Experience-dependent plasticity of gustatory insular cortex circuits and taste preferences.

Early experience with food influences taste preference in adulthood. How gustatory experience influences development of taste preferences and refinement of cortical circuits has not been investigated. Here, we exposed weanling mice to an array of taste solutions and determined the effects on the preference for sweet in adulthood. We demonstrate an experience-dependent shift in sucrose preference persisting several weeks following the termination of exposure. A shift in sucrose palatability, altered neural responsiveness to sucrose, and inhibitory synaptic plasticity in the gustatory portion of the insular cortex (GC) were also induced. The modulation of sweet preference occurred within a restricted developmental window, but restoration of the capacity for inhibitory plasticity in adult GC reactivated the sensitivity of sucrose preference to taste experience. Our results establish a fundamental link between gustatory experience, sweet preference, inhibitory plasticity, and cortical circuit function and highlight the importance of early life nutrition in setting taste preferences.

Comparison of Hemoglobin Values Obtained by Arterial Blood Gas Analysis versus Laboratory Method during Major Head-and-Neck Surgeries.

Background: Accuracy of hemoglobin (Hb) measured by arterial blood gas (ABG) analyzer is considered inferior to laboratory (lab) measurements as it could overestimate Hb levels. Aim of the Study: The study aims to compare Hb measured using ABG versus conventional lab method at the time of major blood loss and in the preoperative and immediate postoperative periods. Settings and Design: It was a prospective, nonrandomized observational study conducted in a tertiary care center. Materials and Methods: The study was conducted in 24 patients undergoing major head-and-neck surgeries. Simultaneous blood samples were sent for Hb measurement by ABG analysis and lab method at induction of anesthesia, when intraoperative blood loss exceeded maximum allowable blood loss, and in the immediate postoperative period. Statistical Analysis Used: Chi-square test, independent sample's t-test, and paired t-test were used for statistical analysis. Results: Mean Hb values obtained by both techniques were significantly different at all time points. Hb obtained by ABG analysis was significantly higher than lab value preoperatively (12.78 ± 2.51 vs. 12.05 ± 2.2, P = 0.038), at maximum blood loss (11.00 ± 2.57 vs. 9.87 ± 2.06, P = 0.006), and in the immediate postoperative period (11.96 ± 2.00 vs. 10.96 ± 2.24 P < 0.001). ABG Hb values were found to be approximately 1 g.dL-1 greater than lab values. Conclusion: Hb measured by ABG analysis was significantly higher than that measured by lab method at the time of major blood loss, preoperatively, and at the immediate postoperative period in patients undergoing major head-and-neck surgeries, with a good correlation of values obtained by both the techniques.

Relationship between polymorphisms in the FAS/FASL death receptor system and progression of low-grade precursor lesions infected with high-risk human papilloma virus.

Squamous intraepithelial lesions (SIL) and cervical cancer are primary due to suboptimal immune response against human papillomavirus (HPV). The FASL/FAS system is a trigger of extrinsic pathway apoptosis. The distribution of polymorphisms rs1800682 (-670 A > G) FAS and rs763110 (-844C > T) FASL was studied in cervical smears from 372 females (182 with stable or regressed low-grade SIL (LSIL) (groupI) and a group of 190 high-grade SIL (HSIL) (groupII). No significant differences were observed for rs1800682 in FAS between the study groups. In contrast, rs763110 CC genotype of FASL was found in 35.7% of group I females, and in 50.5% of group II (p = 0.0027; OR = 1.83 (95% CI = 1.21-2.79)). When only females infected with high-risk HPV were analysed, these differences were even higher (p = 0.0024; OR = 2.21 (95% CI = 1.30-3.75)). CC genotype in FASL seems to be associated with increased risk of LSIL to HSIL progression suggesting a role in HPV tolerance, persistent infection, and HSIL development.

Tropomyosin Receptor Kinase B Expressed in Oligodendrocyte Lineage Cells Functions to Promote Myelin Following a Demyelinating Lesion.

The levels of brain-derived neurotrophic factor (BDNF) in the corpus callosum have previously been shown to have a critical impact on oligodendrocyte (OLG) lineage cells during cuprizone-elicited demyelination. In particular, BDNF+/- mice exhibit greater losses in myelin protein levels compared to wild-type mice after cuprizone. To investigate whether OLGs may directly mediate these effects of BDNF during a lesion in vivo, we used the cuprizone model of demyelination with inducible conditional male knockout mice to specifically delete the high-affinity tropomyosin receptor kinase B (TrkB) receptor from proteolipid protein + OLGs during cuprizone-elicited demyelination and subsequent remyelination. The loss of TrkB during cuprizone-elicited demyelination results in an increased sensitivity to demyelination as demonstrated by greater deficits in myelin protein levels, greater decreases in numbers of mature OLGs, increased numbers of demyelinated axons, and decreased myelin thickness. When mice are removed from cuprizone, they exhibit a delayed recovery in myelin proteins and myelin. Our data indicate that following a demyelinating lesion, TrkB in OLGs positively regulates myelin protein expression, myelin itself, and remyelination.

Técnica del árbol: aprendizajes en su utilización para problematizar necesidades de transformación social, jalisco, méxico / The social learning tree approach: learning in its use to problematize needs of social transformation, jalisco, mexico / Técnica da arvore: aprendizagens em sua utilização para problematizar necessidades de transformação social, jalisco, méxico

Resumen Objetivo: analizar los aprendizajes para gestores y equipos técnicos locales de Promoción de la Salud al utilizar la técnica educativa de "el árbol social", en la problematización de necesidades de transformación social en Jalisco, México, al 2017. Material y métodos: estudio cualitativo fenomenológico desarrollado durante 2017; de 74 participantes de la técnica en cuatro localidades rurales, se seleccionaron a conveniencia 30 informantes, definiéndolos por muestreo teórico. Para el levantamiento de la información, se trabajaron grupos focales, en espacios seleccionados por informantes. Se audio-grabaron entrevistas y analizaron semióticamente. Resultados: aluden ser útil al iniciar procesos de promoción de la salud, identificando y clarificando el trabajo, además de la integración de grupo; así mismo se retoma en la evaluación del proceso. La técnica considera el momento político, histórico y sociocultural del contexto local, interpretando de manera estructural, la situación a abordar. Destacan como limitaciones diversidad de liderazgo y opiniones, lo cual puede desanimar la participación. Finalmente, describen implicaciones éticas como no respetar la cultura y autonomía de las poblaciones para participar. Conclusiones: la técnica educativa permite el encuentro local entre diversos actores para el trabajo intersectorial, revitalizando la gestión territorial con el reconocimiento de los participantes como sujetos auto-reflexivos de su realidad histórica, cambiante y compleja, desarrollándose de manera particular en cada experiencia y contexto, pautado por el momento político, histórico y sociocultural, las habilidades del educador así como la diversidad de liderazgo y opiniones, teniendo presente no perder el respeto a la cultura y la autonomía para participar.

Abstract Objective: To analyze learning for managers and local technical teams of Health Promotion by using the "the social learning tree", educational approach in the problematization of needs of social transformation in Jalisco, Mexico in 2017. Materials and methods: Qualitative phenomenological study developed in 2017 with 74 participants of the approach in four rural localities; 30 informants were selected conveniently defining them through theoretical sampling. For the gathering of information, two focus groups were worked with in spaces selected by informants. Interviews were audio-recorded and semiotically analyzed. Results: The results allude to being useful when initiating processes of Health Promotion, identifying and clarifying the work, in addition to the group integration. Likewise, they are picked up again in the evaluation of the process. The technique considers the political, historical and sociocultural moment of the local context interpreting the situation to be addressed in a structural way. Diversity of leadership and opinions are emphasized as limitations which can discourage participation. Finally, ethical implications such as not respecting the culture and autonomy of the populations to participate are described. Conclusions: The educational approach allows the local gathering of diverse actors for intersectoral work revitalizing territorial management with the recognition of the participants as self-reflective subjects of their changing and complex historical reality developing in a particular way in each experience and context guided by the political, historical and sociocultural moment, the skills of the educator, and the diversity of leadership and opinions keeping in mind not to lose respect for the culture and the autonomy to participate.

Resumo Objetivo: analisar as aprendizagens para gestores e equipes técnicos locais de Promoção da Saúde ao utilizar a técnica educativa "da arvore social", na problematização de necessidades de transformação social em Jalisco, México, ao 2017. Material e métodos: estudo qualitativo fenomenológico desenvolvimento durante 2017; de 74 participantes da técnica em quatro localidades rurais, se selecionaram a conveniência 30 informantes, definindo-os por amostra teórica. Para o levantamento da informação, se trabalharam grupos focais, em espaços selecionados por informantes. Gravaram-se áudios entrevistas e analisaram semiticamente. Resultados: aludem ser útil ao iniciar processos de promoção da saúde identificando e clarificando o trabalho, além da integração de grupo; assim mesmo se retoma na avaliação do processo. A técnica considera o momento político, histórico e sociocultural do contexto local, interpretando de maneira estrutural, a situação a abordar. Destacam como limitações diversidade de liderança e opiniões, o qual pode desanimar a participação. Finalmente, descrevem implicações éticas como não respeitar a cultura e autonomia dos povoados para participar. Conclusões: a técnica educativa permite o encontro local entre diversos atores para o trabalho intersetorial, revitalizando a gestão territorial com o reconhecimento dos participantes como sujeitos auto reflexivos de sua realidade histórica, cambiante e complexa, desenvolvendo-se de maneira particular em cada experiência e contexto, pautado pelo momento político, histórico e sociocultural, as habilidades do educador assim como a diversidade de liderança e opiniões, tendo presente não perder o respeito à cultura e a autonomia para participar.

Homochronic Transplantation of Interneuron Precursors into Early Postnatal Mouse Brains.

Neuronal fate determination and maturation requires an intricate interplay between genetic programs and environmental signals. However, disentangling the roles of intrinsic vs. extrinsic mechanisms that regulate this differentiation process is a conundrum for all developmental neurobiologists. This issue is magnified for GABAergic interneurons, an incredibly heterogeneous cell population that is born from transient embryonic structures and undergo a protracted migratory phase to disperse throughout the telencephalon. To explore how different brain environments affect interneuron fate and maturation, we developed a protocol for harvesting fluorescently labeled immature interneuron precursors from specific brain regions in newborn mice (P0-P2). At this age, interneuron migration is nearly complete and these cells are residing in their final resting environments with relatively little synaptic integration. Following collection of single cell solutions via flow cytometry, these interneuron precursors are transplanted into P0-P2 wildtype postnatal pups. By performing both homotopic (e.g., cortex-to-cortex) or heterotopic (e.g., cortex-to-hippocampus) transplantations, one can assess how challenging immature interneurons in new brain environments affects their fate, maturation, and circuit integration. Brains can be harvested in adult mice and assayed with a wide variety of posthoc analysis on grafted cells, including immunohistochemical, electrophysiological and transcriptional profiling. This general approach provides investigators with a strategy to assay how distinct brain environments can influence numerous aspects of neuron development and identify if specific neuronal characteristics are primarily driven by hardwired genetic programs or environmental cues.

Multiple comorbid neuropathologies in the setting of Alzheimer's disease neuropathology and implications for drug development.

Dementia is often characterized as being caused by one of several major diseases, such as Alzheimer's disease (AD), cerebrovascular disease, Lewy body disease, or a frontotemporal degeneration. Failure to acknowledge that more than one entity may be present precludes attempts to understand interactive relationships. The clinicopathological studies of dementia demonstrate that multiple pathologic processes often coexist. How overlapping pathologic findings affect the diagnosis and treatment of clinical AD and other dementia phenotypes was the topic taken up by the Alzheimer's Association's Research Roundtable in October 2014. This review will cover the neuropathologic basis of dementia, provide clinical perspectives on multiple pathologies, and discuss therapeutics and biomarkers targeting overlapping pathologies and how these issues impact clinical trials.High prevalence of multiple pathologic findings among individuals with clinical diagnosis of AD suggests that new treatment strategies may be needed to effectively treat AD and other dementing illnesses.

Clinician-Reported Outcome Assessments of Treatment Benefit: Report of the ISPOR Clinical Outcome Assessment Emerging Good Practices Task Force.

A clinician-reported outcome (ClinRO) assessment is a type of clinical outcome assessment (COA). ClinRO assessments, like all COAs (patient-reported, observer-reported, or performance outcome assessments), are used to 1) measure patients' health status and 2) define end points that can be interpreted as treatment benefits of medical interventions on how patients feel, function, or survive in clinical trials. Like other COAs, ClinRO assessments can be influenced by human choices, judgment, or motivation. A ClinRO assessment is conducted and reported by a trained health care professional and requires specialized professional training to evaluate the patient's health status. This is the second of two reports by the ISPOR Clinical Outcomes Assessment-Emerging Good Practices for Outcomes Research Task Force. The first report provided an overview of COAs including definitions important for an understanding of COA measurement practices. This report focuses specifically on issues related to ClinRO assessments. In this report, we define three types of ClinRO assessments (readings, ratings, and clinician global assessments) and describe emerging good measurement practices in their development and evaluation. The good measurement practices include 1) defining the context of use; 2) identifying the concept of interest measured; 3) defining the intended treatment benefit on how patients feel, function, or survive reflected by the ClinRO assessment and evaluating the relationship between that intended treatment benefit and the concept of interest; 4) documenting content validity; 5) evaluating other measurement properties once content validity is established (including intra- and inter-rater reliability); 6) defining study objectives and end point(s) objectives, and defining study end points and placing study end points within the hierarchy of end points; 7) establishing interpretability in trial results; and 8) evaluating operational considerations for the implementation of ClinRO assessments used as end points in clinical trials. Applying good measurement practices to ClinRO assessment development and evaluation will lead to more efficient and accurate measurement of treatment effects. This is important beyond regulatory approval in that it provides evidence for the uptake of new interventions into clinical practice and provides justification to payers for reimbursement on the basis of the clearly demonstrated added value of the new intervention.

Knowledge and attitudes towards dementia in adolescent students.

BACKGROUND: Improving people's knowledge, perceptions and attitudes of dementia is important in the formation of dementia-friendly communities. However, at present, there is very little evidence from adolescents, who are already the junior members of such communities and will be carers in their own rights in the future. Our aim was to evaluate adolescents' knowledge and attitudes of dementia. METHODS: Four-hundred and fifty adolescents, aged 15-18 years, from schools in Sussex (UK) were invited to complete a series of questions that assessed their dementia knowledge and attitudes. RESULTS: A total of 359 adolescent students completed the questionnaire. Out of 15 questions on dementia knowledge, participants were on average able to answer less than half correctly (M = 6.65, standard deviation = 2.34). Responses to the attitudes questionnaire showed that adolescent students had both positive and negative attitudes toward dementia. DISCUSSION: There is scope for adolescents attending school to improve their dementia knowledge and attitudes. More effort is needed to embed initial dementia understanding in the school curriculum which will improve awareness about dementia at an earlier age and will enhance dementia-friendly communities.

Ethical challenges in preclinical Alzheimer's disease observational studies and trials: Results of the Barcelona summit.

Alzheimer's disease (AD) is among the most significant health care burdens. Disappointing results from clinical trials in late-stage AD persons combined with hopeful results from trials in persons with early-stage suggest that research in the preclinical stage of AD is necessary to define an optimal therapeutic success window. We review the justification for conducting trials in the preclinical stage and highlight novel ethical challenges that arise and are related to determining appropriate risk-benefit ratios and disclosing individuals' biomarker status. We propose that to conduct clinical trials with these participants, we need to improve public understanding of AD using unified vocabulary, resolve the acceptable risk-benefit ratio in asymptomatic participants, and disclose or not biomarker status with attention to study type (observational studies vs clinical trials). Overcoming these challenges will justify clinical trials in preclinical AD at the societal level and aid to the development of societal and legal support for trial participants.

Significado y percepción frente al VIH/SIDA en mujeres rurales parejas de migrantes, Jalisco, México / Meaning and perception in relation to HIV/AIDS in rural women couples of migrants, Jalisco, Mexico

ResumenObjetivos:Describir el significado y percepción frente VIH/SIDA en mujeres rurales parejas de migrantes del municipio de Cuautla, Jalisco, México, del 2012 al 2013.Materiales y Métodos:Estudio cualitativo, de tipo fenomenológico. Identificación de primeros informantes a través del muestreo teórico, recurriendo a la entrevista a profundidad. Considerando el criterio de saturación teórica, se recurrió a la técnica bola de nieve, trabajando la técnica grupo focal e imagen proyectiva. Las entrevistas e imágenes, fueron analizadas bajo el modelo actancial semiótico.Resultados:Total de 18 informantes, 32 años edad promedio, 66,6 % con estudios de primaria o menos y 83,3 % se dedicadas al hogar. Para la mujer pareja de migrante, el fenómeno migratorio significa la satisfacción de necesidades económicas familiares y comunitarias, experimentando sentimientos de soledad y abandono. El VIH/SIDA lo representan como una enfermedad no curable y de temor, señalando discriminación social al enfermo. Perciben riesgo de contraer esta enfermedad con su pareja al retornar, pero pedir el uso del condón o realización de pruebas de detección de la patología, les implica que su pareja no regrese, situación de mayor relevancia que el riesgo de contagio.Conclusiones:El significado y percepción frente al VIH/SIDA de mujeres parejas de migrantes en Jalisco, México, se configura dentro de los beneficios económicos del fenómeno migratorio y aspectos socioculturales de género, elementos a considerar en la formulación, implementación y evaluación de intervenciones para mejorar conocimientos, actitudes y la emancipación de la mujer, para tomar acciones ante el riesgo de contagio del VIH/SIDA.

AbstractAim:To describe the meaning and perception towards HIV/AIDS in rural women, couples of migrants, of the municipality of Cuautla, Jalisco, Mexico, from 2012 to 2013.Materials and methods: Qualitative study, phenomenological type. Identification of first informants was performed through theoretical sampling, using an in-depth interview. Considering the theoretical saturation approach, researchers resorted to the snowball technique, working the focus group and projective image techniques. The interviews and images, were analyzed under the actancial semiotic model.Results:A total of 18 respondents, 32 years mean age, 66,6 % with a primary education or less; and 83,3 % is devoted to the home. For the couple of migrant women, the phenomenon of migration means the satisfaction of economic needs family and community, experiencing feelings of loneliness and abandonment. HIV/AIDS is represented as a non-curable disease that creates fear, pointing out social discrimination of the sick. Perceived risk of contracting this disease with their partner upon their return, but requesting the use of a condom or testing for the disease, implies for them the risk that their partner doesn't return, a situation of greater relevance than the risk of contagion.Conclusions:The meaning and perception towards HIV/AIDS in women, couples of migrants, in Jalisco, Mexico, is set within the economic benefits of the phenomenon of migration and sociocultural aspects of gender, elements to be considered in the formulation, implementation, and evaluation of interventions to improve knowledge, attitudes and the emancipation of women, to take action before the risk of transmission of HIV/AIDS.

Precompetitive Data Sharing as a Catalyst to Address Unmet Needs in Parkinson's Disease.

Parkinson's disease is a complex heterogeneous disorder with urgent need for disease-modifying therapies. Progress in successful therapeutic approaches for PD will require an unprecedented level of collaboration. At a workshop hosted by Parkinson's UK and co-organized by Critical Path Institute's (C-Path) Coalition Against Major Diseases (CAMD) Consortiums, investigators from industry, academia, government and regulatory agencies agreed on the need for sharing of data to enable future success. Government agencies included EMA, FDA, NINDS/NIH and IMI (Innovative Medicines Initiative). Emerging discoveries in new biomarkers and genetic endophenotypes are contributing to our understanding of the underlying pathophysiology of PD. In parallel there is growing recognition that early intervention will be key for successful treatments aimed at disease modification. At present, there is a lack of a comprehensive understanding of disease progression and the many factors that contribute to disease progression heterogeneity. Novel therapeutic targets and trial designs that incorporate existing and new biomarkers to evaluate drug effects independently and in combination are required. The integration of robust clinical data sets is viewed as a powerful approach to hasten medical discovery and therapies, as is being realized across diverse disease conditions employing big data analytics for healthcare. The application of lessons learned from parallel efforts is critical to identify barriers and enable a viable path forward. A roadmap is presented for a regulatory, academic, industry and advocacy driven integrated initiative that aims to facilitate and streamline new drug trials and registrations in Parkinson's disease.

Clinical Outcome Assessments: Conceptual Foundation-Report of the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force.

An outcome assessment, the patient assessment used in an endpoint, is the measuring instrument that provides a rating or score (categorical or continuous) that is intended to represent some aspect of the patient's health status. Outcome assessments are used to define efficacy endpoints when developing a therapy for a disease or condition. Most efficacy endpoints are based on specified clinical assessments of patients. When clinical assessments are used as clinical trial outcomes, they are called clinical outcome assessments (COAs). COAs include any assessment that may be influenced by human choices, judgment, or motivation. COAs must be well-defined and possess adequate measurement properties to demonstrate (directly or indirectly) the benefits of a treatment. In contrast, a biomarker assessment is one that is subject to little, if any, patient motivational or rater judgmental influence. This is the first of two reports by the ISPOR Clinical Outcomes Assessment - Emerging Good Practices for Outcomes Research Task Force. This report provides foundational definitions important for an understanding of COA measurement principles. The foundation provided in this report includes what it means to demonstrate a beneficial effect, how assessments of patients relate to the objective of showing a treatment's benefit, and how these assessments are used in clinical trial endpoints. In addition, this report describes intrinsic attributes of patient assessments and clinical trial factors that can affect the properties of the measurements. These factors should be considered when developing or refining assessments. These considerations will aid investigators designing trials in their choice of using an existing assessment or developing a new outcome assessment. Although the focus of this report is on the development of a new COA to define endpoints in a clinical trial, these principles may be applied more generally. A critical element in appraising or developing a COA is to describe the treatment's intended benefit as an effect on a clearly identified aspect of how a patient feels or functions. This aspect must have importance to the patient and be part of the patient's typical life. This meaningful health aspect can be measured directly or measured indirectly when it is impractical to evaluate it directly or when it is difficult to measure. For indirect measurement, a concept of interest (COI) can be identified. The COI must be related to how a patient feels or functions. Procedures are then developed to measure the COI. The relationship of these measurements with how a patient feels or functions in the intended setting and manner of use of the COA (the context of use) could then be defined. A COA has identifiable attributes or characteristics that affect the measurement properties of the COA when used in endpoints. One of these features is whether judgment can influence the measurement, and if so, whose judgment. This attribute defines four categories of COAs: patient reported outcomes, clinician reported outcomes, observer reported outcomes, and performance outcomes. A full description as well as explanation of other important COA features is included in this report. The information in this report should aid in the development, refinement, and standardization of COAs, and, ultimately, improve their measurement properties.

CNS biomarkers: Potential from a regulatory perspective: Case study - Focus in low hippocampus volume as a biomarker measured by MRI.

Our objectives are to describe the procedure for qualification advice and opinion from EU regulators on the use of novel methodologies in drug development, the key stakeholders involved and the evidence requirements for qualification opinion. We present a case study of the request from the Coalition Against Major Disease (CAMD) Consortium of the Critical Path (C-Path) Institute for EU regulators׳ qualification opinion on the use of low hippocampal volume as a biomarker for population enrichment in clinical trials of novel drugs in Alzheimer׳s disease (AD). We discuss the main concerns from the regulators, data analysis requests and guidance during the qualification. EU regulators concluded that low hippocampal volume, measured by vMRI and considered as a dichotomized variable (low volume or not), appears to help enriching recruitment into clinical trials aimed at studying drugs that potentially slow the progression of the pre-dementia stage of AD. The biomarker qualification procedure is a dynamic process in which pharmaceutical companies and research consortia can submit further data to update the qualifications and improve the predictive value of the biomarkers.

The European Medicines Agency's strategies to meet the challenges of Alzheimer disease.

Regulatory agencies have a key role in facilitating the development of new drugs for Alzheimer disease, particularly given the challenges associated with early intervention. Here, we highlight the strategies of the European Medicines Agency to help address such challenges.