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Article

Health-Related Quality of Life and Related Factors among Primary Caregivers of Children with Disabilities in Shanghai, China: A Cross-Sectional Study

by Cong Xia; Mei Sun; Xinying Li; Chenhao Lu; Xiu Gao; Jun Lu; Gang Chen

2020

Subjects
  • Health Sciences, Public Health
  • Biology, Ecology
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Health-related quality of life (HRQOL) of caregivers of children with disabilities (CWD) is important for both children’s rehabilitation and caregivers’ life, but the corresponding attention is far from enough in mainland China. Thus, we investigated the HRQOL of 170 caregivers and related factors in Shanghai. The 12-item Short Form Health Survey (SF-12) was used to measure HRQOL. The potential factors were collected, including child characteristics, caregiver characteristics, and environmental factors. Univariate analysis and multiple linear regression were performed to identify the key factors that could be intervened. Compared with the general population, caregivers of CWD had a slightly higher score on the physical component summary (PCS, 52.57 ± 8.41), but the score of mental component summary (MCS, 31.58 ± 7.72) was extremely low. Caregiver’s illness condition, family size, and household income were significant factors of physical HRQOL. Caregivers with illness and caregivers living in an extended family were associated with higher mental HRQOL. Whereas these two factors had opposite effects on physical HRQOL. This finding indicated poor mental HRQOL among caregivers of CWD in Shanghai and thus requiring urgent attention and intervention. Improving physical fitness, maintaining family integration, and providing financial support should be considered when developing intervention for this population.

Article

Virus-like particles as universal influenza vaccines

by Sang-Moo Kang; Min-Chul Kim; Richard W Compans

2012

Subjects
  • Health Sciences, Immunology
  • Biology, General
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Current influenza vaccines are primarily targeted to induce immunity to the influenza virus strain-specific hemagglutinin antigen and are not effective in controlling outbreaks of new pandemic viruses. An approach for developing universal vaccines is to present highly conserved antigenic epitopes in an immunogenic conformation such as virus-like particles (VLPs) together with an adjuvant to enhance the vaccine immunogenicity. In this review, the authors focus on conserved antigenic targets and molecular adjuvants that were presented in VLPs. Conserved antigenic targets that include the hemagglutinin stalk domain, the external domain of influenza M2 and neuraminidase are discussed in addition to molecular adjuvants that are engineered to be incorporated into VLPs in a membrane-anchored form. © 2012 2012 Expert Reviews Ltd.

Article

Frequency drift in MR spectroscopy at 3T

by Steve CN Hui; Mark Mikkelsen; Helge J Zollner; Vishwadeep Ahluwalia; Sarael Alcauter; Laima Baltusis; Deborah A Barany; Laura R Barlow; Robert Becker; Jeffrey Berman; Adam Berrington; Pallab K Bhattacharyya; Jakob Udby Blicher; Wolfgang Bogner; Mark S Brown; Vince D Calhoun; Ryan Castillo; Kim M Cecil; Yeo B Choi; Winnie CW Chu; William T Clarke; Alexander R Craven; Koen Cuypers; Michael Dacko; Camilo de la Fuente-Sandoval; Patricia Desmond; Aleksandra Domagalik; Julien Dumont; Niall W Duncan; Ulrike Dydak; Katherine Dyke; David A Edmondson; Gabriele Ende; Lars Ersland; John C Evans; Alan SR Fermin; Antonio Ferretti; Ariane Fillmer; Tao Gong; Ian Greenhouse; James T Grist; Meng Gu; Ashley D Harris; Katarzyna Hatz; Stefanie Heba; Eva Heckova; John P Hegarty; Kristin-Freiderike Heise; Shiori Honda; Aaron Jacobson; Jacobus FA Jansen; Chrsitopher W Jenkins; Stephen J Johnston; Christoph Juchem; Alayar Kangarlu; Adam B Kerr; Karl Landheer; Thomas Lange; Phil Lee; Swati Rane Levendovszky; Catherine Limperopoulos; Feng Liu; William Lloyd; David J Lythgoe; Maro G Machizawa; Erin L MacMillan; Richard J Maddock; Andrei Manzhurtsev; María L Martinez-Gudino; Jack J Miller; Heline Mirzakhanian; Marta Moreno-Ortega; Paul G Mullins; Shinichiro Nakajima; Jamie Near; Ralph Noeske; Wibeke Nordhoy; Georg Oeltzschner; Raul Osorio-Duran; Maria CG Otaduy; Erick H Pasaye; Ronald Peeters; Scott J Peltier; Ulrich Pilatus; Nenad Polomac; Eric C Porges; Subechhya Pradhan; James Joseph Prisciandaro; Nicolaas A Puts; Caroline D Rae; Francisco Reyes-Madrigal; Timothy PL Roberts; Caroline E Robertson; Jens T Rosenberg; Diana-Georgiana Rotaru; Ruth L O'Gorman Tuura Tuura; Muhammad G Saleh; Kristian Sandberg; Ryan Sangill; Keith Schembri; Anouk Schrantee; Natalia A Semenova; Debra Singel; Rouslan Sitnikov; Jolinda Smith; Yulu Song; Craig Stark; Diederick Stoffers; Stephan P Swinnen; Rongwen Tain; Costin Tanase; Sofie Tapper; Martin Tegenthoff; Thomas Thiel; Marc Thioux; Peter Truong; Pim van Dijk; Nolan Vella; Rishma Vidyasagar; Andrej Vovk; Guangbin Wang; Lars T Westlye; Timothy K Wilbur; William R Willoughby; Martin Wilson; Hans-Jörg Wittsack; Adam J Woods; Yen-Chien Wu; Junqian Xu; Maria Yanez Lopez; David KW Yeung; Qun Zhao; Xiaopeng Zhou; Gasper Zupan; Richard AE Edden

2021

Subjects
  • Health Sciences, Mental Health
  • Health Sciences, Rehabilitation and Therapy
  • Health Sciences, Radiology
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Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI. Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed.

Article

Effects of Pyruvate Kinase M2 (PKM2) Gene Deletion on Astrocyte-Specific Glycolysis and Global Cerebral Ischemia-Induced Neuronal Death

by Beom-Seok Kang; Bo Youg Choi; A-Ra Kho; Song-Hee Lee; Dae-Ki Hong; Min-Kyu Park; Si-Hyun Lee; Chang-Juhn Lee; Hyeun-Wook Yang; Seo-Young Woo; Se-Wan Park; Dong-Yeon Kim; Jae-Bong Park; Won-Suk Chung; Sang-Won Suh

2023

Subjects
  • Health Sciences, Medicine and Surgery
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Ischemic stroke is caused by insufficient blood flow to the brain. Astrocytes have a role in bidirectionally converting pyruvate, generated via glycolysis, into lactate and then supplying it to neurons through astrocyte–neuron lactate shuttle (ANLS). Pyruvate kinase M2 (PKM2) is an enzyme that dephosphorylates phosphoenolpyruvate to pyruvate during glycolysis in astrocytes. We hypothesized that a reduction in lactate supply in astrocyte PKM2 gene deletion exacerbates neuronal death. Mice harboring a PKM2 gene deletion were established by administering tamoxifen to Aldh1l1-CreERT2; PKM2f/f mice. Upon development of global cerebral ischemia, mice were immediately injected with sodium l-lactate (250 mg/kg, i.p.). To verify our hypothesis, we compared oxidative damage, microtubule disruption, ANLS disruption, and neuronal death between the gene deletion and control subjects. We observed that PKM2 gene deletion increases the degree of neuronal damage and impairment of lactate metabolism in the hippocampal region after GCI. The lactate administration groups showed significantly reduced neuronal death and increases in neuron survival and cognitive function. We found that lactate supply via the ANLS in astrocytes plays a crucial role in maintaining energy metabolism in neurons. Lactate administration may have potential as a therapeutic tool to prevent neuronal damage following ischemic stroke.

Article

Plakophilin-1 Protects Keratinocytes from Pemphigus Vulgaris IgG by Forming Calcium-Independent Desmosomes

by Dana K. Tucker; Sara N. Stahley; Andrew Kowalczyk

2014

Subjects
  • Biology, Cell
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Plakophilin-1 (PKP-1) is an armadillo family protein critical for desmosomal adhesion and epidermal integrity. In the autoimmune skin-blistering disease pemphigus vulgaris (PV), autoantibodies (IgG) target the desmosomal cadherin desmoglein 3 (Dsg3) and compromise keratinocyte cell-cell adhesion. Here, we report that enhanced expression of PKP-1 protects keratinocytes from PV IgG-induced loss of cell-cell adhesion. PKP-1 prevents loss of Dsg3 and other desmosomal proteins from cell-cell borders and prevents alterations in desmosome ultrastructure in keratinocytes treated with PV IgG. Using a series of Dsg3 chimeras and deletion constructs, we find that PKP-1 clusters Dsg3 with the desmosomal plaque protein desmoplakin in a manner dependent on the plakoglobin-binding domain of the Dsg3 tail. Furthermore, PKP-1 expression transforms desmosome adhesion from a calcium-dependent to a calcium-independent and hyperadhesive state. These results demonstrate that manipulating the expression of a single desmosomal plaque protein can block the pathogenic effects of PV IgG on keratinocyte adhesion.

Article

FLT3 Mutation Status is a Predictor of Early Death in Pediatric Acute Promyelocytic Leukemia: A Report From The Children's Oncology Group

by Matthew A. Kutny; Barry K. Moser; Kristina Laumann; James H. Feusner; Alan Gamis; John Gregory; Richard A. Larson; Bayard L. Powell; Wendy Stock; Cheryl L. Willman; William G Woods; Soheil Meshinchi

2012

Subjects
  • Health Sciences, Oncology
  • Health Sciences, Pathology
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Background: FLT3 mutations (FLT3/Mut) are prevalent in de novo AML and are associated with early relapse. The prevalence and prognostic significance of FLT3/Mut have not been well defined in childhood acute promyelocytic leukemia (APL). Procedure: Diagnostic specimens from 104 pediatric APL patients were screened for FLT3/Mut (FLT3/ITD or FLT3/ALM). FLT3/Mut status was correlated with disease characteristics and clinical outcome for patients treated on CALGB C9710 (n=50). Results: Forty-two of the 104 patients (40%) had either FLT3/ITD (n=28, 27%) or FLT3/ALM (n=15, 14%). Median diagnostic WBC count was 23,400cells/μl vs. 3,600cells/μl for those with and without FLT3/Mut (P<0.001), and similar results for the cohort of 50 patients treated on C9710 (P<0.001). In patients treated on C9710, presence of a FLT3 mutation was highly correlated with diagnostic WBC count >10,000 (P=0.004), microgranular variant histology (P=0.035), and a lower remission rate (P=0.009). In patients who received ATRA (C9710 or CCG-2911, n=58), those with FLT3/Mut had an induction death rate of 30% (7/23) compared to 3% (1/35) in FLT3/WT patients (P=0.005). In patients with high WBC counts (>10,000), those with FLT3/Mut had a significantly higher risk of induction death versus FLT3/WT patients (47% vs. 0%, P=0.05). FLT3/Mut was not associated with adverse outcome in those who survived induction therapy. Conclusions: FLT3/Mut are prevalent in pediatric APL and are associated with high WBC count and increased induction death. This study provides further evidence for testing APL patients for FLT3/Mut and the potential role for FLT3 inhibitors in this disease.

Article

Properly Substituted Analogues of BIX-01294 Lose Inhibition of G9a Histone Methyltransferase and Gain Selective Anti-DNA Methyltransferase 3A Activity

by Dante Rotili; Domenico Tarantino; Biagina Marrocco; Christina Gros; Véronique Masson; Valérie Poughon; Fréderic Ausseil; Yanqi Chang; Donatella Labella; Sandro Cosconati; Salvatore Di Maro; Ettore Novellino; Michael Schnekenburger; Cindy Grandjenette; Celine Bouvy; Marc Diederich; Xiaodong Cheng; Paola B. Arimondo; Antonello Mai

2014

Subjects
  • Chemistry, Biochemistry
  • Health Sciences, Pharmacy
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Chemical manipulations performed on the histone H3 lysine 9 methyltransferases (G9a/GLP) inhibitor BIX-01294 afforded novel desmethoxyquinazolines able to inhibit the DNA methyltransferase DNMT3A at low micromolar levels without any significant inhibition of DNMT1 and G9a. In KG-1 cells such compounds, when tested at sub-toxic doses, induced the luciferase re-expression in a stable construct controlled by a cytomegalovirus (CMV) promoter silenced by methylation (CMV-luc assay). Finally, in human lymphoma U-937 and RAJI cells, the N-(1-benzylpiperidin-4-yl)-2-(4-phenylpiperazin-1-yl) quinazolin-4-amine induced the highest proliferation arrest and cell death induction starting from 10 μM, in agreement with its DNMT3A inhibitory potency.

Article

Hypoxia augments the calcium-activated chloride current carried by anoctamin-1 in cardiac vascular endothelial cells of neonatal mice

by Ming-Ming Wu; Jie Lou; Bin-Lin Song; Yuan-Feng Gong; Yan-Chao Li; Chang-Jiang Yu; Qiu-Shi Wang; Tian-Xing Ma; Ke Ma; Harrison Hartzell Jr.; Dayue Darrel Duan; Dan Zhao; Zhi-Ren Zhang

2014

Subjects
  • Biology, Cell
  • Health Sciences, Pharmacy
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Background and Purpose The molecular identity of calcium-activated chloride channels (CaCCs) in vascular endothelial cells remains unknown. This study sought to identify whether anoctamin-1 (Ano1, also known as TMEM16A) functions as a CaCC and whether hypoxia alters the biophysical properties of Ano1 in mouse cardiac vascular endothelial cells (CVECs). Experimental Approach Western blot, quantitative real-time PCR, confocal imaging analysis and patch-clamp analysis combined with pharmacological approaches were used to determine whether Ano1 was expressed and functioned as CaCC in CVECs. Key Results Ano1 was expressed in CVECs. The biophysical properties of the current generated in the CVECs, including the Ca2+ and voltage dependence, outward rectification, anion selectivity and the pharmacological profile, are similar to those described for CaCCs. The density of ICl(Ca) detected in CVECs was significantly inhibited by T16A inh-A01, an Ano1 inhibitor, and a pore-targeting, specific anti-Ano1 antibody, and was markedly decreased in Ano1 gene knockdown CVECs. The density of ICl(Ca) was significantly potentiated in CVECs exposed to hypoxia, and this hypoxia-induced increase in the density of ICl(Ca) was inhibited by T16Ainh-A01 or anti-Ano1 antibody. Hypoxia also increased the current density of ICl(Ca) in Ano1 gene knockdown CVECs. Conclusions and Implications Ano1 formed CaCC in CVECs of neonatal mice. Hypoxia enhances Ano1-mediated ICl(Ca) density via increasing its expression, altering the ratio of its splicing variants, sensitivity to membrane voltage and to Ca 2+. Ano1 may play a role in the pathophysiological processes during ischaemia in heart, and therefore, Ano1 might be a potential therapeutic target to prevent ischaemic damage.

Article

HIV-1 non-macrophage-tropic R5 envelope glycoproteins are not more tropic for entry into primary CD4+T-cells than envelopes highly adapted for macrophages

by Thomas Musich; Olivia O'Connell; Maria Paz Gonzalez-Perez; Cynthia Derdeyn; Paul J. Peters; Paul R. Clapham

2015

Subjects
  • Biology, Virology
  • Biology, Microbiology
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Non-mac-tropic HIV-1 R5 viruses are predominantly transmitted and persist in immune tissue even in AIDS patients who carry highly mac-tropic variants in the brain. Non-mac-tropic R5 envelopes (Envs) require high CD4 levels for infection contrasting with highly mac-tropic Envs, which interact more efficiently with CD4 and mediate infection of macrophages that express low CD4. Non-mac-tropic R5 Envs predominantly target T-cells during transmission and in immune tissue where they must outcompete mac-tropic variants. Here, we investigated whether Env+ pseudoviruses bearing transmitted/founder (T/F), early and late disease non-mac-tropic R5 envelopes mediated more efficient infection of CD4+ T-cells compared to those with highly mac-tropic Envs. Results: Highly mac-tropic Envs mediated highest infectivity for primary T-cells, Jurkat/CCR5 cells, myeloid dendritic cells, macrophages, and HeLa TZM-bl cells, although this was most dramatic on macrophages. Infection of primary T-cells mediated by all Envs was low. However, infection of T-cells was greatly enhanced by increasing virus attachment with DEAE dextran and spinoculation, which enhanced the three Env+virus groups to similar extents. Dendritic cell capture of viruses and trans-infection also greatly enhanced infection of primary T-cells. In trans-infection assays, non-mac-tropic R5 Envs were preferentially enhanced and those from late disease mediated levels of T-cell infection that were equivalent to those mediated by mac-tropic Envs. Conclusions: Our results demonstrate that T/F, early or late disease non-mac-tropic R5 Envs do not preferentially mediate infection of primary CD4+ T-cells compared to highly mac-tropic Envs from brain tissue. We conclude that non-macrophage-tropism of HIV-1 R5 Envs in vitro is determined predominantly by a reduced capacity to target myeloid cells via low CD4 rather than a specific adaptation for T-cells entry that precludes macrophage infection.

Article

Impact of Glucose-Lowering Medications on Cardiovascular and Metabolic Risk in Type 2 Diabetes

by Angelo Maria Patti; Ali A. Rizvi; Rosaria Vincenza Giglio; Anca Pantea Stoian; Daniela Ligi; Ferdinando Mannello

2020

Subjects
  • Health Sciences, Health Care Management
  • Health Sciences, Nutrition
  • Health Sciences, Public Health
  • Chemistry, Biochemistry
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Type 2 Diabetes Mellitus (T2DM) is associated with a high risk of atherosclerotic cardiovascular (CV) disease. Among the well-known pathophysiologic factors, crucial roles are played by endothelial dysfunction (caused by oxidative stress and inflammation hyperglycemia-linked), increased activity of nuclear factor kB, altered macrophage polarization, and reduced synthesis of resident endothelial progenitor cells. As consequence, a potentially rapid progression of the atherosclerotic disease with a higher propensity to unstable plaque is arguable, finally leading to significantly increased cardiovascular mortality. Main managements are focused on both prevention and early diagnosis, by targeted treatment of hyperglycemia and vascular complications. Innovative therapeutic approaches for T2DM seek to customize the antidiabetic treatment to each patient in order to optimize glucose-lowering effects, minimize hypoglycemia and adverse effects, and prevent cardiovascular events. The newer drugs (e.g., Glucagon Like Peptide-1 Receptor Agonists, GLP-1 RAs; Sodium GLucose coTransporter-2 inhibitors, SGLT2is; DiPeptidyl Peptidase-4 inhibitors, and DPP4is) impact body weight, lipid parameters, and blood pressure, as well as endothelial (dys)functions, inflammatory markers, biomarkers of both oxidative stress, and subclinical atherosclerosis. The present review summarizes the results of the main trials focused on the cardiovascular safety of these drugs from the CV standpoint.
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