Bile‐duct ligation renders the brain susceptible to hypotension induced neuronal degeneration : implications of ammonia

Hepatic encephalopathy (HE) is a debilitating neurological complication of cirrhosis. By definition, HE is considered a reversible disorder, and therefore HE should resolve following liver transplantation (LT). However, persisting neurological complications are observed in as many as 47% of LT recipients. LT is an invasive surgical procedure accompanied with various perioperative factors such as blood loss and hypotension which could influence outcomes post‐LT. We hypothesize that minimal HE (MHE) renders the brain frail and susceptible to hypotension‐induced neuronal cell death. Six‐week bile duct‐ligated (BDL) rats with MHE and respective SHAM‐controls were used. Several degrees of hypotension (mean arterial pressure of 30, 60 and 90mmHg) were induced via blood withdrawal from the femoral artery and maintained for 120 minutes. Brains were collected for neuronal cell count and apoptotic analysis. In a separate group, BDL rats were treated for MHE with the ammonia‐lowering strategy ornithine phenylacetate (OP; MNK‐6105), administered orally (1g/kg) for 3 weeks before induction of hypotension. Hypotension 30 and 60mmHg (not 90mmHg) significantly decreased neuronal marker expression (NeuN) and cresyl violet staining in the frontal cortex compared to respective hypotensive SHAM‐operated controls as well as non‐hypotensive BDL rats. Neuronal degeneration was associated with an increase in cleaved caspase‐3, suggesting the mechanism of cell death was apoptotic. OP treatment attenuated hyperammonemia, improved anxiety and activity, and protected the brain against hypotension‐induced neuronal cell death. Our findings demonstrate that rats with chronic liver disease and MHE are more susceptible to hypotension‐induced neuronal cell degeneration. This highlights MHE at the time of LT is a risk factor for poor neurological outcome post‐transplant and that treating for MHE pre‐LT might reduce this risk

Impact of uric acid on liver injury and intestinal permeability following resuscitated hemorrhagic shock in rats

BACKGROUND Multiorgan failure is a consequence of severe ischemia-reperfusion injury after traumatic hemorrhagic shock (HS), a major cause of mortality in trauma patients. Circulating uric acid (UA), released from cell lysis, is known to activate proinflammatory and proapoptotic pathways and has been associated with poor clinical outcomes among critically ill patients. Our group has recently shown a mediator role for UA in kidney and lung injury, but its role in liver and enteric damage after HS remains undefined. Therefore, the objective of this study was to evaluate the role of UA on liver and enteric injury after resuscitated HS. METHODS A murine model of resuscitated HS was treated during resuscitation with a recombinant uricase, a urate oxidase enzyme (rasburicase; Sanofi-Aventis, Canada Inc, Laval, Canada), to metabolize and reduce circulating UA. Biochemical analyses (liver enzymes, liver apoptotic, and inflammatory markers) were performed at 24 hours and 72 hours after HS. Physiological testing for enteric permeability and gut bacterial product translocation measurement (plasma endotoxin) were performed 72 hours after HS. In vitro, HT-29 cells were exposed to UA, and the expression of intercellular adhesion proteins (ZO-1, E-cadherin) was measured to evaluate the influence of UA on enteric permeability. RESULTS The addition of uricase to resuscitation significantly reduced circulating and liver UA levels after HS. It also prevented HS-induced hepatolysis and liver apoptotic/inflammatory mediators at 24 hours and 72 hours. Hemorrhagic shock–induced enteric hyperpermeability and endotoxemia were prevented with uricase. CONCLUSIONS After resuscitated HS, UA is an important mediator in liver and enteric injury. Uric acid represents a therapeutic target to minimize organ damage in polytrauma patients sustaining HS

Mid infrared near-field fingerprint spectroscopy of the 2D electron gas in LaAlO3_3/SrTiO3_3 at low temperatures

Confined electron systems, such as 2D electron gases (2DEGs), 2D materials, or topological insulators show great technological promise but their susceptibility to defects often results in nanoscale inhomogeneities with unclear origins. Scattering-type scanning near-field optical microscopy (s-SNOM) is useful to investigate buried confined electron systems non-destructively with nanoscale resolution, however, a clear separation of carrier concentration and mobility was often impossible in s-SNOM. Here, we predict a previously inaccessible characteristic "fingerprint" response of the prototypical LaAlO$_3$/SrTiO$_3$ 2DEG, and verify this using a state-of-the-art tunable narrow-band laser in mid-infrared cryo-s-SNOM at 8 K. Our modelling allows us to separate the influence of carrier concentration and mobility on fingerprint spectra and to characterize 2DEG inhomogeneities on the nanoscale. This spatially resolved information about the local electronic properties can be used to identify the origin of inhomogeneities in confined electron systems, making the s-SNOM fingerprint response a valuable tool for nanoelectronics and quantum technology

The First α Helix of Interleukin (Il)-2 Folds as a Homotetramer, Acts as an Agonist of the IL-2 Receptor β Chain, and Induces Lymphokine-Activated Killer Cells

Interleukin (IL)-2 interacts with two types of functional receptors (IL-2Rαβγ and IL-2Rβγ) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. For the first time, we show that a chemically synthesized fragment of the IL-2 sequence can fold into a molecule mimicking the quaternary structure of a hemopoietin. Indeed, peptide p1–30 (containing amino acids 1–30, covering the entire α helix A of IL-2) spontaneously folds into an α-helical homotetramer and stimulates the growth of T cell lines expressing human IL-2Rβ, whereas shorter versions of the peptide lack helical structure and are inactive. We also demonstrate that this neocytokine interacts with a previously undescribed dimeric form of IL-2Rβ. In agreement with its binding to IL-2Rβ, p1–30 activates Shc and p56lck but unlike IL-2, fails to activate Janus kinase (Jak)1, Jak3, and signal transducer and activator of transcription 5 (STAT5). Unexpectedly, we also show that p1–30 activates Tyk2, thus suggesting that IL-2Rβ may bind to different Jaks depending on its oligomerization. At the cellular level, p1–30 induces lymphokine-activated killer (LAK) cells and preferentially activates CD8low lymphocytes and natural killer cells, which constitutively express IL-2Rβ. A significant interferon γ production is also detected after p1–30 stimulation. A mutant form of p1–30 (Asp20→Lys), which is likely unable to induce vascular leak syndrome, remains capable of generating LAK cells, like the original p1–30 peptide. Altogether, our data suggest that p1–30 has therapeutic potential

Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis

Background & Aims Recent studies suggest that heparins reduce liver fibrosis and the risk of decompensation of liver disease. Here, we evaluated the effects of enoxaparin in several experimental models of advanced cirrhosis. Methods Cirrhosis was induced in male Sprague‐Dawley (SD) rats by: (i) Oral gavage with carbon tetrachloride (CCl4ORAL), (ii) Bile duct ligation (BDL) and (iii) CCl4 inhalation (CCl4INH). Rats received saline or enoxaparin s.c. (40 IU/Kg/d or 180 IU/Kg/d) following various protocols. Blood biochemical parameters, liver fibrosis, endothelium‐ and fibrosis‐related genes, portal pressure, splenomegaly, bacterial translocation, systemic inflammation and survival were evaluated. Endothelial dysfunction was assessed by in situ bivascular liver perfusions. Results Enoxaparin did not ameliorate liver function, liver fibrosis, profibrogenic gene expression, portal hypertension, splenomegaly, ascites development and infection, serum IL‐6 levels or survival in rats with CCl4ORAL or BDL‐induced cirrhosis. Contrarily, enoxaparin worsened portal pressure in BDL rats and decreased survival in CCl4ORAL rats. In CCl4INH rats, enoxaparin had no effects on hepatic endothelial dysfunction, except for correcting the hepatic arterial dysfunction when enoxaparin was started with the CCl4 exposure. In these rats, however, enoxaparin increased liver fibrosis and the absolute values of portal venous and sinusoidal resistance. Conclusions Our results do not support a role of enoxaparin for improving liver fibrosis, portal hypertension or endothelial dysfunction in active disease at advanced stages of cirrhosis. These disease‐related factors and the possibility of a limited therapeutic window should be considered in future studies evaluating the use of anticoagulants in cirrhosis

Genome-wide association study for acute otitis media in children identifies FNDC1 as disease contributing gene

Acute otitis media (AOM) is among the most common pediatric diseases, and the most frequent reason for antibiotic treatment in children. Risk of AOM is dependent on environmental and host factors, as well as a significant genetic component. We identify genome-wide significance at a locus on 6q25.3 (rs2932989, Pmeta=2.15 × 10-09), and show that the associated variants are correlated with the methylation status of the FNDC1 gene (cg05678571, P=1.43 × 10-06), and further show it is an eQTL for FNDC1 (P=9.3 × 10-05). The mouse homologue, Fndc1, is expressed in middle ear tissue and its expression is upregulated upon lipopolysaccharide treatment. In this first GWAS of AOM and the largest OM genetic study to date, we identify the first genome-wide significant locus associated with AOM

Retreat into scientism, paradoxes of transparency, and corruption in education

Um dos sintomas da razão indolente (SANTOS, 2006) é o recuo ao cientificismo, o qual tem sido, particularmente, acentuado nas políticas, cada vez mais hegemônicas, de avaliação, de prestação de contas e de responsabilização. Por isso, um dos objetivos deste texto é o de colocar em causa este aparente consenso cientificista (ou este consenso supostamente transideológico) e fazer uma breve incursão exploratória ao que aqui se designa de paradoxos da transparência. Considera-se que esses paradoxos traduzem a existência de tensões e contradições relativas a uma dimensão central dos discursos políticos e educacionais contemporâneos. Com isso, o artigo pretende dar continuidade a uma linha de pesquisa que tem procurado sublinhar a relevância da necessidade de complexificar e dar maior rigor teórico-conceptual à accountability em educação. Finalmente, tentando abrir caminho para o desenvolvimento de novas articulações e análises, chama-se a atenção para a corrupção na educação cuja complexidade ainda é insuficientemente conhecida e pesquisada, nomeadamente, nas suas relações com as problemáticas da transparência e da accountability. Admite-se que as práticas de corrupção em educação, em muitas situações, são (paradoxalmente) induzidas pela necessidade de dar resposta à governação baseada nos números, nos rankings e nas (supostas) evidências, anulando completamente as expectativas legítimas em torno da transparência dos processos educacionais e das decisões políticas.One symptom of “indolent reason” (SANTOS, 2006) is the retreat into scientism, which is especially marked in the increasingly hegemonic policies surrounding assessment, reporting and accountability. As such, one of the aims of this paper is to call into question this apparent consensus on scientism (a supposedly trans-ideological consensus), and briefly explore what we define as the paradoxes of transparency. These paradoxes are found to reveal the existence of tensions and contradictions concerning a central aspect of current political and educational discourse. In doing so, the article seeks to continue a line of study which has aimed to emphasize the significance of the need for a more complex, and theoretically and conceptually rigorous understanding of accountability in education. Finally, in an attempt to pave the way for further discussion and analysis, attention is drawn to corruption in education, the complex nature of which remains insufficiently understood and studied, notably in terms of its relationship with the problems of transparency and accountability. It is acknowledged that practices of corruption within education are, in many situations, (paradoxically) caused by the need to answer to a system of governance based on numbers, league tables, and (supposed) truths, completely nullifying legitimate expectations about the transparency of educational processes and policy decisions.Trabalho financiado por Fundos Nacionais através da FCT – Fundação para a Ciência e a Tecnologia – no âmbito do Projeto PEst-OE/CED/UI1661/2014.info:eu-repo/semantics/publishedVersio

A united statement of the global chiropractic research community against the pseudoscientific claim that chiropractic care boosts immunity.

BACKGROUND: In the midst of the coronavirus pandemic, the International Chiropractors Association (ICA) posted reports claiming that chiropractic care can impact the immune system. These claims clash with recommendations from the World Health Organization and World Federation of Chiropractic. We discuss the scientific validity of the claims made in these ICA reports. MAIN BODY: We reviewed the two reports posted by the ICA on their website on March 20 and March 28, 2020. We explored the method used to develop the claim that chiropractic adjustments impact the immune system and discuss the scientific merit of that claim. We provide a response to the ICA reports and explain why this claim lacks scientific credibility and is dangerous to the public. More than 150 researchers from 11 countries reviewed and endorsed our response. CONCLUSION: In their reports, the ICA provided no valid clinical scientific evidence that chiropractic care can impact the immune system. We call on regulatory authorities and professional leaders to take robust political and regulatory action against those claiming that chiropractic adjustments have a clinical impact on the immune system

Post-Operative Functional Outcomes in Early Age Onset Rectal Cancer

Background: Impairment of bowel, urogenital and fertility-related function in patients treated for rectal cancer is common. While the rate of rectal cancer in the young (<50 years) is rising, there is little data on functional outcomes in this group. Methods: The REACCT international collaborative database was reviewed and data on eligible patients analysed. Inclusion criteria comprised patients with a histologically confirmed rectal cancer, <50 years of age at time of diagnosis and with documented follow-up including functional outcomes. Results: A total of 1428 (n=1428) patients met the eligibility criteria and were included in the final analysis. Metastatic disease was present at diagnosis in 13%. Of these, 40% received neoadjuvant therapy and 50% adjuvant chemotherapy. The incidence of post-operative major morbidity was 10%. A defunctioning stoma was placed for 621 patients (43%); 534 of these proceeded to elective restoration of bowel continuity. The median follow-up time was 42 months. Of this cohort, a total of 415 (29%) reported persistent impairment of functional outcomes, the most frequent of which was bowel dysfunction (16%), followed by bladder dysfunction (7%), sexual dysfunction (4.5%) and infertility (1%). Conclusion: A substantial proportion of patients with early-onset rectal cancer who undergo surgery report persistent impairment of functional status. Patients should be involved in the discussion regarding their treatment options and potential impact on quality of life. Functional outcomes should be routinely recorded as part of follow up alongside oncological parameters

Genome-wide analysis identifies 12 loci influencing human reproductive behavior.

The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits