clearance in the brain via specific membrane transporters (GLAST and GLT1), thereby preventing the occurrence of excitotoxic events. Although glutamate-mediated mechanisms are thought to contribute to nigral dopaminergic neuron degeneration in Parkinson's disease, detailed information on the organization of glia in the substantia nigra is still lacking. The present study was performed to provide quantitative information on the organization of astroglia and on the relationships between astrocytes and excitatory synapses in the rat substantia nigra. Using immunolabeling of GLT1 and confocal imaging, we found that the substantia nigra was filled with a dense meshwork of immunoreactive astrocyte processes. Stereological analysis performed on electron microscope images revealed that the density of immunoreactive astrocyte plasma membranes was substantial, close to 1 μm²/μm³, in the substantia nigra neuropil, both in the pars compacta and the pars reticulata. Excitatory synapses had on average two thirds of their perimeters free from glia, a disposition that may favor transmitter spillover. The density of glutamatergic synapses, as quantified on confocal images by the simultaneous detection of bassoon and of vesicular glutamate transporter 1 or 2, was very low (0.01 and 0.025 per μm³ in the reticulata and compacta subdivisions, respectively). Thus the ratio of GLT1-expressing glial membrane surface to glutamatergic synapses was very high (40–100 μm²), suggesting an efficient regulation of extracellular glutamate concentrations.     

Cardiovascular autonomic testing in the work-up of cerebellar ataxia: insight from an observational single center study

Journal of Neurology - Cerebellar ataxias are a heterogeneous group of disorders of both genetic and non-genetic origin. In sporadic cases, two entities are recognized: multiple system atrophy of...     

Endovascular management of visceral artery aneurysms: When to watch,when to intervene?

Visceral artery aneurysms (VAA) include splanchnic and renal artery aneurysms. They represent a rare clinical entity, although their detection is rising due to an increased use of cross-sectional imaging. Rupture is the most devastating complication, and is associated with a high morbidity and mortality. In addition, increased percutaneous endovascular interventions have raised the incidence of iatrogenic visceral artery pseudoaneurysms (VAPAs). For this reason, elective repair is preferable in the appropriately chosen patient. Controversy still exists regarding their treatment. Over the past decade, there has been steady increase in the utilization of minimally invasive, non-operative interventions, for vascular aneurysmal disease. All VAAs and VAPAs can technically be fixed by endovascular techniques but that does not mean they should. These catheter-based techniques constitute an excellent approach in the elective setting. However, in the emergent setting it may carry a higher morbidity and mortality. The decision for intervention has to take into account the size and the natural history of the lesion, the risk of rupture, which is high during pregnancy, and the relative risk of surgical or radiological intervention. For splanchnic artery aneurysms, we should recognize that we are not, in reality, well informed about their natural history. For most asymptomatic aneurysms, expectant treatment is acceptable. For large, symptomatic or aneurysms with a high risk of rupture, endovascular treatment has become the first-line therapy. Treatment of VAPAs is always mandatory because of the high risk of rupture. We present our point of view on interventional radiology in the splanchnic arteries, focusing on what has been achieved and the remaining challenges.