RESUMO
Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.
Assuntos
Adaptação Fisiológica/fisiologia , Altitude , Hipertensão Pulmonar/fisiopatologia , Hipóxia/fisiopatologia , Transcriptoma/fisiologia , Animais , Modelos Animais de Doenças , Pulmão/fisiopatologia , Ratos Sprague-Dawley , Remodelação Vascular/fisiologiaRESUMO
Dementia is an important risk factor for delirium, but the optimal strategy for incorporating cognitive impairment into delirium risk assessment at the time of hospital admission is unknown. We compared 2 informant-based screening tools for dementia and mild cognitive impairment [AD8 and D=(MC)] to the Mini Mental State Examination (MMSE) and Mini-cog in predicting hospital-acquired delirium. This prospective cohort study at an academic medical center consisted of 162 medical inpatients over age 50 years without delirium upon admission. Each participant was evaluated using the MMSE, Mini-cog, AD8, and D=(MC) upon admission and was assessed daily for delirium. An MMSE≤24 carried a 5.5 [95% confidence intervals (CI), 2.7-11.1] relative risk for delirium, whereas cognitive impairment detected by the Mini-cog, D=(MC), or AD8 carried a 2-fold risk. Adding the D=(MC) to the MMSE increased the sensitivity for predicting delirium from 52% (range, 32% to 73%) for the MMSE alone to 65% (range, 46% to 85%) if either test was positive. If both were positive, specificity was maximized at 97% (range, 94% to 100%), but sensitivity was 17% (range, 2% to 33%). The MMSE and Mini-cog identify a large proportion of patients at risk for hospital-acquired delirium, but the combination of performance-based and an informant-based screens may maximize specificity and sensitivity.
Assuntos
Cuidadores/psicologia , Delírio/diagnóstico , Delírio/psicologia , Demência/diagnóstico , Demência/psicologia , Hospitalização/tendências , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Seguimentos , Humanos , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Testes Neuropsicológicos , Valor Preditivo dos Testes , Estudos ProspectivosRESUMO
BACKGROUND: Socio-emotional skills are critical to life outcomes such as achievement, well-being and job success. However, existing research has mostly focused on the consequences of socio-emotional skills, with less attention devoted to the role of school climate in the deployment of these skills. AIMS: This study investigated the role of school climate in socio-emotional skills. More specifically, we investigated whether cooperative or competitive school climates are associated with students' socio-emotional skills. SAMPLE: Our study utilized data from the OECD Survey on Social and Emotional Skills, collected from 10 cities across nine countries. Participants were 60,985 students, including 31,187 10-year-olds (49.70% females) and 29,798 15-year-olds (51.6% females). METHODS: We conducted multilevel structural equation modelling to test whether cooperative and competitive climates were associated with socio-emotional skills. These skills include five broad domain skills and 15 more specific skills: task performance (self-control, responsibility and persistence), emotion regulation (stress resistance, emotional control and optimism), collaboration (empathy, trust and cooperation), open-mindedness (tolerance, curiosity and creativity) and engaging with others (sociability, assertiveness and energy). RESULTS: Our findings indicated a positive relationship between a cooperative climate and socio-emotional skills. In contrast, the relationship between a competitive climate and socio-emotional skills was primarily negative. CONCLUSION: This study highlights the contrasting roles of cooperative and competitive climates in students' socio-emotional skills.
Assuntos
Instituições Acadêmicas , Habilidades Sociais , Estudantes , Humanos , Feminino , Masculino , Adolescente , Criança , Estudantes/psicologia , Comportamento Cooperativo , Regulação Emocional/fisiologia , Comportamento Competitivo/fisiologia , Meio SocialRESUMO
This review gives a basic introduction to the biology of protein kinase C, one of the first calcium-dependent kinases to be discovered. We review the structure and function of protein kinase C, along with some of the substrates of individual isoforms. We then review strategies for inhibiting PKC in experimental systems and finally discuss the therapeutic potential of targeting PKC. Each aspect is covered in summary, with links to detailed resources where appropriate.
Assuntos
Proteína Quinase C/fisiologia , Animais , Neoplasias Hematológicas/tratamento farmacológico , Humanos , Resistência à Insulina , Doenças Neurodegenerativas/tratamento farmacológico , Fosforilação , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/química , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológicoRESUMO
Pulmonary arterial hypertension (PAH) is a deadly and uncurable disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. Angiotensin Converting Enzyme 2 (ACE2) and its product, angiotensin-(1-7) [ANG-(1-7)] were expressed in lettuce chloroplasts to facilitate affordable oral drug delivery. Lyophilized lettuce cells were stable up to 28 months at ambient temperature with proper folding, assembly of CTB-ACE2/ANG-(1-7) and functionality. When the antibiotic resistance gene was removed, Ang1-7 expression was stable in subsequent generations in marker-free transplastomic lines. Oral gavage of monocrotaline-induced PAH rats resulted in dose-dependent delivery of ANG-(1-7) and ACE2 in plasma/tissues and PAH development was attenuated with decreases in right ventricular (RV) hypertrophy, RV systolic pressure, total pulmonary resistance and pulmonary artery remodeling. Such attenuation correlated well with alterations in the transcription of Ang-(1-7) receptor MAS and angiotensin II receptor AGTRI as well as IL-1ß and TGF-ß1. Toxicology studies showed that both male and female rats tolerated ~10-fold ACE2/ANG-(1-7) higher than efficacy dose. Plant cell wall degrading enzymes enhanced plasma levels of orally delivered protein drug bioencapsulated within plant cells. Efficient attenuation of PAH with no toxicity augurs well for clinical advancement of the first oral protein therapy to prevent/treat underlying pathology for this disease.
Assuntos
Hipertensão Pulmonar , Animais , Drogas em Investigação , Feminino , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita , Masculino , Monocrotalina , Fragmentos de Peptídeos , Ratos , Ratos Sprague-DawleyRESUMO
There is a clear need for new therapeutics to treat alcoholism. Here, we test our hypothesis that selective inhibitors of neuronal calcium channels will reduce ethanol consumption and intoxication, based on our previous studies using knock-out mice and cell culture systems. We demonstrate that pretreatment with the novel mixed N-type and T-type calcium channel antagonist 1-(6,6-bis(4-fluorophenyl)hexyl)-4-(3,4,5-trimethoxybenzyl)piperazine (NP078585) reduced ethanol intoxication. NP078585 also attenuated the reinforcing and rewarding properties of ethanol, measured by operant self-administration and the expression of an ethanol conditioned place preference, and abolished stress-induced reinstatement of ethanol seeking. NP078585 did not affect alcohol responses in mice lacking N-type calcium channels. These results suggest that selective calcium channel inhibitors may be useful in reducing acute ethanol intoxication and alcohol consumption by human alcoholics.
Assuntos
Intoxicação Alcoólica , Canais de Cálcio Tipo L/fisiologia , Canais de Cálcio Tipo N/fisiologia , Condicionamento Operante/fisiologia , Reforço Psicológico , Intoxicação Alcoólica/tratamento farmacológico , Intoxicação Alcoólica/fisiopatologia , Intoxicação Alcoólica/psicologia , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Canais de Cálcio Tipo N/deficiência , Depressores do Sistema Nervoso Central/administração & dosagem , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Etanol/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Piperazinas/farmacologia , Ratos , Ratos Long-Evans , Reflexo/efeitos dos fármacos , Reflexo/fisiologia , Teste de Desempenho do Rota-Rod , Autoadministração , Estresse Psicológico/fisiopatologiaRESUMO
Neuropathic pain (NeuP) is a syndrome that results from damaged nerves and/or aberrant regeneration. Common etiologies of neuropathy include chronic illnesses and medication use. Chronic disorders, such as diabetes and alcoholism, can cause neuronal injury and consequently NeuP. Certain medications with antineoplastic effects also carry an exquisitely high risk for neuropathy. These culprits are a few of many that are fueling the NeuP epidemic, which currently affects 7%-10% of the population. It has been estimated that approximately 10% and 7% of US adults carry a diagnosis of diabetes and alcohol disorder, respectively. Despite its pervasiveness, many physicians are unfamiliar with adequate treatment of NeuP, partly due to the few reviews that are available that have integrated basic science and clinical practice. In light of the recent Centers for Disease Control and Prevention guidelines that advise against the routine use of µ-opioid receptor-selective opioids for chronic pain management, such a review is timely. Here, we provide a succinct overview of the etiology and treatment options of diabetic and alcohol- and drug-induced neuropathy, three different and prevalent neuropathies fusing the combined clinical and preclinical pharmacological expertise in NeuP of the authors. We discuss the anatomy of pain and pain transmission, with special attention to key ion channels, receptors, and neurotransmitters. An understanding of pain neurophysiology will lead to a better understanding of the rationale for the effectiveness of current treatment options, and may lead to better diagnostic tools to help distinguish types of neuropathy. We close with a discussion of ongoing research efforts to develop additional treatments for NeuP.
RESUMO
OBJECTIVES: To examine whether communication strategies and principles have been utilized in the HIV prevention intervention programs conducted in China. METHODS: Comprehensive literature searches were conducted using PsycINFO, Medline, and Academic Search Complete with combinations of a number of keywords. Studies were included if they (1) were conducted in China and published prior to October 2011; (2) tested interventions promoting HIV/sexual risk reduction; and (3) reported empirical outcome evaluations on HIV knowledge, condom use and other condom-related variables. Data on 11 dimensions were extracted and analyzed, including formative research, theory, message targeting, messenger and channels, process evaluation, evaluation design, outcome measures. RESULTS: The majority of the 45 intervention studies were not theory-based, did not report conducting formative research or process evaluation, used pretest-posttest control group designs, combined nonmedia channels, printed and visual materials, and employed HIV knowledge and condom use as outcome measures. CONCLUSIONS: Many HIV prevention interventions in China have been successful in reducing HIV risk-related outcomes. This literature has its weaknesses; however, the current review illuminates gaps in the literature and points to important future directions for research.