Genotoxicity of synthetic amorphous silica nanoparticles in rats following short‐term exposure. Part 1: Oral route

Synthetic amorphous silica (SAS) in its nanosized form is now used in food applications although the potential risks for human health have not been evaluated. In this study, genotoxicity and oxidative DNA damage of two pyrogenic (NM‐202 and 203) and two precipitated (NM‐200 and ‐201) nanosized SAS were investigated in vivo in rats following oral exposure. Male Sprague Dawley rats were exposed to 5, 10, or 20 mg/kg b.w./day for three days by gavage. DNA strand breaks and oxidative DNA damage were investigated in seven tissues (blood, bone marrow from femur, liver, spleen, kidney, duodenum, and colon) with the alkaline and the (Fpg)‐modified comet assays, respectively. Concomitantly, chromosomal damage was investigated in bone marrow and in colon with the micronucleus assay. Additionally, malondialdehyde (MDA), a lipid peroxidation marker, was measured in plasma. When required, a histopathological examination was also conducted. The results showed neither obvious DNA strand breaks nor oxidative damage with the comet assay, irrespective of the dose and the organ investigated. Similarly, no increases in chromosome damage in bone marrow or lipid peroxidation in plasma were detected. However, although the response was not dose‐dependent, a weak increase in the percentage of micronucleated cells was observed in the colon of rats treated with the two pyrogenic SAS at the lowest dose (5 mg/kg b.w./day). Additional data are required to confirm this result, considering in particular, the role of agglomeration/aggregation of SAS NMs in their uptake by intestinal cells. Environ. Mol. Mutagen. 56:218–227, 2015. © 2014 Wiley Periodicals, Inc.     

A comparison between fast and conventional spin-echo in the detection of multiple sclerosis lesions

Long repetition time (TR) spin-echo (SE) with T₂- or proton density weighting is the sequence of choice to detect the brain lesions of multiple sclerosis (MS). Fast spin-echo (FSE) permits the generation of T₂-weighted images with similar contrast to SE but in a fraction of the time. We compared the sensitivity of FSE and SE in the detection of the brain lesions of MS. Six patients with clinically definite MS underwent brain imaging with both dual echo (long TR, long and short echo time (TE) SE and dual echo FSE. The SE and FSE images were first reviewed independently and then compared. A total of 404 lesions was detected on SE and 398 on FSE. Slightly more periventricular lesions were detected using SE than FSE (145 vs 127), whereas more posterior cranial fossa lesions were detected by FSE (77 vs 57). With both SE and FSE the short TE images revealed more lesions than the long echo. These results suggest that FSE could replace SE as the long TR sequence of choice in the investigation of MS.     

Dynamic gadolinium-enhanced MRI in the detection of spinal arteriovenous malformations

Arteriovenous fistulae and malformations (AVFs and AVMs) of the spinal cord are rare, potentially treatable causes of progressive disability. Although a variety of MRI abnormalities has been described, the diagnosis rests on the findings on selective spinal angiography.Collecting T2^*-weighted MR images during the passage of a gadolinium bolus gives information about perfusion and blood volume. We carried out dynamic MRI in seven patients with vascular abnormalities (5 dural AVFs, 1 intramedullary AVM, 1 cryptic angioma) and in two patients without an AVM. High resolution T1- and T2-weighted sagittal images of the whole spinal cord were first obtained using a multiarray receiver coil. Sagittal radiofrequency spoilt gradient echo images (GE34/25, flip angle 10⁰) were then obtained during bolus injection of gadolinium-DTPA. Abnormalities were seen in all seven patients with AVFs or AVMs. In the patient with an intramedullary AVM and four of the five with dural AVFs transient signal reduction was seen within the perimedullary venous plexus during passage of the bolus. The findings correlated well with those from selective spinal angiography. We conclude that dynamic MRI offers a useful adjunct to angiography and may localise an arteriovenous shunt when conventional MRI fails to do so. In combination with high-resolution imaging of the entire spinal cord the technique may make myelography redundant; it is simple, well tolerated and can be carried out without significant time penalty.     

Recombination does not generate pinworm susceptibility during experimental crosses between two mouse subspecies

The susceptibility to Aspiculuris tetraptera of European Mus musculus hybrids is thought to reflect the disruption of genomic co-adaptation through recombination of the parental genomes. Here, we compared the susceptibility to this parasite between parents and experimental hybrids (intersubspecific until F4, intrasubspecific F1, F2) to clarify the contributions of heterosis and subspecies incompatibility. F1 showed hybrid vigor. Unlike intrasubspecific F2, intersubspecific F2 were less resistant than F1, but revealed no increased susceptibility relative to the parents. Intersubspecific F3 and F4 showed the same hybrid vigor as F1. Heterosis contributed most to the resistance, but the differences between intra- and intersubspecific F2 suggested genomic incompatibilities between subspecies. However, the susceptibility did not increase through the recombination process, showing that disruption of co-adaptation does not directly affect resistance. Even if previous studies still support the selective role of parasites in the current hybrid zone, an alternative hypothesis on the origin of hybrid susceptibility is warranted.     

Epicutaneous immunotherapy protects cashew-sensitized mice from anaphylaxis

Background

The prevalence of tree nut allergy has increased worldwide, and cashew has become one of the most common food allergens. More critically, cashew allergy is frequently associated with severe anaphylaxis. Despite the high medical need, no approved treatment is available and strict avoidance and preparedness for prompt treatment of allergic reactions are considered dual standard of care. In the meantime, Phase III study results suggest investigational epicutaneous immunotherapy (EPIT) may be a relevant and safe treatment for peanut allergy and may improve the quality of life for many peanut allergic children.

Objective

We aimed to evaluate the capacity of EPIT to provide protection against cashew-induced anaphylaxis in a relevant mouse model.

Methods

The efficacy of EPIT was evaluated by applying patches containing cashew allergens to cashew-sensitized mice. As negative control, sham mice received patches containing excipient. Following treatment, mice were challenged orally to cashew and anaphylactic symptoms, as well as plasmatic levels of mast-cell proteases (mMCP)-1/7, were quantified.

Results

Of 16 weeks of EPIT significantly protects against anaphylaxis by promoting a faster recovery of challenged mice. This protection was characterized by a significant reduction of temperature drop and clinical symptoms, 60 minutes after challenge. This was associated with a decrease in mast-cell reactivity as attested by the reduction of mMCP-1/7 in plasma, suggesting that EPIT specifically decrease IgE-mediated anaphylaxis.

Conclusion

We demonstrate that EPIT markedly reduced IgE-mediated allergic reactions in a mouse model of cashew allergy, which suggests that EPIT may be a relevant approach to treating cashew allergy.

     

Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Colorectal cancer screening practices among cancer survivors five years after diagnosis

Background

Colorectal cancer (CRC) has a high incidence worldwide, especially in high-income countries. In France, a national CRC screening program targeting residents aged 50–74 years has been in place since 2009. Little is known about CRC screening practices in cancer survivors, even though some have an increased risk of developing a second cancer in the colorectum. This study aims to identify the barriers to CRC screening among cancer survivors.

Methods

This cross-sectional study based on the French national VICAN survey included individuals diagnosed in 2010 with a cancer in 1 of 11 locations other than the colorectum and interviewed 5 years after diagnosis about various health-related issues. Binary logistic regression was used to identify the factors associated with lack of up-to-date CRC screening in cancer survivors without cancer progression.

Results

Of the 2935 cancer survivors included in the study, 35.3% reported undergoing a screening test in the previous 2 years. The rate of up-to-date CRC screening rose to 49.3% in survivors aged 51–75 years. Among these, lack of CRC screening in the recommended time frame was associated with obesity, current smoking, non-use of complementary medicine, perceived financial difficulties, and poor access to general practitioners.

Conclusions

Barriers to CRC screening can be personal and/or institutional.

     

1p36 deletion syndrome: Review and mapping with further characterization of the phenotype,a new cohort of 86 patients

Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype–phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.