Lowe syndrome

Lowe syndrome (the oculocerebrorenal syndrome of Lowe, OCRL) is a multisystem disorder characterised by anomalies affecting the eye, the nervous system and the kidney. It is a uncommon, panethnic, X-linked disease, with estimated prevalence in the general population of approximately 1 in 500,000. Bilateral cataract and severe hypotonia are present at birth. In the subsequent weeks or months, a proximal renal tubulopathy (Fanconi-type) becomes evident and the ocular picture may be complicated by glaucoma and cheloids. Psychomotor retardation is evident in childhood, while behavioural problems prevail and renal complications arise in adolescence. The mutation of the gene OCRL1 localized at Xq26.1, coding for the enzyme phosphatidylinositol (4,5) bisphosphate 5 phosphatase, PtdIns (4,5)P2, in the trans-Golgi network is responsible for the disease. Both enzymatic and molecular testing are available for confirmation of the diagnosis and for prenatal detection of the disease. The treatment includes: cataract extraction, glaucoma control, physical and speech therapy, use of drugs to address behavioural problems, and correction of the tubular acidosis and the bone disease with the use of bicarbonate, phosphate, potassium and water. Life span rarely exceeds 40 years

Critical animal and media studies: Expanding the understanding of oppression in communication research

Critical and communication studies have traditionally neglected the oppression conducted by humans towards other animals. However, our (mis)treatment of other animals is the result of public consent supported by a morally speciesist-anthropocentric system of values. Speciesism or anthroparchy, as much as any other mainstream ideologies, feeds the media and at the same time is perpetuated by them. The goal of this article is to remedy this neglect by introducing the subdiscipline of Critical Animal and Media Studies. Critical Animal and Media Studies takes inspiration both from critical animal studies – which is so far the most consolidated critical field of research in the social sciences addressing our exploitation of other animals – and from the normative-moral stance rooted in the cornerstones of traditional critical media studies. The authors argue that the Critical Animal and Media Studies approach is an unavoidable step forward for critical media and communication studies to engage with the expanded circle of concerns of contemporary ethical thinking

The ethics of digital well-being: a multidisciplinary perspective

This chapter serves as an introduction to the edited collection of the same name, which includes chapters that explore digital well-being from a range of disciplinary perspectives, including philosophy, psychology, economics, health care, and education. The purpose of this introductory chapter is to provide a short primer on the different disciplinary approaches to the study of well-being. To supplement this primer, we also invited key experts from several disciplines—philosophy, psychology, public policy, and health care—to share their thoughts on what they believe are the most important open questions and ethical issues for the multi-disciplinary study of digital well-being. We also introduce and discuss several themes that we believe will be fundamental to the ongoing study of digital well-being: digital gratitude, automated interventions, and sustainable co-well-being

Correction to: The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position

The genetic architecture of Plakophilin 2 cardiomyopathy

PURPOSE: The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. METHODS: We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. RESULTS: The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10-16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10-16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10-16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. CONCLUSION: This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position

Dignity and Narrative Medicine

Critiques of the dehumanising aspects of contemporary medical practice have generated increasing interest in the ways in which health care can foster a holistic sense of wellbeing. We examine the relationship between two areas of this humanistic endeavour: narrative and dignity. This paper makes two simple arguments that are intuitive but have not yet been explored in detail: that narrative competence of carers is required for maintaining or recreating dignity, and that dignity promotion in health care practice is primarily narrative in form. The multiple meanings that dignity has in a person’s life are what give the concept power and can only be captured by narrative. This has implications for health care practice where narrative work will be increasingly required to support patient dignity in under-resourced and over-subscribed health care system

Low dose radiation and cancer in A-bomb survivors: latency and non-linear dose-response in the 1950–90 mortality cohort

BACKGROUND: Analyses of Japanese A-bomb survivors' cancer mortality risks are used to establish recommended annual dose limits, currently set at 1 mSv (public) and 20 mSv (occupational). Do radiation doses below 20 mSv have significant impact on cancer mortality in Japanese A-bomb survivors, and is the dose-response linear? METHODS: I analyse stomach, liver, lung, colon, uterus, and all-solid cancer mortality in the 0 – 20 mSv colon dose subcohort of the 1950–90 (grouped) mortality cohort, by Poisson regression using a time-lagged colon dose to detect latency, while controlling for gender, attained age, and age-at-exposure. I compare linear and non-linear models, including one adapted from the cellular bystander effect for α particles. RESULTS: With a lagged linear model, Excess Relative Risk (ERR) for the liver and all-solid cancers is significantly positive and several orders of magnitude above extrapolations from the Life Span Study Report 12 analysis of the full cohort. Non-linear models are strongly superior to the linear model for the stomach (latency 11.89 years), liver (36.90), lung (13.60) and all-solid (43.86) in fitting the 0 – 20 mSv data and show significant positive ERR at 0.25 mSv and 10 mSv lagged dose. The slope of the dose-response near zero is several orders of magnitude above the slope at high doses. CONCLUSION: The standard linear model applied to the full 1950–90 cohort greatly underestimates the risks at low doses, which are significant when the 0 – 20 mSv subcohort is modelled with latency. Non-linear models give a much better fit and are compatible with a bystander effect

Akathisia and Newer Second‐Generation Antipsychotic Drugs: A Review of Current Evidence

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/1/phar2404_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155998/2/phar2404.pd

Microsatellite typing and susceptibilities of serial Cryptococcus neoformans isolates from Cuban patients with recurrent cryptococcal meningitis

Contains fulltext : 124337.pdf (publisher's version ) (Open Access)BACKGROUND: Cryptococcus neoformans is commonly associated with meningoencephalitis in immunocompromised patients and occasionally in apparently healthy individuals. Recurrence of infection after initial treatment is not uncommon. We studied C. neoformans isolates from 7 Cuban patients with recurrent cryptococcal meningitis. Antifungal susceptibility and genotyping with microsatellite molecular typing were carried out. METHODS: Isolates (n = 19) were recovered from cerebrospinal fluid, blood, urine and semen. Antifungal susceptibilities for amphotericin B, fluconazole, flucytosine, itraconazole, voriconazole, posaconazole and isavuconazole were tested by CLSI M27A3 broth microdilution method. Genotyping was done using a panel of 9 microsatellite (STR) markers: (CT)n, (TG)n, (TA)n, (CTA)n, (TCT)n, (CCA)n, (TTAT)n, (ATCC)n and (TATT)n. RESULTS: The average number of isolates/patient was 2.71. The mean time interval between the collection of any two isolates was 52.5 days. All strains were identified as C. neoformans var. grubii (serotype Aalpha). Although none of the strains were resistant to the studied drugs, in serial isolates from two patients, MICs values of triazoles increased 4-5 log2 dilutions over time. STR patterns showed 14 distinctive profiles. In three patients the recurrent infection was associated with genotypically identical isolates. The four other patients had relapse isolates which were genotypically different from the initial infecting strain. CONCLUSION: Recurrences of cryptococcal meningitis in our series of patients was not associated with development of drug resistance of the original strain but by an initial infection with different strains or a reinfection with a new strain

Impairment of Immunoproteasome Function by β5i/LMP7 Subunit Deficiency Results in Severe Enterovirus Myocarditis

Proteasomes recognize and degrade poly-ubiquitinylated proteins. In infectious disease, cells activated by interferons (IFNs) express three unique catalytic subunits β1i/LMP2, β2i/MECL-1 and β5i/LMP7 forming an alternative proteasome isoform, the immunoproteasome (IP). The in vivo function of IPs in pathogen-induced inflammation is still a matter of controversy. IPs were mainly associated with MHC class I antigen processing. However, recent findings pointed to a more general function of IPs in response to cytokine stress. Here, we report on the role of IPs in acute coxsackievirus B3 (CVB3) myocarditis reflecting one of the most common viral disease entities among young people. Despite identical viral load in both control and IP-deficient mice, IP-deficiency was associated with severe acute heart muscle injury reflected by large foci of inflammatory lesions and severe myocardial tissue damage. Exacerbation of acute heart muscle injury in this host was ascribed to disequilibrium in protein homeostasis in viral heart disease as indicated by the detection of increased proteotoxic stress in cytokine-challenged cardiomyocytes and inflammatory cells from IP-deficient mice. In fact, due to IP-dependent removal of poly-ubiquitinylated protein aggregates in the injured myocardium IPs protected CVB3-challenged mice from oxidant-protein damage. Impaired NFκB activation in IP-deficient cardiomyocytes and inflammatory cells and proteotoxic stress in combination with severe inflammation in CVB3-challenged hearts from IP-deficient mice potentiated apoptotic cell death in this host, thus exacerbating acute tissue damage. Adoptive T cell transfer studies in IP-deficient mice are in agreement with data pointing towards an effective CD8 T cell immune. This study therefore demonstrates that IP formation primarily protects the target organ of CVB3 infection from excessive inflammatory tissue damage in a virus-induced proinflammatory cytokine milieu