Association of TNF-\u3b1, CTLA4, and PTPN22 polymorphisms with type 1 diabetes and other autoimmune diseases in Brazil

Type 1 diabetes mellitus (T1D) is a complex disorder characterized by an autoimmune response against human pancreatic beta-cells. Patients with T1D can also develop a response toward one or more other factors, such as in autoimmune thyroiditis (AITD) and celiac disease (CD). In the presence of T1D + AITD, the patient is diagnosed with autoimmune polyglandular syndrome type III (APSIII); patients with APSIII may also present with CD. These diseases have a strong genetic component and share many susceptibility genes, suggesting potentially overlapping pathogenic pathways. Polymorphisms in the TNF-\u3b1(rs1800629), CTLA-4 (rs231775), and PTPN22 (rs2476601) genes have been previous associated with T1D; however, there is no consensus regarding their role in T1D and scarce literature focusing on AIDT and/or CD. Thus, we analyzed these genetic variants in 205 Northeast Brazilian patients with T1D and with/without AITD and/or CD, and in 308 healthy controls. The PTPN22 gene variants were associated with T1D susceptibility and APSIII [odds ratio (OR) = 2.57 and 2.77, respectively]. CTLA4 rs231775 and TNF-\u3b1rs1800629 were not associated with T1D onset in the Brazilian population. However, when comparing APSIII individuals in the T1D only group, we observed an association of the TNF-\u3b1SNP in the allelic (P = 0.0442; OR = 0.44) and dominant models (P = 0.0387; OR = 0.40). This study reinforces the importance of CTLA-4 and other variants in unraveling the pathogenic mechanisms of T1D in different populations and in understanding their relationships with the development of other T1D-related autoimmune diseases

Meta-analysis of STAT4 and IFIH1 polymorphisms in type 1 diabetes mellitus patients with autoimmune polyglandular syndrome type III

Type 1 diabetes mellitus (T1D) is an organ-specific autoimmune disease characterized by T-cell mediated self-destruction of insulin-producing \u3b2 cells in the pancreas. T1D patients are prone to develop other glandular autoimmune disorders, such as autoimmune thyroid disease that occurs simultaneously with autoimmune polyglandular syndrome type III (APSIII). Signal transducer and activator of transcription 4 (STAT4) is a well-known regulator of proinflammatory cytokines, and interferon-induced with helicase C domain 1 (IFIH1) is activated in the interferon type I response. Both genes have been examined separately in autoimmune diseases and, in this study, we assessed their joint role in T1D and APSIII. We conducted a case-control study, enrolling 173 T1D patients and 191 healthy controls from northeastern Brazil, to assess the distribution of the rs7574865 and rs3024839 SNPs in STAT4 and the rs3747517 and rs1990760 SNPs in IFIH1 in T1D and APSIII patients. Additionally, we conducted a meta-analysis with the rs7574865 SNP in STAT4 (1392 T1D patients and 1629 controls) and the rs1990760 SNP in IFIH1 (25092 T1D patients and 28544 controls) to examine their association with T1D. Distribution of STAT4 and IFIH1 allelic frequencies did not show statistically significant differences between T1D patients and controls in our study population; however, the meta-analysis indicated that SNPs in STAT4 and IFIH1 are associated with T1D worldwide. Our findings indicate that although STAT4 and IFIH1 SNPs are not associated with T1D in a Brazilian population, they might play a role in susceptibility to T1D on a larger worldwide scale

The global burden of cancer attributable to risk factors, 2010–19: a systematic analysis for the Global Burden of Disease Study 2019

BACKGROUND: Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. METHODS: The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk–outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. FINDINGS: Globally, in 2019, the risk factors included in this analysis accounted for 4·45 million (95% uncertainty interval 4·01–4·94) deaths and 105 million (95·0–116) DALYs for both sexes combined, representing 44·4% (41·3–48·4) of all cancer deaths and 42·0% (39·1–45·6) of all DALYs. There were 2·88 million (2·60–3·18) risk-attributable cancer deaths in males (50·6% [47·8–54·1] of all male cancer deaths) and 1·58 million (1·36–1·84) risk-attributable cancer deaths in females (36·3% [32·5–41·3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20·4% (12·6–28·4) and DALYs by 16·8% (8·8–25·0), with the greatest percentage increase in metabolic risks (34·7% [27·9–42·8] and 33·3% [25·8–42·0]). INTERPRETATION: The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden

Gentle handling temporarily increases c-Fos in the substantia nigra pars compacta

Dopaminergic neurotransmission is involved in the regulation of sleep. In particular, the nigrostriatal pathway is an important center of sleep regulation. We hypothesized that dopaminergic neurons located in substantia nigra pars compacta (SNpc) could be activated by gentle handling, a method to obtain sleep deprivation (SD). Adult male C57/BL6J mice (N = 5/group) were distributed into non-SD (NSD) or SD groups. SD animals were subjected to SD once for 1 or 3 h by gentle handling. Two experiments were performed. The first determined the activation of SNpc neurons after SD, and the second examined the same parameters after pharmacologically induced dopaminergic depletion using intraperitoneal reserpine (2 mg/kg). After 1 or 3 h, SD and NSD mice were subjected to motor evaluation using the open field test. Immediately after the behavioral test, the mice were perfused intracardially to fix the brain and for immunohistochemical analysis of c-Fos protein expression within the SNpc. The open field test indicated that SD for 1 or 3 h did not modify motor behavior. However, c-Fos protein expression was increased after 1 h of SD compared with the NSD and 3-h SD groups. These immunohistochemistry data indicate that these periods of SD are not able to produce dopaminergic supersensitivity. Nevertheless, the increased expression of c-Fos within the SNpc suggests that dopaminergic nigral activation was triggered by SD earlier than motor responsiveness. Dopamine-depleted mice (experiment 2) exhibited a similar increase of c-Fos expression compared to control animals indicating that dopamine neurons are still activated in the 1-h SD group despite the exhaustion of dopamine. This finding suggests that this range (2-5-fold) of neuronal activation may serve as a marker of SD

Spatial and temporal variability of surface water and groundwater before and after the remediation of a Portuguese uranium mine area

The old Senhora das Fontes uranium mine, in central Portugal, consists of quartz veins which penetrated along fracture shear zones at the contact between graphite schist and orthogneiss. The mine was exploited underground until a depth of 90 m and was closed down in 1971. The ores from this mine and two others were treated in the mine area by the heap-leach process which ended in 1982. Seven dumps containing a total of about 33,800 m3 of material and partially covered by natural vegetation were left in the mine area. A remediation process took place from May 2010 to January 2011. The material deposited in dumps was relocated and covered with erosion resisting covers. Surface water and groundwater were collected in the wet season just before the remediation, in the following season at the beginning of the remediation and also after the remediation in the following dry season. Before, at the beginning and after the remediation, surface water and groundwater have an acid-to-alkaline pH, which decreased with the remediation, whereas Eh increased. In general, before the remediation, uranium concentration was up to 83 μg/L in surface water and up to 116 μg/L in groundwater, whereas at the beginning of the remediation it increases up to 183 μg/L and 272 μg/L in the former and the latter, respectively, due to the remobilization of mine dumps and pyrite and chalcopyrite exposures, responsible for the pH decrease. In general, after the remediation, the U concentration decreased significantly in surface water and groundwater at the north part of the mine area, but increased in both, particularly in the latter up to 774 μg/L in the south and southwest parts of this area, attributed to the remobilization of sulphides that caused mobilization of metals and arsenic which migrated to the groundwater flow. Uranium is adsorbed in clay minerals, but also in goethite as indicated by the geochemical modelling. After the remediation, the saturation indices of oxyhydroxides decrease as pH decreases. The remediation also caused decrease in Cd, Co, Cr, Ni, Pb, Zn, Cu, As, Sr and Mn concentrations of surface water and groundwater, particularly in the north part of the mine area, which is supported by the speciation modelling that shows the decrease of most dissolved bivalent species. However, in general, after the remediation, Th, Cd, Al, Li, Pb, Sr and As concentrations increased in groundwater and surface water at south and southwest of the mine area. Before and after the remediation, surface water and groundwater are contaminated in U, Cd, Cr, Al, Mn, Ni, Pb, Cu and As. Remediation caused only some improvement at north of the mine area, because at south and southwest part, after the remediation, the groundwater is more contaminated than before the remediation