Molecular Basis for Defining the Pineal Gland and Pinealocytes as Targets for Tumor Necrosis Factor

The pineal gland, the gland that translates darkness into an endocrine signal by releasing melatonin at night, is now considered a key player in the mounting of an innate immune response. Tumor necrosis factor (TNF), the first pro-inflammatory cytokine to be released by an inflammatory response, suppresses the translation of the key enzyme of melatonin synthesis (arylalkylamine-N-acetyltransferase, Aanat). Here, we show that TNF receptors of the subtype 1 (TNF-R1) are expressed by astrocytes, microglia, and pinealocytes. We also show that the TNF signaling reduces the level of inhibitory nuclear factor kappa B protein subtype A (NFKBIA), leading to the nuclear translocation of two NFKB dimers, p50/p50, and p50/RelA. The lack of a transactivating domain in the p50/p50 dimer suggests that this dimer is responsible for the repression of Aanat transcription. Meanwhile, p50/RelA promotes the expression of inducible nitric oxide synthase (iNOS) and the production of nitric oxide, which inhibits adrenergically induced melatonin production. Together, these data provide a mechanistic basis for considering pinealocytes a target of TNF and reinforce the idea that the suppression of pineal melatonin is one of the mechanisms involved in mounting an innate immune response

The influence of HIV infection on the natural history of hepatocellular carcinoma: results from a global multi-cohort study

Purpose. Conflicting evidence indicates HIV-seropositivity to influence the outcome of patients with hepatocellular carcinoma (HCC), a leading cause of mortality in people with HIV. We aimed to verify whether HIV affected the overall survival (OS) of patients with HCC independent of treatment and geographic origin. Patients and Methods: We designed an international multi-cohort study of HCC patients who did not receive any anticancer treatment accrued from four continents. We estimated the effect of HIV-seropositivity on patients’ OS while accounting for common prognostic factors and demographic characteristics in uni- and multi-variable models. Results: A total of 1588 patients were recruited, 132 of whom were HIV-positive. Most patients clustered within Barcelona Clinic Liver Cancer (BCLC) C/D criteria (n=1168, 74%), Child-Turcotte-Pugh (CTP) Class B (median score 7, IQR 3). At HCC diagnosis the majority of HIV-positive patients (n=65, 64%) had been on anti-retrovirals for a median duration of 8.3 years (IQR 8.59) and had median CD4+ cell counts of 256 (IQR 284) with undetectable HIV RNA (n=68, 52%). OS significantly reduced throughout BCLC stages 0-D (16, 12, 7.5, 3.1 and 3 months, p<0.001). Median OS of HIV-positive patients was half that of HIV-uninfected counterparts: 2.2 months, (bootstrap 95%CI 1.2-3.1) versus 4.1 months (95%CI 3.6-4.4). In adjusted analyses HIV-seropositivity increased the hazard of death by 24% (p=0.0333) independent of BCLC (p<0.0001), CTP (p<0.0001), alpha-fetoprotein (AFP) (p<0.0001), geographical origin (p<0.0001) and male gender (p=0.0016). Predictors of worse OS in HIV-positive patients included CTP (p=0.0071) and AFP (p<0.0001). Conclusions. Despite adequate antiretroviral treatment, HIV-seropositivity is associated with decreased survival in HCC independent of stage, anti-cancer treatment and geographical origin. Mechanistic studies investigating the immuno-biology of HIV-associated HCC are urgently required

Glia-Pinealocyte Network: The Paracrine Modulation of Melatonin Synthesis by Tumor Necrosis Factor (TNF)

The pineal gland, a circumventricular organ, plays an integrative role in defense responses. The injury-induced suppression of the pineal gland hormone, melatonin, which is triggered by darkness, allows the mounting of innate immune responses. We have previously shown that cultured pineal glands, which express toll-like receptor 4 (TLR4) and tumor necrosis factor receptor 1 (TNFR1), produce TNF when challenged with lipopolysaccharide (LPS). Here our aim was to evaluate which cells present in the pineal gland, astrocytes, microglia or pinealocytes produced TNF, in order to understand the interaction between pineal activity, melatonin production and immune function. Cultured pineal glands or pinealocytes were stimulated with LPS. TNF content was measured using an enzyme-linked immunosorbent assay. TLR4 and TNFR1 expression were analyzed by confocal microscopy. Microglial morphology was analyzed by immunohistochemistry. In the present study, we show that although the main cell types of the pineal gland (pinealocytes, astrocytes and microglia) express TLR4, the production of TNF induced by LPS is mediated by microglia. This effect is due to activation of the nuclear factor kappa B (NF-kB) pathway. In addition, we observed that LPS activates microglia and modulates the expression of TNFR1 in pinealocytes. As TNF has been shown to amplify and prolong inflammatory responses, its production by pineal microglia suggests a glia-pinealocyte network that regulates melatonin output. The current study demonstrates the molecular and cellular basis for understanding how melatonin synthesis is regulated during an innate immune response, thus our results reinforce the role of the pineal gland as sensor of immune status

Serotonergic system - Interactions with the circadian timing system.

Componente essencial do sistema de temporização circadiano, o núcleo supraquiasmático (NSQ) possui três aferências principais: o trato retinohipotalâmico (TRH), o trato geniculohipotalâmico (TGH) e as terminações serotonérgicas da rafe. Suas células possuem oscilação circadiana autônoma que resultam na expressão rítmica dos chamados genes do relógio. O presente estudo analisa as concentrações de 5-HT nos núcleos da rafe e NSQ de ratos em livre-curso e mostra que somente os núcleos obscuro e linear apresentam ritmos endógenos com ação determinante do ciclo claro-escuro na no ritmo diário; compara a organização intrínseca do NSQ de primatas e roedores, mostrando organização diferenciada dos terminais serotonérgicos e do TGH em relação aos do TRH sugerindo funções diferentes dessas aferências no NSQ de primatas. Além disso, o padrão de expressão dos genes do relógio no NSQ do primata ao longo do período de atividade mostrou que os genes BMAL1 e Per1 apresentam pico de expressão ao redor do ZT2 e o gene Per2 no ZT7. Os dados demonstram diferenças interespecíficas importantes nas características neuroquímicas e moleculares do NSQ.Essential component of the circadian timing system, the suprachiasmatic nucleus (SCN) receives dense retinohypothalamic RHT, geniculohypothalamic tract GHT and serotonergic innervation arriving from the raphe nuclei. SCN has pacemaker cells that produce rhythmic expression of clock genes. This study investigates the levels of 5-HT in the raphe nuclei and SCN in free running rats and shows endogenous rhythms in the obscurus and linear raphe nuclei, which is regulated by the daily light: dark cycle rhythms. The comparative analysis of the intrinsic structure of the SCN of primates and rodents shows a different organizational pattern of serotonergic and GHT terminals and the RHT terminals, suggesting different actions of serotonin and neuropeptide Y in the control of circadian rhythmicity in primates. Moreover, the pattern of the clock genes SCN expression along the awaken period in the primates show that BMAL1 and Per1 RNAm peaks of expression occur around ZT2 and Per2 around ZT7. These data suggest that the neural organization of the circadian timing system in the studied primate differ from those of the most commonly studied rodents

Sono-vigília, aspectos de memória e melatonina em Síndrome de Williams-Beuren: uma revisão de literatura

A S&#237;ndrome de Williams-Beuren, dist&#250;rbio gen&#233;tico (microdele&#231;&#227;o na regi&#227;o cromoss&#244;mica 7q11.23), apresenta como fen&#243;tipo aparente habilidade social que contrasta com o mau funcionamento cognitivo global e visuo-espacial, problemas na forma receptiva, estrutural e sem&#226;ntica da comunica&#231;&#227;o, al&#233;m de d&#233;ficits na aten&#231;&#227;o, hiperatividade e na mem&#243;ria visuoespacial. Outra caracteristica s&#227;o desordens no ciclo sono-vig&#237;lia, com sono ineficaz, resist&#234;ncia em ir para a cama, acordares durante a noite e sonol&#234;ncia durante o dia. Uma possibilidade ainda n&#227;o explorada nesta s&#237;ndrome seria o padr&#227;o anormal na s&#237;ntese de melatonina, horm&#244;nio capaz de modular a qualidade do sono. Considerando que a qualidade do sono &#233; diretamente influenciada pelos n&#237;veis de melatonina e que tanto a melatonina quanto o sono s&#227;o essenciais para o desenvolvimento adequado das fun&#231;&#245;es cognitivas, buscou-se nesta revis&#227;o de literatura quais estudos investigaram separadamente e ou correlacionaram estes tr&#234;s aspectos (melatonina, sono-vig&#237;lia e mem&#243;ria) na s&#237;ndrome de Williams-Beuren. Para busca, foram utilizadas as bases de dados Medline/Pubmed, SciELO e Lilacs, com os seguintes descritores: "Williams Beuren syndrome, s&#237;ndrome de Williams Beuren, memory, mem&#243;ria, sleep-wake, sono-vig&#237;lia, melatonin e melatonina", por meio de cruzamento e com o conectivo AND. O levantamento bibliogr&#225;fico mostrou que n&#227;o existem na literatura trabalhos que correlacionaram estas tr&#234;s vari&#225;veis entre si nem tampouco trabalhos que investigaram a melatonina na s&#237;ndrome de Williams-Beuren. As investiga&#231;&#245;es sobre sono assim como as investiga&#231;&#245;es sobre mem&#243;ria s&#227;o criticamente discutidas neste trabalho que ressalta a necessidade de estudos que correlacionem estes par&#226;metros, bem como outros fatores comportamentais, cognitivos e bioqu&#237;micos a eles relacionados

Deglutição orofaríngea na insuficiência renal crônica

RESUMO Objetivo: Caracterizar o perfil de deglutição orofaríngea em indivíduos com insuficiência renal crônica (IRC). Métodos: Estudo clínico transversal do qual participaram 20 indivíduos adultos com diagnóstico médico de IRC, durante o período de internação hospitalar. A avaliação objetiva da deglutição foi realizada por videofluoroscopia de deglutição (VFD), sendo a caracterização e classificação dos achados baseada em parâmetros de eficácia e segurança. Além disso, foi aplicada a Functional Oral Intake Scale (FOIS). Resultados: A análise da VFD mostrou que 16indivíduos apresentaram alteração de fase oral e faríngea, três indivíduos apresentaram alterações somente de fase faríngea e um indivíduo apresentou alterações exclusivas de fase oral da deglutição. Além disso, por meio da VFD foi constatada penetração e aspiração laringotraqueal em 30% dos indivíduos. Previamente à realização da VFD, foi verificado que quatro indivíduos (20%) encontravam-se no nível 5 da FOIS, enquanto 16 indivíduos (80%) encontravam-se no nível 7. Após as adequações de alteração da consistência da dieta via oral devido aos prejuízos de segurança e à eficiência da deglutição, a classificação da FOIS passou a representar 6 indivíduos no nível 1, 7 no nível 4, 4 no nível 5 e 3 no nível 6. Conclusão: A caracterização do perfil de deglutição orofaríngea em indivíduos com IRC mostrou alterações de fase oral e faríngea, inclusive com penetração e aspiração laringotraqueal, com necessidade de mudanças no nível de ingestão oral

Correlation between sleep and quality of life in cerebral palsy

PURPOSE: To investigate and correlate the sleep pattern and quality of life in individuals with cerebral palsy (CP) compared to healthy controls. METHODS: Seventy-eight subjects (aged 4-18 years, both genders) comprised two groups: CP, composed of 43 individuals with CP, and control, composed of 35 individuals without neurodevelopmental disorders. General Sleep Habits Questionnaire, Sleep Disturbance Scale for Children, sleep diary, Child Health Questionnaire, and Children's Quality of Life Scale were used. RESULTS: This study identified that 60.5% individuals with CP had sleep disorders. The respiratory disorders (25.6%) and the sleep hyperhidrosis (34.9%) were the most common disturbances in the group with CP. Moreover, 23.2% individuals of the group with CP reported awaking in the middle of the night and 37.2% of them snore, both percentages were higher than those in the control group. The sleep diary showed that individuals in the group with CP spend more time to initiate sleep (around 21 minutes). The group with CP also showed deficits in all parameters analyzed by the Child Health Questionnaire, except in family activity and the sleep-wake pattern, and quality of life showed negative correlation in several respects. CONCLUSION: The altered pattern of sleep in individuals with CP directly affects their physical and emotional well-being.OBJETIVO: Investigar e correlacionar o padrão sono-vigília e a qualidade de vida na paralisia cerebral (PC). MÉTODOS: Setenta e oito indivíduos, de 4 a 18 anos de idade, de ambos os gêneros, compuseram dois grupos: PC, composto por 43 indivíduos com PC; e controle, com 35 indivíduos sem distúrbios no neurodesenvolvimento. Os procedimentos utilizados foram: Questionário de Hábitos de Sono, Escala de Distúrbios do Sono em Crianças, Diário de sono, Questionário de Saúde da Criança e Escala de Qualidade de Vida da Criança. RESULTADOS: Identificou-se que 60,5% dos indivíduos com PC apresentaram distúrbios do sono, sendo os mais comuns, os respiratórios e a hiperhidrose do sono, com 25,6 e 34,9%, respectivamente. Além disso, 23,2% dos indivíduos do grupo PC acordam no meio da noite e 37,2% deles roncam, percentuais estes maiores do que os do grupo controle. O Diário de sono mostrou que os indivíduos do grupo PC demoraram mais para iniciar o sono (em média 21 minutos) do que o grupo controle. Quanto à qualidade de vida, o grupo PC apresentou déficit em todos os parâmetros analisados, exceto em atividade familiar e os distúrbios de sono encontrados e a qualidade de vida indicaram correlação negativa na maioria dos parâmetros. CONCLUSÕES: O padrão de sono alterado nos PCs afeta diretamente aspectos do seu bem-estar físico e emocional.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP

Correlation between sleep and quality of life in cerebral palsy

PURPOSE: To investigate and correlate the sleep pattern and quality of life in individuals with cerebral palsy (CP) compared to healthy controls. METHODS: Seventy-eight subjects (aged 4-18 years, both genders) comprised two groups: CP, composed of 43 individuals with CP, and control, composed of 35 individuals without neurodevelopmental disorders. General Sleep Habits Questionnaire, Sleep Disturbance Scale for Children, sleep diary, Child Health Questionnaire, and Children's Quality of Life Scale were used. RESULTS: This study identified that 60.5% individuals with CP had sleep disorders. The respiratory disorders (25.6%) and the sleep hyperhidrosis (34.9%) were the most common disturbances in the group with CP. Moreover, 23.2% individuals of the group with CP reported awaking in the middle of the night and 37.2% of them snore, both percentages were higher than those in the control group. The sleep diary showed that individuals in the group with CP spend more time to initiate sleep (around 21 minutes). The group with CP also showed deficits in all parameters analyzed by the Child Health Questionnaire, except in family activity and the sleep-wake pattern, and quality of life showed negative correlation in several respects. CONCLUSION: The altered pattern of sleep in individuals with CP directly affects their physical and emotional well-being