Ophthalmoplegic Migraine and Infundibular Dilatation of a Cerebral Artery

Ophthalmoplegic migraine (OM) is a childhood disorder of uncertain etiology manifesting recurrent unilateral headache associated with a transitory oculomotor (usually IIIrd nerve) palsy. Recent publications emphasize the finding on MRI of contrast enhancement in the IIIrd nerve suggesting that OM may be a recurrent inflammatory neuropathy. We report the case of a 7-year-old boy with typical symptoms of this disorder. Angio MR and Angio CT revealed the presence of an infundibular dilatation of a perforating branch of the posterior cerebral artery adjacent to the symptomatic IIIrd nerve. We speculate that this and perhaps other cases of OM may have a different pathophysiology related to compression of the IIIrd nerve by an adjacent vascular structure that could activate the trigeminovascular system and produce migrainous pain

Serum amyloid A proteins reduce bone mass during mycobacterial infections

IntroductionOsteopenia has been associated to several inflammatory conditions, including mycobacterial infections. How mycobacteria cause bone loss remains elusive, but direct bone infection may not be required. MethodsGenetically engineered mice and morphometric, transcriptomic, and functional analyses were used. Additionally, inflammatory mediators and bone turnover markers were measured in the serum of healthy controls, individuals with latent tuberculosis and patients with active tuberculosis. Results and discussionWe found that infection with Mycobacterium avium impacts bone turnover by decreasing bone formation and increasing bone resorption, in an IFN gamma- and TNF alpha-dependent manner. IFN gamma produced during infection enhanced macrophage TNF alpha secretion, which in turn increased the production of serum amyloid A (SAA) 3. Saa3 expression was upregulated in the bone of both M. avium- and M. tuberculosis-infected mice and SAA1 and 2 proteins (that share a high homology with murine SAA3 protein) were increased in the serum of patients with active tuberculosis. Furthermore, the increased SAA levels seen in active tuberculosis patients correlated with altered serum bone turnover markers. Additionally, human SAA proteins impaired bone matrix deposition and increased osteoclastogenesis in vitro. Overall, we report a novel crosstalk between the cytokine-SAA network operating in macrophages and bone homeostasis. These findings contribute to a better understanding of the mechanisms of bone loss during infection and open the way to pharmacological intervention. Additionally, our data and disclose SAA proteins as potential biomarkers of bone loss during infection by mycobacteria.This article is a result of the project HEALTH-UNORTE: Setting-up biobanks and regenerative medicine strategies to boost research in cardiovascular, musculoskeletal, neurological, oncological, immunological and infectious diseases (NORTE-01-0145-FEDER-000039), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). This work was supported by KOG-202108-00929 from the European Haematology Society, awarded to AG. Work in the MS lab was financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operacional Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT - Fundacao para a Ciencia e a Tecnologia/Ministerio da Ciencia, Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-028955 (PTDC/SAU-INF/28955/2017). AG and MS are supported by an Individual Scientific Employment contract (CEECIND/00048/2017; CEECIND/00241/2017 respectively). DS acknowledges the Portuguese Foundation for Science and Technology (FCT) for the Post-Doc fellowship (SFRH/BPD/115341/2016). RP, DS and AF have PhD grants (SFRH/BD/145217/2019; SFRH/BD/143536/2019; 2020.05949.BD, respectively) financed by FCT

The fate of steroid estrogens: Partitioning during wastewater treatment and onto river sediments

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2010 Springer Science+Business Media B.V.The partitioning of steroid estrogens in wastewater treatment and receiving waters is likely to influence their discharge to, and persistence in, the environment. This study investigated the partitioning behaviour of steroid estrogens in both laboratory and field studies. Partitioning onto activated sludge from laboratory-scale Husmann units was rapid with equilibrium achieved after 1 h. Sorption isotherms and Kd values decreased in the order 17α-ethinyl estradiol > 17α-estradiol > estrone > estriol without a sorption limit being achieved (1/n >1). Samples from a wastewater treatment works indicated no accumulation of steroid estrogens in solids from primary or secondary biological treatment, however, a range of steroid estrogens were identified in sediment samples from the River Thames. This would indicate that partitioning in the environment may play a role in the long-term fate of estrogens, with an indication that they will be recalcitrant in anaerobic conditions.EPSR

Ectopic Cushing's Syndrome Unveiling a Metastatic Parotid Carcinoma

Introduction. Adrenocorticotropic hormone (ACTH) ectopic production is a rare cause of Cushing syndrome (CS). The most commonly associated tumours are small-cell lung carcinoma along with bronchial and thymic carcinoids. To date, only 5 cases have been published in the literature featuring ectopic ACTH secretion from metastatic acinic cell carcinoma (ACC) of the parotid gland. We hereby describe a very uncommon case of ectopic CS (ECS) unveiling a metastatic parotid ACC. Case Presentation. A 46-year-old man with hypertension and dyslipidemia diagnosed 4-months before, as well as new-onset diabetes mellitus unveiled 1-month earlier, was referred to emergency department for hypokalemia. Hormonal study and dynamic biochemical tests performed indicated ECS. Imaging and cytological findings pointed toward a likely primary right parotid malignancy with liver metastases. Somatostatin receptor scintigraphy has shown an increased uptake in the parotid gland and mild expression in liver metastasis. The patient underwent right parotidectomy, and histopathologic examination confirmed ACC. Meanwhile, hypercortisolism was managed with metyrapone, ketoconazole, and lanreotide. Despite chemotherapy onset, a rapid disease progression and clinical course deterioration was observed. Conclusion. The present report highlights a rare ECS, exposing a metastatic parotid ACC, with an aggressive and challenging clinical course, representing the first case whose diagnosis of ECS came prior to ACC

Astrocyte-derived TNF and glutamate critically modulate microglia activation by methamphetamine

Methamphetamine (Meth) is a powerful illicit psychostimulant, widely used for recreational purposes. Besides disrupting the monoaminergic system and promoting oxidative brain damage, Meth also causes neuroinflammation, contributing to synaptic dysfunction and behavioral deficits. Aberrant activation of microglia, the largest myeloid cell population in the brain, is a common feature in neurological disorders triggered by neuroinflammation. In this study, we investigated the mechanisms underlying the aberrant activation of microglia elicited by Meth in the adult mouse brain. We found that binge Meth exposure caused microgliosis and disrupted risk assessment behavior (a feature that usually occurs in individuals who abuse Meth), both of which required astrocyte-to-microglia crosstalk. Mechanistically, Meth triggered a detrimental increase of glutamate exocytosis from astrocytes (in a process dependent on TNF production and calcium mobilization), promoting microglial expansion and reactivity. Ablating TNF production, or suppressing astrocytic calcium mobilization, prevented Meth-elicited microglia reactivity and re-established risk assessment behavior as tested by elevated plus maze (EPM). Overall, our data indicate that glial crosstalk is critical to relay alterations caused by acute Meth exposure.This work was financed by FEDER—Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Portugal 2020, and by Portuguese funds through FCT— Fundação para a Ciência e a Tecnologia/Ministério da Ciência (FCT), Tecnologia e Ensino Superior in the framework of the project POCI-01-0145-FEDER-030647 (PTDC/ SAU-TOX/30647/2017) in TS lab. FEDER Portugal (Norte-01-0145-FEDER000008000008—Porto Neurosciences and Neurologic Disease Research Initiative at I3S, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF); FCOMP-01-0124-FEDER-021333). CCP and RS hold employment contracts financed by national funds through FCT –in the context of the program-contract described in paragraphs 4, 5, and 6 of art. 23 of Law no. 57/ 2016, of August 29, as amended by Law no. 57/2017 of July 2019. TC, TOA, AFT, JB, AIS and AM were supported by FCT (SFRH/BD/117148/2016, SFRH/BD/147981/2019, 2020.07188.BD, PD/BD/135450/2017, SFRH/BD/144324/2019, and IF/00753/2014). Work in JBR lab was supported by the FCT project PTDC/ MED-NEU/31318/2017. JFO was also supported by FCT projects PTDC/MED-NEU/31417/2017 and POCI-01- 0145-FEDER-016818; Bial Foundation Grants 207/14 and 037/18, by National funds, through FCT - project UIDB/50026/2020; and by the projects NORTE-01-0145-FEDER000013 and NORTE-01-0145-FEDER-000023, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Funding of i3S Scientific Platforms: Advanced Light Microscopy (ALM), a member of the national infrastructure PPBI-Portuguese Platform of BioImaging (POCI-01–0145-FEDER022122); and Genomics through GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by FCT

Human paraoxonase gene polymorphisms and coronary artery disease risk.

Introdução: As doenças complexas como a doença das artérias coronárias (DAC), a hipertensão e a diabetes, são usualmente causadas pela susceptibilidade individual a múltiplos genes, factores ambientais e pela interacção entre eles. As enzimas da paraoxonase humana (PON), particularmente a PON1, têm sido implicadas na patogenia da aterosclerose e da DAC. Dois polimorfismos comuns na região codificante do gene, com substituição Glutamina (Q) /Arginina (R) na posição 192 e Leucina /Metionina na posição 55 influenciam a actividade da PON1. Vários estudos têm investigado a associação entre os polimorfismos da PON1 e a DAC, com resultados contraditórios. Objectivo: 1- Avaliar a associação dos polimorfismos da PON1 com o risco de DAC. 2-Estudar a interacção destes polimorfismos com outros situados em genes candidatos diferentes, na susceptibilidade para o aparecimento da DAC. Material e Métodos: Estudámos em 298 doentes coronários e 298 controlos saudáveis, através de um estudo caso/controlo, o risco de DAC associado aos polimorfismos da PON1, 192Q/R e 55L/M. Numa segunda fase avaliámos o risco das interacções polimórficas PON1 192 RR + MTHFR 1298 AA; PON1 192 R/R + ECA DD; PON1 192 R/R + ECA 8 GG. Finalmente construímos um modelo de regressão logística (no qual entraram todas as variáveis genéticas, ambientais e bioquímicas, que tinham mostrado significância estatística na análise univariada), para determinar quais as que se relacionavam de forma significativa e independente com DAC. Resultados: Verificámos que o genótipo PON1 55 MM tinha uma distribuição superior na população doente mas não atingia significância estatística como factor de risco para DAC. O PON1 199 RR apresentou um risco relativo 80% superior relativamente à população que o não possuía (p=0,04). A interacção da PON1 192 RR e da MTHFR 1298 AA, polimorfismos sedeados em genes diferentes, apresentou um risco relativo de DAC de 2,76 (OR=2,76;IC=1,20- 6,47; P=0,009), bastante superior ao risco de cada polimorfismo isolado, assim como a associação da PON1 RR + ECA DD (com polimorfismos também sedeados em genes diferentes), que apresentou um risco 337% superior relativamente aos que não possuíam esta associação (OR=4,37;IC=1,47- 13,87; P=0,002). Da mesma forma a associação entre a PON1 RR e ECA 8 GG, revelou um risco ainda mais elevado (OR=6;23; IC=1,67- 27,37; P<0,001). Após modelo de Regressão Logística as variáveis que ficaram na equação representando factores de risco significativos e independentes para DAC, foram os hábitos tabágicos, doença familiar, diabetes, fibrinogénio, Lp (a) e a associação PON1 192 RR + ECA 8 GG. Esta última associação apresentou, na regressão logística, um OR=14,113; p=0,018 Conclusões: O genótipo PON1 192 RR apresentou, se avaliado isoladamente, um risco relativo de DAC 80% superior relativamente à população que não possuía este genótipo. A associação deste polimorfismo com outros polimorfismos sedeados em genes diferentes, codificando para diferentes enzimas e pertencendo a sistemas fisiopatológicos distintos (MTHFR1298 AA, ECA DD e ECA 8 GG), aumentou sempre o risco de eclosão da DAC. Após correcção para os outros factores de risco clássicos e bioquímicos, a associação PON1 192 RR + ECA 8 GG, continuou a ser um factor de risco significativo e independente para CAD.BACKGROUND: Complex diseases such as coronary artery disease (CAD), hypertension and diabetes are usually caused by individual susceptibility to multiple genes, environmental factors, and the interaction between them. The paraoxonase 1 (PON1) enzyme has been implicated in the pathogenesis of atherosclerosis and CAD. Two common polymorphisms in the coding region of the PON1 gene, which lead to a glutamine (Q)/arginine (R) substitution at position 192 and a leucine (L)/methionine (M) substitution at position 55, influence PON1 activity. Studies have investigated the association between these polymorphisms and CAD, but with conflicting results. AIMS: 1) To evaluate the association between PON1 polymorphisms and CAD risk; and 2) to study the interaction between PON1 polymorphisms and others in different candidate genes. METHODS: We evaluated the risk of CAD associated with PON1 Q192R and L55M polymorphisms in 298 CAD patients and 298 healthy individuals. We then evaluated the risk associated with the interaction of the PON1 polymorphisms with ACE DD, ACE 8 GG and MTHFR 1298AA. Finally, using a logistic regression model, we evaluated which variables (genetic, biochemical and environmental) were linked significantly and independently with CAD. RESULTS: We found that the PON1 55MM genotype was more common in the CAD population, but this did not reach statistical significance as a risk factor for CAD, while PON1 192RR presented an 80% higher relative risk compared to the population without this polymorphism. The interaction between PON1 192RR and MTHFR 1298AA, sited in different genes, increased the risk for CAD, compared with the polymorphisms in isolation (OR=2.76; 95% CI=1.20-6.47; p=0.009), as did the association of PON1 192RR with ACE DD, which presented a 337% higher risk compared to the population without this polymorphic association (OR=4.37; 95% CI=1.47-13.87; p=0.002). Similarly, the association between PON1 192RR and ACE 8 GG was linked to an even higher risk (OR=6.23; 95% CI=1.67-27.37; p<0.001). After logistic regression, smoking, family history, fibrinogen, diabetes, Lp(a) and the association of PON1 192RR + ACE 8 GG remained in the regression model and proved to be significant and independent risk factors for CAD. In the regression model the latter association had OR=14.113; p=0.018. CONCLUSION: When analyzed separately, the PON1 192RR genotype presented a relative risk for CAD 80% higher than in the population without this genotype. Its association with other genetic polymorphisms sited in different genes, coding for different enzymes and belonging to different physiological systems, always increased the risk for CAD. After correction for other conventional and biochemical risk factors, the PON1 192RR + ACE 8 GG association remained a significant and independent risk factor for CAD.info:eu-repo/semantics/publishedVersio

Gene-gene interaction affects coronary artery disease risk.

Introdução: Existem vários estudos que comparam doentes coronários e controlos, no sentido de determinar quais os polimorfismos que apresentam risco acrescido de doença das artérias coronárias (DC). Os seus resultados têm sido muitas vezes contraditórios, mas apresentam uma limitação suplementar: avaliam os polimorfismos um a um, quando na natureza os polimorfismos não existem isolados. Põe-se a questão se serão mais importantes associações de polimorfismos mutados no mesmo gene ou em genes diferentes. Objectivo: Com o presente trabalho pretendemos avaliar o risco da associação de polimorfismos em termos de aparecimento de DC no mesmo gene ou em genes diferentes. Metodologia: Estudámos em 298 doentes coronários e 298 controlos sãos o risco associado aos polimorfismos (genótipos considerados de risco), DD da Enzima de Converaão da Angiotensina (ECA) I/D; GG da ECA 8, MM do Angiotensinogénio (AGT) 174; TT do AGT 235; TT da Metiltetrahidrofolato Reductase (MTHFR) 677; AA da MTHFR 1298;RR da Paraoxonase1 (PON1) 192 e MM da PON1 55. Posteriormente avaliámos o risco ligado às associações no mesmo gene (DD da ECA + GG da ECA 8; MM do AGT174 + TT do AGT 235; TT da MTHFR 677 + AA da MTHFR 1298). Finalmente, nos polimorfismos que isoladamente apresentavam significância, avaliámos o risco das associações de polimorfismos a níveis funcionais diferentes (ECA + AGT; ECA + MTHFR; ECA + PON1. Finalmente através de um modelo de regressão logística fomos determinar quais as variáveis que se relacionavam de forma significativa e independente com a DC. Resultados: Os polimorfismos isolados como: ECA DD [P<0.0001], ECA 8 GG [P=0,023], e MTHFR 1298 AA [P=0,049]), apresentaram uma frequência mais elevada nos casos, associando-se de forma significativa ao grupo com DC. A associação de polimorfismos no mesmo gene não teve efeito sinergístico ou aditivo e não aumentou o risco de DC. A associação polimórfica em genes diferentes aumentou o risco de DC quando comparada com o risco do polimorfismo isolado. No caso da associação da ECA DD ou ECA 8 GG com a PON1 192 RR, o risco quadruplicou (OR passou de 1,8 para 4,2). Após regressão logística o hábito tabágico, a história familiar, o fibrinogénio, diabetes, a associação ECA DD ou ECA 8 GG com a MTHFR 1298 AA e a interacção ECA DD ou ECA 8 GG com a PON1 192 RR permaneceram na equação, mostrando ser factores de risco independente para DC. Conclusões: A associação de polimorfismos mutados no mesmo gene nunca aumentou o risco do polimorfismo isolado. A associação com interacção de polimorfismos mutados em genes diferentes, pertencentes a sistemas fisiopatológicos e enzimáticos diferentes, esteve sempre associada a maior risco do que cada polimorfismo por si. Este trabalho levanta, pela primeira vez, a possibilidade de tentativa de compreensão do risco genético coronário em conjunto e não de cada polimorfismo por si.INTRODUCTION: Various studies have compared coronary artery disease (CAD) patients with controls in order to determine which polymorphisms are associated with a higher risk of disease. The results have often been contradictory. Moreover, these studies evaluated polymorphisms in isolation and not in association, which is the way they occur in nature. OBJECTIVE: Our purpose was to evaluate the risk of CAD in patients with associated polymorphisms in the same gene or in differen genes. METHODS: We evaluated the risk associated with ACE DD, ACE 8 CC, ACT 174MM, AGT 235TT, MTHFR 677TT, MTHFR 1298AA, PON1 192RR and PON1 55MM in 298 CAD patients and 298 healthy individuals. We then evaluated the risk of associated polymorphisms in the same gene (ACE DD + ACE 8GG; AGT 174MM + AGT 235TT; MTHFR 677TT + MTHFR 1298AA). Finally, for the isolated polymorphisms which were significant, we evaluated the risk of polymorphism associations at different functional levels (ACE + AGT; ACE + MTHFR; ACE + PON1). Multiple logistic regression was used to identify independent risk factors for CAD. RESULTS: Isolated polymorphisms including ACE DD(p < 0.0001), ACE 8 gg (p=0.023), and MTHFR 1298AA (p = 0.049) presented with a significantly higher frequency in the CAD group. An association of polymorphisms in the same gene did not have an additive or synergistic effect, nor did it increase the risk of CAD. Polymorphic associations in different genes increased the risk of CAD, compared with the isolated polymorphisms. The association of ACE DD or ACE 8 GG with PON1 192RR increased the risk of CA fourfold (1.8 to 4.2). After logistic regression analysis, current smoking, family history, fibrinogen, diabetes, and the ACE DD or ACE 8 GG + MTHFR 1298AA and ACE DD or ACE 8 GG + PON1 192RR associations remained in the, model and proved to be independent predictors of CAD. CONCLUSIONS: The association of polymorphisms in the same gene did not increase the risk of the isolated polymorphism. The association of polymorphisms in genes belonging to different enzyme systems was always linked to increased risk compared to the isolated polymorphisms. This study may contribute to a better understanding of overall genetic risk for CAD rather than that associated with each polymorphism in isolation.info:eu-repo/semantics/publishedVersio

Economic Activity of Firms and Asset Prices

In this review we survey the recent research on the fundamental determinants of stock returns. These studies explore how firms' systematic risk and their investment and production decisions are jointly determined in equilibrium. Models with production provide insights into several types of empirical patterns, including (a) the correlations between firms' economic characteristics and their risk premia, (b) the comovement of stock returns among firms with similar characteristics, and (c) the joint dynamics of asset returns and macroeconomic quantities. Moreover, by explicitly relating firms' stock returns and cash flows to fundamental shocks, models with production connect the analysis of financial markets with the research on the origins of macroeconomic fluctuations

Blood Pressure Variability in Acute Ischemic Stroke: The Role of Early Recanalization

We performed a retrospective study with the aim of investigating the association between blood pressure (BP) variability in the first 24 h after ischemic stroke and functional outcome, regarding arterial recanalization status. A total of 674 patients diagnosed with acute stroke and treated with revascularization therapies were enrolled. Systolic and diastolic BP values of the first 24 h after stroke were collected and their variation quantified through standard deviation. Recanalization state was evaluated at 6 h and clinical outcome at 3 months was assessed by modified Rankin Scale. In multivariate analyses systolic BP variability in the first 24 h post-stroke showed an association with 3 months clinical outcome in the whole population and non-recanalyzed patients. In recanalyzed patients, BP variability did not show a significant association with functional outcome.info:eu-repo/semantics/publishedVersio