Tendências da epidemia de Aids no Brasil após a terapia anti-retroviral

OBJECTIVE: Universal access to antiretroviral therapy starting from 1996 has changed HIV/AIDS epidemic profile in Brazil. The objective of this study was to review the epidemiology of HIV/AIDS epidemic in Brazil. METHODS: Indicators of temporal trends were developed for Brazilian regions from 1990 to 2003 using the Ministry of Health's databases. Exponential regression models adjusted to the 1990-1996 trends were used to estimate expected values for the entire period. RESULTS: The proportion of AIDS hospitalizations has not changed over the study period but there was a decrease in hospitalizations among those using ARV therapy. There was a 2.7 growth in those receiving Highly Active Anti-Retroviral Therapy (HAART) from 1997 to 2003. HIV/AIDS incidence and mortality rates rose up to 1995 in all regions. From 1996, there has been a gradual reduction in mortality rates while incidence rates have increased. In all regions, except in the Northern region, expected incidence rates have been greater than the observed ones in the last years but these differences were statistically significant only in the Southeastern and Midwestern regions. CONCLUSIONS: The observed trend can be explained by universal access to ARV therapy in Brazil, which had a significant impact on HIV/AIDS mortality. But other factors, such as years of epidemic, prevention actions, knowledge on HIV/AIDS, years of schooling, need to be considered as well.OBJETIVO: A terapia anti-retroviral disponível no Brasil a partir de 1996, modificou o curso da epidemia de Aids, alterando sua evolução e tendências. Nesse sentido, o estudo teve por objetivo avaliar a epidemia da Aids no Brasil, nos seus aspectos epidemiológicos. MÉTODOS: Estudo realizado a partir de bases de dados do Ministério da Saúde que caracterizavam a evolução temporal da Aids nas macrorregiões brasileiras, de 1990 a 2003. Foram utilizados modelos de regressão exponencial, ajustados à série temporal de 1990 a 1996 e estimados valores esperados para toda a série. RESULTADOS: O percentual de internações não se modificou no tempo, mas ocorreu diminuição de hospitalizações entre os usuários de terapia anti-retrovial. Houve um incremento de 2,7 vezes no número de indivíduos em uso da terapia, de 1997 a 2003. Incidência e mortalidade apresentaram crescimentos uniformes até 1995, em todas as regiões. A partir de 1996, verificou-se uma redução progressiva da mortalidade, embora a incidência continue crescendo. Em todas as regiões, exceto a Norte, as incidências esperadas foram maiores do que as observadas nos últimos anos, embora as diferenças somente tenham atingido níveis de significância estatística nas regiões Sudeste e Centro-Oeste. CONCLUSÕES: As mudanças observadas no perfil de morbi-mortalidade da epidemia de Aids no Brasil poderiam ser explicadas pelo amplo acesso a terapia anti-retroviral. Tal fato representou um impacto importante sobre a mortalidade por HIV/Aids, porém, outros fatores devem ser considerados, como idade da epidemia, medidas de prevenção, conhecimento sobre HIV/Aids e anos de escolaridade

Cholangiocarcinoma: from molecular biology to treatment

Abstract Cholangiocarcinoma is a rare tumor originating in the bile ducts, which, according to their anatomical location, is classified as intrahepatic, extrahepatic and hilar. Nevertheless, incidence rates have increased markedly in recent decades. With respect to tumor biology, several genetic alterations correlated with resistance to chemotherapy and radiotherapy have been identified. Here, we highlight changes in KRAS and TP53 genes that are normally associated with a more aggressive phenotype. Also IL-6 and some proteins of the BCL-2 family appear to be involved in the resistance that the cholangiocarcinoma presents toward conventional therapies. With regard to diagnosis, tumor markers most commonly used are CEA and CA 19-9, and although its use isolated appears controversial, their combined value has been increasingly advocated. In imaging terms, various methods are needed, such as abdominal ultrasound, computed tomography and cholangiopancreatography. Regarding therapy, surgical modalities are the only ones that offer chance of cure; however, due to late diagnosis, most patients cannot take advantage of them. Thus, the majority of patients are directed to other therapeutic modalities like chemotherapy, which, in this context, assumes a purely palliative role. Thus, it becomes urgent to investigate new therapeutic options for this highly aggressive type of tumor

New occurrence of B chromosomes in Partamonahelleri (Friese, 1900) (Hymenoptera, Meliponini)

Cytogenetic analyses of the stingless bee Partamona helleri collected in the state of Bahia, Northeast Brazil revealed the chromosome numbers n = 18 in the haploid males and 2n = 35 in the diploid females. All karyotypes displayed one large acrocentric B chromosome, which differs from the minute B chromosomes previously described in the populations from southeastern Brazil. Giemsa staining, C-banding and DAPI/CMA3 fluorochrome staining also revealed a remarkable interpopulational divergence regarding both the regular karyotype and the B chromosomes. The B chromosomes found in the samples from Jequié, Bahia, were entirely heterochromatic, while those found in Cravolândia, Bahia, displayed a euchromatic portion at the telomeric end of the long arm. CMA 3 labeling sites varied from seven to eight between the two localities in Bahia, due to the presence of an extra GC-rich block in the karyotype of the samples from Jequié. This is the first report of a large B chromosome in P. helleri and reveals the occurrence of a geographic differentiation within this species

Results from the portuguese register

Objective Our aims were to evaluate the correlation between Juvenile Arthritis Disease Activity Score 27-joint reduced count (JADAS27) with erythrocyte sedimentation rate (ESR) and JADAS27 with C-reactive protein (CRP) scores and to test the agreement of both scores on classifying each disease activity state. We also aimed at verifying the correlation of the 2 scores across juvenile idiopathic arthritis (JIA) categories and to check the correlation between JADAS27-ESR and clinical JADAS27 (JADAS27 without ESR). Methods A nationwide cohort of patients with JIA registered in the Portuguese Register, Reuma.pt, was studied. JADAS27-CRP was adapted by replacing ESR with CRP level as the inflammatory marker. JADAS27-CRP was calculated similarly to JADAS27-ESR as the simple linear sum of its 4 components. Pearson's correlations and K statistics were used in the analyses. Results A total of 358 children had full data to calculate JADAS27; 65.4% were female and the mean ± SD disease duration was 11.8 ± 9.1 years. The correlation coefficient between JADAS27-ESR and JADAS27-CRP was 0.967 (P < 0.0001), although the correlation coefficient between ESR and CRP level was 0.335 (P < 0.0001). The strong correlation between JADAS27-ESR and JADAS27-CRP was maintained when compared within each JIA category. The agreement between JADAS27-ESR and JADAS27-CRP across the 4 activity states was very good, showing 91.1% of the observations in agreement; K = 0.867 (95% confidence interval 0.824-0.91). The correlation between JADAS27 with ESR and JADAS27 without ESR was high (r = 0.97, P < 0.0001). Conclusion JADAS27 based on CRP level correlated closely with JADAS27-ESR across all disease activity states and JIA categories, indicating that both measures can be used in clinical practice. Moreover, the correlation of JADAS27 with and without ESR was also high, suggesting that this tool might be useful even in the absence of laboratorial measures.publishersversionpublishe

Calcium biofortification of Rocha pears, tissues accumulation and physicochemical implications in fresh and heat-treated fruits

Low dietary intake of Ca in humans has been epidemiologically linked to various diseases, which can have serious health consequences over time. Accordingly, the development of an agronomic itinerary for Ca biofortification of Rocha pears and the assessment of physicochemical deviations prompted this study. Two orchards with contrasting soil and water characteristics were selected, characterized through orthophotomaping and, during fruits development, leaves were sprayed twice with Ca(NO3)2 (0.1, 0.3 and 0.6 kg ha - 1) or CaCl2 (0.4, 0.8 and 1.6 kg ha - 1), followed by pulverization only with CaCl2 (first once with 4 kg ha - 1 and then four times with 8 kg ha - 1). During fruits development net photosynthesis, stomatal conductance, transpiration rates, instantaneous and water use efficiency, only showed minor deviations, which indicated that the threshold of toxicity was not surpassed. Calcium contents varied during fruits development and at harvesting the average biofortification index varied between 47 %–63 % and 24 %–59 % in each of the orchards. Besides, the equatorial region of the fruits showed for all treatments (substantially in Ca treated samples) higher Ca contents in the epidermal and in the central regions. Fresh and heat-treated fruits (in a thermomix at 90 ◦C, during 10 min) biofortified with Ca only revealed minor differences and the sensory acceptability did not vary markedly. It is concluded that, although prevailing a heterogeneous distribution of Ca in fruit tissues, high indexes of biofortification in Rocha pears can be prompt in the orchards, without substantial physicochemical changes. Accordingly, agronomic biofortification with Ca can be used as a strategy for benefiting consumer’s healthinfo:eu-repo/semantics/publishedVersio

Implications for Quality and Wine Production

UID/FIS/04559/2020Nowadays, there is a growing concern about micronutrient deficits in food products, with agronomic biofortification being considered a mitigation strategy. In this context, as Zn is essential for growth and maintenance of human health, a workflow for the biofortification of grapes from the Vitis vinifera variety Fernão Pires, which contains this nutrient, was carried out considering the soil properties of the vineyard. Additionally, Zn accumulation in the tissues of the grapes and the implications for some quality parameters and on winemaking were assessed. Vines were sprayed three times with ZnO and ZnSO4 at concentrations of 150, 450, and 900 g ha−1 during the production cycle. Physiological data were obtained through chlorophyll a fluorescence data, to access the potential symptoms of toxicity. At harvest, treated grapes revealed significant increases of Zn concentration relative to the control, being more pronounced for ZnO and ZnSO4 in the skin and seeds, respectively. After winemaking, an increase was also found regarding the control (i.e., 1.59-fold with ZnSO4-450 g ha−1). The contents of the sugars and fatty acids, as well as the colorimetric analyses, were also assessed, but significant variations were not found among treatments. In general, Zn biofortification increased with ZnO and ZnSO4, without significantly affecting the physicochemical characteristics of grapes.publishersversionpublishe

Meglumine antimoniate and miltefosine combined with allopurinol sustain pro-inflammatory immune environments during canine leishmaniosis treatment

Research Areas: Veterinary SciencesCanine leishmaniosis (CanL) caused by Leishmania infantum is a zoonotic disease of global concern. Antileishmanial drug therapies commonly used to treat sick dogs improve their clinical condition, although when discontinued relapses can occur. Thus, the current study aims to evaluate the effect of CanL treatments in peripheral blood, lymph node, and bone marrow cytokine profile associated with clinical recovery. Two groups of six dogs diagnosed with CanL were treated with miltefosine combined with allopurinol and meglumine antimoniate combined with allopurinol (MT+A and MG+A), respectively. At diagnosis and after treatment, during a 3-month follow-up, clinical signs, hematological and biochemical parameters, urinalysis results and antileishmanial antibody titers were registered. Furthermore, peripheral blood, popliteal lymph node, and bone marrow samples were collected to assess the gene expression of IL-2, IL-4, IL-5, IL-10, IL-12, TNF-alpha, TGF-beta, and IFN-gamma by qPCR. In parallel, were also evaluated samples obtained from five healthy dogs. Both treatment protocols promoted the remission of clinical signs as well as normalization of hematological and biochemical parameters and urinalysis values. Antileishmanial antibodies returned to non-significant titers in all dogs. Sick dogs showed a generalized upregulation of IFN-gamma and downregulation of IL-2, IL-4, and TGF-beta, while gene expression of IL-12, TNF-alpha, IL-5, and IL-10 varied between groups and according to evaluated tissue. A trend to the normalization of cytokine gene expression was induced by both miltefosine and meglumine antimoniate combined therapies. However, IFN-gamma gene expression was still up-regulated in the three evaluated tissues. Furthermore, the effect of treatment in the gene expression of cytokines that were not significantly changed by infection, indicates that miltefosine and meglumine antimoniate combined therapy directly affects cytokine generation. Both combined therapies are effective in CanL treatment, leading to sustained pro-inflammatory immune environments that can compromise parasite survival and favor dogs' clinical cure. In the current study, anti-inflammatory and regulatory cytokines do not seem to play a prominent role in CanL or during clinical recovery.info:eu-repo/semantics/publishedVersio

Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt

Methods. We prospectively collected patient and disease characteristics from patients with JIA who started biological therapy. Adverse events were collected during the follow-up period. Predictors of response at 1 year and drug retention rates were assessed at 4 years of treatment for the first biologic agent.Results. A total of 812 JIA patients [65% females, mean age at JIA onset 6.9 years (s.d. 4.7)], 227 received biologic therapy; 205 patients (90.3%) were treated with an anti-TNF as the first biologic. All the parameters used to evaluate disease activity, namely number of active joints, ESR and Childhood HAQ/HAQ, decreased significantly at 6 months and 1 year of treatment. The mean reduction in Juvenile Disease Activity Score 10 (JADAS10) after 1 year of treatment was 10.4 (s.d. 7.4). According to the definition of improvement using the JADAS10 score, 83.3% respond to biologic therapy after 1 year. Fourteen patients discontinued biologic therapies due to adverse events. Retention rates were 92.9% at 1 year, 85.5% at 2 years, 78.4% at 3 years and 68.1% at 4 years of treatment. Among all JIA subtypes, only concomitant therapy with corticosteroids was found to be univariately associated with withdrawal of biologic treatment (P = 0.016).Conclusion. Biologic therapies seem effective and safe in patients with JIA. In addition, the retention rates for the first biologic agent are high throughout 4 years

Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer

© 2022 The Authors; Published by the American Association for Cancer Research. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 International (CC BY-NC-ND)Purpose: Cetuximab is an EGFR-targeted therapy approved for the treatment of RAS wild-type (WT) metastatic colorectal cancer (mCRC). However, about 60% of these patients show innate resistance to cetuximab. To increase cetuximab efficacy, it is crucial to successfully identify responder patients, as well as to develop new therapeutic approaches to overcome cetuximab resistance. Experimental design: We evaluated the value of EGFR effector phospholipase C gamma 1 (PLCγ1) in predicting cetuximab responses, by analyzing progression-free survival (PFS) of a multicentric retrospective cohort of 94 treated patients with mCRC (log-rank test and Cox regression model). Furthermore, we used in vitro and zebrafish xenotransplant models to identify and target the mechanism behind PLCγ1-mediated resistance to cetuximab. Results: In this study, levels of PLCγ1 were found increased in RAS WT tumors and were able to predict cetuximab responses in clinical samples and in vitro and in vivo models. Mechanistically, PLCγ1 expression was found to bypass cetuximab-dependent EGFR inhibition by activating ERK and AKT pathways. This novel resistance mechanism involves a noncatalytic role of PLCγ1 SH2 tandem domains in the propagation of downstream signaling via SH2-containing protein tyrosine phosphatase 2 (SHP2). Accordingly, SHP2 inhibition sensitizes PLCγ1-resistant cells to cetuximab. Conclusions: Our discoveries reveal the potential of PLCγ1 as a predictive biomarker for cetuximab responses and suggest an alternative therapeutic approach to circumvent PLCγ1-mediated resistance to cetuximab in patients with RAS WT mCRC. In this way, this work contributes to the development of novel strategies in the medical management and treatment of patients with mCRC.M. Martins' research was supported by Liga Portuguesa Contra o Cancro (LPCC): Terry Fox Fundation; Investigador FCT- Fundação para a Ciência e Technologia (IF/00409/2014) and IMM Bridge grant; RC-D research was supported by Fundação para a Ciência e Technologia (SFRH/BD/139138/2018). A. Fernandes was supported by LPCC-IMM BIOBANK; R. Fior was supported by Champalimaud Foundation and L. Costa was supported by Merck Serono.info:eu-repo/semantics/publishedVersio

Exploring the correlations between epi indicators of COVID-19 and the concentration of pharmaceutical compounds in Wastewater Treatment Plants in Northern Portugal

The COVID-19 pandemic caused by the SARS-CoV-2 virus led to changes in the lifestyle and human behaviour, which resulted in different consumption patterns of some classes of pharmaceuticals including curative, symptom-relieving, and psychotropic drugs. The trends in the consumption of these compounds are related to their concentrations in wastewater systems, since incompletely metabolised drugs (or their metabolites back transformed into the parental form) may be detected and quantified by analytical methods. Pharmaceuticals are highly recalcitrant compounds and conventional activated sludge processes implemented in wastewater treatment plants (WWTP) are ineffective at degrading these substances. As a results, these compounds end up in waterways or accumulate in the sludge, being a serious concern given their potential effects on ecosystems and public health. Therefore, it is crucial to evaluate the presence of pharmaceuticals in water and sludge to assist in the search for more effective processes. In this work, eight pharmaceuticals from five therapeutic classes were analysed in wastewater and sludge samples collected in two WWTP located in the Northern Portugal, during the third COVID-19 epidemic wave in Portugal. The two WWTP demonstrated a similar pattern with respect to the concentration levels in that period. However, the drugs loads reaching each WWTP were dissimilar when normalising the concentrations to the inlet flow rate. Acetaminophen (ACET) was the compound detected at highest concentrations in aqueous samples of both WWTP (98. 516 g L1 in WWTP2 and 123. 506 g L1in WWTP1), indicating that this drug is extensively used without the need of a prescription, known of general public knowledge as an antipyretic and analgesic agent to treat pain and fever. The concentrations determined in the sludge samples were below 1.65 µg g1 in both WWTP, the highest value being found for azithromycin (AZT). This result may be justified by the physico-chemical characteristics of the compound that favour its adsorption to the sludge surface through ionic interactions. It was not possible to establish a clear relationship between the incidence of COVID-19 cases in the sewer catchment and the concentration of drugs detected in the same period. However, looking at the data obtained, the high incidence of COVID-19 in January 2021 is in line with the high concentration of drugs detected in the aqueous and sludge samples but prediction of drug load from viral load data was unfeasible.This study was supported by the Competitiveness and Internationalisation Operational Programme, Lisbon Regional Operational Programme and Algarve Regional Operational Programme with the support of FEDER, through the Incentive Scheme: research and development activities and investment in testing and optimisation (upscaling) infrastructures in the context of COVID-19, through the Project “SARS CONTROL: Evaluation of the impacts of SARS-CoV-2 on the urban water cycle and the downstream effects on Public Health" (Ref. 070076). Acknowledge is also due to the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit, and by LABBELS – Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020. Strategic funding from FCT to cE3c and BioISI Research Units (UIDB/00329/2020 and UIDB/04046/2020) and to the Associate Laboratory CHANGE (LA/P/0121/2020) is also gratefully acknowledged. ARS holds an FCT grant SFRH/BD/131905/2017 and COVID/BD/151951/2021.ARLR and MFRP acknowledge the financial support from LA/P/0045/2020 (ALiCE), UIDB/50020/2020 and UIDP/50020/2020 (LSRE-LCM), funded by national funds through FCT/MCTES (PIDDAC). ARLR acknowledges FCT funding under DL57/2016 Transitory Norm Programme.info:eu-repo/semantics/publishedVersio