Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives

Phase II Clinical Trial With Pegylated Liposomal Doxorubicin (CAELYX®/Doxil®) and Quality of Life Evaluation (EORTC QLQ-C30) in Adult Patients With Advanced Soft Tissue Sarcomas: A study of the Spanish Group for Research in Sarcomas (GEIS)

Background: Pegylated liposomal doxorubicin (PLD), a formulation with pharmacokinetic differences with respect to doxorubicin (DXR), might benefit patients with advanced soft tissue sarcoma (STS) pretreated with DXR

Evaluation of appendicitis risk prediction models in adults with suspected appendicitis

Background Appendicitis is the most common general surgical emergency worldwide, but its diagnosis remains challenging. The aim of this study was to determine whether existing risk prediction models can reliably identify patients presenting to hospital in the UK with acute right iliac fossa (RIF) pain who are at low risk of appendicitis. Methods A systematic search was completed to identify all existing appendicitis risk prediction models. Models were validated using UK data from an international prospective cohort study that captured consecutive patients aged 16–45 years presenting to hospital with acute RIF in March to June 2017. The main outcome was best achievable model specificity (proportion of patients who did not have appendicitis correctly classified as low risk) whilst maintaining a failure rate below 5 per cent (proportion of patients identified as low risk who actually had appendicitis). Results Some 5345 patients across 154 UK hospitals were identified, of which two‐thirds (3613 of 5345, 67·6 per cent) were women. Women were more than twice as likely to undergo surgery with removal of a histologically normal appendix (272 of 964, 28·2 per cent) than men (120 of 993, 12·1 per cent) (relative risk 2·33, 95 per cent c.i. 1·92 to 2·84; P < 0·001). Of 15 validated risk prediction models, the Adult Appendicitis Score performed best (cut‐off score 8 or less, specificity 63·1 per cent, failure rate 3·7 per cent). The Appendicitis Inflammatory Response Score performed best for men (cut‐off score 2 or less, specificity 24·7 per cent, failure rate 2·4 per cent). Conclusion Women in the UK had a disproportionate risk of admission without surgical intervention and had high rates of normal appendicectomy. Risk prediction models to support shared decision‐making by identifying adults in the UK at low risk of appendicitis were identified

RESEARCH ARTICLE Body-size structure of Central Iberian mammal fauna reveals semidesertic conditions during the middle Miocene Global Cooling Event

We developed new quantitative palaeoclimatic inference models based on the body-size structure of mammal faunas from the Old World tropics and applied them to the Somosaguas fossil site (middle Miocene, central Iberian Peninsula). Twenty-six mammal species have been described at this site, including proboscideans, ungulates, carnivores, insectivores, lagomorphs and rodents. Our analyses were based on multivariate and bivariate regression models correlating climatic data and body-size structure of 63 modern mammal assemblages from Sub-Saharan Africa and the Indian subcontinent. The results showed an average temperature of the coldest month higher than 26ÊC for the Somosaguas fossil site, a mean annual thermal amplitude around 10ÊC, a drought length of 10 months, and an annual total precipitation greater than 200 mm per year, which are climate conditions typical of an ecotonal zone between the savanna and desert biomes. These results are congruent with the aridity peaks described over the middle Aragonian of Spain and particularly in the local biozone E, which includes Somosaguas. The aridity increase detected in this biozone is associated with the Middle Miocene Global Cooling Event. The environment of Somosaguas around 14 Ma was similar to the current environment in the Sahel region of North Africa, the Horn of Africa, the boundary area between the Kalahari and the Namib in Southern Africa, south-central Arabia, or eastern Pakistan and northwestern India. The distribution of modern vegetation in these regions follows a complex mosaic of plant communities, dominated by scattered xerophilous shrublands, semidesert grasslands, and vegetation linked to seasonal watercourses and ponds.Peer reviewe