Whole exome sequence analysis reveals a homozygous mutation in PNPLA2 as the cause of severe dilated cardiomyopathy secondary to neutral lipid storage disease.

Accepted manuscript 12 month embargo, pre-print immediately

A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms.

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the <i>LPA</i> and 1 SNP in the <i>APOE</i> gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the <i>LPA</i> , 1 in the <i>APOE</i> gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, <i>P</i> = 3.35 × 10 <sup>-30</sup> ). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the <i>APOE2</i> -determining allele of rs7412 to be significantly associated with Lp(a) concentrations ( <i>P</i> = 3.47 × 10 <sup>-10</sup> ). Each <i>APOE2</i> allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the <i>TLR2</i> gene with Lp(a) ( <i>P</i> = 3.4 × 10 <sup>-4</sup> ). In summary, we identified a large number of independent SNPs in the <i>LPA</i> gene region, as well as the <i>APOE2</i> allele, to be significantly associated with Lp(a) concentrations

Genetic evidence for a role of adiponutrin in the metabolism of apolipoprotein B-containing lipoproteins

Adiponutrin (PNPLA3) is a predominantly liver-expressed transmembrane protein with phospholipase activity that is regulated by fasting and feeding. Recent genome-wide association studies identified PNPLA3 to be associated with hepatic fat content and liver function, thus pointing to a possible involvement in the hepatic lipoprotein metabolism. The aim of this study was to examine the association between two common variants in the adiponutrin gene and parameters of lipoprotein metabolism in 23 274 participants from eight independent West-Eurasian study populations including six population-based studies [Bruneck (n = 800), KORA S3/F3 (n = 1644), KORA S4/F4 (n = 1814), CoLaus (n = 5435), SHIP (n = 4012), Rotterdam (n = 5967)], the SAPHIR Study as a healthy working population (n = 1738) and the Utah Obesity Case-Control Study including a group of 1037 severely obese individuals (average BMI 46 kg/m2) and 827 controls from the same geographical region of Utah. We observed a strong additive association of a common non-synonymous variant within adiponutrin (rs738409) with age-, gender-, and alanine-aminotransferase-adjusted lipoprotein concentrations: each copy of the minor allele decreased levels of total cholesterol on average by 2.43 mg/dl (P = 8.87 × 10−7), non-HDL cholesterol levels by 2.35 mg/dl (P = 2.27 × 10−6) and LDL cholesterol levels by 1.48 mg/dl (P = 7.99 × 10−4). These associations remained significant after correction for multiple testing. We did not observe clear evidence for associations with HDL cholesterol or triglyceride concentrations. In conclusion, our study suggests that adiponutrin is involved in the metabolism of apoB-containing lipoprotein

Condividere il sapere creativo di Giacomo Verde. Dall’archivio documentale all’archivio empatico. Anna Maria Monteverdi intervista Gabriele Coassin

Patrimoni a rischio sono quegli archivi audiovisivi anni Ottanta (anche di natura tea-trale) non ancora censiti nella loro completezza e che in alcuni casi, necessitano di restauro a fini di conservazione e valorizzazione dei contenuti. dedicato tutta la sua vita alla produzione, all’archiviazione e restauro di materiali d’arte audiovisivi e infine, all’insegnamento; il suo laboratorio (un vero e proprio “museo storico del video”) ha ancora macchine antiche infunzione (116 videoregistratori, 90 proiettori, 74 registratori audio, 138 macchine fotografiche di tutte le epoche) grazie alla costante manutenzione, perfettamente in grado di leggere e duplicare formati oggi obsoleti, di dif-ficile reperibilità anche per Mediateche regionali. Interviene su VHS e Super VHS, video 8, Hi 8, U-Matic -BVU, Betamax, Betacam, Video 2000 per digitalizzarli e acquisire i contenuti prima che questi vadano irrimediabilmente perduti2. Si rivolgono al suo laboratorio Gallerie d’Arte e Musei nazionali non solo per il recupero dei nastri “offesi” dal tempo e dagli sbalzi di temperatura, ma anche per mettere in mostra audiovisivi originali degli anni Settanta e Ottanta che necessitano di lettori non più in uso. A lui dobbiamo anche laproduzione di alcune delle prime opere di video arte di Giacomo Verde con il quale aveva stretto una grande amicizia all’epoca della residenza veneta di Verd

A genome-wide association meta-analysis on apolipoprotein A-IV concentrations.

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 (-)  (44)), rs5104 in APOA4 (P = 1.79 × 10(-)(24)) and rs4241819 in KLKB1 (P = 5.6 × 10(-)(14)). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 (-)  (07)). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10(-)(05)). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations

Impact of Upadacitinib on Atopic Keratoconjunctivitis Exacerbated by Dupilumab Treatment in Atopic Dermatitis Patients: A Prospective Dermatological and Ophthalmological Clinical Evaluation in Common Clinical Practice

introduction: atopic dermatitis (AD) is a prevalent chronic inflammatory skin condition with a substantial impact on patients, particularly due to ocular involvement known as atopic keratoconjunctivitis (AKC). current therapeutic approaches, such as dupilumab, often lead to conjunctivitis, prompting exploration of alternative treatments like upadacitinib. methods: we collected dermatological and ophthalmological prospective clinical evaluations of six adults with moderate-to-severe AD, undergoing treatment with upadacitinib after discontinuation of dupilumab due to the onset of AKC during therapy and the worsening of dermatitis in particular in the head and neck region. clinical evaluations, including EASI scores, itch and sleep NRS, DLQI, and ocular parameters, were performed at baseline (during screening assessment before switching to upadacitinib) and then at week 12 and week 24. clinical evaluation of AKC was performed by a team of ophthalmologists. results: upadacitinib not only improved atopic dermatitis in terms of EASI, itching, and sleep NRS, but also demonstrated a notable reduction in ocular signs and symptoms, as indicated by the visual analogue scale (VAS), the Efron scale, and the ocular surface disease index symptom severity (OSDISS) scores. discussion: our observation of common clinical practice underscores the substantial impact of biological and small-molecule therapies on AD, emphasizing the limitation posed by dupilumab-associated conjunctivitis. switching to upadacitinib significantly improved both clinical and functional ocular outcomes, suggesting its potential as an alternative therapeutic option for AD patients with ocular involvement. conclusion: the presented data provides insights into the complex interplay between systemic therapies and ocular manifestations in AD. upadacitinib emerges as a promising option to address dupilumab-associated conjunctivitis, offering improved quality of life for patients

An In Vitro Intact Globe Expansion Method for Evaluation of Cross-linking Treatments

Purpose. To measure the tissue mechanical response to elevated intraocular pressure (IOP) using intact globe expansion of rabbit eyes. This method examined rabbit kit (2–3 weeks old) eyes as a model for weakened tissue and evaluated riboflavin/ UVA and glyceraldehyde cross-linking treatments. Methods. The ocular shape of enucleated eyes was photographed during a 24-hour period while a controlled IOP was imposed (either low IOP 22 mm Hg or high IOP 85 mm Hg). Untreated controls consisted of kit eyes tested at both low- and high IOP and adult eyes tested at high IOP. Treated kit eyes (dextran controls, riboflavin/UVA treatment of the cornea, and glyceraldehyde treatment of the entire globe) were tested at high IOP. Results. Low IOP elicited negligible creep of the sclera and very gradual creep of the cornea. In contrast, high IOP induced up to an 8% strain in the sclera and a 15% strain in the cornea of rabbit kit eyes. The expansion of adult eyes was less than one third that of kit eyes at the same, high IOP. Riboflavin/UVA treatment of corneas reduced expansion compared with that in both dextran-treated and untreated control corneas. Glyceraldehyde treatment prevented expansion of the cornea and sclera. Conclusions. The intact globe expansion method (GEM) imposes a loading geometry comparable to in vivo conditions and can quantify changes in mechanical stability as a function of testing conditions (e.g., IOP, tissue maturation, and therapeutic cross-linking) with small sample sizes and small variability. Rabbit kit eyes provide a model of weak tissue suitable for screening treatments that strengthen the cornea and sclera

Dupilumab-associated ocular surface disease or atopic keratoconjunctivitis not improved by dupilumab? Upadacitinib may clarify the dilemma: A case report

dupilumab-associated ocular surface disease is a common clinical sign appearing in patients with atopic dermatitis (AD) just few months after dupilumab treatment start, developing in about 25% of patients. atopic keratoconjunctivitis (AKC) is a well-identified clinical entity, defined as a chronic inflammatory disease of eye that affects 25%–40% of patients with AD. most clinical signs of ocular involvement in AD patients treated with dupilumab overlaps the AKC symptoms and signs. we supposed that dupilumab-associated ocular surface disease and AKC represent the same disease but differently called by dermatologists and ophthalmologists. AKC-like disease may develop during dupilumab therapy as a consequence of alternative cytokines pathway activation (e.g. IL33) secondary to IL-4/13 pathway block. the novel upadacitinib drug may bypass ILs pathway through Janus kinases selective inhibition, avoiding positive or negative ILs feedback at the ocular surface level. In this case report, molecular analysis on conjunctival samples showed a lower ocular surface inflammation (lower expression of HLADR) although higher levels of IL4 and IL13 in a patient with AD and AKC during upadacitinib therapy, compared to prior dupilumab treatment. target therapies in patients suffering from AD may prevent ocular and dermatological comorbidities improving quality of life before quality of skin and vision