Alexandra Dias - Academia.edu (original) (raw)

Papers by Alexandra Dias

A proporção de imigrantes nos concelhos de Amadora e Sintra atinge um dos valores mais elevados d... more A proporção de imigrantes nos concelhos de Amadora e Sintra atinge um dos valores mais elevados do país. A equidade na prestação de cuidados tem sido demonstrada como factor de redução das disparidades na saúde que determina a morbilidade e a mortalidade decorrentes da assimetria das populações. Objectivos do estudo -Definir a prevalência dos filhos de imigrantes dos concelhos de Amadora e Sintra; analisar as famílias quanto ao país de origem, integração e procura dos serviços de saúde; avaliar as crianças nos primeiros meses de vida quanto à morbilidade e mortalidade; relacionar as características do contexto físico e social com a saúde/doença. Metodologia -A população estudada é constituída por 1979 nados-vivos e 10 nados-mortos, cujo nascimento ou admissão na sala de partos ocorreu no Hospital Fernando Fonseca (HFF). Resultados -As famílias dos recém-nascidos dos concelhos de Amadora e Sintra que nasceram no HFF são, genericamente, mais privadas sociomaterialmente do que a população da Área Metropolitana de Lisboa e as dos imigrantes estão, ainda, em situação de maior desvantagem. A fragilidade/vulnerabilidade dos imigrantes revela-se nos maus resultados em saúde. Houve maior mortalidade fetal e neonatal e mais patologia durante a gravidez, nomeadamente de doenças infecciosas. Conclusões -Os resultados deste estudo poderão contribuir para reflectir sobre a reorganização dos serviços de cuidados de saúde e para repensar processos de planeamento e modelos de intervenção que culminem numa integração de sucesso nas comunidades imigrantes.

BMJ case reports, 2015

Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome, mainly characterised b... more Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome, mainly characterised by dysregulated immune activation. The syndrome is related to a genetic cause, in the classic primary form, or to identified triggers such as infections, malignancy or rheumatological processes, in the classic secondary form. Epstein-Barr virus (EBV) is the most common agent implicated in hereditary and non-hereditary conditions. We describe a 23-month-old girl who experienced severe clinical deterioration with respiratory distress due a bilateral pleural effusion within the first week of primary EBV infection. Fever, generalised oedema and hepatosplenomegaly, along with a pruritic morbilliform erythematous rash, were the first clinical signs. Respiratory impairment followed with hypoxaemia and the patient was admitted to the intensive care unit for thoracocentesis. Further investigation showed persistent bicytopaenia, hypertriglyceridaemia, hyperferritinaemia and elevated α chain of inte...

The Journal of Infectious Diseases

Journal of immunology (Baltimore, Md. : 1950), 2006

A powerful IFN-gamma response is triggered upon infection with the protozoan parasite, Toxoplasma... more A powerful IFN-gamma response is triggered upon infection with the protozoan parasite, Toxoplasma gondii. Several cell populations, including dendritic cells (DCs), macrophages, and neutrophils, produce IL-12, a key cytokine for IFN-gamma induction. However, it is still unclear which of the above cell populations is its main source. Diphtheria toxin (DT) injection causes transient DC depletion in a transgenic mouse expressing Simian DT receptors under the control of the CD11c promoter, allowing us to investigate the role of DCs in IL-12 production. T. gondii-inoculated DT-treated and control groups were monitored for IL-12 levels and survival. We show in this study that DC depletion abolished IL-12 production and led to mortality. Furthermore, replenishment with wild-type, but not MyD88- or IL-12p35-deficient, DCs rescued IL-12 production, IFN-gamma-induction, and resistance to infection in DC-depleted mice. Taken together, the results presented in this study indicate that DCs const...

Molecular Immunology, 2008

Pediatric Pulmonology, 2014

Children and adolescents with sickle cell disease (SCD) have a higher incidence of sleep patholog... more Children and adolescents with sickle cell disease (SCD) have a higher incidence of sleep pathology and obstructive sleep apnea syndrome (OSAS). The nocturnal hypoxemia is a risk to vaso-occlusive crisis among other SCD morbidities. Our aim was to compare polysomnography (PSG) results in a sample of children with SCD with a sample of children with suspected OSAS without SCD. A retrospective study compared clinical and PSG parameters. A descriptive analysis and t-test were done considering P < 0.05 as significant. PSG was done in 65 children with SCD and 65 control-children. Control sample was selected to be equal to SCD sample considering gender (53.8% were male), age (mean age was 9.4 years (SD ± 4.6) and AHI (mean 3.57 events/hr). Mean efficiency, latency and percentage of sleep phases in both groups showed no statistically significant differences. Mean SpO2 and minimum SpO2 were lower in SCD group and it was statistically significant (P < 0.01). Enuresis was more frequent in the SCD children group (35.4% vs. 6.2%, P < 0.01). Comparing children with and without SCD, sleep architecture was similar in both groups and minimum SpO2 was significantly lower in SCD children although both groups had a similar AHI. This is an important issue in these children, so it is essential to have a sleep evaluation in order to prevent complications and co-morbidities. Pediatr Pulmonol. © 2014 Wiley Periodicals, Inc.

Case Reports, 2011

on behalf of the SAA-WP of the EBMT The diagnosis of aplastic anemia in children requires exclusi... more on behalf of the SAA-WP of the EBMT The diagnosis of aplastic anemia in children requires exclusion of a variety of inherited or acquired BM failure syndromes with similar phenotypes. An efficient diagnostic plan is important because time from diagnosis to 'final' treatment is directly related to outcome regardless of the therapeutic option chosen. The gold standard of therapy remains hematopoietic SCT with a graft of BM cells for those children with matched sibling donors. Conversely for children without a sibling donor the high response and markedly improved overall survival rates of combined immunosuppressive therapy have proven robust, especially when horse derived anti-thymocyte globuline plus ciclosporine A are used. Incomplete response, relapse and progression to myelodysplasia/ leukemia however have emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Regardless of the type of therapeutic approach, patients require centralized treatment in a center of excellence, ongoing monitoring for recurrence of disease and/or therapy-related immediate side effects and long-term effects.

Scandinavian Journal of Immunology, 2001

Bonato VLD, Medeiros AI, Lima VMF, Dias AR, Faccioli LH, Silva CL. Downmodulation of CD18 and CD8... more Bonato VLD, Medeiros AI, Lima VMF, Dias AR, Faccioli LH, Silva CL. Downmodulation of CD18 and CD86 on Macrophages and VLA-4 on Lymphocytes in Experimental Tuberculosis. Scand J Immunol 2001;54:564±573 Development and evaluation of new vaccines and immunotherapy against tuberculosis demand a better understanding of the immune mechanisms in this disease. Costimulatory signals and intercellular contact seem to be pivotal in determining whether recognition of antigen by T cells leads to activation or anergy. In this paper, we show that virulent M. tuberculosis H37Rv downmodulates the ex vivo expression of CD18 and CD86 on peritoneal macrophages and VLA-4 on lymphocytes but does not disturb the in vitro production of interleukin (IL)-12 and interferon (IFN)-g after intraperitoneal infection. In addition, splenocytes from infected mice produce IL-10, while the expression of cell surface receptors is unchanged. The interplay among IL-12, IFN-g and IL-10 in vivo and the downmodulation of cell-surface receptors during the infection at the inflammatory site may contribute to the explanation of the maintenance of infection.

Scandinavian Journal of Immunology, 2002

Histoplasma capsulatum is a fungus found intracellularly in neutrophils and peripheral blood mono... more Histoplasma capsulatum is a fungus found intracellularly in neutrophils and peripheral blood mononuclear cells (PBMCs), suggesting that it is capable of evading damage and survives inside these cells. In this study, we report that neutrophils from H. capsulatum-infected mice, and human neutrophils and mononuclear cells exposed to H. capsulatum presented less apoptosis than those from noninfected animals or cells exposed to medium only. Moreover, cells harvested from infected animals are resistant to apoptosis induced by dexamethasone ± a proapoptotic stimulant. We also show that neutrophils harvested from infected mice and PBMCs from humans exposed to the fungus had a greatly decreased Mac-1 expression. We conclude that H. capsulatum induces an antiapoptotic state on leucocytes, which correlates with decreased cell-surface Mac-1 expression. These facts may represent an escape mechanism for the fungus by delaying cell death and allowing the fungus to survive inside leucocytes.

Journal of the Neurological Sciences, 1997

Journal of Infectious Diseases, 2012

Recent studies have underscored physiological and pathophysiological roles for the tryptophan-deg... more Recent studies have underscored physiological and pathophysiological roles for the tryptophan-degrading enzyme indolamine 2,3-dioxygenase (IDO) in immune counterregulation. However, IDO was first recognized as an antimicrobial effector, restricting tryptophan availability to Toxoplasma gondii and other pathogens in vitro. The biological relevance of these findings came under question when infectious phenotypes were not forthcoming in IDO-deficient mice. The recent discovery of an IDO homolog, IDO-2, suggested that the issue deserved reexamination. IDO inhibition during murine toxoplasmosis led to 100% mortality, with increased parasite burdens and no evident effects on the immune response. Similar studies revealed a counterregulatory role for IDO during leishmaniasis (restraining effector immune responses and parasite clearance), and no evident role for IDO in herpes simplex virus type 1 (HSV-1) infection. Thus, IDO plays biologically important roles in the host response to diverse intracellular infections, but the dominant nature of this roledantimicrobial or immunoregulatorydis pathogen-specific.

Journal of Infectious Diseases, 2012

Journal of Human Genetics, 2008

Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinae... more Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA) n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 ± 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA) 6 /(TA) 6 (n = 37), (TA) 6 /(TA) 7 (n = 60) and (TA) 7 /(TA) 7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age.

Journal of Experimental Medicine, 2008

Innate immune signaling is critical for the development of protective immunity. Such signaling is... more Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LXmediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2 -dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor -associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinfl ammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These fi ndings suggest a new molecular target for drug development for diseases marked by dysregulated infl ammatory responses. on

General and Comparative Endocrinology, 2000

In vivo and in vitro the concentration of vitellogenin (VTG) inside the oocyte can alter VTG prod... more In vivo and in vitro the concentration of vitellogenin (VTG) inside the oocyte can alter VTG production by the liver, modulating the synthesis of 17beta-estradiol (E(2)) by the ovary. To gain a greater insight into this mechanism, the in vitro production of free and conjugated testosterone (T), E(2), and androstenedione (A) by rainbow trout oocytes from the early and middle vitellogenic stage was measured by radioimmunoassay. There was a decreased E(2) production that was greater in September (40%) than October (30%), by the oocytes incubated with the vitellogenic fraction. The production of E(2) conjugated as glucuronide was lower than sulfate (P < 0.05), but similar in control and VTG-incubated oocytes. Levels of free T increased from September to October, and conjugates were both produced at low levels, and no differences were detected between control and incubated VTG oocytes. The decreased synthesis of E(2) by oocytes incubated with VTG was not followed by an increase in the amount of T or conjugated E(2), because there were no differences under the two circumstances. However, there was a reduced synthesis of A with oocytes producing low levels of E(2). These results suggest that the presence of high levels of VTG in the oocyte suppresses the synthesis of A and E(2), affecting the activities of the enzymes C17,20 lyase and aromatase and probably interfering with the heme protein cytochrome P450 which in the ovary catalyses C 17,20 lyase (P450 c17) and aromatase (P450 arom).

European Journal of Immunology, 2014

Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanism... more Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD-1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD-1-deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type-1 cytokine responses (IL-12 and IFN-γ). PD-1 −/− DCs showed no cell intrinsic defect in IL-12 production in vitro. Instead, PD-1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL-10 release, which impaired type-1inflammation during infection. Our results indicate that the absence of PD-1 increases IL-10 production even in the absence of infection. Although the possibility that such increased IL-10 protects against autoimmune damage is speculative, our results show that IL-10 suppresses the development of protective Th1 immune response after T. gondii infection.

A proporção de imigrantes nos concelhos de Amadora e Sintra atinge um dos valores mais elevados d... more A proporção de imigrantes nos concelhos de Amadora e Sintra atinge um dos valores mais elevados do país. A equidade na prestação de cuidados tem sido demonstrada como factor de redução das disparidades na saúde que determina a morbilidade e a mortalidade decorrentes da assimetria das populações. Objectivos do estudo -Definir a prevalência dos filhos de imigrantes dos concelhos de Amadora e Sintra; analisar as famílias quanto ao país de origem, integração e procura dos serviços de saúde; avaliar as crianças nos primeiros meses de vida quanto à morbilidade e mortalidade; relacionar as características do contexto físico e social com a saúde/doença. Metodologia -A população estudada é constituída por 1979 nados-vivos e 10 nados-mortos, cujo nascimento ou admissão na sala de partos ocorreu no Hospital Fernando Fonseca (HFF). Resultados -As famílias dos recém-nascidos dos concelhos de Amadora e Sintra que nasceram no HFF são, genericamente, mais privadas sociomaterialmente do que a população da Área Metropolitana de Lisboa e as dos imigrantes estão, ainda, em situação de maior desvantagem. A fragilidade/vulnerabilidade dos imigrantes revela-se nos maus resultados em saúde. Houve maior mortalidade fetal e neonatal e mais patologia durante a gravidez, nomeadamente de doenças infecciosas. Conclusões -Os resultados deste estudo poderão contribuir para reflectir sobre a reorganização dos serviços de cuidados de saúde e para repensar processos de planeamento e modelos de intervenção que culminem numa integração de sucesso nas comunidades imigrantes.

BMJ case reports, 2015

Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome, mainly characterised b... more Haemophagocytic lymphohistiocytosis (HLH) is a potentially fatal syndrome, mainly characterised by dysregulated immune activation. The syndrome is related to a genetic cause, in the classic primary form, or to identified triggers such as infections, malignancy or rheumatological processes, in the classic secondary form. Epstein-Barr virus (EBV) is the most common agent implicated in hereditary and non-hereditary conditions. We describe a 23-month-old girl who experienced severe clinical deterioration with respiratory distress due a bilateral pleural effusion within the first week of primary EBV infection. Fever, generalised oedema and hepatosplenomegaly, along with a pruritic morbilliform erythematous rash, were the first clinical signs. Respiratory impairment followed with hypoxaemia and the patient was admitted to the intensive care unit for thoracocentesis. Further investigation showed persistent bicytopaenia, hypertriglyceridaemia, hyperferritinaemia and elevated α chain of inte...

The Journal of Infectious Diseases

Journal of immunology (Baltimore, Md. : 1950), 2006

A powerful IFN-gamma response is triggered upon infection with the protozoan parasite, Toxoplasma... more A powerful IFN-gamma response is triggered upon infection with the protozoan parasite, Toxoplasma gondii. Several cell populations, including dendritic cells (DCs), macrophages, and neutrophils, produce IL-12, a key cytokine for IFN-gamma induction. However, it is still unclear which of the above cell populations is its main source. Diphtheria toxin (DT) injection causes transient DC depletion in a transgenic mouse expressing Simian DT receptors under the control of the CD11c promoter, allowing us to investigate the role of DCs in IL-12 production. T. gondii-inoculated DT-treated and control groups were monitored for IL-12 levels and survival. We show in this study that DC depletion abolished IL-12 production and led to mortality. Furthermore, replenishment with wild-type, but not MyD88- or IL-12p35-deficient, DCs rescued IL-12 production, IFN-gamma-induction, and resistance to infection in DC-depleted mice. Taken together, the results presented in this study indicate that DCs const...

Molecular Immunology, 2008

Pediatric Pulmonology, 2014

Children and adolescents with sickle cell disease (SCD) have a higher incidence of sleep patholog... more Children and adolescents with sickle cell disease (SCD) have a higher incidence of sleep pathology and obstructive sleep apnea syndrome (OSAS). The nocturnal hypoxemia is a risk to vaso-occlusive crisis among other SCD morbidities. Our aim was to compare polysomnography (PSG) results in a sample of children with SCD with a sample of children with suspected OSAS without SCD. A retrospective study compared clinical and PSG parameters. A descriptive analysis and t-test were done considering P < 0.05 as significant. PSG was done in 65 children with SCD and 65 control-children. Control sample was selected to be equal to SCD sample considering gender (53.8% were male), age (mean age was 9.4 years (SD ± 4.6) and AHI (mean 3.57 events/hr). Mean efficiency, latency and percentage of sleep phases in both groups showed no statistically significant differences. Mean SpO2 and minimum SpO2 were lower in SCD group and it was statistically significant (P < 0.01). Enuresis was more frequent in the SCD children group (35.4% vs. 6.2%, P < 0.01). Comparing children with and without SCD, sleep architecture was similar in both groups and minimum SpO2 was significantly lower in SCD children although both groups had a similar AHI. This is an important issue in these children, so it is essential to have a sleep evaluation in order to prevent complications and co-morbidities. Pediatr Pulmonol. © 2014 Wiley Periodicals, Inc.

Case Reports, 2011

on behalf of the SAA-WP of the EBMT The diagnosis of aplastic anemia in children requires exclusi... more on behalf of the SAA-WP of the EBMT The diagnosis of aplastic anemia in children requires exclusion of a variety of inherited or acquired BM failure syndromes with similar phenotypes. An efficient diagnostic plan is important because time from diagnosis to 'final' treatment is directly related to outcome regardless of the therapeutic option chosen. The gold standard of therapy remains hematopoietic SCT with a graft of BM cells for those children with matched sibling donors. Conversely for children without a sibling donor the high response and markedly improved overall survival rates of combined immunosuppressive therapy have proven robust, especially when horse derived anti-thymocyte globuline plus ciclosporine A are used. Incomplete response, relapse and progression to myelodysplasia/ leukemia however have emerged as significant long-term issues. Improvements in outcome of alternative donor transplantation and the use of established and novel immunosuppressive agents provide multiple alternatives for treating refractory or relapsed patients. Regardless of the type of therapeutic approach, patients require centralized treatment in a center of excellence, ongoing monitoring for recurrence of disease and/or therapy-related immediate side effects and long-term effects.

Scandinavian Journal of Immunology, 2001

Bonato VLD, Medeiros AI, Lima VMF, Dias AR, Faccioli LH, Silva CL. Downmodulation of CD18 and CD8... more Bonato VLD, Medeiros AI, Lima VMF, Dias AR, Faccioli LH, Silva CL. Downmodulation of CD18 and CD86 on Macrophages and VLA-4 on Lymphocytes in Experimental Tuberculosis. Scand J Immunol 2001;54:564±573 Development and evaluation of new vaccines and immunotherapy against tuberculosis demand a better understanding of the immune mechanisms in this disease. Costimulatory signals and intercellular contact seem to be pivotal in determining whether recognition of antigen by T cells leads to activation or anergy. In this paper, we show that virulent M. tuberculosis H37Rv downmodulates the ex vivo expression of CD18 and CD86 on peritoneal macrophages and VLA-4 on lymphocytes but does not disturb the in vitro production of interleukin (IL)-12 and interferon (IFN)-g after intraperitoneal infection. In addition, splenocytes from infected mice produce IL-10, while the expression of cell surface receptors is unchanged. The interplay among IL-12, IFN-g and IL-10 in vivo and the downmodulation of cell-surface receptors during the infection at the inflammatory site may contribute to the explanation of the maintenance of infection.

Scandinavian Journal of Immunology, 2002

Histoplasma capsulatum is a fungus found intracellularly in neutrophils and peripheral blood mono... more Histoplasma capsulatum is a fungus found intracellularly in neutrophils and peripheral blood mononuclear cells (PBMCs), suggesting that it is capable of evading damage and survives inside these cells. In this study, we report that neutrophils from H. capsulatum-infected mice, and human neutrophils and mononuclear cells exposed to H. capsulatum presented less apoptosis than those from noninfected animals or cells exposed to medium only. Moreover, cells harvested from infected animals are resistant to apoptosis induced by dexamethasone ± a proapoptotic stimulant. We also show that neutrophils harvested from infected mice and PBMCs from humans exposed to the fungus had a greatly decreased Mac-1 expression. We conclude that H. capsulatum induces an antiapoptotic state on leucocytes, which correlates with decreased cell-surface Mac-1 expression. These facts may represent an escape mechanism for the fungus by delaying cell death and allowing the fungus to survive inside leucocytes.

Journal of the Neurological Sciences, 1997

Journal of Infectious Diseases, 2012

Recent studies have underscored physiological and pathophysiological roles for the tryptophan-deg... more Recent studies have underscored physiological and pathophysiological roles for the tryptophan-degrading enzyme indolamine 2,3-dioxygenase (IDO) in immune counterregulation. However, IDO was first recognized as an antimicrobial effector, restricting tryptophan availability to Toxoplasma gondii and other pathogens in vitro. The biological relevance of these findings came under question when infectious phenotypes were not forthcoming in IDO-deficient mice. The recent discovery of an IDO homolog, IDO-2, suggested that the issue deserved reexamination. IDO inhibition during murine toxoplasmosis led to 100% mortality, with increased parasite burdens and no evident effects on the immune response. Similar studies revealed a counterregulatory role for IDO during leishmaniasis (restraining effector immune responses and parasite clearance), and no evident role for IDO in herpes simplex virus type 1 (HSV-1) infection. Thus, IDO plays biologically important roles in the host response to diverse intracellular infections, but the dominant nature of this roledantimicrobial or immunoregulatorydis pathogen-specific.

Journal of Infectious Diseases, 2012

Journal of Human Genetics, 2008

Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinae... more Elevated erythrocyte destruction in sickle cell disease (SCD) results in chronic hyperbilirubinaemia and, in a subset of patients, cholelithiasis occurs. We investigated whether the (TA) n promoter polymorphism in the UDP-glucuronosyltransferase 1A1 gene (UGT1A1) may modify bilirubin metabolism, influencing bilirubinaemia, predisposition to cholelithiasis and subsequent cholecystectomy, in a group of 153 young SCD patients (mean age 12.0 ± 9.0 years) predominantly of Bantu beta S haplotype. The concomitant effect of alpha thalassaemia was also analysed. Among the several UGT1A1 genotypes found, the most frequent were the (TA) 6 /(TA) 6 (n = 37), (TA) 6 /(TA) 7 (n = 60) and (TA) 7 /(TA) 7 (n = 29). These groups of patients did not significantly differ in age, gender ratio and haemoglobin, foetal haemoglobin and reticulocyte levels. On the other hand, total bilirubin levels were significantly different between groups, with an increased (TA) repeat number being associated with higher bilirubinaemia. Furthermore, both cholelithiasis and cholecystectomy were more frequent in groups with higher (TA) repeat number, although the former association was not statistically significant. None of the mentioned parameters is statistically different within UGT1A1 groups with the presence of alpha thalassaemia. Thus, the UGT1A1 promoter polymorphism may represent an important nonglobin genetic modifier of Bantu SCD patients' clinical manifestations, even at a young age.

Journal of Experimental Medicine, 2008

Innate immune signaling is critical for the development of protective immunity. Such signaling is... more Innate immune signaling is critical for the development of protective immunity. Such signaling is, perforce, tightly controlled. Lipoxins (LXs) are eicosanoid mediators that play key counterregulatory roles during infection. The molecular mechanisms underlying LXmediated control of innate immune signaling are of interest. In this study, we show that LX and aspirin (ASA)-triggered LX (ATL) inhibit innate immune signaling by inducing suppressor of cytokine signaling (SOCS) 2 -dependent ubiquitinylation and proteasome-mediated degradation of TNF receptor -associated factor (TRAF) 2 and TRAF6, which are adaptor molecules that couple TNF and interleukin-1 receptor/Toll-like receptor family members to intracellular signaling events. LX-mediated degradation of TRAF6 inhibits proinfl ammatory cytokine production by dendritic cells. This restraint of innate immune signaling can be ablated by inhibition of proteasome function. In vivo, this leads to dysregulated immune responses, accompanied by increased mortality during infection. Proteasomal degradation of TRAF6 is a central mechanism underlying LX-driven immune counterregulation, and a hitherto unappreciated mechanism of action of ASA. These fi ndings suggest a new molecular target for drug development for diseases marked by dysregulated infl ammatory responses. on

General and Comparative Endocrinology, 2000

In vivo and in vitro the concentration of vitellogenin (VTG) inside the oocyte can alter VTG prod... more In vivo and in vitro the concentration of vitellogenin (VTG) inside the oocyte can alter VTG production by the liver, modulating the synthesis of 17beta-estradiol (E(2)) by the ovary. To gain a greater insight into this mechanism, the in vitro production of free and conjugated testosterone (T), E(2), and androstenedione (A) by rainbow trout oocytes from the early and middle vitellogenic stage was measured by radioimmunoassay. There was a decreased E(2) production that was greater in September (40%) than October (30%), by the oocytes incubated with the vitellogenic fraction. The production of E(2) conjugated as glucuronide was lower than sulfate (P < 0.05), but similar in control and VTG-incubated oocytes. Levels of free T increased from September to October, and conjugates were both produced at low levels, and no differences were detected between control and incubated VTG oocytes. The decreased synthesis of E(2) by oocytes incubated with VTG was not followed by an increase in the amount of T or conjugated E(2), because there were no differences under the two circumstances. However, there was a reduced synthesis of A with oocytes producing low levels of E(2). These results suggest that the presence of high levels of VTG in the oocyte suppresses the synthesis of A and E(2), affecting the activities of the enzymes C17,20 lyase and aromatase and probably interfering with the heme protein cytochrome P450 which in the ovary catalyses C 17,20 lyase (P450 c17) and aromatase (P450 arom).

European Journal of Immunology, 2014

Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanism... more Programmed death-1 (PD-1) plays an important role in mediating immune tolerance through mechanisms that remain unclear. Herein, we investigated whether PD-1 prevents excessive host tissue damage during infection with the protozoan parasite, Toxoplasma gondii. Surprisingly, our results demonstrate that PD-1-deficient mice have increased susceptibility to T. gondii, with increased parasite cyst counts along with reduced type-1 cytokine responses (IL-12 and IFN-γ). PD-1 −/− DCs showed no cell intrinsic defect in IL-12 production in vitro. Instead, PD-1 neutralization via genetic or pharmacological approaches resulted in a striking increase in IL-10 release, which impaired type-1inflammation during infection. Our results indicate that the absence of PD-1 increases IL-10 production even in the absence of infection. Although the possibility that such increased IL-10 protects against autoimmune damage is speculative, our results show that IL-10 suppresses the development of protective Th1 immune response after T. gondii infection.