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Daniel FC Mazo,1 Marcelo G de Oliveira,2 Isabel VA Pereira,1 Bruno Cogliati,3 José T Stefano,1 Gabriela FP de Souza,2 Fabíola Rabelo,1 Fabiana R Lima,4 Venâncio A Ferreira Alves,4 Flair J Carrilho,1 Claudia PMS de Oliveira1 1University of São Paulo School of Medicine, Department of Gastroenterology, Clinical Division, Hepatology Branch (LIM-07), Sao Paulo, Brazil; 2Institute of Chemistry, University of Campinas, Campinas, Sao Paulo, Brazil; 3University of Sao Paulo School of Veterinary Medicine and Animal Science, Department of Pathology, Sao Paulo, Brazil; 4University of São Paulo School of Medicine, Department of Pathology (LIM14), São Paulo, Brazil Abstract: S-Nitroso-N-acetylcysteine (SNAC) is a water soluble primary S-nitrosothiol capable of transferring and releasing nitric oxide and inducing several biochemical activities, including modulation of hepatic stellate cell activation. In this study, we evaluated the antifibrotic activity of SNAC in an animal model of nonalcoholic steatohepatitis (NASH) induced in Sprague-Dawley rats fed with a choline-deficient, high trans fat diet and exposed to diethylnitrosamine for 8 weeks. The rats were divided into three groups: SNAC, which received oral SNAC solution daily; NASH, which received the vehicle; and control, which received standard diet and vehicle. Genes related to fibrosis (matrix metalloproteinases [MMP]-13, -9, and -2), transforming growth factor ß-1 [TGFß-1], collagen-1a, and tissue inhibitors of metalloproteinase [TIMP-1 and -2] and oxidative stress (heat-shock proteins [HSP]-60 and -90) were evaluated. SNAC led to a 34.4% reduction in the collagen occupied area associated with upregulation of MMP-13 and -9 and downregulation of HSP-60, TIMP-2, TGFß-1, and collagen-1α. These results indicate that oral SNAC administration may represent a potential antifibrotic treatment for NASH. Keywords: nitric oxide, S-nitroso-N-acetylcysteine, fibrogenesis, NASH, diethylnitrosamine

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Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included.  Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0)  and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Maple Syrup Urine Disease (MSUD) is an autosomal recessive inborn error of metabolism (IEM), responsible for the accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, in addition to their α-keto acids α-ketoisocaproic acid (KIC), α-keto-β-methylvaleric acid (KMV), and α-ketoisovaleric acid (KIV) in the plasma and urine of patients. This process occurs due to a partial or total blockage of the dehydrogenase enzyme activity of branched-chain α-keto acids. Oxidative stress and inflammation are conditions commonly observed on IEM, and the inflammatory response may play an essential role in the pathophysiology of MSUD. We aimed to investigate the acute effect of intracerebroventricular (ICV) administration of KIC on inflammatory parameters in young Wistar rats. For this, sixteen 30-day-old male Wistar rats receive ICV microinjection with 8 µmol KIC. Sixty minutes later, the animals were euthanized, and the cerebral cortex, hippocampus, and striatum structures were collected to assess the levels of pro-inflammatory cytokines (INF-γ; TNF-α, IL-1β). The acute ICV administration of KIC increased INF-γ levels in the cerebral cortex and reduced the levels of INF-γ and TNF-α in the hippocampus. There was no difference in IL-1β levels. KIC was related to changes in the levels of pro-inflammatory cytokines in the brain of rats. However, the inflammatory mechanisms involved in MSUD are poorly understood. Thus, studies that aim to unravel the neuroinflammation in this pathology are essential to understand the pathophysiology of this IEM., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Oxidative stress has been implicated in the progression of severe forms of non-alcoholic fatty liver disease (NAFLD). NADPH oxidase produces reactive oxygen species. In the present study, we investigated for the first time two single nucleotide polymorphisms (SNPs) in the regulatory region of genes encoding NADPH oxidase 4 (NOX4) and p22phox (CYBA) in NAFLD., Methods: A total of 207 biopsy-proven NAFLD patients [simple steatosis (n = 27); nonalcoholic steatohepatitis (NASH) (n = 180)] were evaluated. Genomic DNA was extracted from peripheral blood cells, and polymorphisms in CYBA (unregistered) and NOX4 (rs3017887) were determined by direct sequencing of PCR., Results: Associations of CYBA-675 T/A with high-density lipoprotein (HDL) (TT vs TA vs AA; P < 0.01) and triglycerides (TGL) (TT vs XA; P < 0.01) were observed only in NASH patients. For polymorphisms in the NOX4 gene, NOX4 (rs3017887) CA + AA genotypes was significant associated with alanine aminotransferase (ALT) (CA + AA vs CC; P = 0.02). However, there was no association of SNPs in the CYBA and NOX4 genes encoding the NADPH oxidase system proteins and the presence of NASH. Regarding the clinical results, it was observed that the most advanced degrees of fibrosis occurred in patients diagnosed with type 2 diabetes mellitus (66.9% vs 37.5%, P < 0.01) and those who were more obese (32.2 vs 29.0 kg/m 2 , P < 0.01). In addition, serum glucose and insulin levels increased significantly in the presence of NASH., Conclusions: There were associations between the presence of the allele A in the NOX4 SNP and a higher concentration of ALT in the NAFLD population; between the presence of the AA genotype in the polymorphism of the CYBA-675 T/A CYBA gene and a higher level of TGL and lower HDL in NASH patients. The presence of metabolic syndrome was associated with advanced degrees of fibrosis in NAFLD patients., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

During the 2017 IFOS ENT World Congress, an international expert panel was asked to clarify the role of ENT in the diagnosis process of the obstructive sleep apnea syndrome (OSA) in adults around the world. OSA is a major public health issue throughout the world. OSA is a highly prevalent disease with heavy clinical, social and economical outcomes. This high prevalence raises serious difficulties of diagnosis accessibility if only somnologists are able to confirm OSA diagnosis. First of all, the panellists reviewed the impact of OSA. Secondly, they defined the ENT role stressing ENT legitimacy, professional expertise and academic and institutional tasks. They also defined when somnologists were necessary. For the international panel, the ENT is a major player in the OSA diagnosis process., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: The aim of this study was to compare performance in the Yo-Yo IR1, 20-meter sprint, COD test, loaded and unloaded lower-limb muscle power tests (squat jump [SJ], countermovement jump [CMJ] and jump squat [JS] tests), as well as resting and exercise heart rate variability parameters in high-level senior professional and under-20 (U-20) futsal players., Methods: All the players (18 senior and 15 U-20 male players) performed the Yo-Yo Intermittent Recovery Test level 1 (Yo-Yo IR1), 20-m sprint, COD test, loaded and unloaded lower-limb power tests (SJ, CMJ and JS tests), as well as resting and post-exercise log-transformed root-mean-square difference of successive normal RR intervals (lnRMSSD) recording. The t-test for independent samples and magnitude-based inference were used to compare the groups., Results: Seniors were likely to very likely superior than U-20 in the Yo-Yo IR1 (1506.7±287.1 and 1264.0±397.9 m, P<0.05), and resting (3.43±0.32 and 3.21±0.37 ms) and post-exercise lnRMSSD (2.95±0.39 and 2.48±0.59 ms, P<0.05). Conversely, U-20 players performed very likely to almost certainly better than seniors in the relative mean propulsive power (10.39±1.60 and 9.05±1.57 W/kg, P<0.05), 20-m sprint time (2.92±0.10 and 3.05±0.10 s, P<0.05) and COD (5.50±0.15 and 5.71±0.22 s, P<0.05)., Conclusions: Findings from this cross-sectional study indicate that long-term exposure to futsal may lead to improvement in the aerobic fitness and cardiac autonomic regulation, while impairing the muscle power and speed performance of players. Future longitudinal studies are necessary to confirm the occurrence of such concurrent training adaptations.

Aim: To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls., Methods: This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher's exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed., Results: No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0.651), dyslipidaemia (P = 0.328), hypertension (P = 0.507) or liver histology in these patients. Moreover, in the NASH patients, hypolactasia was an independent risk factor for insulin resistance even after adjusting for gender and age [OR = 5.0 (95%CI: 1.35-20; P = 0.017)]., Conclusion: The LCT-13910 genotype distribution in Brazilian NAFLD patients was the same as that of the general population, but hypolactasia increased the risk of insulin resistance in the NASH patients.

Aim: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal., Methods: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P < 0.05)., Results: In the Brazilian sample, NASH was significantly more frequent among the elderly patients with diabetes (NASH 56 ± 1.1 years old vs S. Steatosis 51 ± 1.5 years old, P = 3.7 x 10(-9)), dyslipidemia (NASH 63% vs S. Steatosis 37%, P = 0.009), higher fasting glucose levels (NASH 124 ± 5.2 vs S. Steatosis 106 ± 5.3, P = 0.001) and Homeostatic Model of Assessment index > 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S. Steatosis groups., Conclusion: There was no difference between the genetic ancestry contribution among Brazilian and Portuguese individuals with NASH and S. Steatosis from each cohort.

Objective: To investigate the role of hypocaloric highprotein diet, a prospective clinical study was conducted in NAFLD patients., Research Methods and Procedures: Pre-versus post-interventional data were analyzed in 48 stable NAFLD patients (submitted to a hypocaloric high-protein diet during 75 days. Variables included anthropometrics (body mass index/ BMI and waist circumference/WC), whole-body and segmental bioimpedance analysis and biochemical tests. Diet compliance was assessed by interviews every two weeks., Results: BMI, WC and body fat mass remained relatively stable (-1.3%, -1.8% and -2.5% respectively, no significance). HDL- cholesterol increased (P < 0.05) whereas total, LDL and VLDL cholesterol, triglycerides, aspartate aminotransferase/ AST, gamma glutamyltransferase/GGT, alkaline phosphatase/ AP, fasting blood glucose and glycated hemoglobin/ HbA1c decreased (P < 0.05). When patients were stratified according to increase (22/48, 45.8%) and decrease (21/48, 43.8%) of BMI, association between weight decrease and liver benefit could be elicited in such circumstances for ALT, AP and AST/ALT ratio. No change could be demonstrated in patients who gained weight. Multivariate assessment confirmed that waist circumference, ferritin, triacylglycerol, and markers of glucose homeostasis were the most relevant associated with liver enzymes., Discussion: Ours results are consistent with the literature of calorie restriction in the management of NAFLD. Changes in lifestyle and weight loss are recommended for NAFLD patients. European guidelines also support this recommendation., Conclusion: This is the first study that demonstrated that a high protein, hypocaloric diet were associated with improvement of lipid profile, glucose homeostasis and liver enzymes in NAFLD independent on BMI decrease or body fat mass reduction.

Aim: To investigate whether increased levels of vimentin citrullinated peptides identified by MS in articular cartilage can be measured in pathologies other than rheumatoid arthritis and be utilised for diagnostic purposes., Methods: A monoclonal antibody against the sequence RLRSSVPGV-citrulline (VICM) was developed and evaluated in a carbon tetrachloride (CCl(4)) (n=52 + 28 controls) rat model of liver fibrosis and two clinical cohorts of adult patients with hepatitis C (HCV) (n=92) and non-alcoholic fatty liver disease (NAFLD) (n=62), and compared to healthy controls., Results: In CCl(4)-treated rats, mean systemic VICM levels increased 31% at week 12 (176 ng/mL, P<0.001), 41.7% at weeks 16 (190 ng/mL, P<0.001), 49.2% at weeks 20 (200 ng/ml, P<0.001), compared to controls (134 ng/mL). VICM levels correlated with total hepatic collagen determined by Sirius red staining of rat livers (r=0.75, P<0.05). In the HCV cohort, when stratified according to the METAVIR F score, VICM levels were 63% higher in F0 (632 ng/mL ±75, p<0.05), 54% in F1 (597 ng/mL ±41.3, p<0.05) and 62% in F2 (628 ng/mL ±59, p<0.05) all compared to controls. In the NAFLD cohort, VICM levels were 20.6% higher in F0 (339 ±12 ng/mL, P<0.05), 23.8% in F1 (348 ±12 ng/mL, P<0.05) and 28.8% in F2 (362 ±25 P<0.05)., Conclusion: We demonstrated increased serological levels of citrullinated and MMP degraded vimentin in an animal model of liver fibrosis and in early fibrosis associated with HCV and NAFLD patients. These data suggest that citrullinated and MMP degraded proteins are also present in liver fibrosis.

Context: Thyroid hormones may interfere with regulation of lipid and carbohydrate metabolism as well as with severity of nonalcoholic fatty liver disease (NAFLD), however results are still debated., Objectives: Retrospective evaluation of clinical and metabolic correlations between hypothyroidism and NAFLD was the target., Methods: Clinical, biochemical and histological investigation of 103 NAFLD patients exhibiting drug-treated hypothyroidism was conducted., Results: Steatosis was present in 32.0% of the population and nonalcoholic steatohepatitis in 68.0%. Females were the majority in both groups, with age of 50.0 ± 1.5 and 56.0 ± 1.1 years, respectively. Hypothyroidism was not rare (15.5%), and multivariate analysis confirmed positive correlation with this disease for insulin (r = 0.213, P = 0.03), glucose homeostasis index "HOMA" (r = 0.221, P = 0.02), aspartate aminotransferase (r = 0.234, P = 0.01) and triglycerides above 150 mg/dL (r = 0.233, P = 0.01). No association between hypothyroidism and steatohepatitis could be established., Conclusion: A link could be identified between hypothyroidism and markers of glucose and lipid homeostasis, but not with severity of NAFLD. The lack of correlation with liver biopsy requires further studies.

Background: Fatty liver disease is a problem in both bariatric patients and in patients with moderate obesity. Tumor necrosis factor (TNF)-alpha has been frequently measured in nonalcoholic steatohepatitis (NASH) with or without diabetes, but less is known about interleukin (IL)-6 and IL-10., Methods: Moderately obese patients (n = 80) with histologically proven steatosis (n = 29) and NASH (n = 51) were recruited. Serum levels of cytokines were documented along with clinical information. The aim was to identify the correlates of such biomolecules in a stable population., Results: Diabetes tended to be more associated with NASH (52.5% instead of 41.4%, P = 0.015), with no difference of age, gender, or body mass index regarding steatosis. For the entire population, cytokine changes were not significant, including TNF-alpha and IL-6. In diabetics only, all markers tended to diminish with NASH, especially IL-10 (P = 0.000). IL-10 correlated with homeostatic model assessment index (P = 0.000) and other variables of glucose homeostasis in diabetes, thus representing a major marker of the disease., Conclusions: (1) Generally inconsistent changes in pro- and anti-inflammatory cytokines occurred when NASH was globally compared to steatosis. (2) In contrast, downregulation of IL-6 and IL-10 was perceived in diabetics with NASH. (3) Arterial hypertension did not play a role in these circumstances. (4) IL-10 maintained strong correlations with glucose metabolism indices. (5) TNF-alpha could not be incriminated for progressive liver damage, as values failed to increase in NASH. (6) Investigations of IL-10 and other counterregulatory cytokines are lacking in this context and deserve further studies.

We report a 40 years old woman with chronic urticaria and acute transverse myelitis associated with systemic lupus erythematosus. The urticaria appeared in her adolescence and after 26 years was followed by photosensitivity, peripheral polyarthritis and acute transverse myelitis, with positive antiphospholipid and antinuclear antibodies. Both chronic urticaria and acute transverse myelitis have been described associated with or appearing as the first manifestation of systemic lupus erythematosus. Transverse myelitis is a rare and still poorly understood condition reported in about 2% of patients with systemic lupus.

Background: Apoptosis is an essential form of cell death, the failure of which can lead to cancer development. Cancer including leukemia is usually treated with chemotherapeutic drugs that can be effective, but frequently problems are encountered that impair the success of the treatment. Butyrate is a short-chain fatty acid that can have many effects on different cells, including apoptosis., Methods: The effect of a combination treatment with butyrate and antineoplastic agents Ara-C, etoposide and vincristine is evaluate on the leukemic cell line THP-1., Results: We show that butyrate increased apoptosis induced by the three agents as seen by measurement of DNA content, annexin exposure and morphological characteristics. We also demonstrate that the process of apoptosis induced by butyrate and chemotherapeutic drugs involves the participation of caspases and induced activation of caspase-3, -8 and -9., Conclusions: We believe that butyrate could be a promising therapeutic agent for the treatment of leukemia in combination with other antineoplastic drugs.

We demonstrated that 4 mM butyrate induces apoptosis in murine peritoneal macrophages in a dose- and time-dependent manner as indicated by studies of cell viability, flow cytometric analysis of annexin-V binding, DNA ladder pattern and the determination of hypodiploid DNA content. The activity of caspase-3 was enhanced during macrophage apoptosis induced by butyrate and the caspase inhibitor z-VAD-FMK (100 microM) inhibited the butyrate effect, indicating the major role of the caspase cascade in the process. The levels of butyrate-induced apoptosis in macrophages were enhanced by co-treatment with 1 microg/ml bacterial lipopolysaccharide (LPS). However, our data indicate that apoptosis induced by butyrate and LPS involves different mechanisms. Thus, LPS-induced apoptosis was only observed when macrophages were primed with IFN-gamma and was partially dependent on iNOS, TNFR1 and IRF-1 functions as determined in experiments employing macrophages from various knockout mice. In contrast, butyrate-induced macrophage apoptosis was highly independent of IFN-gamma priming and of iNOS, TNFR1 and IRF-1 functions.