Use of sepsis-related diagnostic criteria in primary care:a survey among general practitioners

BACKGROUND: Use of sepsis-criteria in hospital settings is effective in realizing early recognition, adequate treatment and reduction of sepsis-associated morbidity and mortality. Whether general practitioners (GPs) use these diagnostic criteria is unknown. OBJECTIVE: To gauge the knowledge and use of various diagnostic criteria. To determine which parameters GPs associate with an increased likelihood of sepsis. METHODS: Two thousand five hundred and sixty GPs were invited and 229 agreed to participate in a survey, reached out to through e-mail and WhatsApp groups. The survey consisted of two parts: the first part aimed to obtain information about the GP, training and knowledge about sepsis recognition, and the second part tested specific knowledge using six realistic cases. RESULTS: Two hundred and six questionnaires, representing a response rate of 8.1%, were eligible for analysis. Gut feeling (98.1%) was the most used diagnostic method, while systemic inflammatory response syndrome (37.9%), quick Sequential Organ Failure Assessment (qSOFA) (7.8%) and UK Sepsis Trust criteria (UKSTc) (1.5%) were used by the minority of the GPs. Few of the responding GPs had heard of either the qSOFA (27.7%) or the UKSTc (11.7%). Recognition of sepsis varied greatly between GPs. GPs most strongly associated the individual signs of the qSOFA (mental status, systolic blood pressure, capillary refill time and respiratory rate) with diagnosing sepsis in the test cases. CONCLUSIONS: GPs mostly use gut feeling to diagnose sepsis and are frequently not familiar with the 'sepsis-criteria' used in hospital settings, although clinical reasoning was mostly in line with the qSOFA score. In order to improve sepsis recognition in primary care, GPs should be educated in the use of available screening tools

Piezo1 Mechanosensitive Ion Channel Mediates Stretch-Induced Nppb Expression in Adult Rat Cardiac Fibroblasts

In response to stretch, cardiac tissue produces natriuretic peptides, which have been suggested to have beneficial effects in heart failure patients. In the present study, we explored the mechanism of stretch-induced brain natriuretic peptide (Nppb) expression in cardiac fibroblasts. Primary adult rat cardiac fibroblasts subjected to 4 h or 24 h of cyclic stretch (10% 1 Hz) showed a 6.6-fold or 3.2-fold (p 20-fold higher in cardiomyocytes than in cardiac fibroblasts, indicating that cardiac fibroblasts were not the main source of Nppb in the healthy heart. Yoda1, an agonist of the Piezo1 mechanosensitive ion channel, increased Nppb expression 2.1-fold (p < 0.05) and significantly induced other extracellular matrix (ECM) remodeling genes. Silencing of Piezo1 reduced the stretch-induced Nppb and Tgfb1 expression in cardiac fibroblasts. In conclusion, our study identifies Piezo1 as mediator of stretch-induced Nppb expression, as well as other remodeling genes, in cardiac fibroblasts

Apert syndrome: the Paris and Rotterdam philosophy

Introduction: Apert syndrome is a rare type of syndromic craniosynostosis. Patients have an explicit phenotype with craniofacial dysmorphologies and severe symmetrical syndactyly of the hands and feet. This review includes background information about the syndrome and several aspects of the treatment. Areas covered: The cause of Apert syndrome is found in unique mutations in the Fibroblast Growth Factors Receptor (FGFR) 2 gene in 99%. It results in cranial suture fusion, craniofacial dysmorphologies and severe symmetrical syndactyly of the hands and feet. Patients with Apert syndrome are at risk for mental retardation, mobility impairment and intracranial hypertension (ICHT). This is the result of a complex interaction between (1) abnormal skull growth, (2) ventriculomegaly, (3) venous outflow obstruction and (4) obstructive sleep apnea (OSA). Mental retardation is mainly determined by the FGFR2 mutation and treatment is directed at protecting the intrinsic potential of neurocognition. Expert Opinion: To prevent ICHT, we prefer an occipital expansion in the first year of life. Screening on ICHT and its underlying causes is necessary at least until the age of ten by means of skull circumference measurements, fundoscopy, optical coherence tomography, MRI and polysomnography. Multicentre studies on long-term outcome are required to validate the rationale of different clinical protocols

Coagulation Factor Xa Induces Proinflammatory Responses in Cardiac Fibroblasts via Activation of Protease-Activated Receptor-1

Coagulation factor (F) Xa induces proinflammatory responses through activation of protease-activated receptors (PARs). However, the effect of FXa on cardiac fibroblasts (CFs) and the contribution of PARs in FXa-induced cellular signalling in CF has not been fully characterised. To answer these questions, human and rat CFs were incubated with FXa (or TRAP-14, PAR-1 agonist). Gene expression of pro-fibrotic and proinflammatory markers was determined by qRT-PCR after 4 and 24 h. Gene silencing of F2R (PAR-1) and F2RL1 (PAR-2) was achieved using siRNA. MCP-1 protein levels were measured by ELISA of FXa-conditioned media at 24 h. Cell proliferation was assessed after 24 h of incubation with FXa ± SCH79797 (PAR-1 antagonist). In rat CFs, FXa induced upregulation of Ccl2 (MCP-1; >30-fold at 4 h in atrial and ventricular CF) and Il6 (IL-6; ±7-fold at 4 h in ventricular CF). Increased MCP-1 protein levels were detected in FXa-conditioned media at 24 h. In human CF, FXa upregulated the gene expression of CCL2 (>3-fold) and IL6 (>4-fold) at 4 h. Silencing of F2R (PAR-1 gene), but not F2RL1 (PAR-2 gene), downregulated this effect. Selective activation of PAR-1 by TRAP-14 increased CCL2 and IL6 gene expression; this was prevented by F2R (PAR-1 gene) knockdown. Moreover, SCH79797 decreased FXa-induced proliferation after 24 h. In conclusion, our study shows that FXa induces overexpression of proinflammatory genes in human CFs via PAR-1, which was found to be the most abundant PARs isoform in this cell type

Cartilage intermediate layer protein 1 (CILP1): a novel mediator of cardiac extracellular matrix remodelling

Heart failure is accompanied by extracellular matrix (ECM) remodelling, often leading to cardiac fibrosis. In the present study we explored the significance of cartilage intermediate layer protein 1 (CILP1) as a novel mediator of cardiac ECM remodelling. Whole genome transcriptional analysis of human cardiac tissue samples revealed a strong association of CILP1 with many structural (e.g. COL1A2 r2¿=¿0.83) and non-structural (e.g. TGFB3 r2¿=¿0.75) ECM proteins. Gene enrichment analysis further underscored the involvement of CILP1 in human cardiac ECM remodelling and TGFß signalling. Myocardial CILP1 protein levels were significantly elevated in human infarct tissue and in aortic valve stenosis patients. CILP1 mRNA levels markedly increased in mouse heart after myocardial infarction, transverse aortic constriction, and angiotensin II treatment. Cardiac fibroblasts were found to be the primary source of cardiac CILP1 expression. Recombinant CILP1 inhibited TGFß-induced ¿SMA gene and protein expression in cardiac fibroblasts. In addition, CILP1 overexpression in HEK293 cells strongly (5-fold p¿<¿0.05) inhibited TGFß signalling activity. In conclusion, our study identifies CILP1 as a new cardiac matricellular protein interfering with pro-fibrotic TGFß signalling, and as a novel sensitive marker for cardiac fibrosis

Vectorial secretion of interleukin-8 mediates autocrine signalling in intestinal epithelial cells via apically located CXCR1

BACKGROUND: In the intestinal mucosa, several adaptations of TLR signalling have evolved to avoid chronic inflammatory responses to the presence of commensal microbes. Here we investigated whether polarized monolayers of intestinal epithelial cells might regulate inflammatory responses by secreting IL-8 in a vectorial fashion (i.e. apical versus basolateral) depending on the location of the TLR stimulus. RESULTS: In the Caco-2 BBE model of polarized villus-like epithelium, apical stimulation with TLR2 and TLR5 ligands resulted in the apical secretion of IL-8. The CXCR1 receptor for IL-8 was expressed only on the apical membrane of Caco-2 BBE cells and differentiated epithelial cells in the human small intestine and colon. Transcriptome analyses revealed that Caco-2 BBE cells respond to stimulation with IL-8 supporting the hypothesis that IL-8 induces G protein-coupled receptor signalling. CONCLUSIONS: These results show that IL-8 induces autocrine signalling via an apical CXCR1 in Caco-2 BBE intestinal epithelial cells and that this receptor is also expressed on the apical surface of differentiated human intestinal epithelial cells in vivo, suggesting an autocrine function for IL-8 secreted in the lumen

Heart-type Fatty acid-binding protein in Acute Myocardial infarction Evaluation (FAME): Background and design of a diagnostic study in primary care

<p>Abstract</p> <p>Background</p> <p>Currently used biomarkers for cardiac ischemia are elevated in blood plasma after a delay of several hours and therefore unable to detect acute coronary syndrome (ACS) in a very early stage. General practitioners (GPs), however, are often confronted with patients suspected of ACS within hours after onset of complaints. This ongoing study aims to evaluate the added diagnostic value beyond clinical assessment for a rapid bedside test for heart-type fatty-acid binding protein (H-FABP), a biomarker that is detectable as soon as one hour after onset of ischemia.</p> <p>Methods</p> <p>Participating GPs perform a blinded H-FABP rapid bedside test (Cardiodetect^®) in patients with symptoms suggestive of ACS such as chest pain or discomfort at rest. All patients, whether referred to hospital or not, undergo electrocardiography (ECG) and venapunction for a plasma troponin test within 12–36 hours after onset of complaints. A final diagnosis will be established by an expert panel consisting of two cardiologists and one general practitioner (blinded to the H-FABP test result), using all available patient information, also including signs and symptoms. The added diagnostic value of the H-FABP test beyond history taking and physical examination will be determined with receiver operating characteristic curves derived from multivariate regression analysis.</p> <p>Conclusion</p> <p>Reasons for presenting the design of our study include the prevention of publication bias and unacknowledged alterations in the study aim, design or data-analysis. To our knowledge this study is the first to assess the diagnostic value of H-FABP <it>outside </it>a hospital-setting. Several previous hospital-based studies showed the potential value of H-FABP in diagnosing ACS. Up to now however it is unclear whether these results are equally promising when the test is used in primary care. The first results are expected in the end of 2008.</p