Sepsis Impairs IFN-γ Production in CD8 T Cells through Changes in Local Chromatin Landscape.

Sepsis is a complex condition of inflammatory and immune dysregulation, triggered by severe infection. In survivors, chronic inflammation and immune dysregulation linger, facilitating the emergence of infections. CD8 dysfunction contributes to immunosuppression in sepsis survivors. We devised an animal model that enabled us to identify and analyze CD8-intrinsic defects induced by sepsis. We adoptively transferred CD45.1 CD8 OT-I T cells into CD45.2 congenic mice and subjected them to cecal ligature and puncture, to induce abdominal sepsis. One month later, we isolated the transferred CD8 cells. Surface marker expression confirmed they had not been activated through the TCR. CD8 OT-I T cells isolated from septic (or sham-operated) mice were transferred to second recipients, which were challenged with OVA-expressing Listeria monocytogenes. We compared effector capacities between OT-I cells exposed to sepsis and control cells. Naive mice that received OT-I cells exposed to sepsis had higher bacterial burden and a shorter survival when challenged with OVA-expressing L. monocytogenes. OT-I cells isolated from septic mice produced less IFN-γ but had conserved activation, expansion potential, and cytotoxic function. We observed lower transcript levels of IFN-γ and of the long noncoding RNA Ifng-as1, a local regulator of the epigenetic landscape, in cells exposed to sepsis. Accordingly, local abundance of a histone modification characteristic of active promoter regions was reduced in sepsis-exposed CD8 T cells. Our results identify a mechanism through which inflammation in the context of sepsis affects CD8 T cell function intrinsically.

3-Hydroxykynurenine targets kainate receptors to promote defense against infection.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxykynurenine (3-HK) protects from lethal bacterial infection. 3-HK, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages through a systemic mechanism that targets kainate-sensitive glutamate receptors. These findings reveal a new pathway by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with important implications for the coordination between the immune and nervous systems in pathological conditions.

A tryptophan metabolite modulates the host response to bacterial infection via kainate receptors.

Bacterial infection involves a complex interaction between the pathogen and host where the outcome of infection is not solely determined by pathogen eradication. To identify small molecules that promote host survival by altering the host-pathogen dynamic, we conducted an in vivo chemical screen using zebrafish embryos and found that treatment with 3-hydroxy-kynurenine protects from lethal gram-negative bacterial infection. 3-hydroxy-kynurenine, a metabolite produced through host tryptophan metabolism, has no direct antibacterial activity but enhances host survival by restricting bacterial expansion in macrophages by targeting kainate-sensitive glutamate receptors. These findings reveal new mechanisms by which tryptophan metabolism and kainate-sensitive glutamate receptors function and interact to modulate immunity, with significant implications for the coordination between the immune and nervous systems in pathological conditions.

Portopulmonary Hypertension: An Updated Review.

Portal hypertension may have major consequences on the pulmonary vasculature due to the complex pathophysiological interactions between the liver and lungs. Portopulmonary hypertension (PoPH), a subset of group 1 pulmonary hypertension (PH), is a serious pulmonary vascular disease secondary to portal hypertension, and is the fourth most common subtype of pulmonary arterial hypertension. It is most commonly observed in cirrhotic patients; however, patients with noncirrhotic portal hypertension can also develop it. On suspicion of PoPH, the initial evaluation is by a transthoracic echocardiogram in which, if elevated pulmonary pressures are shown, patients should undergo right heart catheterization to confirm the diagnosis. The prognosis is extremely poor in untreated patients; therefore, management includes pulmonary arterial hypertension therapies with the aim of improving pulmonary hemodynamics and moving patients to orthotopic liver transplantation (OLT). In this article, we review in detail the epidemiology, pathophysiology, process for diagnosis, and most current treatments including OLT and prognosis in patients with PoPH. In addition, we present a diagnostic algorithm that includes the current criteria to properly select patients with PoPH who are candidates for OLT.

Author Correction: Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Adaptive evolution of virulence and persistence in carbapenem-resistant Klebsiella pneumoniae.

Among the most urgent public health threats is the worldwide emergence of carbapenem-resistant Enterobacteriaceae1-4, which are resistant to the antibiotic class of 'last resort'. In the United States and Europe, carbapenem-resistant strains of the Klebsiella pneumoniae ST258 (ref. 5) sequence type are dominant, endemic6-8 and associated with high mortality6,9,10. We report the global evolution of pathogenicity in carbapenem-resistant K. pneumoniae, resulting in the repeated convergence of virulence and carbapenem resistance in the United States and Europe, dating back to as early as 2009. We demonstrate that K. pneumoniae can enhance its pathogenicity by adopting two opposing infection programs through easily acquired gain- and loss-of-function mutations. Single-nucleotide polymorphisms in the capsule biosynthesis gene wzc lead to hypercapsule production, which confers phagocytosis resistance, enhanced dissemination and increased mortality in animal models. In contrast, mutations disrupting capsule biosynthesis genes impair capsule production, which enhances epithelial cell invasion, in vitro biofilm formation and persistence in urinary tract infections. These two types of capsule mutants have emerged repeatedly and independently in Europe and the United States, with hypercapsule mutants associated with bloodstream infections and capsule-deficient mutants associated with urinary tract infections. In the latter case, drug-tolerant K. pneumoniae can persist to yield potentially untreatable, persistent infection.

Add-on Pyridostigmine Enhances CD4+ T-Cell Recovery in HIV-1-Infected Immunological Non-Responders: A Proof-of-Concept Study.

BACKGROUND: In human immunodeficiency virus (HIV)-infection, persistent T-cell activation leads to rapid turnover and increased cell death, leading to immune exhaustion and increased susceptibility to opportunistic infections. Stimulation of the vagus nerve increases acetylcholine (ACh) release and modulates inflammation in chronic inflammatory conditions, a neural mechanism known as the cholinergic anti-inflammatory pathway (CAP). Pyridostigmine (PDG), an ACh-esterase inhibitor, increases the half-life of endogenous ACh, therefore mimicking the CAP. We have previously observed that PDG reduces ex vivo activation and proliferation of T-cells obtained from people living with HIV. METHODS: We conducted a 16-week proof-of-concept open trial using PDG as add-on therapy in seven HIV-infected patients with discordant immune response receiving combined antiretroviral therapy, to determine whether PDG would promote an increase in total CD4+ T-cells. The trial was approved by the Institutional Research and Ethics Board and registered in ClinicalTrials.gov (NCT00518154). RESULTS: Seven patients were enrolled after signing informed consent forms. We observed that addition of PDG induced a significant increase in total CD4+ T-cells (baseline = 153.1 ± 43.1 vs. week-12 = 211.9 ± 61.1 cells/µL; p = 0.02). Post hoc analysis showed that in response to PDG, four patients (57%) significantly increased CD4+ T-cell counts (responders = 257.8 ± 26.6 vs. non-responders = 150.6 ± 18.0 cells/µL; p = 0.002), and the effect persisted for at least 1 year after discontinuation of PDG. CONCLUSION: Our data indicate that in patients with HIV, add-on PDG results in a significant and persistent increase in circulating CD4+ T-cells.

Impact of ertapenem on antimicrobial resistance in a sentinel group of Gram-negative bacilli: a 6 year antimicrobial resistance surveillance study.

OBJECTIVES: To determine the association between ertapenem and resistance of Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Acinetobacter baumannii-calcoaceticus complex to different antimicrobials while adjusting for relevant hospital factors. METHODS: This was a retrospective time-series study conducted at a tertiary care centre from September 2002 to August 2008. The specific impact of ertapenem on the resistance of these Gram-negative bacilli (GNB) was assessed by multiple linear regression analysis, adjusting for the average length of stay, rate of hospital-acquired infections and use of 10 other antimicrobials, including type 2 carbapenems. RESULTS: Unadjusted analyses revealed significant increases over the duration of the study in the number of GNB resistant to meropenem/imipenem among 1000 isolates each of E. coli (0.46 ±â€Š0.22, P < 0.05), P. aeruginosa (6.26 ±â€Š2.26, P < 0.05), K. pneumoniae (8.06 ±â€Š1.50, P < 0.0005) and A. baumannii-calcoaceticus complex (25.39 ±â€Š6.81, P < 0.0005). Increased resistance to cefepime (and other extended-spectrum cephalosporins) was observed in E. coli (9.55 ±â€Š1.45, P < 0.0005) and K. pneumoniae (15.21 ±â€Š2.42, P < 0.0005). A. baumannii-calcoaceticus complex showed increased resistance to all antimicrobials except amikacin. After controlling for confounders, ertapenem was not significantly associated (P > 0.05) with changes in resistance for any pathogen/antimicrobial combination. CONCLUSIONS: After controlling for confounders, ertapenem was not associated with changes in resistance in a group of sentinel GNB, although significant variations in resistance to different antimicrobials were observed in the unadjusted analyses. These results emphasize the importance of implementation of local resistance surveillance platforms and stewardship programmes to combat the global emergence and spread of antimicrobial resistance.

Genetic variations in toll-like receptor 4 in Mexican-Mestizo patients with intra-abdominal infection and/or pneumonia.

Sepsis is a leading cause of death around the world, and 73-83% of all sepsis cases requiring attention in intensive care units are linked to intra-abdominal infection (IAI) or pneumonia. The activation of innate immunity is central to the manifestation of sepsis, and toll-like receptor (TLR) 4 plays an important role in this activation process. The 299G and 399I alleles of TLR4 have been linked with an increased risk of Gram-negative bacteria (GNB) infections and septic shock in some populations. This case-control study evaluated the prevalence of D299G/T399I polymorphisms in Mexican patients with IAI and/or pneumonia and in healthy controls. Genotyping revealed that 1 in 44 patients (2.3%; CI 95%: 0.05-12.0%) and 4 in 126 controls (3.2%; CI 95%: 0.9-7.9%) were heterozygous for both the D299G and T399l polymorphisms (OR: 0.71, CI 95%: 0.01-7.44, p = NS), confirming the co-segregation of these alleles in this population. Furthermore, the patients with a GNB infection and severe sepsis were not carriers of the risk alleles. In summary, this report shows that the frequency of the D299G and T399I polymorphisms in Mexican-Mestizos is lower than anticipated in comparison with other ethnic groups, emphasizing the variable distribution of TLR4 polymorphisms among different populations. Consequently, this study was not able to detect associations between TLR4 polymorphisms and sepsis in this population.

Acute myelogenous leukemia switch lineage upon relapse to acute lymphoblastic leukemia: a case report.

Acute leukemia, the most common form of cancer in children, accounts for approximately 30% of all childhood malignancies, with acute lymphoblastic leukemia being five times more frequent than acute myeloid leukemia. Lineage switch is the term that has been used to describe the phenomenon of acute leukemias that meet the standard French-American-British system criteria for a particular lineage (either lymphoid or myeloid) upon initial diagnosis, but meet the criteria for the opposite lineage at relapse. Many reports have documented conversions of acute lymphoblastic leukemia to acute myeloid leukemia. Here, we report the case of a 4-year-old child with acute myeloid leukemia, which upon relapse switched to acute lymphoblastic leukemia. The morphologic, phenotypic, and molecular features suggest the origin of a new leukemic clone.

Medical decision making: paternalism versus patient-centered (autonomous) care.

PURPOSE OF REVIEW: Medical literature has increasingly emphasized the need to observe patients' autonomy; however, not all experts agree with this principle. This discord is based on varying credence between the concepts of autonomy and beneficence. In critically ill patients, this conflict involves the patient's family and creates a particular family-physician relationship. The purpose of this review is to assess the evidence on medical decision making and the family-physician relationship. RECENT FINDINGS: The many studies published on this topic reveal that people's preferences around the medical decision-making process vary substantially. Although it is clear that a shared decision approach is popular and desirable to some, it is not universally favored; some patients prefer to leave final treatment decisions up to the doctor. This finding shows a robust moral pluralism, which requires special attention in multicultural societies. For critically ill patients, the diversity of opinion extends to the family, which creates a complex family-physician dynamic and necessitates utilization of particular interaction strategies. SUMMARY: Clinicians must understand the range of preferences in a society and should offer the opportunity to participate in treatment by sharing decision-making responsibility. This would involve assessing the preferences of patients and their families in order to provide care accordingly. Clinicians should then ensure proper information is provided for informed decision making and minimize factors that could have potential adverse effect.