Tailoring modifications in labrenzin synthesis: a-la-carte production of pathway intermediates.

Pederin-family polyketides today constitute a group of more than 30 molecules being produced as natural products by different microorganisms across multitude of ecological niches. They are mostly known for their extreme cytotoxic activity and the decades of long exploration as potential antitumor drugs. The difference in their potency and biological activity lies in the tailoring modifications of the core molecule. Despite the isolation of many pederin-like molecules until the date, only marine bacterium Labrenzia sp. PHM005 was reported as a cultivable producer and able to be genetically modified. Here, we study the role of tailoring enzymes from the lab gene cluster responsible for methylation and hydroxylation of labrenzin core molecule. We managed to produce a spectrum of differently tailored labrenzin analogs for the development of future drugs. This work constitutes one-step forward in understanding the biosynthesis of pederin-family polyketides and provides the tools to modify and overproduce these anticancer drugs in a-la-carte manner in Labrenzia sp. PHM005, but also in other producers in the future.

Cocoa Shell Extract Reduces Blood Pressure in Aged Hypertensive Rats via the Cardiovascular Upregulation of Endothelial Nitric Oxide Synthase and Nuclear Factor (Erythroid-Derived 2)-like 2 Protein Expression.

Cocoa shell is a by-product of cocoa manufacturing. We obtained an aqueous extract (CSE) rich in polyphenols and methylxanthines with antioxidant and vasodilatory properties. We aimed to evaluate the effects of CSE supplementation in aged hypertensive rats on blood pressure and the mechanism implicated. Eighteen-month-old male and female rats exposed to undernutrition during the fetal period who developed hypertension, with a milder form in females, were used (MUN rats). Systolic blood pressure (SBP; tail-cuff plethysmography) and a blood sample were obtained before (basal) and after CSE supplementation (250 mg/kg; 2 weeks, 5 days/week). Plasma SOD, catalase activity, GSH, carbonyls, and lipid peroxidation were assessed (spectrophotometry). In hearts and aortas from supplemented and non-supplemented age-matched rats, we evaluated the protein expression of SOD-2, catalase, HO-1, UCP-2, total and phosphorylated Nrf2 and e-NOS (Western blot), and aorta media thickness (confocal microscopy). MUN males had higher SBP compared with females, which was reduced via CSE supplementation with a significant difference for group, sex, and interaction effect. After supplementation with plasma, GSH, but not catalase or SOD, was elevated in males and females. Compared with non-supplemented rats, CSE-supplemented males and females exhibited increased aorta e-NOS and Nrf2 protein expression and cardiac phosphorylated-Nrf2, without changes in SOD-2, catalase, HO-1, or UCP-2 in cardiovascular tissues or aorta remodeling. In conclusion, CSE supplementation induces antihypertensive actions related to the upregulation of e-NOS and Nrf2 expression and GSH elevation and a possible direct antioxidant effect of CSE bioactive components. Two weeks of supplementation may be insufficient to increase antioxidant enzyme expression.

Clinical Characteristics and Prognostic Impact of Short Physical Performance Battery in Hospitalized Patients with Acute Heart Failure-Results of the PROFUND-IC Registry.

BACKGROUND: Most patients diagnosed with heart failure (HF) are older adults with multiple comorbidities. Multipathological patients constitute a population with common characteristics: greater clinical complexity and vulnerability, frailty, mortality, functional deterioration, polypharmacy, and poorer health-related quality of life with more dependency. OBJECTIVES: To evaluate the clinical characteristics of hospitalized patients with acute heart failure and to determine the prognosis of patients with acute heart failure according to the Short Physical Performance Battery (SPPB) scale. METHODS: Observational, prospective, and multicenter cohort study conducted from September 2020 to May 2022 in patients with acute heart failure as the main diagnosis and NT-ProBNP > 300 pg. The cohort included patients admitted to internal medicine departments in 18 hospitals in Spain. Epidemiological variables, comorbidities, cardiovascular risk factors, cardiovascular history, analytical parameters, and treatment during admission and discharge of the patients were collected. Level of frailty was assessed by the SPPB scale, and dependence, through the Barthel index. A descriptive analysis of all the variables was carried out, expressed as frequencies and percentages. A bivariate analysis of the SPPB was performed based on the score obtained (SPPB ≤ 5 and SPPB > 5). For the overall analysis of mortality, HF mortality, and readmission of patients at 30 days, 6 months, and 1 year, Kaplan-Meier survival curves were used, in which the survival experience among patients with an SPPB > 5 and SPPB ≤ 5 was compared. RESULTS: A total of 482 patients were divided into two groups according to the SPPB with a cut-off point of an SPPB < 5. In the sample, 349 patients (77.7%) had an SPPB ≤ 5 and 100 patients (22.30%) had an SPPB > 5. Females (61%) predominated in the group with an SPPB ≤ 5 and males (61%) in those with an SPPB > 5. The mean age was higher in patients with an SPPB ≤ 5 (85.63 years). Anemia was more frequent in patients with an SPPB ≤ 5 (39.5%) than in patients with an SPPB ≥ 5 (29%). This was also seen with osteoarthritis (32.7%, p = 0.000), diabetes (49.6%, p = 0.001), and dyslipidemia (69.6%, p = 0.011). Patients with an SPPB score > 5 had a Barthel index < 60 in only 4% (n = 4) of cases; the remainder of the patients (96%, n = 96) had a Barthel index > 60. Patients with an SPPB > 5 showed a higher probability of survival at 30 days (p = 0.029), 6 months (p = 0.031), and 1 year (p = 0.007) with (OR = 7.07; 95%CI (1.60-29.80); OR: 3.9; 95%CI (1.30-11.60); OR: 6.01; 95%CI (1.90-18.30)), respectively. No statistically significant differences were obtained in the probability of readmission at 30 days, 6 months, and 1 year (p > 0.05). CONCLUSIONS: Patients admitted with acute heart failure showed a high frequency of frailty as assessed by the SPPB. Patients with an SPPB ≤ 5 had greater comorbidities and greater functional limitations than patients with an SPPB > 5. Patients with heart failure and a Barthel index > 60 frequently presented an SPPB < 5. In daily clinical practice, priority should be given to performing the SPPB in patients with a Barthel index > 60 to assess frailty. Patients with an SPPB ≤ 5 had a higher risk of mortality at 30 days, 6 months, and 1 year than patients with an SPPB ≤ 5. The SPPB is a valid tool for identifying frailty in acute heart failure patients and predicting 30-day, 6-month, and 1-year mortality.

Effect of Supplementation with Coffee and Cocoa By-Products to Ameliorate Metabolic Syndrome Alterations Induced by High-Fat Diet in Female Mice.

Coffee and cocoa manufacturing produces large amounts of waste. Generated by-products contain bioactive compounds with antioxidant and anti-inflammatory properties, suitable for treating metabolic syndrome (MetS). We aimed to compare the efficacy of aqueous extracts and flours from coffee pulp (CfPulp-E, CfPulp-F) and cocoa shell (CcShell-E, CcShell-F) to ameliorate MetS alterations induced by a high-fat diet (HFD). Bioactive component content was assessed by HPLC/MS. C57BL/6 female mice were fed for 6 weeks with HFD followed by 6 weeks with HFD plus supplementation with one of the ingredients (500 mg/kg/day, 5 days/week), and compared to non-supplemented HFD and Control group fed with regular chow. Body weight, adipocyte size and browning (Mitotracker, confocal microscopy), plasma glycemia (basal, glucose tolerance test-area under the curve, GTT-AUC), lipid profile, and leptin were compared between groups. Cocoa shell ingredients had mainly caffeine, theobromine, protocatechuic acid, and flavan-3-ols. Coffee pulp showed a high content in caffeine, protocatechuic, and chlorogenic acids. Compared to Control mice, HFD group showed alterations in all parameters. Compared to HFD, CcShell-F significantly reduced adipocyte size, increased browning and high-density lipoprotein cholesterol (HDL), and normalized basal glycemia, while CcShell-E only increased HDL. Both coffee pulp ingredients normalized adipocyte size, basal glycemia, and GTT-AUC. Additionally, CfPulp-E improved hyperleptinemia, reduced triglycerides, and slowed weight gain, and CfPulp-F increased HDL. In conclusion, coffee pulp ingredients showed a better efficacy against MetS, likely due to the synergic effect of caffeine, protocatechuic, and chlorogenic acids. Since coffee pulp is already approved as a food ingredient, this by-product could be used in humans to treat obesity-related MetS alterations.

Radical Scavenging and Cellular Antioxidant Activity of the Cocoa Shell Phenolic Compounds after Simulated Digestion.

The cocoa industry generates a considerable quantity of cocoa shell, a by-product with high levels of methylxanthines and phenolic compounds. Nevertheless, the digestion process can extensively modify these compounds' bioaccessibility, bioavailability, and bioactivity as a consequence of their transformation. Hence, this work's objective was to assess the influence of simulated gastrointestinal digestion on the concentration of phenolic compounds found in the cocoa shell flour (CSF) and the cocoa shell extract (CSE), as well as to investigate their radical scavenging capacity and antioxidant activity in both intestinal epithelial (IEC-6) and hepatic (HepG2) cells. The CSF and the CSE exhibited a high amount of methylxanthines (theobromine and caffeine) and phenolic compounds, mainly gallic acid and (+)-catechin, which persisted through the course of the simulated digestion. Gastrointestinal digestion increased the antioxidant capacity of the CSF and the CSE, which also displayed free radical scavenging capacity during the simulated digestion. Neither the CSF nor the CSE exhibited cytotoxicity in intestinal epithelial (IEC-6) or hepatic (HepG2) cells. Moreover, they effectively counteracted oxidative stress triggered by tert-butyl hydroperoxide (t-BHP) while preventing the decline of glutathione, thiol groups, superoxide dismutase, and catalase activities in both cell lines. Our study suggests that the cocoa shell may serve as a functional food ingredient for promoting health, owing to its rich concentration of antioxidant compounds that could support combating the cellular oxidative stress associated with chronic disease development.

Nucleophagy contributes to genome stability through degradation of type II topoisomerases A and B and nucleolar components.

The nuclear architecture of mammalian cells can be altered as a consequence of anomalous accumulation of nuclear proteins or genomic alterations. Most of the knowledge about nuclear dynamics comes from studies on cancerous cells. How normal healthy cells maintain genome stability, avoiding accumulation of nuclear damaged material, is less understood. Here, we describe that primary mouse embryonic fibroblasts develop a basal level of nuclear buds and micronuclei, which increase after etoposide-induced DNA double-stranded breaks. Both basal and induced nuclear buds and micronuclei colocalize with the autophagic proteins BECN1 and LC3B (also known as MAP1LC3B) and with acidic vesicles, suggesting their clearance by nucleophagy. Some of the nuclear alterations also contain autophagic proteins and type II DNA topoisomerases (TOP2A and TOP2B), or the nucleolar protein fibrillarin, implying they are also targets of nucleophagy. We propose that basal nucleophagy contributes to genome and nuclear stability, as well as in response to DNA damage.

Ligamentum Teres Cardiopexy Might Not Prevent Gastro-esophageal Reflux After Laparoscopic Sleeve Gastrectomy: Case Series.

Roux-en-Y gastric bypass (RYGB) is considered the gold standard procedure in patients with obesity and gastroesophageal reflux (GERD), but in patients with preoperative hiatal hernia (HH) or GERD, who are unfit for RYGB, there are no clear guidelines. Ligamentum teres cardiopexy (LTC) has been proposed as an effective alternative. The purpose of this study was to analyze medium-term results of LTC procedure associated with laparoscopic sleeve gastrectomy (LSG) in patients with GERD or HH, according to the absence of pathologic acid reflux in esophageal 24 h pH monitoring test, symptom release, or PPI reduction. Five patients underwent LSG-LTC between March 2018 and October 2019. In one patient, the effectiveness of LTC as an anti-reflux procedure could not be assessed because of conversion to RYGB was required. After a follow-up period of 30 [24-42] months and excessive BMI loss of 62.74 ± 18.18%, GERD recurrence was observed in 75% of patients. The study was discontinued due to unsatisfactory preliminary results with LTC. Our results suggest that LTC might not prevent GERD after LSG in patients with preoperative GERD or HH.

Women during Lactation Reduce Their Physical Activity and Sleep Duration Compared to Pregnancy.

Sleep, mental health and physical activity are fundamental for wellbeing, and some of these factors are interrelated. However, these aspects are not usually considered during pregnancy and lactation, which are particularly vulnerable periods. Therefore, our aims were to conduct a cross sectional study to assess the psychological capital, quality of life, sleep hygiene and physical activity in a cohort of women during pregnancy and lactation periods. Women were recruited from Spanish maternity and lactation non-profit associations and social networks through an online platform with the following inclusion criteria: pregnancy (in any period of gestation) or breastfeeding period (≤6 months postpartum). The cohort was categorized into ≤12 weeks of gestation (n = 32), >12 weeks of gestation (n = 119) and lactation (n = 60). The women self-reported the sociodemographic data, obstetric complications and full breastfeeding or mixed practices. In addition, women responded to the psychological capital instrument, the health survey form, the Pittsburg sleep quality index and the pregnancy physical activity questionnaire. Overall, the groups were similar in sociodemographic variables. Women in the lactation period perceived lower social support compared to the gestation period. No statistically differences were found between groups in the psychological capital nor in the general health survey form. However, the models adjusted by employment and civil and economic status and perceived social support, demonstrated that the sleep duration negatively associated with the lactation period (ß = 1.13 ± 0.56; p-Value = 0.016), and the household tasks were associated with this period (ß = 2147.3 ± 480.7; p-Value < 0.001). A decrease in physical daily activities were associated with both the end of gestation and the lactation periods. In addition, the decreasing total activity was associated with the lactation period (ß = 1683.67 ± 688.05; p-Value = 0.016). In conclusion, during lactation, the poorer sleep and physical activity, together with a lower social support of the woman, may lead to deficient mental health adjustment. Our data suggest that women are at higher risk of vulnerability in lactation compared to the gestation period.

Effect of Chronic Altitude Hypoxia on Redox Balance in Preadolescents and Adolescents / Efectos de la hipoxia altitudinal crónica sobre el balance Redox de preadolescentes y adolescentes / Efeito da exposição crônica à hipóxia de altitude no equilíbrio oxidante/antioxidante de crianças e adolescentes

Living at high altitude increases oxidative stress. Likewise, growth and maturation during adolescence can increase levels of reactive oxygen species (ros). Changes in redox profiles have been evaluated in adults living at high altitudes; however, there are no studies on these changes in peripubertal populations living at moderate altitudes, we determine how living at moderate altitude affects the oxidative and inflammatory status of healthy preadolescents and adolescents. Materials and Methods: A cross-sectional study was conducted in healthy male Colombian preadolescents and adoles-cents (9­18 years old, Tanner scale classification) who lived at low altitude (n = 26) or moderate altitude (n = 26). Plasma oxidative and inflammatory status was assessed via spectrophotometry. Oxidative markers included malondialdehyde, 4-hydroxy-trans-2-nonenal, and carbonyl groups. Antioxidant markers included total antioxidant status, glutathione, catalase, superoxide dismutase, uric acid, and thiols. Inflammatory markers included interleukins-1, -6, and -10 and tumor necrosis factor. Results:Only uric acid levels were higher in adolescents (5.34 and 5.66 mg/dl) compared to preadolescents (3.85 and 4.07 mg/dl) in both moderate and low altitude groups, respectively. Participants who lived at mod-erate altitude presented significantly higher levels of malondialdehyde (4.82 and 3.73 nM/mg protein) and lower level of glutathione and thiols (1.21 and 1.26 µmol/mg protein) than in those at low altitude. Their inflammatory profiles did not differ. Conclusion: Oxidant profiles increased in peripubertal popu-lations residing at moderate altitude; this could be owing to antioxidant consumption by ros and active metabolism during puberty.

vivir en altura es un factor que se asocia con el estrés oxidativo. El crecimiento y la maduración pueden ser un estresor adicional. Es insuficiente la evidencia sobre alteraciones del perfil redox en peripúberes residentes a altitudes moderadas. El propósito fue establecer el efecto de vivir en una altitud moderada sobre el perfil redox e inflamatorio en preadolescentes y adolescentes sanos. Materiales y métodos: estudio transversal en varones preadolescentes y adolescentes sanos (9-18 años) que viven en altitud baja (n = 26) o altitud moderada (n = 26). El estado oxidativo plasmático se evaluó mediante espectrofotometría a través de marcadores de oxidación (malondialdehído e hidroxinonenal y grupos carbonilo) y antioxidantes (estado antioxidante total, glutatión, catalasa, superóxido dismutasa, ácido úrico y tioles). El perfil inflamatorio se midió con interleucinas 1, 6, 10 y factor de necrosis tumoral α. Resultados: solo el ácido úrico fue diferente entre adolescentes (5.34 y 5.66 mg/dl para moderada y baja altitud, respectivamente) y preadolescentes (3.85 y 4.07 mg/dl para moderada y baja altitud, res-pectivamente). El grupo de preadolescentes y adolescentes de moderada altitud presentó niveles más altos de malondialdehído (4.82 y 3.73 nM/mg de proteína, respectivamente) y menor glutatión y tioles (1.21 y 1.26 µmol/mg de proteína), en comparación con sus contrapartes de baja altitud. Conclusión: las poblaciones peripúberes que residen en una altitud moderada presentan un perfil oxidante más alto, lo que puede estar relacionado con la depleción de antioxidantes, por una mayor producción de especies reactivas de oxígeno relacionada con la hipoxia y el metabolismo activo de la pubertad.

viver em grandes altitudes é um fator de estresse associado ao estresse oxidativo. Durante a adolescência, os processos de crescimento e maturação podem aumentar as espécies reativas de oxi-gênio. Alterações no perfil redox foram estudadas em adultos expostos a grandes altitudes, mas não em populações peripubertais vivendo em altitudes moderadas. Nosso objetivo é estabelecer o efeito de viver em uma altitude moderada sobre o estado oxidativo e inflamatório em pré-adolescentes e adolescentes saudáveis. Materiais and métodos: foi realizado um estudo transversal em pré-adolescentes e adolescen-tes colombianos saudáveis (9-18 anos, na escala de classificação de Tanner) que viviam em baixa altitude (n = 26) ou altitude moderada (n = 26). O estado oxidativo e inflamatório do plasma foi avaliado por espectrofotometria: 1) Marcadores de oxidação: grupos Malondialdeído + 4-hidroxi-trans-2-nonenal e carbonila; 2) antioxidantes: estado antioxidante total, glutationa, catalase, superóxido dismutase, ácido úrico e tióis; 3) Marcadores de inflamação: interleucinas 1, 6, 10 e fator de necrose tumoral α. Resultados:apenas o ácido úrico foi maior em adolescentes (5,34 e 5,66 mg/dl) em comparação com pré-adolescentes (3,85 e 4,07 mg/dl) dos grupos de altitude moderada e baixa, respectivamente. A altitude moderada apre-sentou níveis significativamente maiores de Malondialdeído (4,82 e 3,73 nM/mg de proteína), e menores níveis de Glutationa e tióis (1,21 e 1,26 µmol/mg de proteína), em comparação com a baixa altitude. Nenhuma diferença foi detectada no perfil inflamatório. Conclusão: as populações peripubertais que residem em altitude moderada apresentam maior perfil oxidante, o que pode estar relacionado ao con-sumo de antioxidantes devido à maior produção de ros relacionada à hipóxia e ao metabolismo ativo por volta da puberdade.

Inflammatory Biomarkers of Traumatic Brain Injury.

Traumatic brain injury (TBI) has a complex pathology in which the initial injury releases damage associated proteins that exacerbate the neuroinflammatory response during the chronic secondary injury period. One of the major pathological players in the inflammatory response after TBI is the inflammasome. Increased levels of inflammasome proteins during the acute phase after TBI are associated with worse functional outcomes. Previous studies reveal that the level of inflammasome proteins in biological fluids may be used as promising new biomarkers for the determination of TBI functional outcomes. In this study, we provide further evidence that inflammatory cytokines and inflammasome proteins in serum may be used to determine injury severity and predict pathological outcomes. In this study, we analyzed blood serum from TBI patients and respective controls utilizing Simple Plex inflammasome and V-PLEX inflammatory cytokine assays. We performed statistical analyses to determine which proteins were significantly elevated in TBI individuals. The receiver operating characteristics (ROC) were determined to obtain the area under the curve (AUC) to establish the potential fit as a biomarker. Potential biomarkers were then compared to documented patient Glasgow coma scale scores via a correlation matrix and a multivariate linear regression to determine how respective biomarkers are related to the injury severity and pathological outcome. Inflammasome proteins and inflammatory cytokines were elevated after TBI, and the apoptosis-associated speck like protein containing a caspase recruitment domain (ASC), interleukin (IL)-18, tumor necrosis factor (TNF)-α, IL-4 and IL-6 were the most reliable biomarkers. Additionally, levels of these proteins were correlated with known clinical indicators of pathological outcome, such as the Glasgow coma scale (GCS). Our results show that inflammatory cytokines and inflammasome proteins are promising biomarkers for determining pathological outcomes after TBI. Additionally, levels of biomarkers could potentially be utilized to determine a patient's injury severity and subsequent pathological outcome. These findings show that inflammation-associated proteins in the blood are reliable biomarkers of injury severity that can also be used to assess the functional outcomes of TBI patients.

Identification of new FK866 analogues with potent anticancer activity against pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal diseases for which chemotherapy has not been very successful yet. FK866 ((E)-N-(4-(1-benzoylpiperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) is a well-known NAMPT (nicotinamide phosphoribosyltransferase) inhibitor with anti-cancer activities, but it failed in phase II clinical trials. We found that FK866 shows anti-proliferative activity in three PDAC cell lines, as well as in Jurkat T-cell leukemia cells. More than 50 FK866 analogues were synthesized that introduce substituents on the phenyl ring of the piperidine benzamide group of FK866 and exchange its buta-1,4-diyl tether for 1-oxyprop-3-yl, (E)-but-2-en-1,4-diyl and 2- and 3-carbon tethers. The pyridin-3-yl moiety of FK866 was exchanged for chlorinated and fluorinated analogues and for pyrazin-2-yl and pyridazin-4-yl groups. Several compounds showed low nanomolar or sub-nanomolar cell growth inhibitory activity. Our best cell anti-proliferative compounds were the 2,4,6-trimethoxybenzamide analogue of FK866 ((E)-N-(4-(1-(2,4,6-trimethoxybenzoyl)piperidin-4-yl)butyl)-3-(pyridin-3-yl)acrylamide) (9), the 2,6-dimethoxybenzamide (8) and 2-methoxybenzamide (4), which exhibited an IC50 of 0.16 nM, 0.004 nM and 0.08 nM toward PDAC cells, respectively.

In vivo production of pederin by labrenzin pathway expansion.

Pederin is a potent polyketide toxin that causes severe skin lesions in humans after contact with insects of genus Paederus. Due to its potent anticancer activities, pederin family compounds have raised the interest of pharmaceutical industry. Despite the extensive studies on the cluster of biosynthetic genes responsible for the production of pederin, it has not yet been possible to isolate and cultivate its bacterial endosymbiont producer. However, the marine bacterium Labrenzia sp. PHM005 was recently reported to produce labrenzin, the closest pederin analog. By cloning a synthetic pedO gene encoding one of the three O-methyltraferase of the pederin cluster into Labrenzia sp. PHM005 we have been able to produce pederin for the first time by fermentation in the new recombinant strain.

Mechanical triangular esophagogastrostomy: Technical aspects and initial results.

INTRODUCTION: Esophageal cancer represents the eighth neoplasm worldwide. The therapeutic approach is interdisciplinary, with surgery being the most effective option. Several techniques have been proposed to perform esophagogastrostomy after esophagectomy, among them mechanical triangular esophagogastrostomy (MT), with a little experience published in the Western literature on the latter. The objective of this study is to describe the technical aspects and initial results of MT anastomosis. METHODS: A retrospective review of the patients who underwent esophagectomy according to the McKeown technique was performed, those in which MT anastomosis was implemented, between October 2017 and March 2020 in our hospital. RESULTS: 14 patients were included, with a mean age of 63 years. The mean operative time was 436 min (360-581), being diagnosed of anastomotic leak (AL) 3 of the 14 patients (21.4%), as well as 3 patients presented anastomotic stenosis (AS). The median stay was 20 days, without any death in the series. DISCUSSION: Multiple publications suggest the superiority in terms of AL and AS of the mechanical triangular anastomosis, which was also observed in our series, in which despite the small sample, a rapid improvement was observed in the indicators after the first cases. Therefore, this type of anastomosis may be a safe option for performing esophagogastric anastomosis after esophagectomy, being necessary more definitive conclusive studies.

Ovary micromorphology and oogenesis in a rhyacodriline oligochaete (Clitellata: Naididae, Rhyacodrilinae).

The main goal of the article is to describe the ovary organization and oogenesis in Peristodrilus montanus, an aquatic oligochaete of the subfamily Rhyacodrilinae. The presented analysis will not only enrich the knowledge about how eggs are formed but, because of the suggested conservatism of ovary organization in clitellate annelids, can contribute to disentangling the complex phylogenetic relationships of the rhyacodrilines within Naididae. The paired, conically shaped ovaries are located in segment XI. They are composed of a dozen or so syncytial germ-line cysts, which are associated with somatic cells. Each germ cell in a cyst has one intercellular bridge that joins it to a central and anuclear cytoplasmic mass, the cytophore. This pattern of cyst organization is typical for all clitellates that have been studied to date. Initially, the germ cells in a cyst undergo a synchronous development, however, there is no synchrony between cysts, and therefore there is a developmental gradient (oogonia, pre-diplotene germ cells, germ cells in diplotene) of oogenesis along the long ovary axis. The cysts are composed of a maximum of 32 cells. Cysts with cells in diplotene detach from the ovaries and the extraovarian phase of oogenesis begins. The developmental synchrony is lost, one cell (an oocyte) per cyst starts to gather cell components and yolk and grows considerably. The remaining cells grow to some extent and function as nurse cells. Like in other microdriles, P. montanus oocytes are rich in yolk; other features of oogenesis are also similar to those that are known from other microdrile taxa. The system of ovary organization found in the studied species is broadly similar to the corresponding features known from Naidinae and Phreodrilidae and, to some extent, in Enchytraeidae. However, this system is different from the one that is known in Tubificinae, Limnodriloidinae and Branchiurinae.

Pancreatic lipoma: diagnostic boom of a rare mesenchymal tumor.

Following the incidental finding of a tumor in a 58-year-old female, diagnosed as pancreatic lipoma, histologically confirmed by fine-needle aspiration biopsy (FNAB) with endoscopic ultrasound (EUS), we made a review in our center between 2018 and 2020, with 14 cases diagnosed of pancreatic lipoma by computarized tomography (CT) or magnetic resonance imaging (MRI).

Identification of trans-AT polyketide clusters in two marine bacteria reveals cryptic similarities between distinct symbiosis factors.

Glutarimide-containing polyketides are known as potent antitumoral and antimetastatic agents. The associated gene clusters have only been identified in a few Streptomyces producers and Burkholderia gladioli symbiont. The new glutarimide-family polyketides, denominated sesbanimides D, E and F along with the previously known sesbanimide A and C, were isolated from two marine alphaproteobacteria Stappia indica PHM037 and Labrenzia aggregata PHM038. Structures of the isolated compounds were elucidated based on 1D and 2D homo and heteronuclear NMR analyses and ESI-MS spectrometry. All compounds exhibited strong antitumor activity in lung, breast and colorectal cancer cell lines. Subsequent whole genome sequencing and genome mining revealed the presence of the trans-AT PKS gene cluster responsible for the sesbanimide biosynthesis, described as sbn cluster. Strikingly, the modular architecture of downstream mixed type PKS/NRPS, SbnQ, revealed high similarity to PedH in pederin and Lab13 in labrenzin gene clusters, although those clusters are responsible for the production of structurally completely different molecules. The unexpected presence of SbnQ homologues in unrelated polyketide gene clusters across phylogenetically distant bacteria, raises intriguing questions about the evolutionary relationship between glutarimide-like and pederin-like pathways, as well as the functionality of their synthetic products.

Mechanical triangular esophagogastrostomy: Technical aspects and initial results. / Esofagogastrostomía triangular mecánica: aspectos técnicos y resultados iniciales.

INTRODUCTION: Esophageal cancer represents the eighth neoplasm worldwide. The therapeutic approach is interdisciplinary, with surgery being the most effective option. Several techniques have been proposed to perform esophagogastrostomy after esophagectomy, among them mechanical triangular esophagogastrostomy, with a little experience published in the Western literature on the latter. The objective of this study is to describe the technical aspects and initial results of triangular esophagogastrostomy anastomosis. METHODS: A retrospective review of the patients who underwent esophagectomy according to the McKeown technique was performed, those in which triangular esophagogastrostomy anastomosis was implemented, between October 2017 and March 2020 in our hospital. RESULTS: A total of 14 patients were included, with a mean age of 63 years. The mean operative time was 436minutes (360-581), being diagnosed of anastomotic leak 3 of the 14 patients (21.4%), as well as 3 patients presented anastomotic stenosis. The median stay was 20 days, without any death in the series. CONCLUSIONS: Multiple publications suggest the superiority in terms of anastomotic leak and anastomotic stenosis of the mechanical triangular anastomosis, which was also observed in our series, in which despite the small sample, a rapid improvement was observed in the indicators after the first cases. Therefore, this type of anastomosis may be a safe option for performing esophagogastric anastomosis after esophagectomy, being necessary more definitive conclusive studies.

Sex Differences in Placental Protein Expression and Efficiency in a Rat Model of Fetal Programming Induced by Maternal Undernutrition.

Fetal undernutrition programs cardiometabolic diseases, with higher susceptibility in males. The mechanisms implicated are not fully understood and may be related to sex differences in placental adaptation. To evaluate this hypothesis, we investigated placental oxidative balance, vascularization, glucocorticoid barrier, and fetal growth in rats exposed to 50% global nutrient restriction from gestation day 11 (MUN, n = 8) and controls (n = 8). At gestation day 20 (G20), we analyzed maternal, placental, and fetal weights; oxidative damage, antioxidants, corticosterone, and PlGF (placental growth factor, spectrophotometry); and VEGF (vascular endothelial growth factor), 11ß-HSD2, p22phox, XO, SOD1, SOD2, SOD3, catalase, and UCP2 expression (Western blot). Compared with controls, MUN dams exhibited lower weight and plasma proteins and higher corticosterone and catalase without oxidative damage. Control male fetuses were larger than female fetuses. MUN males had higher plasma corticosterone and were smaller than control males, but had similar weight than MUN females. MUN male placenta showed higher XO and lower 11ß-HSD2, VEGF, SOD2, catalase, UCP2, and feto-placental ratio than controls. MUN females had similar feto-placental ratio and plasma corticosterone than controls. Female placenta expressed lower XO, 11ß-HSD2, and SOD3; similar VEGF, SOD1, SOD2, and UCP2; and higher catalase than controls, being 11ß-HSD2 and VEGF higher compared to MUN males. Male placenta has worse adaptation to undernutrition with lower efficiency, associated with oxidative disbalance and reduced vascularization and glucocorticoid barrier. Glucocorticoids and low nutrients may both contribute to programming in MUN males.

Infecciones osteoarticulares en niños: experiencia de cinco años

Resumen Introducción: Las infecciones osteoarticulares (IOA) son consideradas una urgencia infectológica en niños. Los principales microorganismos causales son Staphylococcus aureus y Streptococcus pyogenes. Objetivo: Describir las características bio-demográficas y clínicas de pacientes de 2 meses a 15 años hospitalizados entre 2012 y 2017 con diagnóstico de IOA. Pacientes y Métodos: Estudio retrospectivo en un hospital pediátrico. Se revisaron fichas clínicas de pacientes internados con diagnóstico de IOA. Resultados: Se incluyó a 146 pacientes. Un 60,3% fueron de sexo masculino, mediana de edad 3 años 11 meses. El síntoma más frecuente al ingreso fue dolor articular (90%) y la mediana de PCR fue de 43 mg/L. Se obtuvo identificación microbiológica en 48%; de ellos, 67,8 % S. aureus (10,2% resistentes a meticilina). El 94,5% de los pacientes recibió de forma empírica β-lactámico anti-estafilocócico. Un 70,5% de los niños requirió procedimiento quirúrgico. A las 72 h se observó respuesta clínica y a los 4,7 días descenso de parámetros inflamatorios de laboratorio. El 88% de los pacientes cursó sin complicaciones. Conclusiones: Las IOA son más frecuentes en varones, el agente infeccioso más frecuentemente identificado fue S. aureus, por lo cual se sugiere inicio del esquema antimicrobiano con un β-lactámico anti-estafilocócico, ampliando cobertura en pacientes bajo 5 años de edad. A los 5 días del tratamiento antimicrobiano ya hay respuesta clínica y descenso de parámetros inflamatorios.

Abstract Background: Osteoarticular infections (IOA) are considered infectious emergencies. The main microorganisms isolated are Staphylococcus aureus and Streptococcus pyogenes. Aim: To describe demographic and clinical characteristics of patients from 2 months to 15 years old, hospitalized between the years 2012 and 2017 with IOA diagnosis. Methods: Retrospective study in a pediatric hospital. Clinical records of hospitalized patients with IOA were reviewed. Results: 146 met inclusion criteria. 60.3% of the patients were male, median age 3 years 11 months. The main symptom at admission was joint pain (90%) and the median CRP was 43 mg/L. 48% of the patients had microbiological identification; 67.8% were positive for Staphylococcus aureus (10.2% SAMR). 94.5% of the sample received empirical antistaphylococcal beta-lactam treatment and 70,5% had a surgical intervention. Clinical response was observed 72 hours of beginning of treatment, and a decreased in inflammatory laboratory markers was observed at 4.7 days. 88% of patients attended without complications. Conclusions: IOA infections are more common in boys, S. aureus is the main isolated pathogen, so we suggest to initiate the antimicrobial scheme with an antistaphylococcal beta-lactam, adding broad spectrum antimicrobial in children under 5 years. After 5 days of treatment, clinical resolution and decreased inflammatory laboratory parameters were observed.

Influence of Maternal Age and Gestational Age on Breast Milk Antioxidants During the First Month of Lactation.

Breast milk (BM) is beneficial due to its content in a wide range of different antioxidants, particularly relevant for preterm infants, who are at higher risk of oxidative stress. We hypothesize that BM antioxidants are adapted to gestational age and are negatively influenced by maternal age. Fifty breastfeeding women from two hospitals (Madrid, Spain) provided BM samples at days 7, 14 and 28 of lactation to assess total antioxidant capacity (ABTS), thiol groups, reduced glutathione (GSH), superoxide dismutase (SOD) and catalase activities, lipid peroxidation (malondialdehyde, MDA + 4-Hydroxy-Trans-2-Nonenal, HNE), protein oxidation (carbonyl groups) (spectrophotometry) and melatonin (ELISA). Mixed random-effects linear regression models were used to study the influence of maternal and gestational ages on BM antioxidants, adjusted by days of lactation. Regression models evidenced a negative association between maternal age and BM melatonin levels (ß = -7.4 ± 2.5; p-value = 0.005); and a negative association between gestational age and BM total antioxidant capacity (ß = -0.008 ± 0.003; p-value = 0.006), SOD activity (ß = -0.002 ± 0.001; p-value = 0.043) and protein oxidation (ß = -0.22 ± 0.07; p-value = 0.001). In conclusion, BM antioxidants are adapted to gestational age providing higher levels to infants with lower degree of maturation; maternal ageing has a negative influence on melatonin, a key antioxidant hormone.