Annette Plüddemann

Normal ranges of heart rate and respiratory rate in children from birth to 18 years of age: a systematic review of observational studies.

BACKGROUND Although heart rate and respiratory rate in children are measured routinely in acute settings, current reference ranges are not based on evidence. We aimed to derive new centile charts for these vital signs and to compare these centiles with existing international ranges. METHODS We searched Medline, Embase, CINAHL, and reference lists for studies that reported heart rate or respiratory rate of healthy children between birth and 18 years of age. We used non-parametric kernel regression to create centile charts for heart rate and respiratory rate in relation to age. We compared existing reference ranges with those derived from our centile charts. FINDINGS We identified 69 studies with heart rate data for 143,346 children and respiratory rate data for 3881 children. Our centile charts show decline in respiratory rate from birth to early adolescence, with the steepest fall apparent in infants under 2 years of age; decreasing from a median of 44 breaths per min at birth to 26 breaths per min at 2 years. Heart rate shows a small peak at age 1 month. Median heart rate increases from 127 beats per min at birth to a maximum of 145 beats per min at about 1 month, before decreasing to 113 beats per min by 2 years of age. Comparison of our centile charts with existing published reference ranges for heart rate and respiratory rate show striking disagreement, with limits from published ranges frequently exceeding the 99th and 1st centiles, or crossing the median. INTERPRETATION Our evidence-based centile charts for children from birth to 18 years should help clinicians to update clinical and resuscitation guidelines. FUNDING National Institute for Health Research, Engineering and Physical Sciences Research Council.

Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype.

Tumor-associated macrophages (TAM) may have tumor-promoting activity, but it is not clear how their phenotype is achieved. In this study, we demonstrate that ovarian cancer cells switch cocultured macrophages to a phenotype similar to that found in ovarian tumors. Tumor cells caused dynamic changes in macrophage cytokine, chemokine, and matrix metalloprotease mRNA, and protein-inducing mediators that are found in human cancer. Macrophage mannose, mannose receptor, and scavenger receptors (SR-As) were also up-regulated by coculture, but not by conditioned medium. To further validate the model, we studied SR-A regulation on TAM in vitro and in vivo. Coculture of murine macrophages from mice deficient in TNF-α or its receptors revealed that TNF-α was key to SR-A induction via its p75 receptor. SR-A expression was also reduced in TAM from ovarian cancers treated with anti-TNF-α Abs or grown in TNF-α−/− mice. Chemical communication between tumor cells and macrophages may be important in regulating the cancer cytokine microenvironment.

Macrophage heterogeneity in tissues: phenotypic diversity and functions.

During development and throughout adult life, macrophages derived from hematopoietic progenitors are seeded throughout the body, initially in the absence of inflammatory and infectious stimuli as tissue‐resident cells, with enhanced recruitment, activation, and local proliferation following injury and pathologic insults. We have learned a great deal about macrophage properties ex vivo and in cell culture, but their phenotypic heterogeneity within different tissue microenvironments remains poorly characterized, although it contributes significantly to maintaining local and systemic homeostasis, pathogenesis, and possible treatment. In this review, we summarize the nature, functions, and interactions of tissue macrophage populations within their microenvironment and suggest questions for further investigation.

Innate immunity to intracellular pathogens: macrophage receptors and responses to microbial entry

Summary:  Innate immunity to intracellular pathogens encompasses a range of interactions of cellular and humoral activities of the host with the invading microorganism, determining the outcome of infection. Here, we review the particular role of macrophage recognition receptors and effector responses in the uptake of microbes and their products. We place this in context and raise issues for discussion and further experimentation.

The interaction of macrophage receptors with bacterial ligands

Innate immune receptors play a key role in the early recognition of invading bacterial pathogens and initiate the crucial innate immune response. The diverse macrophage receptors recognise Gram-positive and Gram-negative bacteria via conserved structures on the bacterial surface and facilitate phagocytosis and/or signalling, providing the trigger for the adaptive immune response. These receptors include scavenger receptors, C-type lectins, integrins, Toll-like receptors and siglecs. The bacterial ligands generally recognised by these receptors range from lipopolysaccharides on Gram-negative bacteria to peptidoglycan and lipoteichoic acid on Gram-positive bacteria. However, emerging evidence indicates that bacterial proteins are also important ligands; for example, surface proteins from Neisseria meningitidis have been shown to be ligands for class A scavenger receptors. In addition, a group of cytosolic receptors, the NBS-LRR proteins, have been implicated in recognition of bacterial breakdown products. It is becoming increasingly apparent that macrophage receptors can act in conjunction with one another to deliver an appropriate response.

Current and future use of point-of-care tests in primary care: an international survey in Australia, Belgium, The Netherlands, the UK and the USA

Objective Despite the growing number of point-of-care (POC) tests available, little research has assessed primary care clinician need for such tests. We therefore aimed to determine which POC tests they actually use or would like to use (if not currently available in their practice). Design Cross-sectional survey. Setting Primary care in Australia, Belgium (Flanders region only), the Netherlands, the UK and the USA. Participants Primary care doctors (general practitioners, family physicians). Main measures We asked respondents to (1) identify conditions for which a POC test could help inform diagnosis, (2) from a list of tests provided: evaluate which POC tests they currently use (and how frequently) and (3) determine which tests (from that same list) they would like to use in the future (and how frequently). Results 2770 primary care clinicians across five countries responded. Respondents in all countries wanted POC tests to help them diagnose acute conditions (infections, acute cardiac disease, pulmonary embolism/deep vein thrombosis), and some chronic conditions (diabetes, anaemia). Based on the list of POC tests provided, the most common tests currently used were: urine pregnancy, urine leucocytes or nitrite and blood glucose. The most commonly reported tests respondents expressed a wish to use in the future were: D-dimer, troponin and chlamydia. The UK and the USA reported a higher actual and desired use for POC tests than Australia, Belgium and the Netherlands. Our limited data suggest (but do not confirm) representativeness. Conclusions Primary care clinicians in all five countries expressed a desire for POC tests to help them diagnose a range of acute and chronic conditions. Rates of current reported use and desired future use were generally high for a small selection of POC tests, but varied across countries. Future research is warranted to explore how specific POC tests might improve primary care.

Immune Inhibitory Ligand CD200 Induction by TLRs and NLRs Limits Macrophage Activation to Protect the Host from Meningococcal Septicemia

Macrophage activation is essential for protection against bacterial pathogens but needs to be regulated to prevent damage to the host. We show a key role for the immune inhibitory receptor CD200R and its ligand CD200 in the context of infection with the Gram-negative human pathogen Neisseria meningitidis. N. meningitidis induced CD200 but downregulated CD200R on macrophages in a manner dependent on Neisserial lipopolysaccharide, Toll-like receptor-4 (TLR-4), and the MyD88 pathway but independent of a known Neisserial receptor, scavenger receptor A (SR-A). Agonists of the pattern-recognition receptors nucleotide oligomerization domain 2 (NOD2) and NACHT-LRR protein 3 (NALP3) also induced CD200. The NF-κB member c-Rel was essential for TLR-, NOD2-, and NALP3-mediated induction of CD200. CD200(-/-) animals showed higher lethality in response to experimental meningococcal septicemia, induced higher levels of proinflammatory cytokines, and recruited increased numbers of activated leukocytes, despite comparable bacterial clearance. Thus CD200 is induced by TLR-, NOD2-, and NALP3-mediated pathways, limiting their function and protecting the host from excessive inflammation.

Macrophage Scavenger Receptor A Promotes Tumor Progression in Murine Models of Ovarian and Pancreatic Cancer

Alternatively activated macrophages express the pattern recognition receptor scavenger receptor A (SR-A). We demonstrated previously that coculture of macrophages with tumor cells upregulates macrophage SR-A expression. We show in this study that macrophage SR-A deficiency inhibits tumor cell migration in a coculture assay. We further demonstrate that coculture of tumor-associated macrophages and tumor cells induces secretion of factors that are recognized by SR-A on tumor-associated macrophages. We tentatively identified several potential ligands for the SR-A receptor in tumor cell–macrophage cocultures by mass spectrometry. Competing with the coculture-induced ligand in our invasion assay recapitulates SR-A deficiency and leads to similar inhibition of tumor cell invasion. In line with our in vitro findings, tumor progression and metastasis are inhibited in SR-A−/− mice in two in vivo models of ovarian and pancreatic cancer. Finally, treatment of tumor-bearing mice with 4F, a small peptide SR-A ligand able to compete with physiological SR-A ligands in vitro, recapitulates the inhibition of tumor progression and metastasis observed in SR-A−/− mice. Our observations suggest that SR-A may be a potential drug target in the prevention of metastatic cancer progression.

Primary care clinicians’ attitudes towards point-of-care blood testing: a systematic review of qualitative studies

BackgroundPoint-of-care blood tests are becoming increasingly available and could replace current venipuncture and laboratory testing for many commonly used tests. However, at present very few have been implemented in most primary care settings. Understanding the attitudes of primary care clinicians towards these tests may help to identify the barriers and facilitators to their wider adoption. We aimed to systematically review qualitative studies of primary care clinicians’ attitudes to point-of-care blood tests.MethodsWe systematically searched Medline, Embase, ISI Web of Knowledge, PsycINFO and CINAHL for qualitative studies of primary care clinicians’ attitudes towards point-of-care blood tests in high income countries. We conducted a thematic synthesis of included studies.ResultsOur search identified seven studies, including around two hundred participants from Europe and Australia. The synthesis generated three main themes: the impact of point-of-care testing on decision-making, diagnosis and treatment; impact on clinical practice more broadly; and impact on patient-clinician relationships and perceived patient experience. Primary care clinicians believed point-of-care testing improved diagnostic certainty, targeting of treatment, self-management of chronic conditions, and clinician-patient communication and relationships. There were concerns about test accuracy, over-reliance on tests, undermining of clinical skills, cost, and limited usefulness.ConclusionsWe identified several perceived benefits and barriers regarding point-of-care tests in primary care. These imply that if point-of-care tests are to become more widely adopted, primary care clinicians require evidence of their accuracy, rigorous testing of the impact of introduction on patient pathways and clinical practice, and consideration of test funding.

The Macrophage Scavenger Receptor A Is Host-Protective in Experimental Meningococcal Septicaemia

Macrophage Scavenger Receptor A (SR-A) is a major non-opsonic receptor for Neisseria meningitidis on mononuclear phagocytes in vitro, and the surface proteins NMB0278, NMB0667, and NMB1220 have been identified as ligands for SR-A. In this study we ascertain the in vivo role of SR-A in the recognition of N. meningitidis MC58 (serogroup B) in a murine model of meningococcal septicaemia. We infected wild-type and SR-A−/− animals intraperitoneally with N. meningitidis MC58 and monitored their health over a period of 50 hours. We also determined the levels of bacteraemia in the blood and spleen, and measured levels of the pro-inflammatory cytokine interleukin-6 (IL-6). The health of SR-A−/− animals deteriorated more rapidly, and they showed a 33% reduction in survival compared to wild-type animals. SR-A−/− animals consistently exhibited higher levels of bacteraemia and increased levels of IL-6, compared to wild-type animals. Subsequently, we constructed a bacterial mutant (MC58-278-1220) lacking two of the SR-A ligands, NMB0278 and NMB1220. Mutation of NMB0667 proved to be lethal. When mice were infected with the mutant bacteria MC58-278-1220, no significant differences could be observed in the health, survival, bacteraemia, and cytokine production between wild-type and SR-A−/− animals. Overall, mutant bacteria appeared to cause less severe symptoms of septicaemia, and a competitive index assay showed that higher levels of wild-type bacteria were recovered when animals were infected with a 1∶1 ratio of wild-type MC58 and mutant MC58-278-1220 bacteria. These data represent the first report of the protective role of SR-A, a macrophage-restricted, non-opsonic receptor, in meningococcal septicaemia in vivo, and the importance of the recognition of bacterial protein ligands, rather than lipopolysaccharide.