Activation of the innate immune receptor Dectin-1 upon formation of a 'phagocytic synapse'.

Innate immune cells must be able to distinguish between direct binding to microbes and detection of components shed from the surface of microbes located at a distance. Dectin-1 (also known as CLEC7A) is a pattern-recognition receptor expressed by myeloid phagocytes (macrophages, dendritic cells and neutrophils) that detects β-glucans in fungal cell walls and triggers direct cellular antimicrobial activity, including phagocytosis and production of reactive oxygen species (ROS). In contrast to inflammatory responses stimulated upon detection of soluble ligands by other pattern-recognition receptors, such as Toll-like receptors (TLRs), these responses are only useful when a cell comes into direct contact with a microbe and must not be spuriously activated by soluble stimuli. In this study we show that, despite its ability to bind both soluble and particulate β-glucan polymers, Dectin-1 signalling is only activated by particulate β-glucans, which cluster the receptor in synapse-like structures from which regulatory tyrosine phosphatases CD45 and CD148 (also known as PTPRC and PTPRJ, respectively) are excluded (Supplementary Fig. 1). The 'phagocytic synapse' now provides a model mechanism by which innate immune receptors can distinguish direct microbial contact from detection of microbes at a distance, thereby initiating direct cellular antimicrobial responses only when they are required

Mineral analysis of complete dog and cat foods in the UK and compliance with European guidelines

Mineral content of complete pet food is regulated to ensure health of the companion animal population. Analysis of adherence to these regulatory guidelines has not been conducted. Here, mineral composition of complete wet (n = 97) and dry (n = 80) canine and feline pet food sold in the UK was measured to assess compliance with EU guidelines. A majority of foods complied with ≥8 of 11 guidelines (99% and 83% for dry and wet food, respectively), but many failed to provide nutritional minimum (e.g. Cu, 20% of wet food) or exceeded nutritional maximum (e.g. Se, 76% of wet food). Only 6% (6/97) of wet and 38% (30/80) of dry food were fully compliant. Some foods (20–30% of all analysed) had mineral imbalance, such as not having the recommended ratio of Ca:P (between 1:1 to 2:1). Foods with high fish content had high levels of undesirable metal elements such as arsenic. This study highlights broad non-compliance of a range of popular pet foods sold in the UK with EU guidelines (94% and 61% of wet and dry foods, respectively). If fed exclusively and over an extended period, a number of these pet foods could impact the general health of companion animals

Hospital characteristics associated with highly automated and usable clinical information systems in Texas, United States

<p>Abstract</p> <p>Background</p> <p>A hospital's clinical information system may require a specific environment in which to flourish. This environment is not yet well defined. We examined whether specific hospital characteristics are associated with highly automated and usable clinical information systems.</p> <p>Methods</p> <p>This was a cross-sectional survey of 125 urban hospitals in Texas, United States using the Clinical Information Technology Assessment Tool (CITAT), which measures a hospital's level of automation based on physician interactions with the information system. Physician responses were used to calculate a series of CITAT scores: automation and usability scores, four automation sub-domain scores, and an overall clinical information technology (CIT) score. A multivariable regression analysis was used to examine the relation between hospital characteristics and CITAT scores.</p> <p>Results</p> <p>We received a sufficient number of physician responses at 69 hospitals (55% response rate). Teaching hospitals, hospitals with higher IT operating expenses (>$1 million annually), IT capital expenses (>$75,000 annually) and hospitals with larger IT staff (≥ 10 full-time staff) had higher automation scores than hospitals that did not meet these criteria (p < 0.05 in all cases). These findings held after adjustment for bed size, total margin, and ownership (p < 0.05 in all cases). There were few significant associations between the hospital characteristics tested in this study and usability scores.</p> <p>Conclusion</p> <p>Academic affiliation and larger IT operating, capital, and staff budgets are associated with more highly automated clinical information systems.</p

Mucopolysaccharidosis type IIIB may predominantly present with an attenuated clinical phenotype

Mucopolysaccharidosis type IIIB (MPS IIIB, Sanfilippo syndrome type B) is a lysosomal storage disorder caused by deficiency of the enzyme N-acetyl-α-D-glucosaminidase (NAGLU). Information on the natural course of MPS IIIB is scarce but much needed in view of emerging therapies. To improve knowledge on the natural course, data on all 52 MPS IIIB patients ever identified by enzymatic studies in the Netherlands were gathered. Clinical data on 44 patients could be retrieved. Only a small number (n = 9; 21%) presented with a classical MPS III phenotype; all other patients showed a much more attenuated course of the disease characterized by a significantly slower regression of intellectual and motor abilities. The majority of patients lived well into adulthood. First signs of the disease, usually mild developmental delay, were observed at a median age of 4 years. Subsequently, patients showed a slowing and eventually a stagnation of development. Patients with the attenuated phenotype had a stable intellectual disability for many years. Molecular analysis was performed in 24 index patients. The missense changes p.R643C, p.S612G, p.E634K, and p.L497V were exclusively found in patients with the attenuated phenotype. MPS IIIB comprises a remarkably wide spectrum of disease severity, and an unselected cohort including all Dutch patients showed a large proportion (79%) with an attenuated phenotype. MPS IIIB must be considered in patients with a developmental delay, even in the absence of a progressive decline in intellectual abilities. A key feature, necessitating metabolic studies, is the coexistence of behavioral problems

Value of Laboratory Tests in Employer-Sponsored Health Risk Assessments for Newly Identifying Health Conditions: Analysis of 52,270 Participants

Employer-sponsored health risk assessments (HRA) may include laboratory tests to provide evidence of disease and disease risks for common medical conditions. We evaluated the ability of HRA-laboratory testing to provide new disease-risk information to participants.We performed a cross-sectional analysis of HRA-laboratory results for participating adult employees and their eligible spouses or their domestic partners, focusing on three common health conditions: hyperlipidemia, diabetes mellitus, and chronic kidney disease. HRA with laboratory results of 52,270 first-time participants were analyzed. Nearly all participants had access to health insurance coverage. Twenty-four percent (12,392) self-reported one or more of these medical conditions: 21.1% (11,017) self-identified as having hyperlipidemia, 4.7% (2,479) self-identified as having diabetes, and 0.7% (352) self-identified as having chronic kidney disease. Overall, 36% (n = 18,540) of participants had laboratory evidence of at least one medical condition newly identified: 30.7% (16,032) had laboratory evidence of hyperlipidemia identified, 1.9% (984) had laboratory evidence of diabetes identified, and 5.5% (2,866) had laboratory evidence of chronic kidney disease identified. Of all participants with evidence of hyperlipidemia 59% (16,030 of 27,047), were newly identified through the HRA. Among those with evidence of diabetes 28% (984 of 3,463) were newly identified. The highest rate of newly identified disease risk was for chronic kidney disease: 89% (2,866 of 3,218) of participants with evidence of this condition had not self-reported it. Men (39%) were more likely than women (33%) to have at least one newly identified condition (p<0.0001). Among men, lower levels of educational achievement were associated with modestly higher rates of newly identified disease risk (p<0.0001); the association with educational achievement among women was unclear. Even among the youngest age range (20 to 29 year olds), nearly 1 in 4 participants (24%) had a newly identified risk for disease.These results support the important role of employer-sponsored laboratory testing as an integral element of HRA for identifying evidence of previously undiagnosed common medical conditions in individuals of all working age ranges, regardless of educational level and gender

Dectin-1: a role in antifungal defense and consequences of genetic polymorphisms in humans

The clinical relevance of fungal infections has increased dramatically in recent decades as a consequence of the rise of immunocompromised populations, and efforts to understand the underlying mechanisms of protective immunity have attracted renewed interest. Here we review Dectin-1, a pattern recognition receptor involved in antifungal immunity, and discuss recent discoveries of polymorphisms in the gene encoding this receptor which result in human disease

Host genetic signatures of susceptibility to fungal disease

Our relative inability to predict the development of fungal disease and its clinical outcome raises fundamental questions about its actual pathogenesis. Several clinical risk factors are described to predispose to fungal disease, particularly in immunocompromised and severely ill patients. However, these alone do not entirely explain why, under comparable clinical conditions, only some patients develop infection. Recent clinical and epidemiological studies have reported an expanding number of monogenic defects and common polymorphisms associated with fungal disease. By directly implicating genetic variation in the functional regulation of immune mediators and interacting pathways, these studies have provided critical insights into the human immunobiology of fungal disease. Most of the common genetic defects reported were described or suggested to impair fungal recognition by the innate immune system. Here, we review common genetic variation in pattern recognition receptors and its impact on the immune response against the two major fungal pathogens Candida albicans and Aspergillus fumigatus. In addition, we discuss potential strategies and opportunities for the clinical translation of genetic information in the field of medical mycology. These approaches are expected to transfigure current clinical practice by unleashing an unprecedented ability to personalize prophylaxis, therapy and monitoring for fungal disease.This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to AC, and SFRH/BPD/96176/2013 to CC), the Institut Mérieux (Mérieux Research Grant 2017 to CC), and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID Research Grant 2017 to AC)

Role of deficits in pathogen recognition receptors in infection susceptibility

This work was supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (FCT) (IF/00735/2014 to A.C. and SFRH/BPD/96176/2013 to C.C.

Latitudinal gradient in dairy production with the introduction of farming in Atlantic Europe

International audienceThe introduction of farming had far-reaching impacts on health, social structure and demography. Although the spread of domesticated plants and animals has been extensively tracked, it is unclear how these nascent economies developed within different environmental and cultural settings. Using molecular and isotopic analysis of lipids from pottery, here we investigate the foods prepared by the earliest farming communities of the European Atlantic seaboard. Surprisingly, we find an absence of aquatic foods, including in ceramics from coastal sites, except in the Western Baltic where this tradition continued from indigenous ceramic using hunter-gatherer-fishers. The frequency of dairy products in pottery increased as farming was progressively introduced along a northerly latitudinal gradient. This finding implies that early farming communities needed time to adapt their economic practices before expanding into more northerly areas. Latitudinal differences in the scale of dairy production might also have influenced the evolution of adult lactase persistence across Europe