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Background: Even after the development of vaccines, SARS-CoV-2 continues to cause severe pneumonia all over the world. Consequently, in order to improve the management of patients and optimize the use of resources, predictors of disease severity and lung complications after COVID-19 pneumonia are urgently needed. Blood cell count is an easily available and reproducible biomarker. With this study, we aimed to explore the role of eosinophils in predicting disease behavior and pulmonary sequelae at first follow-up with computed tomography (CT)., Methods: we evaluated blood cell count and other inflammatory markers, both at baseline and during hospitalization, in a large population of hospitalized COVID-19 patients., Results: 327 patients were finally enrolled, 214 were classified as low-intensity medical care (LIMC) and 113 as high-intensity medical care. Eosinophils were higher at discharge in the HIMC group [0.1 (0-0.72) vs. 0.05 (0-0.34) × 109/L; p < 0.0001]. Moreover, in the multivariable analysis, age ≥ 62 years (OR 1.76 (1.05-2.8) p = 0.03) and Δ eosinophils ≥ 0.05 (OR 1.75 (1.05-2.9) p = 0.03) were two independent predictors of residual lung abnormalities in the whole patient population at first follow-up., Conclusions: an eosinophil increase during hospitalization could be a potential predictor of pulmonary sequelae in surviving patients after COVID-19 pneumonia.

During the COVID-19 pandemic, immunosuppressed patients showed prolonged SARS-CoV-2 infections, with several studies reporting the accumulation of mutations in the viral genome. The weakened immune system present in these individuals, along with the effect of antiviral therapies, are thought to create a favourable environment for intra-host viral evolution and have been linked to the emergence of new viral variants which strongly challenged containment measures and some therapeutic treatments. To assess whether impaired immunity could lead to the increased instability of viral genomes, longitudinal nasopharyngeal swabs were collected from eight immunocompromised patients and fourteen non-immunocompromised subjects, all undergoing SARS-CoV-2 infection. Intra-host viral evolution was compared between the two groups through deep sequencing, exploiting a probe-based enrichment method to minimise the possibility of artefactual mutations commonly generated in amplicon-based methods, which heavily rely on PCR amplification. Although, as expected, immunocompromised patients experienced significantly longer infections, the acquisition of novel intra-host viral mutations was similar between the two groups. Moreover, a thorough analysis of viral quasispecies showed that the variability of viral populations in the two groups is comparable not only at the consensus level, but also when considering low-frequency mutations. This study suggests that a compromised immune system alone does not affect SARS-CoV-2 within-host genomic variability.

Background: Autistic girls are underdiagnosed compared to autistic boys, even when they experience similar clinical impact. Research suggests that girls present with distinct symptom profiles across a variety of domains, such as language, which may contribute to their underdiagnosis. In this study, we examine sex differences in the temporal dynamics of natural conversations between naïve adult confederates and school-aged children with or without autism, with the goal of improving our understanding of conversational behavior in autistic girls and ultimately improving identification., Methods: Forty-five school-aged children with autism (29 boys and 16 girls) and 47 non-autistic/neurotypical (NT) children (23 boys and 24 girls) engaged in a 5-min "get-to-know-you" conversation with a young adult confederate that was unaware of children's diagnostic status. Groups were matched on IQ estimates. Recordings were time-aligned and orthographically transcribed by trained annotators. Several speech and pause measures were calculated. Groups were compared using analysis of covariance models, controlling for age., Results: Autistic girls used significantly more words than autistic boys, and produced longer speech segments than all other groups. Autistic boys spoke more slowly than NT children, whereas autistic girls did not differ from NT children in total word counts or speaking rate. Autistic boys interrupted confederates' speech less often and produced longer between-turn pauses (i.e., responded more slowly when it was their turn) compared to other children. Within-turn pause duration did not differ by group., Limitations: Our sample included verbally fluent children and adolescents aged 6-15 years, so our study results may not replicate in samples of younger children, adults, and individuals who are not verbally fluent. The results of this relatively small study, while compelling, should be interpreted with caution and replicated in a larger sample., Conclusion: This study investigated the temporal dynamics of everyday conversations and demonstrated that autistic girls and boys have distinct natural language profiles. Specifying differences in verbal communication lays the groundwork for the development of sensitive screening and diagnostic tools to more accurately identify autistic girls, and could inform future personalized interventions that improve short- and long-term social communication outcomes for all autistic children., (© 2023. The Author(s).)

Minimal/measurable residual disease (MRD) monitoring is progressively changing the management of hematologic malignancies. The possibility of detecting the persistence/reappearance of disease in patients in apparent clinical remission offers a refined risk stratification and a treatment decision making tool. Several molecular techniques are employed to monitor MRD, from conventional real-time quantitative polymerase chain reaction (RQ-PCR) to next generation sequencing and digital droplet PCR (ddPCR), in different tissues or compartments through the detection of fusion genes, immunoglobulin and T-cell receptor gene rearrangements or disease-specific mutations. RQ-PCR is still the gold standard for MRD analysis despite some limitations. ddPCR, considered the third-generation PCR, yields a direct, absolute, and accurate detection and quantification of low-abundance nucleic acids. In the setting of MRD monitoring it carries the major advantage of not requiring a reference standard curve built with the diagnostic sample dilution and of allowing to reduce the number of samples below the quantitative range. At present, the broad use of ddPCR to monitor MRD in the clinical practice is limited by the lack of international guidelines. Its application within clinical trials is nonetheless progressively growing both in acute lymphoblastic leukemia as well as in chronic lymphocytic leukemia and non-Hodgkin lymphomas. The aim of this review is to summarize the accumulating data on the use of ddPCR for MRD monitoring in chronic lymphoid malignancies and to highlight how this new technique is likely to enter into the clinical practice., 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 © 2023 Assanto, Del Giudice, Della Starza, Soscia, Cavalli, Cola, Bellomarino, Di Trani, Guarini and Foà.)

Autism was formally recognized by the medical community in the first half of the twentieth century. Almost 100 years later, a small but growing literature has reported sex differences in the behavioral expression of autism. Recent research has also begun to explore the internal experiences of individuals with autism, including social and emotional insight. The current study examines sex differences in language-based markers of social and emotional insight in girls and boys with autism and non-autistic peers during semi-structured clinical interviews. Sixty-four participants aged 5 to 17 years were individually matched on chronological age and full-scale IQ to form four groups: autistic girls, autistic boys, non-autistic girls, and non-autistic boys. Transcribed interviews were scored using four scales that index aspects of social and emotional insight. Results revealed the main effects of diagnosis, such that youth with autism exhibited lower insight than non-autistic youth on scales indexing social cognition and object relations, emotional investment, and social causality. With regards to sex differences, across diagnoses, girls were rated higher than boys on the social cognition and object relations, emotional investment, and social causality scales. Examined within each diagnosis separately, clear sex differences emerged: both autistic and non-autistic girls demonstrated better social cognition and understanding of social causality than boys in their respective diagnostic groups. No within-diagnosis sex differences were found on the emotional insight scales, however. These results suggest that relatively enhanced social cognition and understanding of social causality in girls may be a population-level sex difference that is preserved in autism, despite the core social challenges that characterize this condition. The current findings reveal critical new information about insight into social and emotional thinking and relationships in autistic girls versus boys that have important implications for improving identification and designing effective interventions., (© 2023. The Author(s).)

Background: Autistic individuals frequently experience social communication challenges. Girls are diagnosed with autism less often than boys even when their symptoms are equally severe, which may be due to insufficient understanding of the way autism manifests in girls. Differences in the behavioral presentation of autism, including how people talk about social topics, could contribute to these persistent problems with identification. Despite a growing body of research suggesting that autistic girls and boys present distinct symptom profiles in a variety of domains, including social attention, friendships, social motivation, and language, differences in the way that autistic boys and girls communicate verbally are not yet well understood. Closely analyzing boys' and girls' socially-focused language during semi-structured clinical assessments could shed light on potential sex differences in the behavioral presentation of autistic individuals that may prove useful for identifying and effectively supporting autistic girls. Here, we compare social word use in verbally fluent autistic girls and boys during the interview sections of the ADOS-2 Module 3 and measure associations with clinical phenotype., Methods: School-aged girls and boys with autism (N = 101, 25 females; aged 6-15) were matched on age, IQ, and parent/clinician ratings of autism symptom severity. Our primary analysis compared the number of social words produced by autistic boys and girls (normalized to account for differences in total word production). Social words are words that make reference to other people, including friends and family., Results: There was a significant main effect of sex on social word production, such that autistic girls used more social words than autistic boys. To identify the specific types of words driving this effect, additional subcategories of friend and family words were analyzed. There was a significant effect of sex on friend words, with girls using significantly more friend words than boys. However, there was no significant main effect of sex on family words, suggesting that sex differences in social word production may be driven by girls talking more about friends compared to boys, not family. To assess relationships between word use and clinical phenotype, we modeled ADOS-2 Social Affect (SA) scores as a function of social word production. In the overall sample, social word use correlated significantly with ADOS-2 SA scores, indicating that participants who used more social words were rated as less socially impaired by clinicians. However, when examined in each sex separately, this result only held for boys., Limitations: This study cannot speak to the ways in which social word use may differ for younger children, adults, or individuals who are not verbally fluent; in addition, there were more autistic boys than girls in our sample, making it difficult to detect small effects., Conclusions: Autistic girls used significantly more social words than boys during a diagnostic assessment-despite being matched on age, IQ, and both parent- and clinician-rated autism symptom severity. Sex differences in linguistic markers of social phenotype in autism are especially important in light of the late or missed diagnoses that disproportionately affect autistic girls. Specifically, heightened talk about social topics could complicate autism referral and diagnosis when non-clinician observers expect a male-typical pattern of reduced social focus, which autistic girls may not always exhibit., (© 2022. The Author(s).)

Spirulina platensis is a "super-food" and has attracted researchers' attention due to its anti-inflammatory, antioxidant, and analgesic properties. Herein, we investigated the antinociceptive effects of Spirulina in different rodent behavior models of inflammatory pain. Male Swiss mice were treated with Spirulina (3-300 mg/kg, p.o.), indomethacin (10 mg/kg, p.o.), or vehicle (0.9% NaCl 10 mL/kg). Behavioral tests were performed with administration of acetic acid (0.6%, i.p.), formalin 2.7% (formaldehyde 1%, i.pl.), menthol (1.2 µmol/paw, i.pl.), cinnamaldehyde (10 nmol/paw, i.pl.), capsaicin (1.6 µg/paw, i.pl.), glutamate (20 µmol/paw, i.pl.), or naloxone (1 mg/kg, i.p.). The animals were also exposed to the rotarod and open field test to determine possible effects of Spirulina on locomotion and motor coordination. The quantitative phytochemical assays exhibited that Spirulina contains significant concentrations of total phenols and flavonoid contents, as well as it showed a powerful antioxidant effect with the highest scavenging activity. Oral administration of Spirulina completely inhibited the abdominal contortions induced by acetic acid (ED 50 = 20.51 mg/kg). Spirulina treatment showed significant inhibition of formalin-induced nociceptive behavior during the inflammatory phase, and the opioid-selective antagonist markedly blocked this effect. Furthermore, our data indicate that the mechanisms underlying Spirulina analgesia appear to be related to its ability to modulate TRMP8 and TRPA1, but not by TRPV1 or glutamatergic system. Spirulina represents an orally active and safe natural analgesic that exhibits great therapeutic potential for managing inflammatory pain disorders.

Objective: To conduct a comprehensive evaluation of coagulation profiles - via traditional and whole blood thromboelastometry tests - in COVID-19 positive vs. COVID-19 negative patients admitted to medical wards for acute pneumonia., Patients and Methods: We enrolled all consecutive patients admitted to Internal Medicine wards of Padova University Hospital between 7 March and 30 April 2020 for COVID-19-related pneumonia (cases) vs. non-COVID-19 pneumonia (controls). A group of healthy subjects acted as baseline for thromboelastometry parameters., Results: Fifty-six cases (mean age 64±15 yrs, M/F 37/19) and 56 controls (mean age 76±11 yrs, M/F 35/21) were enrolled. Cases and controls showed markedly hypercoagulable thromboelastometry profiles vs. healthy subjects, mainly characterized by a significantly shorter propagation phase of coagulation (Clot Formation Time, CFT) and significantly increased maximum clot firmness (MCF) (p <0.001 in all comparisons). COVID-19 patients with pneumonia had significantly shorter CFT and higher MCF (p <0.01 and <0.05, respectively in all comparisons) vs. controls., Conclusion: Patients admitted to internal medicine wards for COVID-19 pneumonia presented a markedly prothrombotic state, which seems peculiar to COVID-19 rather than pneumonia itself., (.)

Objective: To conduct a comprehensive evaluation of coagulation profiles-via traditional and whole blood thromboelastometry tests-in coronavirus disease 2019 (COVID-19)-positive vs COVID-19-negative patients admitted to medical wards for acute pneumonia., Patients and Methods: We enrolled all consecutive patients admitted to internal medicine wards of Padova University Hospital between 7 March and 30 April, 2020, for COVID-19-related pneumonia (cases) vs non-COVID-19 pneumonia (controls). A group of healthy individuals acted as baseline for thromboelastometry parameters., Results: Fifty-six cases (mean age, 64±15 years; male/female, 37/19) and 56 controls (mean age, 76±11 years; male/female, 35/21) were enrolled. Cases and controls exhibited markedly hypercoagulable thromboelastometry profiles vs healthy individuals, mainly characterized by a significantly shorter propagation phase of coagulation (clot formation time) and significantly increased maximum clot firmness ( P <.001 for all comparisons). Patients with COVID-19 pneumonia had significantly shorter clot formation time and higher maximum clot firmness ( P <.01 and P <.05, respectively, for all comparisons) than did controls., Conclusion: Patients admitted to internal medicine wards for COVID-19 pneumonia presented a markedly prothrombotic state, which seems peculiar to COVID-19 rather than pneumonia itself., (© 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc.)

Despite thromboprophylaxis, patients with coronavirus disease 2019 (COVID-19) exhibit hypercoagulability and higher venous thromboembolic risk, although its real incidence is still unknown. The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with COVID-19 admitted to both intensive care units (ICUs) and medical wards (MWs). Consecutive patients admitted for COVID-19 to the MW and the ICU at Padua University Hospital, all receiving thromboprophylaxis, underwent systematic ultrasonography of the internal jugular, and the upper and lower limbs veins every 7 days (± 1 day) after the admission; and, if negative, once-weekly until discharge or death. In case of suspected pulmonary embolism, a multidetector computed tomographic angiography was performed. The primary outcome was the proportion of any deep-vein thrombosis (DVT) and symptomatic pulmonary embolism in both groups. An extended blood coagulative test was performed as well. From March 4 to April 30, 2020, a total of 85 patients were investigated, 44 (52%) in MWs and 41 (48%) in the ICU. Despite thromboprophylaxis, VTE occurred in 12 patients in the MWs (27.3%) and 31 patients in the ICU (75.6%) with an odds ratio of 9.3 (95% confidence interval (CI) 3.5-24.5; P < 0.001). Multiple-site DVT occurred in 55.6% of patients (95% CI 39.6-70.5). Increased D-dimer levels significantly correlated with VTE (P = 0.001) and death (P = 0.015). Summarizing, patients with COVID-19 admitted to the MW or ICU showed a high frequency of venous thromboembolism, despite standard-dose or high-dose thromboprophylaxis. Whether thrombosis, particularly asymptomatic events, may play a role in the morbidity and mortality of patients with COVID-19 remain to be clarified., (© 2020 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.)

The COVID-19 pandemic represents an unprecedented global challenge in this century. COVID-19 is a viral respiratory infection, yet the clinical characteristics of this infection differ in spinal cord injury patients from those observed in the general population. Cough and asthenia are the most frequent symptoms in this population. Moreover, infected spinal cord injury patients rarely present complications that require admission to an Intensive Care Unit, in contrast to the general population. Thus, there is a clear need to understand how COVID-19 affects spinal cord injury patients from a molecular perspective. Here, we employed an -omics strategy in order to identify variations in protein abundance in spinal cord injury patients with and without COVID-19. After a quantitative differential analysis using isobaric tags and mass spectrometry and a verification phase, we have found differences mainly related to coagulation and platelet activation. Our results suggest a key role of heparin in the response of spinal cord injury patients to COVID-19 infection, showing a significant correlation between these proteins and heparin dose. Although the number of patients is limited, these data may shed light on new therapeutic options to improve the management these patients and, possibly, those of the general population as well.

Objectives: Several physiological abnormalities that develop during COVID-19 are associated with increased mortality. In the present study, we aimed to develop a clinical risk score to predict the in-hospital mortality in COVID-19 patients, based on a set of variables available soon after the hospitalisation triage., Setting: Retrospective cohort study of 516 patients consecutively admitted for COVID-19 to two Italian tertiary hospitals located in Northern and Central Italy were collected from 22 February 2020 (date of first admission) to 10 April 2020., Participants: Consecutive patients≥18 years admitted for COVID-19., Main Outcome Measures: Simple clinical and laboratory findings readily available after triage were compared by patients' survival status ('dead' vs 'alive'), with the objective of identifying baseline variables associated with mortality. These were used to build a COVID-19 in-hospital mortality risk score (COVID-19MRS)., Results: Mean age was 67±13 years (mean±SD), and 66.9% were male. Using Cox regression analysis, tertiles of increasing age (≥75, upper vs <62 years, lower: HR 7.92; p<0.001) and number of chronic diseases (≥4 vs 0-1: HR 2.09; p=0.007), respiratory rate (HR 1.04 per unit increase; p=0.001), PaO 2 /FiO 2 (HR 0.995 per unit increase; p<0.001), serum creatinine (HR 1.34 per unit increase; p<0.001) and platelet count (HR 0.995 per unit increase; p=0.001) were predictors of mortality. All six predictors were used to build the COVID-19MRS (Area Under the Curve 0.90, 95% CI 0.87 to 0.93), which proved to be highly accurate in stratifying patients at low, intermediate and high risk of in-hospital death (p<0.001)., Conclusions: The COVID-19MRS is a rapid, operator-independent and inexpensive clinical tool that objectively predicts mortality in patients with COVID-19. The score could be helpful from triage to guide earlier assignment of COVID-19 patients to the most appropriate level of care., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: The effects of the Covid-19 health emergency have demonstrated the high vulnerability of people residing in medium and long-stay centers, with high mortality rates. Little data is available about contingency protocols to minimize the spread of the virus in these centers. The goal of this study was to describe the clinical and epidemiological features of patients affected by SARS-CoV-2 and the preventive and management measures adopted at the National Hospital for Paraplegics (Toledo, Castilla-La Mancha, Spain) to minimize the risk of transmission of Covid-19., Methods: A team of specialists in Preventive and Internal Medicine established a protocol for active surveillance, identification of suspected and confirmed cases, and follow-up of contacts. Also, a Unit for the care of confirmed cases was created with personnel specifically trained in Covid-19, to achieve better patient care and optimize the available resources. Descriptive statistical measures have been used to analyze the data., Results: The prevalence of Covid-19 was 12.2%, with a cumulative incidence of 8.2%. After the protocol was established, control of the disease was achieved without hospital transmission after its application. Due to the alarm generated at the start of the pandemic, up to 45% of the requested RT-PCRs did not meet the criteria of the Ministry of Health, all of which were negative. The clinical characteristics of our patients differed slightly from those observed in other studies published in the general population, with cough and asthenia being the most frequent symptoms, present in 69.2% and 38.5%, respectively. 100% of the infected patients did not present complications that required assistance in the Intensive Care Unit., Conclusions: With the application of preventive and organizational actions, we consider that we have presented a low incidence of those infected. The preparation of protocols and their supervision is essential for the rapid identification of cases and optimization of the tests requested. Despite being a medium and long-stay hospital, we have not presented any mortality or complications that required admission to the Intensive Care Unit., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a β-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.

Study Design: Cohort study of patients with spinal cord injury (SCI)., Objectives: To describe the clinical and analytical features of a coronavirus disease 2019 (Covid-19) infected cohort with SCI to enable accurate diagnosis and to outline prevention measures., Setting: This study was conducted at the National Hospital for Paraplegics (Toledo, Spain)., Methods: A cohort analysis of seven patients with SCI infected by Covid-19 was performed. Diagnosis was confirmed with reverse transcriptase polymerase chain reaction (RT-PCR) of nasal exudate or sputum samples. Clinical, analytical, and radiographic findings were registered., Results: RT-PCR detected COVID-19 infection in all patients, affecting males and people with a cervical level of injury more often (five out of seven). The average delay for diagnostic confirmation was 4 days (interquartile range, 1-10). Fever was the most frequent symptom (six out of seven). The second most common symptom was asthenia (four out of seven), followed by dyspnea, cough, and expectoration (three out of seven for each symptom). The Modified Early Warning System score for Covid-19 severity rating was classified as severe in five out of seven cases. All but one patient showed radiological alterations evident in chest X-rays at the time of diagnosis. All patients recovered gradually., Conclusion: Our patients with SCI and Covid-19 infection exhibited fewer symptoms than the general population. Furthermore, they presented similar or greater clinical severity. The clinical evolution was not as pronounced as had been expected. This study recommends close supervision of the SCI population to detect early compatible signs and symptoms of Covid-19 infection.

Background: The healthcare reforms have led to the development of new primary care systems. These models allowed responding to people's needs but with problems in maintaining the relational continuity between the patient and therapist., Materials and Methods: We performed a survey on 12 May 2018, in Messina (Sicily, Italy), during an informational event. Participants were invited to fill in a self-reported Italian questionnaire composed of 12 multiple-choice questions, specifically created by the authors. The tool included the assessment of the social status, the presence of chronic diseases, preference in health care, and evaluation of the services offered in the territory., Results: As for the territorial services, we observed that the general practitioner (GP) was the most appreciated healthcare provider, followed by the nurse., Conclusions: We believe that nurses can represent the most appropriate healthcare figure to potentiate GP's patient management in primary territorial care., Competing Interests: There are no conflicts of interest., (Copyright: © 2019 Journal of Family Medicine and Primary Care.)

Glioblastoma (GBM) is a primary brain tumor whose prognosis is inevitably dismal, leading patients to death in about 15 months from diagnosis. Tumor cells in the mass of the neoplasm are in continuous exchange with cells of the stromal microenvironment, through the production of soluble molecules, among which chemokines play prominent roles. CXCL14 is a chemokine with a pro-tumor role in breast and prostate carcinoma, where it is secreted by cancer associated fibroblasts, and contributes to tumor growth and invasion. We previously observed that CXCL14 expression is higher in GBM tissues than in healthy white matter. Here, we study the effects of exogenously supplemented CXCL14 on key tumorigenic properties of human GBM cell lines. We show that CXCL14 enhances the migration ability and the proliferation of U87MG and LN229 GBM cell lines. None of these effects was affected by the use of AMD3100, an inhibitor of CXCR4 receptor, suggesting that the observed CXCL14 effects are not mediated by this receptor. We also provide evidence that CXCL14 enhances the sphere-forming ability of glioblastoma stem cells, considered the initiating cells, and is responsible for tumor onset, growth and recurrence. In support of our in vitro results, we present data from several GBM expression datasets, demonstrating that CXCL14 expression is inversely correlated with overall survival, that it is enriched at the leading edge of the tumors and in infiltrating tumor areas, and it characterizes mesenchymal and NON G-CIMP tumors, known to have a particularly bad prognosis. Overall, our results point to CXCL14 as a protumorigenic chemokine in GBM.

The ability to selectively respond to one's own name is important for social and language development, and is disrupted in atypically developing populations (e.g., autism spectrum disorder). Research with typically developing samples using event-related potentials (ERPs) has demonstrated that the subject's own name (SON) is differentiated from other stimuli at both early sensory and later cognitive stages of auditory processing. While neural indices of response to name have been researched extensively in adults, no such studies have been conducted with typically developing preschool children or children with autism spectrum disorder (ASD). The present study investigated ERP response to name in a sample of typically developing (TD) preschoolers (n = 19; mean age = 4.3 years) as well as a small, exploratory comparison group of preschoolers with ASD (n = 13; mean age = 4.4 years). TD preschoolers exhibited significantly greater negativity to SON over frontal regions than to an unfamiliar nonsense name, consistent with the adult SON negativity component. This component was present whether the name was spoken by a parent or an unfamiliar adult, suggesting that it reflects SON-specific processing rather than broad self-relevant information processing. Comparing preschoolers with ASD to the TD children revealed a significant SON negativity component across both groups. The amplitude of the SON negativity response was significantly correlated with social variables in the ASD group, though these correlations did not survive correction for multiple comparisons. This study is the first to demonstrate the presence of the SON component in preschool children with and without ASD., Competing Interests: The authors have declared that no competing interests exist.

Background: Narrative abilities are linked to social impairment in autism spectrum disorder (ASD), such that reductions in words about cognitive processes (e.g., think , know ) are thought to reflect underlying deficits in social cognition, including Theory of Mind. However, research suggests that typically developing (TD) boys and girls tell narratives in sex-specific ways, including differential reliance on cognitive process words. Given that most studies of narration in ASD have been conducted in predominantly male samples, it is possible that prior results showing reduced cognitive processing language in ASD may not generalize to autistic girls. To answer this question, we measured the relative frequency of two kinds of words in stories told by autistic girls and boys: nouns (words that indicate object-oriented storytelling) and cognitive process words (words like think and know that indicate mentalizing or attention to other peoples' internal states)., Methods: One hundred two verbally fluent school-aged children [girls with ASD ( N  = 21) and TD ( N  = 19), and boys with ASD ( N  = 41) and TD ( N  = 21)] were matched on age, IQ, and maternal education. Children told a story from a sequence of pictures, and word frequencies (nouns, cognitive process words) were compared., Results: Autistic children of both sexes consistently produced a greater number of nouns than TD controls, indicating object-focused storytelling. There were no sex differences in cognitive process word use in the TD group, but autistic girls produced significantly more cognitive process words than autistic boys, despite comparable autism symptom severity. Thus, autistic girls showed a unique narrative profile that overlapped with autistic boys and typical girls/boys. Noun use correlated significantly with parent reports of social symptom severity in all groups, but cognitive process word use correlated with social ability in boys only., Conclusion: This study extends prior research on autistic children's storytelling by measuring sex differences in the narratives of a relatively large, well-matched sample of children with and without ASD. Importantly, prior research showing that autistic children use fewer cognitive process words is true for boys only, while object-focused language is a sex-neutral linguistic marker of ASD. These findings suggest that sex-sensitive screening and diagnostic methods-preferably using objective metrics like natural language processing-may be helpful for identifying autistic girls, and could guide the development of future personalized treatment strategies., Competing Interests: The Institutional Review Board of the Children’s Hospital of Philadelphia provided approval and oversight for this study. All participants provided consent (parental consent for participants under age 18) and assent when possible.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Objective: Adults with congenital heart disease share some features with those with chronic heart failure. Although microvascular endothelial dysfunction has been described in chronic heart failure, evaluation of the microcirculation in adults with congenital heart disease is lacking. The present study aimed to investigate systemic microvascular reactivity in adults with congenital heart disease., Interventions: The patients initially underwent cardiopulmonary exercise testing. Then, the cutaneous microvascular reactivity was evaluated in these patients using a laser speckle contrast imaging system coupled with skin iontophoresis of endothelial-dependent (acetylcholine) or -independent (sodium nitroprusside) vasodilators and postocclusive reactive hyperemia (PORH) and compared with healthy controls matched for age and sex., Results: Thirty-one patients and 29 healthy controls were evaluated. The basal microvascular flow (P < .0001) and area under the curve in response to acetylcholine (P < .0001) were higher in the patients than in the healthy volunteers. The increase in cutaneous vascular conductance in response to sodium nitroprusside was reduced in the patients compared to the healthy volunteers (P = .0031). No difference in the microvascular response was observed during postocclusive reactive hyperemia. The basal microvascular flow of patients with peak oxygen consumption below 16.0 mL kg -1 min -1 was superior to that of patients with values greater than 16.0 mL kg -1 min -1 (P = .0046)., Conclusions: Adults with congenital heart disease present a higher baseline cutaneous microvascular blood flow than healthy controls and do not present systemic microvascular endothelial dysfunction. Nevertheless, endothelium-independent microvascular reactivity is blunted, suggesting an altered vascular smooth muscle response or vascular structural alterations. Finally, patients with a lower functional capacity presented a greater microvascular basal blood flow than subjects with a higher functional capacity., (© 2018 Wiley Periodicals, Inc.)

Introduction: The effectiveness of direct-acting antiviral (DAA) agents has been demonstrated in clinical trials both in patients with mono and coinfections. The goal of the study was to analyze the effectiveness and toxicity of this therapy in real-life patients with a HIV/HCV coinfection and to identify variables that are associated with an unfavorable outcome., Methods: This was a multicenter ambispective study in a cohort of coinfected patients. Data were collected from eight centers in Castilla-La Mancha from 2014 to 2016. An intent-to-treat analysis was performed and any loss to follow-up, treatment withdrawal or toxicity was considered as a failure., Results: A total of 229 patients were included with a median age of 49.6 years and the majority were male (83%). Fewer than 10% had a detectable HIV-related viral load (VL). The most prevalent HCV genotype was 1 (65.1%). Fifty percent had cirrhotic liver disease and 65% had over 800,000 copies/ml of HCV VL. The global sustained viral response (SVR) was reached by 91.7% of cases. The most commonly used DAA regimen was sofosbuvir/ledipasvir. Ribavirin was included in 52% of regimens, 65.9% of cases completed 12-week regimens and 30% completed 24-week schemes. There were 19 therapy failures. No differences were observed between the various DAA strategies used. No independent predictor was found for SVR., Conclusions: HCV treatment in coinfected patients is highly successful in terms of SVR rate in the real-life setting and toxicity is exceptional. We identified no specific predictors of an unfavorable outcome.

Simvastatin is a lipid-lowering agent that blocks the production of cholesterol through inhibition of 3-hydroxy-methyl-glutaryl coenzyme A (HMG-CoA) reductase. In addition, recent evidence has suggested its anti-inflammatory and antinociceptive actions during inflammatory and pain disorders. Herein, we investigated the effects of simvastatin in an animal model of complex regional pain syndrome-type I, and its underlying mechanisms. Chronic post-ischemia pain (CPIP) was induced by ischemia and reperfusion (IR) injury of the left hind paw. Our findings showed that simvastatin inhibited mechanical hyperalgesia induced by CPIP model in single and repeated treatment schedules, respectively; however simvastatin did not alter inflammatory signs during CPIP model. The mechanisms underlying those actions are related to modulation of transient receptor potential (TRP) channels, especially TRMP8. Moreover, simvastatin oral treatment was able to reduce the nociception induced by acidified saline [an acid-sensing ion channels (ASICs) activator] and bradykinin (BK) stimulus, but not by TRPA1, TRPV1 or prostaglandin-E2 (PGE2). Relevantly, the antinociceptive effects of simvastatin did not seem to be associated with modulation of the descending pain circuits, especially noradrenergic, serotoninergic and dopaminergic systems. These results indicate that simvastatin consistently inhibits mechanical hyperalgesia during neuropathic and inflammatory disorders, possibly by modulating the ascending pain signaling (TRPM8/ASIC/BK pathways expressed in the primary sensory neuron). Thus, simvastatin open-up new standpoint in the development of innovative analgesic drugs for treatment of persistent pain, including CRPS-I.

Vaccine hesitancy has become the focus of growing attention and concern globally despite overwhelming evidence of the value of vaccines in preventing disease and saving the lives of millions of individuals every year. Measuring vaccine hesitancy and its determinants worldwide is important in order to understand the scope of the problem and for the development of evidence-based targeted strategies to reduce hesitancy. Two indicators to assess vaccine hesitancy were developed to capture its nature and scope at the national and subnational level to collect data in 2014: 1) The top 3 reasons for not accepting vaccines according to the national schedule in the past year and whether the response was opinion- or assessment-based and 2) Whether an assessment (or measurement) of the level of confidence in vaccination had taken place at national or subnational level in the previous 5 years. The most frequently cited reasons for vaccine hesitancy globally related to (1) the risk-benefit of vaccines, (2) knowledge and awareness issues, (3) religious, cultural, gender or socio-economic factors. Major issues were fear of side effects, distrust in vaccination and lack of information on immunization or immunization services. The analysis revealed that 29% of all countries had done an assessment of the level of confidence in their country, suggesting that vaccine confidence was an issue of importance. Monitoring vaccine hesitancy is critical because of its influence on the success of immunization programs. To our knowledge, the proposed indicators provide the first global snapshot of reasons driving vaccine hesitancy and depicting its widespread nature, as well as the extent of assessments conducted by countries.

Background and Objectives: Urinary albumin excretion and/or albumin to creatinine ratio are associated with CKD and higher risk of cardiovascular events. Several studies investigated the effect of reduced dietary sodium intake on urinary albumin excretion and/or albumin to creatinine ratio in adult patient populations, but the majority was inconclusive because of insufficient statistical power. A meta-analysis of the randomized, controlled trials available could overcome this problem and lead to more definitive conclusions., Design, Setting, Participants, & Measurements: A systematic search of the online databases available (from 1996 to October of 2014) was conducted of randomized, controlled trials that expressed urinary albumin excretion or albumin to creatinine ratio as the difference between the effects of two different sodium intake regimens. For each study, the mean difference and 95% confidence intervals were pooled using a random effect model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed., Results: Eleven studies met the predefined inclusion criteria and provided 23 cohorts with 516 participants and 1-6 weeks of follow-up time. In the pooled analysis, an average reduction in sodium intake of 92 mmol/d was associated with a 32.1% (95% confidence interval, -44.3 to -18.8) reduction in urinary albumin excretion. The effect of sodium restriction was higher in the cohorts including patients on concomitant renin-angiotensin-aldosterone system-blocking therapy, in the studies with intervention lasting at least 2 weeks, and among participants with evidence of kidney damage. A greater reduction of urinary albumin excretion was associated with a higher decrease in BP during the intervention. The analysis of changes in albumin to creatinine ratio provided similar results., Conclusions: This meta-analysis indicates that sodium intake reduction markedly reduces albumin excretion, more so during concomitant renin-angiotensin-aldosterone system-blocking therapy and among patients with kidney damage., (Copyright © 2015 by the American Society of Nephrology.)

The present study evaluated the antiulcerogenic activity and mechanisms of the aqueous (AqF 100 mg/kg) and ethyl acetate (AcF 50 mg/kg) fractions from Indigofera truxillensis leaves. This dose was selected to assess its activity on ulcer healing and its action on gastric acid and mucus secretion, prostaglandin production and antioxidant enzyme activity (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and glutathione reductase (GSH-Rd)). Gastric ulcer was induced by absolute ethanol. Antisecretory action, mucus and prostaglandin production, healing and antioxidant enzyme activities were evaluated for both fractions. AqF and AcF significantly inhibited the gastric mucosal damage caused by ethanol. This effect was statistically significant at 100 and 50 mg/kg compared with the vehicle. Neither fraction interfered with gastric secretion. AcF increased the PGE(2) production, and both fractions increased mucus production. l-NAME did not alter the gastroprotection exerted by the fractions, but N-ethylmaleimide attenuated only AcF. In the ischemia/reperfusion model both fractions inhibited the mucosal damage. AcF increased SOD, GSH-Px and GSH-Rd activity, but AqF increased only SOD and GSH-Px. In the acetic acid-induced ulcer model AcF only accelerated ulcer healing. These results showed that Indigofera truxillensis acted as a gastroprotective agent, stimulating protective factors and antioxidants enzymes.

Arctium lappa L. has been used in folk medicine as a diuretic, depurative, and digestive stimulant and in dermatological conditions. The mechanisms involved in the anti-ulcerogenic activity of the sesquiterpene onopordopicrin (ONP)-enriched fraction (termed the ONP fraction), obtained from A. lappa leaves, were studied. The gastroprotective mechanism of the ONP fraction was evaluated in experimental in vivo models in rodents, mimicking this disease in humans. ONP fraction (50 mg/kg, p.o.) significantly inhibited the mucosal injury induced by ethanol/HCl solution (75%), indomethacin/bethanecol (68.9%), and stress (58.3%). When the ONP fraction was investigated in pylorus ligature, it did not induce alteration in the gastric volume but did modify the pH and total acid concentration of gastric juice. ONP fraction significantly increased serum somatostatin levels (82.1±4.1 vs. control group 12.7±4 pmol/L) and decreased serum gastrin levels (62.6±6.04 vs. control group 361.5±8.2 μU/mL). Mucus production was not significantly altered by the ONP fraction. Gastroprotection by the ONP fraction was completely inhibited by N-ethylmaleimide treatment and did not modify the effect in the animals pretreated with l-N(G)-nitroarginine methyl ester. These results suggest an antisecretory mechanism involved with the antiulcerogenic effect of the ONP fraction. However, only endogenous sulfhydryls play an important role in gastroprotection of the ONP fraction.

Cannabinoid receptor 2 (CB2) activation is suggested to trigger the peroxisome proliferator-activated receptor-γ (PPARγ) pathway, and agonists of both receptors improve colitis. Recently, the plant metabolite (E)-β-caryophyllene (BCP) was shown to bind to and activate CB2. In this study, we examined the anti-inflammatory effect of BCP in dextran sulfate sodium (DSS)-induced colitis and analyzed whether this effect was mediated by CB2 and PPARγ. Oral treatment with BCP reduced disease activity, colonic macro- and microscopic damage, myeloperoxidase and N-acetylglucosaminidase activities, and levels and mRNA expression of colonic tumor necrosis factor-α, IL-1β, interferon-γ, and keratinocyte-derived chemokine. BCP treatment also inhibited the activation of extracellular signal-regulated kinase 1/2, nuclear factor κB, IκB-kinase α/β, cAMP response element binding and the expression of caspase-3 and Ki-67. Moreover, BCP enhanced IL-4 levels and forkhead box P3 mRNA expression in the mouse colon and reduced cytokine levels (tumor necrosis factor-α, keratinocyte-derived chemokine, and macrophage-inflammatory protein-2) in a culture of macrophages stimulated with lipopolysaccharide. The use of the CB2 antagonist AM630 or the PPARγ antagonist GW9662 significantly reversed the protective effect of BCP. Confirming our results, AM630 reversed the beneficial effect of BCP on pro-inflammatory cytokine expression in IEC-6 cells. These results demonstrate that the anti-inflammatory effect of BCP involves CB2 and the PPARγ pathway and suggest BCP as a possible therapy for the treatment of inflammatory bowel disease., (Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Leaves and bark infusions Anacardium humile St. Hil. (Anacardiaceae), known as in Brazil as "cajuzinho do cerrado", have been used in folk medicine as an alternative treatment for ulcers and gastritis. This study evaluated the gastroprotective activity of an ethyl acetate extract of the leaves of A. humile (AcF) and the mechanism involved in this gastroprotection. Pretreatment concentrations (50, 100, 200 mg x kg⁻¹) were administered by gavage. Following a 60 min. period, all the rats were orally administered 1 mL of absolute ethanol. One hour after the administration of ethanol, all groups were sacrificed, and the gastric ulcer index was calculated. Prostaglandin PGE₂ concentration, gastric adherent mucous, and the participation of nitric oxide (NO) and sulfhydryl compounds in the gastroprotection process were also analyzed using the most effective tested dose (50 mg x kg⁻¹). A histological study of the glandular stomach for the evaluation of the epithelial damage and mucus content was also performed. AcF significantly reduced the gastric damage produced by ethanol. This effect was statistically significant for the 50 mg x kg⁻¹ group compared to control. Also, it significantly increased the PGE₂ (by 10-fold) and mucous production, while pretreatment with NG-nitro-L-arginine methyl ester (L-NAME) or N-ethylmaleimide (NEM) completely abolished the gastroprotection. AcF has a protective effect against ethanol, and this effect, might be due to the augmentation of the protective mechanisms of mucosa.

To elucidate molecular mechanisms underlying oocyte senescence, we investigated whether oocytes from female mice of advanced reproductive age exhibit a precocious postovulatory aging that, in turn, may be responsible for the precocious activation of an apoptotic program. During a 9-h in vitro culture, the frequency of oocytes showing MII aberrations, spontaneous activation, and cellular fragmentation increased in old oocytes (P < 0.05), whereas it did not change in the young group. In old oocytes, the activities of MPF (a complex of the cyclin-dependent kinase cdc2 and cyclin B1) and MAPK (mitogen-activated protein kinase) decreased precociously, showing a first drop as early as 3 h after the beginning of in vitro culture (P < 0.05). Immunoblotting and immunocytochemical analysis revealed that, in oocytes of the old group, reduction of BCL2 expression at protein level occurred earlier than in the young group (P < 0.05) and was not associated to the loss of BCL2 transcripts detected by RT-PCR. These changes are followed by an abrupt increase of the rate of TUNEL-positive oocytes after 24 h of culture to a value of 67% +/- 6%. Exposure of young oocytes to 20 microM roscovitine or 20 microM U0126, specific inhibitors of MPF and MAPK, resulted in the decreased percentage of oocytes showing positive immunostaining for BCL2 and in an increased rate of DNA fragmentation. Present results suggest that the developmental competence of oocytes ovulated by aging mice may be negatively influenced by a downregulation of MPF and MAPK activities that in turn induces the activation of a proapoptotic signaling pathway.