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Introduction: In recent years, neurorehabilitation has moved from a 'bottom-up' to a 'top down' approach. This change has also involved the technological devices developed for motor and cognitive rehabilitation. It implies that during a task or during therapeutic exercises, new 'top-down' approaches are being used to stimulate the brain in a more direct way to elicit plasticity-mediated motor re-learning. This is opposed to 'Bottom up' approaches, which act at the physical level and attempt to bring about changes at the level of the central neural system., Areas Covered: In the present unsystematic review, we present the most promising innovative technological devices that can effectively support rehabilitation based on a top-down approach, according to the most recent neuroscientific and neurocognitive findings. In particular, we explore if and how the use of new technological devices comprising serious exergames, virtual reality, robots, brain computer interfaces, rhythmic music and biofeedback devices might provide a top-down based approach., Expert Commentary: Motor and cognitive systems are strongly harnessed in humans and thus cannot be separated in neurorehabilitation. Recently developed technologies in motor-cognitive rehabilitation might have a greater positive effect than conventional therapies.

The development of somatosensation and affective touch acquires a central role throughout our lives, for several reasons. In adults, these functions are driven by different, neuroanatomically and functionally segregated fibres. To date, very little is known about the basic features of these fibres in childhood and this lack of knowledge is mirrored in the affective touch domain, where there are no studies on the main physiological features of the tactile processes linked to the stimulation of the hairy skin, namely the preferential site of affective touch. Thus, our study aims to analyze (1) tactile sensitivity and tactile acuity of children's hairy forearms; (2) a possible dissociation between somatosensation and the affective touch; and (3) the presence/absence of the perception of affective touch already in childhood. To these aims, participants (160 children, aged 6 to 14 years), were administered with the Von Frey (tactile sensitivity) and the 2 Point Discrimination (tactile acuity) tests. Affective touch was measured following the classic protocol and pleasantness ratings were recorded. Our findings showed a correlation between age and somatosensation, suggesting a progressive reduction of sensitivity and acuity as age grows. Further, there was no overlap between affective touch and somatosensation, suggesting a behavioural segregation. Lastly, we found higher pleasantness ratings for Affective versus Neutral stimulations at all ages and an enhanced preference for Affective as age grows. We concluded that both somatosensation and affective touch are already present as two separate components of touch in childhood and change as a function of age.

Aim: Osteoarthritis (OA) is a whole joint pathology involving cartilage, synovial membrane, meniscus, subchondral bone, and infrapatellar fat pad (IFP). Synovitis has been widely documented in OA suggesting its important role in pathogenesis. The aim of this study was to investigate the role of different joint tissues in promoting synovitis., Materials and Methods: Conditioned media (CM) from cartilage, synovial membrane, meniscus, and IFP were generated from tissues of five patients undergoing total knee replacement and used to stimulate a human fibroblast-like synoviocytes cell line (K4IM). Cytokines, chemokines, and metalloproteases release was analyzed in all CM by Bio-Plex Assay and sulfated glycosaminoglycan (GAG) content by dimethylmethylene blue assay. Gene expression of several markers was evaluated by real-time PCR in K4IM cells stimulated with the CM obtained from joint tissues., Results: CM from all tissues produced high levels of IL-6, IL-8, and CCL2. CCL21, MMP-3, and -13 levels were detected in all CM except IFP. MMP-10 was present only in CM of cartilage and synovial tissues. IL-1β, IL-15, TNF-α, CCL5, and CCL19 were undetectable. However, only K4IM cells stimulated by the CM from OA synovium showed an increase of IL-6, CXCL-8, CCL21, MMP10, and IL-1β expression., Conclusion: Our study showed that K4IM might be a suitable in vitro model for evaluating different cellular pathways in OA studies. Importantly, we demonstrated that in OA, all joint tissues might be involved in the progression of synovitis with a predominant role of synovial membrane itself compared to the other joint tissues.

Background and aims: Pancreas divisum (PD) is the most common congenital variant of the pancreatic ductal system and a potential cause of acute recurrent pancreatitis (ARP). Endoscopic therapy is a therapeutic option for symptomatic PD, but there is limited data on long-term results. We aimed to assess the effect of minor papilla endoscopic sphincterotomy (MiES) in the setting of ARP in patients with PD. Methods: Consecutive patients treated by MiES were included. Clinical data, including gender, age, smoking and drinking habits, number of episodes of acute pancreatitis (AP) as well as technical data pertaining to the endoscopic therapy were reviewed. Patients available for follow-up were contacted to assess the long-term impact of MiES using the Patient's Global Impression of Change (PGIC) questionnaire. Results: A total of 138 patients with PD including 77 patients with ARP underwent MiES; 48 patients were available for long-term follow-up using the PGIC score, with a mean follow-up period of 9.7 years. Procedure-related adverse events developed in 10 cases (12.9%): 5 post-MiES delayed bleeding and 5 mild pancreatitis. MiES was clinically successful in 35 patients (72.9%) who did not experience any more episodes of AP. Improvement in quality of life (PGIC ≥6) occurred in 41/48 patients (85.4%). On multivariate analysis, stenosis of the MiES was the only predictive factor for increased risk of recurrent pancreatitis after initial therapy. Conclusion: MiES resulted an efficient treatment for ARP in patients with PD with clinical benefit, patient satisfaction and improved quality of life even at long-term follow-up.

Introduction: Klinefelter syndrome (KS), also known as 47, XXY, shows increased mortality when compared with mortality rates among the general population. Cardiovascular, hemostatic, metabolic diseases are implicated. Moreover, cardiac congenital anomalies in KS can contribute to the increase in mortality., Areas Covered: In this study, we have systematically reviewed the relationships between KS and the cardiovascular system and the management of cardiovascular complication. In summary, patients with KS display increased cardiovascular risk profile, characterized by increased prevalence of metabolic alterations including dyslipidemia, diabetes mellitus (DM), and abnormalities in biomarkers of cardiovascular disease. KS subjects are characterized by subclinical abnormalities in endothelial function and in left ventricular (LV) systolic and diastolic function, which - when associated with chronotropic incompetence - may negatively influence cardiopulmonary performance. Moreover, KS patients appear to be at a higher risk for cardiovascular disease, due to thromboembolic events with high prevalence of recurrent venous ulcers, venous insufficiency, recurrent venous and arterial thromboembolism leading to deep venous thrombosis or pulmonary embolism., Expert Opinion: Considering the unequivocal finding of increased mortality of KS patients, we suggest a periodic cardiovascular follow up in specialized centers with multidisciplinary care teams that comprise endocrinologists and cardiologists dedicated to KS syndrome.

Gestational Diabetes Mellitus (GDM) is the most common metabolic condition during pregnancy and may result in short- and long-term complications for both mother and offspring. The complexity of phenotypic outcomes seems influenced by genetic susceptibility, nutrient-gene interactions and lifestyle interacting with clinical factors. There is strong evidence that not only the adverse genetic background but also the epigenetic modifications in response to nutritional and environmental factors could influence the maternal hyperglycemia in pregnancy and the foetal metabolic programming. In this view, the correlation between epigenetic modifications and their transgenerational effects represents a very interesting field of study. The present review gives insight into the role of gene variants and their interactions with nutrients in GDM. In addition, we provide an overview of the epigenetic changes and their role in the maternal-foetal transmission of chronic diseases. Overall, the knowledge of epigenetic modifications induced by an adverse intrauterine and perinatal environment could shed light on the potential pathophysiological mechanisms of long-term disease development in the offspring and provide useful tools for their prevention.

Nuclear factor 90 (NF90) is a dual DNA- and RNA-binding protein expressed ubiquitously in mammalian cells, including monocytes. Here, to elucidate the function of NF90 in the immune response, we analyzed systematically its influence on gene expression programs in the human monocytic cell line THP-1 expressing normal or reduced NF90 levels. RNA sequencing analysis revealed many mRNAs showing differential abundance in NF90-silenced cells, many of them encoding proteins implicated in the response to immune stimuli and malaria infection. The transcription of some of them (e.g. TNF, LILRB1, and CCL2 mRNAs) was modulated by silencing NF90. Ribonucleoprotein immunoprecipitation (RIP) analysis further revealed that a subset of these mRNAs associated directly with NF90. To understand how NF90 influenced globally the immune response to malaria infection, lysates of red blood cells infected with Plasmodium falciparum (iRBC lysates) or uninfected/mock-infected (uRBC lysates) were used to treat THP-1 cells as a surrogate of malaria infection. NF90 affected the stability of a few target mRNAs, but influenced more generally the translation and secretion of the encoded cytokines after treatment with either uRBC or iRBC lysates. Taken together, these results indicate that NF90 contributes to repressing the immune response in cells responding to P. falciparum infection and suggest that NF90 can be a therapeutic target in malaria.

Objective: Hearing loss is a common chronic condition in elderly people. The prevalence of disabling hearing loss among the elderly worldwide is 33% and in Italy ranges from 0.6% (profound hearing loss) to 39% (mild hearing loss). We investigated the relationship between self-reported hearing disability and clinician-evaluated hearing status, and its longitudinal consequences in relation to cognitive impairment and functional decline. We hypothesised that subjects who report that they have a hearing disability have a worse functional and cognitive profile than people who do not report having a hearing disability., Methods: We analysed 1171 participants in the InveCe.Ab study, a longitudinal population-based study. We evaluated whether self-reported hearing disability was consistent with clinician-evaluated hearing status (using the Whispered Voice Test; WVT), categorizing this variable as: unaware of hearing loss (UHL), aware of hearing loss (AHL), only subjective hearing loss (OSHL), without hearing loss (noHL). We also examined its relationship with various population characteristics, and its long-term effects on functional and cognitive performance and depressive symptoms., Results: At baseline, hearing loss was found in 13.6% (95% CI: 11.7-15.7) of the participants [17.6% (95% CI: 12.0-24.4) AHL; 82.4% (95% CI: 75.6-88) UHL], while 2.3% (95% CI: 1.4-3.4) of the subjects with normal WVT hearing status had OSHL. Male gender, age, functional and cognitive performance, and depressive symptoms were associated with consistency between self-reported hearing disability and WVT hearing status. Longitudinal analysis revealed worsening functional performance and selective attention, global cognitive deterioration, and depressive symptoms in the AHL group., Conclusions: Our results showed that awareness of hearing disability in the elderly has adverse cognitive and functional consequences over time. When clinicians inform those who are unaware of their hearing problems, they should arrange for prompt referral not only for audiometric evaluation but also for counselling in order to prevent a negative impact of awareness of hearing loss., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: The GEMINI trials have recently shown that a two-drug regimen of dolutegravir plus lamivudine was non-inferior to a three-drug regimen in HIV-infected naïve patients. Accordingly, it is important that physicians be aware and confident about the drug-drug interactions (DDIs) involving dolutegravir, lamivudine, and other medications. Areas covered: Here, we firstly update the available information on the pharmacokinetic features of dolutegravir and lamivudine; subsequently, the articles mainly deals with the predictable DDIs for both antiretroviral drugs, attempting to underline their clinical implications. This review focuses on the DDIs of dolutegravir/lamivudine combined regimen and, therefore, does not provide an exhaustive list of all the potential DDIs involving the two single agents. A MEDLINE Pubmed search for articles published from January 2000 to December 2018 was completed matching the terms dolutegravir or lamivudine with pharmacokinetics, DDIs, and pharmacology. Moreover, additional studies were identified from the reference list of retrieved articles. Expert opinion: The antiretroviral dual regimen of dolutegravir and lamivudine represents an attractive therapeutic option for HIV in terms of DDIs. This is particularly relevant considering that the population with HIV is aging and is increasingly experience age-related comorbidities, increasing pill burden, polypharmacy and the risk of DDIs.

Objective: To evaluate the relationship between fecal calprotectin (FC) and interstitial lung disease (ILD) in systemic sclerosis (SSc)., Methods: The study enrolled 129 outpatients with SSc. Data about disease characteristics, in particular lung involvement, were collected and FC was measured., Results: Patients with ILD (35, 27.1%) had higher values of FC (p < 0.001). In multivariate analysis, these variables were associated with increased risk of ILD: diffuse disease subset, higher modified Rodnan skin score, longer disease duration, higher severity scores, steroid treatment, and higher FC levels, while diverticulosis was protective., Conclusion: ILD is independently associated with increased FC levels in SSc.

Purpose: The discussed topic about gadolinium-based contrast agents (GBCA) safety has recently been revived due to the evidence of hyperintensities observed in the dentate nucleus (DN) and globus pallidus (GP) in the brain of patients with normal kidney function. Several preclinical studies have been conducted to understanding how the use of GBCAs can promote the gadolinium deposition in the brain. Here, we evaluate the impact of chronic cerebral hypoperfusion on gadolinium presence., Methods: T1 hyperintensities and BBB integrity were evaluated by MRI in chronically hypoperfused and healthy rats injected with either gadodiamide or hypertonic saline. Additionally, the assessment of glucose metabolism by PET imaging and the gadolinium content by ICP-MS was performed after the last MR scan., Results: Chronically hypoperfused rats displayed a greater MRI T 1w signal in the DCN and hippocampus compared to Sham-operated animals, suggesting gadolinium accumulation. Dynamic contrast-enhanced (DCE) MRI assessment of BBB permeability revealed loss of integrity (high K trans ) after rat injury in the dentate nuclei and hippocampus. Ex vivo tissue analysis showed greater gadolinium retention in the cerebellum and subcortical regions, supporting the imaging finding. FDG-PET imaging of the cerebellum did not reveal abnormal uptake in the DCN after chronic cerebral hypoperfusion., Conclusion: Higher signal intensity followed by higher Gd concentration observed in DCN and hippocampus of animals subjected to cerebral injury can be associated with an increase in BBB permeability due to the applied vascular dementia animal model. Nonetheless, no glucose metabolism abnormalities were detected in chronically hypoperfused cerebellum.

Macroautophagy/autophagy is a physiological mechanism that is essential for the maintenance of cellular homeostasis and stress adaptation. Defective autophagy is associated with many human diseases, including cancer and neurodegenerative disorders. The emerging implication of epigenetic events in the control of the autophagic process opens new avenues of investigation and offers the opportunity to develop novel therapeutic strategies in diseases associated with dysfunctional autophagy-lysosomal pathways. Accumulating evidence reveals that several methyltransferases and demethylases are essential regulators of autophagy, and recent studies have led to the identification of the lysine demethylase KDM1A/LSD1 as a promising drug target. KDM1A/LSD1 modulates autophagy at multiple levels, participating in the transcriptional control of several downstream effectors. This review summarizes our current understanding of the role of KDM1A/LSD1 in the autophagy regulatory network.

The purpose of this study was to assess metabolic and kinematic parameters (contact and flight time, step length and frequency) while walking at the preferred speed (1.44 ± 0.22 m · s -1 ) and while performing an incremental running test (up to exhaustion) on a motorised treadmill (MT) and on a curved non-motorised treadmill (CNMT). Twenty-five volunteers (24.1 ± 3.4 years; 64.7 ± 11.2 kg) participated in the study. Maximal running speed on MT was significantly larger (P < 0.001) than on CNMT (4.31 ± 0.50 vs. 3.75 ± 0.39 m · s -1 ) but no differences in heart rate or oxygen uptake ( V ˙ O 2 ) were observed at this speed. The energy cost of walking (C w ) and running (C r ) were significantly greater (P < 0.001) on CNMT than on MT (37 and 17%, respectively). No major differences in kinematic parameters were observed at paired, submaximal, running speeds (2.22-3.89 m · s -1 ) but V ˙ O 2 was systematically larger in CNMT (of about 340 ml · min -1  · kg -1 ). This systematic difference can be expressed in terms of a larger "equivalent speed" on CNMT (of about 0.42 m · s -1 ) and should be attributed to factors other than the kinematic ones, such as the belt characteristics (e.g. friction, type of surface and curvature).

Objectives: Nitric oxide (NO) represents the most powerful endogenous molecule with vasodilator action mainly produced by endothelial nitric oxide synthase (eNOS) enzyme. Polymorphisms and epigenetic-sensitive mechanisms can modulate the expression of eNOS gene, leading to the endothelial dysfunction. This review updates on the mechanistic role of NO in the regulation of platelet activation, as well as the impact of eNOS genetic and epigenetic modifications on arterial thrombosis onset., Design: A systematic search was addressed to examination of PubMed databases with the following terms: nitric oxide; arterial thrombosis; endothelial dysfunction; DNA variations; epigenetic modifications; personalized therapy; network medicine., Results: G894T, -786T/C, and 4b/4a variable number tandem repeat (VNTR), are the main classes of polymorphisms harbored in eNOS gene associated to increased arterial thrombosis risk. DNA methylation, histone/non-histone modifications, and microRNA (miRNAs) can modulate eNOS gene expression. Investigators largely focused on the role of miRNAs in modulating NO production in arterial thrombosis development. In detail, miR-195, and miR-582 are inversely correlated both to eNOS and NO levels, thus suggesting novel biomarkers., Conclusion: We are far from incorporating omics pathogenic data from bench to arterial thrombosis bedside. Network medicine is an emerging paradigm that ideally overcomes the current shortcomings of the reductionist approach. Despite several clinical limitations, the network-based analysis of the interactome might reveal the key nodes underlying the perturbations of the arterial thrombosis, thus advancing personalized therapy.

The harmful effects of space radiation pose a serious health risk to astronauts participating in future long-term missions. Such radiation effects must be considered in the design phase of space vessels as well as in mission planning. Crew radioprotection during long periods in deep space (e.g., transit to Mars) represents a major challenge, especially because of the strong restrictions on the passive shielding load allowed on-board the vessel. Novel materials with better shielding performance compared to the "gold standard" high-density polyethylene are therefore greatly needed. Because of the high hydrogen content of hydrides, lithium hydride has been selected as a starting point for further studies of promising candidates to be used as passive shielding materials. In the current experimental campaign, the shielding performance of lithium hydride was assessed by measuring normalized dose, primary beam attenuation and neutron ambient dose equivalent using 430 MeV/u 12 C, 600 MeV/u 12 C and 228 MeV proton beams. The experimental data were then compared to predictions from the Monte Carlo transport codes PHITS and GRAS. The experimental results show an increased shielding effectiveness of lithium hydride compared to reference materials like polyethylene. For instance, the attenuation length for 600 MeV/u 12 C primary particles in lithium hydride is approximately 20% shorter compared to polyethylene. Furthermore, the comparison results between both transport codes indicates that the standard Tripathi-based total reaction cross-section model of PHITS cannot accurately reproduce the presented experimental data, whereas GRAS shows reasonable agreement.

Introduction: Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state. Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination. Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.

Macroautophagy/autophagy is one of the major responses to stress in eukaryotic cells and is implicated in several pathological conditions such as infections, neurodegenerative diseases and cancer. Interestingly, cancer cells take full advantage of autophagy both to support tumor growth in adverse microenvironments and to oppose damages induced by anti-neoplastic therapies. Importantly, different human oncogenes are able to modulate this survival mechanism to support the transformation process, ultimately leading to 'autophagy addiction'. Still, oncogenic signaling events, impinging on the control of autophagy, are poorly characterized, limiting our possibilities to take advantage of these mechanisms for therapeutic purposes. Here, we screened a library of activated kinases for their ability to stimulate autophagy. By this approach, we identified novel potential regulators of the autophagic process and, among them, the IKBKE oncogene. Specifically, we demonstrate that this oncoprotein is able to stimulate autophagy when overexpressed, an event frequently found in breast tumors, and that its activity is strictly required for breast cancer cells to support the autophagic process. Interestingly, different oncogenic pathways typically involved in breast cancer, namely ERBB2 and PI3K-AKT-MTOR, also rely on IKBKE to control this process. Ultimately, we show that IKBKE-dependent autophagy is necessary for breast cancer cell proliferation, suggesting an important supporting role for this oncogene and autophagy in these tumors. Abbreviations: AAK1: AP2 associated kinase 1; AMPK: 5'-prime-AMP-activated protein kinase; AKT1: AKT serine/threonine kinase 1; BAF: bafilomycin A 1 ; CA: constitutively activated; CDK17: cyclin dependent kinase 17; CDK18: cyclin dependent kinase 18; CHUK: conserved helix-loop-helix ubiquitous kinase; EGF: epidermal growth factor; ERBB2: erb-b2 receptor tyrosine kinase 2; FGF: fibroblast growth factor; FM: full medium; GALK2: galactokinase 2; IKBKB: inhibitor of nuclear factor kappa B kinase subunit beta; IKBKE: inhibitor of nuclear factor kappa B kinase subunit epsilon; IKK: IκB kinase complex; KD: kinase dead; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MAPK1: mitogen-activated protein kinase 1; MAPK15: mitogen-activated protein kinase 15; MTORC1: mammalian target of rapamycin kinase complex 1; myr: myristoylation/myristoylated; NFKBIA: NFKB inhibitor alpha; PDGF: platelet derived growth factor; PFKL: phosphofructokinase, liver type; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKCD: protein kinase C delta; SQSTM1: sequestosome 1; TBK1: TANK binding kinase 1; TNBC: triple-negative breast cancer; TSC2: TSC complex subunit 2; WB: western blot; WT: wild-type.

Introduction: Approximately 2.1 million of the estimated 36 million infected with HIV are children or adolescents. International guidelines for HIV-1 Infection suggest starting antiretrovirals (ARV) at the moment of diagnosis. Many factors limit the optimization of antiretroviral therapy in children and adolescents: lack of pediatric formulations, poor adherence, metabolic and pharmacokinetic changes associated withnormal child development and puberty. Areas covered: Three integrase inhibitors are approved by the US Food and Drug Administration and by European Medical Agency for children and adolescents with HIV-1 infection. Raltegravir is approved for children aged 4 weeks to 18 years, while dolutegravir and elvitegravir co-formulated with cobicistat, emtricitabine, and tenofovir alafenamide (E/C/FTC/TAF) are approved for children from 6 years of age. This article evaluates E/C/FTC/TAF as a treatment option. Expert opinion: E/C/FTC/TAF was well tolerated, and the antiretroviral activity and tolerability data of this combination support the use in children and adolescents. However, the studies regarding E/C/FTC/TAF in children and adolescents are scant. Consequently, additional studies investigating its safety and efficacy in children are paramount.

The mechanistic target of rapamycin kinase complex 1 (MTORC1) is a central cellular kinase that integrates major signaling pathways, allowing for regulation of anabolic and catabolic processes including macroautophagy/autophagy and lysosomal biogenesis. Essential to these processes is the regulatory activity of TFEB (transcription factor EB). In a regulatory feedback loop modulating transcriptional levels of RRAG/Rag GTPases, TFEB controls MTORC1 tethering to membranes and induction of anabolic processes upon nutrient replenishment. We now show that TFEB promotes expression of endocytic genes and increases rates of cellular endocytosis during homeostatic baseline and starvation conditions. TFEB-mediated endocytosis drives assembly of the MTORC1-containing nutrient sensing complex through the formation of endosomes that carry the associated proteins RRAGD, the amino acid transporter SLC38A9, and activate AKT/protein kinase B (AKT p-T308). TFEB-induced signaling endosomes en route to lysosomes are induced by amino acid starvation and are required to dissociate TSC2, re-tether and activate MTORC1 on endolysosomal membranes. This study characterizes TFEB-mediated endocytosis as a critical process leading to activation of MTORC1 and autophagic function, thus identifying the importance of the dynamic endolysosomal system in cellular clearance. Abbreviations: CAD: central adrenergic tyrosine hydroxylase-expressing-a-differentiated; ChIP-seq: chromosome immunoprecipitation sequencing; DAPI: 4',6-diamidino-2-phenylindole; DMSO: dimethyl sulfoxide; EDTA: ethylenediaminetetraacetic acid; EEA1: early endosomal antigen 1; EGF: epidermal growth factor; FBS: fetal bovine serum; GFP: green fluorescent protein; GTPase: guanosine triphosphatase; HEK293T: human embryonic kidney 293 cells expressing a temperature-sensitive mutant of the SV40 large T antigen; LAMP: lysosomal-associated membrane protein; LYNUS: lysosomal nutrient-sensing complex; MAP1LC3/LC3: microtubule associated protein 1 light chain 3 alpha/beta; MTOR: mechanistic target of rapamycin kinase; MTORC: mechanistic target of rapamycin kinase complex; OE: overexpression; PH: pleckstrin homology; PtdIns(3,4,5)P 3 : phosphatidylinositol 3,4,5-trisphosphate; RRAGD: Ras related GTPase binding D; RHEB: Ras homolog enriched in brain; SLC38A9: solute carrier family 38 member 9; SQSTM1: sequestosome 1; TFEB: transcription factor EB; TSC2: tuberous sclerosis 2; TMR: tetramethylrhodamine; ULK1: unc-51 like kinase 1; WT: wild type.

There is a complex and not fully elucidated association between pulmonary arterial hypertension (PAH) and coagulation disorders. The goal of this study was to evaluate platelet function, coagulation and fibrinolysis in PAH patients at diagnosis, before PAH-specific treatment initiation. We enrolled 20 healthy controls and 30 PAH patients (20 with connective tissue disease (CTD-PAH) and 10 idiopathic (iPAH)). None of the participants was on any antiplatelet or anticoagulation therapy. Blood samples from PAH patients were collected during the initial right heart catheterization. All subjects were assessed with platelet function analyzer-100 (PFA-100), epinephrine (Epi) and ADP-induced light transmission aggregometry (LTA), thromboelastometry (ROTEM) and endogenous thrombin potential (ETP). Our results showed that Epi and ADP-LTA values were significantly lower in newly diagnosed PAH patients compared to controls. Disaggregation was present in 73% of patients, a characteristic not seen in healthy individuals. In ROTEM assay, CT and CFT measurements were significantly higher and a angle lower compared to controls. ETP testing revealed significantly reduced outcomes in AUC, Cmax and Tmax. When CTD-PAH and iPAH patient groups were compared, iPAH ADP-LTA values were significantly decreased compared to CTD-PAH. In conclusion, newly diagnosed PAH patients presented with decreased platelet aggregation, clot propagation and thrombin generation, along with delayed initiation of the coagulation process. These hemostatic deficits could indicate an "exhaustion" of the coagulation process that could be caused by endothelial dysfunction and chronic activation of the procoagulant pathways. Further studies are warranted to confirm these laboratory findings and assess their potential clinical significance.

The traditional Mediterranean diet (MedDiet) is a well-known dietary pattern associated with longevity and improvement of life quality as it reduces the risk of the most common chronic pathologies, such as cancer and cardiovascular diseases (CVDs), that represent the principal cause of death worldwide. One of the most characteristic foods of MedDiet is olive oil, a very complex matrix, which constitutes the main source of fats and is used in the preparation of foods, both raw as an ingredient in recipes, and in cooking. Similarly, strawberries and raspberries are tasty and powerful foods which are commonly consumed in the Mediterranean area in fresh and processed forms and have attracted the scientific and consumer attention worldwide for their beneficial properties for human health. Besides olive oil and berries, honey has lately been introduced in the MedDiet thanks to its relevant nutritional, phytochemical and antioxidant profile. It is a sweet substance that has recently been classified as a functional food. The aim of this review is to present and discuss the recent evidence, obtained from in vitro, in vivo and epidemiological studies, on the potential roles exerted by these foods in the prevention and progression of different types of cancer and CVDs.

Migraine is a common multifactorial and polygenic neurological disabling disorder characterized by a genetic background and associated to environmental, hormonal and food stimulations. A large series of evidence suggest a strong correlation between nutrition and migraine and indicates several commonly foods, food additives and beverages that may be involved in the mechanisms triggering the headache attack in migraine-susceptible persons. There are foods and drinks, or ingredients of the same, that can trigger the migraine crisis as well as some foods play a protective function depending on the specific genetic sensitivity of the subject. The recent biotechnological advances have enhanced the identification of some genetic factors involved in onset diseases and the identification of sequence variants of genes responsible for the individual sensitivity to migraine trigger-foods. Therefore many studies are aimed at the analysis of polymorphisms of genes coding for the enzymes involved in the metabolism of food factors in order to clarify the different ways in which people respond to foods based on their genetic constitution. This review discusses the latest knowledge and scientific evidence of the role of gene variants and nutrients, food additives and nutraceuticals interactions in migraine.

Lactococcus garvieae is now recognized as a species with clinical significance for human and veterinary medicine. The aim of this study was to evaluate the presence of this pathogen in sand bedding and milk samples. Two farms in Minnesota with problems of clinical and subclinical mastitis due to streptococci-like organisms were selected. Twenty-four Lactococcus garvieae isolates from sand bedding and 18 isolates from quarter milk were comparatively studied using a genotypic approach. RAPD (random amplification of polymorphic DNA) PCR and REP (repetitive element palindromic) PCR experiments highlighted a similar electrophoretic profile. When genes belonging to the core genome of L. garvieae were tested through a MLRT (multilocus restriction typing), we again observed that all L. garvieae isolates coming from sand bedding and milk shared a common profile, distinguishable from previously studied representative L. garvieae strains. These data indicate that the L. garvieae isolated from sand bedding and milk originated from a few strains adapted to persist in the same habitat. This supports the hypothesis that sand bedding can represent a reservoir of L. garvieae strains and be a potential vehicle for their dissemination in dairy farms.

Purpose: To describe multiple evanescent white dot syndrome (MEWDS)-related foveal granularity features on different imaging modalities., Methods: Clinical and multi-imaging files from five patients affected by MEWDS were reviewed. Each image set included: blue fundus autofluorescence (BAF), near-infrared fundus autofluorescence (NIR-FAF), spectral-domain optical coherence tomography (SD-OCT), fluorescein (FA), and indocyanine green (ICGA) angiography. Foveal granularity features were analyzed and described for each technique at baseline and follow-up., Results: At baseline, 4/5 patients did not show white dots at funduscopic examination, but all subjects demonstrated hypo-fluorescent lesions on ICGA and areas of increased BAF. In all patients, foveal granularity was detectable on NIR-FAF as an irregular hypo-fluorescent area, persisting during follow-up visits. The corresponding SD-OCT scans revealed outer retinal layers' disruption resolving overtime., Conclusions: Foveal granularity can be the sole presenting sign of MEWDS. NIR-FAF and SD-OCT should be considered as non-invasive investigations in the detection of MEWDS-related foveal granularity.

Purpose: Hyperthermia treatment quality determines treatment effectiveness as shown by the clinically derived thermal-dose effect relations. SAR based optimization factors are used as possible surrogate for temperature, since they are not affected by thermal tissue properties uncertainty and variations. Previously, target coverage (TC) at the 25% and 50% iso-SAR level was shown predictive for treatment outcome in superficial hyperthermia and the target-to-hot-spot-quotient (THQ) was shown to highly correlate with predictive temperature in deep pelvic hyperthermia. Here, we investigate the correlation with temperature for THQ and TC using an 'intermediate' scenario: semi-deep hyperthermia in the head & neck region using the HYPERcollar3D., Methods: Fifteen patient-specific models and two different planning approaches were used, including random perturbations to circumvent optimization bias. The predicted SAR indicators were compared to predicted target temperature distribution indicators T50 and T90, i.e., the median and 90th percentile temperature respectively., Results: The intra-patient analysis identified THQ, TC25 and TC50 as good temperature surrogates: with a mean correlation coefficient R 2 T50  = 0.72 and R 2 T90 =0.66. The inter-patient analysis identified the highest correlation with TC25 (R 2 T50  = 0.76, R 2 T90 =0.54) and TC50 (R 2 T50  = 0.74, R 2 T 90  = 0.56)., Conclusion: Our investigation confirmed the validity of our current strategy for deep hyperthermia in the head & neck based on a combination of THQ and TC25. TC50 was identified as the best surrogate since it enables optimization and patient inclusion decision making using one single parameter.

Introduction : Colorectal cancer (CRC) represents a major cause of morbidity and mortality in Western countries. Though colonoscopy is the benchmark for CRC diagnosis and management, other alternatives have been proposed. Colon capsule endoscopy (CCE) was first introduced in 2006 as a non-invasive painless technology that utilizes an ingestible, wireless, and disposable capsule to explore the colon, without sedation or air insufflation. Areas covered : To date, the European Society of Gastrointestinal Endoscopy (ESGE) guidelines consider CCE as an option for average-risk colorectal cancer screening patients and in patients with contraindications or unwilling to undergo colonoscopy and/or with an incomplete colonoscopy. Furthermore, Japan's Pharmaceuticals and Medical Devices Agency (JPMDA) and Food and Drug Administration (FDA) approved the use of CCE in patients unwilling or unable to undergo colonoscopy. Expert commentary : CCE accuracy is nearly comparable to conventional colonoscopy for CRC and significant polyps. Moreover, in the setting of incomplete colonoscopy, CCE was demonstrated to have a higher diagnostic yield for significant polyps and to be better tolerated than CTC. However, the use of CCE is still limited. The lesson coming out is that we should explore new populations that are suitable for colon capsules and for which the colon capsule can be an advantage.

Influenza vaccines are a fundamental tool for preventing the disease and reducing its consequences, particularly in specific high-risk groups. In order to be licensed, influenza vaccines have to meet strict criteria established by European Medicines Agency. Although the licensure of influenza vaccines started 65 years ago, Hemagglutination Inhibition and Single Radial Hemolysis are the only serological assays that can ascertain correlates of protection. However, they present evident limitations. The present review focuses on the evaluation of cell-mediated immunity (CMI), which plays an important role in the host immune response in protecting against virus-related illness and in the establishment of long-term immunological memory. Although correlates of protection are not currently available for CMI, it would be advisable to investigate this kind of immunological response for the evaluation of next-generation vaccines.

Primary Objective : The primary aim of this study was to determine the frequency of severe impaired self-awareness (ISA) in patients with severe traumatic brain injury (TBI) and the correlates of selected clinical, neuropsychiatric and cognitive variables. The secondary aim of the study was to assess depression and apathy on the basis of their level of self-awareness. Methods : Thirty patients with severe TBI and 30 demographically matched healthy control subjects (HCs) were compared on measures of ISA, depression, anxiety, alexithymia, neuropsychiatric symptoms and cognitive flexibility. Results : Twenty percent of the patients demonstrated severe ISA. Severe post-acute ISA was associated with more severe cognitive inflexibility, despite the absence of differences in TBI severity, as evidenced by a Glasgow Coma Scale (GCS) score lower than 9 in all cases in the acute phase. Patients with severe ISA showed lower levels of depression and anxiety but tended to show more apathy and to have greater difficulty describing their emotional state than patients with severe TBI who showed minimal or no disturbance in self-awareness. Conclusion : These findings support the general hypothesis that severe ISA following severe TBI is typically not associated with depression and anxiety, but rather with apathy and cognitive inflexibility.

Human papillomavirus (HPV) is causatively associated with cervical cancer (CC), the fourth most common malignant disease of women worldwide. The introduction of first generation prophylactic HPV vaccines in several national vaccination programmes has substantially decreased the global incidence of HPV cervical infections. Despite the success obtained, the two-licenced bivalent and quadrivalent L1 (the major HPV capsid protein) virus-like particle (VLP)-based vaccines (2vHPV and 4vHPV) present some limitations, such as a virus-type restricted protection, the high cost of the manufacture, and an absence of therapeutic activity on the established lesions. The second-generation prophylactic HPV vaccines, constituted by alternative viral components (such as capsomere or minor capsid HPV L2 protein) or made by more cost-effective strategies of production, are undergoing an intense clinical evaluation. This review aims to offer the reader a complete and updated overview on the HPV vaccination. The authors describe the effectiveness and the limitations of the approved HPV vaccines, and highlight the main characteristics of the new generation vaccines. IMPACT STATEMENT What is already known on this subject? CC is the fourth most common cancer of women in the world. HPV is the etiologic cause of almost all CCs. After being approved by the FDA, the first prophylactic 2vHPV and 4vHPV have been implemented into a routine vaccination schedule around the world, substantially decreasing the incidence of HPV and related-diseases in countries with high coverage rates. Currently, research is focusing on finding innovative and alternative systems to produce and deliver new HPV vaccines, overcoming all of the limitations that have partly restricted the potential benefit of previous vaccines on public health. What do the results of this study add? This narrative review was performed to find all the published studies reporting the efficacy and limitations of 2vHPV and 4vHPV, and evaluating the new HPV vaccines under pre- and clinical investigation. What are the implications of these findings for clinical practice and/or further research? Next generation of HPV vaccines will address many, if not all, of the limitations associated with current vaccines and will represent a step forward in the fight against CC.

Introduction : This paper reviews studies that have assessed the treatment of psychiatric disturbances in dystonia, tic disorders, Tourette syndrome, Huntington's disease, and essential tremor. Areas covered : We searched for papers in English in Pubmed using the following keywords: blepharospasm, cervical dystonia, arm dystonia, laryngeal dystonia, spasmodic dysphonia, tic disorders, Tourette syndrome, Huntington's chorea, essential tremor, depression, anxiety, obsessive compulsive disorders, attention deficit hyperactivity disorders, psychosis, apathy. Expert commentary : Although psychiatric disturbances are frequent in hyperkinetic movement disorders, few controlled studies have assessed the treatment of psychiatric disturbances in such disorders. In dystonia, none of the controlled studies conducted to date have demonstrated the efficacy of drug treatment for depression or anxiety. In TS, controlled studies have demonstrated the usefulness of drug treatment on obsessive compulsive disorders and attention deficit hyperactivity disorders. Behavioral interventions may also play a role. No controlled studies have been conducted on HD nor have any studies addressed the treatment of psychiatric disturbances in ET. We conclude that there is the need of controlled studies to better evaluate pharmacological and non-pharmacological treatment of psychiatric disturbances in hyperkinetic movement disorders.

To date, no international guidelines or recommendations for diagnosis or prognosis of patients with disorders of consciousness (DoC) have been established. The International Brain Injury Association's (IBIA) Special Interest Group on Disorders of Consciousness (DoC-SIG) launched an international multicenter survey to compare diagnostic and prognostic procedures across countries and clinical settings. Objectives : To explore which specific diagnostic protocols and prognostic indices were utilized in the care for persons with DoC in different countries and to determine the usage, if any, of national guidelines in the care of such patients. Methods : The questionnaire included 17 questions in two distinct sections (I - clinical and instrumental tools and involvement of caregivers and II - clinical, anamnestic and instrumental markers). Results : Physicians composed 50% of the survey respondents (120) and were all involved in post-acute rehabilitation care. In the majority of countries, respondents reported that there were no national guidelines or recommendations for DoC care. The Glasgow Coma Scale (GCS) and the Coma Recovery Scale-Revised (CRS-R) were the most frequently used clinical scales for diagnostic purposes. The majority of respondents reported the involvement of caregivers in the evaluation of behavioral responsiveness of patient with DoC. The survey indicated that only a few centers performed neurophysiological investigations routinely as diagnostic instrumental procedures. Our results suggest that international guidelines and recommendations for the care of persons with DoC still need to be formulated and ideally agreed to by consensus.

Analyzing the results of molecular dynamics (MD)-based simulations usually entails extensive manipulations of file formats encoding both the topology (e.g., the chemical connectivity) and configurations (the trajectory) of the simulated system. This chapter reviews a number of software libraries developed to facilitate interactive and batch analysis of MD results with scripts written in high-level, interpreted languages. It provides a beginners' introduction to MD analysis presenting a side-by-side comparison of major scripting languages used in MD and shows how to perform common analysis tasks within the Visual Molecular Dynamics (VMD), Bio3D, MDTraj, MDAnalysis, and High-Throughput Molecular Dynamics (HTMD) environments.

Background: Deaths from fentanyl exposure continue to increase in the US. Fentanyl test strips are now available to test urine for presence of fentanyl, but additional testing methods are needed to determine past exposure and to determine exposure to specific analogs., Objectives: To investigate exposure to such analogs through hair testing., Methods: Forty individuals in inpatient detoxification (7.5% female) reporting past-month heroin use were surveyed and provided a hair sample to be tested at a later date. While results could not be provided to patients, they were asked how they would respond if informed that their hair tested positive for fentanyl. UHPLC-MS/MS was used to test for past exposure to fentanyl, six other novel synthetic opioids, and fentanyl biomarkers/metabolites., Results: 27.5% reported known fentanyl use in the past year and 67.5% reported suspected exposure. 97.5% (39 of 40) tested positive for fentanyl, 90.0% tested positive for 4-ANPP (a biomarker) and norfentanyl (a metabolite); 82.5% tested positive for acetyl-fentanyl, 47.5% tested positive for furanyl-fentanyl, and 7.5% tested positive for U-47700. Most participants (82.5%) reported they would warn others about fentanyl if they learned their hair tested positive; 75.0% reported they would try to stop using heroin, and 65.0% reported they would ensure that someone nearby has naloxone to reverse a potential overdose., Conclusions: Hair testing is useful in detecting past exposure to fentanyl, its analogs, and other novel synthetic opioids. Further research is needed to determine whether individuals who use heroin learning about exposure affects drug-taking and treatment-seeking behavior.

Introduction: Patients with obsessive-compulsive disorder (OCD) showed impaired spatial working memory (SWM). We evaluated whether patients and healthy controls (HCs) differed in spatial store capacity, and whether they differed in the relative weight of spatial store capacity and/or executive strategy in SWM., Methods: Thirty inpatients with OCD and 31 age- and education-matched HCs underwent the CANTAB SWM, SRM (a measure of spatial store). The severity of OC symptoms was assessed using the Y-BOCS. Statistical significance: α = 0.05., Results: Patients showed poorer performance than HCs in all neuropsychological outcomes. Both poorer SRM and SWM strategy were significantly associated with poorer SWM in the entire sample. No significant interaction between SRM and Group was found, while a significant interaction between SWM strategy and Group emerged; in patients the magnitude of this association was approximately twofold larger than in HCs. OC symptom severity did not correlate with neuropsychological performance., Conclusions: Patients with OCD had poorer spatial store capacity than HCs. However, the weight of poorer executive strategy in SWM was greater in patients than HCs, whereas the weight of spatial store was similar. We provided a direct evidence that an impairment in the executive component might be the crucial factor influencing the poorer SWM of these patients.

This review concerns three legume trees (family Fabaceae, subfamily Caesalpinioideae) from West Africa, namely Detarium microcarpum , Parkia biglobosa and Dialium guineense , and illustrates their nutritional value and therapeutic properties. These species are an important source of nutrition for West African populations, but their agricultural exploitation is still incomplete. The survey was conducted on Scopus, Web of Science, and Medline, using scientific and common English names of the species as keywords and then selecting papers related to nutritional and medicinal properties. Main food products are fruit pulp and seeds, though leaves can also be used. Most relevant dietary features are high protein, vitamin, and micronutrient contents. Various therapeutic and nutritional benefits of these plants have been documented by ethnobotanical and experimental studies, stimulating an interest for their possible use as functional food or drug sources. Most studied medicinal properties include antidiabetic and antimicrobial activities of D. microcarpum , cardiovascular protective and antidiabetic activities of P. biglobosa , and bilharzia-preventing molluscicidal activity of D. guineense . Phytochemical characterizations have revealed potential sources of active drugs, such as D. guineense saponins and D. microcarpum diterpenes. Scientific results support popular uses of these legume trees, indicating a prominent nutritional and health value.

Researchers' aim was to investigate if patients/physicians characteristics could differently affect males/females health care expenditure. In 2009/2010, a health-related-quality-of-life (HRQL) measure was distributed to 887 general practitioners' (GP) patients in Siena's province-Italy. Severity of diseases was calculated through Cumulative Illness Rating Scale Severity Index (CIRS-SI). Information about GPs' gender and age and patients' gender, age, and socio-economic variables were recorded. 2012 data about pharmaceutical, outpatient and hospital expenditure were obtained. Multivariate regression was carried out. In males, hospital expenditure increased with higher CIRS-SI and female GP whilst in females it was not influenced by any of the variables. Outpatient and pharmaceutical expenditure increased with aging, higher CIRS-SI, and lower HRQL and education, both in males and females. Gender differences in health expenditure determinants emerged for hospital expenditure.

Progeroid syndromes induced by mutations in lamin A or in its interactors - named progeroid laminopathies - are model systems for the dissection of the molecular pathways causing physiological and premature aging. A large amount of data, based mainly on the Hutchinson Gilford Progeria syndrome (HGPS), one of the best characterized progeroid laminopathy, has highlighted the role of lamins in multiple DNA activities, including replication, repair, chromatin organization and telomere function. On the other hand, the phenotypes generated by mutations affecting genes directly acting on DNA function, as mutations in the helicases WRN and BLM or in the polymerase polδ, share many of the traits of progeroid laminopathies. These evidences support the hypothesis of a concerted implication of DNA function and lamins in aging. We focus here on these aspects to contribute to the comprehension of the driving forces acting in progeroid syndromes and premature aging.

Introduction: Inflammatory bowel disease is a chronic inflammation of the gut whose pathogenesis is still unclear. Although no curative therapy is currently available, a number of drugs are used in induction and maintenance therapy; however, for most of these drugs, a high inter-individual variability in response is observed. Among the factors of this variability, genetics plays an important role. Areas covered: This review summarizes the results of pharmacogenetic studies, considering the most important drugs used and in particular aminosalycilates, glucocorticoids, thiopurines, monoclonal antibodies and thalidomide. Most studies used a candidate gene approach, even if significant breakthroughs have been obtained recently from applying genome-wide studies. When available, also investigations considering epigenetics and pharmacogenetic dosing guidelines have been included. Expert opinion: Only for thiopurines, genetic markers identified as predictors of efficacy or adverse events have allowed the development of dosing guidelines. For the other drugs, encouraging results are available and great expectations rely on the study of epigenetics and integration with pharmacokinetic information, especially useful for biologics. However, to improve therapy of IBD patients with these drugs, for implementation in the clinics of pharmacogenetics, informatic clinical decision support systems and training about pharmacogenetics of health providers are needed.

Purpose/Aim of the study. Collagen type XV (ColXV) was identified, in our previews studies, as a novel component of bone extracellular matrix. The present study aims to investigate ColXV localization during mineralization of osteodifferentiated human mesenchymal stem cells (hMSCs)., Material and Methods: hMSCs cultured in osteogenic medium have been analyzed at day 14 and 28 for mineral matrix deposition by alizarin red S staining, ultrastructural analysis and ColXV localization by immunogold electron microscopy., Results: Our data show an intimate association between ColXV and fibrillar components in areas localized far from mineralized nodules., Conclusions: We have demonstrated the efficacy of ultrastructural analysis, combined with immunocytochemistry, to establish a temporal and spatial localization of ColXV. This data, added to previous evidences, contribute to validate the negative effects of calcium deposits on ColXV expression.

O-acetylserine sulfhydrylase (OASS) is the pyridoxal 5'-phosphate dependent enzyme that catalyses the formation of L-cysteine in bacteria and plants. Its inactivation is pursued as a strategy for the identification of novel antibiotics that, targeting dispensable proteins, holds a great promise for circumventing resistance development. In the present study, we have investigated the reactivity of Salmonella enterica serovar Typhimurium OASS-A and OASS-B isozymes with fluoroalanine derivatives. Monofluoroalanine reacts with OASS-A and OASS-B forming either a stable or a metastable α-aminoacrylate Schiff's base, respectively, as proved by spectral changes. This finding indicates that monofluoroalanine is a substrate analogue, as previously found for other beta-halogenalanine derivatives. Trifluoroalanine caused different and time-dependent absorbance and fluorescence spectral changes for the two isozymes and is associated with irreversible inhibition. The time course of enzyme inactivation was found to be characterised by a biphasic behaviour. Partially distinct inactivation mechanisms for OASS-A and OASS-B are proposed.

Background: In the BEAUTY study we investigated whether utilizing non-invasive monitoring of hemodynamic parameters combined with a drug selection algorithm (integrated hemodynamic management-IHM) compared to conventional drug selection may improve home BP in patients with uncontrolled hypertension., Methods: Uncontrolled (office systolic blood pressure (SBP) > 140 mmHg and ambulatory daytime SBP >135 mmHg while taking ≥2 antihypertensive drugs) essential hypertensive patients were referred to 5 European Hypertension Excellence Centers and, if eligible, were randomized into IHM-guided vs conventional treatment adjustment. Home blood pressure (BP) was taken with 2 repeated readings at 1-2 min intervals in the morning and in the evening (before drug intake and eating) during the week preceding the visit at the outpatient clinic after 5 min rest using a validated semi-automatic oscillometric arm cuff device and with a correct cuff bladder placement. Home blood pressure was measured in a sub-group of patients (n = 84) not significantly different from the other patients., Results: Home SBP changed from 152.1+/-15.8 and 149.8+/-11.8 mmHg to 131.0 +/-11.1 and 139.6+/-12.8 mmHg in IHM group (n = 46) and Control group (n = 38), respectively, showing significantly greater reduction in IHM than in Control group (d= -10.9 mmHg, 95% CI -17.77, -4.02), p = 0.002. The reduction remained significant after multiple adjustments, particularly for baseline home SBP, recruiting center, age, sex and BMI (SBP IHM-Control = -9,63 mmHg, 95% CI -14.28, -5.11) mmHg, p < 0.0001)., Conclusion: Drug selection algorithm based on non-invasive hemodynamic monitoring induced larger reduction in home BP compared to conventional drug selection in uncontrolled hypertensive patients referred to European Hypertension Excellence Centers. Although the main BEAUTY study was negative, these home BP measurements taken by patients themselves may suggest that the integrated hemodynamic monitoring is useful in patients with uncontrolled hypertension. This finding might depend on specific features of home BP measurements which could make it recommended BP measurement method for drug trials.

The activation of a β-class carbonic anhydrase (CAs, EC 4.2.1.1) from Mycobacterium tuberculosis, encoded by the gene Rv3273 (mtCA 3), was investigated using a panel of natural and non-natural amino acids and amines. mtCA 3 was effectively activated by D-DOPA, L-Trp, dopamine and serotonin, with K A s ranging between 8.98 and 12.1 µM. L-His and D-Tyr showed medium potency activating effects, with K A s in the range of 17.6-18.2 µM, whereas other amines and amino acids were relatively ineffective activators, with K A s in the range of 28.9-52.2 µM. As the physiological roles of the three mtCAs present in this pathogen are currently poorly understood and considering that inhibition of these enzymes has strong antibacterial effects, discovering molecules that modulate their enzymatic activity may lead to a better understanding of the factors related to the invasion and colonisation of the host during Mycobacterium tuberculosis infection.

Total hip arthroplasty (THA) improve the patients' quality of life, and one of the most important problems after surgery is to optimize postoperative pain management. It has been shown that pain is intimately linked to the fear of movement, the so-called kinesiophobia, which can affect the entire perioperative period and quality of life in people undergoing THA. In this study, we aimed to present a new integrative approach called IARA model specifically focused on educational interventions such as knowledge and awareness of illness, guided imagery, and drawings to help the patient achieve full autonomy and confidence about the perioperative period and surgery. The Hip Injury and Osteoarthritis Outcome Score (HOOS), Tampa Scale Kinesiophobia (TSK) questionnaire, and Numeric Rating Scale 0-10 have been used to test the efficacy of IARA. The main finding in the present study was the effectiveness of IARA model in improving indexes of pain (p < 0.01) and QoL (p < 0.01) and to keep kinesiophobia levels low in patients undergoing THA.

Introduction: Chronic hepatitis C virus (HCV) infection has been associated with myriad extrahepatic manifestations, often resulting from aberrant immune responses. Among the most common immune-mediated manifestations of HCV infection, mixed cryoglobulinemia is the best known extra-hepatic complication. Areas covered: Here we review less common extrahepatic manifestations of HCV infection, with ascertained or presumed immune pathogenesis and the role of the new all oral direct-acting antiviral agents. Rheumatologic, dermatologic, ophthalmologic, renal, pulmonary, hematologic, cardiovascular, and neuropsychiatric manifestations of HCV infection have been considered. Expert commentary: Pathogenesis of HCV-induced aberrant immune responses resulting in peculiar clinical manifestations is not restricted to a single mechanism. A sound approach would therefore consider implementation of an etiologic treatment, through use of antiviral medications, to stop upstream in the pathogenic process all the immune mechanisms leading to hepatic and extrahepatic abnormalities. With the recent introduction of interferon-free, direct antiviral agents, capable of warranting cure for nearly all HCV-infected patients subjected to therapy, both common and uncommon extrahepatic manifestations of chronic hepatitis C are expected to no longer constitute a matter of comorbidity in the course of HCV infection.

Objective: To assess whether previous training in surgery influences performance on da Vinci Skills Simulator and da Vinci robot. Material and methods: In this prospective study, thirty-seven participants (11 medical students, 17 residents, and 9 attending surgeons) without previous experience in laparoscopy and robotic surgery performed 26 exercises at da Vinci Skills Simulator. Thirty-five then executed a suture using a da Vinci robot. Results: The overall scores on the exercises at the da Vinci Skills Simulator show a similar performance among the groups with no statistically significant pair-wise differences ( p  < .05). The quality of the suturing based on the unedited videos of the test run was similar for the intermediate (7 (4, 10)) and expert group (6.5 (4.5, 10)), and poor for the untrained groups (5 (3.5, 9)), without statistically significant difference ( p  < .05). Conclusion: This study showed, for subjects new to laparoscopy and robotic surgery, insignificant differences in the scores at the da Vinci Skills Simulator and at the da Vinci robot on inanimate models.

The activation of the δ-class carbonic anhydrase (CAs, EC 4.2.1.1) from the diatom Thalassiosira weissflogii (TweCAδ) was investigated using a panel of natural and non-natural amino acids and amines. The most effective activator of TweCAδ was d-Tyr (K A of 51 nM), whereas several other amino acids and amines, such as L-His, L-Trp, d-Trp, dopamine and serotonin were submicromolar activators (K A s from 0.51 to 0.93 µM). The most ineffective activator of TweCAδ was 4-amino-l-Phe (18.9 µM), whereas d-His, l-/d-Phe, l-/d-DOPA, l-Tyr, histamine, some pyridyl-alkylamines, l-adrenaline and aminoethyl-piperazine/morpholine were moderately potent activators (K A s from 1.34 to 8.16 µM). For any δ-CA, there are no data on the crystal structure, homology modelling and the amino acid residues that are responsible for proton transfer to the active site are currently unknown making it challenging to provide a detailed rational for these findings. However, these data provide further evidence that this class of underexplored CA deserves more attention.

The inhibition of α-, β-, γ-, and δ-class carbonic anhydrases (CAs, EC 4.2.1.1) from bacteria (Vibrio cholerae and Porphyromonas gingivalis) and diatoms (Thalassiosira weissflogii) with a panel of N'-aryl-N-hydroxy-ureas is reported. The α-/β-CAs from V. cholerae (VchCAα and VchCAβ) were effectively inhibited by some of these derivatives, with K I s in the range of 97.5 nM - 7.26 µM and 52.5 nM - 1.81 µM, respectively, whereas the γ-class enzyme VchCAγ was less sensitive to inhibition (K I s of 4.75 - 8.87 µM). The β-CA from the pathogenic bacterium Porphyromonas gingivalis (PgiCAβ) was not inhibited by these compounds (K I s > 10 µM) whereas the corresponding γ-class enzyme (PgiCAγ) was effectively inhibited (K I s of 59.8 nM - 6.42 µM). The δ-CA from the diatom Thalassiosira weissflogii (TweCAδ) showed effective inhibition with these derivatives (K I s of 33.3 nM - 8.74 µM). As most of these N-hydroxyureas are also ineffective as inhibitors of the human (h) widespread isoforms hCA I and II (K I s > 10 µM), this class of derivatives may lead to the development of CA inhibitors selective for bacterial/diatom enzymes over their human counterparts and thus to anti-infectives or agents with environmental applications.

Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC 50  = 4.8 μM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation. This analysis led us to confirm the hypothesised binding mode of VS6 and to identify a new derivative that is about 6-fold more active than VS6 (compound 3, IC 50  = 0.76 μM).