[Hemoperitoneum secondary to a malignant tumor of the sheath of the peripheral nerve in the liver]. / Hemoperitoneo secundario a tumor maligno de la vaina del nervio periférico en hígado.

Malignant peripheral nerve sheath tumors are frequently associated with neurofibromatosis type 1. They are usually located in the extremities or in the axial area. Its visceral location is very rare and its hepatic origin is infrequent. They tend to be aggressive with a poor response to chemotherapy and radiotherapy, so surgical management is the best treatment option. We present the case of a young man with neurofibromatosis type 1, who presented with hemoperitoneum as a complication of a malignant tumor of the peripheral nerve sheath located in the liver.

Mesenchymal stem cells induce an immunosuppressive microenvironment in pituitary tumors.

BACKGROUND: The tumor microenvironment (TME) includes diverse cellular components such as mesenchymal stem cells (MSC) and immune cells among others. MSC have been isolated from different tumors and they favor tumor cell growth, however, their role in pituitary tumors (PT) remains unknown. Herein we report the presence of MSCs in 2 ACTH-secreting PT causing Cushing disease (MCU), 2 nonfunctioning adenomas of gonadotrope differentiation (MNF) and 2 non tumoral pituitary glands (MS). METHODS: We have analyzed their transcriptomic profiles by RNAseq and compared MSC in terms of their immunosuppressive effects against lymphoid T cell and macrophage populations by means of co-cultures and flow cytometry. RESULTS: Our transcriptomic analysis revealed molecular differences between MSC derived from non-tumoral pituitaries and MSC derived from PT. Two distinct subpopulations of MSC, one displaying immunosuppressive properties and the other with increased pro-proliferative capabilities, regardless of their origin. MSC derived from ACTH- and nonfunctioning PT, but not those derived from non-tumoral glands significantly inhibited the proliferation of activated T cells, favored the generation of Tregs and promote M2 macrophage polarization. Such immunosuppressive effects were correlated with an upregulation of programmed death ligand 1 and intracellular expression of macrophage colony stimulating factor (M-CSF) and IL-10. Importantly, MSC derived from ACTH-PT showed a higher immunosuppressive potential than MSC isolated from nonfunctioning tumors. CONCLUSION: This study demonstrates the presence of at least two MSC subpopulations in the pituitary gland and suggests that immunosuppressive effects of MSC may have important implications in PT growth.

Interaction between Akkermansia muciniphila and Diet Is Associated with Proinflammatory Index in School-Aged Children.

BACKGROUND: Imbalance in the intestinal microbiota can lead to chronic low-grade inflammation. Diet may influence this association. In this study, we aimed to evaluate the interaction between Akkermansia muciniphila (A. muciniphila) and dietary patterns using a proinflammatory index. METHODS: We conducted a cross-sectional study with school-aged children. We quantified the relative abundance (RA) of A. muciniphila in feces using a polymerase chain reaction. We collected dietary information through employing a food frequency questionnaire and generated dietary patterns using principal component analysis. We generated a proinflammatory index from serum levels of interleukin-6, interleukin-10, tumor necrosis factor alpha, and adiponectin validated by receptor operating characteristic curves. We evaluated the association between A. muciniphila and the proinflammatory index using logistic regression, including an interaction term with dietary patterns. RESULTS: We found that children with a low RA of A. muciniphila and a high intake of simple carbohydrates and saturated fats had increased odds of being high on the proinflammatory index. However, when the consumption of this dietary pattern is low, children with a low RA of A. muciniphila had decreased odds of being high on the proinflammatory index. CONCLUSIONS: Our results suggest that the simultaneous presence of A. muciniphila and diet have a more significant impact on the presence of being high on the proinflammatory index compared to both factors separately.

Human Bone Marrow Mesenchymal Stem Cells Promote the M2 Phenotype in Macrophages Derived from STEMI Patients.

Acute ST-elevation myocardial infarction (STEMI) leads to myocardial injury or necrosis, and M1 macrophages play an important role in the inflammatory response. Bone marrow mesenchymal stem/stromal cells (BM-MSCs) are capable of modulating macrophage plasticity, principally due to their immunoregulatory capacity. In the present study, we analyzed the capacity of MSCs to modulate macrophages derived from monocytes from patients with STEMI. We analyzed the circulating levels of cytokines associated with M1 and M2 macrophages in patients with STEMI, and the levels of cytokines associated with M1 macrophages were significantly higher in patients with STEMI than in controls. BM-MSCs facilitate the generation of M1 and M2 macrophages. M1 macrophages cocultured with MSCs did not have decreased M1 marker expression, but these macrophages had an increased expression of markers of the M2 macrophage phenotype (CD14, CD163 and CD206) and IL-10 and IL-1Ra signaling-induced regulatory T cells (Tregs). M2 macrophages from patients with STEMI had an increased expression of M2 phenotypic markers in coculture with BM-MSCs, as well as an increased secretion of anti-inflammatory cytokines and an increased generation of Tregs. The findings in this study indicate that BM-MSCs have the ability to modulate the M1 macrophage response, which could improve cardiac tissue damage in patients with STEMI.

Comparing fine needle biopsy techniques in solid pancreatic lesions: A prospective randomized study.

INTRODUCTION: Endoscopic ultrasound-guided fine-needle biopsies (EUS-FNB) are the best technique for sampling solid pancreatic lesions. However, the most appropriate biopsy technique has not been standardized using Fine Needle Biopsy (FNB) needles. The aim of this work was to identify the best biopsy technique to achieve the best tissue integrity and cause the least blood contamination. MATERIAL AND METHODS: Patients ≥18 years of age with solid pancreatic lesions who underwent EUS-FNB at our institution from January 2020 to May 2021 were consecutively selected. Three passes were performed with each of the threee techniques to obtain tissue: suction with 10 ml of vacuum, capillary, and wet. An independent pathologist evaluated the received tissue integrity and the degree of blood contamination of each sample according to scales. RESULTS: Seventy-five patients were recruited for our study. A superior tissue integrity was observed using the wet-suction technique in lesions located in the body and/or tail of the pancreas, and an average score of 4.40 (p = 0.027) was assigned for this technique. Regarding the contamination of the sample in the whole cohort, the simple-suction technique shown a higher contamination, 1.55 (p < 0.001). There was no statistically significant difference among the techniques when evaluating tissue integrity or contamination in lesions larger or smaller than 3 cm. CONCLUSION: When performing EUS-FNB for solid pancreatic lesions located in the head/uncinated process, the three methods provided similar diagnostic yields. The wet-suction technique had a higher score in tissue integrity when lesions were located in the body and/or tail of the pancreas.

Interferon-tau (IFN-τ) Has Antiproliferative Effects, Induces Apoptosis, and Inhibits Tumor Growth in a Triple-negative Breast Cancer Murine Tumor Model.

BACKGROUND/AIM: Resistant triple-negative breast cancer (TNBC) is a subtype of this disease that is resistant to conventional chemotherapy agents. IFN-τ is a cytokine that has recently been shown to have immunoregulatory and antitumor effects. The present study aimed to examine the antiproliferative and apoptosis effects of IFN-τ in breast cancer cells and the antitumor effect in a murine tumor model of TNBC. MATERIALS AND METHODS: Murine breast cancer 4T1 cells were cultured and treated with ovine IFN-τ and through MTT and Caspase-Glo 3/7 assays, viability and cell death were determined. In addition, the antitumor effect of IFN-τ was determined in a murine tumor model of TNBC. RESULTS: Ovine IFN-τ showed a concentration-dependent antiproliferative effect on 4T1 murine breast cancer cells. Also, treatment of 4T1 cells with IFN-τ induced the activation of caspase 3 and 7, which is indicative of apoptotic cell death. Moreover, we detected an increase in the expression of type I interferon receptor (IFNAR1/2) in cells treated with IFN-. The intratumoral application of IFN-τ in mice inhibited tumor growth compared to the control non-treated group, and the effect was associated with the increased expression of GM-CSF. CONCLUSION: Ovine IFN-τ may be an effective immunotherapeutic cytokine for the treatment of TNBC.

Mesenchymal Stem/Stromal Cells Derived from Cervical Cancer Promote M2 Macrophage Polarization.

Macrophages with the M2 phenotype promote tumor development through the immunosuppression of antitumor immunity. We previously demonstrated the presence of mesenchymal stem/stromal cells (MSCs) in cervical cancer (CeCa-MSCs), suggesting an immune protective capacity in tumors, but to date, their effect in modulating macrophage polarization remains unknown. In this study, we compared the capacities of MSCs from normal cervix (NCx) and CeCa to promote M2 macrophage polarization in a coculture system. Our results demonstrated that CeCa-MSCs, in contrast to NCx-MSCs, significantly decreased M1 macrophage cell surface marker expression (HLA-DR, CD80, CD86) and increased M2 macrophage expression (CD14, CD163, CD206, Arg1) in cytokine-induced CD14+ monocytes toward M1- or M2-polarized macrophages. Interestingly, compared with NCx-MSCs, in M2 macrophages generated from CeCa-MSC cocultures, we observed an increase in the percentage of phagocytic cells, in the intracellular production of IL-10 and IDO, the capacity to decrease T cell proliferation and for the generation of CD4+CD25+FoxP3+ Tregs. Importantly, this capacity to promote M2 macrophage polarization was correlated with the intracellular expression of macrophage colony-stimulating factor (M-CSF) and upregulation of IL-10 in CeCa-MSCs. Furthermore, the presence of M2 macrophages was correlated with the increased production of IL-10 and IL-1RA anti-inflammatory molecules. Our in vitro results indicate that CeCa-MSCs, in contrast to NCx-MSCs, display an increased M2-macrophage polarization potential and suggest a role of CeCa-MSCs in antitumor immunity.

Suicidios de indígenas en Valle del Cauca, Cauca y Nariño (Colombia) antes (2018-2019) y durante la pandemia de la COVID-19 (2020-2021) / Indigenous suicides in Valle del Cauca, Cauca and Nariño (Colombia) before (2018-2019) and during the COVID-19 pandemic (2020-2021)

RESUMEN Introducción : El Centro para el Control y Prevención de Enfermedades (CDC) define el suicidio como el acto de autoagresión con la intención de causar la muerte propia de manera voluntaria. En pueblos indígenas de países como Canadá, Australia, Groenlandia, Estados Unidos, Nueva Zelanda, Brasil y Siberia, se evidencia que este evento sucede con mayor frecuencia que en la población general, principalmente como consecuencia del colonialismo y las dificultades que enfrentan las comunidades indígenas, factores que se citan hoy como comunes a nivel mundial. Método : Estudio cuantitativo, descriptivo y retrospectivo en el que se analizaron 48 casos de suicidios de indígenas del suroccidente colombiano, ocurridos durante el período de prepandemia (2018-2019) y pandemia de la COVID-19 (2020-2021), registrados en el Instituto Nacional de Medicina Legal y Ciencias Forenses (INMLYCF) de los departamentos de Valle del Cauca, Cauca y Nariño. Resultados : En la región estudiada se suicidaron más personas durante el período pandémico (2020-2021). Las víctimas fueron, predominantemente, individuos del sexo masculino, de edad joven (entre 19 y 26 años), con estudios de primaria y bachillerato, que tenían ocupación de agricultores o estudiantes, que usaron el ahorcamiento como modalidad principal para acabar con su vida, y cuya razón de suicidio más frecuente era el conflicto con la pareja o expareja. Conclusiones : La tasa de suicidio en indígenas en el Valle del Cauca, Cauca y Nariño fue más alta que la registrada en la población general de los mismos departamentos durante la pandemia de la COVID-19 (2020-2021). Es necesario considerar factores socioculturales y trayectorias del evento suicida en el seno de cada comunidad distintivamente estudiada.

ABSTRACT Introduction : The Center for Disease Control and Prevention (CDC) defines suicide as an act of self-harm with the intent to cause a voluntary death. In indigenous peoples from countries such as Canada, Australia, Greenland, the United States, New Zealand, Brazil and Siberia, it is evident that this event occurs more frequently than in the general population, mainly as a consequence of colonialism and difficulties faced by indigenous communities, factors that are now considered as common throughout the world. Methods : A retrospective, descriptive, quantitative and retrospective study that analyzes 48 cases of suicide in indigenous people from Southwestern Colombia during the COVID-19 pre-pandemic (2018-2019) and pandemic (2020-2021) periods and registered in the National Institute of Legal Medicine and Forensic Sciences of the departments of Valle del Cauca, Cauca and Nariño. Results : In the studied region more people committed suicide during the pandemic period (2020-2021). The victims were, predominantly, males of young ages (between 19 and 26 years), with a primary and high school educational level, of primary and high school, with farmer or student occupations, use of hanging as the main modality, and conflict with partner or ex-partner as the most frequently cited reason. Conclusions : The suicide rate among indigenous people in the departments of Cauca Valley, Cauca and Nariño was higher than that recorded in the general population of the same departments during the COVID-19 pandemic (2020-2021). It is necessary to consider sociocultural factors and the trajectories of the suicide event within each distinctly studied community.

Low-Dose Aspirin Has Antiproliferative and Apoptosis Effects in HPV16 Tumor Cells and Delays Tumor Development and Growth in an Experimental Model.

OBJECTIVES: The purpose of this study was to investigate the effect of aspirin on epithelial HPV16-transformed cells and its antitumor effects, in an experimental HPV16-positive tumor model. DESIGN: The design of the study is experimental (in vitro and in vivo). PARTICIPANTS/MATERIALS, SETTING, AND METHODS: SiHa and BMK-16/myc cells were treated with aspirin and cell proliferation was determined by MTT; Caspase-Glo 3/7 Assay was used to determine apoptosis. The tumor-bearing mice group was treated with 50 mg/gr/day of aspirin (orally) during 30 days and the antitumor effect was determined. RESULTS: Here, we provide evidence that aspirin has a negative effect on proliferation and induces apoptosis in the human (SiHa) and murine (BMK-16/myc) HPV16 cells. Furthermore, aspirin showed inhibition of tumor growth, and in mice treated with aspirin prior to implantation of tumor cells, the tumor growth was delayed. Also, the effect of aspirin increased survival in tumor-bearing mice and in mice pre-treated with aspirin. LIMITATIONS: It is necessary to carry out in vitro and in vivo studies of the molecular mechanisms involved in the effects of aspirin on tumor cells. CONCLUSION: Aspirin showed antiproliferative effects in tumor cells and inhibited tumor progression and could be effective as a chemopreventive agent. Thus, aspirin deserves further exploration for the treatment of cervical cancer and other neoplasms.

Altered Vaginal Microbiota Composition Correlates With Human Papillomavirus and Mucosal Immune Responses in Women With Symptomatic Cervical Ectopy.

Cervical ectopy is a benign condition of the lower genital tract that is frequently detected in women of reproductive age. Although cervical ectopy is regarded as a physiological condition, some women experience symptoms such as leucorrhoea, persistent bleeding and recurrent vaginal infections that require medical intervention. Cervical ectopy has not been linked to cervical cancer, but it is thought to facilitate the acquisition of sexually transmitted diseases (STDs), like Human Papillomavirus (HPV) infection, as it provides a favorable microenvironment for virus infection and dissemination. We and others have described the presence of oncogenic HPV types in women with symptomatic cervical ectopy. The relevance of this finding and the impact of symptomatic cervical ectopy on the cervicovaginal microenvironment (vaginal microbiota, immune and inflammatory responses) are currently unknown. To shed some light into the interplay between HPV, the vaginal microbiota and mucosal immune and inflammatory responses in the context of this condition, we enrolled 156 women with symptomatic cervical ectopy and determined the presence of HPV using a type-specific multiplex genotyping assay. Overall, HPV was detected in 54.48% women, oncogenic HPV types were found in more than 90% of HPV-positive cases. The most prevalent HPV types were HPV16 (29.4%), HPV31 (21.17%) and HPV18 (15.29%). Next, we evaluated the vaginal microbial composition and diversity by 16S rDNA sequencing, and quantified levels of cytokines and chemokines by flow cytometry using bead-based multiplex assays in a sub-cohort of 63 women. IL-21 and CXCL9 were significantly upregulated in HPV-positive women (p=0.0002 and p=0.013, respectively). Women with symptomatic cervical ectopy and HPV infection had increased diversity (p<0.001), and their vaginal microbiota was enriched in bacterial vaginosis-associated anaerobes (Sneathia, Shuttleworthia, Prevotella, and Atopobium) and depleted in Lactobacillus spp. Furthermore, the vaginal microbiota of women with symptomatic cervical ectopy and HPV infection correlated with vaginal inflammation (IL-1ß, rho=0.56, p=0.0004) and increased mucosal homeostatic response (IL-22, rho=0.60, p=0.0001). Taken together, our results suggest that HPV infection and dysbiotic vaginal communities could favor a vaginal microenvironment that might delay the recovery of the cervical epithelium in women with symptomatic cervical ectopy and favor STDs acquisition.

High Relative Abundance of Staphylococcus aureus and Serum Cytokines Are Associated with Cardiometabolic Abnormalities in Children.

Background: The alteration in the composition of the gut microbiota has been associated with an increased risk of developing cardiovascular and metabolic diseases. The present study evaluated the association between the relative abundance (RA) of intestinal Staphylococcus aureus and the inflammatory response with cardiometabolic alterations in children. Methods: This cross-sectional study included 1142 children (age 6-12 years), which were classified by degree of adiposity. Anthropometry, cardiometabolic markers, and RA of intestinal S. aureus were measured. Cytokine concentrations were available in 626 children. Path coefficients (PC) were estimated by path analysis. Results: RA of S. aureus was positively associated with cholesterol PC = 24.98 (95% CI 10.76 to 39.21) and negatively with triglycerides PC = -13.10 (95% CI -22.73 to -3.48). Body mass index (BMI) Z-scores had significant mediation effects on the association between RA of S. aureus with waist circumference PC = 2.87 (95% CI 0.58 to 5.16), triglycerides PC = 6.63 (95% CI 1.29 to 11.98), low-density lipoproteins (LDL) PC = 1.73 (95% CI 0.27 to 3.18), and high-density lipoproteins PC = -1.20 (95% CI -2.19 to -0.22). Interleukin 6 (IL-6) was negatively associated with glucose PC = -3.01 (95% CI -5.85 to -0.17) and LDL PC = -8.65 (95% CI -16.54 to -0.77), and interleukin 10 (IL-10) was positively associated with glucose PC = 3.37 (95% CI 0.47 to 6.26). Conclusions: It is suggested that the RA of S. aureus, IL-6, and IL-10 are associated with cardiometabolic alterations in children, where BMI Z-scores have an important mediating effect for the development of these.

Immigrant IBD Patients in Spain Are Younger, Have More Extraintestinal Manifestations and Use More Biologics Than Native Patients.

BACKGROUND: Previous studies comparing immigrant ethnic groups and native patients with IBD have yielded clinical and phenotypic differences. To date, no study has focused on the immigrant IBD population in Spain. METHODS: Prospective, observational, multicenter study comparing cohorts of IBD patients from ENEIDA-registry who were born outside Spain with a cohort of native patients. RESULTS: We included 13,524 patients (1,864 immigrant and 11,660 native). The immigrants were younger (45 ± 12 vs. 54 ± 16 years, p < 0.001), had been diagnosed younger (31 ± 12 vs. 36 ± 15 years, p < 0.001), and had a shorter disease duration (14 ± 7 vs. 18 ± 8 years, p < 0.001) than native patients. Family history of IBD (9 vs. 14%, p < 0.001) and smoking (30 vs. 40%, p < 0.001) were more frequent among native patients. The most prevalent ethnic groups among immigrants were Caucasian (41.5%), followed by Latin American (30.8%), Arab (18.3%), and Asian (6.7%). Extraintestinal manifestations, mainly musculoskeletal affections, were more frequent in immigrants (19 vs. 11%, p < 0.001). Use of biologics, mainly anti-TNF, was greater in immigrants (36 vs. 29%, p < 0.001). The risk of having extraintestinal manifestations [OR: 2.23 (1.92-2.58, p < 0.001)] and using biologics [OR: 1.13 (1.0-1.26, p = 0.042)] was independently associated with immigrant status in the multivariate analyses. CONCLUSIONS: Compared with native-born patients, first-generation-immigrant IBD patients in Spain were younger at disease onset and showed an increased risk of having extraintestinal manifestations and using biologics. Our study suggests a featured phenotype of immigrant IBD patients in Spain, and constitutes a new landmark in the epidemiological characterization of immigrant IBD populations in Southern Europe.

High Vitamin D Concentrations Restore the Ability to Express LL37 by M. tuberculosis-Infected Human Macrophages.

Vitamin D has an immunomodulatory function and is involved in eliminating pathogens. Vitamin D deficiencies reported in Type 2 diabetes mellitus (T2DM) patients make them more susceptible to developing tuberculosis (TB). The macrophages are the immune cells that control intracellular pathogens by producing the antimicrobial peptide cathelicidin-LL37. This pathway involves TLR activation by pathogens, vitamin D receptor (VDR) ligation, and the enzyme 1α-hydroxylase Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1). However, it is not clear whether the biological actions of vitamin D are affected by high glucose concentrations. This study aimed to evaluate the vitamin D contribution in the expression of VDR and CYP27B1, involved in the conversion of an inactive to an active form of vitamin D in the infected macrophages using M. tuberculosis as an infection model. The expression of LL37 and the nucleus translocation of VDR were evaluated as the readout of the response of vitamin D and determined if those processes are affected by glucose concentrations. Macrophages from healthy donors were cultured under glucose concentrations of 5.5, 15, or 30 mM, stimulated with vitamin D in inactive (25(OH)D3) or active (1,25(OH)2D3) forms, and infected with M. tuberculosis. The vitamin D-dependent induction of LL37 and the expression of VDR and CYP27B1 genes were analyzed by qPCR, and VDR translocation was analyzed in nuclear protein extracts by ELISA. M. tuberculosis downregulated the expression of LL37 regardless of the glucose concentration, whereas VDR and CYP27B1 upregulated it regardless of the glucose concentration. After evaluating two concentrations of vitamin D, 1 nM or 1 µM, the high concentration (1 µM) was necessary to restore the induction of LL37 expression in M. tuberculosis-infected macrophages. High concentrations of the inactive form of vitamin D restore the infected macrophages' ability to express LL37 regardless of the glucose concentration. This finding supports the idea that vitamin D administration in patients with T2DM could benefit TB control and prevention.

In Vitro Evidence of Differential Immunoregulatory Response between MDA-MB-231 and BT-474 Breast Cancer Cells Induced by Bone Marrow-Derived Mesenchymal Stromal Cells Conditioned Medium.

Inside tumors, cancer cells display several mechanisms to create an immunosuppressive environment. On the other hand, by migration processes, mesenchymal stromal cells (MSCs) can be recruited by different cancer tumor types from tissues as distant as bone marrow and contribute to tumor pathogenesis. However, the impact of the immunoregulatory role of MSCs associated with the aggressiveness of breast cancer cells by soluble molecules has not been fully elucidated. Therefore, this in vitro work aimed to study the effect of the conditioned medium of human bone marrow-derived-MSCs (hBM-MSC-cm) on the immunoregulatory capability of MDA-MB-231 and BT-474 breast cancer cells. The hBM-MSC-cm on MDA-MB-231 cells induced the overexpression of TGF-ß, IDO, and IL-10 genes. Additionally, immunoregulation assays of mononuclear cells (MNCs) in co-culture with MDA-MB-231 and hBM-MSC-cm decreased lymphocyte proliferation, and increased proteins IL-10, TGF-ß, and IDO while also reducing TNF levels, shooting the proportion of regulatory T cells. Conversely, the hBM-MSC-cm did not affect the immunomodulatory capacity of BT-474 cells. Thus, a differential immunoregulatory effect was observed between both representative breast cancer cell lines from different origins. Thus, understanding the immune response in a broader tumor context could help to design therapeutic strategies based on the aggressive behavior of tumor cells.

Gas Exchange Impairment During COVID-19 Recovery.

BACKGROUND: Persistent impairment of pulmonary function and exercise capacity has been known to last for months or even years in the survivors who recovered from other coronavirus pneumonia. Some reports showed that subjects with coronavirus disease 2019 pneumonia after being discharged could have several sequelae, but there are few studies on gas exchange and exercise capacity complications in these subjects. AIMS: To describe residual gas exchange abnormalities during recovery from coronavirus disease 2019 pneumonia. METHODS: In an observational study, ∼90 d after onset of disease, we scheduled almost 200 subjects for an out-patient visit with pulmonary function testing and computed tomography of the lungs. Lung mechanics by using body plethysmography, gas exchange with diffusing lung capacity for carbon monoxide determined by the single-breath technique (DLCOsb) and diffusing lung capacity for nitric oxide determined by the single-breath technique (DLNOsb), and exercise ability by using the 6-min walk test (6MWT) were measured in the subjects. The results were compared between those who required invasive mechanical ventilation and those who did not. RESULTS: A total of 171 subjects were included, the majority (96%) had signs of residual pneumonia (such as an excess of high attenuation areas) on computed tomography of the lungs. The DLCOSB results were below the lower limit of the normal range in 29.2% of the subjects; during the 6MWT, 67% experienced oxygen desaturation ([Formula: see text]) > 4%; and, in 81 (47%), the dropped below 88%. Subjects who required invasive mechanical ventilation (49.7%) were more likely to have lower lung volumes, more gas exchange abnormality, less exercise capacity and more radiologic abnormality. CONCLUSIONS: Subjects who recovered from severe COVID-19 pneumonia continued to have abnormal lung function and abnormal radiologic findings.

Induction of Therapeutic Protection in an HPV16-Associated Mouse Tumor Model Through Targeting the Human Papillomavirus-16 E5 Protein to Dendritic Cells.

HPV E5 is an oncoprotein mainly expressed in premalignant lesions, which makes it an important target for a vaccine to prevent or cure cervical cancer (CC). In this study, we evaluated whether E5 targeted to DEC-205, present in dendritic cells (DCs), could induce a therapeutic protection against HPV16-induced tumor cells in a mouse model. The HPV-16 E5 (16E5) protein was cross-linked to a monoclonal antibody (mAb) specific to mouse DEC-205 (anti-DEC-205:16E5) or to an isotype control mAb (isotype:16E5). Rotavirus VP6 was cross-linked to the mouse anti-DEC-205 mAb (anti-DEC-205:VP6) as a non-specific antigen control. BALB/c mice were inoculated subcutaneously (s.c.) with the 16E5-expressing BMK-16/myc tumor cells, and 7 and 14 days later the mice were immunized s.c. with the conjugates, free 16E5 or PBS in the presence of adjuvant. Tumor growth was monitored to evaluate protection. A strong protective immune response against the tumor cells was induced when the mice were inoculated with the anti-DEC-205:16E5 conjugate, since 70% of the mice controlled the tumor growth and survived, whereas the remaining 30% developed tumors and died by day 72. In contrast, 100% of the mice in the control groups died by day 30. The anti-DEC-205:16E5 conjugate was found to induce 16E5-specific memory T cells, with a Th1/Th17 profile. Both CD4+ and CD8+ T cells contributed to the observed protection. Finally, treating mice that had developed tumors with an anti-PD-1 mAb, delayed the tumor growth for more than 20 days. These results show that targeting 16E5 to DEC-205, alone or combined with an immune checkpoint blockade, could be a promising protocol for the treatment of the early stages of HPV-associated cancer.

Effect of Ulnar Head Offset on Distal Radioulnar Joint Stability.

PURPOSE: A complete ulnar head replacement may be indicated in cases of distal radial ulnar joint (DRUJ) dysfunction to address bony pathology in lieu of using a constrained total DRUJ prosthesis. Complete ulnar head implants are simple, but they may be unstable if soft tissue tension is not adequately restored. We hypothesized that incorporating an increased offset in the complete ulnar head replacement would lead to increased tension on the distal oblique interosseous ligament, increased contact force at the DRUJ, and improved joint stability. METHODS: Using a specially designed jig, we measured instability by comparing displacement under load (stiffness) of the DRUJ in 10 cadaveric specimens under 4 different conditions: (1) intact, (2) native head after excision of the triangular fibrocartilage complex, (3) replacement of the ulnar head with a standard offset ulnar head, and (4) replacement of the ulnar head with an increased offset ulnar head. No soft tissue repair was done. We measured anteroposterior displacement under load with maximum translation of 10 mm or maximum loads of 50 N. We tested all specimens with the forearm positioned in neutral, supination, and pronation. RESULTS: Excising the triangular fibrocartilage complex decreased the average stiffness of the DRUJ to 46% of the intact state, creating a simulated state of DRUJ instability. Replacing the ulnar head with the standard offset head increased average stiffness to 54% of the intact state. Increasing the ulnar head offset with the simulated total ulnar head replacement increased average stiffness to 77% of the intact state. CONCLUSIONS: An increased offset ulnar head replacement improves DRUJ stability compared with a standard anatomic offset ulnar head replacement. CLINICAL RELEVANCE: Understanding DRUJ morphology and offset is important in the treatment of DRUJ arthritis and instability.

New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

Coexistence of Meesmann Corneal Dystrophy and a Pseudo-Unilateral Lattice Corneal Dystrophy in a Patient With a Novel Pathogenic Variant in the Keratin K3 Gene: A Case Report.

PURPOSE: This study aims to clinically and genetically report a case of coexisting Meesmann corneal dystrophy (MECD) and pseudo-unilateral lattice corneal dystrophy (LCD). METHODS: Clinical characterization was supported by a complete ophthalmological evaluation, including visual acuity measurement and slit-lamp examination. Molecular diagnosis was performed by whole-exome sequencing analyzing the gelsolin, keratin K3 (KRT3), keratin K12, and transforming growth factor-beta-induced genes. RESULTS: A 57-year-old woman presented with recurrent corneal erosions over 17 years and visual impairment in both eyes. Ophthalmological evaluation revealed multiple central tiny cysts in the epithelium of both eyes and lattice linear lesions only in the right cornea. In both eyes, a corneal posterior crocodile shagreen degeneration could also be observed. These findings were compatible with a MECD and a unilateral LCD. Molecular analysis identified the novel heterozygous nucleotide substitution c.1492G>A (amino acid change p.Glu498Lys) in the KRT3 gene, in cosegregation with the MECD familial phenotype. However, no genetic evidence supported the unique LCD phenotype observed in the patient. CONCLUSIONS: To the best of our knowledge, this is the first report of a pseudo-unilateral LCD in a patient with coexistent MECD. Moreover, the genetic analysis showed a novel mutation in the previously MECD-associated gene KRT3.

Human Bone Marrow Mesenchymal Stem/Stromal Cells Exposed to an Inflammatory Environment Increase the Expression of ICAM-1 and Release Microvesicles Enriched in This Adhesive Molecule: Analysis of the Participation of TNF-α and IFN-γ.

Bone marrow mesenchymal stem/stromal cells (BM-MSCs) have immunoregulatory capacity; therefore, they have been used in different clinical protocols in which it is necessary to decrease the immune response. This capacity is mainly regulated by TNF-α and IFN-γ, and it has been observed that cell-cell contact, mainly mediated by ICAM-1, is important for MSCs to carry out efficient immunoregulation. Therefore, in the present work, we analyzed the effect of TNF-α alone or in combination with IFN-γ on the expression of ICAM-1. Besides, given the importance of cell contact in the immunoregulatory function of MSCs, we analyzed whether these cells release ICAM-1+ microvesicles (MVs). Our results show for the first time that TNF-α is capable of increasing the early expression of ICAM-1 in human BM-MSCs. Also, we observed that TNF-α and IFN-γ have a synergistic effect on the increase in the expression of ICAM-1. Furthermore, we found that BM-MSCs exposed to an inflammatory environment release MVs enriched in ICAM-1 (MVs-ICAM-1high). The knowledge generated in this study will contribute to the improvement of in vitro conditioning protocols that favor the therapeutic effect of these cells or their products.