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Tracheostomy (TQT) has emerged as a valuable alternative for patients with orotracheal intubation, especially those under prolonged mechanical ventilation (VMP), as in the case of chronic obstructive pulmonary disease (COPD). This population presents additional challenges, and the available information regarding their progression in specialized centers is limited in Argentina.A descriptive, retrospective, and cross-sectional study was conducted at Santa Catalina Neurorehabilitation Clinic between August 2015 and December 2018. Patients with COPD referred to the Intensive Care Unit (ICU), tracheostomized, and subsequently referred to the Center for Ventilation Disconnection and Rehabilitation (CDVMR) were included. Cases with missing data or derived from other CDVMRs were excluded. Clinical records and interviews were employed to collect demographic and progression data.Out of the 27 COPD patients included (4.9% of 555), the majority were males (63%) with an average age of 68.1 years. Most were admitted with AVMi, and 11 (45.8%) were successfully disconnected, while 11 (40.7%) were decannulated. Survival and home discharge were more frequent in decannulated patients (81.8% were discharged) compared to non-decannulated ones (50% deceased, and none were discharged).COPD patients undergoing TQT and VMP, who succeed in being decannulated, seem to have better prospects for survival and home discharge compared to those who do not have the cannula removed. There is a suggestion for the need for additional analytical studies to confirm these findings and improve the understanding of this specific population., (Universidad Nacional de Córdoba)

PYHIN proteins are only found in mammals and play key roles in the defense against bacterial and viral pathogens. The corresponding gene locus shows variable deletion and expansion ranging from 0 genes in bats, over 1 in cows, and 4 in humans to a maximum of 13 in mice. While initially thought to act as cytosolic immune sensors that recognize foreign DNA, increasing evidence suggests that PYHIN proteins also inhibit viral pathogens by more direct mechanisms. Here, we examined the ability of all 13 murine PYHIN proteins to inhibit HIV-1 and murine leukemia virus (MLV). We show that overexpression of p203, p204, p205, p208, p209, p210, p211, and p212 strongly inhibits production of infectious HIV-1; p202, p207, and p213 had no significant effects, while p206 and p214 showed intermediate phenotypes. The inhibitory effects on infectious HIV-1 production correlated significantly with the suppression of reporter gene expression by a proviral Moloney MLV-eGFP construct and HIV-1 and Friend MLV LTR luciferase reporter constructs. Altogether, our data show that the antiretroviral activity of PYHIN proteins is conserved between men and mice and further support the key role of nuclear PYHIN proteins in innate antiviral immunity.

Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

Repeated emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased fitness underscores the value of rapid detection and characterization of new lineages. We have developed PyR 0 , a hierarchical Bayesian multinomial logistic regression model that infers relative prevalence of all viral lineages across geographic regions, detects lineages increasing in prevalence, and identifies mutations relevant to fitness. Applying PyR 0 to all publicly available SARS-CoV-2 genomes, we identify numerous substitutions that increase fitness, including previously identified spike mutations and many nonspike mutations within the nucleocapsid and nonstructural proteins. PyR 0 forecasts growth of new lineages from their mutational profile, ranks the fitness of lineages as new sequences become available, and prioritizes mutations of biological and public health concern for functional characterization.

Subtype C is the most prevalent clade of human immunodeficiency virus type 1 (HIV-1) worldwide. The reasons for this are poorly understood. Here, we demonstrate that a characteristic additional third nuclear factor κB (NF-κB) binding site in the long terminal repeat (LTR) promoter allows subtype C HIV-1 strains to evade restriction by nuclear PYHIN proteins, which sequester the transcription factor Sp1. Further, other LTR alterations are responsible for rare PYHIN resistance of subtype B viruses. Resistance-conferring mutations generally reduce the dependency of HIV-1 on Sp1 for virus production and render LTR transcription highly responsive to stimulation by NF-κB/p65. A third NF-κB binding site increases infectious virus yield in primary CD4 + T cells in an γ-interferon-inducible protein 16 (IFI16)-dependent manner. Comprehensive sequence analyses suggest that the frequency of circulating PYHIN-resistant HIV-1 strains is increasing. Our finding that an additional NF-κB binding site in the LTR confers resistance to nuclear PYHIN proteins helps to explain the dominance of clade C HIV-1 strains., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Polyoxometalates (POMs), molecular metal oxide anions, are inorganic clusters with promising antiviral activity. Herein we report increased anti-HIV-1 activity of a POM when electrostatically combined with organic counter-cations. To this end, Keggin-type cerium tungstate POMs have been combined with organic methyl-caffeinium (Caf) cations, and their cytotoxicity, antiviral activity and mode of action have been studied. The novel compound, Caf 4 K[β 2 -CeSiW 11 O 39 ]×H 2 O, exhibits sub-nanomolar antiviral activity and inhibits HIV-1 infectivity by acting on an early step of the viral infection cycle. This work demonstrates that combination of POM anions and organic bioactive cations can be a powerful new strategy to increase antiviral activity of these inorganic compounds., (© 2021 The Authors. ChemMedChem published by Wiley-VCH GmbH.)

IFI16 is an important player of the host intrinsic immune response. Among others, it has been reported to sense intermediate products of HIV-1 reverse transcription in the cytosol and to sequester the transcription factor Sp1 in the nucleus to attenuate viral gene expression. Here, we present three different methods to reduce IFI16 protein expression levels in HIV-1 primary target cells. These techniques can be adapted for the investigation of other cellular factors in primary macrophages and CD4 + T lymphocytes. For complete details on the use and execution of this protocol, please refer to Hotter et al. (2019) and Bosso et al. (2020)., Competing Interests: The authors declare no competing interests., (© 2020 The Author(s).)

Innate immune sensors and restriction factors are cellular proteins that synergize to build an effective first line of defense against viral infections. Innate sensors are usually constitutively expressed and capable of detecting pathogen-associated molecular patterns (PAMPs) via specific pattern recognition receptors (PRRs) to stimulate the immune response. Restriction factors are frequently upregulated by interferons (IFNs) and may inhibit viral pathogens at essentially any stage of their replication cycle. Members of the Pyrin and hematopoietic interferon-inducible nuclear (HIN) domain (PYHIN) family have initially been recognized as important sensors of foreign nucleic acids and activators of the inflammasome and the IFN response. Accumulating evidence shows, however, that at least three of the four members of the human PYHIN family restrict viral pathogens independently of viral sensing and innate immune activation. In this review, we provide an overview on the role of human PYHIN proteins in the innate antiviral immune defense and on viral countermeasures.

Background: Bariatric surgery is well established as a treatment for obesity and associated complications. This procedure improves metabolic homeostasis through changes in energy expenditure. We hypothesized that sleeve gastrectomy (SG) improves metabolic homeostasis by modulating energy expenditure and enhancing thermogenesis through increasing the expression level of meteorin-like protein (METRNL) and fibronectin type III domain-containing protein 5 (FNDC5/Irisin) through uncoupling proteins 1/2/3 (UCP1, UCP2, and UCP3)., Objectives: To study the effect of SG on the levels of proteins involved in thermogenesis process., Setting: Laboratory rats at Kuwait University., Methods: Male Sprague-Dawley rats, aged 4 to 5 weeks, were divided into 2 groups, control (n = 11) and diet-induced obesity (DIO) (n = 22). The control group was fed regular rat chow ad libitum, whereas the DIO group was fed cafeteria diet "high-fat/carbohydrate diet" ad libitum. At 21 weeks, rats in the DIO group that weighed 20% more than the control group animals underwent surgery. These rats were randomly subdivided into Sham and SG operation groups. Gene expression was evaluated, and enzyme-linked immunosorbent assays were employed to assess the changes in gene and protein levels in tissue and circulation., Results: The protein expression data revealed an increase in METRNL levels in the muscles and white adipose tissue of SG animals. METRNL level in circulation in SG animals was reduced compared with control and Sham rats. The level of Irisin increased in the muscle of SG animals compared with the control and Sham group animals; however, a decrease in Irisin level was observed in the white adipose tissue and brown adipose tissue of SG animals compared with controls. Gene expression analysis revealed decreased METRNL levels in muscle tissues in the SG group compared with the control group animals. Increased expression of FNDC5 (Irisin), UCP2, and UCP3 in the muscle tissue of SG animals was also observed. Furthermore, the levels of UCP1, UCP2, UCP3, and METRNL in the brown adipose tissue of SG animals were upregulated. No significant alteration in the gene expression of Irisin was observed in brown adipose tissue., Conclusions: Sleeve gastrectomy induces weight loss through complex mechanisms that may include browning of fat., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Members of the family of pyrin and HIN domain containing (PYHIN) proteins play an emerging role in innate immunity. While absent in melanoma 2 (AIM2) acts a cytosolic sensor of non-self DNA and plays a key role in inflammasome assembly, the γ-interferon-inducible protein 16 (IFI16) restricts retroviral gene expression by sequestering the transcription factor Sp1. Here, we show that the remaining two human PYHIN proteins, i.e. myeloid cell nuclear differentiation antigen (MNDA) and pyrin and HIN domain family member 1 (PYHIN1 or IFIX) share this antiretroviral function of IFI16. On average, knock-down of each of these three nuclear PYHIN proteins increased infectious HIV-1 yield from human macrophages by more than an order of magnitude. Similarly, knock-down of IFI16 strongly increased virus transcription and production in primary CD4+ T cells. The N-terminal pyrin domain (PYD) plus linker region containing a nuclear localization signal (NLS) were generally required and sufficient for Sp1 sequestration and anti-HIV-1 activity of IFI16, MNDA and PYHIN1. Replacement of the linker region of AIM2 by the NLS-containing linker of IFI16 resulted in a predominantly nuclear localization and conferred direct antiviral activity to AIM2 while attenuating its ability to form inflammasomes. The reverse change caused nuclear-to-cytoplasmic relocalization of IFI16 and impaired its antiretroviral activity but did not result in inflammasome assembly. We further show that the Zn-finger domain of Sp1 is critical for the interaction with IFI16 supporting that pyrin domains compete with DNA for Sp1 binding. Finally, we found that human PYHIN proteins also inhibit Hepatitis B virus and simian vacuolating virus 40 as well as the LINE-1 retrotransposon. Altogether, our data show that IFI16, PYHIN1 and MNDA restrict HIV-1 and other viral pathogens by interfering with Sp1-dependent gene expression and support an important role of nuclear PYHIN proteins in innate antiviral immunity., Competing Interests: NO authors have competing interests.

The mechanism for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection requires the binding of the virus to the angiotensin-converting enzyme 2 (ACE2) receptor, well-known for its role in counteracting ACE. ACE2 is involved in modulating blood pressure and establishing blood pressure homeostasis. Recently, a critical debatable question has arisen whether using antihypertensive medications will have a favorable impact on people infected with SARS-CoV-2 or a deleterious one, mainly because angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-receptor blocker (ARB) therapy can modulate the expression of ACE2 protein. The concern is that the use of ACEIs and ARBs will increase the expression of ACE2 and increase patient susceptibility to viral host cell entry and propagation. On the other hand, several genetic association studies have examined the relationship between ACE2 genetic variants and the risk of developing hypertension in different ethnic populations. In this review, we discuss the ongoing arguments in the literature about ACE2's role in mortality rate among coronavirus disease 2019 (COVID-19) patients comorbid with hypertension and critically evaluate the current debate about the usage or discontinuation of ACEI/ARB antihypertensive drugs. Moreover, we explore the two opposing roles that ACE2 genetic variants might be playing in COVID-19 by reducing ACE2 receptor effectiveness and mitigating SARS-CoV-2 infectivity., (© 2020 Dasman Diabetes Institute.)

Restriction factors are structurally and functionally diverse cellular proteins that constitute a first line of defense against viral pathogens. Exceptions exist, but typically these proteins are upregulated by interferons (IFNs), target viral components, and are rapidly evolving due to the continuous virus-host arms race. Restriction factors may target HIV replication at essentially each step of the retroviral replication cycle, and the suppression of viral transcription and the degradation of viral RNA transcripts are emerging as major innate immune defense mechanisms. Recent data show that some antiviral factors, such as the tripartite motif-containing protein 22 (TRIM22) and the g-IFN-inducible protein 16 (IFI16), do not target HIV-1 itself but limit the availability of the cellular transcription factor specificity protein 1 (Sp1), which is critical for effective viral gene expression. In addition, several RNA-interacting cellular factors including RNAse L, the NEDD4-binding protein 1 (N4BP1), and the zinc finger antiviral protein (ZAP) have been identified as important immune effectors against HIV-1 that may be involved in the maintenance of the latent viral reservoirs, representing the major obstacle against viral elimination and cure. Here, we review recent findings on specific cellular antiviral factors targeting HIV-1 transcription or viral RNA transcripts and discuss their potential role in viral latency.

The interferon γ-inducible protein 16 (IFI16) is known as immune sensor of retroviral DNA intermediates. We show that IFI16 restricts HIV-1 independently of immune sensing by binding and inhibiting the host transcription factor Sp1 that drives viral gene expression. This antiretroviral activity and ability to bind Sp1 require the N-terminal pyrin domain and nuclear localization of IFI16, but not the HIN domains involved in DNA binding. Highly prevalent clade C HIV-1 strains are more resistant to IFI16 and less dependent on Sp1 than other HIV-1 subtypes. Furthermore, inhibition of Sp1 by IFI16 or pharmacologically by Mithramycin A suppresses reactivation of latent HIV-1 in CD4 + T cells. Finally, IFI16 also inhibits retrotransposition of LINE-1, known to engage Sp1, and murine IFI16 homologs restrict Friend retrovirus replication in mice. Thus, IFI16 restricts retroviruses and retrotransposons by interfering with Sp1-dependent gene expression, and evasion from this restriction may facilitate spread of HIV-1 subtype C., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Infectious diseases and cancers are leading causes of death and pose major challenges to public health. The human peptidome encompasses millions of compounds that display an enormous structural and functional diversity and represents an excellent source for the discovery of endogenous agents with antimicrobial and/or anticancer activity. Here, we discuss how to exploit the human peptidome for novel antimicrobial and anticancer agents through the generation of peptide libraries from human body fluids and tissues and stepwise purification of bioactive compounds., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Human cytomegalovirus (HCMV) persistently infects 40% to 100% of the human population worldwide. Experimental and clinical evidence indicates that humoral immunity to HCMV plays an important role in restricting virus dissemination and protecting the infected host from disease. Specific immunoglobulin preparations from pooled plasma of adults selected for high titers of HCMV antibodies have been used for the prevention of CMV disease in transplant recipients and pregnant women. Even though incubation of HCMV particles with these preparations leads to the neutralization of viral infectivity, it is still unclear whether the antibody-treated HCMV particles (referred to here as HCMV-Ab) enter the cells and modulate antiviral immune responses. Here we demonstrate that HCMV-Ab did enter macrophages. HCMV-Ab did not initiate the expression of immediate early antigens (IEAs) in macrophages, but they induced an antiviral state and rendered the cells less susceptible to HCMV infection upon challenge. Resistance to HCMV infection seemed to be due to the activation of intrinsic restriction factors and was independent of interferons. In contrast to actively infected cells, autologous NK cells did not degranulate against HCMV-Ab-treated macrophages, suggesting that these cells may not be eliminated by innate effector cells. Interestingly, HCMV-Ab-treated macrophages stimulated the proliferation of autologous adaptive CD4 + and CD8 + T cells. Our findings not only expand the current knowledge on virus-antibody immunity but may also be relevant for future vaccination strategies. IMPORTANCE Human cytomegalovirus (HCMV), a common herpesvirus, establishes benign but persistent infections in immunocompetent hosts. However, in subjects with an immature or dysfunctional immune system, HCMV is a major cause of morbidity and mortality. Passive immunization has been used in different clinical settings with variable clinical results. Intravenous hyperimmune globulin preparations (IVIg) are obtained from pooled adult human plasma selected for high anti-CMV antibody titers. While HCMV neutralization can be shown in vitro using different systems, data are lacking regarding the cross-influence of IVIg administration on the cellular immune responses. The aim of this study was to evaluate the effects of IVIg on distinct components of the immune response against HCMV, including antigen presentation by macrophages, degranulation of innate natural killer cells, and proliferation of adaptive CD4 + and CD8 + T cells., (Copyright © 2017 American Society for Microbiology.)

Objectives: The effectiveness of the active humidification systems (AHS) in patients already weaned from mechanical ventilation and with an artificial airway has not been very well described. The objective of this study was to evaluate the performance of an AHS in chronically tracheostomized and spontaneously breathing patients., Methods: Measurements were quantified at three levels of temperature (T°) of the AHS: level I, low; level II, middle; and level III, high and at different flow levels (20 to 60 L/minute). Statistical analysis of repeated measurements was performed using analysis of variance and significance was set at a P<0.05., Results: While the lowest temperature setting (level I) did not condition gas to the minimum recommended values for any of the flows that were used, the medium temperature setting (level II) only conditioned gas with flows of 20 and 30 L/minute. Finally, at the highest temperature setting (level III), every flow reached the minimum absolute humidity (AH) recommended of 30 mg/L., Conclusion: According to our results, to obtain appropiate relative humidity, AH and T° of gas one should have a device that maintains water T° at least at 53℃ for flows between 20 and 30 L/m, or at T° of 61℃ at any flow rate.

Background: Most of the studies referring cuff tubes' issues were conducted on intubated patients. Not much is known about the cuff pressure performance in chronically tracheostomized patients disconnected from mechanical ventilation., Objective: To evaluate cuff pressure (CP) variation in tracheostomized, spontaneously breathing patients in a weaning rehabilitation center., Materials and Methods: Experimental setup to test instruments in vitro, in which the gauge (TRACOE) performance at different pressure levels was evaluated in six tracheostomy tubes, and a clinical setupin which CP variation over 24 h, every 4 h, and for 6 days was measured in 35 chronically tracheostomized clinically stable, patients who had been disconnected from mechanical ventilation for at least 72 h. The following data were recorded: Tube brand, type, and size; date of the tube placed; the patient's body position; the position of the head; axillary temperature; pulse and respiration rates; blood pressure; and pulse oximetry., Results: In vitro difference between the initial pressure (IP) and measured pressure (MP) was statistically significant (P < 0.05). The difference between the IP and MP was significant when selecting for various tube brands (P < 0.05). In the clinical set-up, 207 measurements were performed and the CP was >30 cm H2O in 6.28% of the recordings, 20-30 cm H2O in 42.0% of the recordings, and <20 cm H2O in 51.69% of the recordings., Conclusion: The systematic CP measurement in chronically tracheostomized, spontaneously breathing patients showed high variability, which was independent of tube brand, size, type, or time of placement. Consequently, measurements should be made more frequently.

Whole genome amplification systems were developed to meet the increasing research demands on DNA resources and to avoid DNA shortage. The technology enables amplification of nanogram amounts of DNA into microgram quantities and is increasingly used in the amplification of DNA from multiple origins such as blood, fresh frozen tissue, formalin-fixed paraffin-embedded tissues, saliva, buccal swabs, bacteria, and plant and animal sources. This chapter focuses on the use of GenomePlex(®) tissue Whole Genome Amplification Kit, to amplify DNA directly from archived tissue. In addition, this chapter documents our unique experience with the utilization of GenomePlex(®) amplified DNA using several molecular techniques including metaphase Comparative Genomic Hybridization, array Comparative Genomic Hybridization, and real-time quantitative polymerase chain reaction assays. GenomePlex(®) is a registered trademark of Rubicon Genomics Incorporation.

Background: Sclerosing cholangitis is a chronic cholestatic liver disease of unknown etiology. Immunologic and genetic factors may be involved in the pathogenesis of the disease, characterized by fibrosis involving bile ducts, which can progress to biliary cirrhosis and cholangiocarcinoma (8%-30%). Sclerosing cholangitis is frequently associated with inflammatory bowel diseases, especially ulcerative colitis (60%-80%), which may require a proctocolectomy with ileal pouch anal anastomosis if there is no response to therapy or the appearance of colonic carcinoma., Patients and Methods: Among 1629 liver recipients from 1990 to 2008, 47 (2.9%) had sclerosing cholangitis as the cause of cirrhosis. Forty two percent of these also had associated inflammatory bowel disease with 34% displaying ulcerative colitis. Eight patients died after liver transplantation (OLT) in the absence of recurrence of sclerosing cholangitis. Among the remaining 39 patients, 17 (43.6%) developed recurrent of sclerosing cholangitis; three required re-OLT, and among these three patients, one developed another recurrence. After OLT, ulcerative colitis persisted in an active state in eight patients, requiring proctocolectomy with ileal pouch-anal anastomosis for three patients (median time after OLT was 78.6 months)., Results: One of the three patients who had proctocolectomy had an immediate complication, a pelvic hematoma, which required a surgical approach. One patient developed acute pouchitis 15 months after OLT, medically treated with antibiotics and corticoids. Histology of the colectomy specimen demonstrated colorectal cancer in two patients (pT3N0 and pT2N0) and high-grade dysplasia in the remaining subjects. All patients displayed a cure of their colonic disease (median follow-up 14 months) despite two patients developing recurrence of the liver disease., Conclusion: Proctocolectomy with ileal pouch anal anastomosis is safe in patients who underwent OLT for sclerosing cholangitis in association with ulcerative colitis. If not surgically treated, patients may receive immunosuppression to prevent rejection and disease recurrence, avoiding at the same time the occurrence of "de novo" neoplasms. Mammalian target or rapamycin inhibitors may have an important role but this must be established with randomized controlled trials.

Aims and Background: Anal cancer is a rare condition. The inguinal lymph nodes are the most common site of metastasis in this neoplasm. The inguinal lymph node status is an important prognostic indicator and the presence of metastases is an independent prognostic factor for local failure and overall mortality. Depending on the primary tumor size and histological differentiation, metastasis to superficial inguinal lymph nodes occurs in 15-25% of cases., Methods and Study Design: To evaluate the inguinal lymph node status we performed a search for the sentinel node in a female patient affected by squamous and carcinoma., Results: Identification and examination of the sentinel node was positive and postoperative histology showed the presence of bilateral lymph node metastases., Conclusions: We suggest that examination of the sentinel node in anal cancer could be an efficient way to establish the inguinal lymph node status, which would help the clinician to plan and perform adequate treatment.