Insulin signalling in heart involves insulin receptor substrates-1 and - 2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway

Objective: Hyperinsulinemia is a common feature of obesity and hypertension and may be associated with abnormal metabolism and growth of heart muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we investigate the initial steps of insulin signalling in rat heart. Methods: After insulin infusion in the cava vein of male Wistar rats, the insulin receptor, insulin receptor substrates-1 and -2, phosphatidylinositol 3- kinase activity and Janus kinase (JAK) 2 engagement were studied by immunoprecipitation and immunoblot of heart extracts. Results: An insulin load induces rapid autophosphorylation of the insulin receptor which is followed by the phosphorylation of insulin receptor substrates-1 and -2. The phosphorylation of these early intracellular substrates leads to the association of the p85 subunit of phosphatidylinositol 3-kinase and subsequent activation of its catalytic p110 subunit. Besides activation of the lipid metabolising enzyme phosphatidylinositol 3-kinase, the phosphorylation of insulin receptor substrates-1 and -2 engages the intracellular kinase JAK 2 and induces JAK 2-STAT 1 complex formation. Conclusion: We demonstrate that the early steps of insulin signalling in heart include the phosphorylation-activation of the insulin receptor, engagement of insulin receptor substrates-1 and -2 with the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway-JAK 2-STAT 1

Diet-induced Obesity Induces Endoplasmic Reticulum Stress And Insulin Resistance In The Amygdala Of Rats.

Insulin acts in the hypothalamus, decreasing food intake (FI) by the IR/PI3K/Akt pathway. This pathway is impaired in obese animals and endoplasmic reticulum (ER) stress and low-grade inflammation are possible mechanisms involved in this impairment. Here, we highlighted the amygdala as an important brain region for FI regulation in response to insulin. This regulation was dependent on PI3K/AKT pathway similar to the hypothalamus. Insulin was able to decrease neuropeptide Y (NPY) and increase oxytocin mRNA levels in the amygdala via PI3K, which may contribute to hypophagia. Additionally, obese rats did not reduce FI in response to insulin and AKT phosphorylation was decreased in the amygdala, suggesting insulin resistance. Insulin resistance was associated with ER stress and low-grade inflammation in this brain region. The inhibition of ER stress with PBA reverses insulin action/signaling, decreases NPY and increases oxytocin mRNA levels in the amygdala from obese rats, suggesting that ER stress is probably one of the mechanisms that induce insulin resistance in the amygdala.3443-

Draft of Cheyenne & Arapahoe Report

https://digitalcommons.assumption.edu/mallet-manuscripts/1030/thumbnail.jp

An Eye for Possibilities in the Development of Children with Cerebral Palsy: Neurobiology and Neuropsychology in a Cultural-Historical Dynamic Understanding

Taking children with Cerebral Palsy (CP) as an example, the article seeks an understanding ofchildren with disabilities that connects neuropsychological theories of neural development withthe situated cognition perspective and the child as an active participant in its social practices. Theearly brain lesion of CP is reconceptualised as a neurobiological constraint that exists in therelations between the neural, cognitive and social levels. Through a multi-method study of twochildren with CP, it is analysed how neurobiological constraints arise, evolve and sometimes areresolved through local matches between the child and its social practices. The result is discussedas support of a developmental science approach that includes processes at the social practice levelalong with knowledge of biological processes

Detection of human papillomavirus DNA and p53 codon 72 polymorphism in prostate carcinomas of patients from Argentina

BACKGROUND: Infections with high-risk human papillomaviruses (HPVs), causatively linked to cervical cancer, might also play a role in the development of prostate cancer. Furthermore, the polymorphism at codon 72 (encoding either arginine or proline) of the p53 tumor-suppressor gene is discussed as a possible determinant for cancer risk. The HPV E6 oncoprotein induces degradation of the p53 protein. The aim of this study was to analyse prostate carcinomas and hyperplasias of patients from Argentina for the presence of HPV DNA and the p53 codon 72 polymorphism genotype. METHODS: HPV DNA detection and typing were done by consensus L1 and type-specific PCR assays, respectively, and Southern blot hybridizations. Genotyping of p53 codon 72 polymorphism was performed both by allele specific primer PCRs and PCR-RFLP (Bsh1236I). Fischer's test with Woolf's approximation was used for statistical analysis. RESULTS: HPV DNA was detected in 17 out of 41 (41.5 %) carcinoma samples, whereas all 30 hyperplasia samples were HPV-negative. Differences in p53 codon 72 allelic frequencies were not observed, neither between carcinomas and hyperplasias nor between HPV-positive and HPV-negative carcinomas. CONCLUSION: These results indicate that the p53 genotype is probably not a risk factor for prostate cancer, and that HPV infections could be associated with at least a subset of prostate carcinomas

Genome Analysis Linking Recent European and African Influenza (H5N1) Viruses

Although linked, these viruses are distinct from earlier outbreak strains

Insulin Resistance in HIV-Patients: Causes and Consequences

Here we review how immune activation and insulin resistance contribute to the metabolic alterations observed in HIV-infected patients, and how these alterations increase the risk of developing CVD. The introduction and evolution of antiretroviral drugs over the past 25 years has completely changed the clinical prognosis of HIV-infected patients. The deaths of these individuals are now related to atherosclerotic CVDs, rather than from the viral infection itself. However, HIV infection, cART, and intestinal microbiota are associated with immune activation and insulin resistance, which can lead to the development of a variety of diseases and disorders, especially with regards to CVDs. The increase in LPS and proinflammatory cytokines circulating levels and intracellular mechanisms activate serine kinases, resulting in insulin receptor substrate-1 (IRS-1) serine phosphorylation and consequently a down regulation in insulin signaling. While lifestyle modifications and pharmaceutical interventions can be employed to treat these altered metabolic functions, the mechanisms involved in the development of these chronic complications remain largely unresolved. The elucidation and understanding of these mechanisms will give rise to new classes of drugs that will further improve the quality of life of HIV-infected patients, over the age of 50

The Role of Hepatocyte Growth Factor (HGF) in Insulin Resistance and Diabetes

In obesity, insulin resistance (IR) and diabetes, there are proteins and hormones that may lead to the discovery of promising biomarkers and treatments for these metabolic disorders. For example, these molecules may impair the insulin signaling pathway or provide protection against IR. Thus, identifying proteins that are upregulated in IR states is relevant to the diagnosis and treatment of the associated disorders. It is becoming clear that hepatocyte growth factor (HGF) is an important component of the pathophysiology of IR, with increased levels in most common IR conditions, including obesity. HGF has a role in the metabolic flux of glucose in different insulin sensitive cell types; plays a key role in β-cell homeostasis; and is capable of modulating the inflammatory response. In this review, we discuss how, and to what extent HGF contributes to IR and diabetes pathophysiology, as well as its role in cancer which is more prevalent in obesity and diabetes. Based on the current literature and knowledge, it is clear that HGF plays a central role in these metabolic disorders. Thus, HGF levels could be employed as a biomarker for disease status/progression, and HGF/c-Met signaling pathway modulators could effectively regulate IR and treat diabetes

O que influencia o desejo de ter um filho nos jovens adultos

Enquadramento: O Índice Sintético de Fecundidade (ISF) português é dos mais baixos da Europa. No entanto, o desejo de cada individuo jovem ter um filho, sem qualquer restrição é superior ao valor de referência para a substituição de gerações. Objectivos: Compreender a relação entre as variáveis sociodemográficas, as variáveis de contexto sexual e reprodutivo e as variáveis psicológicas com o desejo de ter um filho. Métodos: Estudo quantitativo, descritivo-correlacional. A amostra é não probabilistica por conveniência com uma média de idade de 20,79 anos (dp=2,785). O protocolo de investigação foi um questionário que caracteriza o perfil sociodemográfico, sexual e reprodutivo da amostra. Foi incluído o “QVPM” (Matos& Costa, 2001), “QVA” (Matos& Costa, 2001), “Questionário de desejo de ter um filho” (Leal, 1999) e escala de Auto estima de (Rosenberg, 1965, adaptado 1999). Resultados: É no sexo feminino e no grupo etário ≤ 19 anos que o desejo de ter um filho é maior. O desejo de ter um filho diminui com a idade. Ter namorado(a), pertencer a uma família alargada, não ter irmãos e ser proveniente de uma zona rural estão relacionados com maior desejo de ter um filho, no entanto sem diferenças estatísticas significativas. Os estudantes do primeiro ano apresentam maior desejo de ter um filho no futuro e este diminui conforme a progressão no ensino (ano de curso) e aproximação do mercado de trabalho. Os que apresentam maior desejo de ser pais com base em sentimentos relativos à parentalidade frequentam menos a consulta de planeamento familiar. Observaram-se diferenças estatísticas significativas entre o número de filhos desejado no futuro e o desejo de ter um filho. O nível de conhecimento sobre fertilidade não influencia o desejo de ter um filho. Quanto maior a ansiedade de separação da mãe (vinculação à mãe), a dependência da vinculação amorosa, a ansiedade de separação do pai (vinculação ao pai) e a auto estima, maior é o desejo de ter um filho. Conclusões: O desejo de ter um filho é um construto ao longo da vida, pelo que os enfermeiros acompanhando o ciclo vital do individuo contribuem para a promoção e capacitação da parentalidade nomeadamente através da: avaliação e promoção do vinculo parental e promoção da saúde sexual e reprodutiva. Palavras chave: Jovem adulto, parentalidade, vinculação amorosa, auto estima.Abstract: Framework: The Portuguese Synthetic Fertility Index (ISF) is among the lowest in Europe. However, the desire of each young individual to have a child without any restriction is higher than the reference value for the replacement of generations. Objective: Understand the relationship between sociodemographic variables, sexual and reproductive health variables, and psychological variables with the desire to have a child. Methods: Quantitative, descriptive-correlational study. A non-probabilistic for convenience sampling with an average age of 20.79 years (sd = 2.785). The research protocol was a questionnaire that characterizes the sociodemographic, sexual and reproductive profile of the sample and includes the “QVPM” (Matos& Costa, 2001), “QVA” (Matos& Costa, 2001), “Questionário de desejo de ter um filho” (Leal, 1999) and Rosenberg Self – esteem scale (Rosenberg, 1965, adap.1999). Results: It is in the female sex and in the age group ≤ 19 years that the desire to have a child is higher. The desire to have a child decreases with age. Having a boyfriend, belonging to an extended family, not having siblings and being from the countryside are related to higher desire to have a child, however without significant statistical differences. In the first year students the desire to have a child is higher and this decreases with the progression in school’s year and the approaching of labor market. Those who are more likely to be parents based on feelings about parenting are less likely to attend family planning visits. Significant statistical differences were observed between the number of children desired in the future and the desire to have a child. The level of knowledge about fertility does not influence the desire to have a child. The greater the separation anxiety of the mother (attachment to the mother), the dependence of the love bond, the separation anxiety of the father (attachment to the father) and the self esteem, the greater is the desire to have a child. Conclusions: The desire to have a child is a lifelong construct, so the nurses by accompanying the individual's life cycle contribute to the promotion and training of parenting, namely through: evaluation and promotion of parental attachment and promotion of sexual and reproductive health. Descriptors: Young adult, parenting, attachment, self esteem

Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor-targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes