An adenosine derivative promotes mitochondrial supercomplexes reorganization and restoration of mitochondria structure and bioenergetics in a diethylnitrosamine-induced hepatocellular carcinoma model.

Hepatocellular carcinoma (HCC) progression is associated with dysfunctional mitochondria and bioenergetics impairment. However, no data about the relationship between mitochondrial supercomplexes (hmwSC) formation and ATP production rates in HCC are available. Our group has developed an adenosine derivative, IFC-305, which improves mitochondrial function, and it has been proposed as a therapeutic candidate for HCC. We aimed to determine the role of IFC-305 on both mitochondrial structure and bioenergetics in a sequential cirrhosis-HCC model in rats. Our results showed that IFC-305 administration decreased the number and size of liver tumors, reduced the expression of tumoral markers, and reestablished the typical architecture of the hepatic parenchyma. The livers of treated rats showed a reduction of mitochondria number, recovery of the mtDNA/nDNA ratio, and mitochondrial length. Also, IFC-305 increased cardiolipin and phosphatidylcholine levels and promoted hmwSC reorganization with changes in the expression levels of hmwSC assembly-related genes. IFC-305 in HCC modified the expression of several genes encoding elements of electron transport chain complexes and increased the ATP levels by recovering the complex I, III, and V activity. We propose that IFC-305 restores the mitochondrial bioenergetics in HCC by normalizing the quantity, morphology, and function of mitochondria, possibly as part of its hepatic restorative effect.

Androgen receptor deficiency is associated with reduced aromatase expression in the ventromedial hypothalamus of male cichlids.

Social behaviors are regulated by sex steroid hormones, such as androgens and estrogens. However, the specific molecular and neural processes modulated by steroid hormones to generate social behaviors remain to be elucidated. We investigated whether some actions of androgen signaling in the control of social behavior may occur through the regulation of estradiol synthesis in the highly social cichlid fish, Astatotilapia burtoni. Specifically, we examined the expression of cyp19a1, a brain-specific aromatase, in the brains of male A. burtoni lacking a functional ARα gene (ar1), which was recently found to be necessary for aggression in this species. We found that cyp19a1 expression is higher in wild-type males compared to ar1 mutant males in the anterior tuberal nucleus (ATn), the putative fish homolog of the mammalian ventromedial hypothalamus, a brain region that is critical for aggression across taxa. Using in situ hybridization chain reaction, we determined that cyp19a1+ cells coexpress ar1 throughout the brain, including in the ATn. We speculate that ARα may modulate cyp19a1 expression in the ATn to govern aggression in A. burtoni. These studies provide novel insights into the hormonal mechanisms of social behavior in teleosts and lay a foundation for future functional studies.

Levosulpiride for the treatment of diabetic macular oedema: a phase 2 randomized clinical trial.

BACKGROUND/OBJECTIVE: The prokinetic levosulpiride elevates vasoinhibin levels in the vitreous of patients with proliferative diabetic retinopathy (PDR) suggesting clinical benefits due to the anti-vasopermeability and anti-angiogenic properties of vasoinhibin. We investigated the biological activity of levosulpiride in centre-involving diabetic macular oedema (DME). PATIENTS/METHODS: Prospective, randomized, double-blinded, dual-centre, phase 2 trial in patients with centre-involving DME orally treated with placebo (n = 17) or levosulpiride (n = 17) for 8 weeks or in patients with PDR undergoing elective pars plana vitrectomy and receiving placebo (n = 18) or levosulpiride (n = 18) orally for the 1 week before vitrectomy. RESULTS: Levosulpiride improved changes from baseline in best-corrected visual acuity (p ≤ 0.037), central foveal thickness (CFT, p ≤ 0.013), and mean macular volume (MMV, p ≤ 0.002) at weeks 4, 6, and 8 compared to placebo. At 8 weeks, the proportion of eyes gaining ≥5 ETDRS letters at 4 m (41% vs. 28%), losing ≥21 µm in CFT (55% vs. 28%), and dropping ≥0.06 mm3 in MMV (65% vs. 29%) was higher after levosulpiride than placebo. The overall grading of visual and structural parameters improved with levosulpiride (p = 0.029). Levosulpiride reduced VEGF (p = 0.025) and PlGF (p = 0.008) levels in the vitreous of PDR patients. No significant adverse side-effects were detected. CONCLUSIONS: Oral levosulpiride for 8 weeks improved visual and structural outcomes in patients with centre-involving DME by mechanisms that may include intraocular upregulation of vasoinhibin and downregulation of VEGF and PlGF. Larger clinical trials evaluating long-term efficacy and safety are warranted.

An adenosine derivative prevents the alterations observed in metabolic syndrome in a rat model induced by a rich high-fat diet and sucrose supplementation.

Metabolic syndrome is a multifactorial disease with high prevalence worldwide. It is related to cardiovascular disease, diabetes, and obesity. Approximately 80% of patients with metabolic syndrome have some degree of fatty liver disease. An adenosine derivative (IFC-305) has been shown to exert protective effects in models of liver damage as well as on elements involved in central metabolism; therefore, here, we evaluated the effect of IFC-305 in an experimental model of metabolic syndrome in rats induced by a high-fat diet and 10% sucrose in drinking water for 18 weeks. We also determined changes in fatty acid uptake in the Huh-7 cell line. In the experimental model, increases in body mass, serum triglycerides and proinflammatory cytokines were induced in rats, and the adenosine derivative significantly prevented these changes. Interestingly, IFC-305 prevented alterations in glucose and insulin tolerance, enabling the regulation of glucose levels in the same way as in the control group. Histologically, the alterations, including mitochondrial morphological changes, observed in response to the high-fat diet were prevented by administration of the adenosine derivative. This compound exerted protective effects against metabolic syndrome, likely due to its action in metabolic regulation, such as in the regulation of glucose blood levels and hepatocyte fatty acid uptake.

Liver fibrotic development is reduced through inflammation prevention by an adenosine derivative compound.

BACKGROUND: Liver fibrosis is a global health problem, and studying its development provides important information to address its treatment. Here, we characterized the effects of an adenosine compound (IFC-305) on preventing fibrosis and liver inflammation. METHODS: We studied the impact of IFC-305 on a carbon tetrachloride-induced liver fibrosis model in Wistar male rats at 4, 6, and 8 weeks. The effects were characterized by liver tissue histology, macrophages identification by flow cytometry with CD163+/CD11b/c+ antibodies, hepatic and plasmatic cytokine levels employing MILLIPLEX MAP and ELISA, Col1a1 and Il6 gene expression by RTqPCR, lipoperoxidation by TBARS reaction, and reactive oxygen species using 2'-7'dichlorofluorescin diacetate. RESULTS: CCl4-induced liver fibrosis and inflammation were significantly reduced in rats treated with IFC-305 at 6 and 8 weeks. In addition, we observed diminished expression of Col1a1; a decrease in the inflammatory cytokines IL-1ß, IL-6, MCP-1, TNF-α, and IL-4 a; reduction in inflammatory macrophages; inhibition of lipoperoxidation; and ROS production in Kupffer cells. CONCLUSION: This study showed that IFC-305 can inhibit liver fibrosis establishment by regulating the immune response during CCl4-induced damage. The immunomodulatory action of IFC-305 supports its use as a potential therapeutic strategy for preventing liver fibrosis.

A qualitative analysis of female patient perspectives on physician communication regarding sexual dysfunction associated with pelvic radiotherapy.

BACKGROUND: Sexual dysfunction is a known side effect of pelvic radiotherapy, resulting from a complex intersection of physiologic and psychosocial factors. Maintaining sexual function is relevant to long-term quality of life and is an important aspect of survivorship. Many female patients report being insufficiently informed before treatment about the potential sexual side effects of radiation therapy. AIM: To elucidate how radiation oncologists communicate sexual function side effects with their female patients and how discussing sexual side effects of cancer treatment can positively affect patient-physician rapport. METHODS: Semistructured interviews in English and Spanish were conducted with 20 female participants who received pelvic radiation as part of their cancer treatment. Patients responded to advertisements or were referred by physicians. All interviews were conducted virtually between June and October 2021. Thematic analysis was conducted with NVivo. Patients also completed an online demographics survey in REDCap. OUTCOMES: We found 4 primary themes addressing patient perspectives on patient-physician communication of sexual dysfunction and how it affected the cancer care experience. RESULTS: Theme 1: This may be expected, but I didn't expect it! The participants who were not properly informed about sexual side effects felt blindsided and embarrassed about their symptoms. Theme 2: I do not feel like a woman anymore . . . The psychological impact included lower self-esteem and no longer feeling sexy nor like a woman. Theme 3: Fine, I'll deal with this myself! Patients turned to the internet rather than their doctors for answers once they began experiencing symptoms, and they found information, normalization, and community online. Theme 4: Ask me about my sex life and find out if sex is a priority for me. Participants emphasized that their radiation oncologist should take a sexual history early to monitor sexual dysfunction and to identify individual patient priorities surrounding sex posttreatment. CLINICAL IMPLICATIONS: This evidence provides a guide to patient-physician communication that may help to mitigate the impacts of radiotherapy on female sexual function as well as the negative impact that the absence of communication about sexual dysfunction may have on patient-physician trust. STRENGTHS AND LIMITATIONS: While this project did have a small sample size, there is considerable diversity in race, education level, and age, with interviews conducted in Spanish and English. CONCLUSION: Overall these findings provide physicians with important information about the unmet information needs of patients and their preferences for how to help them feel more prepared and less distressed when sexual dysfunction occurs.

Cuban American Perspectives on Sexual Dysfunction Following Pelvic Radiotherapy: A Qualitative Study.

Participation in sexual medicine research may depend on a patient's willingness to speak openly about sex, sexual function, or other sensitive topics. These topics may be difficult or uncomfortable to talk about, and this discomfort may be further amplified when a patient comes from a cultural background that stigmatizes open conversation about sex and sexuality. We used qualitative analysis to better understand the intersection between cultural identity, the experience of sexual dysfunction as a side-effect of pelvic radiotherapy, and willingness to communicate about sexual dysfunction with healthcare providers, in Cuban American women in Miami, Florida. Doing so, we found four unique themes among Cuban American participants regarding the intersection of national identity, Hispanic identity, Catholic religion, and their experience of radiotherapy-related sexual dysfunction: Marianismo, Machismo, Familismo, and Espiritismo. These themes, a reflection of the cohort's shared identity, were found to have an effect on participant views of sexual health, romantic relationships, coping strategies, and relative comfort discussing problems with intercourse. These cultural values served as barriers to openly discussing sexual dysfunction with not just medical providers and research teams but also their partners, families, and friends. In order to encourage Cuban American participation in sexual medicine studies, future research should evaluate strategies to overcome these barriers.

Systematic Review of Comparisons Between Plastic and Silicone Dilators: Revealing a Knowledge Gap.

INTRODUCTION: Vaginal stenosis is a distressing side effect of radiation therapy that can impair quality of life. Dilator therapy is an option for patients undergoing pelvic radiotherapy to mitigate vaginal stenosis. Currently, the dilators given to patients by most hospitals are made of plastic, compared to silicone dilators which are available on the market for purchase. OBJECTIVES: We conducted a systematic literature review to find information to guide clinical recommendations to pelvic radiotherapy patients on potential differences regarding the use of plastic vs silicone dilators with regard to efficacy, cost, and patient preferences. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and PubMed using Emtree terms. To be included in the review, papers needed to: focus on female patients undergoing radiation therapy, assess a vaginal dilator, measure any dilator intervention outcome, and specifically compare plastic vs silicone dilators for any measured outcome (either qualitative or quantitative). RESULTS: The initial search yielded 195 articles. Two area experts, with a third expert for arbitration, read each article and found that none met all review inclusion criteria. No studies were found that compared silicone to plastic dilators with regard to efficacy in treating vaginal stenosis due to radiation therapy, no studies were found that compared cost or cost-effectiveness of the 2 dilator types, and no studies were found comparing patient preferences or experiences (eg, comfort, adherence, ease of use) between the 2 dilator types. CONCLUSION: The materials used to create dilators have never been rigorously compared in the context of radiotherapy-related vaginal stenosis. Institutions and patients have no data to guide their choice. Significantly more research at the patient and institutional level is needed to explore the potential long-term quality of life and cost benefits of improved adherence with silicone dilator use, and to guide shared decision-making regarding dilator choice. Morgan O, Lopez MD, Martinez AJC, et al. Systematic Review of Comparisons Between Plastic and Silicone Dilators: Revealing a Knowledge Gap. Sex Med Rev 2022;10:513-519.

Systematic Review of Comparisons Between Plastic and Silicone Dilators: Revealing a Knowledge Gap.

INTRODUCTION: Vaginal stenosis is a distressing side effect of radiation therapy that can impair quality of life. Dilator therapy is an option for patients undergoing pelvic radiotherapy to mitigate vaginal stenosis. Currently, the dilators given to patients by most hospitals are made of plastic, compared to silicone dilators which are available on the market for purchase. OBJECTIVES: We conducted a systematic literature review to find information to guide clinical recommendations to pelvic radiotherapy patients on potential differences regarding the use of plastic vs silicone dilators with regard to efficacy, cost, and patient preferences. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and PubMed using Emtree terms. To be included in the review, papers needed to: focus on female patients undergoing radiation therapy, assess a vaginal dilator, measure any dilator intervention outcome, and specifically compare plastic vs silicone dilators for any measured outcome (either qualitative or quantitative). RESULTS: The initial search yielded 195 articles. Two area experts, with a third expert for arbitration, read each article and found that none met all review inclusion criteria. No studies were found that compared silicone to plastic dilators with regard to efficacy in treating vaginal stenosis due to radiation therapy, no studies were found that compared cost or cost-effectiveness of the 2 dilator types, and no studies were found comparing patient preferences or experiences (eg, comfort, adherence, ease of use) between the 2 dilator types. CONCLUSION: The materials used to create dilators have never been rigorously compared in the context of radiotherapy-related vaginal stenosis. Institutions and patients have no data to guide their choice. Significantly more research at the patient and institutional level is needed to explore the potential long-term quality of life and cost benefits of improved adherence with silicone dilator use, and to guide shared decision-making regarding dilator choice.

Eye Salvage with Intra-Arterial and Intra-Vitreal Chemotherapy in Patients with Retinoblastoma: 8-Year Single-Institution Experience in Colombia.

INTRODUCTION: Intra-arterial chemotherapy (IAC) is useful for eye preservation in advanced retinoblastoma (Rb). Intra-vitreal chemotherapy (IvitC) is the latest treatment for vitreous seeds. METHODS: The present study is a retrospective assessment of 100 eyes, treated with primary or secondary IAC alone or with IvitC. We evaluated demographic and clinical variables, eye salvage, associated adverse events, and patient survival. Data were analyzed using descriptive statistics. Kaplan-Meier survival curves and Cox hazard ratios were utilized to assess the effect of demographic and clinical variables over eye salvage. RESULTS: Bilateral Rb was observed in 61% of patients, and 57% of eyes received secondary treatment. Forty eyes needed intra-arterial plus IvitC and 62 presented advanced disease (group D and E). Three- and 5-year ocular survival probabilities were 75 and 68%. We found a higher risk in group D and E eyes and those requiring 2 or more routes for ophthalmic artery catheterization. Patients coming from other countries also showed increased risk. Using primary or secondary treatment, or IvitC, did not affect this risk. Overall rates of survival and eye salvages were 98.8 and 73%, and we had a 100% catheterization success and none ophthalmic arterial occlusions. CONCLUSIONS: In an upper middle-income country such as Colombia, a specialized institution counting with therapeutic alternatives and a multidisciplinary team can reach rates of patient survival and eye salvage similar to those of high-income countries.

Dermatological and Ophthalmological Inflammatory, Infectious, and Tumoral Tattoo-Related Reactions: A Systematic Review.

PURPOSE: The purpose of this work was to review the scientific evidence about dermatological and ophthalmological inflammatory, infectious, and tumoral tattoo-related reactions published in the literature. METHODS: We conducted a literature search from January 1, 2000 to July 15, 2020 in MEDLINE, COCHRANE, EMBASE, and LILACS. Limits regarding the language and period of publication were used. A data collection form was designed in Excel. Four reviewers independently extracted relevant details about the design and the results of each study. RESULTS: One hundred four studies were included, most of them were conducted in Europe and North America. The remaining studies were conducted in Asia, South America, Africa, and Oceania. We included 52 case reports, 21 cross-sectional studies, 20 case series, 10 case-control studies, and 1 cohort study. Eighty-six studies described skin tattoos, of which 7 were publications of eyebrow tattoos and 6 of eyelid tattoos, and 5 articles included cases of subconjunctival tissue tattoos (eyeball). Fifty-seven studies described local reactions related to tattoos and 47 studies reported systemic reactions or reactions in different locations from the tattoo site. The types of reactions described in the studies were: infections in 45 studies, inflammatory reactions in 53 studies, neoplasia in 4 studies, and hypertrichosis in 2 studies. CONCLUSION: This literature review evidenced a close relationship between the application of tattoos on dermatological and ophthalmological tissues, and the possible immunological complications, neoplasms, and infectious complications. Dermatologists and ophthalmologists should be aware of the consequences caused by even small amounts of ink applied on skin and eyes, generating the need for strict regulations for its use.

Epidemiología de las alteraciones ponderales / epidemiology of alterations ponderal

Introducción: La obesidad es un problema de salud pública a nivel mundial, que compromete a población de altos y bajos recursos por igual y presenta un efecto deletéreo de alto impacto en la fisiopatogenia de la enfermedad cardiovascular. Objetivo: Determinar la prevalencia de sobrepeso y obesidad en nuestra población. Materiales y métodos: Estudio descriptivo, retrospectivo, de corte transversal, incluyó 1024 mujeres de 25 a 65 años residentes de CABA y GBA, que concurrieron a la "Campaña de Prevención del cáncer cervicouterino y detección temprana del cáncer de mama" realizada entre el 9 y 13 de Marzo de 2020 a cargo del Servicio de Ginecología del Hospital de Clínicas "José de San Martín". Se registraron talla y peso. Se calculó el índice de masa corporal (IMC) a través de una fórmula predeterminada. Se excluyeron las pacientes con insuficiencia ovárica prematura y menopausia temprana. Resultados: Se dividió a las pacientes en premenopáusicas y postmenopáusicas. Del grupo de mujeres premenopáusicas (70,61% n=723), el IMC promedio fue de 28,18 kg/m2 (DS 5,86); 0,42% presentó bajo peso (IMC promedio 17,65 kg/m2 DS 0,05), 32,37% normopeso (IMC promedio 22,32 kg/m2 DS 1,68), 32,09% sobrepeso (IMC promedio 27,26 kg/m2 DS 0,22) y 35,13% presentó obesidad (IMC promedio 34,53 kg/m2 DS 4,38). Del grupo de mujeres postmenopáusicas (29,39% n=301) el IMC promedio fue de 29,47 kg/m2 (DS 5,76); ninguna presentó bajo peso, 20,27% presentó normopeso (IMC promedio 22,71 kg/m2 DS 1,6), 40,53% sobrepeso (IMC promedio 27,47 kg/m2 DS 1,43) y 39,2% fueron obesas (IMC promedio 35,04 kg/m2 DS 4,72). Conclusiones: Se observó un aumento en la prevalencia de sobrepeso y obesidad en la postmenopausia que podría explicarse no sólo por el aumento de la edad sino también por los cambios hormonales que acompañan a la postmenopausia. Destaca la importancia del médico ginecólogo en prevención (AU)

Introduction: Obesity is a global public health challenge that affects both high- and low-income populations equally and has a high-impact deleterious effect on the physiopathological origin of cardiovascular disease. Objective: To determine the prevalence of overweight and obesity in our population.Material and methods: This descriptive, retrospective, cross-sectional study included 1024 women of 25 to 65 years old who were living in the Buenos Aires Metropolitan Area (AMBA) and were screened at the "Cervical Cancer Prevention and Breast Cancer Early Detection Campaign" conducted from March 9 to 13, 2020 in the Gynecology Department of Hospital de Clínicas "José de San Martín". Height and weight measurements were performed. Body mass index (BMI) was calculated using a predetermined formula. Patients with premature ovarian failure and early menopause were excluded from the study. Results: Patients were divided into premenopausal and postmenopausal. In the group of premenopausal women (70.61% n=723), the average BMI was 28.18 kg/m2 (SD 5.86); 0.42% were underweight (average BMI 17.65 kg/m2 SD 0.05); 32.37% had normal weight (average BMI 22.32 kg/m2 SD 1.68); 32.09% were overweight (average BMI 27.26 kg/m2 SD 0.22) and 35.13% had obesity (average BMI 34.53 kg/m2 SD 4.38). In the group of postmenopausal women (29.39% n=301) the average BMI was 29.47 kg/m2 (SD 5.76); none was underweight, 20.27% had normal weight (average BMI 22.71 kg/m2 SD 1.6), 40.53% were overweight (average BMI 27.47 kg/m2 SD 1.43) and 39.2% were obese (average BMI 35.04 kg/m2 SD 4.72). Conclusions: An increased prevalence of overweight and obesity has been observed in postmenopause, which could be explained not only by aging but also by the hormonal changes associated with postmenopause. Gynecologists play and important role in prevention (AU)

Levosulpiride Increases the Levels of Prolactin and Antiangiogenic Vasoinhibin in the Vitreous of Patients with Proliferative Diabetic Retinopathy.

Purpose: High circulating levels of the hormone prolactin (PRL) protect against experimental diabetic retinopathy (DR) due to the retinal accumulation of vasoinhibin, a PRL fragment that inhibits blood vessel permeability and growth. A phase 2 clinical trial is investigating a new therapy for DR based on elevating serum PRL levels with levosulpiride, a prokinetic dopamine D2 receptor blocker. Here, we tested whether levosulpiride-induced hyperprolactinemia elevates PRL and vasoinhibin in the vitreous of volunteer patients with proliferative DR (PDR) undergoing elective pars plana vitrectomy. Methods: Patients were randomized to receive placebo (lactose pill, orally TID; n = 19) or levosulpiride (25 mg orally TID; n = 18) for the 7 days before vitrectomy. Vitreous samples from untreated non-diabetic (n = 10) and PDR (n = 17) patients were also studied. Results: Levosulpiride elevated the systemic (101 ± 13 [SEM] vs. 9.2 ± 1.3 ng/mL, P < 0.0001) and vitreous (3.2 ± 0.4 vs. 1.5 ± 0.2 ng/mL, P < 0.0001) levels of PRL, and both levels were directly correlated (r = 0.58, P < 0.0002). The vitreous from non-diabetic patients or from PDR patients treated with levosulpiride, but not from placebo-treated PDR patients, inhibited the basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-induced proliferation of endothelial cells in culture. Vasoinhibin-neutralizing antibodies reduced the vitreous antiangiogenic effect. Matrix metalloproteases (MMPs) in the vitreous cleaved PRL to vasoinhibin, and their activity was higher in non-diabetic than in PDR patients. Conclusions: Levosulpiride increases the levels of PRL in the vitreous of PDR patients and promotes its MMP-mediated conversion to vasoinhibin, which can inhibit angiogenesis in DR. Translational Relevance: These findings support the potential therapeutic benefit of levosulpiride against vision loss in diabetes.

Neuroibromatosis tipo l: relación genotipo-fenotipo / Type 1 neurofibromatosis: genotype-phenotype relationship

RESUMEN INTRODUCCIÓN: La neurofibromatosis (enfermedad de von Recklinghausen) es una enfermedad autosómica dominante que presenta principalmente manifestaciones cutáneas y neurológicas. El objetivo es describir actualmente si existe o no relación entre las mutaciones encontradas en los pacientes con neurofibromatosis tipo 1 y las características clínicas que presentan. MÉTODOS: Se realizó un artículo de revisión narrativa para evaluar la relación con el genotipo y fenotipo de los pacientes con neurofibromatosis tipo 1. Se revisaron las bases de datos PubMed, Embase y Lilacs. Se utilizaron los siguientes términos Mesh: Neurofibromatosis, neurofibromatosis tipo 1, genes, genotipo, fenotipo, mutaciones, secuenciación de exoma. Los estudios identificados fueron revisados y analizados. Se presentan los datos de manera cualitativa. RESULTADOS: De 425 artículos, 62 contenían la información necesaria para hacer el análisis. A pesar de que algunos estudios han presentado evidencia de asociación en relación a las mutaciones encontradas y la clínica, realmente no existe una correlación genotipo-fenotipo comprobada en neurofibromatosis tipo 1. Esto sugiere que para los fenotipos discordantes con genotipo similar existen otros factores que deben considerarse tales como la epigenética, alteraciones genéticas o incluso factores ambientales. CONCLUSIONES: Es necesario realizar estudios con cohortes más grande de pacientes para seguir estudiando si existe una relación directa o no.

SUMMARY INTRODUCTION: Neurofibromatosis (von Recklinghausen disease) is an autosomal dominant disease that mainly presents cutaneous and neurological manifestations. The objective is to describe if there is a relationship between the mutations found in patients with neurofibromatosis type 1 and the clinical characteristics they present. METHODS: A narrative review of the literature was carried out in relation to the genotype and phenotype of patients with Neurofibromatosis type 1 using PubMed, Embase, and Lilacs. The following Mesh terms were used: Neurofibromatosis, neurofibromatosis type 1, genes, genotype, phenotype, mutations, exome sequencing. The identified studies were reviewed and analyzed. Data are presented qualitatively RESULTS: Of 425 articles, 62 contained the information necessary to make the analysis. Although some studies have presented evidence of association in relation to the mutations found and the clinical one, there is still no proven genotype-phenotype correlation in neurofibromatosis type 1. This suggests that, for discordant phenotypes with a similar genotype, there are other factors that must be considered such as epigenetics, genetic alterations or even environmental factors. CONCLUSIONS: It is necessary to perform studies with larger cohort of patients to continue studying whether there is a direct relationship or not.

Genome-wide 5-hydroxymethylcytosine (5hmC) emerges at early stage of in vitro differentiation of a putative hepatocyte progenitor.

A basic question linked to differential patterns of gene expression is how cells reach different fates despite using the same DNA template. Since 5-hydroxymethylcytosine (5hmC) emerged as an intermediate metabolite in active DNA demethylation, there have been increasing efforts to elucidate its function as a stable modification of the genome, including a role in establishing such tissue-specific patterns of expression. Recently we described TET1-mediated enrichment of 5hmC on the promoter region of the master regulator of hepatocyte identity, HNF4A, which precedes differentiation of liver adult progenitor cells in vitro. Here, we studied the genome-wide distribution of 5hmC at early in vitro differentiation of human hepatocyte-like cells. We found a global increase in 5hmC as well as a drop in 5-methylcytosine after one week of in vitro differentiation from bipotent progenitors, at a time when the liver transcript program is already established. 5hmC was overall higher at the bodies of overexpressed genes. Furthermore, by modifying the metabolic environment, an adenosine derivative prevents 5hmC enrichment and impairs the acquisition of hepatic identity markers. These results suggest that 5hmC could be a marker of cell identity, as well as a useful biomarker in conditions associated with cell de-differentiation such as liver malignancies.

Gerenciamento do comportamento seguro para manutenção da vida na Estação Antártica Brasileira / Management of safe behavior to maintain life at the Brazilian Antarctic Station / Gestión del comportamiento seguro para mantenimiento de la vida en la Estación Antártica Brasileña

Em regiões polares, o gerenciamento do comportamento seguro é fundamental às operações de abastecimento para manutenção da vida (OPAMV). O objetivo deste estudo foi analisar aspectos do comportamento seguro nas OPAMV na Estação Antártica Comandante Ferraz (EACF) durante o inverno. A pesquisa foi descritiva, de abordagem qualitativa e procedimento de triangulação de observações e levantamento de dados. Foram realizadas observações da rotina de trabalho e entrevistas com a tripulação da Força Aérea Brasileira (n=12) e com o grupo-base (GB) da EACF (N=30). A autonomia do GB no trabalho minimiza o impacto das características extremas do inverno. As OPAMV na EACF repercutem diretamente na subsistência e na manutenção de laços afetivos externos. O estudo do gerenciamento do comportamento seguro aponta fatores com potencial de reduzirem riscos de acidentes e adoecimentos, impactando na permanência salutar no contexto. O aperfeiçoamento dos estudos pode contribuir para a atenção dos fatores humanos em condições polares.

In polar regions, the management of safe behavior is fundamental to supply operations to maintain life (OPML). The objective of this study was to control OPML at the Comandante Ferraz Antarctic Station during the winter. The research was descriptive, with a qualitative approach and the procedure of triangulation of observations and survey. Routine questions and interviews with the crew (n = 12) and with the base group (BG) of Ferraz Station (N = 30) were conducted. The autonomy of the BG in the work minimizes the impact of extreme winter characteristics. OPML at Ferraz Station has direct repercussions on subsistence and on the maintenance of external affective bonds. The study of safe behavior points to factors with the potential to reduce the risks of accidents and illness, having impact on healthy permanence in this context. Improvement of these studies can contribute to attending to human factors in polar conditions.

En regiones polares, la gestión del comportamiento seguro es fundamental para las operaciones de aprovisionamiento y el mantenimiento de la vida (OPAMV). El objetivo de este estudio fue analizar aspectos del comportamiento seguro en las OPAMV en la Estación Antártica Comandante Ferraz (EACF) durante el invierno. La investigación fue descriptiva, cualitativa y de triangulación de observaciones y datos. Se realizaron observaciones de rutina de trabajo y entrevistas con la tripulación de la Fuerza Aérea Brasileña (n = 12) y con el grupo base (GB) de la EACF (N = 30). La autonomía del GB minimiza el impacto de las características extremas del invierno. Las OPAMV en la EACF repercuten directamente en la subsistencia y mantenimiento de vínculos afectivos externos. El estudio de la gestión del comportamiento seguro indica riesgos de accidentes y enfermedades, afectando a la permanencia saludable en el contexto. El perfeccionamiento de los estudios puede contribuir a la atención de los factores humanos en condiciones polares.

Diminished S-adenosylmethionine biosynthesis and its metabolism in a model of hepatocellular carcinoma is recuperated by an adenosine derivative.

S-adenosylmethionine (SAM), biosynthesis from methionine and ATP, is markedly decreased in hepatocellularular carcinoma (HCC) for a diminution in ATP levels, and the down regulation of the liver specific MAT1a enzyme. Its metabolic activity is very important in the transmethylation reactions, the methionine cycle, the biosynthesis of glutathione (GSH) and the polyamine pathway, which are markedly affected in the HCC. The chemo-preventive effect of IFC305 in HCC induced by DEN, and the increase of ATP and SAM in CCl4-induced cirrhosis have been previously demonstrated. The aim of this work was to test whether this chemo-preventive effect is mediated by the induction of SAM biosynthesis and its metabolic flow. SAM hepatic levels and the methionine cycle were recovered with IFC305 treatment, restoring transmethylation and transsulfuration activities. IFC305 treatment, increased MAT1a levels and decrease MAT2a levels through modulation of their post-transcriptional regulation. This occurred through the binding of the AUF1 (binding factor 1 AU-rich sites) and HuR (human antigen R) ribonucleoproteins to Mat1a and Mat2a messenger RNAs, which maintained their nuclear localization. Finally, the compound inhibited the polyamine pathway favoring the recuperation of the normal methionine and one carbon cycle recuperating the metabolic flow of methionine, which probably facilitated its HCC chemo-preventive effect.

Chemoprotective and antiobesity effects of tocols from seed oil of Maqui-berry: Their antioxidative and digestive enzyme inhibition potential.

Maqui-berry (Aristotelia chilensis) is the emerging Chilean superfruit with high nutraceutical value. Until now, the research on this commodity was focused on the formulations enriched with polyphenols from the pulp. Herein, contents of tocols were compared in the seed oil of Maqui-berry obtained through three different extraction methods followed by determining their antioxidative and enzyme inhibitions in-vitro. Firstly, oilseed was extracted with n-hexane (Soxhlet method), chloroform/methanol/water (Bligh and Dyer method) and pressing (industrial). These samples were used to access their effects against DPPH, HORAC, ORAC, FRAP, Lipid-peroxidation (TBARS), α-amylase, α-glucosidase, and pancreatic lipase. All the isomers of tocopherol and tocotrienol were identified, and ß-sitosterol was the only sterol found in higher amounts than other vegetable oils. The Bligh and Dyer method could lead to the highest antioxidative capacity compared to Soxhlet and press methods likely because the latter have a higher amount of tocopherols. Further, seed oil from Maqui berry and their tocols (α, ß, γ, δ-tocopherols, tocotrienols, and ß-sitosterol) warrant clinical investigation for their antioxidative and antiobesity potential. Taken together, these findings provide relevant and suitable conditions for the industrial processing of Maqui-berry.

Désiré-Magloire Bourneville and his contributions to pediatric neurology.

Désiré-Magloire Bourneville ought to be thought of as the father of Pediatric Neurology for his significant contributions to the field. He worked as a physician, politician, writer, and editor. He was the first to describe the autosomal dominant genetic condition known as "tuberous sclerosis complex", after conducting an autopsy on a young female patient, where the main finding in the central nervous system was multiple dense tubers. The patient had refractory epilepsy and intellectual disability. His work was based on the study of epilepsy and idiocy, and he was also an advocate of public health and social medicine education; creating day hospital programs for children with this type of neurologic disease.

Désiré-Magloire Bourneville and his contributions to pediatric neurology / Désiré-Magloire Bourneville y sus aportes a la neurología pediátrica

ABSTRACT Désiré-Magloire Bourneville ought to be thought of as the father of Pediatric Neurology for his significant contributions to the field. He worked as a physician, politician, writer, and editor. He was the first to describe the autosomal dominant genetic condition known as "tuberous sclerosis complex", after conducting an autopsy on a young female patient, where the main finding in the central nervous system was multiple dense tubers. The patient had refractory epilepsy and intellectual disability. His work was based on the study of epilepsy and idiocy, and he was also an advocate of public health and social medicine education; creating day hospital programs for children with this type of neurologic disease.

RESUMEN Désiré-Magloire Bourneville debería ser considerado como el padre de la Neurología Pediátrica por sus importantes contribuciones en este campo. Trabajó como médico, político, escritor y editor. Hizo las primeras descripciones de la condición genética autosómica dominante conocida como "Complejo de esclerosis tuberosa", después de realizar una autopsia en una paciente joven, en la que el principal hallazgo en el sistema nervioso central fueron múltiples lesiones tipo tubérculos. La paciente tenía epilepsia refractaria y discapacidad intelectual como síntomas asociados. Su trabajo se basó en el estudio de la epilepsia y la idiotez, a su vez fue un defensor de salud pública y la educación en medicina social; creando programas de hospital diurno para niños con diferentes tipos de enfermedades neurológicas.