Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes.

Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration

Age-related changes in cervical sagittal range of motion and alignment

Study Design Retrospective cohort study. Objective To compare sagittal cervical range of motion (ROM) and alignment in young versus middle-aged adults. Methods One hundred four asymptomatic adults were selected randomly out of 791 subjects who underwent lateral cervical radiographs in neutral, flexion, and extension positions. They were divided into two groups: young (age 20 to 29, 52 people) and middle-aged adults (age 50 to 59, 52 people). We determined the ROMs of upper cervical (occipital–C2 angle), midcervical (C2–C7 angle), and cervicothoracic spine (cervicosternal angle). We compared the alignment differences of the two groups by calculating the distances between C2 and C7 plumb lines, and C2 central-offset distance. Results In neutral position, there was no significant difference between young and middle-aged adults. However, in flexion, C2–C7 angle, distance between C2–C7 plumb lines, and C2 central-offset distance decreased with age. In extension, C2–C7 angle and C2 central-offset distance decreased with age. During flexion and extension, midcervical ROM and the range of C2 central-offset distance decreased in the middle-aged group. However, there was no difference between the two age groups in the ROM of the upper cervical and the cervicothoracic regions during flexion and extension. Conclusion We found that, despite of the presence of age-related cervical alignment changes, the only difference between the two groups was in the sagittal ROM of the midcervical spine during flexion and extension. Only the ROM of the midcervical spine appears to change significantly, consistent with findings that these levels are most likely to develop both symptomatic and asymptomatic degenerative changes

Realization of giant magnetoelectricity in helimagnets

We show that low field magnetoelectric (ME) properties of helimagnets Ba0.5Sr1.5Zn2(Fe1-xAlx)12O22 can be efficiently tailored by Al-substitution level. As x increases, the critical magnetic field for switching electric polarization is systematically reduced from ~1 T down to ~1 mT, and the ME susceptibility is greatly enhanced to reach a giant value of 2.0 x 10^4 ps/m at an optimum x = 0.08. We find that control of nontrivial orbital moment in the octahedral Fe sites through the Al-substitution is crucial for fine tuning of magnetic anisotropy and obtaining the conspicuously improved ME characteristics

Increasing trends in hospital care burden of atrial fibrillation in Korea, 2006 through 2015

ObjectiveTemporal changes in the healthcare burden of atrial fibrillation (AF) are less well known in rapidly ageing Asian countries. We examined trends in hospitalisations, costs, treatment patterns and outcomes related to AF in Korea.MethodsUsing the National Health Insurance Service (NHIS) database involving the entire adult Korean population (n=41 701 269 in 2015), we analysed a nationwide AF cohort representing 931 138 patients with AF. We studied all hospitalisations due to AF from 2006 to 2015.ResultsOverall, hospitalisations for AF increased by 420% from 767 to 3986 per 1 million Korean population from 2006 to 2015. Most admissions occurred in patients aged ≥70 years, and the most frequent coexisting conditions were hypertension, heart failure and chronic obstructive pulmonary disease. Hospitalisations mainly due to major bleeding and AF control increased, whereas hospitalisations mainly due to ischaemic stroke and myocardial infarction decreased. The total cost of care increased even after adjustment for inflation from €68.4 million in 2006 to €388.4 million in 2015, equivalent to 0.78% of the Korean NHIS total expenditure. Overall in-hospital mortality decreased from 7.5% in 2006 to 4.3% in 2015. The in-hospital mortality was highest in patients ≥80 years of age (7.7%) and in patients with chronic kidney disease (7.4%).ConclusionsAF hospitalisations have increased exponentially over the past 10 years in Korea, in association with an increase in comorbid chronic diseases. Mortality associated with AF hospitalisations decreased during the last decade, but hospitalisation costs have markedly increased.</jats:sec

Impact of frailty on early rhythm control outcomes in older adults with atrial fibrillation: A nationwide cohort study

PurposeRhythm-control therapy administered early following the initial diagnosis of atrial fibrillation (AF) has superior cardiovascular outcomes compared to rate-control therapy. Frailty is a key factor in identifying older patients’ potential for improvement after rhythm-control therapy. This study evaluated whether frailty affects the outcome of early rhythm-control therapy in older patients with AF.MethodsFrom the Korean National Health Insurance Service database (2005–2015), we collected 20,611 populations aged ≥65 years undergoing rhythm- or rate-control therapy initiated within 1 year of AF diagnosis. Participants were emulated by the EAST-AFNET4 trial, and stratified into non-frail, moderately frail, and highly frail groups based on the hospital frailty risk score (HFRS). A composite outcome of cardiovascular-related mortality, myocardial infarction, hospitalization for heart failure, and ischemic stroke was compared between rhythm- and rate-control.ResultsEarly rhythm-control strategy showed a 14% lower risk of the primary composite outcome in the non-frail group [weighted incidence 7.3 vs. 8.6 per 100 person-years; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.79–0.93, p &lt; 0.001] than rate-control strategy. A consistent trend toward a lower risk of early rhythm-control was observed in the moderately frail (HR 0.91, 95% CI 0.81–1.02, p = 0.09) and highly frail (HR 0.93, 95% CI 0.75–1.17, p = 0.55) groups.ConclusionAlthough the degree attenuated with increasing frailty, the superiority of cardiovascular outcomes of early rhythm-control in AF treatment was maintained without increased risk for safety outcomes. An individualized approach is required on the benefits of early rhythm-control therapy in older patients with AF, regardless of their frailty status

Detailed analysis of phenotypes and genotypes in megalencephaly-capillary malformation-polymicrogyria syndrome caused by somatic mosaicism of PIK3CA mutations

Abstract Background Megalencephaly-capillary malformation-polymicrogyria syndrome (MCAP) belongs to a group of conditions called the PIK3CA-related overgrowth spectrum (PROS). The varying phenotypes and low frequencies of each somatic mosaic variant make confirmative diagnosis difficult. We present 12 patients who were diagnosed clinically and genetically with MCAP. Genomic DNA was extracted mainly from the skin of affected lesions, also from peripheral blood leukocytes and buccal epithelial cells, and target panel sequencing using high-depth next-generation sequencing technology was performed. Results Macrocephaly was present in 11/12 patients (92%). All patients had normal body asymmetry. Cutaneous vascular malformation was found in 10/12 patients (83%). Megalencephaly or hemimegalencephaly was noted in all 11 patients who underwent brain magnetic resonance imaging. Arnold–Chiari type I malformation was also seen in 10 patients. Every patient was identified as having pathogenic or likely pathogenic variants of the PIK3CA gene. The variant allele frequency (VAF) ranged from 6.3 to 35.3%, however, there was no direct correlation between VAF and the severity of associated anomalies. c.2740G > A (p.Gly914Arg) was most commonly found, in four patients (33%). No malignancies developed during follow-up periods. Conclusions This is the first and largest cohort of molecularly diagnosed patients with MCAP in Korea. Targeted therapy with a PI3K-specific inhibitor, alpelisib, has shown successful outcomes in patients with PROS in a pilot clinical study, so early diagnosis for genetic counseling and timely introduction of emerging treatments might be achieved in the future through optimal genetic testing

Interlaboratory comparison study of the Colony Forming Efficiency assay for assessing cytotoxicity of nanomaterials

Nanotechnology has gained importance in the past years as it provides opportunities for industrial growth and innovation. However, the increasing use of manufactured nanomaterials (NMs) in a number of commercial applications and consumer products raises also safety concerns and questions regarding potential unintended risks to humans and the environment. Since several years the European Commission’s Joint Research Centre (JRC) is putting effort in the development, optimisation and harmonisation of in vitro test methods suitable for screening and hazard assessment of NMs. Work is done in collaboration with international partners, in particular the Organisation for Economic Co-operation and Development (OECD). This report presents the results from an interlaboratory comparison study of the in vitro Colony Forming Efficiency (CFE) cytotoxicity assay performed in the frame of OECD's Working Party of Manufactured Nanomaterials (WPMN). Twelve laboratories from European Commission, France, Italy, Japan, Poland, Republic of Korea, South Africa and Switzerland participated in the study coordinated by JRC. The results show that the CFE assay is a suitable and robust in vitro method to assess cytotoxicity of NMs. The assay protocol is well defined and is easily and reliably transferable to other laboratories. The results obtained show good intra and interlaboratory reproducibility of the assay for both the positive control and the tested nanomaterials. In conclusion the CFE assay can be recommended as a building block of an in vitro testing battery for NMs toxicity assessment. It could be used as a first choice method to define dose-effect relationships for other in vitro assays.JRC.I.4-Nanobioscience