Prekallikrein inhibits innate immune signaling in the lung and impairs host defense during pneumosepsis in mice

Prekallikrein (PKK, also known as Fletcher factor and encoded by the gene KLKB1 in humans) is a component of the contact system. Activation of the contact system has been implicated in lethality in fulminant sepsis models. Pneumonia is the most frequent cause of sepsis. We sought to determine the role of PKK in host defense during pneumosepsis. To this end, mice were infected with the common human pathogen Klebsiella pneumoniae via the airways, causing an initially localized infection of the lungs with subsequent bacterial dissemination and sepsis. Mice were treated with a selective PKK-directed antisense oligonucleotide (ASO) or a scrambled control ASO for 3 weeks prior to infection. Host response readouts were determined at 12 or 36 h post-infection, including genome-wide messenger RNA profiling of lungs, or mice were followed for survival. PKK ASO treatment inhibited constitutive hepatic Klkb1 mRNA expression by >80% and almost completely abolished plasma PKK activity. Klkb1 mRNA could not be detected in lungs. Pneumonia was associated with a progressive decline in PKK expression in mice treated with control ASO. PKK ASO administration was associated with a delayed mortality, reduced bacterial burdens, and diminished distant organ injury. While PKK depletion did not influence lung pathology or neutrophil recruitment, it was associated with an upregulation of multiple innate immune signaling pathways in the lungs already prior to infection. Activation of the contact system could not be detected, either during infection in vivo or at the surface of Klebsiella in vitro. These data suggest that circulating PKK confines pro-inflammatory signaling in the lung by a mechanism that does not involve contact system activation, which in the case of respiratory tract infection may impede early protective innate immunity. © 2019 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Socio-demographic and modifiable risk factors of diabetes and hypertension among resource constrained patients from rural areas in Mdantsane Township in South Africa

BackgroundRecently, developing countries have shown a dramatic increase in non-communicable diseases (NCDs). The burden of NCDs in South Africa has increased over the past years resulting in an estimated 37% of all- cause mortality and 16% of disability-adjusted life years. Currently, diabetes mellitus (DM) and hypertension (HTN) are the two most prevalent NCDs associated with the rapid increase in mortality.ObjectiveTo demonstrate the socio-demographic and modifiable risk factors of diabetes mellitus (DM) and hypertension (HTN) among South African adults.MethodsA cross-sectional analytical study was conducted in the Cecilia Makiwane Hospital serving the residents of Mdantsane. Relevant socio-demographic data, anthropometric measurements, triplicate blood pressure, fasting blood glucose and lipogram analysis were obtained from 265 outpatients.ResultsMultivariate anlysis shows that; salt intake, smoking, elevated triglycerides and decreased high-density lipoprotein levels were significantly associated with DM with adjusted odds ratio of 0.18 (p=0.002), 0.26 (p=0.048), 2.19 (p=0.006) and 0.38 (p=0.001), respectively. Overweight and obesity were significantly associated with hypertension with odds ratio of 0.03 (p=0.01) and 0.06 (p=0.006), respectively.ConclusionThe burden of DM and HTN on society can be drastically reduced with simple lifestyle changes, development of preventative strategies, large-scale screening and better disease management in South Africa.     

ImmunoGlobulin galaxy (IGGalaxy) for simple determination and quantitation of immunoglobulin heavy chain rearrangements from NGS

Background

Toxic shock syndrome (TSS) is caused by an overwhelming host-mediated response to bacterial superantigens produced mainly by Staphylococcus aureus and Streptococcus pyogenes. TSS is characterized by aberrant activation of T cells and excessive release of pro-inflammatory cytokines ultimately resulting in capillary leak, septic shock, multiple organ dysfunction and high mortality rates. No therapeutic or vaccine has been approved by the U.S. Food and Drug Administration for TSS, and novel therapeutic strategies to improve clinical outcome are needed. Mesenchymal stromal (stem) cells (MSCs) are stromal cells capable of self-renewal and differentiation. Moreover, MSCs have immunomodulatory properties, including profound effects on activities of T cells and macrophages in specific contexts. Based on the critical role of host-derived immune mediators in TSS, we hypothesized that MSCs could modulate the host-derived proinflammatory response triggered by Staphylococcal enterotoxin B (SEB) and improve survival in experimental TSS.

Methods

Effects of MSCs on proinflammatory cytokines in peripheral blood were measured in wild-type C57BL/6 mice injected with 50 μg of SEB. Effects of MSCs on survival were monitored in fatal experimental TSS induced by consecutive doses of D-galactosamine (10 mg) and SEB (10 μg) in HLA-DR4 transgenic mice.

Results

Despite significantly decreasing serum levels of IL-2, IL-6 and TNF induced by SEB in wild-type mice, human MSCs failed to improve survival in experimental TSS in HLA-DR4 transgenic mice. Similarly, a previously described downstream mediator of human MSCs, TNF-stimulated gene 6 (TSG-6), did not significantly improve survival in experimental TSS. Furthermore, murine MSCs, whether unstimulated or pre-treated with IFNγ, failed to improve survival in experimental TSS.

Conclusions

Our results suggest that the immunomodulatory effects of MSCs are insufficient to rescue mice from experimental TSS, and that mediators other than IL-2, IL-6 and TNF are likely to play critical mechanistic roles in the pathogenesis of experimental TSS.     

Corporate law and corporate psychopaths

For more than three decades there has been a growing interest, and concern, in the role that psychopathy plays in corporate affairs. The literature in this field is essentially interdisciplinary, drawing heavily on advances in neuroscience, behavioural and organisational psychology and criminology. In this paper, the authors open a line of enquiry on the role that law can play in the regulation, and remedies, available to deal with dysfunctional and psychopathic management. In this paper we argue that the impact of corporate psychopaths – particularly the sub-clinical types – is sometimes potentially devastating for the organisation, its mission, its employees and, where they exist, shareholders. In this article we outline the nature of corporate psychopathy and its impact on corporate entities and outline a range of potential legal remedies.     

Mucosal colonic tube fistula with antireflux wrap for antegrade colonic enema

Antegrade enemas can provide children with excellent faecal continence in situations where adequate control has been compromised because of underlying congential anomaly or poor surgical outcome in their treatment. The enema is often delivered through an appendicostomy. If the appendix is absent or utilized for another purpose, then placement of a chait tube or caecostomy button can provide access to the colon for the enema. However, these devices may be associated with breakages, accidental removal and leakage and replacement may require another operative procedure under a general anaesthetic. Full thickness colonic tubes can also be constructed at any point along the colon but in the author’s experience, they can be associated with significant leakage of both gas and faecal material. The construction of a mucosal colonic tube with anti-reflux wrap is a technique that avoids the above problems and offers a distinctive advantage in selected situations. The technique relies on tabularising mucosa alone to create a continent fistula. Six children with severe soiling underwent the technique. The outcomes were evaluated using a modified quality of life score (QOLI) [1, 2]. The score included assessment of soiling, staining, odour, self-esteem and socialization measure. Technical evaluation included analysis of the ease of catheterization and continence of the mucosal fistula site. All six patients had dramatic improvement in their faecal continence with complete resolution of soiling in all six. Follow up median is 42 months and the range is 6–48 months. QOLI scores improved from a total of 4.75 to 18.5. Possible range is 0–21. All the six fistula sites catheterize easily and no stenosis or faecal leakage has occurred. Two patients required treatment of minor granulations at the entry site of the fistula during the early healing phase.