Germline mutations including the rare pathogenic variant c.3206delC in the ATM gene cause ataxia teleangiectasia-associated primary central nervous system lymphoma

We here report the case of a 2-year-old patient with a primary central nervous system lymphoma of B-cell origin. Due to their past medical history of repeated respiratory tract infections and the marked chemotherapy-associated toxicity and infectious comorbidity, we suspected that the patient also suffered from an inherited immune deficiency disorder. Despite the lack of classical pathognomonic symptoms for ataxia teleangiectasia and missing evidence for a cancer predisposition syndrome in the family, genetic testing identified biallelic germline mutations, including the rare pathogenic variant c.3206delC (p.Pro1069Leufs*2), in the ataxia telangiectasia-mutated (ATM) gene. The case highlights the importance of searching for immune deficiency disorders associated with primary central nervous system lymphoma before treatment initiation and the urgent need to develop novel treatment strategies for cancer patients with underlying immunodeficiency syndromes

Four-year follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder

Background: Despite the high prevalence of fetal alcohol spectrum disorder (FASD), there are few interventions targeting its core neurocognitive and behavioral deficits. FASD is often conceptualized as static and permanent, but interventions that capitalize on brain plasticity and critical developmental windows are emerging. We present a long-term follow-up study evaluating the neurodevelopmental effects of choline supplementation in children with FASD 4 years after an initial efficacy trial. Methods: The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2-5-year-olds with FASD. Participants include 31 children (16 placebo; 15 choline) seen 4 years after trial completion. The mean age at follow-up was 8.6 years. Diagnoses were 12.9% fetal alcohol syndrome (FAS), 41.9% partial FAS, and 45.1% alcohol-related neurodevelopmental disorder. The follow-up included measures of intelligence, memory, executive functioning, and behavior. Results: Children who received choline had higher non-verbal intelligence, higher visual-spatial skill, higher working memory ability, better verbal memory, and fewer behavioral symptoms of attention deficit hyperactivity disorder than the placebo group. No differences were seen for verbal intelligence, visual memory, or other executive functions. Conclusions: These data support choline as a potential neurodevelopmental intervention for FASD and highlight the need for long-term follow-up to capture treatment effects on neurodevelopmental trajectories. Trial registration: ClinicalTrials.Gov #NCT01149538; Registered: June 23, 2010; first enrollment July 2, 2010

Lymphotoxin β receptor signaling promotes tertiary lymphoid organogenesis in the aorta adventitia of aged ApoE−/− mice

Atherosclerosis involves a macrophage-rich inflammation in the aortic intima. It is increasingly recognized that this intimal inflammation is paralleled over time by a distinct inflammatory reaction in adjacent adventitia. Though cross talk between the coordinated inflammatory foci in the intima and the adventitia seems implicit, the mechanism(s) underlying their communication is unclear. Here, using detailed imaging analysis, microarray analyses, laser-capture microdissection, adoptive lymphocyte transfers, and functional blocking studies, we undertook to identify this mechanism. We show that in aged apoE−/− mice, medial smooth muscle cells (SMCs) beneath intimal plaques in abdominal aortae become activated through lymphotoxin β receptor (LTβR) to express the lymphorganogenic chemokines CXCL13 and CCL21. These signals in turn trigger the development of elaborate bona fide adventitial aortic tertiary lymphoid organs (ATLOs) containing functional conduit meshworks, germinal centers within B cell follicles, clusters of plasma cells, high endothelial venules (HEVs) in T cell areas, and a high proportion of T regulatory cells. Treatment of apoE−/− mice with LTβR-Ig to interrupt LTβR signaling in SMCs strongly reduced HEV abundance, CXCL13, and CCL21 expression, and disrupted the structure and maintenance of ATLOs. Thus, the LTβR pathway has a major role in shaping the immunological characteristics and overall integrity of the arterial wall

Environmental considerations for subseabed geological storage of CO2: a review

Many countries are now using or investigating offshore geological storage of CO2 as a means to reduce atmospheric CO2 emissions. Although associated research often focuses on deep-basin geology (e.g. seismic, geomagnetics), environmental data on the seabed and shallow subseabed is also crucial to (1) detect and characterise potential indicators of fluid seeps and their potential connectivity to targeted storage reserves, (2) obtain baseline environmental data for use in future monitoring, and (3) acquire information to facilitate an improved understanding of ecosystem processes for use in impact prediction. This study reviews the environmental considerations, including potential ecological impacts, associated with subseabed geological storage of CO2. Due to natural variations in CO2 levels in seafloor sediments, baseline CO2 measurements and knowledge of physical–chemical processes affecting the regional distribution of CO2 and pH are critical for the design of appropriate monitoring strategies to assess potential impacts of CO2 seepage from subseabed storage reservoirs. Surficial geological and geophysical information, such as that acquired from multibeam sonar and sub-bottom profiling, can be used to investigate the connectivity between the deep reservoirs and the surface, which is essential in establishing the reservoir containment properties. CO2 leakage can have a pronounced effect on sediments and rocks which in turn can have carryover effects to biogeochemical cycles. The effects of elevated CO2 on marine organisms are variable and species-specific but can also have cascading effects on communities and ecosystems, with marine benthic communities at some natural analogue sites (e.g. volcanic vents) showing decreased diversity, biomass, and trophic complexity. Despite their potential applications, environmental surveys and data are still not a standard and integral part of subseabed CO2 storage projects. However, the habitat mapping and seabed characterisation methodology that underpins such surveys is well developed and has a strong record of providing information to industry and decision makers. This review provides recommendations for an integrated and interdisciplinary approach to offshore geological storage of CO2, which will benefit national programs and industry and will be valuable to researchers in a broad range of disciplines