Modelling three-dimensional cancer-associated cachexia and therapy: the molecular basis and therapeutic potential of interleukin-6 transignalling blockade

Background: Causes and mechanisms underlying cancer cachexia are not fully understood, and currently, no therapeutic approaches are available to completely reverse the cachectic phenotype. Interleukin-6 (IL-6) has been extensively described as a key factor in skeletal muscle physiopathology, exerting opposite roles through different signalling pathways. Methods: We employed a three-dimensional ex vivo muscle engineered tissue (X-MET) to model cancer-associated cachexia and to study the effectiveness of selective inhibition of IL-6 transignalling in counteracting the cachectic phenotype. Conditioned medium (CM) derived from C26 adenocarcinoma cells was used as a source of soluble factors contributing to the establishment of cancer cachexia in the X-MET model. A dose of 1.2 ng/mL of glycoprotein-130 fused chimaera (gp130Fc) was added to cachectic culture medium to neutralize IL-6 transignalling. Results: C26-conditioned medium induced a cachectic-like phenotype in the X-MET, leading to a decline of muscle mass (−60%; P < 0.001), a reduction in myosin expression (−92.4%; P < 0.005) and a reduction of the contraction frequency spectrum (−94%). C26-conditioned medium contains elevated amounts of IL-6 (8.61 ± 4.09 pg/mL) and IL6R (56.85 ± 10.96 pg/mL). These released factors activated the signal transducer and activator of transcription 3 (STAT3) signalling in the C26_CM X-MET system (phosphorylated STAT3/TOTAL +54.6%; P < 0.005), which in turn promote an enhancement of Il-6 (+69.2%; P < 0.05) and Il6r (+43%; P < 0.05) gene expression, suggesting the induction of a feed-forward loop. The selective neutralization of IL-6 transignalling, by gp130Fc, in C26_CM X-MET prevented the hyperactivation of STAT3 (−55.8%; P < 0.005), countered the reduction of cross-sectional area (+28.2%; P < 0.05) and reduced the expression of proteolytic factors including muscle ring finger-1 (−88%; P < 0.005) and ATROGIN1 (−92%; P < 0.05), thus preserving the robustness and increasing the contractile force (+20%) of the three-dimensional muscle system. Interestingly, the selective inhibition of IL-6 transignalling modulated gene regulatory networks involved in myogenesis and apoptosis, normalizing the expression of pro-apoptotic miRNAs, including miR-31 (−53.2%; P < 0.05) and miR-34c (−65%; P < 0.005), and resulting in the reduction of apoptotic pathways highlighted by the sensible reduction of cleaved caspase 3 (−92.5%; P < 0.005) in gp130Fc-treated C26_CM X-MET. Conclusions: IL-6 transignalling appeared as a promising target to counter cancer cachexia-related alterations. The X-MET model has proven to be a reliable drug-screening tool to identify novel therapeutic approaches and to test them in preclinical studies, significantly reducing the use of animal models

Rodenticidal Effects of Zinc Phosphide and Strychnine of Nontarget Species

When three rodenticide treatments—zinc phosphide (prebaited) and strychnine (both with and without prebait)were evaluated, zinc phosphide was the most effective in reducing active burrows of prairie dogs; but, it also resulted in a reduction in deer mouse densities. One month after treatment, counts of fecal pellets of eastern cottontails were greater on areas treated with strychnine without prebait than on sites treated with zinc phosphide. Eight months after treatment, no differences could be detected among rodenticides for either leporid. Horned lark densities were reduced 61% on sites treated with strychnine only

Rodenticidal Effects of Zinc Phosphide and Strychnine of Nontarget Species

When three rodenticide treatments—zinc phosphide (prebaited) and strychnine (both with and without prebait)were evaluated, zinc phosphide was the most effective in reducing active burrows of prairie dogs; but, it also resulted in a reduction in deer mouse densities. One month after treatment, counts of fecal pellets of eastern cottontails were greater on areas treated with strychnine without prebait than on sites treated with zinc phosphide. Eight months after treatment, no differences could be detected among rodenticides for either leporid. Horned lark densities were reduced 61% on sites treated with strychnine only

Shirt sponsorship by gambling companies in the English and Scottish Premier Leagues: global reach and public health concerns

While the nature of gambling practices is contested, a strong evidence base demonstrates that gambling can become a serious disorder and have a range of detrimental effects for individuals, communities and societies. Over the last decade, football in the UK has become visibly entwined with gambling marketing. To explore this apparent trend, we tracked shirt sponsors in both the English and Scottish Premier Leagues since 1992 and found a pronounced increase in the presence of sponsorship by gambling companies. This increase occurred at the same time the Gambling Act 2005, which liberalized rules, was introduced. We argue that current levels of gambling sponsorship in UK football, and the global visibility it provides to gambling brands, is a public health concern that needs to be debated and addressed. We recommend that legislators revisit the relationship between football in the UK and the sponsorship it receives from the gambling industry

Monitoring of Communication Precursors in Extremely Low Birth Weight (ELBW) Newborns by Video Analysis Method: Preliminary Results

Background: The survival of extremely low birth weight infants (ELBW) has increased worldwide. Even in the absence of major disabilities, ELBW infants show difficulty in simple language functions. It is relevant to assess early abilities, which are the base of early linguistic skills, in order to implement customized intervention programs in ELBW infants. Aims: To evaluate communication precursors of language development in ELBW infants at 12 and 24 months of correct age (C.A). To investigate the correlation of linguistic and communicative prerequisites with mental development outcome at 24 months CA. Method: 52 ELBW neonates (mean gestational age 26.6 weeks, mean birth weight was 775 g) who were admitted to the neonatal intensive care unit of the University Hospital of Modena, were enrolled. Data were collected from archived audio-video recordings of neurodevelopmental follow-up visits. Video analysis of communicative and linguistic developmental was performed at 12 and 24 months CA. Neurodevelopmental outcome was evaluated with Mental Developmental Scales (GMDS-R). Results: The video-analysis showed that infants at 12 months CA used predominantly eye contacts and gestural turns, while vocal turns were scant. At 24 months CA, a significant change in eye contacts, vocal turns, gestural turns, and utterances (p < 0.001) occurred. The total number of utterances (p = 0.036) and eye contacts (p = 0.045) were significantly correlated to the Development Quotient (DQ) of Hearing and Language scale. Moreover, a significant correlation was found with the Personal-Social scale vocal turns (p = 0.009) and the total number of utterances (p = 0,02). Finally, the Global Quotient of the GMDS-R was related to the Vocal Turns (p = 0.034) and the total number of Utterances (p = 0.013). Conclusions: ELBW infants at 12 months CA use predominantly eye contacts and gestural turns to communicate with adults. At 24 months CA, the child’s communicative intention evolves from gestural to verbal communication. The latter is characterized by an increase in both vocal turns and the number of utterances produced during interaction. The video analysis we implement appears to be a sensitive tool for early assessment of communication and language development and to refine early intervention

Deployment characterization of a floatable tidal energy converter on a tidal channel, Ria Formosa, Portugal

This paper presents the results of a pilot experiment with an existing tidal energy converter (TEC), Evopod 1 kW floatable prototype, in a real test case scenario (Faro Channel, Ria Formosa, Portugal). A baseline marine geophysical, hydrodynamic and ecological study based on the experience collected on the test site is presented. The collected data was used to validate a hydro-morphodynamic model, allowing the selection of the installation area based on both operational and environmental constraints. Operational results related to the description of power generation capacity, energy capture area and proportion of energy flux are presented and discussed, including the failures occurring during the experimental setup. The data is now available to the scientific community and to TEC industry developers, enhancing the operational knowledge of TEC technology concerning efficiency, environmental effects, and interactions (i.e. device/environment). The results can be used by developers on the licensing process, on overcoming the commercial deployment barriers, on offering extra assurance and confidence to investors, who traditionally have seen environmental concerns as a barrier, and on providing the foundations whereupon similar deployment areas can be considered around the world for marine tidal energy extraction.Acknowledgements The paper is a contribution to the SCORE project, funded by the Portuguese Foundation for Science and Technology (FCT e PTDC/ AAG-TEC/1710/2014). Andre Pacheco was supported by the Portu- guese Foundation for Science and Technology under the Portuguese Researchers' Programme 2014 entitled “Exploring new concepts for extracting energy from tides” (IF/00286/2014/CP1234). Eduardo GGorbena has received funding for the OpTiCA project from the ~ Marie Skłodowska-Curie Actions of the European Union's H2020- MSCA-IF-EF-RI-2016/under REA grant agreement n [748747]. The authors would like to thank to the Portuguese Maritime Authorities and Sofareia SA for their help on the deployment.info:eu-repo/semantics/publishedVersio

Shifting boundaries between the normal and the pathological:the case of mild intellectual disability

When disorders fade into normality, how can the threshold between normality and disorder be determined? In considering mild intellectual disability, I argue that economic factors partly determine thresholds. We tend to assume that the relationship between disorder, need and services is such that: first, a cut-off point between the disordered and the normal is determined; second, a needy population is identified; and third, resources are found (or at least should be found) to meet this need. However, the changing definitions of intellectual disability can best be understood if we think of this happening in reverse. That is, first, certain resources are thought obtainable, and then a cut-off point for disorder is selected which supplies an appropriately sized ‘needy population’

Drawing a line in the sand: affect and testimony in autism assessment teams in the UK.

Diagnosis of autism in the UK is generally made within a multidisciplinary team setting and is primarily based on observation and clinical interview. We examined how clinicians diagnose autism in practice by observing post-assessment meetings in specialist autism teams. Eighteen meetings across four teams based in the south of England and covering 88 cases were audio-recorded, transcribed and analysed using thematic analysis. We drew out two themes, related to the way in which clinicians expressed their specialist disciplinary knowledge to come to diagnostic consensus: Feeling Autism in the Encounter; and Evaluating Testimonies of Non-present Actors. We show how clinicians produce objective accounts through their situated practices and perform diagnosis as an act of interpretation, affect and evaluation to meet the institutional demands of the diagnostic setting. Our study contributes to our understanding of how diagnosis is accomplished in practice.Wellcome Trust Investigator Awar

A comparison of the development of audiovisual integration in children with autism spectrum disorders and typically developing children

This study aimed to investigate the development of audiovisual integration in children with Autism Spectrum Disorder (ASD). Audiovisual integration was measured using the McGurk effect in children with ASD aged 7–16 years and typically developing children (control group) matched approximately for age, sex, nonverbal ability and verbal ability. Results showed that the children with ASD were delayed in visual accuracy and audiovisual integration compared to the control group. However, in the audiovisual integration measure, children with ASD appeared to ‘catch-up’ with their typically developing peers at the older age ranges. The suggestion that children with ASD show a deficit in audiovisual integration which diminishes with age has clinical implications for those assessing and treating these children

Regional white matter hyperintensity volume, not hippocampal atrophy, predicts incident Alzheimer disease in the community

Background: New-onset Alzheimer disease (AD) is often attributed to degenerative changes in the hippocampus. However, the contribution of regionally distributed small vessel cerebrovascular disease, visualized as white matter hyperintensities (WMHs) on magnetic resonance imaging, remains unclear. Objective: To determine whether regional WMHs and hippocampal volume predict incident AD in an epidemiological study. Design: A longitudinal community-based epidemiological study of older adults from northern Manhattan, New York. Setting: The Washington Heights/Inwood Columbia Aging Project. Participants: Between 2005 and 2007, 717 participants without dementia received magnetic resonance imaging scans. A mean (SD) of 40.28 (9.77) months later, 503 returned for follow-up clinical examination and 46 met criteria for incident dementia (45 with AD). Regional WMHs and relative hippocampal volumes were derived. Three Cox proportional hazards models were run to predict incident dementia, controlling for relevant variables. The first included all WMH measurements; the second included relative hippocampal volume; and the third combined the 2 measurements. Main Outcome: Measure Incident AD. Results: White matter hyperintensity volume in the parietal lobe predicted time to incident dementia (hazard ratio [HR] = 1.194; P = .03). Relative hippocampal volume did not predict incident dementia when considered alone (HR = 0.419; P = .77) or with the WMH measures included in the model (HR = 0.302; P = .70). Including hippocampal volume in the model did not notably alter the predictive utility of parietal lobe WMHs (HR = 1.197; P = .049). Conclusions: The findings highlight the regional specificity of the association of WMHs with AD. It is not clear whether parietal WMHs solely represent a marker for cerebrovascular burden or point to distinct injury compared with other regions. Future work should elucidate pathogenic mechanisms linking WMHs and AD pathology