Hospital autopsy for prevention of sudden cardiac death

In the past 20 years, cardiovascular mortality has decreased in highincome countries in response to the adoption of preventive measures to reduce the burden of coronary artery disease and heart failure. Despite these encouraging results, cardiovascular diseases are responsible for approximately 17 million deaths every year in the world, approximately 25% of which are sudden cardiac death. The risk of sudden cardiac death is higher in men than in women, and it increases with age due to the higher prevalence of coronary artery disease in older age. Accordingly, the sudden cardiac death rate is estimated to range from 1.40 per 100 000 person-years in women to 6.68 per 100 000 person-years in men. Sudden cardiac death in younger individuals has an estimated incidence of 0.46\u20133.7 events per 100 000 person-years, corresponding to a rough estimate of 1100\u20139000 deaths in Europe and 800\u20136200 deaths in the USA every year. Cardiac diseases associated with sudden cardiac death differ in young vs. older individuals. In the young there is a predominance of channelopathies and cardiomyopathies, myocarditis and substance abuse, while in older populations, chronic degenerative diseases predominate. In younger persons, the cause of sudden cardiac death may be elusive even after autopsy, because conditions such as inherited channelopathies or drug-induced arrhythmias that are devoid of structural abnormalities are epidemiologically relevant in this age group. Identification of the cause of an unexpected death provides the family with partial understanding and rationalization of the unexpected tragedy, which facilitates the coping process and allows an understanding of whether the risk of sudden death may extend to family members. Accordingly, author present their experience with autopsies of unexplained sudden death young victims in which a cardiac origin was suspected and the relevance of a standardized protocol for heart examination and histological sampling, as well as for toxicology and molecular investigation

Mitochondrial fission as a driver of stemness in tumor cells : mDIVI1 inhibits mitochondrial function, cell migration and cancer stem cell (CSC) signalling

Mitochondria are dynamic organelles frequently undergoing fission and fusion events to maintain their integrity, bioenergetics and spatial distribution, which is fundamental to the processes of cell survival. Disruption in mitochondrial dynamics plays a role in cancer. Therefore, proteins involved in regulating mitochondrial dynamics are potential targets for treatment. mDIVI1 is an inhibitor of the mitochondrial fission protein DRP1, which induces i) mitochondrial oxidative stress and ii) effectively reduces mitochondrial metabolism. We show here that mDIVI1 is able to inhibit 3D tumorsphere forming capacity, cell migration and stemness-related signalling in breast cancer cells, indicating that mDIVI1 can potentially be used for the therapeutic elimination of cancer stem cells (CSCs)

Treatment of epilepsy in patients with Alzheimer’s disease

Introduction: Epilepsy is significantly more frequent in AD patients than in age-matched controls, even though the true extent of the phenomenon is not clear yet. Areas covered: In this review, we describe in detail the available data on the pharmacological treatment of epilepsy in patients with AD. We also briefly describe general principles of AEDs use in elderly, as well as the potential cognitive profile of AEDs and safety of concomitant psychotropic drugs in patients with epilepsy and AD. Expertcommentary: As some preclinical data suggest a role of epileptiform discharges in cognitive decline in AD, a prompt diagnosis and treatment of seizures in these patients should be pursued. The few data on the use of AEDs in AD patients suggest that newer AEDs (in particular lamotrigine and levetiracetam) might be good choices. Experimental data even support a potential role of some AEDs in modifying the disease course of AD

Impairment of lysosomal activity as a therapeutic modality targeting cancer stem cells of embryonal rhabdomyosarcoma cell line RD.

Rhabdomyosarcoma is the most frequent soft tissue sarcoma in children and adolescents, with a high rate of relapse that dramatically affects the clinical outcome. Multiagent chemotherapy, in combination with surgery and/or radiation therapy, is the treatment of choice. However, the relapse rate is disappointingly high and identification of new therapeutic tools is urgently needed. Under this respect, the selective block of key features of cancer stem cells (CSC) appears particularly promising. In this study, we isolated rhabdomyosarcoma CSC with stem-like features (high expression of NANOG and OCT3/ 4, self-renewal ability, multipotency). Rhabdomyosarcoma CSC showed higher invasive ability and a reduced cytotoxicity to doxorubicin in comparison to native cells, through a mechanism unrelated to the classical multidrug resistance process. This was dependent on a high level of lysosome acidity mediated by a high expression of vacuolar ATPase (V-ATPase). Since it was not associated with other paediatric cancers, like Ewing\u2019s sarcoma and neuroblastoma, V-ATPase higher expression in CSC was rhabdomyosarcoma specific. Inhibition of lysosomal acidification by the V-ATPase inhibitor omeprazole, or by specific siRNA silencing, significantly enhanced doxorubicin cytoxicity. Unexpectedly, lysosomal targeting also blocked cell growth and reduced the invasive potential of rhabdomyosarcoma CSC, even at very low doses of omeprazole (10 and 50 mM, respectively). Based on these observations, we propose lysosome acidity as a valuable target to enhance chemosensitivity of rhabdomyosarcoma CSC, and suggest the use of anti-V-ATPase agents in combination with standard regimens as a promising tool for the eradication of minimal residual disease or the prevention of metastatic disease

Expanding Glucocerebrosidase Involvement in Neurodegeneration: D419H Mutation Causing Dementia with Lewy Bodies

Mutations in the glucocerebrosidase gene (GBA) are a common genetic risk factor for Dementia with Lewy Bodies (DLB). Hereby, we describe an Italian family with three DLB relatives harboring the D419H GBA variant. The pedigree analysis indicates a dominant inheritance pattern, suggesting that heterozygous GBA mutations may differently affect the risk of Parkinson-dementia syndromes. This should be taken into account for genetic counseling in relatives of patients with GBA associated Parkinson’s Disease/DLB

Actigraphic sleep detection: an artificial intelligence approach

Objective: Polysomnography is the gold standard for sleep monitoring, despite its many drawbacks: it is complex, costly and rather invasive. Medical-grade actigraphy represents an acceptably accurate alternative for the estimation of sleep patterns in normal, healthy adult populations and in patients suspected of certain sleep disorders. An increasing number of consumer-grade accelerometric devices populate the “quantified-self” market but the lack of validation significantly limits their reliability. Our aim was to prototype and validate a platform-free artificial neural network (ANN) based algorithm applied to a high performance, open source device (Axivity AX3), to achieve accurate actigraphic sleep detection. Methods: 14 healthy subjects (29.35 14.40 yrs, 7 females) were equipped for 13.3 2.58 h with portable polysomnography (pPSG), while wearing the Axivity AX3. The AX3 was set to record 3D accelerations at 100 Hz, with a dynamic range of 8 g coded at 10 bit. For the automatic actigraphy-based sleep detection, a 4 layer artificial neural network has been trained, validated and tested against the pPSG-based expert visual sleep-wake scoring. Results: When compared to the pPSG gold standard scoring, the ANN-based algorithm reached high concordance (85.3 0.06%), specificity (87.3 0.04%) and sensitivity (84.6 0.1%) in the detection of sleep over 30-sec epochs. Moreover there were no statistical differences between pPSG and actigraphy-based Total Sleep Time and Sleep Efficiency measurements (Wilcoxon test). Conclusions: The high concordance rate between ANN-actigraphy scoring and the standard visual pPSG one suggests that this approach could represent a viable method for collecting objective sleep-wake data using a high performance, open source actigraph

An RbAp48-like gene regulates adult stem cells in planarians.

Retinoblastoma-associated proteins 46 and 48 (RbAp46 and RbAp48) are factors that are components of different chromatin-modelling complexes, such as polycomb repressive complex 2, the activity of which is related to epigenetic gene regulation in stem cells. To date, no direct findings are available on the in vivo role of RbAp48 in stem-cell biology. We recently identified DjRbAp48 — a planarian ( Dugesia japonica ) homologue of human RBAP48 — expression of which is restricted to the neoblasts, the adult stem cells of planarians. In vivo silencing of DjRbAp48 induces lethality and inability to regenerate, even though neoblasts proliferate and accumulate after wounding. Despite a partial reduction in neoblast number, we were always able to detect a significant number of these cells in DjRbAp48 RNAi animals. Parallel to the decrease in neoblasts, a reduction in the number of differentiated cells and the presence of apoptotic-like neoblasts were detectable in RNAi animals. These findings suggest that DjRbAp48 is not involved in neoblast maintenance, but rather in the regulation of differentiation of stem-cell progeny. We discuss our data, taking into account the possibility that DjRbAp48 might control the expression of genes necessary for cell differentiation by influencing chromatin architecture

Acid microenvironment promotes cell survival of human bone sarcoma through the activation of cIAP proteins and NF-κB pathway

Extracellular acidification is a very common cause of stress in tumor microenvironment and of Darwinian pressure. In acid areas of the tumor, most cancer cells are-albeit slowly proliferating-more resistant to cell death than those in well-perfused regions. Tumor acidosis can directly regulate the expression of pro-survival proteins since a low extracellular pH activates the caspase-dependent cell death machinery. This mechanism has never been explored in bone sarcomas. We cultured osteosarcoma and Ewing sarcoma cells under low pH (pH 6.5), and we performed deep-sequencing and protein analysis. Both in in vitro and in vivo models, acidification activity enhanced tumor cells survival. However, we did not observe any change in ERK1 phosphorylation. On the contrary, both at the mRNA and protein level, we found a significant induction of TRAF adaptor proteins and of cIAP proteins (BIRC2 and/or BIRC3). As a consequence, the downstream nuclear transcription factor kappa B (NF-κB) survival pathway was increased. Furthermore, the treatment with the cIAP inhibitor LCL161 reverted the protection from apoptosis under low pH. In vitro results were confirmed both in Ewing sarcoma xenograft and in osteosarcoma patients, since the analysis of tumor tissues demonstrated that the levels of expression of TRAF1 or NF-κB1 significantly correlate with the level of expression of the vacuolar ATPase (V-ATPase), the most important proton pump in eukaryotes. Moreover, in the tissue sections of xenograft model, the nuclear translocation of RelB, a key subunit of the NF-κB transcriptional complex, localized in the tumor region that also corresponded to the acid microenvironment associated with the highest levels of expression of LAMP2 and V-ATPase, in the internal area of the tumor, as revealed by immunohistochemistry. Our data confirm that tumor acid microenvironment activates a stress-regulated switch to promote cell survival of bone sarcoma, and support the hypothesis that this mechanism is mediated by the recruitment of TRAF/cIAP complexes. Altogether, these results suggest that TRAF/cIAP can be considered as a target for anti-cancer therapies

Mapping Cortical Degeneration in ALS with Magnetization Transfer Ratio and Voxel-Based Morphometry

Pathological and imaging data indicate that amyotrophic lateral sclerosis (ALS) is a multisystem disease involving several cerebral cortical areas. Advanced quantitative magnetic resonance imaging (MRI) techniques enable to explore in vivo the volume and microstructure of the cerebral cortex in ALS. We studied with a combined voxel-based morphometry (VBM) and magnetization transfer (MT) imaging approach the capability of MRI to identify the cortical areas affected by neurodegeneration in ALS patients. Eighteen ALS patients and 18 age-matched healthy controls were examined on a 1.5T scanner using a high-resolution 3D T1 weighted spoiled gradient recalled sequence with and without MT saturation pulse. A voxel-based analysis (VBA) was adopted in order to automatically compute the regional atrophy and MT ratio (MTr) changes of the entire cerebral cortex. By using a multimodal image analysis MTr was adjusted for local gray matter (GM) atrophy to investigate if MTr changes can be independent of atrophy of the cerebral cortex. VBA revealed several clusters of combined GM atrophy and MTr decrease in motor-related areas and extra-motor frontotemporal cortex. The multimodal image analysis identified areas of isolated MTr decrease in premotor and extra-motor frontotemporal areas. VBM and MTr are capable to detect the distribution of neurodegenerative alterations in the cortical GM of ALS patients, supporting the hypothesis of a multi-systemic involvement in ALS. MT imaging changes exist beyond volume loss in frontotemporal cortices