Multiple QTL influence the serum Lp(a) concentration: a genome-wide linkage screen in the PROCARDIS study

The serum concentration of lipoprotein Lp (a) is known to be highly heritable and associated with cardiovascular risk. A genome-wide variance component linkage analysis was performed to localise quantitative trait loci (QTLs) influencing Lp(a) levels in a large cohort collected in the PROCARDIS coronary heart disease study. Highly significant linkage was detected at the previously described LP(a) locus on chromosome 6q27 (LOD 108). Taking into account the effect of the locus detected on chromosome 6, a highly significant LOD score was detected on chromosome 13q22-31 (LOD 7.0). Another significant region of linkage was observed on chromosomes 11p14-15 (LOD 3.5).The significant peak at 13q22-31 shows an essential overlap with a locus modulating cholesterol in familial hypercholesterolemia. If the gene underlying these loci is the same, it will be a promising candidate target for manipulating LDL-cholesterol and Lp(a). We also detected linkage at a previously identified locus influencing Lp(a) on chromosome 1q23 (LOD 1.5). Our findings provide new and confirmatory information about genomic regions involved in the quantitative variation of Lp(a) and serve as a basis for further studies of candidate genes in these regions.     

EphA2-mediated mesenchymal–amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts

Tumor progression is deeply influenced by epigenetic changes induced by tumor stroma. Cancer-associated fibroblasts (CAFs) have been reported to promote epithelial–mesenchymal transition in cancer cells, thereby enhancing their aggressiveness and stem-like properties. As CAFs are able to recruit endothelial progenitor cells (EPCs) to tumor site, we aim to investigate their interplay for prostate carcinoma progression. Both prostate CAFs and cancer cells actively recruit EPCs, known to affect tumor progression through increased vasculogenesis. EPCs synergize with CAFs to further promote epigenetic plasticity of cancer cells, through a mesenchymal-to-amoeboid transition. Indeed, after fibroblasts have engaged epithelial–mesenchymal transition in cancer cells, a further shift towards amoeboid motility is promoted by EPCs through contact-mediated triggering of the bidirectional ephrinA1/EphA2 signaling. The activation of ephrinA1 reverse pathway enhances EPC-induced neo-vascularization, thus promoting tumor growth, while EphA2 forward signaling elicits mesenchymal–amoeboid transition in cancer cells, favoring their adhesion to endothelium, transendothelial migration, and lung metastatic colonization. We therefore underscore that the metastatic advantage given by tumor microenvironment embraces different motility strategies and propose EphA2-targeted tools as useful adjuvants in anti-metastatic treatments.     

Novel FARS2 variants in patients with early onset encephalopathy with or without epilepsy associated with long survival

Mitochondrial translation is essential for the biogenesis of the mitochondrial oxidative phosphorylation system (OXPHOS) that synthesizes the bulk of ATP for the cell. Hypomorphic and loss-of-function variants in either mitochondrial DNA or in nuclear genes that encode mitochondrial translation factors can result in impaired OXPHOS biogenesis and mitochondrial diseases with variable clinical presentations. Compound heterozygous or homozygous missense and frameshift variants in the FARS2 gene, that encodes the mitochondrial phenylalanyl-tRNA synthetase, are commonly linked to either early-onset epileptic mitochondrial encephalopathy or spastic paraplegia. Here, we expand the genetic spectrum of FARS2-linked disease with three patients carrying novel compound heterozygous variants in the FARS2 gene and presenting with spastic tetraparesis, axial hypotonia and myoclonic epilepsy in two cases.Subject terms: Metabolic disorders, Mutation     

Pearls and Potential Pitfalls for Correct Diagnosis of Ovarian Cystadenofibroma in MRI: A Pictorial Essay

Ovarian cystadenofibroma is a benign ovarian tumor that is characterized by a consistent percentage of masses, which remain indeterminate in ultrasonography and require magnetic resonance (MR) investigation; they may mimic borderline or malignant lesions. Three main morphologic patterns, resembling different ovarian neoplasms, can be identified in cystadenofibromas: multilocular solid lesions, unilocular cystic lesions with parietal thickening, and purely cystic masses. However, a cystoadenofibroma has typical features, such as T2-weighted hypointensity associated with no restrictions in diffusion-weighted imaging (the so-called “dark-dark appearance”) and progressive post-contrast enhancement (type I perfusion curve). The purpose of this study was to review the features of ovarian cystadenofibromas in MR imaging and to suggest pearls and pitfalls regarding their correct diagnosis.     

Impaired reading not due to visual field loss in a patient with a right-hemipsheric lesion

We describe a right-handed patient (M.B.), who developed left hemianopsia and a severe reading impairment after right occipital–parietal hemorrhage. The pattern of his reading deficit was very similar to that of pure alexia (alexia-without-agraphia): extremely slow reading times with frequent grapheme substitutions and omissions. A test of letter reading while controlling for saccadic eye movements and hemifield of presentation ruled out hemianoptic alexia. Although there have already been reports of reading impairments in right handers following right- hemispheric lesions, ours is, to the best of our knowledge, the first where visual field loss can be definitely excluded as the main cause. Based on a standard neuropsychological assessment and on additional behavioral tests, we argue that M.B.’s difficulties are unlikely to be due to right-hemisphere dominance for language. After considering several candidate explanations, we suggest that M.B.’s symptoms may be related to an impairment in attentional processes related to reading.     

Ovarian hyper-stimulation syndrome after spontaneous conception

Ovarian hyperstimulation syndrome (OHSS) is rather frequent (1–5%) in women submitted to superovulation with gonadotropins for in vitro fertilisation (IVF), whereas it is very rare in case of spontaneous ovulation. Spontaneous OHSS (sOHSS) was previously described to be associated to hydatiform mole, multiple conception, hypothyroidism in pregnancy. It may also depend on activating mutations of the FSH receptor (FSHR) gene that cause ovarian hyper-responsiveness to circulating FSH or even cross-responsiveness of FSHR to hormones having a structure similar to FSH, such as hCG or TSH. We report, herein, a case of sOHSS in a woman who conceived spontaneously. We checked the presence of all possible factors that could explain the onset of the syndrome, and we evidenced hypothyroidism and abnormally elevated hCG levels in the second trimester of pregnancy. The thorough molecular biology study of FSHR gene did not detect exonic mutations, but revealed the presence of intronic mutations whose role in the onset of sOHSS is still uncertain.     

Cognitive assessment in multiple sclerosis—an Italian consensus

The aim of this consensus paper was to define the state of the art on cognitive assessment of persons with multiple sclerosis (PwMS), with the purpose of providing recommendations for the Italian centers involved in MS management. While there are no formal guidelines published regarding the assessment of cognitive function in MS, on the basis of an expert opinion meeting, held in Milan (Italy) on July 4, 2016, we report the recommendations of a panel of Italian experts including MS neurologists and neuropsychologists for the assessment and follow-up of cognitive function in adult MS subjects.     

The duration of inpatient admission predicts cognitive functioning at discharge in patients with bipolar disorder

Previous studies of cognitive functioning in bipolar disorder generally indicate that a more severe course of illness is associated with greater cognitive impairment. In particular, a history of greater number and longer duration of mood episodes predicts enduring cognitive deficits in euthymic patients. Shifting the focus of this investigation to the cognitive effects of a discrete mood episode, the current study aimed to explore whether patients who require a longer hospitalization to stabilize from an acute episode of mood disturbance present with more compromised cognitive functioning during the phase of early recovery. For this purpose, the study examined the link between the duration of inpatient admission and neuropsychological test scores at the time of discharge in 41 patients with bipolar disorder. Participants were assigned to long (n = 20) and short (n = 21) stay groups using a median split (M = 12). Results indicated that longer admissions were associated with more severe deficits in executive functioning at discharge after controlling for residual mood symptoms and previous number of psychiatric admissions. Findings from the current study may inform discharge planning for patients with bipolar disorder after an extended hospital stay.     

Evaluation of official procedures for suicide prevention in hospital from a forensic psychiatric and a risk management perspective

Abstract

Background: Suicide is a severe public health problem, in 2008 the Italian ministerial recommendation n° 4 on the management of suicide defined key areas for the identification of suicidal risk in hospital wards. The guidelines are important in defining professional liability issues, in line with Law 24 of 8/3/2017 ‘Gelli-Bianco’. Our study aimed to investigate the appropriateness of the official documents on suicide prevention delivered by Italian hospitals and their compliance with the ministerial recommendation.

Methods: The Italian hospitals’ public procedures on suicide prevention issued between 2008 and 2019 (n?=?33) were retrieved thorough web search and further evaluated according to their compliance with the 2008 Italian ministerial recommendations.

Results: The guidelines documents were generally in line with the ministerial recommendation. However, we found a lack of implementation in the specific training of health professionals. Most guidelines provided no risk stratification, nor specific procedures for different risk degrees or diagnoses. More than half of the documents did not report standardised tools for the assessment of suicidal risk.

Conclusions: The public procedures on suicide prevention in Italian hospitals present general indications, leaving room for interpretation. Public procedures should be implemented with greater attention to the elements of judgement in the assessment of suicidal risk.

• KEY POINTS

• Procedures for suicide prevention are of uttermost importance for psychiatrist working in hospital.

• Standards in suicide risk evaluations are needed.

• Comparison between procedures can improve risk assessment and evaluation