Late cardiotoxicity after low dose of anthracycline therapy for acute lymphoblastic leukemia in childhood

Introduction Late cardiotoxicity is a known complication of anthracycline therapy but the long-term effects of low cumulative doses are not well documented. We studied late cardiotoxicity in survivors of childhood acute lymphoblastic leukemia (ALL) treated with low anthracycline doses 10 to 20 years earlier. Methods Seventy-seven ALL survivors who received a cumulative anthracycline dose <250 mg/m(2) and were at least 10 years after treatment were evaluated for signs of clinical heart failure. Cardiac function was assessed by echocardiography including tissue Doppler measurements of the septal mitral annulus in 37 ALL survivors 10.6-18.3 years (median 13.3 years) after anthracycline treatment with cumulative doses of 180 (n=19) or 240 mg/m(2) (n=18). The control group consisted of 30 healthy volunteers matched for age, sex, BSA, and BMI. Results No clinical relevant cardiotoxicity was found. Left ventricular shortening fraction (SF) was significantly reduced in male ALL survivors. Three of the 19 male ALL survivors had an SF below 30%. Male ALL survivors showed a significantly lower early filling velocity to atrial contraction velocity ratio but myocardial velocity during early filling was comparable between patients and controls. ALL survivors had a significantly longer isovolumetric relaxation time (IVRT). Thirty percent of the ALL survivors have an abnormal IVRT compared to the normal range of the controls. Conclusion and implications for cancer survivors At a median of 13.3 years after exposure to cumulative doses of anthracyclines of 180 or 240 mg/m(2), no clinical relevant cardiotoxicity was found but subclinical cardiac abnormalities were present in 30% of the patients

Variability in expression of a familial 2.79 Mb microdeletion in chromosome14q22.1-22.2

Deletions in chromosome 14q22-23 have been associated with variable manifestations including malformations of the eye, limbs, palate, and brain, and with developmental and growth delay. Haploinsufficiency of BMP4, OTX2 and possibly SIX6 are thought to contribute to the phenotype. We present a three generation family with four individuals carrying a 2.79 Mb microdeletion 14q22.1-22.2 encompassing BMP4 but not OTX2 nor SIX6. The highly variable manifestations in this family range from multiple congenital malformations with Robin sequence, microphthalmia, postaxial polydactyly, and developmental delay in the index patient to cleft uvula, growth delay, and mild developmental delay in her sister. The adults have a normal intelligence, postaxial polydactyly, and short stature or early cataract. Genotype-phenotype correlations suggest that the severity of eye manifestations in 14q22 deletions are influenced by the size of the deletion, but the marked intrafamilial variability observed in this family, as well as in familial BMP4 or OTX2 intragenic mutations points to additional modifiers outside this region. © 2012 Wiley Periodicals, Inc.status: publishe

A complex Xp11.22 deletion in a patient with syndromic autism: Exploration of FAM120C as a positional candidate gene for autism

We present a male patient with sporadic Aarskog syndrome, cleft palate, mild intellectual disability, and autism spectrum disorder (ASD). A submicroscopic discontiguous deletion was detected on chromosome Xp11.2 encompassing FGD1, FAM120C, and PHF8. That the deletion encompassed FGD1 (exons 2-8) explains the Aarskog features while the deletion of PHF8 most likely explains the cleft palate and mild intellectual disability. We identify FAM120C as a novel X-linked candidate gene for autism for two reasons: first, a larger deletion encompassing FAM120C segregates with autism in a previously reported family and second, there is recent evidence that FAM120C interacts with CYFIP1, part of the FMRP (Fragile X Mental Retardation Protein) network. In the current study, resequencing of FAM120C in 87 Belgian male patients with autism spectrum disorder identified no novel mutations. Expression of Fam120c in mouse tissues showed enriched expression in pituitary, cerebellum, cortex, and pancreatic islets of Langerhans. Additionally, we found a cortical expression pattern of Fam120c similar to that of Fmr1. In conclusion, FAM120C is a novel candidate gene for autism spectrum disorder based on genetic evidence and the brain expression pattern. Thereby we highlight a role for FMRP network genes in ASD. © 2014 Wiley Periodicals, Inc.status: publishe

Ocean alkalinity enhancement through enhanced silicate weathering in coastal areas: a long-term mesocosm study

Enhanced silicate weathering (ESW) in coastal environments is a promising method for ocean alkalinity enhancement. The idea behind ESW is to generate alkalinity by application of silicate minerals in coastal areas, where waves, currents and bioturbation can speed up the weathering rate. Due to its potentially large CO2 sequestration capacity and relatively high technological readiness, allowing rapid upscaling, coastal ESW currently receives substantial interest from researchers and policymakers. However, the vast majority of studies on ESW have been conducted in idealised laboratory conditions, while research on the method in natural environments is lacking. As a result, the CO2 sequestration efficiency and environmental risks when applying ESW in the field remain largely unknown. Here we present results from the first and longest-running mesocosm experiment investigating ESW and associated CO2 uptake in coastal marine sediments. Using tanks containing one square meter of natural seafloor each, we have studied biogeochemical cycling in sediment treated with the fast-weathering silicate mineral olivine. Lugworms (Arenicola marina) were added to some tanks to investigate the effect of bioturbation on the olivine dissolution rate, as well as the impact of olivine addition on biota. In the mesocosms, we quantified the sedimentary release of alkalinity and other weathering end-products (trace metals and dissolved silicate). Five years into the experiment, olivine dissolution is obvious from an elevated sedimentary alkalinity release and decreased average olivine grain size. The elevated alkalinity release has further led to higher CO2 sequestrations in tanks with olivine. Based on the results from this unique mesocosm setup, we will discuss the large-scale effect of ESW on biogeochemical cycling in coastal ecosystems