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

The autoimmune disease, type 1 diabetes, presents a unique set of challenges to the clinical scientist trying to understand its aetiology. The β cells of the islets of Langerhans, which represent the immune system's target, are located within the pancreas, one of the more inaccessible organs in the body. The islets are too small to be imaged reliably with current technologies. It is estimated that approximately 1 million islet clusters, comprised of 1–2000 β cells each, are scattered throughout the pancreas, surrounded by exocrine cells and ducts filled with proteolytic enzymes. These enzymes are responsible for both the tendency of the pancreas to undergo rapid autolysis after death and for the inherent danger of pancreatic biopsy, which is considered widely as too hazardous a procedure for mere research purposes, even if inclusion of islets in the tissue sample could be guaranteed. To add to the problems of obtaining tissue for research, major advances in protocols for the management of disease at first clinical presentation and a greater public and physician awareness of the symptoms and signs of hyperglycaemia over recent decades have reduced the incidence of acutely fatal type 1 diabetes to a negligible level and hence all but ended the supply of diseased organs for study. Small wonder that there are so many unknowns in this disease.

Against this backdrop, a paper in the current issue of Clinical & Experimental Immunology [1] offers a unique insight into many hotly debated issues in this field, while inevitably raising several more. Willcox et al. [1] obtained what is probably the largest and most complete collection of post-mortem pancreatic organs from patients with type 1 diabetes, including many cases close to onset. These were assembled by one of the co-authors on the current paper, Alan Foulis, during the 1980s, through painstaking collection of paraffin blocks from post-mortem analyses conducted during the 25-year period from 1959 to 1984 in the United Kingdom [2]. The outcome is a definitive study of the lymphocytic infiltrates in the immediate microenvironment of the β cells as they are killed during the evolution of type 1 diabetes. Has the murderer been caught red-handed?

Post-mortem analysis of islet pathology in type 1 diabetes illuminates the life and death of the β cell

The development of the mucosal immune system in the human fetus has been studied in some detail. Aggregates of T and B cells form early Peyer's patches by 16 weeks gestation and by 19 weeks organised Peyer's patches with T and B cell zones are seen. T cells populate the mucosal lamina propria and epithelium from 11 weeks gestation and increase in number thereafter. As in the adult, most intraepithelial lymphocytes are CD8+ and most lamina propria T cells are CD4+. By 20 weeks, villus epithelial cells are HLA-DR+ and secretory component is also expressed. In the absence of lumenal stimulation in the fetus there is no intestinal secretory IgA antibody response. A few IgA plasma cells are present in fetal salivary glands but the number does not dramatically increase until after birth.

Ontogenetic aspects of the intestinal immune system in man

Human T-cell receptor expression

B cells are present in human fetal intestine from approximately 14 weeks of gestation. Here we show that this population includes mature, dividing B cells. These are large cells with dendritic processes, resembling human thymic B cells. In addition, we observed IgM+, light chain-, and CD20- cells and local expression of V pre-B, demonstrating that the human fetal intestine is a site of B cell development. Ig V(H)DJ(H) gene sequencing can confirm clonal identity of B cells. Identification of the same IgV(H)4-34 sequence in serial sections in two fetuses confirmed local accumulation of related cells in each case. IgV(H)4-34 was also amplified from an additional two samples, and the D and J repertoire compared with a unique database of unselected V(H)4-34 genes from postnatal gut. Distinguishing characteristics of Ig lambda genes in postnatal gut were also studied in the fetus. According to these parameters, fetal and postnatal B cells are unrelated.

https://jlb.onlinelibrary.wiley.com/doi/pdf/10.1189/jlb.72.2.279

B cell development and proliferation of mature B cells in human fetal intestine.

Previous studies have suggested that the gut-associated lymphoid tissue (GALT) of man is distinct from that of laboratory animals, but it is not clear whether this is due to environmental or true species difference. We have made a comparative study of rats and baboons because, like rats, baboons are herbivorous and relatively unhygienic but they are phylogenetically much more closely related to man.

Jo Spencer

Papers

Post-mortem analysis of islet pathology in type 1 diabetes illuminates the life and death of the β cell

Ontogenetic aspects of the intestinal immune system in man

Human T-cell receptor expression

B cell development and proliferation of mature B cells in human fetal intestine.

A comparative study of the gut-associated lymphoid tissue of primates and rodents.