Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats.

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective ß3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1ß, and IL-6 gene expression and IL-1ß and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.

Combined effect of physical exercise and hormone replacement therapy on cardiovascular and metabolic health in postmenopausal women: A systematic review and meta-analysis.

The cardioprotective effect of postmenopausal hormone replacement therapy (HRT) has been demonstrated in several studies. Similarly, physical exercise has yielded positive results. However, the effects of their combination remain inconclusive. This review describes the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We searched the Scopus, Web of Science, PubMed, and Embase databases and included randomized controlled trials published up to December 2021 on the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We identified 148 articles, of which only seven met the inclusion criteria (386 participants; 91 [23%] HRT + exercise; 104 [27%] HRT; 103 [27%] exercise; 88 [23%] placebo). The combined treatment further decreased systolic blood pressure (SBP) compared to the isolated effect of aerobic training (AT) (mean difference [MD]=-1.69; 95% confidence interval [CI]=-2.65 to -0.72, n=73). Nevertheless, it attenuated the decrease in diastolic blood pressure (DBP) (MD=0.78; 95%CI: 0.22-1.35, n=73), and the increase in peak oxygen consumption (VO2 peak) promoted by exercise (AT + HRT=2.8±1.4 vs AT + placebo=5.8±3.4, P=0.02). The combination of AT and oral HRT improved SBP. However, AT alone seemed to have a better effect on physical fitness and DBP in postmenopausal women.

Combined effect of physical exercise and hormone replacement therapy on cardiovascular and metabolic health in postmenopausal women: A systematic review and meta-analysis

The cardioprotective effect of postmenopausal hormone replacement therapy (HRT) has been demonstrated in several studies. Similarly, physical exercise has yielded positive results. However, the effects of their combination remain inconclusive. This review describes the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We searched the Scopus, Web of Science, PubMed, and Embase databases and included randomized controlled trials published up to December 2021 on the combined effects of physical exercise and hormone therapy on cardiovascular and metabolic health in postmenopausal women. We identified 148 articles, of which only seven met the inclusion criteria (386 participants; 91 [23%] HRT + exercise; 104 [27%] HRT; 103 [27%] exercise; 88 [23%] placebo). The combined treatment further decreased systolic blood pressure (SBP) compared to the isolated effect of aerobic training (AT) (mean difference [MD]=-1.69; 95% confidence interval [CI]=-2.65 to -0.72, n=73). Nevertheless, it attenuated the decrease in diastolic blood pressure (DBP) (MD=0.78; 95%CI: 0.22-1.35, n=73), and the increase in peak oxygen consumption (VO2 peak) promoted by exercise (AT + HRT=2.8±1.4 vs AT + placebo=5.8±3.4, P=0.02). The combination of AT and oral HRT improved SBP. However, AT alone seemed to have a better effect on physical fitness and DBP in postmenopausal women.

Brain glucose hypometabolism and hippocampal inflammation in Goto-Kakizaki rats

Brain glucose hypometabolism and neuroinflammation are early pathogenic manifestations in neurological disorders. Neuroinflammation may also disrupt leptin signaling, an adipokine that centrally regulates appetite and energy balance by acting on the hypothalamus and exerting neuroprotection in the hippocampus. The Goto-Kakizaki (GK) rat is a non-obese type 2 diabetes mellitus (T2DM) animal model used to investigate diabetes-associated molecular mechanisms without obesity jeopardizing effects. Wistar and GK rats received the maintenance adult rodent diet. Also, an additional control group of Wistar rats received a high-fat and high-sugar diet (HFHS) provided by free consumption of condensed milk. All diets and water were provided ad libitum for eight weeks. Brain glucose uptake was evaluated by 2-deoxy-2-[fluorine-18] fluoro-D-glucose under basal (saline administration) or stimulated (CL316,243, a selective β3-AR agonist) conditions. The animals were fasted for 10-12 h, anesthetized, and euthanized. The brain was quickly dissected, and the hippocampal area was sectioned and stored at -80°C in different tubes for protein and RNA analyses on the same animal. GK rats exhibited attenuated brain glucose uptake compared to Wistar animals and the HFHS group under basal conditions. Also, the hippocampus of GK rats displayed upregulated leptin receptor, IL-1β, and IL-6 gene expression and IL-1β and the subunit of the transcription factor NF-κB (p-p65) protein expression. No significant alterations were detected in the hippocampus of HFHS rats. Our data indicated that a genetic predisposition to T2DM has significant brain deteriorating features, including brain glucose hypometabolism, neuroinflammation, and leptin signaling disruption in the hippocampal area.

SCN5A compound heterozygosity mutation in Brugada syndrome: Functional consequences and the implication for pharmacological treatment.

AIMS: SCN5A gene encodes the α-subunit of Nav1.5, mainly found in the human heart. SCN5A variants are the most common genetic alterations associated with Brugada syndrome (BrS). In rare cases, compound heterozygosity is observed; however, its functional consequences are poorly understood. We aimed to analyze the functional impact of de novo Nav1.5 mutations in compound heterozygosity in distinct alleles (G400R and T1461S positions) previously found in a patient with BrS. Moreover, we evaluated the potential benefits of quinidine to improve the phenotype of mutant Na+ channels in vitro. MATERIALS AND METHODS: The functional properties of human wild-type and Nav1.5 variants were evaluated using whole-cell patch-clamp and immunofluorescence techniques in transiently expressed human embryonic kidney (HEK293) cells. KEY FINDINGS: Both variants occur in the highly conservative positions of SCN5A. Although all variants were expressed in the cell membrane, a significant reduction in the Na+ current density (except for G400R alone, which was undetected) was observed along with abnormal biophysical properties, once the variants were expressed in homozygosis and heterozygosis. Interestingly, the incubation of transfected cells with quinidine partially rescued the biophysical properties of the mutant Na+ channel. SIGNIFICANCE: De novo compound heterozygosis mutations in SNC5A disrupt the Na+ macroscopic current. Quinidine could partially reverse the in vitro loss-of-function phenotype of Na+ current. Thus, our data provide, for the first time, a detailed biophysical characterization of dysfunctional Na+ channels linked to compound heterozygosity in BrS as well as the benefits of the pharmacological treatment using quinidine on the biophysical properties of Nav1.5.

Evening preference correlates with regional brain volumes in the anterior occipital lobe.

Chronotype or diurnal preference is a questionnaire-based measure influenced both by circadian period and by the sleep homeostat. In order to further characterize the biological determinants of these measures, we used a hypothesis-free approach to investigate the association between the score of the morningness-eveningness questionnaire (MEQ) and the Munich chronotype questionnaire (MCTQ), as continuous variables, and volumetric measures of brain regions acquired by magnetic resonance imaging (MRI). Data were collected from the Baependi Heart Study cohort, based in a rural town in South-Eastern Brazil. MEQ and anatomical 1.5-T MRI scan data were available from 410 individuals, and MCTQ scores were available from a subset of 198 of them. The average MEQ (62.2 ± 10.6) and MCTQ (average MSFsc 201 ± 85 min) scores were suggestive of a previously reported strong general tendency toward morningness in this community. Setting the significance threshold at P > .002 to account for multiple comparisons, we observed a significant association between lower MEQ score (eveningness) and greater volume of the left anterior occipital sulcus (ß = -0.163, p = .001) of the occipital lobe. No significant associations were observed for MCTQ. This may reflect the smaller dataset for MCTQ, and/or the fact that MEQ, which asks questions about preferred timings, is more trait-like than the MCTQ, which asks questions about actual timings. The association between MEQ and a brain region dedicated to visual information processing is suggestive of the increasingly recognized fluidity in the interaction between visual and nonvisual photoreception and the circadian system, and the possibility that chronotype includes an element of masking.

In silico approach of modified melanoma peptides and their immunotherapeutic potential.

Melanoma is a type of skin cancer with increasing incidence worldwide and high lethality. Conventional forms of treatment are not effective in advanced cancer stages. Hence, immunotherapeutic approaches have been tested to modulate immune response against tumor cells. Some vaccine models using tumor-associated antigens (TAAs) such as glycoprotein 100 (gp100) have been studied, but their expected effectiveness has not been shown until now. Antigen immunogenicity is a crucial point to improve the immune response, and therefore mutations are inserted in peptide sequences. It is possible to understand the interactions which occur between peptides and immune system molecules through computer simulation, and this is essential in order to guide efficient vaccine models. In this work, we have calculated the interaction binding energies of crystallographic data based on modified gp100 peptides and HLA-A*0201 using density functional theory (DFT) and the molecular fractionation with conjugated caps (MFCC) approach. Our results show the most relevant residue-residue interactions, the impact of three mutations in their binding sites, and the main HLA-A*0201 amino acids for peptide-HLA binding.

Mitochondria, endoplasmic reticulum and innate immune dysfunction in mood disorders: Do Mitochondria-Associated Membranes (MAMs) play a role?

Mood disorders like major depression and bipolar disorder (BD) are among the most prevalent forms of mental illness. Current knowledge of the neurobiology and pathophysiology of these disorders is still modest and clear biological markers are still missing. Thus, a better understanding of the underlying pathophysiological mechanisms to identify potential therapeutic targets is a prerequisite for the design of new drugs as well as to develop biomarkers that help in a more accurate and earlier diagnosis. Multiple pieces of evidence including genetic and neuro-imaging studies suggest that mood disorders are associated with abnormalities in endoplasmic-reticulum (ER)-related stress responses, mitochondrial function and calcium signalling. Furthermore, deregulation of the innate immune response has been described in patients diagnosed with mood disorders, including depression and BD. These disease-related events are associated with functions localized to a subdomain of the ER, known as Mitochondria-Associated Membranes (MAMs), which are lipid rafts-like domains that connect mitochondria and ER, both physically and biochemically. This review will outline the current understanding of the role of mitochondria and ER dysfunction under pathological brain conditions, particularly in major depressive disorder (MDD) and BD, that support the hypothesis that MAMs can act in these mood disorders as the link connecting ER-related stress response and mitochondrial impairment, as well as a mechanisms behind sterile inflammation arising from deregulation of innate immune responses. The role of MAMs in the pathophysiology of these pathologies and its potential relevance as a potential therapeutic target will be discussed.

Genotoxicity effects on Geophagus brasiliensis fish exposed to Doce River water after the environmental disaster in the city of Mariana, MG, Brazil / Efeitos da genotoxicidade em peixes da espécie Geophagus brasiliensis expostos a água do Rio Doce após o desastre ambiental na cidade de Marina, MG, Brasil

Abstract The Doce River basin has suffered the largest environmental accident ever occurred in Brazil with the influx of tailings from Fundão and Santarém, belonging to Samarco mining company, due to the disaster in Mariana. A spill between 50 and 60 million m3 of tailings was estimated by the company. According to Samarco, the wastewater was composed mainly of clay, silt and heavy metals like iron, copper and manganese. Thereby, the objective of the present study was evaluated the genotoxic damage in juvenile of Geophagus brasiliensis (Quoy e Gaimard, 1824) exposed to Doce river water before (DRWBA - Doce River water before acident) and after (DRWAA - Doce River water after acident) the influx of tailings from the Germano and Santarém Dam disasters in Mariana, MG, Brazil. For this, 24 individuals of the species G. brasiliensis (obtained on IFES/ALEGRE fish culture) were submitted to a bioassay with three treatments and eight replicates. The treatments were: 1) Control water (water from the urban water supply system, filtered with a 0.45 µm membrane), 2) DRBA and 3) DRAA. After 96 h, these fishes were anesthetized to remove blood for evaluation of genotoxic damage (micronucleus and comet). For the bioassay, a total of 80 L of The Doce River water were collected before the influx of tailings and after the influx and then submitted to metal quantification analysis. Fish exposed to DRWBA and DRWAA treatments showed a significant increase in both the number of erythrocyte micronuclei and the DNA damage index in relation to the control fish; however, they did not present any differences between the two treatments. The results demonstrate that the DRWBA treatment was already genotoxic for the fish, mainly due to dissolved Cu concentrations in the water. The DRWAA treatment probably presented genotoxicity due to the increase in the dissolved fraction and synergistic effects of several metals found in the tailings of the Mariana accident.

Resumo A bacia do Rio Doce sofreu o maior acidente ambiental com o influxo de rejeitos de Fundão e Santarém, pertencentes à empresa de mineração Samarco, devido ao desastre em Mariana. Um derramamento entre 50 e 60 milhões de m3 de rejeitos foi estimado pela empresa. De acordo com a Samarco, o rejeito despejado era composto principalmente de argila, silte e alguns metais pesados como ferro, cobre e manganês. Com isso, o presente estudo teve como objetivo avaliar os danos genotóxicos em juvenis de Geophagus brasilienses expostos a água do rio Doce antes (DRWAA - água do Rio Doce antes do acidente) e depois (DRWBA- água do Rio Doce depois do acidente) da chegada dos rejeitos do rompimento das barragens de Germano e Santarém em Mariana, MG, Brasil. Para isso, 24 indivíduos da espécie G. brasilienses (obtidos na piscicultura do IFES/ALEGRE) foram submetidos a um bioensaio com três tratamentos e oito réplicas. Os tratamentos eram: 1) Controle (com água do abastecimento urbano, filtrada com filtro analítico de 0,45 µm); 2) DRWBA e 3) DRWAA. Após um período de 96 h, esses peixes foram anestesiados para retirada de sangue para avaliação dos danos genotóxicos (micronúcleo e cometa). Para a realização do bioensaio, um total de 80 L de água do Rio Doce foram coletados antes da chegada dos rejeitos e outros 80 L foram coletados depois da chegada dos rejeitos e ambas foram submetidas a análises de quantificação de metal. Os peixes expostos ao DRWBA e ao DRWAA apresentaram um aumento significativo na quantidade de micronúcleos eritrocitários e no índice de danos do DNA em relação aos peixes controle, no entanto não apresentaram diferenças entre si. Os resultados obtidos demonstram que a DRWBA já era genotóxica para os peixes, principalmente, em função das concentrações de Cu dissolvido na água. A DRWAA apresentou genotixicidade, provavelmente, em função do aumento da fração dissolvida e do efeito sinérgico de diversos metais presentes nos rejeitos do acidente de Mariana.

Heritability of semantic verbal fluency task using time-interval analysis.

Individual variability in word generation is a product of genetic and environmental influences. The genetic effects on semantic verbal fluency were estimated in 1,735 participants from the Brazilian Baependi Heart Study. The numbers of exemplars produced in 60 s were broken down into time quartiles because of the involvement of different cognitive processes-predominantly automatic at the beginning, controlled/executive at the end. Heritability in the unadjusted model for the 60-s measure was 0.32. The best-fit model contained age, sex, years of schooling, and time of day as covariates, giving a heritability of 0.21. Schooling had the highest moderating effect. The highest heritability (0.17) was observed in the first quartile, decreasing to 0.09, 0.12, and 0.0003 in the following ones. Heritability for average production starting point (intercept) was 0.18, indicating genetic influences for automatic cognitive processes. Production decay (slope), indicative of controlled processes, was not significant. The genetic influence on different quartiles of the semantic verbal fluency test could potentially be exploited in clinical practice and genome-wide association studies.

Metabolic syndrome alters relationships between cardiometabolic variables, cognition and white matter hyperintensity load.

Cardiometabolic risk factors influence white matter hyperintensity (WMH) development: in metabolic syndrome (MetS), higher WMH load is often reported but the relationships between specific cardiometabolic variables, WMH load and cognitive performance are uncertain. We investigated these in a Brazilian sample (aged 50-85) with (N = 61) and without (N = 103) MetS. Stepwise regression models identified effects of cardiometabolic and demographic variables on WMH load (from FLAIR MRI) and verbal recall performance. WMH volume was greater in MetS, but verbal recall performance was not impaired. Age showed the strongest relationship with WMH load. Across all participants, systolic blood pressure (SBP) and fasting blood glucose were also contributors, and WMH volume was negatively associated with verbal recall performance. In non-MetS, higher HbA1c, SBP, and number of MetS components were linked to poorer recall performance while higher triglyceride levels appeared to be protective. In MetS only, these relationships were absent but education exerted a strongly protective effect on recall performance. Thus, results support MetS as a construct: the clustering of cardiometabolic variables in MetS alters their individual relationships with cognition; instead, MetS is characterised by a greater reliance on cognitive reserve mechanisms. In non-MetS, strategies to control HbA1c and SBP should be prioritised as these have the largest impact on cognition.

Both serotonergic and noradrenergic systems modulate the development of tolerance to chronic stress in rats with lesions of the serotonergic neurons of the median raphe nucleus.

Acute exposure to stress induces significant behavioural changes, while repeated exposure to the same stressor leads to the development of tolerance to stress. The development of tolerance appears to involve the serotonergic projections from the Median Raphe Nucleus (MnRN) to the dorsal Hippocampus (dH), since rats with lesions of this pathway does not develop tolerance to stress. Previous data from our laboratory showed that treatment with imipramine, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor, lead to the development of tolerance. However, it remains to be elucidated whether such tolerance involves the participation of the noradrenergic system, apart from the serotonergic projections. Therefore, the aim of this work was to investigate the behavioural and neurochemical effects of chronic treatment with desipramine (NA reuptake inhibitor) or fluoxetine (5-HT reuptake inhibitor) in chronically stressed rats with lesions of the serotonergic neurons of the MnRN. Male Wistar rats with or without lesion in the MnRN were submitted or not to acute (2 h) or chronic restraint (2 h/seven days) stress and tested in the elevated pus maze (EPM). Treatment with fluoxetine, desipramine (10 mg/kg) or saline was performed twice daily (12-12 h interval), for 7 consecutive days. EPM test was conducted 24 h after the treatment. Fluoxetine attenuated the anxiogenic-induced effect of lesion in chronically restrained rats, without changing serotonin and noradrenaline levels in the hippocampus of lesioned rats. A similar profile was also observed after treatment with desipramine. These results suggest that both the serotonergic and the noradrenergic systems are involved in the development of tolerance to chronic stress. Additionally, the integrity of the serotonergic pathway of the MnRN-dH is not essential for the anxiolytic-like effects of these drugs.

Metabolites related to eGFR: Evaluation of candidate molecules for GFR estimation using untargeted metabolomics.

BACKGROUND: Metabolomics can be used to identify novel metabolites related to renal function and that could therefore be used for estimating GFR. We evaluated metabolites replicated and related to eGFR in 3 studies (CKD and general population). METHODS: Metabolomics was performed by GC-MS. The Progredir Cohort (n = 454, class 3 and 4 CKD) was used as the derivation study and adjusted linear regression models on eGFR-CKDEPI were built. Bonferroni correction was applied for selecting metabolites to be independently validated in the Diabetic Nephropathy Study (n = 56, macroalbuminuric DN) and in the Baependi Heart Study (BHS, n = 1145, general population). RESULTS: In the Progredir Cohort, 72 metabolites where associated with eGFR. Of those, 11 were also significantly associated to eGFR in the DN Study and 8 in the BHS. Four metabolites were replicated and significantly associated to eGFR in all 3 studies: d-threitol, myo-inositol, 4-deoxierythronic acid and galacturonic acid. In addition, pseudouridine was strongly correlated to eGFR only in the 2 CKD populations. CONCLUSIONS: Our results demonstrate metabolites that are potential biomarkers of renal function: d-threitol, myo-inositol, 4-deoxierythronic acid, galacturonic acid and pseudouridine. Further investigation is needed to determine their performance against otherwise gold-standard methods, most notably among those with normal eGFR.

Genotoxicity effects on Geophagus brasiliensis fish exposed to Doce River water after the environmental disaster in the city of Mariana, MG, Brazil.

The Doce River basin has suffered the largest environmental accident ever occurred in Brazil with the influx of tailings from Fundão and Santarém, belonging to Samarco mining company, due to the disaster in Mariana. A spill between 50 and 60 million m3 of tailings was estimated by the company. According to Samarco, the wastewater was composed mainly of clay, silt and heavy metals like iron, copper and manganese. Thereby, the objective of the present study was evaluated the genotoxic damage in juvenile of Geophagus brasiliensis (Quoy e Gaimard, 1824) exposed to Doce river water before (DRWBA - Doce River water before acident) and after (DRWAA - Doce River water after acident) the influx of tailings from the Germano and Santarém Dam disasters in Mariana, MG, Brazil. For this, 24 individuals of the species G. brasiliensis (obtained on IFES/ALEGRE fish culture) were submitted to a bioassay with three treatments and eight replicates. The treatments were: 1) Control water (water from the urban water supply system, filtered with a 0.45 µm membrane), 2) DRBA and 3) DRAA. After 96 h, these fishes were anesthetized to remove blood for evaluation of genotoxic damage (micronucleus and comet). For the bioassay, a total of 80 L of The Doce River water were collected before the influx of tailings and after the influx and then submitted to metal quantification analysis. Fish exposed to DRWBA and DRWAA treatments showed a significant increase in both the number of erythrocyte micronuclei and the DNA damage index in relation to the control fish; however, they did not present any differences between the two treatments. The results demonstrate that the DRWBA treatment was already genotoxic for the fish, mainly due to dissolved Cu concentrations in the water. The DRWAA treatment probably presented genotoxicity due to the increase in the dissolved fraction and synergistic effects of several metals found in the tailings of the Mariana accident.

Thyrotropin and free thyroxine levels and coronary artery disease: cross-sectional analysis of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

Data on the association between subclinical thyroid dysfunction and coronary artery disease (CAD) is scarce. We aimed to analyze the association between thyroid function and CAD using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). We included subjects with normal thyroid function (0.4-4.0 mIU/L, and normal free thyroxine, FT4, or 0.8 to 1.9 ng/dL), subclinical hypothyroidism (SCHypo; TSH>4.0 mIU/L and normal FT4), and subclinical hyperthyroidism (SCHyper; TSH<0.4 mIU/L and normal FT4) evaluated by coronary computed tomography angiography. We excluded individuals using medications that interfere in thyroid function or with past medical history of cardiovascular disease. Logistic regression models evaluated the presence of CAD, segment involvement score (SIS) >4, and segment severity score (SSS) >4 of coronary arteries as the dependent variables, and quintiles of TSH and FT4 as the independent variables, adjusted for demographical data and cardiovascular risk factors. We included 767 subjects, median age 58 years (IQR=55-63), 378 (49.3%) women, 697 euthyroid (90.9%), 57 (7.4%) with SCHypo, and 13 (1.7%) with SCHyper. No association between TSH and FT4 quintiles and CAD prevalence was noted. Similarly, no association between TSH levels and the extent or severity of CAD, represented by SIS>4 and SSS>4 were seen. Restricting analysis to euthyroid subjects did not alter the results. TSH levels were not significantly associated with the presence, extent, or severity of CAD in a middle-aged healthy population.

-318C/T polymorphism of the CTLA-4 gene is an independent risk factor for RBC alloimmunization among sickle cell disease patients.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule is expressed on T-lymphocyte membrane and negatively influences the antigen-presenting process. Reduced expression of CTLA-4 due to gene polymorphisms is associated with increased risk of autoimmune disorders, whose physiopathology is similar to that of post-transfusion red blood cell (RBC) alloimmunization. Our goal was to evaluate if polymorphisms of CTLA-4 gene that affect protein expression are associated with RBC alloimmunization. This was a case-control study in which 134 sickle cell disease (SCD) patients and 253 non-SCD patients were included. All patients were genotyped for the polymorphisms 49A/G and -318C/T of CTLA-4 gene. The genotype frequency of -318C/T differed significantly between alloimmunized and nonalloimmunized SCD patients, irrespective of clinical confounders (p = .016). SCD patients heterozygous for -318T allele presented higher risk of alloantibody development (OR: 5.4, CI: 1.15-25.6). In conclusion, the polymorphism -318C/T of CTLA-4 gene is associated with RBC alloimmunization among SCD patients. This highlights the role played by CTLA-4 on post-transfusion alloantibody development.

Impact of periodontal disease on quality of life: a systematic review.

The diagnosis of periodontal disease is commonly based on objective evaluations of the patient's medical/dental history as well as clinical and radiographic examinations. However, periodontal disease should also be evaluated subjectively through measures that quantify its impact on oral health-related quality of life. The aim of this study was to evaluate the impact of periodontal disease on quality of life among adolescents, adults and older adults. A systematic search of the literature was performed for scientific articles published up to July 2015 using electronic databases and a manual search. Two independent reviewers performed the selection of the studies, extracted the data and assessed the methodological quality. Thirty-four cross-sectional studies involving any age group, except children, and the use of questionnaires for the assessment of the impact of periodontal disease on quality of life were included. Twenty-five studies demonstrated that periodontal disease was associated with a negative impact on quality of life, with severe periodontitis exerting the most significant impact by compromising aspects related to function and esthetics. Unlike periodontitis, gingivitis was associated with pain as well as difficulties performing oral hygiene and wearing dentures. Gingivitis was also negatively correlated with comfort. The results indicate that periodontal disease may exert an impact on quality of life of individuals, with greater severity of the disease related to greater impact. Longitudinal studies with representative samples are needed to ensure validity of the findings.

Age and Alzheimer's disease gene expression profiles reversed by the glutamate modulator riluzole.

Alzheimer's disease (AD) and age-related cognitive decline represent a growing health burden and involve the hippocampus, a vulnerable brain region implicated in learning and memory. To understand the molecular effects of aging on the hippocampus, this study characterized the gene expression changes associated with aging in rodents using RNA-sequencing (RNA-seq). The glutamate modulator, riluzole, which was recently shown to improve memory performance in aged rats, prevented many of the hippocampal age-related gene expression changes. A comparison of the effects of riluzole in rats against human AD data sets revealed that many of the gene changes in AD are reversed by riluzole. Expression changes identified by RNA-Seq were validated by qRT-PCR open arrays. Riluzole is known to increase the glutamate transporter EAAT2's ability to scavenge excess glutamate, regulating synaptic transmission. RNA-seq and immunohistochemistry confirmed an increase in EAAT2 expression in hippocampus, identifying a possible mechanism underlying the improved memory function after riluzole treatment.