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The water channel aquaporin-4 (AQP4) is crucial for water balance in the mammalian brain. AQP4 has two main canonical isoforms, M23, which forms supramolecular structures called Orthogonal Arrays of Particles (OAP) and M1, which does not, along with two extended isoforms (M23ex and M1ex). This study examines these isoforms' roles, particularly AQP4ex, which influences water channel activity and localization at the blood-brain barrier. Using mice lacking both AQP4ex isoforms (AQP4ex-KO) and lacking both AQP4M23 isoforms (OAP-null) mice, we explored brain water dynamics under osmotic stress induced by an acute water intoxication (AWI) model. AQP4ex-KO mice had lower basal brain water content than WT and OAP-null mice. During AWI, brain water content increased rapidly in WT and AQP4ex-KO mice, but was delayed in OAP-null mice. AQP4ex-KO mice had the highest water content increase at 20 min. Immunoblot analysis showed stable total AQP4 in WT mice initially, with increases at 30 min. AQP4ex and its phosphorylated form (p-AQP4ex) levels rose quickly, but the p-AQP4ex/AQP4ex ratio dropped at 20 min. AQP4ex-KO mice showed a compensatory rise in canonical AQP4 at 20 min post-AWI. These findings highlight the important role of AQP4ex in water content dynamics in both normal and pathological states. To evaluate brain waste clearance, amyloid-β (Aβ) removal was assessed using a fluorescent Aβ intra-parenchyma injection model. AQP4ex-KO mice demonstrated markedly impaired Aβ clearance, with extended diffusion distances and reduced fluorescence in cervical lymph nodes, indicating inefficient drainage from the brain parenchyma. Mechanistically, the polarization of AQP4 at astrocytic endfeet is essential for efficient clearance flow, aiding interstitial fluid movement into the CSF and lymphatic system. In AQP4ex-KO mice, disrupted polarization forces reliance on slower, passive diffusion for solute clearance, significantly reducing Aβ removal efficiency and altering extracellular space dynamics. Our results underscore the importance of AQP4ex in both brain water homeostasis and solute clearance, particularly Aβ. These findings highlight AQP4ex as a potential therapeutic target for enhancing waste clearance mechanisms in the brain, which could have significant implications for treating brain edema and neurodegenerative diseases like Alzheimer's., (© 2024. The Author(s).)

Estetrol (E4) is a natural estrogen synthesized only during pregnancy. It has strong neuroprotective and antioxidative activities. The aim of the present study was to define the neuroprotective potency of E4 encapsulated either in liposome (Lipo-E4) or in drug-in cyclodextrin (HP-β-CD) in liposome (DCL) system, and compare them with a single use of E4. In vitro studies were performed in an oxidative stress model of primary hippocampal neuronal cell cultures, followed by the lactate dehydrogenase activity and cell proliferation assays. In vivo studies were conducted by using a model of neonatal hypoxic-ischemic encephalopathy in immature rat pups. Brain samples were studied by (immuno)histochemistry for the detection of survived cells, expression of microtubule-associated protein-2, myelin basic protein, doublecortin and vascular-endothelial growth factor. Concentrations of glial fibrillary acidic protein in blood serum were studied by ELISA. In vitro, cell proliferation was significantly up-regulated in cultures treated either by DCL-E4 or E4 compared to the control cells, whereas DCL-E4 treated cells had significantly higher survival rate than the cells treated by E4 alone. Evaluation of brain samples showed that DCL-E4 and a high dose of E4 alone significantly preserve the grey and the white matter loses, and diminish GFAP expression in blood. Although DCL-E4 and E4 have similar effect on neurogenesis in the hippocampus and the cortex, DCL-E4 treatment significantly up-regulates angiogenesis in the hippocampus compared to a single use of E4. Present work reveals for the first time that liposome-encapsulated E4 might be a better alternative to a single use of E4., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Autism spectrum disorder (ASD) is one of the most common neurodevelopment disorders, characterized by a multifactorial etiology based on the interaction of genetic and environmental factors. Recent evidence supports the neurobiological hypothesis based on neuroinflammation theory. To date, there are no sufficiently validated diagnostic and prognostic biomarkers for ASD. Therefore, we decided to investigate the potential diagnostic role for ASD of two biomarkers well known for other neurological inflammatory conditions: the glial fibrillary acidic protein (GFAP) and the neurofilament (Nfl). Nfl and GFAP serum levels were analyzed using SiMoA technology in a group of ASD patients and in a healthy control group (CTRS), age- and gender-matched. Then we investigated the distribution, frequency, and correlation between serum Nfl and GFAP levels and clinical data among the ASD group. The comparison of Nfl and GFAP serum levels between ASD children and the control group showed a mean value of these two markers significantly higher in the ASD group (sNfL mean value ASD pt 6.86 pg/mL median value ASD pt 5.7 pg/mL; mean value CTRS 3.55 pg/mL; median value CTRS 3.1 pg; GFAP mean value ASD pt 205.7 pg/mL median value ASD pt 155.4 pg/mL; mean value CTRS 77.12 pg/mL; median value CTRS 63.94 pg/mL). Interestingly, we also found a statistically significant positive correlation between GFAP levels and hyperactivity symptoms ( p -value <0.001). Further investigations using larger groups are necessary to confirm our data and to verify in more depth the potential correlation between these biomarkers and ASD clinical features, such as the severity of the core symptoms, the presence of associated symptoms, and/or the evaluation of a therapeutic intervention. However, these data not only might shed a light on the neurobiology of ASD, supporting the neuroinflammation and neurodegeneration hypothesis, but they also might support the use of these biomarkers in the early diagnosis of ASD, to longitudinally monitor the disease activity, and even more as future prognostic biomarkers.

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. Starting from week 24, the B subsets recovered; however, at week 48, CD19+/CD38+ and CD19+/CD25+ reached values near the baseline, while the Bmem were significantly lower. The T cell subsets remained unchanged except for CD4+/CD25+, which increased compared to W0. The LS changes were not predictive of NEDA achievement. The sNfL levels were significantly lower at week 24 ( p = 0.046) vs. baseline. These results could demonstrate how cladribine, by inflammatory activity depletion, can also reduce axonal damage, according to the sNfL levels.

Background: To address health inequities, the American Association of Colleges of Nursing, Institute of Medicine, and Association of American Medical Colleges recommend holistic admissions review (HAR) to increase health professional diversity., Method: This cross-sectional study collected admissions criteria from 1,547 nursing programs. Criteria were categorized according to the experiences, attributes, and academic metrics (EAM) model, and programs were dichotomized into those with holistic admissions criteria versus none., Results: Only 43% of nursing programs considered holistic admissions criteria. Regionally, rates varied from 35% in the South to 54% in the West. The rate of HAR integration exceeded 67% in only six states., Conclusion: Nursing programs have not widely integrated HAR despite evidence that academic metric use alone disadvantages qualified underrepresented students. HAR implementation can be facilitated by standardizing how HAR is operationalized and applying best evidence to rubric development that appropriately weighs admissions criteria based on the EAM model, and also training reviewers for unbiased candidate evaluation. [ J Nurs Educ . 2022;61(7):361-366.] .

GBM is the most aggressive brain tumor among adults. It is characterized by extensive vascularization, and its further growth and recurrence depend on the formation of new blood vessels. In GBM, tumor angiogenesis is a multi-step process involving the proliferation, migration and differentiation of BMECs under the stimulation of specific signals derived from the cancer cells through a wide variety of communication routes. In this review, we discuss the dynamic interaction between BMECs and tumor cells by providing evidence of how tumor cells hijack the BMECs for the formation of new vessels. Tumor cell-BMECs interplay involves multiple routes of communication, including soluble factors, such as chemokines and cytokines, direct cell-cell contact and extracellular vesicles that participate in and fuel this cooperation. We also describe how this interaction is able to modify the BMECs structure, metabolism and physiology in a way that favors tumor growth and invasiveness. Finally, we briefly reviewed the recent advances and the potential future implications of some high-throughput 3D models to better understanding the complexity of BMECs-tumor cell interaction.

AQP4ex is a recently discovered isoform of AQP4 generated by a translational readthrough mechanism. It is strongly expressed at the astrocyte perivascular endfeet as a component of the supramolecular membrane complex, commonly called orthogonal array of particles (OAP), together with the canonical isoforms M1 and M23 of AQP4. Previous site-directed mutagenesis experiments suggested the potential role of serine 331 and serine 335 , located in the extended peptide of AQP4ex, in water channel activity by phosphorylation. In the present study we evaluated the effective phosphorylation of human AQP4ex. A small scale bioinformatic analysis indicated that only Ser 335 is conserved in human, mouse and rat AQP4ex. The phosphorylation site of Ser 335 was assessed through generation of phospho-specific antibodies in rabbits. Antibody specificity was first evaluated in binding phosphorylated peptide versus its unphosphorylated analog by ELISA, which was further confirmed by site-directed mutagenesis experiments. Western blot and immunofluorescence experiments revealed strong expression of phosphorylated AQP4ex ( p -AQP4ex) in human brain and localization at the perivascular astrocyte endfeet in supramolecular assemblies identified by BN/PAGE experiments. All together, these data reveal, for the first time, the existence of a phosphorylated form of AQP4, at Ser 335 in the extended sequence exclusive of AQP4ex. Therefore, we anticipate an important physiological role of p -AQP4ex in human brain water homeostasis.

The pathogenic mechanisms that underlie the progression of remote degeneration after spinal cord injury (SCI) are not fully understood. In this study, we examined the relationship between endoplasmic reticulum (ER) stress and macroautophagy, hereafter autophagy, and its contribution to the secondary damage and outcomes that are associated with remote degeneration after SCI. Using a rat model of spinal cord hemisection at the cervical level, we measured ER stress and autophagy markers in the axotomized neurons of the red nucleus (RN). In SCI animals, mRNA and protein levels of markers of ER stress, such as GRP78, CHOP, and GADD34, increased 1 day after the injury, peaking on Day 5. Notably, in SCI animals, the increase of ER stress markers correlated with a blockade in autophagic flux, as evidenced by the increase in microtubule-associated protein 2 light chain 3 (LC3-II) and p62/SQSTM1 (p62) and the decline in LAMP1 and LAMP2 levels. After injury, treatment with guanabenz protected neurons from UPR failure and increased lysosomes biogenesis, unblocking autophagic flux. These effects correlated with greater activation of TFEB and improved neuronal survival and functional recovery-effects that persisted after suspension of the treatment. Collectively, our results demonstrate that in remote secondary damage, impairments in autophagic flux are intertwined with ER stress, an association that contributes to the apoptotic cell death and functional damage that are observed after SCI., (© 2022. The Author(s).)

Intercellular communication is a key biological mechanism that is fundamental to maintain tissue homeostasis. Extracellular vesicles (EVs) have emerged as critical regulators of cell-cell communication in both physiological and pathological conditions, due to their ability to shuttle a variety of cell constituents, such as DNA, RNA, lipids, active metabolites, cytosolic, and cell surface proteins. In particular, endothelial cells (ECs) are prominently regulated by EVs released by neighboring cell types. The discovery that cancer cell-derived EVs can control the functions of ECs has prompted the investigation of their roles in tumor angiogenesis and cancer progression. In particular, here, we discuss evidence that supports the roles of exosomes in EC regulation within the tumor microenvironment and in vascular dysfunction leading to atherosclerosis. Moreover, we survey the molecular mechanisms and exosomal cargoes that have been implicated in explanations of these regulatory effects.

Femicide is defined as the gender-related killings of women and girls or as an any intentional murder of women and it represents a worldwide health issue. Although it has gained a growing attention across the public and the media, true data on its prevalence and a characterization of the phenomenon are still scarce. The aim of the present study was to evaluate the characteristics of female homicides and femicides, which are necessary to design and monitor effective preventive efforts. Post-mortem examination reports of female homicides occurred in the judicial district of Bologna over a period of 70 years were revised. Characteristics of victims and perpetrators, circumstantial and post-mortem data were extracted. Overall, 172 female homicides were observed, including 103 femicides, with no significant changes over time. The mean age of victims increased over time and showed a statistically significant association with the victim-perpetrator relationship. Homicides committed by non-intimate partner family members increased. Our study unveiled that, in the past decades, femicide was a hidden but constant social phenomenon, despite the social, cultural and juridical changes. The research in forensic pathology could help bring to light trends, characteristics and risk factors to be considered for strategies to counteract violence against women., Competing Interests: Declaration of Interest None., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Glioblastoma multiforme (GBM) is characterized by a remarkable cellular and molecular heterogeneity that make the behavior of this tumor highly variable and resistant to therapy. In addition, the most serious clinical complication of GBM and other brain tumors is the development of vasogenic edema which dramatically increase the intracranial pressure. In the present study we evaluate the expression, supramolecular organization and spatial distribution of AQP4 and AQP4ex, the new readthrough isoform of AQP4, in relationship with the degree of vasogenic brain edema and tumor progression. To this purpose, tissue samples from regions of tumor core, peritumoral and non-infiltrated tissues of each GBM patient (n = 31) were analyzed. Immunofluorescence experiments revealed that the expression of AQP4ex was almost absent in tumoral regions while the canonical AQP4 isoforms appear mostly delocalized. In peritumoral tissues, AQP4 expression was found altered in those perivascular astrocyte processes where AQP4ex appeared reduced and partially delocalized. Protein expression levels measured by immunoblot showed that global AQP4 was reduced mainly in the tumor core. Notably, the relative amount of AQP4ex was more severely reduced starting from the peritumoral region. BN-PAGE experiments showed that the supramolecular organization of AQP4 is only partially affected in GBM. Edema assessment by magnetic resonance imaging revealed that the level of AQP4ex downregulation correlated with edema severity. Finally, the degree of BBB alteration, measured with sodium fluorescein content in GBM biopsies, correlated with the edema index and AQP4ex downregulation. Altogether these data suggest that the AQP4ex isoform is critical in the triggering event of progressive downregulation and mislocalization of AQP4 in GBM, which may affect the integrity of the BBB and contributes to accumulation of edema in the peritumoral tissue. Thus, AQP4ex could be considered as a potential early biomarker of GBM progression., (© 2022. The Author(s).)

Introduction: The relationship between serum neurofilament light chain (sNfL) and myelin oligodendrocyte glycoprotein antibody (MOG-Ab) status has not been yet investigated in children with the acquired demyelinating syndrome (ADS). Objective and Methods: The sNfL levels and MOG-Abs were measured by ultrasensitive single-molecule array and cell-based assay in a cohort of 37 children with ADS and negativity for serum anti-aquaporin 4 (AQP4) antibodies. The sNfL levels were compared in MOG-Ab+/MOG-Ab- and in two subgroups MOG-Ab+ with/without encephalopathy. Results: About 40% ADS resulted in MOG-Ab+. MOG-Ab+ were younger at sampling (median = 9.8; range = 2.17-17.5 vs. 14.7/9-17; p = 0.002) with lower frequency of cerebrospinal fluid oligoclonal bands positivity (27% vs. 70%; p = 0.013) compared to MOG-Ab-. About 53% of MOG-Ab+ presented encephalopathy at onset, 1/22 of MOG-Ab- ( p = 0.0006). Higher sNfL levels ( p = 0.0001) were found in MOG-Ab+ (median/range = 11.11/6.8-1,129) and MOG-Ab- (median/range = 11.6/4.3-788) compared to age-matched controls (median/range = 2.98/1-4.53), without significant difference. MOG-Ab+ with encephalopathy resulted significantly younger at sampling (median/range: 4.5/2.17-11.17 vs. 14.16/9.8-17.5; p = 0.004), had higher sNfL levels (median/range:75.24/9.1-1,129 vs. 10.22/6.83-50.53; p = 0.04), and showed a trend for higher MOG-Ab titer (0.28/0.04-0.69 vs. 0.05/0.04-0.28; p = 0.1) in comparison to those without encephalopathy. Discussion: We confirmed high sNfL levels in pediatric ADS independently from the MOG-Ab status. Encephalopathy at onset is associated more frequently with MOG Ab+ children with higher sNfL levels and MOG titer. These findings suggest a role of acute demyelination in association with axonal damage in the pathogenesis of encephalopathy in pediatric ADS., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Simone, Palazzo, Mastrapasqua, Bollo, Pompamea, Gabellone, Marzulli, Giordano, De Giacomo, Frigeri, Ruggieri and Margari.)

Background/aims: The ability of astrocytes to control extracellular volume homeostasis is critical for brain function and pathology. Uncovering the mechanisms of cell volume regulation by astrocytes will be important for identifying novel therapeutic targets for neurological conditions, such as those characterized by imbalances to hydro saline challenges (as in edema) or by altered cell volume regulation (as in glioma). One major challenge in studying the astroglial membrane channels involved in volume homeostasis in cell culture model systems is that the expression patterns of these membrane channels do not resemble those observed in vivo. In our previous study, we demonstrated that rat primary astrocytes grown on nanostructured interfaces based on hydrotalcite-like compounds (HTlc) in vitro are differentiated and display molecular and functional properties of in vivo astrocytes, such as the functional expression of inwardly rectifying K + channel (Kir 4.1) and Aquaporin-4 (AQP4) at the astrocytic microdomain. Here, we take advantage of the properties of differentiated primary astrocytes in vitro to provide an insight into the mechanism underpinning astrocytic cell volume regulation and its correlation with the expression and function of AQP4, Transient Receptor Potential Vanilloid 4
(TRPV4), and Volume Regulated Anion Channel (VRAC)., Methods: The calcein quenching method was used to study water transport and cell volume regulation. Calcium imaging and electrophysiology (patch-clamp) were used for functional analyses of calcium dynamics and chloride currents. Western blot and immunofluorescence were used to analyse the expression and localization of the channel proteins of interest., Results: We found that the increase in water permeability, previously observed in differentiated astrocytes, occurs simultaneously with more efficient regulatory volume increase and regulatory volume decrease. Accordingly, the magnitude of the hypotonic induced intracellular calcium response, typically mediated by TRPV4, as well as the hypotonic induced VRAC current, was almost twice as high in differentiated astrocytes. Interestingly, while we confirmed increased AQP4 expression in the membrane of differentiated astrocytes, the expression of the channels TRPV4 and Leucine-Rich Repeats-Containing 8-A (LRRC8-A) were comparable between differentiated and non-differentiated astrocytes., Conclusion: The reported results indicate that AQP4 up-regulation observed in differentiated astrocytes might promote higher sensitivity of the cell to osmotic changes, resulting in increased magnitude of calcium signaling and faster kinetics of the RVD and RVI processes. The implications for cell physiology and the mechanisms underlying astrocytic interaction with nanostructured interfaces are discussed., Competing Interests: The authors have no conflicts of interest to declare., (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)

Background and purpose: Immunoadsorption (IA) is an antibody-depleting therapy used to treat neuromyelitis optica spectrum disorder (NMOSD) associated to antiaquaporin 4 (anti-AQP4-IgG) and antimyelin oligodendrocyte glycoprotein (anti-MOG-IgG) serum autoantibodies. Our aim was to evaluate longitudinal changes of serum MOG-IgG and AQP4-IgG antibody titer and to correlate it with the clinical status. Methods: Autoantibody titer and clinical features of two MOG-IgG+/AQP4-IgG- and two AQP4-IgG+/MOG-IgG- patients with NMOSD were collected at baseline (T0), after 6 IA courses (T1), and then 2 weeks (T2) and 6 months after treatment (T3). A fluorescent ratiometric assay was used for a quantitative detection of MOG and AQP4 antibodies, based on HEK-293 cells transfected with the full-length hMOG fused to GFP or h-AQP4-M23 isoform fused to m-cherry, respectively. We defined the antibody titer as MOG quantitative ratio (MOGqr) and AQP4 quantitative ratio (AQP4qr). Results: In Case 1, the MOGqr dropped from 0.98 at T0 to 0.14 at T3, and in Case 2, it decreased from 0.96 at T0 to undetectable at T3. In Case3, the AQP4qr remained high: 0.90 at T0 and 0.92 at T3. In Case 4, the AQP4qr decreased from 0.50 at T0 to undetectable at T3. Complete recovery was found in Cases 1, 2, and 4. Conclusions: Semiquantitative ratiometric method accurately detects even slight variation of MOG-IgG and AQP4-IgG titer, suggesting it may be useful to monitor the antibody titer during the disease course and maintenance immunotherapy., Competing Interests: MT has served on scientific Advisory Boards for Biogen, Novartis, Roche, Merck, and Genzyme; has received speaker honoraria from Biogen Idec, Merck, Roche, Teva, Sanofi-Genzyme, and Novartis; and has received research grants for her Institution from Biogen Idec, Merck, Roche, and Novartis. PI has served on scientific advisory boards for Biogen Idec and has received funding for travel and/or speaker honoraria from Sanofi-Aventis, Biogen Idec, Teva, and Novartis. DP received advisory board membership, speaker's honoraria, travel support, research grants, consulting fees, or clinical trial support from Almirall, Bayer Schering, Biogen, Celgene, Excemed, Genzyme, Merck, Mylan, Novartis, Sanofi, Roche, and Teva. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bollo, Iaffaldano, Ruggieri, Palazzo, Mastrapasqua, Manni, Paolicelli, Frigeri and Trojano.)

The combined event of a suicide and the killing of a pet has been hardly explored in forensic literature, but it is not rare at all. In the reported case the dead corpse of a 60-year old mentally ill woman and the carcass of a dog were found on the bed of a private apartment. In light of death scene investigation, necroscopic examination and toxicological analyses death was attributed to licit drug intoxication and self-strangulation after lethal poisoning of the dog. Due to the presence of two lethal means (cervical noose and drugs), acting in chronological order, the event was classified as a secondary complex suicide. Moreover, the woman, although mentally ill, was a psychiatrist. Thus, her professional background, namely the easy access to psychiatric drugs together with her knowledge of drug composition and properties lead to suppose an occupation related suicide. The comprehensive analysis of all the available information, including death scene investigation, occupational, necroscopic and toxicological data, resulted of the utmost importance for a proper reconstruction of the events and are recommended in complex cases such as occupation related planned complex suicides combined to the killing of pets., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: The decomposition process of human bodies in marine environment is not well understood, and it is influenced by external variables related to the geographical area where the body is submerged. We report the application of two decomposition scores, the Heaton's score and the van Daalen's score, on a casuistry of human bodies recovered from the Northern Adriatic Sea. The aims of this study are to verify whether the marine environment of a Mediterranean climate area may affect the applicability of both scores and to develop a prediction model that can be applied on bodies recovered in salt water., Methods: A retrospective study was performed on 61 human bodies recovered between 2005 and 2019 from coastal water of the Northern Adriatic Sea nearby the Italian regions Emilia-Romagna and Marche. For each of the 61 cases included, the Total Aquatic Decomposition Score (TADS) was calculated with the Heaton's score and the Van Daalen's score. The prediction model was assessed through multiple regression analyses, and the determination coefficients (r 2 ) between TADS and PMSI (expressed in days) and between TADS and Accumulate Degrees Days (ADD) were studied. The prediction model was applied to the entire case sample, to bodies recovered during the warm season and to bodies recovered during the cold season., Results: All bodies were recovered floating, and a very poor scavenging activity was observed. The regression analyses showed a strong correlation between the TADS and the total case sample using both scores and both independent variables (PMSI and ADD). The determination coefficients were greater than 0.95 also when considering the total case sample., Discussion: The proposed prediction models are not significantly influenced by seasonality, contrarily to what observed on bodies recovered in fresh water in the same climate area. However, the ADD model, which also consider the water temperature, should be preferred for higher decomposition stages. This study helps increase the accuracy of PMSI estimation in bodies recovered from a marine environment of the Northern Adriatic Sea., Competing Interests: Declaration of Competing Interest The Author(s) declare(s) that there is no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: A proper antalgic treatment is based on the use of titrated drugs to provide adequate relief and a good tolerability profile. Therapies have a variable effectiveness among subjects depending on medical and genetic conditions. CYP2D6 variations determine a different clinical response to most analgesic drugs commonly used in daily clinical practice by influencing the drugs' pharmacokinetics. This study was a monocentric clinical trial exploring the CYP2D6 variants in 100 patients with a diagnosis of chronic pain., Methods: DNA was extracted to evaluate the genotype and to classify patients as normal-fast (gNMs-F), normal-slow (gNMs-S), ultrarapid (gUMs), intermediate (gIMs), and poor metabolizers (gPMs) using the Activity Score (AS). Information on therapies and general side effects experienced by patients was collected. Nongenetic co-factors were evaluated to examine the discrepancy between metabolic profile predicted from genotype (gPh) and metabolic profile (phenocopying)., Results: The distribution of our data underlined the prevalence of the gNMs-F (67%), whereas gNMs-S were 24%, gIMs 6%, gPMs 3%, and no gUMs were found, resulting in 33% of patients with reduced metabolic activity. In the analyzed population sample, 86% and 56% of patients, respectively, took at least one or two drugs inhibiting in vitro activity of the CYP2D6 enzyme., Conclusions: Over one-third of the enrolled patients showed altered CYP2D6 enzymatic metabolic activity, with a risk of phenocopying potentially due to polypharmacology., Trial Registration: ClinicalTrials.gov ID: NCT03411759., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Hospital acquired infections have been associated with the contamination of flexible endoscopes caused by a failure of the reprocessing procedure. Microbiological surveillance of endoscope reprocessing is valuable for assessing contamination by pathogens. The aim of this study is to evaluate microbiological contamination of endoscopes after reprocessing, and the involvement of reprocessing procedures adopted in endoscopy units of an Italian teaching-hospital., Methods: The study was carried out, on several dates in 2014, in 11 endoscopic operation units equipped with 100 endoscopes (18 bronchoscopes, 41 gastroduodenoscopes, 29 colonoscopes, 12 laryngoscopes) and 9 Automated Endoscope Reprocessors. Presence/absence of common pathogens and indicator micro-organisms (including multi-drug resistant bacteria) and Total Microbiological Count (TMC) were obtained from the biopsy channels of endoscopes after reprocessing, from final rinse water of automated endoscope reprocessors and from tap water applying standard microbiological culture methods. Following the European Guidelines for quality assurance in reprocessing, the post-reprocessing criteria were "absence of indicator micro-organisms and absence of TMC in samples obtained from endoscopes' channels"., Results: A total of 180 samples were collected (143 endoscopes, 25 Automated Endoscope Reprocessors and 12 water supply). Compliance to the European Guidelines was achieved for 112 out of the 180 (62.2%) samples analyzed. Presence of indicator micro-organisms (mainly Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa and other Gram-negative non-fermenting bacteria) was found in 51 out of 143 endoscopes (35.7%). Multi-drug resistant bacteria were also found. Presence of pathogen micro-organisms was statistically associated with the increase of TMC level, but not with time after reprocessing., Conclusion: The study provides information about the microbiological quality of endoscope reprocessing procedures adopted by different endoscopic operation units. The high prevalence of contaminated endoscopes provides evidence of the need to improve the quality of reprocessing.

Translational readthrough (TRT) of aquaporin-4 (AQP4) has remarkably expanded the importance of this new post-transcriptional mechanism, as well as the regulation potential of AQP4. The TRT isoform of AQP4, named AQP4ex, is central for both AQP4 polarization and water channel activity in the central nervous system (CNS). Here we evaluate the relevance of the TRT mechanism by analyzing whether AQP4ex is also expressed in peripheral tissues and whether the expression of AQP4ex is necessary for its polarized expression as it occurs in perivascular astrocyte processes. To this purpose, AQP4ex null mice were used, and analysis was performed by immunolocalization and immunoblot. The results demonstrate that AQP4ex is expressed in kidney, stomach, trachea and skeletal muscle with the same localization pattern as the canonical AQP4 isoforms. AQP4ex protein levels vary from 6% to about 13% of the total AQP4 protein levels in peripheral tissues. Immunogold electron microscopy experiments demonstrated the localization of AQP4ex at the astrocytic endfeet, and experiments conducted on AQP4ex null mice CNS confirmed that the expression of AQP4ex is necessary for anchoring of the perivascular AQP4. Without the readthrough isoform, AQP4 assemblies are mis-localized, being uniformly distributed on the astrocyte processes facing the neuropile. No alteration of AQP4 polarization was found in AQP4ex null kidney, stomach, trachea or skeletal muscle, suggesting that AQP4ex does not have a role for proper membrane localization of AQP4 in peripheral tissues. We conclude that a dual role for AQP4ex is limited to the CNS., Competing Interests: The authors declare no conflicts of interest.

The water channel protein aquaporin-4 (AQP4) and the gap junction forming proteins connexin-43 (Cx43) and connexin-30 (Cx30) are astrocytic proteins critically involved in brain water and ion homeostasis. While AQP4 is mainly involved in water flux across the astrocytic endfeet membranes, astrocytic gap junctions provide syncytial coupling allowing intercellular exchange of water, ions, and other molecules. We have previously shown that mice with targeted deletion of Aqp4 display enhanced gap junctional coupling between astrocytes. Here, we investigate whether uncoupling of the astrocytic syncytium by deletion of the astrocytic connexins Cx43 and Cx30 affects AQP4 membrane localization and expression. By using quantitative immunogold cytochemistry, we show that deletion of astrocytic connexins leads to a substantial reduction of perivascular AQP4, concomitant with a down-regulation of total AQP4 protein and mRNA. Isoform expression analysis shows that while the level of the predominant AQP4 M23 isoform is reduced in Cx43/Cx30 double deficient hippocampal astrocytes, the levels of M1, and the alternative translation AQP4ex isoform protein levels are increased. These findings reveal a complex interdependence between AQP4 and connexins, which are both significantly involved in homeostatic functions and astrogliopathologies., Competing Interests: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

The encapsulation into liposomes of several types of molecules presents the advantages to protect the activity of these molecules and to target specific tissues. Nevertheless, a major obstacle remains the incomplete understanding of nano-bio interactions. Specifically, the impact that inclusion of drug into liposomes or of drug-in-cyclodextrin-in liposomes (DCL) could have on the molecular and cellular mechanism of drug action is largely unknown. As a proof of concept, we evaluated the impact of 17β-estradiol (E2) included into liposomes or DCL on estrogen receptor (ER)α signaling pathways. Indeed, ERα relays the pleiotropic actions of E2 in physiology and pathophysiology through two major pathways: (1) the genomic/nuclear effects associated to the transcriptional activity of the ERα and (2) the rapid/nongenomic/membrane-initiated steroid signaling (MISS) effects related to the induction of fast signaling pathways occurring when ERα is anchored to the plasma membrane. We evidenced that the inclusion of E2 into liposomes (Lipo-E2) or into DCL (DCL-E2) prevented the activation of the rapid/nongenomic/extranuclear/MISS pathway of ERα, while the activation of the genomic/nuclear pathway was maintained. These results support that Lipo-E2 and DCL-E2 could be a useful tool to delineate the complex molecular mechanisms associated to ERα. In conclusion, this study supports the notion that inclusion of drugs into liposomes or DCL could modify some specific pathways of their molecular and cellular mechanisms of action. These results emphasized that attention should be paid to nano-bio interactions induced by the use of nanovectors in medicine., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: The methods developed in recent years for the assessment of the Postmortem Submersion Interval (PMSI) have proven to be promising, but are strictly related to specific geographical areas or climates. The aim of this study is to assess the suitability of two of the most recent total aquatic decomposition scores (TADS) for the determination of the PMSI in bodies recovered from fresh water in an area of Mediterranean climate in the last 15 years. To do this, the correlation coefficient (r 2 ) between PMSI and Accumulate Degrees Days (ADD) or PMSI and days was studied., Methods: The correlation between PMSI (expressed in days or in ADD) and the TADS was evaluated considering: (a) bodies recovered during the entire period; (b) bodies recovered during the cold season; (c) bodies recovered during the warm season. A linear regression analysis was set comparing the statistical significance of a model plotting TADS versus ADD, and another model plotting TADS versus PMSI (expressed in days) for both scores., Results: Scores were scarcely applicable when considering the entire casuistry, as regression models showed low r 2 values, but both scores showed high correlations after dividing the cases into 2 groups. In fact, after performing the seasonal partition, we observed a strong correlation between PMSI and TADS, using either of the scores., Conclusion: This study helps increase the accuracy, reliability, and validity of PMI estimation in bodies recovered from freshwater in an area of temperate climate, such as Northern Italy, supporting the need to establish regionally-specific equations for estimating PMI in a forensic context., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tra gli antipsicotici cosiddetti "di terza generazione", dotati di agonismo parziale sui recettori D 2 , cariprazina è in particolare contraddistinta da agonismo parziale D 3 /D 2 con affinità particolarmente elevata per i recettori D 3 , oltre che da un'azione di antagonismo 5HT2B e 5TH2A e agonismo parziale 5TH1A. L'insieme di queste attività recettoriali conferisce a cariprazina un profilo di azione sia sui sintomi positivi sia su quelli negativi, offrendo nuove opportunità di trattamento per disturbi dello spettro schizofrenico. In particolare, cariprazina potrebbe rappresentare una valida alternativa per pazienti che presentano sintomi negativi e cognitivi prominenti e che presentano una risposta sub-ottimale ad altre molecole antipsicotiche. L'obiettivo di questa rassegna è quello di presentare alcuni casi clinici in cui la risposta parziale o sub-ottimale a un precedente trattamento antipsicotico ha suggerito l'opportunità di uno switch a cariprazina, nonché di illustrare le modalità e l'esito dello switch. La discussione dei casi clinici vuole fornire alcune informazioni utili per l'utilizzo di cariprazina nella pratica clinica quotidiana.

Background: Exercise programmes are often recommended for managing ankylosing spondylitis (AS), to reduce pain and improve or maintain functional capacity., Objectives: To assess the benefits and harms of exercise programmes for people with AS., Search Methods: We searched CENTRAL, the Cochrane Library, MEDLINE Ovid, EMBASE Ovid, CINAHL EBSCO, PEDro, Scopus, and two trials registers to December 2018. We searched reference lists of identified systematic reviews and included studies, handsearched recent relevant conference proceedings, and contacted experts in the field., Selection Criteria: We included reports of randomised controlled trials (RCT) of adults with AS that compared exercise therapy programmes with an inactive control (no intervention, waiting list) or usual care., Data Collection and Analysis: We used standard Cochrane methodology., Main Results: We included 14 RCTs with 1579 participants with AS. Most participants were male (70%), the median age was 45 years (range 39 to 47), and the mean symptom duration was nine years. The most frequently used exercises were those designed to help improve strength, flexibility, stretching, and breathing. Most exercise programmes were delivered along with drug therapy or a biological agent. We judged most of the studies at unclear or high risk of bias for several domains. All 14 studies provided data obtained immediately upon completion of the exercise programme. The median exercise programme duration was 12 weeks (interquartile range (IQR) 8 to 16). Three studies (146 participants) provided data for medium-term follow-up (< 24 weeks after completion of the exercise programmes), and one (63 participants) for long-term follow-up (> 24 weeks after completion of the exercise programmes). Nine studies compared exercise programmes to no intervention; five studies compared them to usual care (including physiotherapy, medication, or self-management).Exercise programmes versus no interventionAll data were obtained immediately upon completion of the exercise programme.For physical function, measured by a self-reporting questionnaire (the Bath Ankylosing Spondylitis Functional Index (BASFI) scale, 0 to 10; lower is better), moderate-quality evidence showed a no important clinically meaningful improvement with exercise programmes (mean difference (MD) -1.3, 95% confidence interval (CI) -1.7 to -0.9; 7 studies, 312 participants; absolute reduction 13%, 95% CI 17% to 9%).For pain, measured on a visual analogue scale (VAS, 0 to 10, lower is better), low-quality evidence showed an important clinically meaningful reduction of pain with exercise (MD -2.1, 95% CI -3.6 to -0.6; 6 studies, 288 participants; absolute reduction 21%, 95% CI 36% to 6%).For patient global assessment of disease activity, measured by a self-reporting questionnaire (the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scale, 0 to 10, lower is better), moderate-quality evidence showed no important clinically meaningful reduction with exercise (MD -0.9, 95% CI -1.3 to -0.5; 6 studies, 262 participants; absolute reduction 9%, 95% CI 13% to 5%).For spinal mobility, measured by a self-reporting questionnaire (the Bath Ankylosing Spondylitis Metrology Index (BASMI) scale, 0 to 10, lower is better), very low-quality evidence showed an improvement with exercise (MD -0.7 95%, -1.3 to -0.1; 5 studies, 232 participants) with no important clinical meaningful benefit (absolute reduction 7%, 95% CI 13% to 1%).For fatigue, measured on a VAS (0 to 10, lower is better), very low-quality evidence showed a no important clinically meaningful reduction with exercise (MD -1.4, 95% CI -2.7 to -0.1; 2 studies, 72 participants; absolute reduction 14%, 95% CI 27% to 1%).Exercise programmes versus usual careAll data were obtained immediately upon completion of the exercise programme.For physical function, measured by the BASFI scale, moderate-quality evidence showed an improvement with exercise (MD -0.4, 95% CI -0.6 to -0.2; 5 studies, 1068 participants). There was no important clinical meaningful benefit (absolute reduction 4%, 95% CI 6% to 2%).For pain, measured on a VAS (0 to 10, lower is better), moderate-quality evidence showed a reduction of pain with exercise (MD -0.5, 95% CI -0.9 to -0.1; 2 studies, 911 participants; absolute reduction 5%, 95% CI 9% to 1%). No important clinical meaningful benefit was found.For patient global assessment of disease activity, measured by the BASDAI scale, low-quality evidence showed a reduction with exercise (MD -0.7, 95% CI -1.3 to -0.1; 5 studies, 1068 participants), but it was not clinically important (absolute reduction 7%, 95% CI 13% to 1%) with important clinical meaningful benefitFor spinal mobility, measured by the BASMI scale, very low-quality evidence found a no important clinically meaningful improvement with exercise (MD -1.2, 95% CI -2.8 to 0.5; 2 studies, 85 participants; absolute reduction 12%, 95% CI 5% less to 28% more). There was no important clinical meaningful benefit.None of the studies measured fatigue.Adverse effectsWe found very low-quality evidence of the effect of exercise versus either no intervention, or usual care. We are uncertain of the potential for harm of exercises, due to low event rates, and a limited number of studies reporting events., Authors' Conclusions: We found moderate- to low-quality evidence that exercise programmes probably slightly improve function, may reduce pain, and probably slightly reduce global patient assessment of disease activity, when compared with no intervention, and measured upon completion of the programme. We found moderate- to low-quality evidence that exercise programmes probably have little or no effect on improving function or reducing pain, when compared with usual care, and may have little or no effect on reducing patient assessment of disease activity, when measured upon completion of the programmes. We are uncertain whether exercise programmes improve spinal mobility, reduce fatigue, or induce adverse effects.

Bloodstain pattern analysis has a key role in crime scene reconstruction; however, it can be hampered by diverse confounding factors, such as insect activity which may lead to the production of small artifactual bloodstains, commonly referred to as fly artifacts (FA). Although several techniques aimed at distinguishing human bloodstains and FA have been developed, actually, no standardized and reproducible methodology is available. The aim of our study was to test the use of scanning electron microscopy (SEM) to distinguish human bloodstains from FA produced by Sarcophaga carnaria. FA and bloodstains have been produced on five different deposition surfaces under experimental conditions. After visual analysis, bloodstains and FA were analyzed at standard low (× 40-× 300) and high (× 600-× 1200) magnification through a Philips SEM 515. Although differential diagnosis between bloodstains and FA resulted often inconclusive at visual analysis, SEM analysis allowed the identification of additional key distinctive morphological features. In particular, on the surface of FA, small crystal-like and/or amorphous material deposits were observed. Such deposits were absent on bloodstains which, on the other hand, displayed red blood cells stacked in "rouleaux." Basing on these results and under our experimental conditions, SEM analysis resulted suitable to perform a differential diagnosis between bloodstains and FA produced from the insect activity of Sarcophaga carnaria.

Acute myocarditis is related to a significant number of sudden deaths among young adults and its diagnosis is often demanded to post-mortem investigations performed on a forensic setting. Eosinophilic myocarditis (EM) is a rare form of myocarditis that is pathologically characterized by myocardial inflammation with eosinophils, often in association with elevated levels of circulating blood eosinophils. The sudden death of a 19-year-old boy with no past medical history is reported. Diagnosis of fatal acute EM was performed after a comprehensive investigation including an in-depth analysis of anamnestic and circumstantial data, and complete autopsy followed by toxicologic and cardio-pathological investigations. Discussion focuses on the forensic issues related to diagnosis and therapy of this rare form of acute myocarditis. As acute EM may be patchy, extensive myocardial sampling is mandatory in order to recognize the extent and the phase of the disease. An early diagnosis is the basis for a timely therapy, which is the key-point for prevent extensive myocardial damage, allowing a better outcome, especially when EM is acute and necrotizing. However, as demonstrated from the case herein reported, the course of EM is sometimes fulminant and does not allow any therapy nor even clinical diagnosis. Finally, this paper serves as reminder to consider this infrequent disease in differential diagnosis when facing with a sudden death, even in a young subject and in the absence of any prodrome., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: In patients with affective disorders, benzodiazepines (BZDs) are frequently administered at the onset, sometimes inappropriately. We sought to identify clinical variables associated with first BZD prescription in a large sample of patients with affective disorders., Methods: Four hundred sixty patients with mood or anxiety disorders attending different psychiatric services were assessed comparing those who received BZD as first treatment (BZD w/) and those who did not (BZD w/o)., Results: More than one third (35.7%) of the total sample had received BZDs as first prescription. In relation to mood disorders, BZD w/ subjects more frequently (a) had not a psychiatrist as first therapist, (b) had anxious symptoms at onset, (c) had adjustment disorder as first diagnosis, (d) were treated as outpatients. In relation to specific diagnoses, (a) personal decision of treatment for major depressive disorder, (b) outpatient status for bipolar disorder and (c) longer duration of untreated illness for adjustment disorder were more frequently associated with first BZD prescription. For anxiety disorders, the presence of stressful life events and the diagnoses of panic disorder or specific phobias were more frequently observed in BZD w/ patients., Conclusion: Patients with affective disorders frequently received BZDs as first prescription with significant differences between and within mood and anxiety disorders., (© 2019 John Wiley & Sons, Ltd.)

Brain water homeostasis is essential for the appropriate control of neuronal activity. Furthermore, the encasement of the central nervous system (CNS) by a hard structure, greatly limits its tolerance for the volume changes occurring with acute brain edema, which quickly leads to severe damage or death.The recent discovery of the extended isoform of AQP4 (AQP4ex), generated by translational readthrough, revealed a potential new mechanism of water transport regulation and polarization at the blood-brain-barrier level.In the present study we used CRISPR/Cas9 technology to generate an AQP4ex -/- mouse model and evaluate the effect on the overall AQP4 expression, polarization, supramolecular organization in orthogonal arrays of particles (OAPs) and neuromyelitis optica (NMO-IgG) autoantibodies binding.AQP4ex removal did not cause a decrease in total AQP4 protein expression but completely suppressed the specific location of AQP4 at the astrocyte endfeet. Without AQP4ex, AQP4 was mislocalized and α-syntrophin expression, the selective partner for AQP4 localization, was partially altered. The supramolecular organization of AQP4 in OAPs was subtly altered. Indeed, the absence of AQP4ex reduced the size of AQP4-OAPs but the number of AQP4-OAP pools remained largely the same. More importantly, AQP4ex resulted critical for the binding of pathogenic human NMO-IgG autoantibodies to the brain. Indeed, the absence of AQP4ex completely abolished the binding of NMO-IgG at the perivascular astrocyte endfeet.This study provides the first direct evidence in vivo on the specific role of AQP4ex in AQP4 perivascular OAPs assembly and confinement and reveals AQP4ex as new and important player in neuromyelitis optica.

Background: This study aims to illustrate the differences between approaches proposed for apportioning disability to different diseases in a multicausal situation, i.e. the unadjusted attributable fraction (AF), the adjusted AF, the average AF and the attribution method (AM). This information is useful to better interpret results obtained from cross-sectional data and help policy makers decide on public health strategies., Methods: Data for 29 931 individuals, representative of the French household population, who participated in the 2008-09 cross-sectional Disability-Health Survey, were included. Disability was defined as any limitation reported with the Global Activity Limitation Indicator. Unadjusted AFs were calculated using Levin's formula. Adjusted AFs were estimated for each disease by calculating predicted probabilities of disability for each individual in the dataset, under the assumption that the individual is unexposed to this specific disease (logistic model). Average AFs are based on the same methodology, but have the additional advantage that the average AFs for different diseases sum to the total AF associated with eliminating all diseases. AM accounts for competing risks and partitions total disability prevalence into additive contributions of different diseases and background disability (additive model)., Results: All methods obtained similar results with respect to the estimates of the disease contribution to disability prevalences and to ranking of the diseases, except unadjusted AFs, as the method ignores multimorbidity. Confounders other than diseases, such as age and gender, should be accurately taken into account., Conclusions: Conceptual differences, strengths and limitations of the different approaches were discussed., (© The Author(s) 2018; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Thermal imaging (TI) allows the detection of thermal patterns emitted from objects as a function of their temperature in the long-infrared spectrum and produces visible images displaying temperature differences. The aim of this pilot study was to test TI to visualize the coronary circulation of swine hearts. Thirty swine hearts were prepared for ex situ coronarography, and thermal images were acquired through a FlirOne thermal camera (FLIR Systems®) paired with a Google Android Smartphone. Coronary arteries were cannulated, namely the anterior interventricular artery, the circumflex branch of the left coronary artery, and the right coronary artery. The heart was cooled, and contrast medium (CM) consisting of distilled water heated to 40 °C was injected in a coronary vessel, while thermal images were captured. These steps were repeated for each coronary vessel and under experimentally simulated coronary heart disease. Thermal imaging coronarography (TIC) allowed a clear representation of the morphology and course of the coronary vessels and of experimentally simulated coronary heart disease, moreover, demonstrated to be easy to perform during or after autopsies on ex situ hearts, non-destructive, reproducible, and cheap. On the basis of these preliminary results, TIC might allow a subsequent more focused and comprehensive cardiopathological examination of the heart, which remains mandatory for the definitive diagnosis of coronary heart disease. Although these preliminary results seem encouraging, further systematic studies on human hearts, both normal and pathological, are necessary for estimating the sensitivity and specificity of the proposed method and to draw any definitive conclusion.

Background: This study aimed 1) to assess whether the contribution of chronic conditions to disability varies according to the educational attainment, 2) to disentangle the contributions of the prevalence and of the disabling impact of chronic conditions to educational disparities., Methods: Data of the 2008-09 Disability Health Survey were examined ( N  = 23,348). The disability indicator was the Global Activity Limitation Indicator (GALI). The attribution method based on an additive hazard model was used to estimate educational differences in disabling impacts and in the contributions of diseases to disability. Counterfactual analyses were used to disentangle the contribution of differences in disease prevalence vs. disabling impact., Results: In men, the main contributors to educational difference in disability prevalence were arthritis (contribution to disability prevalence: 5.7% (95% CI 5.4-6.0) for low-educated vs. 3.3% (3.0-3.9) for high-educated men), spine disorders (back/neck pain, deformity) (3.8% (3.6-4.0) vs. 1.9% (1.8-2.1)), chronic obstructive pulmonary diseases (2.4% (2.3-2.6) vs. 0.6% (0.5-0.7)) and ischemic heart /peripheral artery diseases (4.1% (3.9-4.3) vs. 2.4% (2.2-3.0)). In women, arthritis (9.5% (9.1-9.9) vs. 4.5%, (4.1-5.2)), spine disorders (4.5% (4.3-4.7) vs. 2.1% 1.9-2.3) and psychiatric diseases (3.1% (3.0-3.3) vs. 1.1% (1.0-1.3)) contributed most to education gap in disability. The educational differences were equally explained by differences in the disease prevalence and in their disabling impact., Conclusions: Public health policies aiming to reduce existing socioeconomic disparities in disability should focus on musculoskeletal, pulmonary, psychiatric and ischemic heart diseases, reducing their prevalence as well as their disabling impact in lower socioeconomic groups., Competing Interests: HVO is the editor in chief of the journal but he was blinded of the submission process. No other competing interest was declared.This study was planned as a research project. It was performed in collaboration with the French National Institute of Statistics. This study was declared of public interest by the CNIS (Conseil National d’Information Statistique) and was approved by the CNIL (Commission Nationale de l’Informatique et des Liberte’s, French law no. 78–17). According to the French law, written informed consent was not required for this type of study.Not applicable.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Weight gain during breast cancer treatment has not been explained yet. This study aimed to explore eating experience and its relationship with weight gain and sweet preference and intake in women in chemotherapy treatment for breast cancer. Thirty-one patients indicated for adjuvant (n = 16) or neoadjuvant (n = 15) chemotherapy containing anthracyclines were evaluated. Weight, sweet preference in cashew juice (weight/volume, 3, 6, 12, 24, and 36%), and sweet food intake frequency ["healthy sweets" (HS) for fruits and natural juices and "nonhealthy sweets" (NHS) for other sweets] were assessed prior to initiating (T0) and after the fourth chemotherapy cycle (T1). A semistructured interview was applied at T1. At baseline, patients were 46.7 ± 11.6 years old and the mean body mass index (BMI) was 29.3 ± 7.1 kg/m 2 . The patients' weight and BMI increased, as did the HS intake, with positive correlation between HS intake and weight change (r = 0.38; P = 0.039). Baseline sweet preference is correlated to NHS intake at T0 (r = 0.51; P = 0.004) and influences NHS intake change. The interview analysis showed opposite food behaviors: at times driven by self-care and, at other times, driven by the emotional vulnerability, which may contribute to the weight gain observed.

Major interplaying causes of heat stroke (HS) and fatal hyperthermia are climate, physical activity, artificial extreme ambient temperatures, confinement in a small compartment, and effects of drugs and chemicals, combined with predispositions and complications. A common and unfortunate cause of HS is vehicular hyperthermia (VH) death. Hyperthermia in a vehicle is a type of environmental thermal disorder, involving victim's susceptibility, confinement with restraint, and possible influences of drugs and poisons, including exhaust gas containing complex fumes, carbon dioxide and monoxide. Whereas VH typically occurs when babies or young children are being left unattended in parked vehicles in direct sunlight, it has been reported only anecdotally for adult subjects. Three cases of adult fatal VH will be herein presented. In each presented case the corpse was found enclosed in a vehicle on spring/summer days. During crime scene investigation (CSI) psychoactive substances were found near to the corpses leading to the suspect of a suicidal fatal drug intoxication. Basing on this misleading suspect in Case 2 and 3 a forensic expert was not charged for the CSI and a fatal VH was not suspected nor properly investigated. Later, a comprehensive autopsy, including biochemical and toxicological analyses, excluded a death related to natural causes, fatal intoxications, ketoacidosis and traumas. On the other hand, the reconstruction of the temperature, the humidity, the heat index and the related risk of HS allowed the diagnosis of fatal VH in all the reported cases. In particular, death occurred because of the long-lasting stay into a hot parked vehicle which was facilitated from self-administration of psychoactive drugs with related neuro-depression. This case series confirms that a comprehensive CSI followed by an autopsy including histology, biochemical and toxicological analysis remains mandatory in cases of forensic interest, as well as when a corpse is found enclosed in a vehicle. Anyway, sometimes the diagnosis of heat-related fatalities remains a medley of investigative and medicolegal observations., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: There is no agreement for the performance assessment of patients who practice exercises.. (2 points to withdraw) This assessment is currently left to the physiotherapist's personal judgement. We studied the agreement among physiotherapists in rating patient performance during exercises recommended for chronic low-back pain (LBP)., Methods: A vignette-based method was used. We first identified ten exercises recommended for LBP in the literature. Then, 42 patients with chronic LBP participating in a rehabilitation program were videotaped during their performance of one of the ten exercises. A vignette was an exercise video preceded by clinical information. Ten physiotherapists from primary (4) and tertiary care (6) viewed the 42 vignettes twice, one month apart, and rated patient performance from zero (worse performance) to ten (excellent performance) by considering the position and duration of the contraction or stretching. Intra-class correlation coefficients (ICCs) and 95% confidence intervals (95% CIs) were computed to assess inter- and intra-rater reliability., Results: The overall inter-rater agreement was fair (ICC 0.48 [95% CI 0.33-0.56]) but was better for stretching exercises (0.55 [0.35-0.64]) than strengthening exercises (0.42 [0.20-0.52]) and for tertiary-care physiotherapists (0.66 [0.54-0.76]) than primary-care physiotherapists (0.28 [0.09-0.37]). The intra-rater agreement was overall good (0.72 [0.57-0.81] to 0.88 [0.79-0.94]). It was better for stretching exercises (from 0.68 [0.46-0.81] to 0.96 [0.91-0.98]) than strengthening exercises (from 0.68 [0.38-0.84]) to 0.82 [0.56-0.92])., Conclusion: The agreement in rating patient performance of exercises for LBP is good among physiotherapists trained in managing LBP but is low among non-trained physiotherapists.

Prostate cancer is a significant burden and cause of mortality in Latin America. This article reviews the treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC) and provides consensus recommendations to assist Latin American prostate cancer specialists with clinical decision making. A multidisciplinary expert panel from Latin America reviewed the available data and their individual experience to develop clinical consensus opinions for the use of life-prolonging agents in mCRPC, with consideration given to factors influencing patient selection and treatment monitoring. There is a lack of level 1 evidence for the best treatment sequence or combinations in mCRPC. In this context, consensus recommendations were provided for the use of taxane-based chemotherapies, androgen receptor axis-targeted agents and targeted alpha therapy, for patients in Latin America. Prostate-specific antigen (PSA) changes alone, during treatment, should be treated with caution; PSA may not be a suitable biomarker for radium-223. Bone scans and computed tomography are the standard imaging modalities in Latin America. Imaging should be prompted during treatment where symptomatic decline and/or significant worsening of laboratory evaluations are reported, or where a course of therapy has been completed and another antineoplastic agent is under consideration. Recommendations and guidance for treatment options in Latin America are provided in the context of country-level variable access to approved agents and technologies for treatment monitoring. Patients should be treated with the purpose of prolonging overall survival and preserving quality of life through increasing the opportunity to administer all available life-prolonging therapies when appropriate.

The term "planned complex suicide" means the combination of more than one method of suicide, planned to prevent failure of the first method to ensure a fatal outcome. Professional skills and tools are sometimes used to plan and perpetrate the suicide. A case of planned complex suicide of a mechanical engineer working with furnaces in a tube factory is herein reported. The suicide was committed in a rudimental furnace set up in the victim's apartment using his professional skills, by assembling furniture, mattresses, books and flammable liquid present in the house. Three-dimensional models of the crime scene before and after the realization of the "homemade furnace" are proposed. The discussion will focus on the importance of a comprehensive analysis of the professional background of the victim to infer the manner of death for the identification of complex and occupation-related suicides.

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system (CNS) caused by autoantibodies (NMO-IgG) against the water channel aquaporin-4 (AQP4). Though AQP4 is also expressed outside the CNS, for example in skeletal muscle, patients with NMO generally do not show clinical/diagnostic evidence of skeletal muscle damage. Here, we have evaluated whether AQP4 supramolecular organization is at the basis of the different tissue susceptibility. Using immunofluorescence we found that while the sera of our cohort of patients with NMO gave typical perivascular staining in the CNS, they were largely negative in the skeletal muscle. This conclusion was obtained using human, rat and mouse skeletal muscle including the AQP4-KO mouse. A biochemical analysis using a new size exclusion chromatography approach for AQP4 suprastructure fractionation revealed substantial differences in supramolecular AQP4 assemblies and isoform abundance between brain and skeletal muscle matching a lower binding affinity of NMO-IgG to muscle compared to the brain. Super-resolution microscopy analysis with g-STED revealed different AQP4 organization in native tissues, while in the brain perivascular astrocyte endfoot membrane AQP4 was mainly organized in large interconnected and raft-like clusters, in the sarcolemma of fast-twitch fibres AQP4 aggregates often appeared as small, relatively isolated linear entities. In conclusion, our results provide evidence that AQP4 supramolecular structure is different in brain and skeletal muscle, which is likely to result in different tissues susceptibility to the NMO disease., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Objective: Obsessive-compulsive disorder (OCD) is associated with variable risk of suicide and prevalence of suicide attempt (SA). The present study aimed to assess the prevalence of SA and associated sociodemographic and clinical features in a large international sample of OCD patients., Methods: A total of 425 OCD outpatients, recruited through the International College of Obsessive-Compulsive Spectrum Disorders (ICOCS) network, were assessed and categorized in groups with or without a history of SA, and their sociodemographic and clinical features compared through Pearson's chi-squared and t tests. Logistic regression was performed to assess the impact of the collected data on the SA variable., Results: 14.6% of our sample reported at least one SA during their lifetime. Patients with an SA had significantly higher rates of comorbid psychiatric disorders (60 vs. 17%, p<0.001; particularly tic disorder), medical disorders (51 vs. 15%, p<0.001), and previous hospitalizations (62 vs. 11%, p<0.001) than patients with no history of SA. With respect to geographical differences, European and South African patients showed significantly higher rates of SA history (40 and 39%, respectively) compared to North American and Middle-Eastern individuals (13 and 8%, respectively) (χ2=11.4, p<0.001). The logistic regression did not show any statistically significant predictor of SA among selected independent variables., Conclusions: Our international study found a history of SA prevalence of ~15% in OCD patients, with higher rates of psychiatric and medical comorbidities and previous hospitalizations in patients with a previous SA. Along with potential geographical influences, the presence of the abovementioned features should recommend additional caution in the assessment of suicide risk in OCD patients.

Background: The global range of motion of the arm is the result of a coordinated motion of the shoulder complex including glenohumeral (GH), scapulothoracic, sternoclavicular and acromioclavicular joints., Methods: This study is a non-systematic review of kinematic patterns in degenerated shoulders. It is a based on our own research on the kinematics of the shoulder complex and clinical experience., Results: For patients with subacromial impingement syndrome without rotator-cuff tears, most kinematic studies showed a small superior humeral translation relative to the glenoid and decreased scapular lateral rotation and posterior tilt. These scapular kinematic modifications could decrease the subacromial space and favor rotator-cuff tendon injury. For patients with shoulder pain and restricted mobility, the studies showed a significant increase in scapular lateral rotation generally seen as a compensation mechanism of GH decreased range of motion. For patients with multidirectional GH instability, the studies found an antero-inferior decentering of the humeral head, decreased scapular lateral rotation and increased scapular internal rotation., Conclusion: The clinical or instrumented assessment of the shoulder complex with a degenerative pathology must include the analysis of scapula-clavicle and trunk movements complementing the GH assessment. Depending on the individual clinical case, scapular dyskinesis could be the cause or the consequence of the shoulder degenerative pathology. For most degenerative shoulder pathologies, the rehabilitation program should take into account the whole shoulder complex and include first a scapular and trunk postural-correcting strategy, then scapulothoracic muscle rehabilitation (especially serratus anterior and trapezius inferior and medium parts) and finally neuromotor techniques to recover appropriate upper-limb kinematic schemas for daily and/or sports activities., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

We aimed to determine whether a 5-day intensive inpatient spa and exercise therapy and educational program is more effective than usual care in improving the rate of returning to work at 1 year for patients with subacute and chronic low back pain (LBP) on sick leave for 4 to 24 weeks. We conducted a 12-month randomized controlled trial. LBP patients were assigned to 5-day spa (2 hr/day), exercise (30 min/day) and education (45 min/day) or to usual care. The primary outcome was the percentage of patients returning to work at 1 year after randomization. Secondary outcomes were pain, disability and health-related quality of life at 1 year and number of sick leave days from 6 to 12 months. The projected recruitment was not achieved. Only 88/700 (12.6%) patients planned were enrolled: 45 in the spa therapy group and 43 in the usual care group. At 1 year, returning to work was 56.3% versus 41.9% (OR 1.69 [95% CI 0.60-4.73], p = 0.32) respectively. There was no significant difference for any of the secondary outcomes. However, our study lacked power.