RESUMO
Fully elucidating the burden that Lennox-Gastaut syndrome (LGS) places on individuals with the disease and their caregivers is critical to improving outcomes and quality of life (QoL). This systematic literature review evaluated the global burden of illness of LGS, including clinical symptom burden, care requirements, QoL, comorbidities, caregiver burden, economic burden, and treatment burden (PROSPERO ID: CRD42022317413). MEDLINE, Embase, and the Cochrane Library were searched for articles that met predetermined criteria. After screening 1442 deduplicated articles and supplementary manual searches, 113 articles were included for review. A high clinical symptom burden of LGS was identified, with high seizure frequency and nonseizure symptoms (including developmental delay and intellectual disability) leading to low QoL and substantial care requirements for individuals with LGS, with the latter including daily function assistance for mobility, eating, and toileting. Multiple comorbidities were identified, with intellectual disorders having the highest prevalence. Although based on few studies, a high caregiver burden was also identified, which was associated with physical problems (including fatigue and sleep disturbances), social isolation, poor mental health, and financial difficulties. Most economic analyses focused on the high direct costs of LGS, which arose predominantly from medically treated seizure events, inpatient costs, and medication requirements. Pharmacoresistance was common, and many individuals required polytherapy and treatment changes over time. Few studies focused on the humanistic burden. Quality concerns were noted for sample representativeness, disease and outcome measures, and reporting clarity. In summary, a high burden of LGS on individuals, caregivers, and health care systems was identified, which may be alleviated by reducing the clinical symptom burden. These findings highlight the need for a greater understanding of and better definitions for the broad spectrum of LGS symptoms and development of treatments to alleviate nonseizure symptoms.
Assuntos
Cuidadores , Efeitos Psicossociais da Doença , Síndrome de Lennox-Gastaut , Qualidade de Vida , Humanos , Cuidadores/psicologia , Cuidadores/economia , Deficiência Intelectual/economia , Deficiência Intelectual/terapia , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/psicologia , Sobrecarga do Cuidador/psicologiaRESUMO
Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) are rare developmental and epileptic encephalopathies associated with seizure and nonseizure symptoms. A comprehensive understanding of how many individuals are affected globally, the diagnostic journey they face, and the extent of mortality associated with these conditions is lacking. Here, we summarize and evaluate published data on the epidemiology of DS and LGS in terms of prevalence, incidence, diagnosis, genetic mutations, and mortality and sudden unexpected death in epilepsy (SUDEP) rates. The full study protocol is registered on PROSPERO (CRD42022316930). After screening 2172 deduplicated records, 91 unique records were included; 67 provided data on DS only, 17 provided data on LGS only, and seven provided data on both. Case definitions varied considerably across studies, particularly for LGS. Incidence and prevalence estimates per 100 000 individuals were generally higher for LGS than for DS (LGS: incidence proportion = 14.5-28, prevalence = 5.8-60.8; DS: incidence proportion = 2.2-6.5, prevalence = 1.2-6.5). Diagnostic delay was frequently reported for LGS, with a wider age range at diagnosis reported than for DS (DS, 1.6-9.2 years; LGS, 2-15 years). Genetic screening data were reported by 63 studies; all screened for SCN1A variants, and only one study specifically focused on individuals with LGS. Individuals with DS had a higher mortality estimate per 1000 person-years than individuals with LGS (DS, 15.84; LGS, 6.12) and a lower median age at death. SUDEP was the most frequently reported cause of death for individuals with DS. Only four studies reported mortality information for LGS, none of which included SUDEP. This systematic review highlights the paucity of epidemiological data available for DS and especially LGS, demonstrating the need for further research and adoption of standardized diagnostic criteria.
Assuntos
Epilepsias Mioclônicas , Síndrome de Lennox-Gastaut , Humanos , Síndrome de Lennox-Gastaut/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/mortalidade , Prevalência , Incidência , Morte Súbita Inesperada na Epilepsia/epidemiologia , Saúde Global/estatística & dados numéricosRESUMO
The regulation of the serotonin transporter (SERT) by guanine nucleotide-binding protein alpha (Gα) q was investigated using Gαq knockout mice. In the absence of Gαq, SERT-mediated uptake of 5-hydroxytryptamine (5HT) was enhanced in midbrain and frontal cortex synaptosomes, but only in female mice. The mechanisms underlying this sexual dimorphism were investigated using quantitative western blot analysis revealing brain region-specific differences. In the frontal cortex, SERT protein expression was decreased in male knockout mice, seemingly explaining the sex-dependent variation in SERT activity. The differential expression of Gαi1 in female mice contributes to the sex differences in the midbrain. In fact, Gαi1 levels inversely correlate with 5HT uptake rates across both sexes and genotypes. Likely due to differential SERT regulation as well as sex differences in the expression of tryptophan hydroxylase 2, Gαq knockout mice also displayed sex- and genotype-dependent alterations in total 5HT tissue levels as determined by high-performance liquid chromatography. Gαq inhibitors, YM-254890 and BIM-46187, differentially affected SERT activity in both, synaptosomes and cultured cells. YM-254890 treatment mimicked the effect of Gαq knockout in the frontal cortex. BIM-46187, which promotes the nucleotide-free form of Gα proteins, substantially inhibited 5HT uptake, prompting us to hypothesise that Gαq interacts with SERT similarly as with G-protein-coupled receptors and inhibits SERT activity by modulating transport-associated conformational changes. Taken together, our findings reveal a novel mechanism of SERT regulation and impact our understanding of sex differences in diseases associated with dysregulation of serotonin transmission, such as depression and anxiety.
Assuntos
Encéfalo/metabolismo , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/deficiência , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Caracteres Sexuais , Sinaptossomos/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Feminino , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Knockout , Peptídeos Cíclicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Sinaptossomos/efeitos dos fármacosRESUMO
Urea is the major nitrogen-containing product of protein metabolism, and the urea cycle is intrinsically linked to nitric oxide (NO) production via the common substrate L-arginine. Urea accumulates in the brain in neurodegenerative states, including Alzheimer's and Huntington's disease. Urea transporter B (UT-B, SLC14A1) is the primary transport protein for urea in the CNS, identified most abundantly in astrocytes. Moreover, enhanced expression of the Slc14a1 gene has been reported under neurodegenerative conditions. While the role of UT-B in disease pathology remains unclear, UT-B-deficient mice display behavioural impairment coupled with urea accumulation, NO disruption and neuronal loss. Recognising the role of inflammation in neurodegenerative disease pathology, the current short study evaluates the role of UT-B in regulating inflammatory responses. Using the specific inhibitor UTBinh-14, we investigated the impact of UT-B inhibition on LPS-induced changes in BV2 microglia and N2a neuroblastoma cells. We found that UTBinh-14 significantly attenuated LPS-induced production of TNFα and IL-6 from BV2 cells, accompanied by reduced release of NO. While we observed a similar reduction in supernatant concentration of IL-6 from N2a cells, the LPS-stimulated NO release was further augmented by UTBinh-14. These changes were accompanied by a small, but significant downregulation in UT-B expression in both cell types following incubation with LPS, which was not restored by UTBinh-14. Taken together, the current evidence implicates UT-B in regulation of inflammatory responses in microglia and neuronal-like cells. Moreover, our findings offer support for the further investigation of UT-B as a novel therapeutic target for neuroinflammatory conditions.
Assuntos
Inflamação/tratamento farmacológico , Proteínas de Membrana Transportadoras/metabolismo , Microglia/efeitos dos fármacos , Neuroblastoma/metabolismo , Animais , Linhagem Celular Tumoral , Inflamação/induzido quimicamente , Interleucina-6/metabolismo , Lipopolissacarídeos , Camundongos , Microglia/metabolismo , Óxido Nítrico/metabolismo , Pirimidinas/uso terapêutico , Tiofenos/uso terapêutico , Triazóis/uso terapêutico , Fator de Necrose Tumoral alfa/metabolismo , Transportadores de UreiaRESUMO
BACKGROUND: Infective endocarditis (IE) is associated with significant morbidity and mortality. Non-adherence to IE guidelines and recommendations is frequent, and may adversely impact patient outcomes. AIM: To assess the impact of non-adherence to components of existing IE guidelines and recommendations on a composite outcome consisting of any of the following: mortality, unplanned cardiac surgery, embolic event or relapse of positive blood culture within six months of diagnosis. METHODS: A single centre, retrospective cohort study. RESULTS: Amongst 157 patients, there was inconsistent adherence to: initial diagnosis of an infective condition (87%), timely administration of antimicrobial therapy (82%), appropriateness of predominant antimicrobial regime (94%), appropriate management of the portal of entry (86%), multidisciplinary input (75%), end of antimicrobial therapy repeat echocardiography (60%) and adherence to indications for surgery (76%). Inpatient mortality was 12.1% (n = 19) and the composite adverse outcome occurred in 36 (22.9%) patients. In multivariate logistic regression analysis, infection of prosthetic device (adjusted odds ratio [95% confidence interval]; 2.43 [1.07-5.50]) and non-adherence to surgical guidelines (aOR 3.67 [1.60-8.47]) were significantly associated with an adverse outcome. CONCLUSIONS: Our data suggests that adherence to differing components of IE management guidelines and recommendations varies and that non-adherence to surgical aspects of guidelines has the biggest impact in determining outcomes.
Assuntos
Endocardite Bacteriana , Endocardite , Ecocardiografia , Endocardite/tratamento farmacológico , Endocardite/cirurgia , Endocardite Bacteriana/tratamento farmacológico , Endocardite Bacteriana/cirurgia , Humanos , Razão de Chances , Estudos RetrospectivosRESUMO
Lymphoedema is a long-term chronic condition that results from lymphatic insufficiency and may cause skin changes, which can cause discomfort and impact patient' quality of life. The four cornerstones of lymphoedema management are exercise, lymphatic massage, compression and skin care. This article critically examines self-management in lymphoedema focusing on skin care. Patients may initially demonstrate enthusiasm to undertake the required skin care independently. However, psychosocial factors, such as financial burden and physical restraints, can affect motivation and behaviours over time. A patient's knowledge of the importance of skin care self-management should not be limited to the initial assessment, but should be continually assessed throughout their lymphoedema journey. The ongoing provision of patient-centred care may have psychological and behavioural benefits and help optimise skin care self-management.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Linfedema/enfermagem , Autogestão/métodos , Higiene da Pele/enfermagem , Efeitos Psicossociais da Doença , Humanos , Linfedema/economia , Linfedema/psicologia , Motivação , Educação de Pacientes como Assunto , Assistência Centrada no Paciente , Autogestão/psicologia , Higiene da Pele/métodos , Higiene da Pele/psicologiaRESUMO
BACKGROUND: Chronic diseases are the leading cause of morbidity and mortality worldwide. The primary health care setting is an effective avenue for the management and prevention of chronic diseases. Dietitians working in this setting assist with the management of modifiable risk factors of chronic diseases. However, health care professionals report challenges in providing care in this setting because of time and financial constraints. Information technology offers the potential to improve health care quality, safety, efficiency, and cost-efficiency, but there exists limited understanding of dietitians' application of technology in this setting. OBJECTIVE: The objective of this study was to explore the perceptions of primary care dietitians about using information technology in their workplace. METHODS: We recruited 20 Australian primary care dietitians using purposive and snowball sampling for semistructured telephonic interviews. Interview questions aimed to gain an understanding of dietitians' perceptions about sharing patient outcomes through a national database and the benefits, disadvantages, feasibility, and barriers of using information technology. Interviews were audiorecorded, transcribed verbatim, and thematically analyzed for emerging themes and subthemes. Finally, the technologies used by participants were collated by name and researched for their key attributes. RESULTS: The following 4 distinct themes emerged from the data: information technology improving the efficiency of practice tasks, experiencing barriers to using information technology in practice, information technology enhancing outcomes through education and monitoring, and information technology for sharing information with others. Participants identified several advantages and disadvantages of using technology and expressed willingness to share patient outcomes using a Web-based database. CONCLUSIONS: This study suggests that information technology is perceived to have benefits to dietitians and patients in primary health care. However, to achieve the optimal benefit, support is required to overcome barriers to integrate information technology into practice better. Further development of patient management systems and standardized Web-based data collection systems are needed to support better usage by dietitians.
Assuntos
Dietética/métodos , Tecnologia da Informação/normas , Nutricionistas/normas , Local de Trabalho/psicologia , Feminino , Humanos , Masculino , Pesquisa QualitativaRESUMO
OBJECTIVE: The aims of the present study were to examine the Zn intake and characteristics of Zn supplement users and non-users and to survey Zn supplements that are commercially available. DESIGN: Cross-sectional national nutrition survey (2007 Australian Children's Nutrition and Physical Activity Survey) and a review of commercially available Zn supplements. SETTING: Australia. SUBJECTS: Children (n 4834) aged 2-16 years. RESULTS: Zn supplement use was associated with younger age, being female, having a lower BMI and consuming a vegetarian or modified diet. Supplement users had significantly higher intakes of Zn than non-users in all age and gender subgroups. Adolescent boys aged 14-16 years who did not use Zn supplements were at highest risk of inadequate Zn intake (15 % compared with 1 % of users). Conversely, children aged 2-3 years were at highest risk of exceeding the recommended upper limit of Zn intake (86-87 % of users and 64-71 % of non-users), followed by children aged 4-8 years (9-29 % of users and 3-12 % of non-users). The most common sources of Zn supplements consumed by children were multi-vitamin and mineral preparations (92 %), followed by Zn-only supplements (5 %) and Zn-containing cold and flu, or cold sore supplements (3 %). A survey of commercially available Zn supplements revealed that the median elemental Zn content was 2 and 25 mg for multi-vitamin and mineral preparations and Zn-only supplements, respectively. CONCLUSIONS: Based on these data, widespread Zn supplement use among young children is unlikely to be warranted. The impact of exceeding the upper limit of Zn intake on biomarkers of Zn toxicity requires further investigation.
Assuntos
Suplementos Nutricionais/estatística & dados numéricos , Estado Nutricional/efeitos dos fármacos , Oligoelementos/administração & dosagem , Zinco/administração & dosagem , Adolescente , Fatores Etários , Austrália , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Masculino , Inquéritos Nutricionais , Recomendações Nutricionais , Fatores SexuaisRESUMO
INTRODUCTION: Sarcopenia is an independent predictor of poor post-operative outcomes following major surgery. Inflammatory bowel disease (IBD) consists of Crohn's disease (CD) and ulcerative colitis (UC), which are chronic inflammatory conditions involving the gastrointestinal system. Evidence demonstrates that up to 60% of patients with IBD have sarcopenia. Despite advances in medical management, more than 15% of patients with UC and 80% with CD eventually require surgical intervention. The primary aim of the study was to assess the impact of sarcopenia on post-operative anastomotic leak rates. METHODS: A retrospective cohort study of patients at Royal Perth Hospital who underwent major abdominal surgery for management of IBD between January 2010 and December 2020 was performed. Sarcopenia was assessed according to the skeletal muscle index at the level of the third lumbar vertebrae using the cut off 52.4 and 38.5 cm2 /m2 for men and women, respectively. RESULTS: A total of 147 patients were included. The prevalence of sarcopenia within the study population was 36.1%. Patients with sarcopenia were significantly taller (P = 0.025) and were more likely to be on pre-operative steroid medications (P = 0.045). There was no difference in the remaining baseline characteristics between sarcopenic and non-sarcopenic patients. Patients with sarcopenia were more likely to develop a post-operative anastomotic leak (OR:11.303, 95% CI, 1.53-83.51, P = 0.017), grade IV complications (OR:6.79, 95%CI:1.1-43.6, P = 0.044) and require total parenteral nutrition (TPN) (OR:3.212, 95% CI:1.3-8.1, P = 0.013). CONCLUSIONS: Sarcopenia significantly increases the risk of major post-operative complications for patients with IBD undergoing colorectal surgery.
Assuntos
Colite Ulcerativa , Cirurgia Colorretal , Doença de Crohn , Doenças Inflamatórias Intestinais , Sarcopenia , Fístula Anastomótica/epidemiologia , Fístula Anastomótica/etiologia , Doença Crônica , Colite Ulcerativa/cirurgia , Doença de Crohn/complicações , Doença de Crohn/cirurgia , Feminino , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/cirurgia , Masculino , Estudos Retrospectivos , Sarcopenia/complicações , Sarcopenia/epidemiologiaRESUMO
Alzheimer's disease (AD) is characterized by accumulation and deposition of Abeta peptides in the brain. Abeta deposition in cerebrovessels occurs in many AD patients and results in cerebral amyloid angiopathy (AD/CAA). Since Abeta can be transported across blood-brain barrier (BBB), aberrant Abeta trafficking across BBB may contribute to Abeta accumulation in the brain and CAA development. Expression analyses of 273 BBB-related genes performed in this study showed that the drug transporter, ABCG2, was significantly upregulated in the brains of AD/CAA compared with age-matched controls. Increased ABCG2 expression was confirmed by Q-PCR, Western blot, and immunohistochemistry. Abcg2 was also increased in mouse AD models, Tg-SwDI and 3XTg. Abeta alone or in combination with hypoxia/ischemia failed to stimulate ABCG2 expression in BBB endothelial cells; however, conditioned media from Abeta-activated microglia strongly induced ABCG2 expression. ABCG2 protein in AD/CAA brains interacted and coimmunoprecipitated with Abeta. Overexpression of hABCG2 reduced drug uptake in cells; however, interaction of Abeta(1-40) with ABCG2 impaired ABCG2-mediated drug efflux. The role of Abcg2 in Abeta transport at the BBB was investigated in Abcg2-null and wild-type mice after intravenous injection of Cy5.5-labeled Abeta(1-40) or scrambled Abeta(40-1). Optical imaging analyses of live animals and their brains showed that Abcg2-null mice accumulated significantly more Abeta in their brains than wild-type mice. The finding was confirmed by immunohistochemistry. These results suggest that ABCG2 may act as a gatekeeper at the BBB to prevent blood Abeta from entering into brain. ABCG2 upregulation may serve as a biomarker of CAA vascular pathology in AD patients.
Assuntos
Transportadores de Cassetes de Ligação de ATP/biossíntese , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Barreira Hematoencefálica/metabolismo , Angiopatia Amiloide Cerebral/metabolismo , Proteínas de Neoplasias/biossíntese , Fragmentos de Peptídeos/metabolismo , Regulação para Cima/fisiologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Animais , Barreira Hematoencefálica/patologia , Linhagem Celular , Células Cultivadas , Angiopatia Amiloide Cerebral/genética , Angiopatia Amiloide Cerebral/patologia , Resistência a Múltiplos Medicamentos , Humanos , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Proteínas de Neoplasias/deficiência , Proteínas de Neoplasias/genéticaRESUMO
Toll-like receptor 2 (TLR2) is a primary sensor for pathogens, including those derived from gram-positive bacteria. It can also mediate the effects of endogenous inflammatory signals such as ß-amyloid peptide (Aß), thus promoting the microglial activation and subsequent neuronal dysfunction, characteristic of chronic neuroinflammatory conditions. More recently, a role for TLR2 has been proposed in the pathogenesis of disorders associated with acute inflammation, including anxiety and depression. The current study aims to characterise the acute effects of the TLR2 agonist lipoteichoic acid (LTA) on microglial activation and neuronal integrity, and to evaluate the influence of LTA exposure on sensitivity to the inflammation and neuronal dysfunction associated with Aß. Using BV2 and N2a cells as an in vitro model, we highlight that acute exposure to LTA robustly promotes inflammatory cytokine and nitric oxide (NO) production in microglia but also in neurons, similar to that reported under longer-term and chronic inflammatory conditions. Moreover, we find that exposure to LTA can enhance sensitivity to subthreshold Aß, promoting an 'M1'-like phenotype in microglia and provoking dysregulation of neuronal activity in acute hippocampal slices. Anti-inflammatory agents, including mimetics of brain-derived neurotrophic factor (BDNF), have proven effective at alleviating chronic neuroinflammatory complications. We further examined the effects of 7,8,3-trihydroxyflavone (7,8,3-THF), a small-molecule TrkB agonist, on LTA-induced microglial activation. We report that 7,8,3-THF can significantly ameliorate interleukin (IL)-6 and NO production in LTA-stimulated BV2 cells. Taken together, our findings offer support for exploration of TLR2 as a potential target for therapeutic intervention into acute neuroinflammatory conditions. Moreover we propose that exposure to gram-positive bacterial pathogens may promote sensitivity to the inflammatory changes characteristic of the aged brain.
Assuntos
Inflamação/metabolismo , Inflamação/fisiopatologia , Lipopolissacarídeos/toxicidade , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/fisiopatologia , Ácidos Teicoicos/toxicidade , Receptor 2 Toll-Like/agonistas , Doença Aguda , Peptídeos beta-Amiloides/toxicidade , Animais , Linhagem Celular , Ciclo-Oxigenase 2/metabolismo , Citocinas/metabolismo , Flavonas/farmacologia , Inflamação/induzido quimicamente , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Modelos Teóricos , Doenças do Sistema Nervoso/induzido quimicamente , Neurônios/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Nitritos/metabolismo , Receptor trkB/agonistas , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Alzheimer's disease (AD) is characterized by overproduction of A beta derived from APP cleavage via beta- and gamma-secretase pathway. Recent evidence has linked altered cholesterol metabolism to AD pathogenesis. In this study, we show that AD brain had significant cholesterol retention and high beta- and gamma-secretase activities as compared to age-matched non-demented controls (ND). Over one-half of AD patients had an apoE4 allele but none of the ND. beta- and gamma-secretase activities were significantly stimulated in vitro by 40 and 80 microM cholesterol in AD and ND brains, respectively. Both secretase activities in AD brain were more sensitive to cholesterol (40 microM) than those of ND (80 microM). Filipin-stained cholesterol overlapped with BACE and A beta in AD brain sections. Cholesterol (10-80 microM) added to N2a cultures significantly increased cellular cholesterol, beta- and gamma-secretase activities and A beta secretion. Similarly, addition of cholesterol (20-80 microM) to cell lysates stimulated both in vitro secretase activities. Ergosterol slightly decreased beta-secretase activity at 20-80 microM, but strongly inhibited gamma-secretase activity at 40 microM. Cholesterol depletion reduced cellular cholesterol, beta-secretase activity and A beta secretion. Transcription factor profiling shows that several key nuclear receptors involving cholesterol metabolism were significantly altered in AD brain, including decreased LXR-beta, PPAR and TR, and increased RXR. Treatment of N2a cells with LXR, RXR or PPAR agonists strongly stimulated cellular cholesterol efflux to HDL and reduced cellular cholesterol and beta-/gamma-secretase activities. This study provides direct evidence that cholesterol homeostasis is impaired in AD brain and suggests that altered levels or activities of nuclear receptors may contribute to cholesterol retention which likely enhances beta- and gamma-secretase activities and A beta production in human brain.
Assuntos
Doença de Alzheimer/metabolismo , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/biossíntese , Encéfalo/metabolismo , Colesterol/metabolismo , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Animais , Encéfalo/enzimologia , Encéfalo/patologia , Linhagem Celular Tumoral , Células Cultivadas , Ativação Enzimática/fisiologia , Feminino , Humanos , Masculino , CamundongosRESUMO
Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor composed of HIF-1alpha and HIF-1beta subunits and involved in the regulation of gene expression in adaptive response to hypoxia. This study reports that the inflammatory cytokine interleukin-1beta (IL-1beta) shares common features of other known HIF-1alpha-regulated genes. Both human and mouse IL-1beta genes carry multiple HIF-1-binding sites in their promoter regions and are up-regulated by hypoxia and CoCl2 in human and mouse astrocytes in parallel with up-regulation of HIF-1alpha mRNA and protein. Inhibition of HIF-1alpha degradation by proteasome inhibitor, MG-132, potentiated hypoxia-induced IL-1beta release from human astrocytes, and this response was blocked in the presence of CdCl2. Mouse astrocytes with Hif1alpha+/- genotype demonstrated attenuated up-regulation of both HIF-1alpha and IL-1beta by hypoxia and CoCl2. Mutation of HIF-1-binding sites in the IL-1beta promoter abolished hypoxia-induced transactivation of the reporter gene transfected into human astrocytes. Similarly, HIF-1 binding "decoy" oligonuleotide transfected into astrocytes inhibited both hypoxia-induced transactivation of the HIF-1 reporter gene and IL-1beta secretion from transfected astrocytes. Collectively, the evidence suggests that the transcriptional activation of IL-1beta in astrocytes exposed to hypoxia occurs via HIF-1.
Assuntos
Astrócitos/metabolismo , Regulação da Expressão Gênica/fisiologia , Fator 1 Induzível por Hipóxia/fisiologia , Interleucina-1/metabolismo , Análise de Variância , Animais , Antimutagênicos/farmacologia , Astrócitos/efeitos dos fármacos , Western Blotting/métodos , Hipóxia Celular/fisiologia , Cobalto/farmacologia , Inibidores de Cisteína Proteinase/farmacologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Ensaio de Imunoadsorção Enzimática/métodos , Feto/citologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-1/genética , Leupeptinas/farmacologia , Camundongos , Camundongos Transgênicos , Modelos Biológicos , Mutagênese/fisiologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Fatores de Tempo , Transfecção/métodos , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
OBJECTIVE: Children with severe obesity have greater risk of adverse health outcomes. The purpose of this study was to assess trends in the prevalence of morbid and severe obesity in Australian children between 1985 and 2012. METHODS: Secondary analysis of four national Australian cross-sectional surveys of measured height/weight in 7-15 year olds: Australian Health and Fitness Survey 1985 (n = 8,486), National Nutrition Survey 1995 (n = 1,541), the National Children's Nutrition and Physical Activity Survey 2007 (n = 2,585) and the National Health Survey 2012 (n = 2,940). International Obesity Taskforce cut-point was used for morbid obesity (equivalent to a BMI ≥35kg/m2 at age 18 years). Severe obesity class 2 was defined as BMI ≥120% and <140% of the 95th percentile of the CDC 2000 growth charts or a BMI ≥35 and <40, and severe obesity class 3 as BMI ≥140% of the 95th percentile or a BMI ≥40. RESULTS: Between 1985 and 2012 the prevalence of morbid obesity increased from 0.2% to 1.8%, class 2 severe obesity from 0.3% to 2.0%, and class 3 from 0.1% to 0.5%. Children with morbid obesity represented 11.3% of children with obesity in 1985 and increased to 22.5% in 2012 (P = 0.005). Children with severe obesity represented 19.3% of children with obesity in 1985 and increased to 32.0% in 2012 (P = 0.016). The greatest increase was observed between 1995 and 2007. The proportion of children who were classified as morbidly or severely obese was not significantly different between 2007 and 2012, nor was it significantly different between age and sex groups. CONCLUSION: Prevalence of morbid and severe obesity among children is low, but has significantly increased between 1985 and 2012. In contrast to overweight and obese children, children with morbid obesity require tertiary intervention. Failure to treat these children will have significant implications for the individual child and community.
Assuntos
Obesidade Mórbida/epidemiologia , Adolescente , Austrália/epidemiologia , Índice de Massa Corporal , Criança , Humanos , PrevalênciaRESUMO
BACKGROUND: Aß transport (flux) across the blood-brain barrier (BBB) is thought to contribute to the pathogenesis of Alzheimer's disease as well as to elimination of toxic amyloid from the brain by immunotherapy. Several BBB transporters have been implicated in Aß exchange between brain parenchyma and the circulation, including efflux transporters P-glycoprotein/ABCB1 and BCRP/ABCG2. Here we describe an application of in vivo optical imaging methods to study Aß transport across the BBB in wild-type or animals deficient in specific efflux transporters. METHODS/DESIGN: Synthetic human Aß1-40 or scrambled Aß40-1 peptides were labeled with the near-infrared fluorescent tracer, Cy5.5. The free tracer or Cy5.5-labeled peptides were injected intravenously into Abcb1-KO or Abcg2-KO mice or their corresponding wild-type controls. The animals were imaged prospectively at different time points over a period of 8 hours using eXplore Optix small animal imager. At the end of the observation, animals were sacrificed by perfusion, their brains were imaged ex-vivo and sectioned for immunofluorescence analyses. DISCUSSION: After appropriate circulation time, the fluorescence concentration in the head ROI measured in vivo was close to background values in both wild-type and Abcb1-KO or Abcg2-KO mice injected with either free dye or scrambled Aß40-1-Cy5.5. In animals injected with Aß1-40-Cy5.5, the deficiency in either Abcb1 or Abcg2 resulted in significant increases in fluorescence concentration in the head ROIs 2 hours after injection compared to wild-type animals. Fluorescence decay (elimination rate) over 2-8 hours after injection was similar between wild-type (t1/2 = 1.97 h) and Abcg2-KO (t1/2 = 2.34 h) and was slightly faster (t1/2 = 1.38 h) in Abcb1-KO mice. In vivo time-domain imaging method allows prospective, dynamic analyses of brain uptake/elimination of fluorescently-labeled compounds, including Aß. Deficiency of either of the two major efflux pumps, Abcb1 and Abcg2, implicated in Aß trafficking across the BBB, resulted in increased accumulation of peripherally-injected Aß1-40 in the brain.