PAX2 Mutation-Related Renal Hypodysplasia: Review of the Literature and Three Case Reports

Paired box 2 (PAX2)-related disorder is an autosomal dominant genetic disorder associated with kidney and eye abnormalities and can result in end stage renal disease (ESRD). Despite reported low prevalence of PAX2 mutations, the prevalence of PAX2 related disorders may have been underestimated in past studies. With improved genetic sequencing techniques, more genetic abnormalities are being detected than ever before. Here, we report three patients from two families with PAX2 mutations identified within 1 year. Two patients were adults with chronic kidney disease and were followed for decades without correct diagnoses, including one with ESRD who had even undergone kidney transplant. The third patient was a neonate in whom PAX2-related disorder manifested as oligohydramnios, coloboma, and renal failure that progressed to ESRD within 1 year after birth. The phenotypes of PAX2 gene mutation were shown to be highly variable, even within the same family. Early detection promoted genetic counseling and guided clinical management. The appropriate time point for genetic study is an important issue. Clinicians must be more alert for PAX2 mutation when facing patients with congenital kidney and urinary tract anomalies, chronic kidney disease of unknown etiology, involvement of multiple systems, and/or a family history of renal disease.

Cellular Senescence in Sarcopenia: Possible Mechanisms and Therapeutic Potential

Aging promotes most degenerative pathologies in mammals, which are characterized by progressive decline of function at molecular, cellular, tissue, and organismal levels and account for a host of health care expenditures in both developing and developed nations. Sarcopenia is a prominent age-related disorder in musculoskeletal system. Defined as gradual and generalized chronic skeletal muscle disorder, sarcopenia involves accelerated loss of muscle mass, strength and function, which is associated with increased adverse functional outcomes and evolutionally refers to muscle wasting accompanied by other geriatric syndromes. More efforts have been made to clarify mechanisms underlying sarcopenia and new findings suggest that it may be feasible to delay age-related sarcopenia by modulating fundamental mechanisms such as cellular senescence. Cellular senescence refers to the essentially irreversible growth arrest mainly regulated by p53/p21CIP1 and p16INK4a/pRB pathways as organism ages, possibly detrimentally contributing to sarcopenia via muscle stem cells (MuSCs) dysfunction and the senescence-associated secretory phenotype (SASP) while cellular senescence may have beneficial functions in counteracting cancer progression, tissue regeneration and wound healing. By now diverse studies in mice and humans have established that targeting cellular senescence is a powerful strategy to alleviating sarcopenia. However, the mechanisms through which senescent cells contribute to sarcopenia progression need to be further researched. We review the possible mechanisms involved in muscle stem cells (MuSCs) dysfunction and the SASP resulting from cellular senescence, their associations with sarcopenia, current emerging therapeutic opportunities based on targeting cellular senescence relevant to sarcopenia, and potential paths to developing clinical interventions genetically or pharmacologically.

Validation of a Computerized Version of the Trait Subscale of the Physical Appearance State and Trait Anxiety Scale in Mexican Preadolescents

Anxiety is a feeling of fear, dread or restlessness and can develop into a weight-related disorder. The objective was to analyze the psychometric properties of the trait anxiety subscale of the Physical Appearance State and Trait Anxiety Scale (PASTAS), as well as the invariance in Mexican preadolescents. The sample consisted of 604 participants, 285 female and 319 male, whose ages ranged between 11 and 12 years (M = 11.37; SD = 0.48). The questionnaire’s factor structure was analyzed using confirmatory factor analyses. The analyses show the viability and adequacy of a two-factor structure (weight and non-weight factors) both for the total sample and for the populations of male and female. The two-factor structure showed adequate reliability and validity fit indicators. The factor structure, the factor loadings and intercepts are considered invariant according to the variable sex; however, differences between female and male participants were found for levels of anxiety caused by physical appearance. In conclusion, the PASTAS can be considered a convenient instrument to assess the variables related to anxiety generated by one’s physical appearance, as well as allowing more participants to be quickly assessed.

Speech characteristics of parkinson disease

Objective: Parkinson Disease (PD) is known the second most frequent neurodegenerative age-related disorder after Alzheimer’s disease. Although over the six million people worldwide suffer from PD, the main cause of the disease remains are unknown. Speech and language impairments have emerged in most patients with PD during the course of the disease. However, clinical profiles or characteristics that might differentiate individuals with PD who are predisposed to speech and language deficits are generally overlooked. Moreover, factors that expedite language disability have still been remained elusive. It is thought that the awareness of speech and language impairments in PD can significantly help to maintain language abilities as the disease progresses and also may contribute to improving communication skills with patients. For this reason, the present study aims to constitute a comprehensive frame for the speech and language characteristics of individuals with PD

A Network-Based Analysis of Disease Complication Associations for Obstetric Disorders in the UK Biobank

Background: Recent studies have found that women with obstetric disorders are at increased risk for a variety of long-term complications. However, the underlying pathophysiology of these connections remains undetermined. A network-based view incorporating knowledge of other diseases and genetic associations will aid our understanding of the role of genetics in pregnancy-related disease complications. Methods: We built a disease–disease network (DDN) using UK Biobank (UKBB) summary data from a phenome-wide association study (PheWAS) to elaborate multiple disease associations. We also constructed egocentric DDNs, where each network focuses on a pregnancy-related disorder and its neighboring diseases. We then applied graph-based semi-supervised learning (GSSL) to translate the connections in the egocentric DDNs to pathologic knowledge. Results: A total of 26 egocentric DDNs were constructed for each pregnancy-related phenotype in the UKBB. Applying GSSL to each DDN, we obtained complication risk scores for additional phenotypes given the pregnancy-related disease of interest. Predictions were validated using co-occurrences derived from UKBB electronic health records. Our proposed method achieved an increase in average area under the receiver operating characteristic curve (AUC) by a factor of 1.35 from 55.0% to 74.4% compared to the use of the full DDN. Conclusion: Egocentric DDNs hold promise as a clinical tool for the network-based identification of potential disease complications for a variety of phenotypes.

When Saturday comes: football, public disorder and Liverpool's urban crisis, c. 1965–1985

This article uses oral histories, media representations and local archives to examine how football-related disorder in Liverpool impacted the lived experiences of local communities and informed perceptions, reactions and solutions to the city's unfolding urban crisis. It traces how the aggressive architectural transformation of the city's stadiums wrought significant and unintended consequences upon supporters and inner-city communities alike. By conceptualizing the stadium as a succinct example through which to view the anxieties that surrounded problematic urban spaces, it examines the relationship between the governance, materiality and use of the inner city during the urban crisis.

Biallelic ANGPT2 loss-of-function causes severe early-onset non-immune hydrops fetalis

BackgroundHydrops fetalis, a pathological fluid accumulation in two or more body compartments, is aetiologically heterogeneous. We investigated a consanguineous family with recurrent pregnancy loss due to severe early-onset non-immune hydrops fetalis.Methods and resultsWhole exome sequencing in four fetuses with hydrops fetalis revealed that they were homozygous for the angiopoietin-2 (ANGPT2) variant Chr8 (GRCh37/Hg19): 6385085T>C, NM_001147.2:c.557A>G. The substitution introduces a cryptic, exonic splice site predicted to result in loss of 10 nucleotides with subsequent shift in reading frame, leading to a premature stop codon. RNA analysis in the heterozygous parents demonstrated loss of detectable mutant allele, indicative of loss-of-function via nonsense-mediated mRNA decay. Serum ANGPT2 levels were reduced in the parents. In a pregnancy with a healthy, heterozygous child, transiently increased fetal nuchal translucency was noted.ConclusionPathogenic heterozygous ANGPT2 missense variants were recently shown to cause autosomal dominant primary lymphoedema. ANGPT2 is a ligand of the TIE1-TIE2 (tyrosine kinase with immunoglobulin-like and epidermal growth factor-like domains 1 and 2) pathway. It is critical to the formation and remodelling of blood and lymphatic vessels and is involved in vessel maintenance. ANGPT2 knockout mice die from generalised lymphatic dysfunction. We show here that a homozygous pathogenic variant causes loss-of-function and results in severe early-onset hydrops fetalis. This is the first report of an autosomal recessive ANGPT2-related disorder in humans.

541 Prevalence of amyloid transthyretin cardiomyopathy in elderly subjects from the general population: first results from the catch study

Aims Amyloid transthyretin cardiomyopathy (ATTR-CM) has become treatable. Wild-type ATTR-CM is an age-related disorder. Establishing the exact prevalence of ATTR-CM in elderly subjects from the general population may be useful for healthcare providers and policy makers alike. Methods and results The characterizing the burden of Amyloid Transthyretin CardiomyopatHy in the elderly (CATCH) study is a population screening on all subjects aged ≥65 years followed by general practitioners working at the Casa della Salute in Terricciola, in an area of Tuscany where there is no cluster of variant ATTR. The study started on 12 March 2021 and is ongoing. The first step of the evaluation includes clinical history and physical examination, electrocardiogram, transthoracic echocardiogram, and blood sampling with measurement of N-terminal pro-B-type natriuretic peptide and high-sensitivity (hs) troponin T. The following elements are searched: (i) any clinical red flag of amyloidosis (history of carpal tunnel syndrome, lumbar spine stenosis, etc.), (ii) interventricular septal thickness ≥12 mm or other echocardiographic red flags, and (iii) hs-troponin T higher than the upper reference limit (14 ng/l). Patients with any of these elements are referred to a second step including diphosphonate scintigraphy and the search for a monoclonal protein in the serum and urine. The standard diagnostic workup for CA is then followed until the diagnosis is confirmed or discarded. As of 31 October 2021, 514 subjects ≥65 years have been evaluated for possible participation. Among them, 135 (26%) could not be contacted, were reluctant to enter the study, died before being contacted, or were bedridden. Out of the other 379 subjects, 329 (87%) have already undergone the first step. Forty percent of individuals (n = 132) have been referred to the second step. Thirteen subjects have declined (10%); 69 patients have undergone diphosphonate scintigraphy, and the search for a monoclonal protein (while the other 50 are awaiting these exams). Two subjects showed an intense myocardial uptake of the diphosphonate tracer (Perugini score 2–3) and no monoclonal protein, and were then diagnosed with ATTR-CM. They were both women, aged 83 and 78 years, both mildly symptomatic for dyspnoea (New York Heart Association II) and with unexplained hypertrophy. The search for TTR gene mutation was negative in the first case and is still ongoing in the second. Based on these preliminary data, the prevalence of ATTR-CM in the elderly population can be calculated as 2/266 = 0.8% (Figure). Conclusions The CATCH study is expected to enroll at least 1000 subjects and will provide the first data on the epidemiology of ATTR-CM in elderly subjects. Based on an interim analysis, almost 1 in 100 individuals ≥65 years has ATTR-CM.