Vascular dysfunction programmed in male rats by topiramate during peripubertal period.

AIM: The present study evaluated whether topiramate (TPM) treatment during the peripubertal period affects vascular parameters of male rats and whether oxidative stress plays a role in these changes. MAIN METHODS: Rats were treated with TPM (41 mg/kg/day, gavage) or vehicle (CTR group) from the postnatal day (PND) 28 to 50. At PND 51 and 120 the rats were evaluated for: thoracic aorta reactivity to phenylephrine, in the presence (Endo+) or absence of endothelium (Endo-), to acetylcholine and to sodium nitroprusside (SNP), aortic thickness and endothelial nitric oxide synthase (eNOS) expression. In serum were analyzed: the antioxidant capacity by ferric reducing antioxidant power assay; endogenous antioxidant reduced glutathione, and superoxide anion. Results were expressed as mean ± s.e.m., differences when p < 0.05. STATISTICS: Two-way ANOVA (and Tukey's) or Student t-test. KEY FINDINGS: At PND 51, the contraction induced by phenylephrine in Endo+ ring was higher in TPM when compared to CTR. At PND 120, the aortic sensitivity to acetylcholine in TPM rats was reduced in comparison with CTR. The aortic eNOs expression and the aortic thickness were similar between the groups. At PND 51 and 120, TPM group presented a decrease in antioxidants when compared to CTR groups and at PND 120, in TPM group the superoxide anion was increased. SIGNIFICANCE: Taken together, the treatment of rats with TPM during peripubertal period promoted permanent impairment of endothelial function probably mediated by oxidative stress.

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease.

Background: The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives: To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods: The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results: The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions: The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Contexto: O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos: Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos: Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados: Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões: O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

Development of a Melting-Curve-Based Multiplex Real-Time PCR Assay for the Simultaneous Detection of Viruses Causing Respiratory Infection.

The prompt and accurate identification of the etiological agents of viral respiratory infections is a critical measure in mitigating outbreaks. In this study, we developed and clinically evaluated a novel melting-curve-based multiplex real-time PCR (M-m-qPCR) assay targeting the RNA-dependent RNA polymerase (RdRp) and nucleocapsid phosphoprotein N of SARS-CoV-2, the Matrix protein 2 of the Influenza A virus, the RdRp domain of the L protein from the Human Respiratory Syncytial Virus, and the polyprotein from Rhinovirus B genes. The analytical performance of the M-m-qPCR underwent assessment using in silico analysis and a panel of reference and clinical strains, encompassing viral, bacterial, and fungal pathogens, exhibiting 100% specificity. Moreover, the assay showed a detection limit of 10 copies per reaction for all targeted pathogens using the positive controls. To validate its applicability, the assay was further tested in simulated nasal fluid spiked with the viruses mentioned above, followed by validation on nasopharyngeal swabs collected from 811 individuals. Among them, 13.4% (109/811) tested positive for SARS-CoV-2, and 1.1% (9/811) tested positive for Influenza A. Notably, these results showed 100% concordance with those obtained using a commercial kit. Therefore, the M-m-qPCR exhibits great potential for the routine screening of these respiratory viral pathogens.

IL36G genetic variant is independently associated with susceptibility, severity and joint involvement in psoriasis.

Psoriasis (PsO) is a chronic, immune-mediated, inflammatory and polygenic dermatosis associated with both physical and psychological burden that can be triggered by injury, trauma, infections and medications. The etiology of PsO is not fully elucidated but genetic, epigenetic and environmental factors are all likely to play a role. A case-control study was carried out to evaluate the frequency of the IL36G C>T (rs13392494) and the IL36G A>G (rs7584409) variants and their association with susceptibility, joint involvement and severity of PsO. The study included 154 patients with PsO and 154 controls from Brazilian population. The severity of PsO was assessed by the Psoriasis Area and Severity Index (PASI). The IL36G (rs13392494 and rs7584409) variants were genotyped by allelic discrimination assay using the real-time polymerase chain reaction. The association between the IL36G genetic variants and the study variables was analyzed in allelic, dominant, codominant, overdominant, recessive, and haplotype models. The main results were that PsO patients were older (p < 0.001) and had higher body mass index (p < 0.001) than controls; 95.8% of the patients had plaque PsO, 16.1% had psoriatic arthritis (PsA), and 27.9% had PASI > 10. The IL36G rs1339294 variant showed no association with PsO in all genetic models while the IL36G rs7584409 variant showed a protective effect in PsO. However, the G allele of the IL36G rs7584409 in the dominant model was positively associated with PASI > 10 (p = 0.031). Moreover, patients with the GG genotype of the IL36G rs7584409 variant had about 5.0 times more chance of PsA than those with the AA genotype (p = 0.014). Regarding the haplotypes, the C/A in a recessive model (CACA versus C/G and T/A carriers) was associated with PsO (p = 0.035) while the C/G haplotype in a dominant model (C/A carriers versus C/G and T/A carriers) showed a protective effect for PsO (p = 0.041). In conclusion, the G allele of the IL36G rs7584409 variant was associated with protection to PsO; however, in patients with PsO, this same allele was associated with moderate to severe disease and PsA. These results suggest that the IL36G rs7584409 variant may be used as a possible genetic biomarker to predict severity and joint involvement of PsO.

Biogenic silver nanoparticle exhibits schistosomicidal activity in vitro and reduces the parasitic burden in experimental schistosomiasis mansoni.

Schistosomiasis is a neglected tropical parasitic disease that affects millions of people, being the second most prevalent parasitic disease worldwide. The current treatment has limited effectiveness, drug-resistant strains, and is not effective in different stages of the disease. This study investigated the antischistosomal activity of biogenic silver nanoparticles (Bio-AgNp) against Schistosoma mansoni. Bio-AgNp presented direct schistosomicidal activity on newly transformed schistosomula causing plasma membrane permeabilization. In S. mansoni adult worms, reduced the viability and affected the motility, increasing oxidative stress parameters, and inducing plasma membrane permeabilization, loss of mitochondrial membrane potential, lipid bodies accumulation, and autophagic vacuoles formation. During the experimental schistosomiasis mansoni model, Bio AgNp restored body weight, reduced hepatosplenomegaly, and decrease the number of eggs and worms in feces and liver tissue. The treatment also ameliorates liver damage and reduces macrophage and neutrophil infiltrates. A reduction in count and size was evaluated in the granulomas, as well as a change to an exudative-proliferative phase, with a local increase of IFN-γ. Together our results showed that Bio-AgNp is a promising therapeutic candidate for studies of new therapeutic strategies against schistosomiasis.

Gestational exposure to continuous light impairs the development of the female reproductive system in adult Wistar rat offspring.

INTRODUCTION: It has been suggested that maternal exposure to constant light during the gestational period could be considered as a chronic stressor, impairing offspring development by interfering in neuroendocrine and behavior responses. OBJECTIVE: This study aimed to evaluate whether maternal exposure to continuous light during pregnancy affects the adult reproductive system in the female offspring. MATERIALS AND METHODS: Pregnant Wistar rats were allocated into light-dark (LD) group, exposed to light and dark photoperiod during gestation, and the light-light (LL) group, exposed to a photoperiod of constant light during gestation. After birth, pups were maintained under normal light-dark photoperiod until adulthood. At postnatal day 90, blood was collected from the female offspring, to analyze plasma luteinizing hormone (LH) and progesterone levels, and the uterus and ovaries were harvested for morphometric, histological, and oxidative stress evaluations. RESULTS AND DISCUSSION: Female exposure to continuous light during the intrauterine period resulted in the adult reduction of LH and increased progesterone plasma levels, and uterine injuries a higher number of endometrial glands and reduced levels of antioxidant enzymes, such as glutathione reductase and glutathione S-transferase. In these experimental conditions, gestational continuous light exposure disturbs sex hormone balance and reduces the antioxidant enzymatic activity in the uterus of female offspring in adult life.

Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke.

The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24 h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.

An MGMT Allelic Variant Can Affect Biochemical Relapse in Prostate Cancer Patients.

BACKGROUND/AIM: Prostate cancer (PCa) is one of the most frequent neoplasms in men around the world. In recent years, the search for new biomarkers with greater prognostic potential for PCa has intensified. This study aimed to evaluate single nucleotide polymorphisms (SNPs) and a combined panel of these polymorphisms in relation to biochemical recurrence in patients who were through prostatectomy, with an average of 7 years of follow-up. MATERIALS AND METHODS: Patients diagnosed with PCa (n=197) participated in this cohort study. Thirteen SNPs were analyzed: rs2279115 (BCL-2), rs26677604 (CASP3), rs1052571 (CASP9), rs11781886 (NKX3-1), rs2735343 (PTEN), rs2494750 (AKT1), rs2699887 (PI3KCA), rs3195676 (AMACR), rs17302090 (AR), rs2536 (mTOR), rs1695 (GSTP1), rs2308321 (MGMT) and rs1544410 (VDR). Variants were combined and four main panels were defined: cell death, cell survival, growth receptors, and metabolism. Genotyping was performed by real-time PCR. RESULTS: We did not observe any significant relation between the panels of variants analyzed, apart from the rare allele (G) of rs2308321 (MGMT) that was associated with a higher risk of recurrence (p=0.036) when compared to the prevalent (A) in the allelic model. CONCLUSION: This MGMT variant occurs in an exon, and it could potentially affect DNA repair and, therefore, the biochemical relapse of PCa patients.

MTHFR 677C>T (rsRS1801133) variant is associated with hyperhomocysteinemia but not with clinical severity in patients with peripheral arterial disease / A variante MTHFR 677C>T (RS1801133) está associada a hiperhomocisteinemia, mas não a gravidade clínica em pacientes com doença arterial periférica

Abstract Background The MTHFR 677C>T variant's involvement with hyperhomocysteinemia and peripheral arterial disease (PAD) is still unclear. Objectives To evaluate associations between the MTHFR 677C>T (rs1801133) variant and susceptibility to and severity of PAD and homocysteine (Hcy) levels. Methods The study enrolled 157 PAD patients and 113 unrelated controls. PAD severity and anatomoradiological categories were assessed using the Fontaine classification and the Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC), respectively. The variant was genotyped using real-time polymerase chain reaction and Hcy levels were determined using chemiluminescence microparticle assay. Results The sample of PAD patients comprised 60 (38.2%) females and 97 (61.8%) males. Patients were older and had higher Hcy than controls (median age of 69 vs. 45 years, p<0.001; and 13.66 µmol/L vs. 9.91 µmol/L, p=0.020, respectively). Hcy levels and the MTHFR 677C>T variant did not differ according to Fontaine or TASC categories. However, Hcy was higher in patients with the CT+TT genotypes than in those with the CC genotype (14.60 µmol/L vs. 12.94 µmol/L, p=0.008). Moreover, patients with the TT genotype had higher Hcy than those with the CC+CT genotypes (16.40 µmol/L vs. 13.22 µmol/L, p=0.019), independently of the major confounding variables. Conclusions The T allele of MTHFR 677C>T variant was associated with higher Hcy levels in PAD patients, but not in controls, suggesting a possible interaction between the MTHFR 677C>T variant and other genetic, epigenetic, or environmental factors associated with PAD, affecting modulation of Hcy metabolism.

Resumo Contexto O envolvimento da variante MTHFR 677C>T na hiperhomocisteinemia e na doença arterial periférica (DAP) ainda não está claro. Objetivos Avaliar a associação da variante MTHFR 677C>T (rs1801133) com suscetibilidade e gravidade da DAP e valores séricos de homocisteína (Hcy). Métodos Este estudo caso-controle envolveu 157 pacientes com DAP e 113 controles não relacionados. A gravidade e as categorias anatomorradiológicas da DAP foram avaliadas pela classificação de Fontaine e pelo Inter-Society Consensus for the Management of Peripheral Arterial Disease, respectivamente. A genotipagem foi realizada por meio de reação em cadeia da polimerase em tempo real, e os valores de Hcy foram determinados por ensaio de micropartículas de quimioluminescência. Resultados Entre os pacientes com DAP, 97 (61,8%) eram homens e 60 (38,2%) eram mulheres, com mediana de idade de 69 anos. Os pacientes com DAP eram mais velhos e apresentaram valores mais elevados de Hcy do que os controles (mediana de 69 vs. 45 anos de idade, p < 0,001; 13,66 µmol/L vs. 9,91 µmol/L, p = 0,020, respectivamente). Os valores de Hcy foram mais elevados em pacientes com os genótipos CT+TT do que aqueles com o genótipo CC (14,60 µmol/L vs. 12,94 µmol/L, p = 0,008). Além disso, os pacientes com o genótipo TT apresentaram valores mais elevados de Hcy do que aqueles com os genótipos CC+CT (16,40 µmol/L vs. 13,22 µmol/L, p = 0,019, respectivamente), independentemente das principais variáveis confundidoras. Conclusões O alelo T da variante MTHFR 677C>T foi associado a valores mais elevados de Hcy nos pacientes com DAP, mas não em controles, sugerindo uma possível interação entre a variante genética MTHFR 677C>T e outros fatores genéticos, epigenéticos ou ambientais associados com a DAP na modulação do metabolismo da Hcy.

USE OF MOUTHWASH AND DENTIFRICE CONTAINING AN ANTIMICROBIAL PHTHALOCYANINE DERIVATIVE FOR THE REDUCTION OF CLINICAL SYMPTOMS OF COVID-19: A RANDOMIZED TRIPLE-BLIND CLINICAL TRIAL.

PURPOSE: This clinical trial aimed to evaluate the use of mouthwash and dentifrice containing an antimicrobial phthalocyanine derivative (APD) to reduce the clinical symptoms in patients with COVID-19. METHODS: This randomized, triple-blind clinical trial enrolled 134 patients aged 18 years or older who underwent COVID-19 testing through the use of nasopharyngeal swab RT-qPCR in a reference center for the diagnosis of COVID-19, had no clinical contraindications to mouthwash and gargle, and had access to cell phones with communication applications. According to the use of a mouthwash and dentifrice containing antimicrobial phthalocyanine derivatives (APD), patients were randomly assigned (1:1) to the APD or non-APD (control) group. All participants were instructed to floss twice a day, brush teeth for 2 minutes 3 times a day, and gargle/rinse (5 mL) for 1 min/3 times a day for 7 days. An online questionnaire was sent to collect data on the clinical symptoms of COVID-19 3 times: T0 (baseline before using the oral hygiene products), T3 (3 days after), and T7 (7 days after). The investigators, patients, and outcome assessors were blinded to group assignment. The Mann-Whitney, Chi-Square, Fisher's exact, and Cochran's tests were used according to the nature of the variables studied, with the level of significance set at P < .05. RESULTS: No statistically significant difference was found in the prevalence of symptoms between groups at baseline. A statistically significant reduction in clinical symptoms was found in the control group (fatigue, shortness of breath, hoarse voice, sore throat, nasal congestion, and chest pain) and APD group (cough, fatigue, shortness of breath, hyposmia/anosmia, dysgeusia, hoarse voice, sore throat, nasal congestion, chest pain, diarrhea, and irritability/confusion) during the follow-up period. There were statistically significant differences, with a higher prevalence of symptoms in the control group at T3 and T7. Dysgeusia, sore throat, and irritability/confusion were less prevalent in the APD group at T3, and shortness of breath, hyposmia/anosmia, dysgeusia, hoarse voice, sore throat, diarrhea, and irritability/confusion were more prevalent in the control group at T7. CONCLUSIONS: Based on this methodology, the results demonstrated that the regular use of mouthwash and dentifrice-containing APD had a positive impact on the clinical symptoms, as reported by patients with COVID-19.

FOXP3 variants are independently associated with transforming growth factor Β1 plasma levels in female patients with inflammatory bowel disease.

OBJECTIVE: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-ß1 plasma levels. METHOD: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-ß1 were determined using immunofluorimetric assay. RESULTS: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-ß1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-ß1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. CONCLUSIONS: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.

In COVID-19, NLRP3 inflammasome genetic variants are associated with critical disease and these effects are partly mediated by the sickness symptom complex: a nomothetic network approach.

In coronavirus disease (COVID-19), the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Acute infections are accompanied by a sickness symptom complex (SSC) which is highly conserved and protects against infections and hyperinflammation. The aim of this study is to delineate the associations of COVID-19, SSC and NLPR3 rs10157379 T > C and NLPR3 rs10754558 C > G variants; and the protective role of SSC in SARS-CoV-2 infection. We recruited COVID-19 patients, 308 with critical, 63 with moderate and 157 with mild disease. Increased SSC protects against SARS, critical disease, and death due to COVID-19. Increasing age, male sex and rs10754558 CG significantly reduce SSC protection. The rs10157379 CT and rs10754558 GG genotypes are positively associated with SARS. Partial Least Squares analysis shows that a) 41.8% of the variance in critical COVID-19 symptoms is explained by SSC and oxygen saturation (inversely associated), inflammation, chest computed tomography abnormalities, increased body mass index, SARS and age (positively associated); and b) the effects of the NLRP3 rs10157379 and rs10754558 variants on critical COVID-19 are mediated via SSC (protective) and SARS (detrimental). SSC includes anosmia and dysgeusia, and maybe gastrointestinal symptoms. In conclusion, intersections among the rs10754558 variant, age, and sex increase risk towards critical COVID-19 by attenuating SSC. NLRP3 variants play an important role in SARS, and severe and critical COVID-19 especially in elderly male individuals with reduced SSC and with increased BMI, hypertension, and diabetes type 2.

Cyantraniliprole impairs reproductive parameters by inducing oxidative stress in adult female wistar rats.

Cyantraniliprole is a synthetic insecticide used to control pests of up to 23 different types of crops. It is able to modulate ryanodine-like calcium channels, which are widely found in the organism of insects and mammals. The objective of this research was to verify the possible reproductive effects of adult female Wistar rats exposure to cyantraniliprole. Animals (67 days old) were exposed to the chemical at doses of 10 or 150 mg/kg/day, orally, for 28 consecutive days (control animals received only the vehicle). Vaginal secretions were collected during the exposure period to assess the regularity of the estrous cycle; the liver, kidneys, pituitary gland, adrenal gland, uterus, and ovaries were collected and weighed; reproductive organs were assessed for histopathological evaluation and for biochemical markers of oxidative stress and progesterone plasma level was measured. Both doses caused negative changes in the morphology and redox system of the uterus and ovaries. Animals exposed to 10 mg/kg also exhibited higher level of plasma progesterone, elevated levels of lipid peroxidation in reproductive organs, increased superoxide dismutase activity in the uterus and glutathione peroxidase activity on the ovary, while the 150 mg/kg group exhibited an increment in estrous cycle length and diminished uterine glandular epithelium. Based on these results, we conclude that cyantraniliprole may have acted as an endocrine disruptor, and its effects are mediated by oxidative stress.

TGFB1 (rs1800470 and rs1800469) variants are independently associated with disease activity and autoantibodies in rheumatoid arthritis patients.

To evaluate the association between TGFB1 + 869 T > C (rs1800470) and TGFB1-509 C > T (rs1800469) variants with susceptibility for rheumatoid arthritis (RA), disease activity, presence of rheumatoid factor (RF), anti-cyclic citrullinated peptide (anti-CCP) and TGF-ß1 plasma levels. A total of 262 patients with RA and 168 control individuals were tested for the TGFB1 variants using a TaqMan genotyping assay. Disease activity score in 28 joints (DAS28) classified RA patients into two groups of disease activity: remission/mild (DAS28 < 3.2) and moderate/severe (DAS28 ≥ 3.2). TGFB1 + 869 T > C and -509 C > T variants, independently or in haplotype combination, were not associated with RA's susceptibility. Patients with the TGFB1-509 TT genotype had a higher frequency of DAS28 ≥ 3.2 (OR 2.58, 95% CI 1.04-6.42, p = 0.041). The TGFB1 + 869 CC genotype in seropositive patients for RF or anti-CCP was associated with decreased TGF-ß1 levels (p = 0.032 and p = 0.039, respectively). Patients with the TGFB1 + 869 C allele and elevated RF titles demonstrated a higher frequency of DAS28 ≥ 3.2 (p = 0.037). The TGFB1 + 869 T > C variant was associated with diminished TGF-ß1 plasma levels and moderate/severe activity disease only in seropositive RF patients. This is the first study showing that TGF-ß1 plasma levels can be modulated by the interaction between the TGFB1 + 869 T > C variant and autoantibodies. However, the TGFB1-509 C > T variant was associated with moderate/severe activity disease, independently of autoantibodies positivity. Thus, our findings suggest that TGFB1 + 869 T > C and -509 C > T variants can predict activity disease in different RA patient subgroups.

Immune-inflammatory, coagulation, adhesion, and imaging biomarkers combined in machine learning models improve the prediction of death 1 year after ischemic stroke.

Some clinical, imaging, and laboratory biomarkers have been identified as predictors of prognosis of acute ischemic stroke (IS). The aim of this study was to evaluate the prognostic validity of a combination of clinical, imaging, and laboratory biomarkers in predicting 1-year mortality of IS. We evaluated 103 patients with IS within 24 h of their hospital admission and assessed demographic data, IS severity using the National Institutes of Health Stroke Scale (NIHSS), carotid intima-media thickness (cIMT), and degree of stenosis, as well as laboratory variables including immune-inflammatory, coagulation, and endothelial dysfunction biomarkers. The IS patients were categorized as survivors and non-survivors 1 year after admission. Non-survivors showed higher NIHSS and cIMT values, lower antithrombin, Protein C, platelet counts, and albumin, and higher Factor VIII, von Willebrand Factor (vWF), white blood cells, tumor necrosis factor (TNF)-α, interleukin (IL)-10, high-sensitivity C-reactive protein (hsCRP), and vascular cellular adhesion molecule 1 (VCAM-1) than survivors. Neural network models separated non-survivors from survivors using NIHSS, cIMT, age, IL-6, TNF-α, hsCRP, Protein C, Protein S, vWF, and platelet endothelial cell adhesion molecule 1 (PECAM-1) with an area under the receiving operating characteristics curve (AUC/ROC) of 0.975, cross-validated accuracy of 93.3%, sensitivity of 100% and specificity of 85.7%. In conclusion, imaging, immune-inflammatory, and coagulation biomarkers add predictive information to the NIHSS clinical score and these biomarkers in combination may act as predictors of 1-year mortality after IS. An early prediction of IS outcome is important for personalized therapeutic strategies that may improve the outcome of IS.

FOXP3 variants are independently associated with transforming growth factor B1 plasma levels in female patients with inflammatory bowel disease

Abstract Objective: The aim of this study was to evaluate the association of -924 G>A (rs2232365) and -3279 C>A (rs3761548) FOXP3 variants with IBD susceptibility, clinical and endoscopic activity, and IL-10 and TGF-β1 plasma levels. Method: The study included 110 IBD female patients, 60 with Ulcerative Colitis (UC) and 50 with Crohn's Disease (CD), and 154 female controls. FOXP3 variants were determined with Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP). Plasma levels of IL-10 and TGF-β1 were determined using immuno-fluorimetric assay. Results: AA genotype of rs2232365 and rs3761548 was associated with CD (OR = 3.147, 95% CI 1.015-9.758, p = 0.047) and UC (OR = 3.221, 95% CI 1.050-9.876, p = 0.041) susceptibility, respectively. However, were not associated with TGF-β1 and IL-10 levels, and endoscopic/clinical activity disease. GAGA haplotype was associated with IBD (OR = 4.003, 95% CI 1.100-14.56, p = 0.035) and UC susceptibility (OR = 6.107, 95% CI 1.609-23.18, p = 0.008). In addition, IBD patients with the GAGA haplotype had lower TGF-β1 levels (p = 0.041). Moreover, G/C haplotype (dominant model) had a protective effect of 60% in CD susceptibility and lower Endoscopic Severity Index. Conclusions: These results suggest that FOXP3 variants could exert a role in the Treg, which could be one of the factors involved in the susceptibility and pathogenesis of IBD.

Beneficial effects of a mouthwash containing an antiviral phthalocyanine derivative on the length of hospital stay for COVID-19: randomised trial.

The risk of contamination and dissemination by SARS-CoV-2 has a strong link with nasal, oral and pharyngeal cavities. Recently, our research group observed the promising performance of an anionic phthalocyanine derivative (APD) used in a mouthwash protocol without photoexcitation; this protocol improved the general clinical condition of patients infected with SARS-CoV-2. The present two-arm study evaluated in vitro the antiviral activity and cytotoxicity of APD. Additionally, a triple-blind randomized controlled trial was conducted with 41 hospitalized patients who tested positive for COVID-19. All the included patients received World Health Organization standard care hospital treatment (non-intensive care) plus active mouthwash (experimental group AM/n = 20) or nonactive mouthwash (control group NAM/n = 21). The adjunct mouthwash intervention protocol used in both groups consisted one-minute gargling/rinsing / 5 times/day until hospital discharge. Groups were compared considering age, number of comorbidities, duration of symptoms prior admission and length of hospital stay (LOS). The associations between group and sex, age range, presence of comorbidities, admission to Intensive care unit (ICU) and death were also evaluated. The in vitro evaluation demonstrated that APD compound was highly effective for reduction of SARS-CoV-2 viral load in the 1.0 mg/mL (99.96%) to 0.125 mg/mL (92.65%) range without causing cytotoxicity. Regarding the clinical trial, the median LOS of the AM group was significantly shortened (4 days) compared with that of the NAM group (7 days) (p = 0.0314). Additionally, gargling/rinsing with APD was very helpful in reducing the severity of symptoms (no ICU care was needed) compared to not gargling/rinsing with APD (28.6% of the patients in the NAM group needed ICU care, and 50% of this ICU subgroup passed way, p = 0.0207). This study indicated that the mechanical action of the protocol involving mouthwash containing a compound with antiviral effects against SARS-CoV-2 may reduce the symptoms of the patients and the spread of infection. The use of APD in a mouthwash as an adjuvant the hospital COVID-19 treatment presented no contraindication and reduced the hospital stay period.Trial registration: The clinical study was registered at REBEC-Brazilian Clinical Trial Register (RBR-58ftdj).