Recombinant CD5 and CD6 Ectodomains Induce Antiparasitic and Immunomodulatory Effects in Secondary Cystic Echinococcosis.

Scavenger receptors participate in a wide range of biological functions after binding to multiple non-self or altered self-ligands. Among them, CD5 and CD6 are lymphocyte scavenger receptors known to interact with different microbial-associated molecular patterns, and the administration of the recombinant soluble ectodomains of human CD5 (rshCD5) and/or CD6 (rshCD6) has shown therapeutic/prophylactic potential in experimental models of fungal, bacterial and echinococcal infections. The latter is a zoonosis caused by the larval stage of the cestode parasite Echinococcus granulosus sensu lato, which in humans can induce secondary cystic echinococcosis (CE) after the spillage of protoscoleces contained within fertile cysts, either spontaneously or during surgical removal of primary hydatid cysts. Herein, we have analysed the mechanisms behind the significant protection observed in the mouse model of secondary CE following prophylactic administration of rshCD5 or rshCD6. Our results show that both molecules exhibit intrinsic antiparasitic activities in vitro, as well as immunomodulatory functions during early secondary CE, mainly through Th1/Th17 cytokine bias and promotion of peritoneal polyreactive antibodies. These data support the relevance of the parasite components bound by rshCD5 and rshCD6, as well as the potential of their prophylactic administration as a useful strategy to reduce secondary CE in patients.

Low switched memory B cells are associated with no humoral response after SARS-CoV-2 vaccine boosters in kidney transplant recipients.

Introduction: The humoral response after SARS-CoV-2 vaccination and boosters in kidney transplant recipients (KTRs) is heterogeneous and depends on immunosuppression status. There is no validated immune measurement associated with serological response in clinical practice. Multicolor flow cytometric immunophenotyping could be useful for measuring immune response. This study aimed to study B- and T-cell compartments through Standardized EuroFlow PID Orientation after SARS-CoV-2 vaccination and their association with IgG SARS-CoV-2 seropositivity status after two doses or boosters. Methods: We conducted a multicenter prospective study to evaluate humoral response after SARS-CoV-2 vaccination in KTRs. Heterologous regimen: two doses of inactivated SARS-CoV-2 and two boosters of BNT162b2 mRNA (n=75). Homologous vaccination: two doses of BNT162b2 mRNA and one BNT162b2 mRNA booster (n=13). Booster doses were administrated to KTRs without taking into account their IgG SARS-CoV-2 seropositivity status. Peripheral blood samples were collected 30 days after the second dose and after the last heterologous or homologous booster. A standardized EuroFlow PID Orientation Tube (PIDOT) and a supervised automated analysis were used for immune monitoring cellular subsets after boosters. Results: A total of 88 KTRs were included and divided into three groups according to the time of the first detected IgG SARS-CoV-2 seropositivity: non-responders (NRs, n=23), booster responders (BRs, n=41), and two-dose responders (2DRs, n=24). The NR group was more frequent on mycophenolate than the responder groups (NRs, 96%; BRs, 80%; 2DRs, 42%; p=0.000). Switched memory B cells in the 2DR group were higher than those in the BR and NR groups (medians of 30, 17, and 10 cells/ul, respectively; p=0.017). Additionally, the absolute count of central memory/terminal memory CD8 T cells was higher in the 2DR group than in the BR and NR groups. (166, 98, and 93 cells/ul, respectively; p=0.041). The rest of the T-cell populations studied did not show a statistical difference. Conclusion: switched memory B cells and memory CD8 T-cell populations in peripheral blood were associated with the magnitude of the humoral response after SARS-CoV-2 vaccination. Boosters increased IgG anti-SARS-CoV-2 levels, CM/TM CD8 T cells, and switched MBCs in patients with seropositivity after two doses. Interestingly, no seropositivity after boosters was associated with the use of mycophenolate and a lower number of switched MBCs and CM/TM CD8 T cells in peripheral blood.

Case Report: Mycosis fungoides as an exclusive manifestation of common variable immunodeficiency in a family with a NFKB2 gene mutation.

Background: Common variable immunodeficiency disorders (CVIDs), which are primary immunodeficiencies characterized by the failure of primary antibody production, typically present with recurrent bacterial infections, decreased antibody levels, autoimmune features, and rare atypical manifestations that can complicate diagnosis and management. Although most cases are sporadic, approximately 10% of the patients may have a family history of immunodeficiency. Genetic causes involving genes related to B-cell development and survival have been identified in only a small percentage of cases. Case presentation: We present the case of a family with two brothers who presented with mycosis fungoides as an exclusive symptom of a common variable immunodeficiency disorder (CVID). Whole-exome sequencing of the index patient revealed a pathogenic variant of the NFKB2 gene. Based on this diagnosis and re-evaluation of other family members, the father and brother were diagnosed with this rare immune and preneoplastic syndrome. All CVID-affected family members presented with mycosis fungoides as their only symptom, which is, to the best of our knowledge, the first case to be reported. Conclusion: This case highlights the importance of high-throughput sequencing techniques for the proper diagnosis and treatment of hereditary hematological disorders.

Efectividad de la crioterapia suministrada por enfermeras para lesiones preneoplásicas del cuello uterino

Introducción. El cáncer de cuello uterino es un problema de salud pública relevante en países de ingresos medios y bajos. El seguimiento de mujeres con tamización positiva y el acceso a tratamiento para neoplasia intraepitelial cervical (NIC) son retos mayores en estos países. Objetivo. Evaluar la efectividad de la crioterapia suministrada por enfermeras en casos de neoplasia intraepitelial de cérvix. Materiales y métodos. Se hizo la inspección visual directa con ácido acético y solución yodada (VIA-VILI), y se practicó colposcopia con biopsia, a mujeres entre los 25 y los 59 años, residentes en zonas de bajos ingresos de Bogotá. Profesionales de enfermería entrenados ofrecieron tratamiento inmediato con crioterapia a mujeres positivas en la inspección visual. Se les practicó colposcopia con biopsia antes del tratamiento y en un control a los 12 meses. Se evaluó la efectividad mediante tasas de curación (resultado: sin lesión) y regresión de NIC2/3 (resultado: ≤NIC1), por verificación colposcópica e histológica. Resultados. Se tamizaron 4.957 mujeres. En total, 499 fueron positivas y 472 aceptaron el tratamiento inmediato. Recibieron crioterapia por enfermería 365 mujeres (11 NIC2/3). La tasa de curación fue del 72 % (IC95%: 39-94 %) por verificación colposcópica, y del 40 % (IC95%: 22-85 %) por histología. Las tasas de regresión fueron del 100 y el 60 %, respectivamente. Se reportaron dos eventos adversos no graves relacionados. Conclusiones. Las tasas de curación y regresión por verificación colposcópica son similares a las reportadas con crioterapia administrada por médicos. El tamaño de la muestra con NIC2/3 dificulta la comparación por tipo de verificación. Los hallazgos apoyan la implementación de estrategias de "ver y tratar" por parte de enfermería en poblaciones con acceso limitado a servicios de salud.

Introduction. Cervical cancer is a relevant public health problem for low- and middleincome countries. Follow-up of positive-screened women and compliance with treatment of precancerous lesions are major challenges for these settings. Objective. To evaluate the efficacy of cryotherapy delivered by nurses for cervical intraepithelial neoplasia (CIN). Materials and methods. Direct visual inspection with acetic acid and lugol iodine (VIA- VILI), and colposcopy/biopsy were performed on women 25 to 59 years old, residents of low-income areas in Bogotá, Colombia. Trained nurses offered immediate cryotherapy to every woman with positive visual inspection. Colposcopy/biopsy was performed before treatment and at a 12-month follow-up. The effectiveness was measured as cure (outcome: no-lesion) and regression (outcome: CIN1) rates of CIN2/3 using colposcopic and histological verification. Results. A group of 4.957 women with VIA/VILI was valuated. In total, 499 were screen positive and 472 accepted immediate treatment. A total of 365 women (11 CIN2/3) received cryotherapy by nurses. Cure rate was 72% (95%CI: 39%-94%) and 40% (95%CI: 22%- 85%) by colposcopic and histological verification, respectively. Regression rates were 100% and 60%. There were two related non-serious adverse events. Conclusions. Cure and regression rates by colposcopic verification are like those reported for cryotherapy delivered by doctors. The sample size (CIN2/3) hinders comparisons by type of verification. Our findings support the implementation of screen-and-treat algorithms by nurses among populations with limited access to health services.

Association of the rs17782313, rs17773430 and rs34114122 Polymorphisms of/near MC4R Gene with Obesity-Related Biomarkers in a Spanish Pediatric Cohort.

Obesity is a multifactorial disease whose onset and development are shaped by the individual genetic background. The melanocortin 4 receptor gene (MC4R) is involved in the regulation of food intake and energy expenditure. Some of the single nucleotide polymorphisms (SNPs) of this gene are related to obesity and metabolic risk factors. The present study was undertaken to assess the relationship between three polymorphism SNPs, namely, rs17782313, rs17773430 and rs34114122, and obesity and metabolic risk factors. One hundred seventy-eight children with obesity aged between 7 and 16 years were studied to determine anthropometric variables and biochemical and inflammatory parameters. Our results highlight that metabolic risk factors, especially alterations in carbohydrate metabolism, were related to rs17782313. The presence of the minor C allele in the three variants (C-C-C) was significantly associated with anthropometric measures indicative of obesity, such as the body mass and fat mass indexes, and increased the values of insulinemia to 21.91 µIU/mL with respect to the wild type values. Our study suggests that the C-C-C haplotype of the SNPs rs17782313, rs17773430 and rs34114122 of the MC4R gene potentiates metabolic risk factors at early ages in children with obesity.

Effectiveness of cryotherapy delivered by nurses for treatment of cervical preneoplasic lesions / Efectividad de la crioterapia suministrada por enfermeras para lesiones preneoplásicas del cuello uterino.

Introduction. Cervical cancer is a relevant public health problem for low- and middleincome countries. Follow-up of positive-screened women and compliance with treatment of precancerous lesions are major challenges for these settings. Objective. To evaluate the efficacy of cryotherapy delivered by nurses for cervical intraepithelial neoplasia (CIN). Materials and methods. Direct visual inspection with acetic acid and lugol iodine (VIAVILI), and colposcopy/biopsy were performed on women 25 to 59 years old, residents of low-income areas in Bogotá, Colombia. Trained nurses offered immediate cryotherapy to every woman with positive visual inspection. Colposcopy/biopsy was performed before treatment and at a 12-month follow-up. The effectiveness was measured as cure (outcome: no-lesion) and regression (outcome: CIN1) rates of CIN2/3 using colposcopic and histological verification. Results. A group of 4.957 women with VIA/VILI was valuated. In total, 499 were screen positive and 472 accepted immediate treatment. A total of 365 women (11 CIN2/3) received cryotherapy by nurses. Cure rate was 72% (95%CI: 39%-94%) and 40% (95%CI: 22%-85%) by colposcopic and histological verification, respectively. Regression rates were 100% and 60%. There were two related non-serious adverse events. Conclusions. Cure and regression rates by colposcopic verification are like those reported for cryotherapy delivered by doctors. The sample size (CIN2/3) hinders comparisons by type of verification. Our findings support the implementation of screen-and-treat algorithms by nurses among populations with limited access to health services.

Introducción. El cáncer de cuello uterino es un problema de salud pública relevante en países de ingresos medios y bajos. El seguimiento de mujeres con tamización positiva y el acceso a tratamiento para neoplasia intraepitelial cervical (NIC) son retos mayores en estos países. Objetivo. Evaluar la efectividad de la crioterapia suministrada por enfermeras en casos de neoplasia intraepitelial de cérvix. Materiales y métodos. Se hizo la inspección visual directa con ácido acético y solución yodada (VIA-VILI), y se practicó colposcopia con biopsia, a mujeres entre los 25 y los 59 años, residentes en zonas de bajos ingresos de Bogotá. Profesionales de enfermería entrenados ofrecieron tratamiento inmediato con crioterapia a mujeres positivas en la inspección visual. Se les practicó colposcopia con biopsia antes del tratamiento y en un control a los 12 meses. Se evaluó la efectividad mediante tasas de curación (resultado: sin lesión) y regresión de NIC2/3 (resultado: ≤NIC1), por verificación colposcópica e histológica. Resultados. Se tamizaron 4.957 mujeres. En total, 499 fueron positivas y 472 aceptaron el tratamiento inmediato. Recibieron crioterapia por enfermería 365 mujeres (11 NIC2/3). La tasa de curación fue del 72 % (IC95%: 39-94 %) por verificación colposcópica, y del 40 % (IC95%: 22-85 %) por histología. Las tasas de regresión fueron del 100 y el 60 %, respectivamente. Se reportaron dos eventos adversos no graves relacionados.Conclusiones. Las tasas de curación y regresión por verificación colposcópica son similares a las reportadas con crioterapia administrada por médicos. El tamaño de la muestra con NIC2/3 dificulta la comparación por tipo de verificación. Los hallazgos apoyan la implementación de estrategias de "ver y tratar" por parte de enfermería en poblaciones con acceso limitado a servicios de salud.

Tumor de músculo liso uterino de potencial maligno incierto (STUMP): reporte de caso y revisión de la literatura / Uterine smooth muscle tumor of uncertain malignant potential (STUMP): case report and literature review

Myometrial smooth muscle neoplasms are the most common gynecologic tumors with a prevalence of 70-80% at age 50. Among women undergoing hysterectomy or myomectomy for a suspected diagnosis of leiomyoma, 0.01% receive a diagnosis of STUMP. Clinically, the average age of presentation is between 41-48 years. Tumors ranging from 3 to 30 cm have been described. Signs and symptoms are similar to leiomyomas, such as abnormal uterine bleeding, anemia, dysmenorrhea, pelvic pain, pelvic mass, infertility or other types of pain secondary to compression of adjacent organs. Due to the limited literature available, there is no definite management consensus, and treatment and follow-up options are limited to observational studies. The standard treatment is total hysterectomy with or without bilateral salpingo-oophorectomy; if fertility has already been completed, there is no role for adjuvant hormonal therapy or chemotherapy. The overall 5-year survival is 92-100%. A case of a 31-year-old woman with STUMP is presented.

CD6 deficiency impairs early immune response to bacterial sepsis.

CD6 is a lymphocyte-specific scavenger receptor expressed on adaptive (T) and innate (B1a, NK) immune cells, which is involved in both fine-tuning of lymphocyte activation/differentiation and recognition of bacterial-associated molecular patterns (i.e., lipopolysaccharide). However, evidence on CD6's role in the physiological response to bacterial infection was missing. Our results show that induction of monobacterial and polymicrobial sepsis in Cd6 -/- mice results in lower survival rates and increased bacterial loads and pro-inflammatory cytokine levels. Steady state analyses of Cd6 -/- mice show decreased levels of natural polyreactive antibodies, concomitant with decreased cell counts of spleen B1a and marginal zone B cells. Adoptive transfer of wild-type B cells and mouse serum, as well as a polyreactive monoclonal antibody improve Cd6 -/- mouse survival rates post-sepsis. These findings support a nonredundant role for CD6 in the early response against bacterial infection, through homeostatic expansion and functionality of innate-related immune cells.

Reduced Free Fatty Acid Receptor 4 Gene Expression is Associated With Extreme Obesity and Insulin Resistance in Children.

OBJECTIVES: Free fatty acid receptor 4 (FFAR4) is a G-protein-coupled membrane receptor highly expressed in macrophages that triggers anti-inflammatory effects and promotes insulin sensitization. We have previously found significant associations between the FFAR4 rs11187533 single nucleotide polymorphism (SNP) and various obesity comorbidity parameters. We aimed to verify the FFAR4 expression levels in children with obesity and the associated comorbidities. METHODS: Thirty-eight children with obesity were studied. Clinical and anthropometric evaluation was performed. A venous sample under fasting conditions was obtained. Biochemical study included parameters of metabolic risk. DNA was extracted and genotyped for the rs11187533 FFAR4 SNP. Real-time PCR technique was performed to investigate the gene expression. Relative FFAR4 mRNA levels were determined according to the 2-ΔΔCt method. RESULTS: Significant differences in FFAR4 expression levels between the CC and CT-TT genotypes of the rs11187533 FFAR4 SNP were observed (P = 0.034). The minor allele T presented higher levels of FFAR4 expression. We found that a loss of FFAR4 expression was associated with extreme obesity (P = 0.032). The lowest FFAR4 expression levels were observed in children who had higher insulin (P = 0.008) and homeostasis model assessment insulin resistance values (P = 0.012) and lower quantitative insulin-sensitivity check index (P = 0.033). CONCLUSIONS: The underexpression of FFAR4 was associated with extreme obesity and parameters indicative of obesity comorbidities in children. This under expression could be partially influenced by the presence of the C allele rs11187533 FFAR4 SNP.

Unraveling post-translational modifications in Echinococcus granulosus sensu lato.

Echinococcus granulosus sensu lato (s.l.) is the helminth parasite responsible for cystic echinococcosis, a neglected tropical disease currently affecting millions of people worldwide. Incomplete knowledge on the parasite biochemistry contributes, at least partially, to the limited development of useful biotechnological advances for the infection control. In this sense, little information is available regarding post-translational modifications (PTMs) occurring in E. granulosus s.l. proteins, which ultimately may affect the performance of biotechnological products to be developed. Therefore, we report here a proteomic analysis of the parasite PTMs identified through FindMod software applied to a set of tegumental proteins previously characterized by mass spectrometry (MALDI-TOF/TOF) analysis of protein spots from a 2D electrophoresis gel. Manual searches for already annotated proteins exhibiting such PTMs were also performed within proteome databases of E. granulosus s.l. and other platyhelminthes. In addition, key enzymes involved in PTMs modifications were searched for within E. granulosus s.l. proteome. Finally, the presence of selected PTMs was further confirmed by a high-resolution proteomic approach (nanoLC-MS/MS). A set of 22 different PTMs most likely to be present in the parasite was suggested, 9 of them with high confidence as they were identified in the same m/z fragment by both proteomic techniques (acetylation, deamidation, deamidation followed by methylation, mono- and di-hydroxylation, mono- and di-methylation, S-nitrosylation and phosphorylation). Interestingly, 5 PTMs were herein identified for the first time in E. granulosus s.l. proteins. Our results expand the scarcely studied topic of PTMs in platyhelminthes.

Melatonin Levels in Children with Obesity Are Associated with Metabolic Risk and Inflammatory Parameters.

Melatonin, the hormone of circadian rhythm regulation, is involved in the modulation of mitochondrial activity through its antioxidant and anti-inflammatory properties. Alteration of circadian rhythms such as sleep is related to obesity and metabolic pathogenesis in adulthood, but studies during childhood are scarce. The present study investigated the association of melatonin with metabolic and inflammatory markers in children with (n = 113) and without obesity (n = 117). Melatonin was measured in saliva four and two hours before bedtime, and after one hour of sleep. Cardiometabolic factors, high sensitivity C-reactive protein, immune markers (monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, tumor necrosis α and interferon-γ), leptin and ghrelin were determined. Sleep duration was recorded by a questionnaire. The melatonin level at 1 h after sleep was found to be increased more than twofold in children with obesity (90.16 (57.16-129.16) pg/mL) compared to controls (29.82 (19.05-61.54) pg/mL, p < 0.001) and was related to fat mass (rho = 0.294, p < 0.001); melatonin levels at 1 h after sleep were inversely correlated with high-density lipoprotein cholesterol. Positive correlation was found with apolipoprotein B, adipokines, high sensitivity C-reactive protein, plasminogen activator inhibitor-1 and tumor necrosis factor-α. Shorter sleep duration and earlier waking times were recorded in children with obesity. In conclusion, melatonin in children with obesity appears to be involved in the global metabolic and inflammatory alteration of this condition.

Ultrastructural characterization of the tegument in protoscoleces of Echinococcus ortleppi.

Cystic echinococcosis is a globally distributed zoonosis caused by cestodes of the Echinococcus granulosus sensu lato (s.l.) complex, with Echinococcus ortleppi mainly involved in cattle infection. Protoscoleces show high developmental plasticity, being able to differentiate into either adult worms or metacestodes within definitive or intermediate hosts, respectively. Their outermost cellular layer is called the tegument, which is important in determining the infection outcome through its immunomodulating activities. Herein, we report an in-depth characterization of the tegument of E. ortleppi protoscoleces performed through a combination of scanning and transmission electron microscopy techniques. Using electron tomography, a three-dimensional reconstruction of the tegumental cellular territories was obtained, revealing a novel structure termed the 'tegumental vesicular body' (TVB). Vesicle-like structures, possibly involved in endocytic/exocytic routes, were found within the TVB as well as in the parasite glycocalyx, distal cytoplasm and close inner structures. Furthermore, parasite antigens (GST-1 and AgB) were unevenly localised within tegumental structures, with both being detected in vesicles found within the TBV. Finally, the presence of host (bovine) IgG was also assessed, suggesting a possible endocytic route in protoscoleces. Our data forms the basis for a better understanding of E. ortleppi and E. granulosus s.l. structural biology.

Vitamin D receptor gene ApaI and FokI polymorphisms and its association with inflammation and oxidative stress in vitamin D sufficient Caucasian Spanish children.

BACKGROUND: Vitamin D has gone from being just one vitamin to being an important prohormone with multiple effects on different tissue types. The mechanism of action of the active form or calcitriol is mediated by the intracellular vitamin D receptor (VDR). The interaction of the VDR with calcitriol modulates the expression of target genes involved in cell proliferation and cytokine production. Several studies have explored the effects of vitamin D deficiency in inflammatory disorders. Furthermore, some mutations in the VDR can affect its functionality. The focus of this study was to explore associations between VDR single nucleotide polymorphisms (SNPs) and markers of inflammation and oxidative stress in vitamin D sufficient children. METHODS: This is a cross-sectional study of a Caucasian Spanish population including 155 healthy children (87 males, 68 females) aged 10 to 14 years. FokI, ApaI and TaqI SNPs of the VDR gene were genotyped. Routine biochemistry, serum levels of interleukin-6, tumor necrosis factor-α, interferon-γ, 8-isoprostaglandin F2α and nitrates were determined. RESULTS: The homozygous major allele AA in the FokI SNP was associated with increased levels of high-density lipoprotein cholesterol in a recessive inheritance mode (P=0.025). The minor allele A of ApaI was significantly associated with decreased serum tumor necrosis factor-α and 8-isoprostaglandin F2α in an additive mode (P=0.016 and P=0.020 respectively). No significant associations were observed between the TaqI SNP and any of the parameters evaluated. Haplotype analysis confirmed the significance of the relationships between ApaI and FokI SNPs and parameters associated with inflammation and oxidative stress. CONCLUSIONS: Genetic variations of VDR are associated with subtle changes in metabolic, inflammatory and oxidative stress markers. These results may provide a better understanding of the relationships between vitamin D and these clinical parameters.

Polyreactive antibodies as potential humoral biomarkers of host resistance to cystic echinococcosis.

Polyreactive antibodies (pAb) bind to a broad range of unrelated structures, providing hosts with functional components able to rapidly recognize and protect against different pathogens. However, their roles against helminth parasites are still unexplored. Here, pAb profiles were analysed in cystic echinococcosis (CE), a zoonosis caused by the cestode Echinococcus granulosus sensu lato. Levels of anti-DNP (2,4-dinitrophenyl-hapten) antibodies were measured as a surrogate parameter of pAb in different biological settings. Firstly, levels of serum and peritoneal pAb were measured during early experimental secondary CE, using both high (Balb/c) and low (C57Bl/6) susceptible mouse strains. Serum pAb mostly differed in normal mice, being pAb levels of IgG subclasses with poor anti-parasite activities predominant in Balb/c animals. Conversely, peritoneal pAb isotypes/subclasses with efficient anti-parasite activities predominated in normal and infected C57Bl/6 mice. Secondly, sera from potentially resistant patients, susceptible individuals and healthy donors were analysed, showing higher pAb levels of the IgA and IgG-particularly IgG1-isotypes in potentially resistant individuals compared to control groups. Finally, since remarkable differences were observed in pAb profiles according to the intrinsic host susceptibility to the infection, we proposed here that pAb might be considered as potential humoral biomarkers for host resistance to CE.

The Lymphocytic Scavenger Receptor CD5 Shows Therapeutic Potential in Mouse Models of Fungal Infection.

Invasive fungal diseases represent an unmet clinical need that could benefit from novel immunotherapeutic approaches. Host pattern recognition receptors (e.g., Toll-like receptors, C-type lectins, or scavenger receptors) that sense conserved fungal cell wall constituents may provide suitable immunotherapeutic antifungal agents. Thus, we explored the therapeutic potential of the lymphocyte class I scavenger receptor CD5, a nonredundant component of the antifungal host immune response that binds to fungal ß-glucans. Antifungal properties of the soluble ectodomain of human CD5 (shCD5) were assessed in vivo in experimental models of systemic fungal infection induced by pathogenic species (Candida albicans and Cryptococcus neoformans). In vitro mechanistic studies were performed by means of fungus-spleen cell cocultures. shCD5-induced survival of lethally infected mice was dose and time dependent and concomitant with reduced fungal load and increased leukocyte infiltration in the primary target organ. Additive effects were observed in vivo after shCD5 was combined with suboptimal doses of fluconazole. Ex vivo addition of shCD5 to fungus-spleen cell cocultures increased the release of proinflammatory cytokines involved in antifungal defense (tumor necrosis factor alpha and gamma interferon) and reduced the number of viable C. albicans organisms. The results prompt further exploration of the adjunctive therapeutic potential of shCD5 in severe invasive fungal diseases.

Melatonin Content of Human Milk: The Effect of Mode of Delivery.

Objective: Cesarean section rates are increasing in developed countries and could be performed as an emergency or elective procedure. Our research aim was to determine whether elective cesarean section influences the melatonin content, the main circadian hormone, in human milk. Methods: Twenty-one women after vaginal delivery and 18 women after elective cesarean section were included. Only healthy mothers with normal newborns exclusively breastfed were recruited. Two samples of human milk were collected for each woman at three stages of lactation: colostrum, transitional milk, and mature milk; at each stage, one daytime sample and another nighttime sample were obtained. In total, 228 milk samples were studied. The melatonin content was analyzed by enzyme-linked immunosorbent assay. Results: Melatonin rhythmicity with higher melatonin content at night was maintained at each of the three stages of lactation, regardless of the type of delivery. A higher melatonin content was found in daytime colostrum after cesarean section with respect to colostrum obtained from mothers after vaginal delivery (30.3 pg/mL versus 14.7 pg/mL, p = 0.020). Melatonin content decreased progressively throughout the course of lactation in both groups. This decrease was significant when comparing transitional milk to colostrum in the cesarean group, both in the daytime (p = 0.016) and nighttime samples (p = 0.048). Conclusions: Cesarean section is associated with an increase in daytime colostrum melatonin. No difference was observed in mature milk with respect to vaginal delivery. Melatonin values in human milk decrease during the first month of lactation and circadian rhythmicity was observed irrespective of the mode of delivery.

Encephalopathy in severe SARS-CoV2 infection: Inflammatory or infectious?

Concerning the letter by Moriguchi et al., we describe our experience with a case of encephalopathy with and atypical damage on magnetic resonance imaging (MRI) in a patient with severe infection due to the SARS-CoV2 virus. A 56-year-old woman, without previous pathologies, developed cough, fever, and respiratory failure for five days, after returning from a 6-day trip to Venice. Chest radiography shows a large bilateral interstitial infiltrate. In the first 24 hours, she was admitted to the Intensive Care Unit (ICU) for severe respiratory failure and positive protein chain reaction-PCR in nasal exudate. She needed intubation for ten days. In the first 48 hours outside the ICU, she developed an acute confusional syndrome (hyperactive delirium). Neurological examination showed temporal-spatial disorientation and incoherent fluent speech. An electroencephalogram (EEG) showed generalized hypovoltaic activity. Cranial magnetic resonance imaging showed a bilateral and symmetrical increase in the supratentorial white matter's signal intensity, with a discrete thickening of both temporal lobes, with a slight increase in signal intensity and a sequence of normal diffusion. The lumbar puncture showed no changes (glucose 71 mg/dL, protein 30 mg/dL, 1 leukocyte). Within 72 hours of starting symptoms, she was neurologically asymptomatic. Our final diagnosis was an inflammatory encephalopathy related to a SARS-CoV2 infection.

The rs11187533 C>T Variant of the FFAR4 Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity.

INTRODUCTION: Genetic factors can modulate the development of associated comorbidities in obesity. It has been shown that loss-of-function variants of the free fatty acid receptor 4 (FFAR4) gene negatively affect obesity comorbidities such as insulin resistance and fatty liver disease. OBJECTIVE: To test the relationships of metabolic factors in children with obesity with variants of the FFAR4 gene. METHODS: We performed an association study of 3 single nucleotide polymorphisms (SNPs) of FFAR4 (rs10882273 T>C, rs12243124 T>C, and rs11187533 C>T) covering the last intron and last exon of FFAR4 in a cohort of 203 children with obesity. Cardiometabolic factors were determined, including parameters related to insulin resistance, liver injury, and high-sensitivity C-reactive protein as an inflammatory marker. RESULTS: Significant genotype - phenotype interactions occurred between the rs11187533 SNP and glucose levels (p = 0.011). Moreover, we identified 2 marginally significant associations between this SNP and the hepatic enzymes alanine aminotransferase (p = 0.022) and gamma-glutamyltransferase (p = 0.015). The homozygous minor allele genotype (TT) was associated with a decrease in glucose levels. CONCLUSION: The homozygous minor allele genotype of the rs11187533 SNP might be protective against metabolic consequences accompanying obesity and could allow the identification of metabolically healthy obese individuals at early ages.

Visual techniques for cervical cancer screening in Colombia / Técnicas visuales en la tamización del cáncer de cuello uterino

INTRODUCTION: Direct visual inspection for cervical cancer screening remains controversial, whereas colposcopy-biopsy is considered the gold standard for diagnosis of preneoplastic cervical lesions. OBJECTIVES: To determine the rates of cervical intraepithelial neoplasia grade 2 or more and of false positives for colposcopy and direct visual inspection. MATERIALS AND METHODS: Women aged 25-59 underwent direct visual inspection with acetic acid (VIA), Lugol's iodine (VIA-VILI), and colposcopy. Punch biopsies were obtained for all positive tests. Using histology as the gold standard, detection and false positive rates were compared for VIA, VIA-VILI, and colposcopy (two thresholds). Sensitivity and false positive ratios with the corresponding 95% confidence intervals were estimated. RESULTS: We included 5,011 women in the analysis and we obtained 602 biopsies. Positivity rates for colposcopy high-grade and low-grade diagnosis were 1.6% and 10.8%. Positivity rates for VIA and VIA-VILI were 7.4% and 9.9%. VIA showed a significantly lower detection rate than colposcopy with low-grade diagnosis as the threshold (SR=0.72; 95% CI 0.57-0.91), and significantly lower false positive rate (FPR=0.70; 95% CI 0.65-0.76). No differences between VIA-VILI and colposcopy low-grade threshold were observed. VIA and VIA-VILI showed significantly higher detection and false positive rates than colposcopy high-grade threshold. Sensitivity rates for visual inspection decreased with age and false positive rates increased. For all age groups, false positive rates for VIA and VIA-VILI were significantly higher than colposcopy. CONCLUSIONS: Detection rates for VIA-VILI similar to colposcopy low-grade threshold represent a chance to reduce cervical cancer mortality through see-and-treat approaches among women with limited access to health care. Lower detection rates suggest reviewing high-grade colposcopy findings as the threshold for biopsy in certain settings.

Introducción. La inspección visual directa para la tamización del cáncer cervical sigue siendo controversial, mientras que la colposcopia y la biopsia siguen considerándose como métodos de referencia para diagnosticar lesiones cervicales precancerosas. Objetivo. Determinar las tasas de detección de neoplasia intraepitelial cervical de grado 2 y de los falsos positivos en la colposcopia y la inspección visual directa. Materiales y métodos. Se seleccionaron mujeres de 25 a 59 años sometidas a citología convencional, inspección visual directa con ácido acético y disolución de Lugol y colposcopia. Se practicó biopsia en todas las pruebas positivas. Utilizando la histología como el medio de verificación de referencia, se compararon las tasas de detección y de falsos positivos de cada prueba. Se estimaron las razones de sensibilidad y de falsos positivos con los correspondientes intervalos de confianza. Resultados. Se incluyeron 5.011 mujeres. Las colposcopias positivas de alto y bajo grado correspondieron a 1,6 y 10,8 %, respectivamente. La inspección visual directa con ácido acético y solución yodada de Lugol fue positiva en 7,4 y 9,9 %, respectivamente. La inspección visual directa con ácido acético tuvo tasas de detección y falsos positivos significativamente menores que la coloscopia con umbral de bajo grado (razón de sensibilidad: 0,72; IC95% 0,57-0,91; razón de falsos positivos: 0,70; CI95% 0,65-0,76); no hubo diferencias entre la inspección visual directa con solución yodada de Lugol y la colposcopia con dicho umbral. Las tasas de detección y de falsos positivos de los dos tipos de inspección visual fueron significativamente más altas que las de la colposcopia con el umbral de alto grado. Las tasas de detección de la inspección visual disminuyeron con la edad y las de falsos positivos aumentaron. Conclusiones: Las tasas de detección similares para la inspección visual directa con ácido acético o con solución yodada de Lugol y la colposcopia con umbral de bajo grado representan una oportunidad para reducir la mortalidad por cáncer de cuello uterino cuando el acceso a los servicios de salud es limitado. Las tasas de detección más bajas para la colposcopia con umbral de alto grado sugieren la necesidad de revisar dicho umbral en ciertos entornos.