Active Cytomegalovirus Infection in Patients with Septic Shock

Cytomegalovirus reactivation occurred in one third of patients and was associated with prolonged ventilation and stay in an intensive care unit

Compound Markov counting processes and their applications to modeling infinitesimally over-dispersed systems

We propose an infinitesimal dispersion index for Markov counting processes. We show that, under standard moment existence conditions, a process is infinitesimally (over-) equi-dispersed if, and only if, it is simple (compound), i.e. it increases in jumps of one (or more) unit(s), even though infinitesimally equi-dispersed processes might be under-, equi- or over-dispersed using previously studied indices. Compound processes arise, for example, when introducing continuous-time white noise to the rates of simple processes resulting in Levy-driven SDEs. We construct multivariate infinitesimally over-dispersed compartment models and queuing networks, suitable for applications where moment constraints inherent to simple processes do not hold.Comment: 26 page

Present state and future perspectives of using pluripotent stem cells in toxicology research

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed

Role of Interleukin 36γ in Host Defense Against Tuberculosis

Tuberculosis remains a major killer worldwide, not the least because of our incomplete knowledge of protective and pathogenic immune mechanism. The roles of the interleukin 1 (IL-1) and interleukin 18 pathways in host defense are well established, as are their regulation through the inflammasome complex. In contrast, the regulation of interleukin 36γ (IL-36γ), a recently described member of the IL-1 family, and its immunological relevance in host defense remain largely unknown. Here we show that Mycobacterium tuberculosis infection of macrophages induces IL-36γ production in a 2-stage-regulated fashion. In the first stage, microbial ligands trigger host Toll-like receptor and MyD88-dependent pathways, leading to IL-36γ secretion. In the second stage, endogenous IL-1β and interleukin 18 further amplify IL-36γ synthesis. The relevance of this cytokine in the control of M. tuberculosis is demonstrated by IL-36γ-induced antimicrobial peptides and IL-36 receptor-dependent restriction of M. tuberculosis growth. Thus, we provide first insight into the induction and regulation of the proinflammatory cytokine IL-36γ during tuberculosis

Actionable Nutrigenetics for Genetically Based Diseases? A New Critical Path to P4 Medicine

Nutrigenomics and nutrigenetics are receiving growing attention from a diverse range of stakeholders including health care professionals, citizens, governments, insurers and industry. Currently there is special focus on research on how our food influences us and might cause discomfort or even symptoms of disease, but also the fact that several food intolerances are caused by genetic alterations. The strong interest expressed by certain segments of the general population for predictive and preventive diagnostic testing in relation to diet and ways in which this can improve overall health led to a fast growing market of nutrigenetic based tests. This puts pressures and challenges on governments and insurers for how best to reimburse new genetic tests. These discussions are best informed by a sound understanding of nutrigenetics science and technology, its promises and challenges, which are addressed in this paper. For example, some of the most common food intolerances caused by genetic variations are lactose intolerance, inherited fructose intolerance, congenital sucrase isomaltase deficiency (sucrose intolerance), celiac disease, glucose-6-phosphate deficiency (favism), alcohol intolerance and hemochromatosis. The increasing understanding of molecular mechanisms associated with these conditions is stimulating the development of a broad range of diagnostics allowing any person with adequate resources to have their genetic predispositions determined. However, many of the currently available tests cover only one of the above mentioned diseases or a small set of responsible mutations, which is in strong contrast to the evolution of medicine towards a more holistic approach as, for example, P4 medicine. Additionally, available tests are often not based on evidence or other guidelines for genetic test development as recommended by the ACCE evidentiary framework. In this paper we discuss the most common nutrigenetic diseases and their potential and demonstrated impacts on public health, as well as ways to devise personalized diet informed by human genomics variation in the future