To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012”. A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict-of-interest (COI) policy was developed at the onset of the process and enforced throughout. A stand-alone meeting was held for all panel members in December 2015. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The panel consisted of five sections: hemodynamics, infection, adjunctive therapies, metabolic, and ventilation. Population, intervention, comparison, and outcomes (PICO) questions were reviewed and updated as needed, and evidence profiles were generated. Each subgroup generated a list of questions, searched for best available evidence, and then followed the principles of the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system to assess the quality of evidence from high to very low, and to formulate recommendations as strong or weak, or best practice statement when applicable. The Surviving Sepsis Guideline panel provided 93 statements on early management and resuscitation of patients with sepsis or septic shock. Overall, 32 were strong recommendations, 39 were weak recommendations, and 18 were best-practice statements. No recommendation was provided for four questions. Substantial agreement exists among a large cohort of international experts regarding many strong recommendations for the best care of patients with sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for these critically ill patients with high mortality.

https://link.springer.com/content/pdf/10.1007%2Fs00134-017-4683-6.pdf

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016

The increased understanding of the immune mechanisms of rheumatoid arthritis has led to the development of a considerable number of new therapeutic agents that alter the natural history of the disease and reduce mortality.

/pdf/the-pathogenesis-of-rheumatoid-arthritis-5ec7s76zig.pdf

The pathogenesis of rheumatoid arthritis.

The hepatic stellate cell has surprised and engaged physiologists, pathologists, and hepatologists for over 130 years, yet clear evidence of its role in hepatic injury and fibrosis only emerged following the refinement of methods for its isolation and characterization. The paradigm in liver injury of activation of quiescent vitamin A-rich stellate cells into proliferative, contractile, and fibrogenic myofibroblasts has launched an era of astonishing progress in understanding the mechanistic basis of hepatic fibrosis progression and regression. But this simple paradigm has now yielded to a remarkably broad appreciation of the cell's functions not only in liver injury, but also in hepatic development, regeneration, xenobiotic responses, intermediary metabolism, and immunoregulation. Among the most exciting prospects is that stellate cells are essential for hepatic progenitor cell amplification and differentiation. Equally intriguing is the remarkable plasticity of stellate cells, not only in their variable intermediate filament phenotype, but also in their functions. Stellate cells can be viewed as the nexus in a complex sinusoidal milieu that requires tightly regulated autocrine and paracrine cross-talk, rapid responses to evolving extracellular matrix content, and exquisite responsiveness to the metabolic needs imposed by liver growth and repair. Moreover, roles vital to systemic homeostasis include their storage and mobilization of retinoids, their emerging capacity for antigen presentation and induction of tolerance, as well as their emerging relationship to bone marrow-derived cells. As interest in this cell type intensifies, more surprises and mysteries are sure to unfold that will ultimately benefit our understanding of liver physiology and the diagnosis and treatment of liver disease.

/pdf/hepatic-stellate-cells-protean-multifunctional-and-enigmatic-1ctrvjmfhn.pdf

Hepatic Stellate Cells: Protean, Multifunctional, and Enigmatic Cells of the Liver

Objective:To provide an update to “Surviving Sepsis Campaign Guidelines for Management of Sepsis and Septic Shock: 2012.”Design:A consensus committee of 55 international experts representing 25 international organizations was convened. Nominal groups were assembled at key international meetings (for

Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016.

Eukaryotic cells can initiate several distinct programmes of self-destruction, and the nature of the cell death process (non-inflammatory or proinflammatory) instructs responses of neighbouring cells, which in turn dictates important systemic physiological outcomes Pyroptosis, or caspase 1-dependent cell death, is inherently inflammatory, is triggered by various pathological stimuli, such as stroke, heart attack or cancer, and is crucial for controlling microbial infections Pathogens have evolved mechanisms to inhibit pyroptosis, enhancing their ability to persist and cause disease Ultimately, there is a competition between host and pathogen to regulate pyroptosis, and the outcome dictates life or death of the host

/pdf/pyroptosis-host-cell-death-and-inflammation-4f2vauj8tx.pdf

Pyroptosis: host cell death and inflammation

We performed a detailed histological and immunohistological study on both fresh-frozen and paraffin-embedded tissue from full-thickness jejunal biopsy specimens taken from three patients with immunoproliferative small-intestinal disease (IPSID). In all three patients, the mucosal infiltrate consisted of "centrocyte-like" (CCL) cells forming lymphoepithelial lesions and plasma cells. In one patient, the mucosal infiltrate was strikingly follicular. Immunohistochemistry showed alpha 1 heavy chain, but no light chain, in the perinuclear space and cytoplasm of the CCL cells and in the plasma cells. In two patients, the plasma cells (but not the CCL cells) also contained alpha 2 heavy chain. In the case showing a follicular pattern, the extrafollicular CCL cells and most of the cells within the mucosal follicles expressed alpha 1 heavy chain, but a minor and variable population of cells expressed polytypic IgM. The dendritic reticulum cells stained for alpha 1 (but not alpha 2) heavy chain, mu chain, and both light chains. In all cases, the CCL cells did not stain for common acute lymphoblastic leukaemia antigen (CALLA); in the follicles, CALLA negative cells displaced a residual CALLA-positive population to the periphery and merged with the CALLA negative cells outside the follicles. These findings confirm the homology between IPSID and low-grade B-cell "Western" lymphomas arising in mucosa-associated lymphoid tissue; they suggest that the follicular pattern sometimes seen in these lymphomas is caused by selective colonization of reactive follicles by CCL tumor cells.

Immunoproliferative small-intestinal disease. An immunohistochemical study.

Lymphomas of the gastrointestinal tract, salivary glands, lung and thyroid are grouped together as tumours arising in mucosa-associated lymphoid tissue. The great majority of them are of B-cell origin but distinctive T-cell lymphomas are also recognized in the gastrointestinal tract. These lymphomas tend to remain localized for prolonged periods but, whereas the B-cell group respond favourably to local therapy, the T-cell group are associated with severe morbidity and their overall prognosis is extremely poor. Accepted histological classifications of non-Hodgkin's lymphomas are difficult to apply to these tumours. In this paper their morphological features are reviewed; recent findings based on immunohistochemistry and DNA analysis are presented; and the biological behaviour of these tumours is discussed insofar as they offer insight into mucosal immunological mechanisms.

Malignant lymphoma of mucosa‐associated lymphoid tissue

The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori

Background
Follicular structures resembling germinal centres (GCs) that are characterized by follicular dendritic cell (FDC) networks have long been recognized in chronically inflamed tissues in autoimmune diseases, including the synovium of rheumatoid arthritis (RA). However, it is debated whether these ectopic structures promote autoimmunity and chronic inflammation driving the production of pathogenic autoantibodies. Anti-citrullinated protein/peptide antibodies (ACPA) are highly specific markers of RA, predict a poor prognosis, and have been suggested to be pathogenic. Therefore, the main study objectives were to determine whether ectopic lymphoid structures in RA synovium: (i) express activation-induced cytidine deaminase (AID), the enzyme required for somatic hypermutation and class-switch recombination (CSR) of Ig genes; (ii) support ongoing CSR and ACPA production; and (iii) remain functional in a RA/severe combined immunodeficiency (SCID) chimera model devoid of new immune cell influx into the synovium.

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Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium

T cells in explants of human fetal small intestine in organ culture were stimulated in situ with PWM or anti-CD3 antibody to test the hypothesis that activated T cells produce enteropathy in human small intestine. T cell activation was measured by the appearance of CD25+ cells in the lamina propria of the explants and IL-2 production into the organ culture supernatant. We have previously shown that the number of T cells in human fetal gut increased between 14 and 22 wk gestation. Accordingly, after the addition of PWM to cultured explants of fetal intestine the number of CD25+ cells in the lamina propria and the amounts of IL-2 secreted into the organ culture supernatant increased with the age of the explanted tissue. The addition of PWM also produced an age-related enteropathy, most noticeably crypt epithelial cell hyperplasia and villous atrophy, with relatively minor changes in 14-17-wk-old intestine but severe tissue damage in 18-22-wk-old fetal intestine. These enteropathic effects were also produced when mucosal T cells were activated with anti-CD3 mAb. Cyclosporin A completely inhibited the PWM-induced development of CD25+ cells and related tissue damage. These experiments show that activated T cells in human small intestine produce enteropathy. The model provides a new system with which to dissect the mechanisms of T cell-mediated intestinal damage.

/pdf/evidence-that-activated-mucosal-t-cells-play-a-role-in-the-454dbik8x2.pdf

Jo Spencer

Papers

Immunoproliferative small-intestinal disease. An immunohistochemical study.

Malignant lymphoma of mucosa‐associated lymphoid tissue

The response of cells from low-grade B-cell gastric lymphomas of mucosa-associated lymphoid tissue to Helicobacter pylori

Ectopic Lymphoid Structures Support Ongoing Production of Class-Switched Autoantibodies in Rheumatoid Synovium

Evidence that activated mucosal T cells play a role in the pathogenesis of enteropathy in human small intestine.