The transcription factor OCT6 promotes the dissolution of the naïve pluripotent state by repressing Nanog and activating a formative state gene regulatory network.

In the mouse embryo, the transition from the preimplantation to the postimplantation epiblast is governed by changes in the gene regulatory network (GRN) that lead to transcriptional, epigenetic, and functional changes. This transition can be faithfully recapitulated in vitro by the differentiation of mouse embryonic stem cells (mESCs) to epiblast-like cells (EpiLCs), that reside in naïve and formative states of pluripotency, respectively. However, the GRN that drives this conversion is not fully elucidated. Here we demonstrate that the transcription factor OCT6 is a key driver of this process. Firstly, we show that Oct6 is not expressed in mESCs but is rapidly induced as cells exit the naïve pluripotent state. By deleting Oct6 in mESCs, we find that knockout cells fail to acquire the typical morphological changes associated with the formative state when induced to differentiate. Additionally, the key naïve pluripotency TFs Nanog, Klf2, Nr5a2, Prdm14, and Esrrb were expressed at higher levels than in wild-type cells, indicating an incomplete dismantling of the naïve pluripotency GRN. Conversely, premature expression of Oct6 in naïve cells triggered a rapid morphological transformation mirroring differentiation, that was accompanied by the upregulation of the endogenous Oct6 as well as the formative genes Sox3, Zic2/3, Foxp1, Dnmt3A and FGF5. Strikingly, we found that OCT6 represses Nanog in a bistable manner and that this regulation is at the transcriptional level. Moreover, our findings also reveal that Oct6 is repressed by NANOG. Collectively, our results establish OCT6 as a key TF in the dissolution of the naïve pluripotent state and support a model where Oct6 and Nanog form a double negative feedback loop which could act as an important toggle mediating the transition to the formative state.

Exploring the Benefits of Nutritional and Chemical Characteristics of Touriga Nacional and Arinto Varieties (Vitis vinifera L.).

Environmental degradation leads to an unsustainable food system. In addition to this issue, the consumption of foods that improve people's health and well-being is recommended. One of the alternatives is undoubtedly the use of by-products of winemaking, namely in the form of grape pomace flour (GPF). To verify the benefits of using the Touriga Nacional and Arinto (Vitis vinifera L.) flour varieties, analytical determinations were made to identify and quantify different components. In terms of nutritional characterization, the Touriga Nacional GPF showed results that indicate better nutritional quality than the Arinto GPF. The Touriga Nacional and Arinto samples had protein contents of 10.13% and 8.38%, polyunsaturated fatty acids of 6.66% and 5.18%, soluble dietary fiber of 14.3% and 1.7%, and insoluble dietary fiber of 55.1% and 46.4%, respectively. The anthocyanins, proanthocyanidins, and flavonols presented in samples were detected by HPLC-DAD/ESI-MS. Atomic absorption spectrometry revealed elevated concentrations of certain elements in Touriga Nacional compared to Arinto, with the former showing higher levels of aluminum (130 mg/kg) and iron (146 mg/kg) against the latter's Al (120 mg/kg) and Fe (112 mg/kg) content. GPF could become a valuable ingredient due to its nutritional quality and high content of various polyphenols.

Exome Sequencing has a high diagnostic rate in sporadic congenital hypopituitarism and reveals novel candidate genes.

CONTEXT: The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital Hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported. OBJECTIVE: We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina. METHODS: We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date. RESULTS: Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes high loss of function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (e.g. PTPN6, ARID5B). CONCLUSION: Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.

TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism.

OBJECTIVE: Achieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical models and clinical trials for chronic hepatitis B (CHB). However, little is known regarding its action on immune effectors within the liver. Our aim was to characterise the transcriptomic changes and intercellular communication events induced by SLGN in the hepatic microenvironment. DESIGN: We identified TLR8-expressing cell types in the human liver using publicly available single-cell RNA-seq data and established a method to isolate Kupffer cells (KCs). We characterised transcriptomic and cytokine KC profiles in response to SLGN. SLGN's indirect effect was evaluated by RNA-seq in hepatocytes treated with SLGN-conditioned media (CM) and quantification of HBV parameters following infection. Pathways mediating SLGN's effect were validated using transcriptomic data from HBV-infected patients. RESULTS: Hepatic TLR8 expression takes place in the myeloid compartment. SLGN treatment of KCs upregulated monocyte markers (eg, S100A12) and downregulated genes associated with the KC identity (eg, SPIC). Treatment of hepatocytes with SLGN-CM downregulated NTCP and impaired HBV entry. Cotreatment with an interleukin 6-neutralising antibody reverted the HBV entry inhibition. CONCLUSION: Our transcriptomic characterisation of SLGN sheds light into the programmes regulating KC activation. Furthermore, in addition to its previously described effect on established HBV infection and adaptive immunity, we show that SLGN impairs HBV entry. Altogether, SLGN may contribute through KCs to remodelling the intrahepatic immune microenvironment and may thus represent an important component of future combinations to cure HBV infection.

Real-World Outcome of Treatment with Single-Agent Ibrutinib in Italian Patients with Chronic Lymphocytic Leukemia: Final Results of the EVIdeNCE Study.

Real-world data in clinical practice are needed to confirm the efficacy and safety that ibrutinib has demonstrated in clinical trials of patients with chronic lymphocytic leukemia (CLL). We described the real-world persistence rate, patterns of use, and clinical outcomes in 309 patients with CLL receiving single-agent ibrutinib in first line (1L, n = 118), 2L (n = 127) and ≥3L (n = 64) in the prospective, real-world, Italian EVIdeNCE study. After a median follow-up of 23.9 months, 29.8% of patients discontinued ibrutinib (1L: 24.6%, 2L: 29.9%, ≥3L: 39.1%), mainly owing to adverse events (AEs)/toxicity (14.2%). The most common AEs leading to discontinuation were infections (1L, ≥3L) and cardiac events (2L). The 2-year retention rate was 70.2% in the whole cohort (1L: 75.4%, 2L: 70.1%, ≥3L: 60.9%). The 2-year PFS and OS were, respectively, 85.4% and 91.7% in 1L, 80.0% and 86.2% in 2L, and 70.1% and 80.0% in ≥3L. Cardiovascular conditions did not impact patients' clinical outcomes. The most common AEs were infections (30.7%), bleeding (12.9%), fatigue (10.0%), and neutropenia (9.7%), while grade 3-4 atrial fibrillation occurred in 3.9% of patients. No new safety signals were detected. These results strongly support ibrutinib as a valuable treatment option for CLL.

Therapeutic Potential in Wound Healing of Allogeneic Use of Equine Umbilical Cord Mesenchymal Stem Cells.

Wound healing after skin injury is a complex process, particularly in equines where leg wounds are prevalent and their repair is complicated due to the anatomical characteristics. Conventional treatments are not effective enough. The umbilical cord offers an unlimited source of adult mesenchymal stem cells (ucMSCs) from Wharton's jelly tissue. The present study aims to demonstrate the safety and therapeutic potential of the allogeneic use of equine ucMSCs (e-ucMSCs) in the healing of severe equine leg wounds. The methods employed were the isolation, culture and expansion of e-ucMSCs. Flow cytometry and a PCR assay were used for cell characterization. This study included an immunomodulation assay, a murine pre-clinical trial and the first phase of an equine clinical trial. Our results showed that e-ucMSCs express a functional HLA-G homolog, EQMHCB2. In the immunomodulation assay, the e-ucMSCs inhibited the proliferation of activated equine peripheral blood mononuclear cells (e-PBMCs). In the murine pre-clinical trial, e-ucMSCs reduced healing time by 50%. In the equine clinical trial, the injection of e-ucMSCs into severe leg lesions improved the closure time and quality of the tissues involved, regenerating them without fibrous tissue scar formation. In conclusion, the results of this study suggest that e-ucMSCs can be used allogeneically for wound healing by creating a tolerogenic environment.

Medically assisted reproduction and mental health in adolescence: evidence from the UK Millennium Cohort Study.

BACKGROUND: The number and proportion of children conceived through medically assisted reproduction (MAR) is steadily increasing yet the evidence on their mental health in adolescence is inconclusive. Two main mechanisms with opposite effects can explain differences in mental health outcomes by conception mode: while more advantaged parental characteristics could positively influence it, higher parental stress could have a negative influence. METHODS: Linear and logistic estimations on a longitudinal population-based birth cohort study of 9,897 individuals to investigate whether adolescents conceived through MAR are more likely than naturally conceived (NC) children to experience mental health problems at age 17, as reported by adolescents themselves and their parents. We test whether this association is confounded and/or mediated by parental background characteristics collected when the cohort member was around 9 months old (maternal age, maternal education level, ethnicity, income quintile), family structure variables measured in adolescence (number of siblings in the household at age 15, parental household structure at age 14) or maternal distress at age 14. RESULTS: Children conceived naturally and through MAR self-reported similar mental health outcomes. The only differences between MAR and NC adolescents are in the parental reports, with parents who conceived through MAR reporting their children had 3.82 (95% CI: 1.140 to 11.54) and 2.35 (95% CI: 1.145 to 4.838) higher odds of falling within the high category of SDQ total difficulties and emotional symptoms scales, respectively. The results did not change on adjustment for mediators, such as maternal distress, number of siblings in the household and parental household structure. CONCLUSIONS: The results reveal a lack of or small differences in MAR adolescents' mental health outcomes compared to children who were conceived naturally. While the results based on the parental reports could suggest that MAR adolescents are at higher risk of suffering from mental health problems, the differences are small and not supported by adolescents' own reports. The difference between MAR and NC adolescent's parental report might reflect differences in parental concern, their relationship or closeness and can help to reconcile the mixed findings of previous studies.

Synthesis and Characterization of Bi4Ti3O12 Nanoparticles Obtained via Pulsed Laser Ablation in Liquids.

Bismuth titanate (BTO) nanoparticles were obtained by pulsed laser ablation in liquid media (PLAL). Distilled water, ethanol, isopropanol, and acetone were used as media for laser ablation experiments, in which the colloidal solutions were obtained. Laser ablation was carried out using the second harmonic and fundamental wavelength of a pulsed Nd:YAG laser (532 nm and 1064 nm, respectively) with laser fluences of 25 and 12 mJ/cm2, respectively. Transmission electron microscopy was utilized for morphological characterization. BTO nanoparticles obtained have spherical shapes with orthorhombic structure and the average size distribution depended on the liquid media nature. In alcohols, BTO NPs were spherical with a carbon layer around them. X-ray diffraction, UV-Vis absorption spectra, and X-ray photoelectron spectroscopy were used to confirm the structural, optical, and elemental properties of the ablated products. The presented results show that PLAL is a viable technique for the synthesis of high-quality BTO nanoparticles with enhanced optical properties for possible applications in photocatalysis.

Empowering Schools to Implement Effective Research-Based Reading Remediation Delivers Long-Lasting Improvements to Children's Reading Trajectories.

There is a wide gap between what research evidence identifies as effective reading intervention and what is currently offered in schools. This effectiveness study reports the results of a long-term research/school system partnership that is implementing reading intervention for children with reading difficulties in community schools. In Study 1, growth-curve analyses revealed significant long-term shifts in the reading trajectories of children (n = 731) from Kindergarten to Grade 5 as a function of receiving the Empower™ Reading: Decoding and Spelling intervention. Long-term outcomes were higher in children who received intervention in Grade 2 than in Grade 3, supporting the benefit of earlier intervention. In Study 2, we compare reading outcomes before and after children participated in school system-led intervention (Empower™ Reading, n = 341) to results from previously reported researcher-led intervention and business-as-usual controls. Children in both school system-led and researcher-led interventions showed greater improvement than controls on standardized measures of decoding and reading comprehension. Among school system participants, greater gains were seen for those with stronger reading skills at pre-test. Findings demonstrate successful school system implementation of research-originated and validated reading intervention. Researcher/school system partnerships may be integral in closing the research-practice gap.

Plasma sodium concentration in older patients as an indicator of severity in emergencies: Results from the Emergency Department and Elder Needs-16 study. / Estudio EDEN-16: sodio plasmático determinado a la llegada a urgencias como indicador de gravedad en pacientes ancianos.

OBJECTIVES: To study baseline factors associated with hypo- and hypernatremia in older patients attended in emergency departments (EDs) and explore the association between these dysnatremias and indicators of severity in an emergency. MATERIAL AND METHODS: We included patients attended in 52 Spanish hospital EDs aged 65 years or older during a designated week. All included patients had to have a plasma sodium concentration on record. Patients were distributed in 3 groups according to sodium levels: normal, 135-145 mmol/L; hyponatremia, 135 mmol/L; or hypernatremia > 145 mmol/L. We analyzed associations between sodium concentration and 24 variables (sociodemographic information, measures of comorbidity and baseline functional status, and ongoing treatment for hypo- or hypernatremia). Indicators of the severity in emergencies were need for hospitalization, in-hospital mortality, prolonged ED stay (> 12 hours) in discharged patients, and prolonged hospital stay (> 7 days) in admitted patients. We used restricted cubic spline curves to analyze the associations between sodium concentration and severity indicators, using 140 mmol/L as the reference. RESULTS: A total of 13 368 patients were included. Hyponatremia was diagnosed in 13.5% and hypernatremia in 2.9%. Hyponatremia was associated with age ($ 80 years), hypertension, diabetes mellitus, an active neoplasm, chronic liver disease, dementia, chemotherapy, and needing help to walk. Hypernatremia was associated with needing help to walk and dementia. The percentages of cases with severity indicators were as follows: hospital admission, 40.8%; in-hospital mortality, 4.3%; prolonged ED stay, 15.9%; and prolonged hospital stay, 49.8%. Odds ratios revealed associations between lower sodium concentration cut points in patients with hyponatremia and increasing need for hospitalization (130 mmol/L, 2.24 [IC 95%, 2.00-2.52]; 120 mmol/L, 4.13 [3.08-5.56]; and 110 mmol/L, 7.61 [4.53-12.8]); risk for in-hospital death (130 mmol/L, 3.07 [2.40-3.92]; 120 mmol/L, 6.34 [4.22- 9.53]; and 110 mmol/L, 13.1 [6.53-26.3]); and risk for prolonged ED stay (130 mmol/L, 1.59 [1.30-1.95]; 120 mmol/L, 2.77 [1.69-4.56]; and 110 mmol/L, 4.83 [2.03-11.5]). Higher sodium levels in patients with hypernatremia were associated with increasing need for hospitalization (150 mmol/L, 1.94 [1.61-2.34]; 160 mmol/L, 4.45 [2.88-6.87]; 170 mmol/L, 10.2 [5.1-20.3]; and 180 mmol/L, 23.3 [9.03-60.3]); risk for in-hospital death (150 mmol/L, 2.77 [2.16-3.55]; 160 mmol/L, 6.33 [4.11-9.75]; 170 mmol/L, 14.5 [7.45-28.1]; and 180 mmol/L, 33.1 [13.3-82.3]); and risk for prolonged ED stay (150 mmol/L, 2.03 [1.48-2.79]; 160 mmol/L, 4.23 [2.03-8.84]; 170 mmol/L, 8.83 [2.74-28.4]; and 180 mmol/L, 18.4 [3.69-91.7]). We found no association between either type of dysnatremia and prolonged hospital stay. CONCLUSION: Measurement of sodium plasma concentration in older patients in the ED can identify hypo- and hypernatremia, which are associated with higher risk for hospitalization, death, and prolonged ED stays regardless of the condition that gave rise to the dysnatremia.

OBJETIVO: Estudiar los factores basales asociados a hiponatremia e hipernatremia en pacientes mayores atendidos en urgencias y la relación de estas disnatremias con eventos indicadores de gravedad. METODO: Se incluyeron durante una semana a todos los pacientes atendidos en 52 servicios de urgencias hospitalarios españoles de edad $ 65 años con determinación de sodio plasmático. Se formaron tres grupos: sodio normal (135-145 mmol/L), hiponatremia ( 135 mmol/L) e hipernatremia (> 145 mmol/L). Se investigó la relación de 24 factores sociodemográficos, de comorbilidad, estado funcional basal y tratamiento crónico con hipo e hipernatremia. Como eventos de gravedad se recogieron necesidad de hospitalización, mortalidad intrahospitalaria, estancia prolongada en urgencias (> 12 horas) en dados de alta y hospitalización prolongada (> 7 días) en hospitalizados, y se analizó su relación con la concentración de sodio mediante curvas spline cúbicas restringidas ajustadas, tomando el valor 140 mmol/L como referencia. RESULTADOS: Se incluyeron 13.368 pacientes (13,5% hiponatremia, 2,9% hipernatremia). La hiponatremia se asoció a edad $ 80 años, hipertensión arterial, diabetes mellitus, neoplasia activa, hepatopatía crónica, demencia, tratamiento con quimioterápicos y ayuda para la deambulación, y la hipernatremia a dependencia, necesidad de ayuda para deambular y demencia. La hospitalización fue del 40,8%, la mortalidad intrahospitalaria del 4,3%, la estancia prolongada en urgencias del 15,9% y la hospitalización prolongada del 49,8%. A mayor hiponatremia, mayor necesidad de hospitalización (sodio 130 mmol/L: OR:2,24; IC 95%: 2,00-2,52; 120 mmol/L: 4,13, 3,08-5,56; 110 mmol/L: 7,61, 4,53-12,8), mortalidad intrahospitalaria (130 mmol/L: 3,07, 2,40-3,92; 120 mmol/L: 6,34, 4,22-9,53; 110 mmol/L: 13,1, 6,53-26,3) y estancia prolongada en urgencias (130 mmol/L: 1,59, 1,30-1,95; 120 mmol/L: 2,77, 1,69-4,56; 110 mmol/L: 4,83, 2,03-11,5), y a mayor hipernatremia mayor necesidad de hospitalización (150 mmol/L: 1,94, 1,61-2,34; 160 mmol/L: 4,45, 2,88-6,87; 170 mmol/L: 10,2, 5,1-20,3; 180 mmol/L: 23,3, 9,03-60,3), mortalidad intrahospitalaria (150 mmol/L: 2,77, 2,16-3,55; 160 mmol/L: 6,33, 4,11-9,75; 170 mmol/L: 14,5, 7,45-28,1; 180 mmol/L: 33,1, 13,3-82,3) y estancia prolongada en urgencias (150 mmol/L: 2,03, 1,48-2,79; 160 mmol/L: 4,23, 2,03-8,84; 170 mmol/L: 8,83, 2,74-28,4; 180 mmol/L: 18,4, 3,69-91,7). No hubo asociación entre estas disnatremias y hospitalización prolongada. CONCLUSIONES: El sodio plasmático determinado en urgencias en pacientes mayores permite identificar hiponatremias e hipernatremias, las cuales se asocian a un riesgo incrementado de hospitalización, mortalidad y estancia prolongada en urgencias independientemente de la causa que haya generado la disnatremia.

Medically assisted reproduction and mental health: a 24-year longitudinal analysis using Finnish register data.

BACKGROUND: Medically assisted reproduction can negatively affect women's mental health, particularly when the treatments do not result in a live birth. Although the number of women relying on medically assisted reproduction to conceive has grown rapidly, our knowledge about the mental health effects before, during, and after treatment is limited. OBJECTIVE: This study aimed to understand the long-term association between medically assisted reproduction and mental health outcomes for women before, during, and after their treatments, and according to whether the treatment resulted in a live birth. STUDY DESIGN: Using Finnish register data for the period from 1995 to 2018, we estimated the probability of psychotropic purchases (antidepressants, anxiolytics, hypnotics, and sedatives) for 3 groups of women who: (1) gave birth after natural conception, (2) gave birth after medically assisted reproduction treatments, or (3) underwent medically assisted reproduction but remained childless. We followed up women for up to 12 years before and 12 years after the reference date, which corresponded to the conception date for women who had a first live birth either after a natural or a medically assisted conception, or the date of the last medically assisted reproduction treatment for women with no live birth by the end of 2017. We estimated linear probability models before and after adjustment for sociodemographic characteristics. RESULTS: The results show that women who did not have a live birth after undergoing medically assisted reproduction treatments purchased more psychotropics than women who gave birth after conceiving naturally or through medically assisted reproduction, and that these differences did not attenuate over time. Twelve years after the reference date, 17.73% (95% confidence interval, 16.82-18.63) of women who underwent medically assisted reproduction but remained childless purchased psychotropics vs 11.11% of women who gave birth after natural conception (95% confidence interval, 10.98-11.26) and 12.17% (95% confidence interval, 11.65-12.69) of women who gave birth after medically assisted reproduction treatments. In addition, women who conceived naturally and through medically assisted reproduction had very similar psychotropic use patterns from 3 years before conception to 4 years after, and over the long term. Adjustment for women's sociodemographic characteristics did not change the results. CONCLUSION: The similarities in psychotropic purchases of women who had a live birth, whether naturally or through medically assisted reproduction, suggest that the higher psychotropic use among women who remained childless after undergoing medically assisted reproduction were likely driven more by involuntary childlessness than by treatment-related stress. The results highlight the importance of counseling for women undergoing medically assisted reproduction treatments, especially if their attempts to conceive are unsuccessful.

Púrpura de Schönlein Henoch en paciente adulto

RESUMEN La púrpura de Schönlein-Henoch es una vasculitis por fragmentación de leucocitos inmunomediada que afecta a pequeños vasos sanguíneos. Los cuatro componentes clínicos esenciales son púrpuras, dolor abdominal, artralgia y afectación renal. El caso trata de una mujer de 50 años que ingresa por dolor abdominal y hematoquecia de 72 horas de evolución, posterior a laparotomía exploratoria. Al examen físico presenta lesiones purpúricas en tronco y extremidades inferiores de 2 meses de aparición. En paraclínicos se observa hemograma con plaquetas normales, proteínas en orina 500 mg/dL, proteinuria 2,4 g/24 hs. Ante sospecha de vasculitis con plausible inclusión cutáneo-renal, se pide anticuerpos antinucleares, ANCA y se realiza biopsia cutánea evidenciándose una vasculitis neutrofílica necrotizante de pequeños vasos. En la biopsia renal se observa en inmunofluorescencia directa depósito de IgA, C3 positivo. En relación clínica de la proteinuria y compromiso cutáneo junto con la confirmación de biopsia renal se concluye en diagnóstico de púrpura de Schönlein Henoch. El interés de este caso radica en la inconsistencia de esta patología en los adultos, a pesar de que bien podría ser de una gravedad más notable dado que existe un mayor peligro de falla renal persistente.

ABSTRACT Schönlein-Henoch purpura is an immune-mediated leukocyte fragmentation vasculitis that affects small blood vessels. The four essential clinical components are purpura, abdominal pain, arthralgia, and renal involvement. This case concerns a 50-year-old woman who is admitted due to abdominal pain and hematochezia of 72 hours of evolution, after an exploratory laparotomy. On physical examination, she presents purpuric lesions on the trunk and lower extremities of 2 months of appearance. In paraclinical tests, a blood count with normal platelets, urine protein 500 mg/dL, and proteinuria 2.4 g/24 hours are observed. Suspecting vasculitis with plausible cutaneous-renal inclusion, antinuclear antibodies and ANCA are requested, and a skin biopsy is performed, showing necrotizing neutrophilic vasculitis of small vessels. In the renal biopsy, IgA deposit, C3 positive is observed in the direct immunofluorescence. In the clinical relationship of proteinuria and skin involvement together with the confirmation of renal biopsy, the diagnosis of Schönlein-Henoch purpura is concluded. The interest of this case lies in the inconsistency of this pathology in adults, despite the fact that it could be more serious given that there is a greater risk of persistent renal failure.

Meckel's Diverticulum: The "Great Mimic" but Often a Forgotten Cause of Acute Abdomen during Pregnancy.

Meckel's diverticulitis is an extremely rare event during pregnancy. Its diagnosis is often difficult and can result in higher maternal and fetal morbimortality. We describe a case of a 40-year-old healthy pregnant woman at 33 weeks of gestation who presented with abdominal pain and tender abdomen, leukocytosis, and elevated PCR. The imagiological exams were not conclusive. After an urgent caesarean section due to worsening of clinical status and nonreassuring fetal well-being, a laparotomy revealed a distended, necrotic, and perforated Meckel's diverticulum.

MgO-ZrO2 Ceramic Composites for Silicomanganese Production.

The deterioration of the refractory lining represents a significant problem for the smooth operation in the ferroalloys industry, particularly in the production of silicomanganese, due to the periodic requirements of substitution of the damaged refractory. Within this context, magnesia refractories are commonly employed in the critical zones of the furnaces used in silicomanganese production since the slag involved in the process has a basic character. The behavior of MgO-ZrO2 ceramic composites with different ZrO2 nanoparticles (0, 1, 3, and 5 wt.%) contents in the presence of silicomanganese slags is proposed in this manuscript. XPS, XRD and SEM-EDX were used to evaluate the properties of the ceramic composite against the silicomanganese slag. The static corrosion test was used to evaluate the corrosion of the refractory. Results suggest that corrosion is controlled by the change in slag viscosity due to the reaction between CaZrO3 and the melted slag. Besides, ZrO2 nanoparticles located at both triple points and grain boundaries act as a barrier for the slag advance within the refractory. The utilization of MgO refractories with ZrO2 nanoparticles can extend the life of furnaces used to produce silicomanganese.

Platelet number and function alterations in preclinical models of sterile inflammation and sepsis patients: implications in the pathophysiology and treatment of inflammation.

Platelets are the blood cells in charge of maintaining the body hemostasis, recognising the damaged vessel wall, and providing the appropriate cellular surface for the coagulation cascade to act locally. Additionally, platelets are active immunomodulators. At the crossroads of hemostasis and inflammation, platelets may exert either beneficial actions or participate in pathological manifestations, and have been associated with the prothrombotic nature of multi-organ failure in systemic inflammation. Platelet number alterations have been reported in septis, and platelet transfusions are given to thrombocytopenic patients. However, the risk to develop transfusion related acute lung injury (TRALI) is higher in sepsis patients. In this manuscript we show that platelets produced during inflammation in preclinical mouse models of sterile inflammation display lower aggregation capacity when stimulating certain receptors, while responses through other receptors remain intact, and we name them "inflammation-conditioned" platelets. In a cohort of sepsis patients, we observed, as previously reported, alterations in the number of platelets and platelet hyperreactivity. Furthermore, we identified a receptor-wise platelet aggregation response disbalance in these patients, although not similar to platelets from preclinical models of sterile inflammation. Interestingly, we generated evidence supporting the notion that platelet aggregation capacity disbalance was partially triggered by plasma components from sepsis patients. Our findings have implications in the indication of platelet transfusions in sepsis patients: Are fully functional platelets suitable for transfusion in sepsis patients? Current Clinical Trials (RESCUE) will answer whether platelet production stimulation with thrombopoietin receptor agonists (TPO-RAs) could be a substitute of platelet transfusions.

In vitro antimicrobial activity of Douro wines against clinical Helicobacter pylori strains / strains121In vitro antimicrobial activity of Douro wines against clinical helicobacter pylori strains / Actividad antimicrobiana in vitro de los vinos del Duero sobre cepas clínicas de Helicobacter pylori

Abstract Aim. In vitro antimicrobial activities of seven wines (5 reds and 2 whites) from the Douro region (Iberian Peninsule) against eleven clinical strains of Helicobacter pylori were evaluated. Methods. The disk diffusion method, using Columbia Agar supplemented with horse blood (CAB), were used to determine the antimicrobial properties of some wine components against H. pylori strains. Potential interactions of antioxidants contained in the wines and two antimicrobials (amoxicillin and metronidazole) were studied by the disk diffusion method. Results. All the tested strains showed growth in CAB supplemented with 9% of the tested wines but none of them grew in media supplemented with 45% and 67.5% of wine. Similarly, all the tested strains grew in media with the concentration of proanthocyanidins present in the different types of the studied wines. The Minimal Inhibitory Concentration (MIC) values of the wine antioxidant components tested (benzoic acid, catechin, quercetin, and resveratrol) indicate that resveratrol was the most powerful inhibitory substance against H. pylori. An effect of potentiation between amoxicillin and metronidazole and the antioxidants tested was also established. The interaction of amoxicillin and resveratrol or metronidazole and catechin increased the antimicrobial activity against H. pylori. Conclusions. The results obtained suggested a potential role of resveratrol as a chemopreventive agent for H. pylori infection.

Resumen Objetivo. Se evaluó las actividades antimicrobianas in vitro de siete vinos (5 tintos y 2 blancos) de la región del Duero (Peninsula Ibérica) frente a once cepas de Helicobacter pylori de origen clínico. Métodos. Para determinar las propiedades antimicrobianas de algunos componentes del vino sobre las cepas de H. pylori se utilizaron las técnicas de difusión en disco en placas de agar Columbia suplementado con sangre de caballo (CAB). La potential interacción entre las sustancias antioxidantes presentes en los vinos y dos antimicrobianos (amoxicilina y metronidazol) se determinó usando la técnica de difusión en disco. Resultados. Todas las cepas ensayadas mostraron crecimiento en CAB suplementado con el 9% de los vinos analizados, pero no se obtuvo crecimiento de ninguna de las cepas en medios suplementados con el 45% y el 67,5% de vino. Asimismo, todas las cepas ensayadas crecieron en medios con la concentración de proantocianidinas presentes en los diferentes tipos de vinos estudiados. Los valores de concentración mínima inhibitoria (CMI) de los componentes antioxidantes de los vinos ensayados (ácido benzoico, catequina, quercetina y resveratrol) indican que el resveratrol fue la sustancia más potente en la inhibición del crecimiento de H. pylori. También se estableció un efecto de potenciación entre amoxicilina y metronidazol y los antioxidantes ensayados. Las interacciones amoxicilina + resveratrol y metronidazol + catequina aumentaron la actividad antimicrobiana contra H. pylori. Conclusiones. Los resultados obtenidos sugieren un papel potencial del resveratrol como agente quimiopreventivo de la infección por H. pylori.

HLA-G gene editing in tumor cell lines as a novel alternative in cancer immunotherapy.

Cancer immunotherapies based mainly on the blockade of immune-checkpoint (IC) molecules by anti-IC antibodies offer new alternatives for treatment in oncological diseases. However, a considerable proportion of patients remain unresponsive to them. Hence, the development of novel clinical immunotherapeutic approaches and/or targets are crucial.W In this context, targeting the immune-checkpoint HLA-G/ILT2/ILT4 has caused great interest since it is abnormally expressed in several malignancies generating a tolerogenic microenvironment. Here, we used CRISPR/Cas9 gene editing to block the HLA-G expression in two tumor cell lines expressing HLA-G, including a renal cell carcinoma (RCC7) and a choriocarcinoma (JEG-3). Different sgRNA/Cas9 plasmids targeting HLA-G exon 1 and 2 were transfected in both cell lines. Downregulation of HLA-G was reached to different degrees, including complete silencing. Most importantly, HLA-G - cells triggered a higher in vitro response of immune cells with respect to HLA-G + wild type cells. Altogether, we demonstrated for the first time the HLA-G downregulation through gene editing. We propose this approach as a first step to develop novel clinical immunotherapeutic approaches in cancer.

Which impact for proton pump inhibitors in SARS-CoV-2 pneumonia.

Identification of risk factors for severe outcome of SARS-CoV-2 infection is an important issue in COVID-19 management. Much attention has been focused on comorbidities as well as drugs taken by patients. Usage of proton pump inhibitors (PPIs) appears to potentially influence disease course. These drugs are known to reduce stomach acid and also modulate the immune system. Their use, prior to and during COVID-19 infection, seems to predispose to the development of more severe pneumonia and therefore to a greater risk of mortality. Instead, the use of histamine receptor 2 antagonists (H2RAs) seems to be associated with a better outcome in patients with COVID-19, in terms of symptoms, risk of intubation and death. As PPIs are essential for treatment of many disorders, usage of these drugs should be balanced considering the benefits and risk ratio, in order to guarantee their correct use for the necessary time. It remains to be clarified whether the detrimental effects, in terms of COVID-19 severe outcome, are due to PPIs or to the underlying disease for which they are administered. New controlled-randomized trials are required to better understand their impact in SARS-CoV-2 infections. *Vanvitelli/Monaldi COVID Group: Adriano Cristinziano, Carolina Delle Donne, Cecilia Calabrese, Fabio Perrotta, Filippo Scialò, Francesco Lassandro, Gennaro Mazzarella, Giorgio Paoli, Leonardo De Luca, Maria Galdo, Miriam Buonincontro, Roberta Cianci, Rosalba Donizzetti, Stefano Sanduzzi Zamparelli, Tullio Valente, Vito D'Agnano, Vittorio Bisogni.

Amphiphilic tricationic Zn(II)phthalocyanine provides effective photodynamic action to eradicate broad-spectrum microorganisms.

A novel tricationic Zn(II)phthalocyanine derivative, (NCH3)3ZnPc3+, was synthesized by ring expansion reaction of boron(III) [2,9(10),16(17)-trinitrosubphthalocyaninato]chloride. First, the reaction of this subphthalocyanine with 2,3-naphthalenedicarbonitrile and Zn(CH3COO)2 catalyzed by 8-diazabicyclo[5.4.0]undec-7-ene was used to obtain the A3B-type nitrophthalocyanine. After reduction of nitro groups with Na2S and exhaustive methylation of amino groups, (NCH3)3ZnPc3+ was formed in good yields. In addition, the tetracationic analog (NCH3)4ZnPc4+ was synthesized to compare their properties. The absorption and fluorescence spectra showed the Q-bands and the red emission, respectively, which are characteristic of the Zn(II)phthalocyanine derivatives in N,N-dimethylformamide. Furthermore, photodynamic activity sensitized by these compounds was studied in the presence of different molecular probes to sense the formation of reactive oxygen species. (NCH3)3ZnPc3+ efficiently produced singlet molecular oxygen and also it sensitized the formation of superoxide anion radical in the presence of NADH, while the photodynamic activity of (NCH3)4ZnPc4+ was very poor, possibly due to the partial formation of aggregates. Furthermore, the decomposition of L-tryptophan induced by (NCH3)3ZnPc3+ was mainly mediated by a type II mechanism. Antimicrobial photodynamic inactivation sensitized by these phthalocyanines was evaluated in Staphylococcus aureus, Escherichia coli, and Candida albicans, as representative microbial cells. In cell suspensions, (NCH3)3ZnPc3+ was rapidly bound to microbial cells, showing bioimages with red fluorescence emission. After 5 min of irradiation with visible light, (NCH3)3ZnPc3+ was able to completely eliminate S. aureus, E. coli and C. albicans, using 1.0, 2.5 and 5.0 µM phthalocyanine, respectively. In contrast, a low photoinactivation activity was found with (NCH3)4ZnPc4+ as a photosensitizer. Therefore, the amphiphilic tricationic phthalocyanine (NCH3)3ZnPc3+ is a promising photosensitizing structure for application as a broad-spectrum antimicrobial phototherapeutic agent.

Real-world effectiveness and tolerability of Zelesse cream® for treating vulvovaginitis in adult women: an observational, prospective study.

OBJECTIVE: To assess the efficacy, acceptability, and tolerability of a vaginal cream based on plant extracts for treating signs and symptoms of vulvovaginitis (VV) (Zelesse cream®), either as monotherapy (non-infectious VV) or adjuvant to antimicrobial therapy (infectious VV). METHODS: This prospective, observational, multicenter study included women who attended outpatient offices for VV. The severity of signs (vaginal discharge, erythema, and edema) and symptoms (pruritus, burning, and dysuria) was assessed before and after 15±5 days of daily treatment with Zelesse cream on a 4-point scale (18-point global score). RESULTS: The study included 58 women aged 43.0±13.2 years, including 42 who were treated with Zelesse cream only and 16 who used Zelesse cream as adjuvant to antimicrobial therapy. All participants showed significantly reduced scores and absolute prevalence of individual signs and symptoms in both groups. Similarly, the median signs/symptoms decreased by 4.0 and 8.0 points in women using Zelesse only and those using Zelesse plus antimicrobial therapy, respectively. This product was well tolerated and had high acceptability. CONCLUSIONS: Zelesse cream relieves signs and symptoms of VV, either as monotherapy in non-infectious VV or as adjuvant to antimicrobial therapy in infectious VV. Future randomized, placebo-controlled trials with larger sample sizes are warranted.