Incidence of Lyme disease in the United Kingdom and association with fatigue: A population-based, historical cohort study.

BACKGROUND: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned. METHODS AND FINDINGS: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible. CONCLUSIONS: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis

PTCH1+/− Dermal Fibroblasts Isolated from Healthy Skin of Gorlin Syndrome Patients Exhibit Features of Carcinoma Associated Fibroblasts

Gorlin's or nevoid basal cell carcinoma syndrome (NBCCS) causes predisposition to basal cell carcinoma (BCC), the commonest cancer in adult human. Mutations in the tumor suppressor gene PTCH1 are responsible for this autosomal dominant syndrome. In NBCCS patients, as in the general population, ultraviolet exposure is a major risk factor for BCC development. However these patients also develop BCCs in sun-protected areas of the skin, suggesting the existence of other mechanisms for BCC predisposition in NBCCS patients. As increasing evidence supports the idea that the stroma influences carcinoma development, we hypothesized that NBCCS fibroblasts could facilitate BCC occurence of the patients. WT (n = 3) and NBCCS fibroblasts bearing either nonsense (n = 3) or missense (n = 3) PTCH1 mutations were cultured in dermal equivalents made of a collagen matrix and their transcriptomes were compared by whole genome microarray analyses. Strikingly, NBCCS fibroblasts over-expressed mRNAs encoding pro-tumoral factors such as Matrix Metalloproteinases 1 and 3 and tenascin C. They also over-expressed mRNA of pro-proliferative diffusible factors such as fibroblast growth factor 7 and the stromal cell-derived factor 1 alpha, known for its expression in carcinoma associated fibroblasts. These data indicate that the PTCH1+/− genotype of healthy NBCCS fibroblasts results in phenotypic traits highly reminiscent of those of BCC associated fibroblasts, a clue to the yet mysterious proneness to non photo-exposed BCCs in NBCCS patients

Attenuated expression of tenascin-c in ovalbumin-challenged STAT4-/- mice

<p>Abstract</p> <p>Background</p> <p>Asthma leads to structural changes in the airways, including the modification of extracellular matrix proteins such as tenascin-C. The role of tenascin-C is unclear, but it might act as an early initiator of airway wall remodelling, as its expression is increased in the mouse and human airways during allergic inflammation. In this study, we examined whether Th1 or Th2 cells are important regulators of tenascin-C in experimental allergic asthma utilizing mice with impaired Th1 (STAT4-/-) or Th2 (STAT6-/-) immunity.</p> <p>Methods</p> <p>Balb/c wildtype (WT), STAT4-/- and STAT6-/- mice were sensitized with intraperitoneally injected ovalbumin (OVA) followed by OVA or PBS airway challenge. Airway hyperreactivity (AHR) was measured and samples were collected. Real time PCR and immunohistochemistry were used to study cytokines and differences in the expression of tenascin-C. Tenascin-C expression was measured in human fibroblasts after treatment with TNF-α and IFN-γ <it>in vitro</it>.</p> <p>Results</p> <p>OVA-challenged WT mice showed allergic inflammation and AHR in the airways along with increased expression of TNF-α, IFN-γ, IL-4 and tenascin-C in the lungs. OVA-challenged STAT4-/- mice exhibited elevated AHR and pulmonary eosinophilia. The mRNA expression of TNF-α and IFN-γ was low, but the expression of IL-4 was significantly elevated in these mice. OVA-challenged STAT6-/- mice had neither AHR nor pulmonary eosinophilia, but had increased expression of mRNA for TNF-α, IFN-γ and IL-4. The expression of tenascin-C in the lungs of OVA-challenged STAT4-/- mice was weaker than in those of OVA-challenged WT and STAT6-/- mice suggesting that TNF-α and IFN-γ may regulate tenascin-C expression <it>in vivo</it>. The stimulation of human fibroblasts with TNF-α and IFN-γ induced the expression of tenascin-C confirming our <it>in vivo </it>findings.</p> <p>Conclusions</p> <p>Expression of tenascin-C is significantly attenuated in the airways of STAT4-/- mice, which may be due to the impaired secretion of TNF-α and IFN-γ in these mice.</p

MALDI-MSI and label-free LC-ESI-MS/MS shotgun proteomics to investigate protein induction in a murine fibrosarcoma model following treatment with a vascular disrupting agent

Tumour vasculature is notoriously sinusoidal and leaky, and is hence susceptible to vascular disruption. Microtubule destabilising drugs such as the combretastatins form the largest group of tumour vascular disrupting agents (VDAs) and cause selective shutdown of tumour blood flow within minutes to hours, leading to secondary tumour cell death. Targeting the tumour vasculature is a proven anticancer strategy but early treatment response bio-markers are required for personalising treatment planning. Protein induction following treatment with combretastatin A4-phosphate (CA4P) was examined in a mouse fibrosarcoma model (fs 188), where tumour cells express only the matrix-bound isoform of vascular endothelial growth factor A (VEGF188). These tumours are relatively resistant to vascular disruption by CA4P and hence a study of protein induction following treatment could yield insights into resistance mechanisms. The distribution of a number of proteins induced following treatment were visualised by MALDI-MSI. Responses identified were validated by LC-ESI-MS/MS and immunohistochemical (IHC) staining. Significant changes in proteins connected with necrosis, cell structure, cell survival and stress-induced molecular chaperones were identified. Protein-protein interactions were identified using STRING 9.0 proteomic network software. These relationship pathways provided an insight into the activity of the active tumour milieu and a means of linking the identified proteins to their functional partners

Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers

Pattern recognition underpins innate immunity; the accurate identification of danger, including infection, injury, or tumor, is key to an appropriately targeted immune response. Pathogen detection is increasingly well defined mechanistically, but the discrimination of endogenous inflammatory triggers remains unclear. Tenascin-C, a matrix protein induced upon tissue damage and expressed by tumors, activates toll-like receptor 4 (TLR4)-mediated sterile inflammation. Here we map three sites within tenascin-C that directly and cooperatively interact with TLR4. We also identify a conserved inflammatory epitope in related proteins from diverse families, and demonstrate that its presence targets molecules for TLR detection, while its absence enables escape of innate immune surveillance. These data reveal a unique molecular code that defines endogenous proteins as inflammatory stimuli by marking them for recognition by TLRs

Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs

Background: Gram-positive and Gram-negative bacteria are main causes of pneumonia or acute lung injury. They are recognized by the innate immune system via toll-like receptor-2 (TLR2) or TLR4, respectively. Among all organs, the lungs have the highest expression of TLR2 receptors, but little is known about the pulmonary consequences of their activation. Here we studied the effects of the TLR2/6 agonist MALP-2, the TLR2/1 agonist Pam 3Cys and the TLR4 agonist lipopolysaccharide (LPS) on pro-inflammatory responses in isolated lungs. Methodology/Principal Findings: Isolated perfused mouse lungs were perfused for 60 min or 180 min with MALP-2 (25 ng/ mL), Pam3Cys (160 ng/mL) or LPS (1 mg/mL). We studied mediator release by enzyme linked immunosorbent assay (ELISA), the activation of mitogen activated protein kinase (MAPK) and AKT/protein kinase B by immunoblotting, and gene induction by quantitative polymerase chain reaction. All agonists activated the MAPK ERK1/2 and p38, but neither JNK or AKT kinase. The TLR ligands upregulated the inflammation related genes Tnf, Il1b, Il6, Il10, Il12, Ifng, Cxcl2 (MIP-2a) and Ptgs2. MALP-2 was more potent than Pam 3Cys in inducing Slpi, Cxcl10 (IP10) and Parg. Remarkable was the strong induction of Tnc by MALP2, which was not seen with Pam 3Cys or LPS. The growth factor related genes Areg and Hbegf were not affected. In addition, all three TLR agonists stimulated the release of IL-6, TNF, CXCL2 and CXCL10 protein from the lungs

Advances in tenascin-C biology

Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology

Diagnosis codelist - Lyme disease codes

Read codes for Lyme disease. These support a publication titled "Incidence of Lyme disease in the United Kingdom and association with fatigue: a population-based, historical cohort study"

Diagnosis/symptom codelist - fatigue codes

Read codes for fatigue (including symptoms of fatigue and diagnoses of post-viral fatigue and ME/CFS). These support the paper, "Incidence of Lyme disease in the United Kingdom and association with fatigue: a population-based, historical cohort study"