Noncoding variation of the gene for ferritin light chain in hereditary and age-related cataract

PURPOSE: Cataract is a clinically and genetically heterogeneous disorder of the ocular lens and an important cause of visual impairment. The aim of this study was to map and identify the gene underlying autosomal dominant cataract segregating in a four-generation family, determine the lens expression profile of the identified gene, and test for its association with age-related cataract in a case-control cohort. METHODS: Genomic DNA was prepared from blood leukocytes, and genotyping was performed by means of single-nucleotide polymorphism markers and microsatellite markers. Linkage analyses were performed using the GeneHunter and MLINK programs, and mutation detection was achieved by dideoxy cycle sequencing. Lens expression studies were performed using reverse-transcription polymerase chain reaction (RT–PCR) and in situ hybridization. RESULTS: Genome-wide linkage analysis with single nucleotide polymorphism markers in the family identified a likely disease-haplotype interval on chromosome 19q (rs888861-[~17Mb]-rs8111640) that encompassed the microsatellite marker D19S879 (logarithm of the odds score [Z]=2.03, recombination distance [θ]=0). Mutation profiling of positional-candidate genes detected a heterozygous, noncoding G-to-T transversion (c.-168G>T) located in the iron response element (IRE) of the gene coding for ferritin light chain (FTL) that cosegregated with cataract in the family. Serum ferritin levels were found to be abnormally elevated (~fourfold), without evidence of iron overload, in an affected family member; this was consistent with a diagnosis of hereditary hyperferritinemia-cataract syndrome. No sequence variations located within the IRE were detected in a cohort of 197 cases with age-related cataract and 102 controls with clear lenses. Expression studies of human FTL, and its mouse counterpart FTL1, in the lens detected RT–PCR amplicons containing full-length protein-coding regions, and strong in situ localization of FTL1 transcripts to the lens equatorial epithelium and peripheral cortex. CONCLUSIONS: The data are consistent with robust transcription of FTL in the lens, and suggest that whereas variations clustered in the IRE of the FTL gene are directly associated with hereditary hyperferritinemia-cataract syndrome, such IRE variations are unlikely to play a significant role in the genetic etiology of age-related cataract

New treatment methods for myocardial infarction

For a long time, cardiovascular clinicians have focused their research on coronary atherosclerotic cardiovascular disease and acute myocardial infarction due to their high morbidity, high mortality, high disability rate, and limited treatment options. Despite the continuous optimization of the therapeutic methods and pharmacological therapies for myocardial ischemia–reperfusion, the incidence rate of heart failure continues to increase year by year. This situation is speculated to be caused by the current therapies, such as reperfusion therapy after ischemic injury, drugs, rehabilitation, and other traditional treatments, that do not directly target the infarcted myocardium. Consequently, these therapies cannot fundamentally solve the problems of myocardial pathological remodeling and the reduction of cardiac function after myocardial infarction, allowing for the progression of heart failure after myocardial infarction. Coupled with the decline in mortality caused by acute myocardial infarction in recent years, this combination leads to an increase in the incidence of heart failure. As a new promising therapy rising at the beginning of the twenty-first century, cardiac regenerative medicine provides a new choice and hope for the recovery of cardiac function and the prevention and treatment of heart failure after myocardial infarction. In the past two decades, regeneration engineering researchers have explored and summarized the elements, such as cells, scaffolds, and cytokines, required for myocardial regeneration from all aspects and various levels day and night, paving the way for our later scholars to carry out relevant research and also putting forward the current problems and directions for us. Here, we describe the advantages and challenges of cardiac tissue engineering, a contemporary innovative therapy after myocardial infarction, to provide a reference for clinical treatment

Genotype–Phenotype Analysis of RPGR Variations: Reporting of 62 Chinese Families and a Literature Review

PurposeRPGR is the most common cause of X-linked retinitis pigmentosa (RP), of which female carriers are also frequently affected. The aim of the current study was to explore the RPGR variation spectrum and associated phenotype based on the data from our lab and previous studies.MethodsVariants in RPGR were selected from exome sequencing data of 7,092 probands with different eye conditions. The probands and their available family members underwent comprehensive ocular examinations. Similar data were collected from previous reports through searches in PubMed, Web of Science, and Google Scholar. Systematic analyses of genotypes, phenotypes and their correlations were performed.ResultsA total of 46 likely pathogenic variants, including nine missense and one in-frame variants in RCC1-like domain and 36 truncation variants, in RPGR were detected in 62 unrelated families in our in-house cohort. In addition, a total of 585 variants, including 491 (83.9%) truncation variants, were identified from the literature. Systematic analysis of variants from our in-house dataset, literature, and gnomAD suggested that most of the pathogenic variants of RPGR were truncation variants while pathogenic missense and in-frame variants were enriched in the RCC1-like domain. Phenotypic variations were present between males and female carriers, including more severe refractive error but better best corrected visual acuity (BCVA) in female carriers than those in males. The male patients showed a significant reduction of BCVA with increase of age and males with exon1-14 variants presented a better BCVA than those with ORF15 variants. For female carriers, the BCVA also showed significant reduction with increase of age, but BCVA in females with exon1-14 variants was not significant difference compared with those with ORF15 variants.ConclusionMost pathogenic variants of RPGR are truncations. Missense and in-frame variants located outside of the RCC1-like domain might be benign and the pathogenicity criteria for these variants should be considered with greater caution. The BCVA and refractive error are different between males and female carriers. Increase of age and location of variants in ORF15 contribute to the reduction of BCVA in males. These results are valuable for understanding genotypes and phenotypes of RPGR

Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families.

PurposeThe Pakistan Punjab population has been a rich source for identifying genes causing or contributing to autosomal recessive retinal degenerations (arRD). This study was carried out to delineate the genetic architecture of arRD in the Pakistani population.MethodsThe genetic origin of arRD in a total of 144 families selected only for having consanguineous marriages and multiple members affected with arRD was examined. Of these, causative mutations had been identified in 62 families while only the locus had been identified for an additional 15. The remaining 67 families were subjected to homozygosity exclusion mapping by screening of closely flanking microsatellite markers at 180 known candidate genes/loci followed by sequencing of the candidate gene for pathogenic changes.ResultsOf these 67 families subjected to homozygosity mapping, 38 showed homozygosity for at least one of the 180 regions, and sequencing of the corresponding genes showed homozygous cosegregating mutations in 27 families. Overall, mutations were detected in approximately 61.8 % (89/144) of arRD families tested, with another 10.4% (15/144) being mapped to a locus but without a gene identified.ConclusionsThese results suggest the involvement of unmapped novel genes in the remaining 27.8% (40/144) of families. In addition, this study demonstrates that homozygosity mapping remains a powerful tool for identifying the genetic defect underlying genetically heterogeneous arRD disorders in consanguineous marriages for both research and clinical applications

Robust Anti‐Tumor T Cell Response with Efficient Intratumoral Infiltration by Nanodisc Cancer Immunotherapy

Potent anti‐tumor T cell response and efficient intratumoral T cell infiltration are the major challenges for therapeutic cancer vaccines. To address these issues, a nanovaccine system is designed to promote anti‐tumor T cell responses, and intratumoral infiltration is examined in various murine tumor models. Subcutaneous vaccination with nanodiscs carrying human papillomavirus (HPV)‐16 E7 antigen elicits as high as ∼32% E7‐specific CD8α+ T cell responses in circulation, representing a 29‐fold improvement over the soluble peptide vaccination. Importantly, nanodisc vaccination also promotes robust intratumoral T cell infiltration and eliminates HPV16 E6/E7‐expressing TC‐1 tumors at mucosal sites, including lungs, inner lip, and intravaginal tissues. In a benchmark study with a live Listeria vaccine combined with anti‐PD‐1 IgG, nanodiscs plus anti‐PD‐1 immune checkpoint blockade elicits comparable levels of T cell responses with anti‐tumor efficacy. Furthermore, compared with Complete Freund’s Adjuvant combined with tetanus toxoid, nanodisc vaccination in HLA‐A02 mice generates >200‐fold stronger IFN‐γ+ T cell responses against a neoantigen from an HLA‐A02 melanoma patient. Overall, these results show that the nanodisc system is a promising cancer vaccine platform for inducing anti‐tumor T cell responses.Efficient infiltration of T cells in solid cancer is a major challenge for cancer immunotherapy. A nanoparticle vaccine system is developed to promote T cell infiltration into peripheral mucosal tissues and eliminate disseminated tumors. Nanodiscs are broadly applicable with a wide range of tumor antigens, thus providing a versatile and potent vaccine platform for eliciting T cell immunity.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/3/adtp202000094.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/2/adtp202000094-sup-0001-SuppMat.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156420/1/adtp202000094_am.pd

Sex Differences in Abnormal Intrinsic Functional Connectivity After Acute Mild Traumatic Brain Injury

Mild traumatic brain injury (TBI) is considered to induce abnormal intrinsic functional connectivity within resting-state networks (RSNs). The objective of this study was to estimate the role of sex in intrinsic functional connectivity after acute mild TBI. We recruited a cohort of 54 patients (27 males and 27 females with mild TBI within 7 days post-injury) from the emergency department (ED) and 34 age-, education-matched healthy controls (HCs; 17 males and 17 females). On the clinical scales, there were no statistically significant differences between males and females in either control group or mild TBI group. To detect whether there was abnormal sex difference on functional connectivity in RSNs, we performed independent component analysis (ICA) and a dual regression approach to investigate the between-subject voxel-wise comparisons of functional connectivity within seven selected RSNs. Compared to female patients, male patients showed increased intrinsic functional connectivity in motor network, ventral stream network, executive function network, cerebellum network and decreased connectivity in visual network. Further analysis demonstrated a positive correlation between the functional connectivity in executive function network and insomnia severity index (ISI) scores in male patients (r = 0.515, P = 0.006). The abnormality of the functional connectivity of RSNs in acute mild TBI showed the possibility of brain recombination after trauma, mainly concerning male-specific

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat

Correction to: Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

The original version of this article unfortunately contained a mistake