Spatial association of homicide rate with violence, sociodemographic, and public security factors: global burden of disease study 2018 for municipalities in Brazil.

OBJECTIVES: To analyse spatial-temporal changes and spatial association of homicide rates with violence, sociodemographic, public security and human rights indicators in Brazilian municipalities. STUDY DESIGN: An ecological study using homicide estimates from the Global Burden of Disease and population from the Brazilian Ministry of Health, 2000 to 2018. The explanatory variables come from the systems of mortality, notifications of violence and security, and the Brazilian Institute of Geography and Statistics. METHODS: Moran indices and maps identified clusters of high and low risk for homicides in three trienniums (p < 0.05). Multivariate linear and spatial regressions estimated explanatory factors' contributions for the last triennium. RESULTS: Municipalities with high rates of homicides (>34/100,000) doubled, reaching 21.5 %. Those rates were concentrated in big cities, and increased in smaller municipalities. Increases in critical areas were found in the Northeast and North regions: more than 40 % in the states of Sergipe, Bahia, Ceará, Rio Grande do Norte and Roraima. Decreases occurred in the Southeast and Midwest regions: more than 35 % in São Paulo and Rio de Janeiro states. The spatial model, with an 18.9 % higher R2 (0.706), showed a positive association for records of violence, Blacks, low-level education, municipalities >50,000 inhabitants and municipalities with homicide and municipal police. CONCLUSIONS: An increase in and the interiorisation of homicide risk areas in Brazil was observed, with displacement among regions (from the Southeast to the North/Northeast). The level of violence was the main explanatory factor for homicides. Territorial space proved to be important to understand and prevent lethal crime.

Effect of autohemotherapy in the treatment of viral infections - a systematic review.

OBJECTIVE: To analyze the literature to determine whether autohemotherapy has any effect either clinically or on the immune system on viral diseases on the last ten years. STUDY DESIGN: Systematic review. METHODS: Searches from the year 2010, with at least 5 patients were conducted in PubMed/MEDLINE, Embase, Scopus, Cochrane, LILACS, SciELO, and Web of Science databases. Hand searches were performed in systematic reviews and literature reviews related to autohemotherapy. Unpublished manuscripts were hand-searched in specialized journals. RESULTS: Eight articles were included. Hepatitis B virus, hepatitis C virus, and Coronavirus were evaluated. Autohemotherapy had good results in hepatitis C, hepatitis B, and Coronavirus. CONCLUSION: Autohemotherapy is a safe practice that improves symptoms in the treatment of hepatitis B virus, hepatitis C virus, and Coronavirus. It is necessary to perform more prospective comparative studies with homogeneous protocols.

131I-Induced Graves' disease in patients treated for toxic multinodular goitre: systematic review and descriptive analysis.

BACKGROUND: Graves' disease (GD) arising after the treatment of toxic multinodular goitre (TMNG) with radioiodine has long been described but it remained unclear whether GD was in fact iodine induced, its incidence, risk factors, natural history and treatment outcomes. METHODS: A systematic search using The Cochrane Library, Medline and PubMed Central allowed the pooling of data from 3633 patients with thyroid autonomy, 1340 patients with TMNG, to fill gaps in knowledge, regarding the clinical expression of iodine-induced GD (131I-IGD) in adults. RESULTS: 131I-IGD developed in 0-5.3% of those with thyroid autonomy (first year) and in 5-5.4% of those with TMNG, 3-6 months after treatment. Patients with toxic adenoma were less affected. 131I-IGD was more common in patients with pre-treatment direct or indirect signs of autoimmunity: positive anti-TPO (p < 0.05), glandular hypoechogenicity, TRAbs within reference range, diffuse uptake on 99mTc-pertechnetate scans (p < 0.05), findings that may increase the risk tenfold. 131I-IGD manifested 3 months after 131I, justifying 15.4-29% of cases of relapse. The rate of spontaneous remission was 17-20% (6 months) and the rate of relapse after a second 131I treatment 22-25%. The use of an uptake-based administered 131I activity led to a greater proportion of euthyroid patients (78% compared to 25-50% with the mass-based approach). CONCLUSIONS: GD may be triggered by 131I. The incidence of the condition is low. Several risk factors were consistently identified; some have shown to raise the risk significantly. 131I-IGD seems more treatment resistant than iodine-independent GD and the best resolution rates were achieved with uptake-based selected iodine activities.

Two separate effects contribute to regulatory T cell defect in systemic lupus erythematosus patients and their unaffected relatives.

Forkhead box P3 (FoxP3)+ regulatory T cells (Tregs ) are functionally deficient in systemic lupus erythematosus (SLE), characterized by reduced surface CD25 [the interleukin (IL)-2 receptor alpha chain]. Low-dose IL-2 therapy is a promising current approach to correct this defect. To elucidate the origins of the SLE Treg phenotype, we studied its role through developmentally defined regulatory T cell (Treg ) subsets in 45 SLE patients, 103 SLE-unaffected first-degree relatives and 61 unrelated healthy control subjects, and genetic association with the CD25-encoding IL2RA locus. We identified two separate, uncorrelated effects contributing to Treg CD25. (1) SLE patients and unaffected relatives remarkably shared CD25 reduction versus controls, particularly in the developmentally earliest CD4+ FoxP3+ CD45RO- CD31+ recent thymic emigrant Tregs . This first component effect influenced the proportions of circulating CD4+ FoxP3high CD45RO+ activated Tregs . (2) In contrast, patients and unaffected relatives differed sharply in their activated Treg CD25 state: while relatives as control subjects up-regulated CD25 strongly in these cells during differentiation from naive Tregs , SLE patients specifically failed to do so. This CD25 up-regulation depended upon IL2RA genetic variation and was related functionally to the proliferation of activated Tregs , but not to their circulating numbers. Both effects were found related to T cell IL-2 production. Our results point to (1) a heritable, intrathymic mechanism responsible for reduced CD25 on early Tregs and decreased activation capacity in an extended risk population, which can be compensated by (2) functionally independent CD25 up-regulation upon peripheral Treg activation that is selectively deficient in patients. We expect that Treg -directed therapies can be monitored more effectively when taking this distinction into account.

Prediction of disease severity in neuromyelitis optica by the levels of interleukin (IL)-6 produced during remission phase.

T helper type 17 (Th17) cytokines have been implicated in the pathogenesis of neuromyelitis optica (NMO). As humanized anti-interleukin (IL)-6R (tocilizumab) immunoglobulin (Ig)G has been used as disease-modifying therapy for NMO, the objective of our study was to investigate the role of endogenous IL-6 on NMO-derived CD4(+) T cell behaviour. High production of IL-6, IL-17 and IL-21 by CD4(+) T-cells was detected in NMO patients. Further, IL-21 and IL-6 levels were related directly to the level of neurological disabilities. The addition of anti-IL-6R IgG not only reduced directly the production of these cytokines, but also almost abolished the ability of activated autologous monocytes in enhancing IL-6, IL-17 and IL-21 release by CD4(+) T cells. In contrast, the production of IL-10 was amplified in those cell cultures. Further, anti-IL-6R monoclonal antibodies (mAb) also potentiated the ability of glucocorticoid in reducing Th17 cytokines. Finally, the in-vivo and in-vitro IL-6 levels were significantly higher among those patients who experienced clinical relapse during 2-year follow-up. In summary, our results suggest a deleterious role of IL-6 in NMO by favouring, at least in part, the expansion of corticoid-resistant Th17 cells.

Alveolar hemorrhage in systemic lupus erythematosus: a cohort review.

Diffuse alveolar hemorrhage (DAH) is a rare but potentially catastrophic manifestation with a high mortality. Among rheumatologic diseases, it occurs most frequently in patients with systemic lupus erythematosus (SLE) and systemic vasculitis. Despite new diagnostic tools and therapies, it remains a diagnostic and therapeutic challenge. The aim of this work was to characterize the SLE patients with an episode of alveolar hemorrhage followed in our Clinical Immunology Unit (CIU). A retrospective chart review was carried out for all patients with SLE followed in CIU between 1984 and the end of 2013. We reviewed the following data: demographic characteristics, clinical and laboratory data, radiologic investigations, histologic studies, treatment, and outcome. We identified 10 episodes of DAH, corresponding to seven patients, all female. These represent 1.6% of SLE patients followed in our Unit. The age at DAH attack was 42.75 ± 18.9 years. The average time between diagnosis of SLE and the onset of DAH was 7.1 years. Three patients had the diagnosis of SLE and the DAH attack at the same time. Disease activity according to SLEDAI was high, ranging from 15 to 41. All patients were treated with methylprednisolone, 37.5% cyclophosphamide and 28.6% plasmapheresis. The overall mortality rate was 28.6%.

Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients.

OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications.

Association between vitamin D receptor (VDR) gene polymorphisms and systemic lupus erythematosus in Portuguese patients.

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown origin, in which both genetic and environmental factors are involved. One such environmental factor is vitamin D, a vital hormone that plays a specific function in the immune system homeostasis, acting through a nuclear receptor (VDR) expressed in all immune cells. Several polymorphisms of the gene that encodes this receptor have been described. Though inconsistently, these polymorphisms have been associated with clinical manifestations and SLE development.The aim of this study was to determine the possible association between VDR gene polymorphisms (BsmI, ApaI, TaqI e FokI) and SLE susceptibility and severity, in a cohort of lupus patients from the north of Portugal.A total of 170 patients (F = 155, M = 15; age = 45 ± 13.4 years) with SLE (diagnosed according the American College of Rheumatology criteria) with at least five years of disease evolution and followed in the Autoimmune Disease Clinical Immunology Unit of Centro Hospitalar do Porto were studied. Patients and 192 ethnicity-matched controls were genotyped for BsmI (rs1544410), ApaI (rs7975232), TaqI (rs731236) and FokI (rs2228570) polymorphisms by TaqMan allelic discrimination assay. Disease severity was assessed by SLICC damage score, number of affected organs, number of severe flares and pharmacological history.SLE patients with the CT genotype of FokI polymorphism have a higher SLICC value (p = 0.031). The same result was observed for the group of patients with the TT genotype of TaqI polymorphism (p = 0.046). No differences were observed in VDR genotype between patients and controls. Also, we observed that the other clinical features analysed were not influenced by VDR polymorphisms.Our study confirms a possible role of VDR gene polymorphisms in SLE. A positive association was found between VDR polymorphisms and SLE severity (chronic damage). The presence of CT genotype of FokI and TT genotype of TaqI seems to confer a worse prognosis and may constitute a risk factor for higher long-term cumulative damage in SLE patients.

Epicardial adipose tissue and coronary artery calcification in psoriasis patients.

BACKGROUND: Psoriasis is a chronic, immune-mediated disease associated with several cardio-metabolic comorbidities, accelerated atherosclerosis and cardiovascular disease (CVD). Other causes beyond systemic inflammation and traditional cardiovascular risk factors (CVRF) may be implicated in the increased risk of CVD observed in these patients. Epicardial adipose tissue (EAT), a type of visceral adipose tissue surrounding the heart and coronary vessels has been implicated in the development of coronary artery disease, by endocrine mechanisms, but particularly by local inflammation. OBJECTIVE: To compare EAT volumes in psoriasis patients and controls using multidetector computed tomography (MDCT) and to analyse if eventual differences were independent from abdominal visceral adiposity; to determine, within psoriasis patients, its relation with subclinical atherosclerosis and other markers of cardiometabolic risk. METHODS: One hundred patients with severe psoriasis, without CVD underwent MDCT, with EAT and abdominal visceral fat (AVF) assessment and coronary artery calcification (CAC) quantification and were compared with 202 control patients. RESULTS: EAT volume was increased in psoriasis patients compared to control subjects, independently from age, sex and AVF, being, on average, 15.2 ± 4.41 mL higher (95% CI: 6.5-26.0, P = 0.001) than in controls. Moreover, psoriasis patients had a statistically significant higher risk of having subclinical atherosclerosis (OR 2.52, 95% CI: 1.23-5.16) than controls, after adjusting for traditional CVRF. Within psoriasis patients EAT volume was associated with subclinical atherosclerosis, independently of age, sex, psoriasis duration, classical CVRF and AVF. CONCLUSION: This study showed that psoriasis was associated with increased EAT volume independently of visceral abdominal fat and with subclinical atherosclerosis. Within psoriasis patients EAT volume was independently associated with CAC. EAT may be another important contributor to the higher cardiovascular risk observed in psoriasis.

CCR5-Delta32: implications in SLE development.

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease with strong genetic and environmental components. Previous studies have shown increased levels of several chemokines in active SLE. C-C chemokine receptor type 5 (CCR5) is involved in the recruitment of inflammatory cells into tissues, and mechanisms modulating CCR5 expression and function may interfere in SLE development, influencing the clinical course of the disease. The aim of this study was to evaluate the possible association between the CCR5∆32 base-pair deletion polymorphism and SLE disease in a group of Portuguese patients. A total of 219 patients with SLE and 205 healthy individuals were studied. The frequency of CCR5/∆32 heterozygotes was lower in patients with SLE than in controls (8% vs. 15% OR = 0.5162; P = 0.0319), suggesting a protective association between CCR5∆32 allele and SLE. These results highlight the protective role of Th1 cells that express CCR5 in SLE pathogenesis.

Dietary management of urea cycle disorders: European practice.

BACKGROUND: There is no published data comparing dietary management of urea cycle disorders (UCD) in different countries. METHODS: Cross-sectional data from 41 European Inherited Metabolic Disorder (IMD) centres (17 UK, 6 France, 5 Germany, 4 Belgium, 4 Portugal, 2 Netherlands, 1 Denmark, 1 Italy, 1 Sweden) was collected by questionnaire describing management of patients with UCD on prescribed protein restricted diets. RESULTS: Data for 464 patients: N-acetylglutamate synthase (NAGS) deficiency, n=10; carbamoyl phosphate synthetase (CPS1) deficiency, n=29; ornithine transcarbamoylase (OTC) deficiency, n=214; citrullinaemia, n=108; argininosuccinic aciduria (ASA), n=80; arginase deficiency, n=23 was reported. The majority of patients (70%; n=327) were aged 0-16y and 30% (n=137) >16y. Prescribed median protein intake/kg body weight decreased with age with little variation between disorders. The UK tended to give more total protein than other European countries particularly in infancy. Supplements of essential amino acids (EAA) were prescribed for 38% [n=174] of the patients overall, but were given more commonly in arginase deficiency (74%), CPS (48%) and citrullinaemia (46%). Patients in Germany (64%), Portugal (67%) and Sweden (100%) were the most frequent users of EAA. Only 18% [n=84] of patients were prescribed tube feeds, most commonly for CPS (41%); and 21% [n=97] were prescribed oral energy supplements. CONCLUSIONS: Dietary treatment for UCD varies significantly between different conditions, and between and within European IMD centres. Further studies examining the outcome of treatment compared with the type of dietary therapy and nutritional support received are required.

Is there a cure for systemic lupus erythematosus?

The morbidity and mortality of systemic lupus erythematosus (SLE) is a subject of intense relevance in the literature, yet descriptions of prolonged and sustained remissions or even cure are barely reported. In recent decades the life expectancy in SLE patients has improved, but the quality of life seems to be poor compared with other chronic diseases and with the general population. The immunopathogenesis of SLE is complex and not fully understood, so patients have been treated with nonspecific immunosuppressive therapies. But in recent years, because of advances in basic science, targeted therapies have been developed. Despite the progress made in treating SLE, currently a cure in SLE seems to be a myth. SLE it seems, remains incurable. A specific treatment has not emerged to directly abrogate a disease-specific autoimmune response. Relapsing manifestations and complications of treatment still remain important markers of morbidity.

Genetic association of miRNA-146a with systemic lupus erythematosus in Europeans through decreased expression of the gene.

A recent genome-wide association study revealed a variant (rs2431697) in an intergenic region, between the pituitary tumor-transforming 1 (PTTG1) and microRNA (miR-146a) genes, associated with systemic lupus erythematosus (SLE) susceptibility. Here, we analyzed with a case-control design this variant and other candidate polymorphisms in this region together with expression analysis in order to clarify to which gene this association is related. The single-nucleotide polymorphisms (SNPs) rs2431697, rs2910164 and rs2277920 were genotyped by TaqMan assays in 1324 SLE patients and 1453 healthy controls of European ancestry. Genetic association was statistically analyzed using Unphased. Gene expression of PTTG1, the miRNAs miR-3142 and primary and mature forms of miR-146a in peripheral blood mononuclear cells (PBMCs) were assessed by quantitative real-time PCR. Of the three variants analyzed, only rs2431697 was genetically associated with SLE in Europeans. Gene expression analysis revealed that this SNP was not associated with PTTG1 expression levels, but with the microRNA-146a, where the risk allele correlates with lower expression of the miRNA. We replicated the genetic association of rs2341697 with SLE in a case-control study in Europeans and demonstrated that the risk allele of this SNP correlates with a downregulation of the miRNA 146a, potentially important in SLE etiology.

Leishmania chagasi naturally resistant to nitric oxide isolated from humans and dogs with visceral leishmaniasis in Brazil.

Nitric oxide (NO) plays an important role as a leishmanicidal agent in murine macrophages. NO resistant Escherichia coli and Mycobacterium tuberculosis have been associated with poor outcomes of their resulting diseases. NO resistant Leishmania braziliensis has also been identified and exacerbates the clinical course of human leishmaniasis. We report, for the first time, natural resistance of Leishmania chagasi promastigotes to NO. These parasites were isolated from humans and dogs with visceral leishmaniasis. We also demonstrate that this resistance profile was associated with a greater survival capacity and a greater parasite burden in murine macrophages, independent of activation and after activation by IFN-γ and LPS.

Th17/Regulatory T cells ratio evolution: A prospective study in a group of healthy pregnant women.

During pregnancy, the maternal immune system is challenged to tolerate a semi-allogenic fetus. A shift toward a tolerogenic profile is essential to ensure a healthy fetal and placental development. One of the most important mechanisms involved in the maternal immune tolerance towards the fetal antigens is expressed in the activity of the regulatory T (Treg) and Th17 cells. The behavior and equilibrium of these two T lymphocyte populations were rarely studied in normal healthy pregnancies through the beginning of gestation to the postpartum period. We conducted a prospective longitudinal observational study where peripheral blood lymphocyte subsets were analyzed in each trimester of pregnancy and postpartum period in a group of healthy pregnant women. Our study observed a consistent reduction in peripheric Treg cell count through all pregnancy while the Th17 cell count remained stable. The Th17/Treg ratio increases significantly throughout pregnancy to the postpartum period. These changes could be justified by the migration of the immunotolerant Treg cells to the maternal decidua and lead to the establishment of a systemic pro-inflammatory profile by the end of pregnancy. This data could explain why systemic syndromes like preeclampsia develop in susceptible women during the second half of pregnancy or why many autoimmune disorders flourish in the first weeks postpartum.

Mechanism of Action of Limonene in Tumor Cells: A Systematic Review and Meta-Analysis.

BACKGROUND: Cancer is a complex, multifactorial disease, and a major public health problem, as it is a leading cause of morbidity and mortality worldwide. Although treatments have significantly improved, still more effective drugs are searched. One source for these drugs is natural products (NPs). One NP that has shown anticancer activity is Limonene. However, the mechanisms of limonene's antiproliferative, anticancer and antineoplastic activity are not fully understood. OBJECTIVE: The objective of this study is to undertake a systematic review and meta-analysis of the literature on this subject. METHODS: A comprehensive literature search was performed using the Scopus, MEDLINE-PubMed, Web of Science, and Science Direct databases using the keywords: "limonene", "cancer", "neoplasm", and "tumor". The inclusion criteria were: in vivo and in vitro studies on the use of limonene in cancer published in English, Portuguese and Spanish until December 2019. Review articles, meta-analyses, abstracts, conference papers, editorials/ letters and case reports were excluded. RESULTS: The search identified 3568 articles, of which, 126 were selected for full reading, with 11 papers meeting the review criteria. Six more papers were added from the references of the initial 11 texts, giving a total of 17 papers. There was a high level of agreement in inclusion/exclusion (Kappa index > 80%). The risk of bias in the texts was shown to be high. CONCLUSION: The meta-analysis suggests that limonene acts mainly on tumor regression induced apoptosis and is a promising natural product for use in the treatment of several types of cancer.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

Hemophagocytic syndrome as one of the main primary manifestations in acute systemic lupus erythematosus--case report and literature review.

Hemophagocytic syndrome is an unusual but fatal disorder characterized by pancytopenia and activation of macrophages. We describe one case of acute systemic lupus erythematosus with an unusual presentation of hemophagocytic syndrome not related to infection. The patient presented with pancytopenia related to increasing hemophagocytic activity of histiocytes in the bone marrow. Concomitant class IV World Health Organization lupus nephritis, serositis, high titer of antinuclear factor and positive test for anti-DNA antibody fitted the diagnostic criteria of systemic lupus erythematosus. She also presented with alveolar hemorrhage and lupus myocarditis. She underwent immunosuppressive therapy with recovery from the hemophagocytic syndrome. Therefore, diagnosis of acute lupus hemophagocytic syndrome was made. The clinical presentation, laboratory diagnosis, and management of the patient are discussed and the literature was reviewed and presented, with emphasis on a possible distinct lupus subset, which includes a more aggressive systemic disease with heart involvement.