Cerebrospinal fluid cortisol and clinical disease progression in MCI and dementia of Alzheimer's type.

Increased peripheral and central nervous system cortisol levels have been reported in Alzheimer's disease (AD) and may reflect dysfunction of cerebral components of the hypothalamic-pituitary-adrenal (HPA) axis. However, brain exposure to high cortisol concentrations may also accelerate disease progression and cognitive decline. The objectives of this study were to investigate whether HPA-axis dysregulation occurs at early clinical stages of AD and whether plasma and CSF cortisol levels are associated with clinical disease progression. Morning plasma and CSF cortisol concentrations were obtained from the subjects with AD dementia, mild cognitive impairment of AD type (MCI-AD), MCI of other type (MCI-O), and controls with normal cognition included in a multicenter study from the German Dementia Competence Network. A clinical and neuropsychological follow-up was performed in a subgroup of participants with MCI-AD, MCI-O, and AD dementia. CSF cortisol concentrations were increased in the subjects with AD dementia or MCI-AD compared with subjects with MCI-O or normal cognition. After controlling for possible confounders including CSF measures of amyloid beta1-42 and total tau, higher baseline CSF cortisol levels were associated with faster clinical worsening and cognitive decline in MCI-AD. The findings suggest that HPA-axis dysregulation occurs at the MCI stage of AD and may accelerate disease progression and cognitive decline.

Expression and functional role of the prorenin receptor in the human adrenocortical zona glomerulosa and in primary aldosteronism.

OBJECTIVES: Prorenin can be detected in plasma of hypertensive patients. If detected in patients with primary aldosteronism could implicate prorenin in the development of primary aldosteronism. To address this issue, we measured the plasma prorenin levels in primary aldosteronism patients, the expression of the prorenin receptor (PRR) in the normal human adrenocortical zona glomerulosa and aldosterone-producing adenoma (APA), and we investigated the functional effects of PRR activation in human adrenocortical cells. METHOD: Plasma renin activity, aldosterone, and active and total trypsin-activated renin were measured in primary aldosteronism patients, essential hypertensive patients, and healthy individuals, and then prorenin levels were calculated. Localization and functional role of PRR were investigated in human and rat tissues, and aldosterone-producing cells. RESULTS: Primary aldosteronism patients had detectable plasma levels of prorenin. Using digital-droplet real-time PCR, we found a high PRR-to-porphobilinogen deaminase ratio in both the normal adrenal cortex and APAs. Marked expression of the PRR gene and protein was also found in HAC15 cells. Immunoblotting, confocal, and immunogold electron microscopy demonstrated PRR at the cell membrane and intracellularly. Renin and prorenin significantly triggered both CYP11B2 expression (aldosterone synthase) and ERK1/2 phosphorylation, but only CYP11B2 transcription was prevented by aliskiren. CONCLUSION: The presence of detectable plasma prorenin in primary aldosteronism patients, and the high expression of PRR in the normal human adrenal cortex, APA tissue, CD56+ aldosterone-producing cells, along with activation of CYP11B2 synthesis and ERK1/2 phosphorylation, suggest that the circulating and locally produced prorenin may contribute to the development or maintenance of human primary aldosteronism.

The CXCR4/CXCR7/CXCL12 Axis Is Involved in a Secondary but Complex Control of Neuroblastoma Metastatic Cell Homing.

Neuroblastoma (NB) is one of the most deadly solid tumors of the young child, for which new efficient and targeted therapies are strongly needed. The CXCR4/CXCR7/CXCL12 chemokine axis has been involved in the progression and organ-specific dissemination of various cancers. In NB, CXCR4 expression was shown to be associated to highly aggressive undifferentiated tumors, while CXCR7 expression was detected in more differentiated and mature neuroblastic tumors. As investigated in vivo, using an orthotopic model of tumor cell implantation of chemokine receptor-overexpressing NB cells (IGR-NB8), the CXCR4/CXCR7/CXCL12 axis was shown to regulate NB primary and secondary growth, although without any apparent influence on organ selective metastasis. In the present study, we addressed the selective role of CXCR4 and CXCR7 receptors in the homing phase of metastatic dissemination using an intravenous model of tumor cell implantation. Tail vein injection into NOD-scid-gamma mice of transduced IGR-NB8 cells overexpressing CXCR4, CXCR7, or both receptors revealed that all transduced cell variants preferentially invaded the adrenal gland and typical NB metastatic target organs, such as the liver and the bone marrow. However, CXCR4 expression favored NB cell dissemination to the liver and the lungs, while CXCR7 was able to strongly promote NB cell homing to the adrenal gland and the liver. Finally, coexpression of CXCR4 and CXCR7 receptors significantly and selectively increased NB dissemination toward the bone marrow. In conclusion, CXCR4 and CXCR7 receptors may be involved in a complex and organ-dependent control of NB growth and selective homing, making these receptors and their inhibitors potential new therapeutic targets.

Mid-gut ACTH-secreting neuroendocrine tumor unmasked with (18)F-dihydroxyphenylalanine-positron emission tomography.

Ectopic ACTH Cushing's syndrome (EAS) is often caused by neuroendocrine tumors (NETs) of lungs, pancreas, thymus, and other less frequent locations. Localizing the source of ACTH can be challenging. A 64-year-old man presented with rapidly progressing fatigue, muscular weakness, and dyspnea. He was in poor condition and showed facial redness, proximal amyotrophy, and bruises. Laboratory disclosed hypokalemia, metabolic alkalosis, and markedly elevated ACTH and cortisol levels. Pituitary was normal on magnetic resonance imaging (MRI), and bilateral inferior petrosal sinus blood sampling with corticotropin-releasing hormone stimulation showed no significant central-to-periphery gradient of ACTH. Head and neck, thoracic and abdominal computerized tomography (CT), MRI, somatostatin receptor scintigraphy (SSRS), and (18)F-deoxyglucose-positron emission tomography (FDG-PET) failed to identify the primary tumor. (18)F-dihydroxyphenylalanine (F-DOPA)-PET/CT unveiled a 20-mm nodule in the jejunum and a metastatic lymph node. Segmental jejunum resection showed two adjacent NETs, measuring 2.0 and 0.5 cm with a peritoneal metastasis. The largest tumor expressed ACTH in 30% of cells. Following surgery, after a transient adrenal insufficiency, ACTH and cortisol levels returned to normal values and remain normal over a follow-up of 26 months. Small mid-gut NETs are difficult to localize on CT or MRI, and require metabolic imaging. Owing to low mitotic activity, NETs are generally poor candidates for FDG-PET, whereas SSRS shows poor sensitivity in EAS due to intrinsically low tumor concentration of type-2 somatostatin receptors (SST2) or to receptor down regulation by excess cortisol. However, F-DOPA-PET, which is related to amine precursor uptake by NETs, has been reported to have high positive predictive value for occult EAS despite low sensitivity, and constitutes a useful alternative to more conventional methods of tumor localization. LEARNING POINTS: Uncontrolled high cortisol levels in EAS can be lethal if untreated.Surgical excision is the keystone of NETs treatment, thus tumor localization is crucial.Most cases of EAS are caused by NETs, which are located mainly in the lungs. However, small gut NETs are elusive to conventional imaging and require metabolic imaging for detection.FDG-PET, based on tumor high metabolic rate, may not detect NETs that have low mitotic activity. SSRS may also fail, due to absent or low concentration of SST2, which may be down regulated by excess cortisol.F-DOPA-PET, based on amine-precursor uptake, can be a useful method to localize the occult source of ACTH in EAS when other methods have failed.

Catecholamine metabolism in paraganglioma and pheochromocytoma: similar tumors in different sites?

Pheochromocytoma (PHEO) and paraganglioma (PGL) are catecholamine-producing neuroendocrine tumors that arise respectively inside or outside the adrenal medulla. Several reports have shown that adrenal glucocorticoids (GC) play an important regulatory role on the genes encoding the main enzymes involved in catecholamine (CAT) synthesis i.e. tyrosine hydroxylase (TH), dopamine β-hydroxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT). To assess the influence of tumor location on CAT metabolism, 66 tissue samples (53 PHEO, 13 PGL) and 73 plasma samples (50 PHEO, 23 PGL) were studied. Western blot and qPCR were performed for TH, DBH and PNMT expression. We found a significantly lower intra-tumoral concentration of CAT and metanephrines (MNs) in PGL along with a downregulation of TH and PNMT at both mRNA and protein level compared with PHEO. However, when PHEO were partitioned into noradrenergic (NorAd) and mixed tumors based on an intra-tumoral CAT ratio (NE/E >90%), PGL and NorAd PHEO sustained similar TH, DBH and PNMT gene and protein expression. CAT concentration and composition were also similar between NorAd PHEO and PGL, excluding the use of CAT or MNs to discriminate between PGL and PHEO on the basis of biochemical tests. We observed an increase of TH mRNA concentration without correlation with TH protein expression in primary cell culture of PHEO and PGL incubated with dexamethasone during 24 hours; no changes were monitored for PNMT and DBH at both mRNA and protein level in PHEO and PGL. Altogether, these results indicate that long term CAT synthesis is not driven by the close environment where the tumor develops and suggest that GC alone is not sufficient to regulate CAT synthesis pathway in PHEO/PGL.

Urinary and plasma catecholamines and metanephrines in dogs with pheochromocytoma, hypercortisolism, nonadrenal disease and in healthy dogs.

BACKGROUND: Diagnosis of pheochromocytoma (PC) is based on a combination of clinical suspicion, finding an adrenal mass, increased plasma, and urine concentrations of catecholamine metabolites and is finally confirmed with histopathology. In human medicine, it is controversial whether biochemically testing plasma is superior to testing urine. OBJECTIVES: To measure urinary and plasma catecholamines and metanephrines in healthy dogs, dogs with PC, hypercortisolism (HC), and nonadrenal diseases (NAD) and to determine the test with the best diagnostic performance for dogs with PC. ANIMALS: Seven PC dogs, 10 dogs with HC, 14 dogs with NAD, 10 healthy dogs. METHODS: Prospective diagnostic clinical study. Urine and heparin plasma samples were collected and stored at -80°C before analysis using high-pressure liquid chromatography (HPLC) coupled to electrochemical detection or tandem mass spectrometry were performed. Urinary variables were expressed as ratios to urinary creatinine concentration. RESULTS: Dogs with PC had significantly higher urinary normetanephrine and metanephrine : creatinine ratios and significantly higher plasma-total and free normetanephrine and plasma-free metanephrine concentrations compared to the 3 other groups. There were no overlapping results of urinary normetanephrine concentrations between PC and all other groups, and only one PC dog with a plasma normetanephrine concentration in the range of the dogs with HC and NAD disease. Performances of total and free plasma variables were similar. Overlap of epinephrine and norepinephrine results between the groups was large with both urine and plasma. CONCLUSION AND CLINICAL IMPORTANCE: Measurement of normetanephrine is the preferred biochemical test for PC and urine was superior to plasma.

Estimativa dos impactos econômicos decorrentes de eventual introdução do huanglongbing (HLB) no estado da Bahia

A Bahia é o segundo mais importante Estado produtor de citros do Brasil, responsável por 5,5% da produção do País. 80% da produção vem de propriedades de base familiar, as quais dependem desse cultivo para seu sustento econômico. O Huanglongbing (HLB) nunca foi registrado na Bahia, mas está disseminando-se em outros três Estados do Brasil (São Paulo, Paraná e Minas Gerais), um dos quais faz fronteira com a Bahia. Assim, este estudo teve como objetivo estimar o impacto econômico potencial de uma eventual introdução do HLB na Bahia. Foram utilizados os modelos de Gompertz e logístico associados a diferentes estratos de idade das plantas para estimar, respectivamente, a evolução da incidência e da severidade da doença no parque citrícola baiano, num horizonte de 20 anos. O progresso da doença foi usado para estimar os danos à produção em três cenários. No cenário-base (A), os esforços da agência estadual de defesa agropecuária previniria a entrada do HLB. No cenário B, a doença seria introduzida e não haveria esforços para seu controle, levando a uma disseminação nos anos seguintes. No cenário C, após a detecção da doença, os produtores adotariam medidas de controle: eliminação de plantas sintomáticas e supressão das populações do inseto vetor. Os custos do controle foram calculados considerando-se a necessidade de pulverizações, inspeções periódicas e eliminação das plantas doentes. O valor presente líquido (VPL) foi usado para comparar os três cenários. Os resultados indicam que as perdas seriam muito significativas caso o HLB fosse introduzido na Bahia. Assim sendo, se as medidas de controle não fossem aplicadas, os prejuízos poderiam superar R$1,8 bilhão.

Central serous chorioretinopathy: Recent findings and new physiopathology hypothesis.

Central serous chorioretinopathy (CSCR) is a major cause of vision threat among middle-aged male individuals. Multimodal imaging led to the description of a wide range of CSCR manifestations, and highlighted the contribution of the choroid and pigment epithelium in CSCR pathogenesis. However, the exact molecular mechanisms of CSCR have remained uncertain. The aim of this review is to recapitulate the clinical understanding of CSCR, with an emphasis on the most recent findings on epidemiology, risk factors, clinical and imaging diagnosis, and treatments options. It also gives an overview of the novel mineralocorticoid pathway hypothesis, from animal data to clinical evidences of the biological efficacy of oral mineralocorticoid antagonists in acute and chronic CSCR patients. In rodents, activation of the mineralocorticoid pathway in ocular cells either by intravitreous injection of its specific ligand, aldosterone, or by over-expression of the receptor specifically in the vascular endothelium, induced ocular phenotypes carrying many features of acute CSCR. Molecular mechanisms include expression of the calcium-dependent potassium channel (KCa2.3) in the endothelium of choroidal vessels, inducing subsequent vasodilation. Inappropriate or over-activation of the mineralocorticoid receptor in ocular cells and other tissues (such as brain, vessels) could link CSCR with the known co-morbidities observed in CSCR patients, including hypertension, coronary disease and psychological stress.

Agricultural land use and human presence around breeding sites increase stress-hormone levels and decrease body mass in barn owl nestlings.

Human activities can have a suite of positive and negative effects on animals and thus can affect various life history parameters. Human presence and agricultural practice can be perceived as stressors to which animals react with the secretion of glucocorticoids. The acute short-term secretion of glucocorticoids is considered beneficial and helps an animal to redirect energy and behaviour to cope with a critical situation. However, a long-term increase of glucocorticoids can impair e.g. growth and immune functions. We investigated how nestling barn owls (Tyto alba) are affected by the surrounding landscape and by human activities around their nest sites. We studied these effects on two response levels: (a) the physiological level of the hypothalamus-pituitary-adrenal axis, represented by baseline concentrations of corticosterone and the concentration attained by a standardized stressor; (b) fitness parameters: growth of the nestlings and breeding performance. Nestlings growing up in intensively cultivated areas showed increased baseline corticosterone levels late in the season and had an increased corticosterone release after a stressful event, while their body mass was decreased. Nestlings experiencing frequent anthropogenic disturbance had elevated baseline corticosterone levels, an increased corticosterone stress response and a lower body mass. Finally, breeding performance was better in structurally more diverse landscapes. In conclusion, anthropogenic disturbance affects offspring quality rather than quantity, whereas agricultural practices affect both life history traits.

O valor da ressonância magnética na detecção de nódulos hepáticos utilizando-se diversas técnicas ponderadas em T2: existe consenso?

Desde o início da década de 80 a ressonância magnética vem sendo utilizada para o estudo do abdome e principalmente na detecção de nódulos hepáticos. As imagens ponderadas em T2 são as que trouxeram maior benefício quando comparadas à tomografia computadorizada com contraste. Inúmeras técnicas e seqüências de ressonância magnética ponderadas em T2 surgiram desde então, na tentativa de aumentar a eficácia diagnóstica, com menores tempos de exame. Neste sentido, foram publicados inúmeros trabalhos demonstrando a utilidade de seqüências rápidas e ultra-rápidas, com e sem supressão de gordura, em apnéia, com sincronizador respiratório e com bobinas de sinergia, entre outros avanços tecnológicos. No entanto, não há um consenso sobre qual a técnica mais apropriada e sensível para a detecção de lesões hepáticas focais. Neste artigo fazemos uma revisão bibliográfica e análise crítica das diversas técnicas de imagens ponderadas em T2, no que diz respeito às suas sensibilidades na detecção de nódulos hepáticos.

Angiografia por ressonância magnética: aspectos técnicos de um método de estudo vascular não-invasivo

As primeiras técnicas de angiografia por ressonância magnética (angio-RM) utilizavam seqüências sensíveis ao fluxo sanguíneo para estabelecimento do contraste vascular. Há três técnicas fundamentadas neste princípio: contraste de fase ("phase-contrast"), TOF ("time-of-flight") e as técnicas de sangue escuro ("black blood"). Estas seqüências, de aquisição demorada, são mais suscetíveis a artefatos de movimento, perda de sinal em áreas de estenoses ou turbilhonamento de fluxo, e apresentam ainda baixa sensibilidade à detecção do fluxo lento. O uso do contraste paramagnético para estudos angiográficos pela ressonância magnética ofereceu um método simples, rápido e de excelente detalhamento vascular, baseando o contraste da imagem no realce do sinal vascular em oposição à supressão dos demais tecidos. Metodologias modernas que priorizam a obtenção do espaço k central, responsável pelo contraste da imagem, e o aperfeiçoamento das técnicas de planejamento do intervalo temporal para aquisição dos dados foram fatores fundamentais para o aprimoramento técnico da angio-RM. O papel atual da angio-RM como ferramenta diagnóstica merece destaque na avaliação de anomalias anatômicas, estenoses, oclusões e complicações vasculares pós-cirúrgicas, principalmente nos casos de transplantes de órgãos. Suas principais vantagens estão na não utilização do contraste iodado ou radiação ionizante, rapidez e fácil execução, mínima invasividade e possibilidade de avaliar complementarmente o parênquima de órgãos adjacentes de interesse diagnóstico.

Emprego da tomografia computadorizada na detecção de alterações das adrenais em doentes com tuberculose

Neste estudo foram avaliadas, por meio de tomografia computadorizada, as adrenais em indivíduos sem tuberculose (grupo 1 - G1) e com tuberculose (grupo 2 - G2). A dimensão ântero-posterior, a espessura e o comprimento das adrenais foram comparados no G1 e no G2. Foram também avaliadas a duração da doença com a ocorrência de alteração morfológica no G2, e a distribuição segundo o sexo, a idade e a cor da pele no G1 e no G2. Neste estudo houve diferença nas dimensões ântero-posterior e espessura da adrenal direita entre o G1 e o G2. Observou-se maior ocorrência do sexo masculino e de indivíduos de pele branca no G2. Não houve associação entre a duração da doença e a ocorrência de alteração morfológica no G2. Maior ocorrência da alteração morfológica tipo alargamento foi observada no G2. Os principais achados pela tomografia computadorizada, nos pacientes com tuberculose, foram alargamento da adrenal sem calcificação, alargamento da adrenal com calcificação puntiforme e calcificação de aspecto residual da adrenal.

Aspectos técnicos da ressonância magnética de mama com meio de contraste: revisão da literatura

Com a difusão do uso de meios de contraste, avanços na tecnologia das bobinas de superfície e desenvolvimento de protocolos rápidos de aquisição de imagens, a ressonância magnética (RM) de mama com meio de contraste tem-se mostrado importante modalidade na detecção, diagnóstico e estadiamento do câncer de mama. Apesar desses avanços, existem alguns pontos não consensuais no que diz respeito aos aspectos técnicos e critérios de interpretação de imagem da RM contrastada de mama. Neste artigo fazemos revisão bibliográfica dos parâmetros de interpretação de imagens e aspectos técnicos da RM de mama, incluindo considerações sobre a "performance" do equipamento, bobinas de radiofreqüência dedicadas, modo de utilização de contraste paramagnético, técnicas de supressão de gordura, planos de aquisição, seqüências de pulso e fontes de artefato.

Prevalência de artefatos em exames de ressonância magnética do abdome utilizando a seqüência GRASE: comparável com as melhores seqüências rápidas?

OBJETIVO: Determinar a freqüência global de artefatos na seqüência "gradient and spin echo" (GRASE), por tipo e grau do artefato, em exames de ressonância magnética de abdome; realizar comparação entre as seqüências GRASE e duas seqüências TSE previamente selecionadas como aquelas com melhor relação sinal-ruído e menor incidência de artefatos. MATERIAIS E MÉTODOS: Foi realizado estudo prospectivo, autopareado, em 86 pacientes submetidos a ressonância magnética de abdome superior, sendo adquiridas a seqüência GRASE com sincronizador respiratório e supressão de gordura e seis seqüências TSE ponderadas em T2. Dentre as seis seqüências TSE, foram previamente selecionadas aquelas com melhor relação sinal-ruído e menor número de artefatos, que foram as realizadas com supressão de gordura e com sincronizador respiratório, sendo uma com bobina de corpo (seqüência 1) e outra com bobina de sinergia (seqüência 2). A análise das imagens foi realizada por dois observadores em consenso, quanto a presença, grau e tipo de artefato. Posteriormente os dados foram analisados estatisticamente, através do teste de Friedman e do qui-quadrado. RESULTADOS: A freqüência absoluta de artefatos nas seqüências utilizadas foi de 65,02%. Os artefatos mais encontrados nas três seqüências estudadas foram os de respiração (30%) e de pulsação (33%). Apenas 3% dos casos apresentaram algum tipo de artefato que dificultava a análise das imagens. As freqüências de artefatos nas diversas seqüências foram: GRASE, 67,2%; seqüência TSE 1, 62,2%; seqüência TSE 2, 65,5%. Não houve diferença estatisticamente significante na freqüência de artefatos encontrados nas seqüências GRASE e nas seqüências TSE (p = 0,845; NS). CONCLUSÃO: As seqüências GRASE e TSE ponderadas em T2 com sincronizador respiratório e com supressão de gordura, independentemente da bobina utilizada, apresentam freqüentemente artefatos, porém com incidência semelhante e geralmente sem interferência na avaliação das imagens.