CTNSmRNA as a potential treatment for nephropathic cystinosis

Messenger RNA (mRNA) therapies are emerging in different disease areas, but have not yet reached the kidney field. Our aim was to study the feasibility to correct the genetic defect in nephropathic cystinosis using synthetic mRNA. Cystinosis is a prototype disorder of proximal tubular dysfunction caused by mutations in the CTNS gene, encoding the lysosomal cystine-H+ symporter cystinosin, and leading to cystine accumulation in all cells of the body. The kidneys are the first and most severely affected organs, presenting glomerular and proximal tubular dysfunction. Cysteamine is the current therapeutic standard that reduces cellular cystine levels, but has many side effects and does not restore kidney function. Here, we show that synthetic mRNA is safe and effective to reintroduce functional cystinosin using lipofection in CTNS-/- kidney cells and following direct injection in ctns-/- zebrafish larvae. CTNS mRNA therapy results in prompt lysosomal expression of the functional protein and decreases cellular cystine accumulation for up to 14 days. In the ctns-/- zebrafish, CTNS mRNA therapy improves proximal tubular reabsorption, reduces proteinuria, and restores brush border expression of the multi-ligand receptor megalin. We propose that mRNA-based therapy, if sufficient kidney targeting can be achieved, may be a new approach to treat cystinosis

Collaborative database to track Mass Mortality Events in the Mediterranean Sea

Anthropogenic climate change, and global warming in particular, has strong and increasing impacts on marine ecosystems (Poloczanska et al., 2013; Halpern et al., 2015; Smale et al., 2019). The Mediterranean Sea is considered a marine biodiversity hotspot contributing to more than 7% of world\u2019s marine biodiversity including a high percentage of endemic species (Coll et al., 2010). The Mediterranean region is a climate change hotspot, where the respective impacts of warming are very pronounced and relatively well documented (Cramer et al., 2018). One of the major impacts of sea surface temperature rise in the marine coastal ecosystems is the occurrence of mass mortality events (MMEs). The first evidences of this phenomenon dated from the first half of \u201980 years affecting the Western Mediterranean and the Aegean Sea (Harmelin, 1984; Bavestrello and Boero, 1986; Gaino and Pronzato, 1989; Voultsiadou et al., 2011). The most impressive phenomenon happened in 1999 when an unprecedented large scale MME impacted populations of more than 30 species from different phyla along the French and Italian coasts (Cerrano et al., 2000; Perez et al., 2000). Following this event, several other large scale MMEs have been reported, along with numerous other minor ones, which are usually more restricted in geographic extend and/or number of affected species (Garrabou et al., 2009; Rivetti et al., 2014; Marb\ue0 et al., 2015; Rubio-Portillo et al., 2016, authors\u2019 personal observations). These events have generally been associated with strong and recurrent marine heat waves (Crisci et al., 2011; Kersting et al., 2013; Turicchia et al., 2018; Bensoussan et al., 2019) which are becoming more frequent globally (Smale et al., 2019). Both field observations and future projections using Regional Coupled Models (Adloff et al., 2015; Darmaraki et al., 2019) show the increase in Mediterranean sea surface temperature, with more frequent occurrence of extreme ocean warming events. As a result, new MMEs are expected during the coming years. To date, despite the efforts, neither updated nor comprehensive information can support scientific analysis of mortality events at a Mediterranean regional scale. Such information is vital to guide management and conservation strategies that can then inform adaptive management schemes that aim to face the impacts of climate change

Prevalence of and factors associated with homebound status among adults in urban and rural Spanish populations

BACKGROUND: There is a marked growth in the number of homebound older adults, due mainly to increased life expectancy. Although this group has special characteristics and needs, it has not been properly studied. This study thus aimed to measure the prevalence of homebound status in a community-dwelling population, and its association with both socio-demographic, medical and functional characteristics and the use of health care and social services. METHODS: We used instruments coming under the WHO International Classification of Functioning (ICF) framework to carry out a cross-sectional study on populations aged 50 years and over in the province of Zaragoza (Spain), covering a total of 1622 participants. Persons who reported severe or extreme difficulty in getting out of the house in the last 30 days were deemed to be homebound. We studied associations between homebound status and several relevant variables in a group of 790 subjects who tested positive to the WHODAS-12 disability screening tool. RESULTS: Prevalence of homebound status was 9.8 % (95 % CI: 8.4 to 11.3 %). Homebound participants tended to be older, female and display a lower educational level, a higher number of diseases, poorer cognition and a higher degree of disability. In fully adjusted models including disability as measured with the ICF-Checklist, the associated variables (odds ratios and [95 % confidence intervals]) were: female gender (3.75 [2.10–6.68]); urban population (2.36 [1.30–4.29]); WHODAS-12 disability (6.27 [2.56–15.40]); depressive symptoms (2.95 [1.86–4.68]); moderate pain (2.37 [1.30–4.31] and severe pain (3.03 [1.31–7.01]), as compared to the group with no/mild pain; hospital admissions in the previous 3 months (2.98 [1.25–7.11]); and diabetes (1.87 [1.03–3.41]). Adjustment for ICF-Checklist disability had a notable impact on most associations. CONCLUSIONS: The study shows that homebound status is a common problem in our setting, and that being disabled is its main determinant. Socio-demographic characteristics, barriers and chronic diseases can also be assumed to be playing a role in the onset of this condition, indicating the need for further research, including longitudinal studies on its incidence and associated factors

Retrieval of a retained capsule endoscopy through a metallic colonic stent in a patient with a neoplastic obstruction

We present a case of a 77-year-old woman with a history of iron-deficiency anemia. An upper GI endoscopy and colonoscopy were performed in 2019 without significant findings other than colonic diverticula. A year later, a small bowel capsule endoscopy (SBCE) ruled out any pathological lesions in the small bowel, reaching the cecum without complications. However, one month after ingestion of SBCE the patient was admitted to the emergency department due to nausea, abdominal bloating and tenderness. Abdominal CT-Scan revealed a stenosis in the descending colon with an image of a metallic foreign body consistent with a retained capsule and important dilation of the proximal colon (Fig. 1A). A colonoscopy was performed showing a stenotic mucosal lesion that was suspicious for colonic neoplasia located at 50 cm from the anal verge. Multiple biopsies were taken. Afterwards, a self-expandable metal colonic stent of 90 mm × 25 mm was deployed under radiologic and endoscopic control (Fig. 1B, C) resulting in the drainage of fecal material and solving the obstructive syndrome. SBCE was successfully retrieved under radiologic control using a polypectomy snare through the metal stent (Fig. 1D). Finally, the patient was discharged. Pathological reports confirmed a colorectal adenocarcinoma and the patient is currently awaiting for oncologic surgery