An emerging ribosomopathy affecting the skeleton due to biallelic variations in NEPRO

Cartilage hair hypoplasia (CHH), anauxetic dysplasia 1, and anauxetic dysplasia 2 are rare metaphyseal dysplasias caused by biallelic pathogenic variants in RMRP and POP1, which encode the components of RNAse‐MRP endoribonuclease complex (RMRP) in ribosomal biogenesis pathway. Nucleolus and neural progenitor protein (NEPRO), encoded by NEPRO (C3orf17), is known to interact with multiple protein subunits of RMRP. We ascertained a 6‐year‐old girl with skeletal dysplasia and some features of CHH. RMRP and POP1 did not harbor any causative variant in the proband. Parents‐child trio exomes revealed a candidate biallelic variant, c.435G>C, p.(Leu145Phe) in NEPRO. Two families with four affected individuals with skeletal dysplasia and a homozygous missense variant, c.280C>T, p.(Arg94Cys) in NEPRO, were identified from literature and their published phenotype was compared in detail to the phenotype of the child we described. All the five affected individuals have severe short stature, brachydactyly, skin laxity, joint hypermobility, and joint dislocations. They also have short metacarpals, broad middle phalanges, and metaphyseal irregularities. Protein modeling and stability prediction showed that the mutant protein has decreased stability. Both the reported variants are in the same domain of the protein. Our report delineates the clinical and radiological characteristics of an emerging ribosomopathy caused by biallelic variants in NEPRO.     

In vivo evaluation of white matter pathology in patients of progressive supranuclear palsy using TBSS

Introduction

The purpose of this research is to study white matter (WM) changes in patients of progressive supranuclear palsy (PSP) using automated analysis of diffusion tensor imaging (DTI) indices.

Methods

This was a prospective study comprising of 24 patients of PSP and 26 matched healthy controls. Fractional anisotropy, mean diffusivity (MD), axial diffusivity, and radial diffusivity (RD) changes were studied in the WM of the PSP patients using an automated analysis technique, tract-based spatial statistics (TBSS). Two subtypes of PSP, i.e., classic Richardson’s syndrome (PSP-RS) and parkinsonian type (PSP-P), were also compared among themselves to identify relative severity of WM changes as well as identify spatial distribution of the differences. Clinicoradiological correlation was done to determine the strength of correlation between WM abnormalities identified using TBSS and clinical scores.

Results

There were areas of significant abnormality seen in the frontoparietal cerebral WM, thalamus, midbrain tectum, superior cerebellar peduncle, and cerebellar WM. The abnormalities were more spatially widespread on MD and RD maps. Compared to PSP-P, the patients of PSP-RS had more spatial abnormalities localized to the frontal WM. There was no correlation between the observed WM changes and clinical rating scales.

Conclusions

The TBSS analysis showed widespread WM abnormalities in PSP patients including areas which have been shown to be involved in previous pathological studies. PSP-RS showed more severe white matter abnormality compared to the PSP-P subtype.     

Alcohol consumption and risk of stroke: a meta-analysis

Context  Observational studies suggest that heavy alcohol consumption may increase the risk of stroke while moderate consumption may decrease the risk. Objective  To examine the association between alcohol consumption and relative risk of stroke. Data Sources  Studies published in English-language journals were retrieved by searching MEDLINE (1966–April 2002) using Medical Subject Headings alcohol drinking, ethanol, cerebrovascular accident, cerebrovascular disorders, and intracranial embolism and thrombosis and the key word stroke; Dissertation Abstracts Online using the keywords stroke and alcohol; and bibliographies of retrieved articles. Study Selection  From 122 relevant retrieved reports, 35 observational studies (cohort or case control) in which total stroke, ischemic stroke, or hemorrhagic (intracerebral or total) stroke was an end point; the relative risk or relative odds and their variance (or data to calculate them) of stroke associated with alcohol consumption were reported; alcohol consumption was quantified; and abstainers served as the reference group. Data Extraction  Information on study design, participant characteristics, level of alcohol consumption, stroke outcome, control for potential confounding factors, and risk estimates was abstracted independently by 3 investigators using a standardized protocol. Data Synthesis  A random-effects model and meta-regression analysis were used to pool data from individual studies. Compared with abstainers, consumption of more than 60 g of alcohol per day was associated with an increased relative risk of total stroke, 1.64 (95% confidence interval [CI], 1.39-1.93); ischemic stroke, 1.69 (95% CI, 1.34-2.15); and hemorrhagic stroke, 2.18 (95% CI, 1.48-3.20), while consumption of less than 12 g/d was associated with a reduced relative risk of total stroke, 0.83 (95%, CI, 0.75-0.91) and ischemic stroke, 0.80 (95% CI, 0.67-0.96), and consumption of 12 to 24 g/d was associated with a reduced relative risk of ischemic stroke, 0.72 (95%, CI, 0.57-0.91). The meta-regression analysis revealed a significant nonlinear relationship between alcohol consumption and total and ischemic stroke and a linear relationship between alcohol consumption and hemorrhagic stroke. Conclusions  These results indicate that heavy alcohol consumption increases the relative risk of stroke while light or moderate alcohol consumption may be protective against total and ischemic stroke.      

Delayed Mitogenic Stimulation Decreases DNA Damage Assessed by Micronucleus Assay in Human Peripheral Blood Lymphocytes After 60Co Irradiation

While contradictory reports are available on the yield of dicentric chromosomes (DC) in blood samples stored at different temperature and stimulated to enter into cell cycle, various times gap followed by exposure, limited information is available on the micronucleus (MN) assay. As scoring the micronuclei frequency from the blood lymphocytes of exposed individuals is an alternative to the gold standard DC assay for triage applications, we examined radiation induced MN yield in delayed mitogenic stimulation after irradiation of in vitro. Peripheral blood lymphocytes (PBL) were exposed to low LET (⁶⁰Co) radiation dose (0.1 to 5Gy) and incubated at 37°C for 2, 6 and 24 hours. The MN frequency obtained in blood samples stimulated 2 hours post-irradiation showed a dose dependent increase and used to construct the dose-response curve. Further, the results also showed that blood samples stimulated twenty four hours of post-irradiation, a significant reduction (p<0.05) in MN frequencies were obtained when compared to that of blood samples stimulated two hours and six hours after post-irradiation (0.5, 1, 3 and 5Gy). The observed result suggests that the prolonged PBL storage without mitogenic stimulation could lead to interphase cell death and a delayed blood sampling could results in underestimation of dose in biological dosimetry.     

Radiation-induced bystander effects and adaptive response in murine lymphocytes

Purpose:?To study the bystander effects of γ-radiation in murine lymphocytes using irradiated conditioned medium (ICM) generated from irradiated lymphocytes.

Methods:?Proliferation response of unirradiated lymphocytes to mitogen concanavalin A (con A) in presence of ICM, collected from γ-irradiated lymphocytes (⁶⁰Co source; 0.35 Gy/min; 0.1 – 1 Gy), was studied by ³H-thymidine incorporation and also by dye dilution using carboxyfluorescein succinimidyl ester (CFSE). Expression of proliferation markers, interleukin 2 receptor α chain (CD25) and cyclin D in ICM treated lymphocytes was analyzed by labeling with specific antibodies. Intracellular reactive oxygen species (ROS) and apoptosis were estimated by flow cytometry using dichlorodihydrofluorescein diacetate (H₂DCFDA) and propidium iodide, respectively. Nitric oxide (NO) was measured using Griess reagent.

Results:?Proliferation response to con A in unirradiated lymphocytes was enhanced in the presence of ICM with maximum enhancement observed in the presence of 0.5 Gy ICM. Augmentation of proliferation in the presence of ICM was accompanied by an increase in CD25 and cyclin D expression, enhanced ROS and NO generation. ICM pretreated lymphocytes showed adaptive response to radiation which was not abrogated by wortmannin, a phosphatidyl inositol 3-kinase (PI3K) inhibitor.

Conclusion:?Soluble factors released from irradiated lymphocytes initiate a signaling cascade in unirradiated lymphocytes resulting in increased response to mitogen and radioresistance which may have an important role in radiation-induced immunomodulation.