The anti-inflammatory activities of Staphylococcus aureus

Staphylococcus aureus is a versatile and harmful pathogen in both hospital- and community-associated infections that range from superficial to systemic infections. S. aureus engages a multitude of mechanisms to subvert the innate immune response of the host, including inhibition of complement activation and neutralization of anti-microbial peptides. In addition, inflammatory cell and phagocyte recruitment is an integral part of the innate defense to staphylococcal infection and comprises a well-coordinated multi-step cascade of adhesive events. Recent and rapidly growing experimental evidence indicates the existence of a machinery of anti-adhesive and anti-chemotactic moieties of S. aureus that allow the bacterium to interfere with specific adhesive steps of the homing mechanism of leukocytes. Understanding the functions of these S. aureus-derived anti-inflammatory agents could also provide the platform for designing new therapies in several inflammatory and autoimmune diseases.     

Junctional adhesion molecule-C regulates vascular endothelial permeability by modulating VE-cadherin-mediated cell-cell contacts

We recently reported that junctional adhesion molecule (JAM)-C plays a role in leukocyte transendothelial migration. Here, the role of JAM-C in vascular permeability was investigated in vitro and in vivo. As opposed to macrovascular endothelial cells that constitutively expressed JAM-C in cell-cell contacts, in quiescent microvascular endothelial cells, JAM-C localized mainly intracellularly, and was recruited to junctions upon short-term stimulation with vascular endothelial growth factor (VEGF) or histamine. Strikingly, disruption of JAM-C function decreased basal permeability and prevented the VEGF- and histamine-induced increases in human dermal microvascular endothelial cell permeability in vitro and skin permeability in mice. Permeability increases are essential in angiogenesis, and JAM-C blockade reduced hyperpermeability and neovascularization in hypoxia-induced retinal angiogenesis in mice. The underlying mechanisms of the JAM-C-mediated increase in endothelial permeability were studied. JAM-C was essential for the regulation of endothelial actomyosin, as revealed by decreased F-actin, reduced myosin light chain phosphorylation, and actin stress fiber formation due to JAM-C knockdown. Moreover, the loss of JAM-C expression resulted in stabilization of VE-cadherin-mediated interendothelial adhesion in a manner dependent on the small GTPase Rap1. Together, through modulation of endothelial contractility and VE-cadherin-mediated adhesion, JAM-C helps to regulate vascular permeability and pathologic angiogenesis.     

Scaling rules for diffusive drug delivery in tumor and normal tissues

Delivery of blood-borne molecules and nanoparticles from the vasculature to cells in the tissue differs dramatically between tumor and normal tissues due to differences in their vascular architectures. Here we show that two simple measures of vascular geometry--δ(max) and λ--readily obtained from vascular images, capture these differences and link vascular structure to delivery in both tissue types. The longest time needed to bring materials to their destination scales with the square of δ(max), the maximum distance in the tissue from the nearest blood vessel, whereas λ, a measure of the shape of the spaces between vessels, determines the rate of delivery for shorter times. Our results are useful for evaluating how new therapeutic agents that inhibit or stimulate vascular growth alter the functional efficiency of the vasculature and more broadly for analysis of diffusion in irregularly shaped domains.     

Vulvovaginitis: clinical features, aetiology, and microbiology of the genital tract.

AIM: To clarify the contribution of clinical and environmental factors and infection to the aetiology of vulvovaginitis in premenarchal girls, and to determine clinical indicators of an infectious cause. DESIGN: It was necessary first to define normal vaginal flora. Cases were 50 premenarchal girls > 2 years old with symptoms of vulvovaginitis; 50 controls were recruited from girls in the same age group undergoing minor or elective surgery. RESULTS: Interview questionnaire showed no difference between cases and controls in regards to hygiene practices, exposure to specific irritants, or history of possible sexual abuse. Normal vaginal flora was similar to that described in previous studies, with the exception of organisms likely to be associated with sexual activity. 80% of cases had no evidence of an infectious cause. In the 10 cases in whom an infectious cause was found, there was significantly more visible discharge and distinct redness of the genital area on examination compared with other cases. CONCLUSIONS: The findings suggest that vulvovaginitis in this age group is not usually infectious or necessarily related to poor hygiene, specific irritants or sexual abuse, although any of these can present with genital irritation. The possibility of sexual abuse should always be considered when a child presents with genital symptoms, but our data indicate it is not a common contributing factor. Infection is generally associated with vaginal discharge and moderate or severe inflammation.     

Use of retail data in the assessment of natural experiments: the case of Reducing the Strength,an intervention to reduce alcohol availability

BackgroundRetailers routinely collect data about people's purchasing behaviours and access to consumer products associated with health and wellbeing. Here we discuss how retail data can be used in public health research and consider potential strengths and limitations to such research. To illustrate the discussion we refer to an evaluation of an intervention called Reducing the Strength, whereby off-licence shops and supermarkets voluntarily stopped selling inexpensive superstrength (≥6·5% alcohol by volume) beers and ciders.MethodsMonthly data from a large retail chain (East of England Co-operative Society) were obtained for three UK counties (141 stores). In one county the intervention started 12 months earlier than the others, allowing for a pre–post study design with a delayed implementation comparator. Difference-in-differences analysis of unit alcohol sales controlled for socioenvironmental confounders and shop-level characteristics including shop size, parking facilities, cash machines, opening hours, and other factors.FindingsThe retail data detailed shop-level characteristics and sales data such as prices, quantities, product brands, alcohol content, sales, and factors affecting sales. The wide geographical coverage, shop-level data, including data for potential confounding factors, and frequent timepoints made the retail data well-suited for a quasi-experimental evaluation capitalising on temporal and spatial variations in intervention exposure. Limitations of this study include a lack of longitudinal data for individual customers, and shops that are not covered by the data. Qualitative interviews with shop workers and customers, and triangulation using alternative data sources can help to address limitations. Alternative sources of retail data such as private sector consultants who specialise in collecting shop-level and sales data for a range of companies might also address some limitations; however, there are potential barriers of expense, accessibility, and coverage associated with the use of such consultants.InterpretationIncreasingly, researchers recognise the potential of retail data for evaluating interventions affecting social determinants of health and inequalities, such as local access to alcohol. However, shop-level data have frequently proved difficult for researchers to obtain. By obtaining such data we have been able to assess, using a quasi-experimental design, the effects of removing strong, cheap beers and ciders from shops. We have also been able to explore in more detail how to optimise the strengths and address some limitations of the data in ways that could potentially assist others planning to use this important data source in their research.FundingThe study is funded as part of the School of Public Health Research by NHS National Institute of Health Research. AJ, SA, and JW contributed as employees of Public Health Suffolk, Suffolk County Council.     

Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is physically palpated as a hard tumor with an unfavorable prognosis. Assessing physical features and their association with pathological features could help to elucidate the mechanism of physical abnormalities in cancer tissues. A total of 93 patients who underwent radical surgery for pancreatic and bile duct cancers at a single center hospital during a 28-month period were recruited for this study that aimed to estimate the stiffness of PDAC tissues compared to the other neoplasms and assess relationships between tumor stiffness and pathological features. Physical alterations and pathological features of PDAC, with or without preoperative therapy, were analyzed. The immunological tumor microenvironment was evaluated using multiplexed fluorescent immunohistochemistry. The stiffness of PDAC correlated with the ratio of Azan-Mallory staining, α-smooth muscle actin, and collagen I-positive areas of the tumors. Densities of CD8⁺ T cells and CD204⁺ macrophages were associated with tumor stiffness in cases without preoperative therapy. Pancreatic ductal adenocarcinoma treated with preoperative therapy was softer than that without, and the association between tumor stiffness and immune cell infiltration was not shown after preoperative therapy. We observed the relationship between tumor stiffness and immunological features in human PDAC for the first time. Immune cell densities in the tumor center were smaller in hard tumors than in soft tumors without preoperative therapies. Preoperative therapy could alter physical and immunological aspects, warranting further study. Understanding of the correlations between physical and immunological aspects could lead to the development of new therapies.     

Neurological adverse events post allogeneic hematopoietic cell transplantation: major determinants of morbidity and mortality

Journal of Neurology - Despite advances in the field, diagnosis and management of the wide spectrum of neurological events post allogeneic hematopoietic cell transplantation (alloHCT) remain...