Importancia en el sistema de salud de la infección por Treponema pallidum, la enfermedad de Chagas y el virus de la inmunodeficiencia humana 1 en amerindios de Argentina: un estudio observacional

El objetivo de este trabajo fue estimar la prevalencia de Treponema pallidum, Trypanosoma cruzi y virus de la inmunodeficiencia humana (HIV-1) en 5 comunidades originarias de Argentina. Para ello, se realizó un estudio retrospectivo en 857 individuos (112 kollas, 298 mbyá-guaraníes, 79 sagua huarpes, 368 wichis) desde el 2007 hasta el 2010. Se realizó el diagnóstico completo para T. pallidum, T. cruzi y HIV-1. En todas las comunidades se confirmaron infecciones por T. pallidum y T. cruzi con una prevalencia total del 4,2 y del 16,8%, respectivamente. Aunque no se detectó HIV-1, sífilis y Chagas, representan un desafío para el sistema de salud, teniendo que reforzarse las estrategias de salud pública teniendo en cuenta el aislamiento socio-económico que sufren estas poblaciones.The objective of this study was to estimate the prevalence of Treponema pallidum, Trypanosoma cruzi and Human immunodeficiency virus 1 (HIV-1) in five Amerindian populations of Argentina. A retrospective study was conducted among 857 Amerindian populations (112 Kollas, 298 Mbyá-guaraníes, 79 Sagua Huarpes, 368 Wichis) from 2007 to 2010. Screening and confirmation of T. pallidum, T. cruzi and HIV-1 were performed. T. pallidum and T. cruzi infections were detected in all communities with an overall prevalence rate of 4.2% and 16.8%, respectively. Although HIV was not detected, syphilis and Chagas’ disease represent a challenge for the health care system and the reinforcement of public health strategies is necessary considering the socioeconomic isolation of these populations.Fil: Eirin, Maria Emilia. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigación en Ciencias Veterinarias y Agronómicas. Instituto de Biotecnología; ArgentinaFil: Delfino, Cecilia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Pedrozo, Williams René. Provincia de Misiones. Banco de Sangre Central; ArgentinaFil: Malan, Richard. Provincia de Misiones. Banco de Sangre Central; ArgentinaFil: Puca, Alberto. Laboratorio de Bioquímica "A. A. Puca"; ArgentinaFil: de Rissio, Ana María. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud. Instituto Nacional de Parasitología; ArgentinaFil: Espejo, Rogelio. Provincia de San Juan. Ministerio de Salud. Hospital Público "Dr. Guillermo Rawson". Laboratorio Central; ArgentinaFil: Gallo Vaulet, Maria Lucia. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Rodríguez Fermepin, Marcelo. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Bioquímica Clínica; ArgentinaFil: Biglione, Mirna Marcela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; ArgentinaFil: Berini, Carolina Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas en Retrovirus y Sida. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Biomédicas en Retrovirus y Sida; Argentin

Highlighting chromosome loops in DNA-picked chromatin (DPC).

"Growing evidence supports the concept that dynamic intra-and inter-chromosomal links between specific loci contribute to the creation of cell type-specific gene expression profiles. Therefore, analysis of the establishment of peculiar functional correlations between sites, also distant on linear DNA, that govern the transcriptional process appears to be of fundamental relevance. We propose here an experimental approach showing that 17 beta-estradiol-induced transcription associates to formation of loops between the promoter and termination regions of hormone-responsive genes. This strategy reveals as a tool to be also suitably used, in conjunction with automated techniques, for an extensive analysis of sites shared by multiple genes for induced expression.

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers

Minimally invasive vs. open segmental resection of the splenic flexure for cancer: a nationwide study of the Italian Society of Surgical Oncology-Colorectal Cancer Network (SICO-CNN)

Background Evidence on the efficacy of minimally invasive (MI) segmental resection of splenic flexure cancer (SFC) is not available, mostly due to the rarity of this tumor. This study aimed to determine the survival outcomes of MI and open treatment, and to investigate whether MI is noninferior to open procedure regarding short-term outcomes. Methods This nationwide retrospective cohort study included all consecutive SFC segmental resections performed in 30 referral centers between 2006 and 2016. The primary endpoint assessing efficacy was the overall survival (OS). The secondary endpoints included cancer-specific mortality (CSM), recurrence rate (RR), short-term clinical outcomes (a composite of Clavien-Dindo > 2 complications and 30-day mortality), and pathological outcomes (a composite of lymph nodes removed >= 12, and proximal and distal free resection margins length >= 5 cm). For these composites, a 6% noninferiority margin was chosen based on clinical relevance estimate. Results A total of 606 patients underwent either an open (208, 34.3%) or a MI (398, 65.7%) SFC segmental resection. At univariable analysis, OS and CSM were improved in the MI group (log-rank test p = 0.004 and Gray's tests p = 0.004, respectively), while recurrences were comparable (Gray's tests p = 0.434). Cox multivariable analysis did not support that OS and CSM were better in the MI group (p = 0.109 and p = 0.163, respectively). Successful pathological outcome, observed in 53.2% of open and 58.3% of MI resections, supported noninferiority (difference 5.1%; 1-sided 95%CI - 4.7% to infinity). Successful short-term clinical outcome was documented in 93.3% of Open and 93.0% of MI procedures, and supported noninferiority as well (difference - 0.3%; 1-sided 95%CI - 5.0% to infinity). Conclusions Among patients with SFC, the minimally invasive approach met the criterion for noninferiority for postoperative complications and pathological outcomes, and was found to provide results of OS, CSM, and RR comparable to those of open resection

Molecularly Targeted Therapies for Gastric Cancer. State of the Art

Many phase III trials failed to demonstrate a survival benefit from the addition of molecular therapy to conventional chemotherapy for advanced and metastatic gastric cancer, and only three agents were approved by the FDA. We examined the efficacy and safety of novel drugs recently investigated. PubMed, Embase and Cochrane Library were searched for phase III randomized controlled trials published from January 2016 to December 2020. Patients in the experimental arm received molecular therapy with or without conventional chemotherapy, while those in the control arm had conventional chemotherapy alone. The primary outcomes were overall and progression-free survival. The secondary outcomes were the rate of tumor response, severe adverse effects, and quality of life. Eight studies with a total of 4223 enrolled patients were included. The overall and progression-free survival of molecular and conventional therapy were comparable. Most of these trials did not find a significant difference in tumor response rate and in the number of severe adverse effects and related deaths between the experimental and control arms. The survival benefits of molecular therapies available to date for advanced and metastatic gastric cancer are rather unclear, mostly due to inaccurate patient selection, particularly concerning oncogene amplification and copy number

Innate immunity and cellular senescence: The good and the bad in the developmental and aged brain

Ongoing studies evidence cellular senescence in undifferentiated and specialized cells from tissues of all ages. Although it is believed that senescence plays a wider role in several stress responses in the mature age, its participation in certain physiological and pathological processes throughout life is coming to light. The "senescence machinery" has been observed in all brain cell populations, including components of innate immunity (e.g., microglia and astrocytes). As the beneficial versus detrimental implications of senescence is an open question, we aimed to analyze the contribution of immune responses in regulatory mechanisms governing its distinct functions in healthy (development, organogenesis, danger patrolling events) and diseased brain (glioma, neuroinflammation, neurodeneration), and the putative connection between cellular and molecular events governing the 2 states. Particularly this review offers new insights into the complex roles of senescence both as a chronological event as age advances, and as a molecular mechanism of brain homeostasis through the important contribution of innate immune responses and their crosstalk with neighboring cells in brain parenchyma. We also highlight the impact of the recently described glymphatic system and brain lymphatic vasculature in the interplay between peripheral and central immune surveillance and its potential implication during aging. This will open new ways to understand brain development, its deterioration during aging, and the occurrence of several oncological and neurodegenerative diseases

A donor splice site mutation in CISD2 generates multiple truncated, non-functional isoforms in Wolfram syndrome type 2 patients

Abstract Background Mutations in the gene that encodes CDGSH iron sulfur domain 2 (CISD2) are causative of Wolfram syndrome type 2 (WFS2), a rare autosomal recessive neurodegenerative disorder mainly characterized by diabetes mellitus, optic atrophy, peptic ulcer bleeding and defective platelet aggregation. Four mutations in the CISD2 gene have been reported. Among these mutations, the homozygous c.103 + 1G > A substitution was identified in the donor splice site of intron 1 in two Italian sisters and was predicted to cause a exon 1 to be skipped. Methods Here, we employed molecular assays to characterize the c.103 + 1G > A mutation using the patient’s peripheral blood mononuclear cells (PBMCs). 5′-RACE coupled with RT-PCR were used to analyse the effect of the c.103 + 1G > A mutation on mRNA splicing. Western blot analysis was used to analyse the consequences of the CISD2 mutation on the encoded protein. Results We demonstrated that the c.103 + 1G > A mutation functionally impaired mRNA splicing, producing multiple splice variants characterized by the whole or partial absence of exon 1, which introduced amino acid changes and a premature stop. The affected mRNAs resulted in either predicted targets for nonsense mRNA decay (NMD) or non-functional isoforms. Conclusions We concluded that the c.103 + 1G > A mutation resulted in the loss of functional CISD2 protein in the two Italian WFS2 patients