word count: 175 words 27 Text word count: 5421 words 28 Abstract (175 words) 29Hand, foot and mouth disease (HFMD), caused by enterovirus 71 (EV71), presents 30 mild to severe disease, and sometimes fatal neurological and respiratory 31 manifestations. However, reasons for the severe pathogenesis remain undefined. To 32 investigate this, infection and viral kinetics of EV71 isolates from clinical disease (mild, 33 moderate and severe) from Sarawak, Malaysia, were characterized in human 34 rhabdomyosarcoma (RD), neuroblastoma (SH-SY5Y) and peripheral blood 35 mononuclear cells (PBMCs). High resolution transcriptomics was used to decipher 36 EV71-host interactions in PBMCs. Ingenuity analyses revealed similar pathways 37 triggered by all EV71 isolates, although the extent of activation varied. Importantly, 38 several pathways were found to be specific to the severe isolate, including triggering 39 receptor expressed on myeloid cells 1 (TREM-1) signaling. Depletion of TREM-1 in 40 EV71-infected PBMCs with peptide LP17 resulted in decreased levels of pro-41 inflammatory genes, and reduced viral loads for the moderate and severe isolates. 42Mechanistically, this is the first report describing the transcriptome profiles during 43 EV71 infections in primary human cells, and the involvement of TREM-1 in the severe 44 disease pathogenesis, thus providing new insights for future treatment targets. 45 48 mouth, feet and bottoms (1-3). Outbreaks of HFMD are caused by human enterovirus 49 group A members (HE-A), mainly coxsackieviruses A16, A6 and A10, and enterovirus 50 71 (EV71) (1, 4, 5). While often benign and self-limiting (2), the disease can cause 51 cardiopulmonary and neurological complications such as myocarditis, brainstem 52 encephalitis, aseptic meningitis, and neurogenic pulmonary edema, which can be fatal 53 (6, 7). The severe manifestations of HFMD are often associated with cases of EV71 54 infections, rather than coxsackievirus A16 (8). 55
Testicular germ cell tumour presenting as thyrotoxicosisWe wish to raise four important points regarding the diagnosis, aetiology and management of beta human chorionic gonadotropin (bhCG)-induced hyperthyroidism. 1 1. bhCG-induced hyperthyroidism is characterized by very high levels of bhCG and these may cross-react in some TSH assays, 2,3 giving apparently normal rather than suppressed TSH values. Since many laboratories o¡er TSH as the ¢rst-line test in investigating thyroid dysfunction, the diagnosis of bhCGinduced hyperthyroidism may be missed.2. bhCG exists as several isoforms dependent on carbohydrate content. Desialated isoforms, which are produced more abundantly in cases of bhCG-induced hyperthyroidism, have greater thyrotrophic activity than the more common sialated isoforms. 4,5 Therefore, the quality rather than the quantity of bhCG is important in the development of bhCG-induced hyperthyroidism. This also explains why the very high bhCG levels in pregnancy are not usually associated with thyrotoxicosis.3. The most common and often the only presenting sign of bhCG-induced thyrotoxicosis in men is tachycardia, 2,6,7 as exempli¢ed in this case. Other features include very high oestradiol concentrations with gynaecomastia and the presence of widespread metastatic disease. 2,6,7 4. Tumour bhCG-induced hyperthyroidism may require standard anti-thyroid treatment, but almost invariably responds to e¡ective tumour chemotherapy. Tumour relapse may also be associated with recurrence of the thyrotoxicosis. 2
IntroductionThe spectrum of encephalitis, a condition of brain inflammation and leucocyte infiltration, is expanding. Modern peripheral testing has resulted in fewer brain-biopsies. Consequently, our understanding of leucocyte-subsets driving inflammation is poorly understood.MethodsThe Walton Centre Brain-Bank was screened over 10 years, identifying all cases of biopsy and post-mortem tissue with encephalitis. Tissue underwent haemotoxylin/eosin stain, and immunohistochemical analysis for CD3, CD4, CD8, CD68, and CD79a. The immediate perivascular and surrounding parenchymal infiltrate quantitatively assessed.ResultsOf nine cases, two were herpes simplex virus (HSV), four immune-mediated, and three of unknown cause. In comparison to those of unknown cause, HSV had a greater proportion of CD4 and CD68 positive cells in the perivascular and immediate parenchyma respectively (p=0.007 and p=0.004). Neutrophils were only identified in HSV. Immune-mediated cases generally had a limited inflammatory infiltrate, similarly to unknown cases. Although one paraneoplastic case had a marked inflammatory infiltrate, including CD8 positive cells.ConclusionsOur study describes potentially important differences in the relative leucocyte populations in the parenchyma of patients with encephalitis, which may have diagnostic and therapeutic implications. Further studies are planned to distinguish invading macrophage/monocytes from resident microglia in a transgenic murine model.
P19 Figure 1 A549 cells plated on an iCelligence 8-well gold electrode coated plate were incubated with TNFR1 dAb™, a dummy dAb or Adalimumab™ for 1 h then exposed to exogenous TNF or vehicle control. Electrical impedance was measured continuously over 50 h. Trough normalised impedance was measured over 50 h post treatment (n = 3-5).
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