Background: Severe neonatal jaundice (SNJ) and the associated long-term health sequelae are a significant problem in low-income countries (LIC) where measurement of total serum bilirubin (TSB) is often unavailable. Transcutaneous bilirubinometry (TcB) provides the opportunity for non-invasive, point-of-care monitoring. Few studies have evaluated its agreement with TSB levels during phototherapy in LIC.Aim: To determine agreement between TcB and TSB during phototherapy in a Haitian newborn population and to establish whether TcB can be safely used to guide treatment during phototherapy when TSB is unavailable.Methods: A single-centre prospective study (February to May 2017) in Cap Haïtien, northern Haiti was undertaken. Newborns <7 days of age with clinically detected jaundice were eligible for inclusion. A TcB device (JM-103) was used to screen for newborn jaundice along with a parallel TSB. A strip of black tape was placed across the sternum during phototherapy and uncovered for subsequent TcB measurements. Decisions about phototherapy treatment were based upon UK National Institute of Clinical Excellence (NICE) threshold criteria. Paired TSB and TcB measurements were compared using Bland–Altman methods.Results: The final analysis included 70 parallel TSB/TcB measurements from 35 infants within the first 5 days of life. Nineteen (54.3%) were male and 12 (34.3%) were <35 weeks. Thirty-two (91.4%) were receiving phototherapy. There was good agreement between TSB and TcB. Compared with TSB, TcB tended to over-estimate bilirubin (mean difference 11.1 µmol/L, 95% CI −10.2–32.5 µmol/L). However, at higher bilirubin levels (>250 µmol/L), TcB tended to under-estimate bilirubin compared with TSB and the difference increased.Conclusion: In an LIC setting in which serum bilirubin testing is not commonly available, TcB demonstrates good agreement with TSB and can be safely used to guide jaundice treatment during phototherapy but can lead to over-treatment at lower bilirubin levels and are more inaccurate at higher levels. For TcB levels >250 µmol, confirmation with serum bilirubin should be performed, if available, to avoid under-estimation.Abbreviations: LIC: low income countries; LMIC: low and middle income countries; TcB: transcutaneous bilirubinometry; TSB: transcutaneous serum biliubin
The alpha7 subunit-containing nicotinic acetylcholine receptor (alpha7nAChR) is an essential component in the vagus nerve-based cholinergic anti-inflammatory pathway that regulates the levels of TNF, high mobility group box 1 (HMGB1), and other cytokines during inflammation. Choline is an essential nutrient, a cell membrane constituent, a precursor in the biosynthesis of acetylcholine, and a selective natural alpha7nAChR agonist. Here, we studied the anti-inflammatory potential of choline in murine endotoxemia and sepsis, and the role of the alpha7nAChR in mediating the suppressive effect of choline on TNF release. Choline (0.1-50 mM) dose-dependently suppressed TNF release from endotoxin-activated RAW macrophage-like cells, and this effect was associated with significant inhibition of NF-kappaB activation. Choline (50 mg/kg, intraperitoneally [i.p.]) treatment prior to endotoxin administration in mice significantly reduced systemic TNF levels. In contrast to its TNF suppressive effect in wild type mice, choline (50 mg/kg, i.p.) failed to inhibit systemic TNF levels in alpha7nAChR knockout mice during endotoxemia. Choline also failed to suppress TNF release from endotoxin-activated peritoneal macrophages isolated from alpha7nAChR knockout mice. Choline treatment prior to endotoxin resulted in a significantly improved survival rate as compared with saline-treated endotoxemic controls. Choline also suppressed HMGB1 release in vitro and in vivo, and choline treatment initiated 24 h after cecal ligation and puncture (CLP)-induced polymicrobial sepsis significantly improved survival in mice. In addition, choline suppressed TNF release from endotoxin-activated human whole blood and macrophages. Collectively, these data characterize the anti-inflammatory efficacy of choline and demonstrate that the modulation of TNF release by choline requires alpha7nAChR-mediated signaling.
Despite many attempts to develop novel therapies, EBV-specific therapies currently remain largely investigational, and EBV-associated malignancies are often associated with a worse prognosis. Therefore, there is a clear demand for EBV-specific therapies for both prevention and treatment of virus-associated malignancies.
Abstract Organophosphate (OP) toxicants remain an active threat to public health and to warfighters in the military. Current countermeasures require near immediate administration following OP exposure and are reported to have controversial efficacies. Acetylcholinesterase (AChE) fused to the human immunoglobulin 1 (IgG1) Fc domain (AChE‐Fc) is a potential bioscavenger for OP toxicants, but a reproducible AChE‐Fc biomanufacturing strategy remains elusive. This report is the first to establish a comprehensive laboratory‐scale bioprocessing strategy that can reproducibly produce AChE‐Fc and AChE(W86A)‐Fc which is a mutated AChE protein with reduced enzymatic activity. Characterization studies revealed that AChE‐Fc and AChE(W86A)‐Fc are N ‐glycosylated dimeric fusion glycoproteins but only AChE‐Fc had the capability to bind to paraoxon (a model OP). This AChE‐Fc fusion glycoprotein bioprocessing strategy can be leveraged during industrial biomanufacturing development, while the research‐grade AChE‐Fc proteins can be used to determine the potential clinical relevance of the countermeasure against OP toxicants.
Arthritic toe pathologies frequently lead to the development of painful apical pressure skin lesions that can compromise gait and affect quality of life. Historically conservative treatments involve the use of a toe prop with the intended aim of reducing plantar pressure from the apex of the digit. However, the effect of toe prop treatment on plantar digital pressure has not been investigated.Twenty two subjects were recruited with lesser digital deformities and associated apical skin lesions. Individual pressure sensors were placed on the apices of the lesser toes and pressure was recorded under three toe prop conditions (leather, gel and silicone mould). A modified comfort index was utilised to assess the comfort of each condition.Significant difference (p < 0.05) in mean peak pressure was observed at the apex of the 2nd toe when using the gel (p < 0.001) and silicone (p < 0.001) toe prop compared to no toe prop. There was also a significant difference in the mean pressure time integral at the apex of the 2nd toe when using gel (p < 0.001) and silicone (p < 0.004) toe props. There was no significant correlation between comfort and the recorded peak pressures. However, there was an indication that the silicone toe prop was more comfortable.As compared to the leather and silicone mould toe props, gel toe props were found to be the most effective for reducing peak pressure and pressure time integral on the apex of the second digit in patients with claw or hammer toe deformity.
Two weeks' isolation is widely recommended for people commencing treatment for pulmonary tuberculosis (TB). The evidence that this corresponds to clearance of potentially infectious tuberculous mycobacteria in sputum is not well established. This World Health Organization-commissioned review investigated sputum sterilisation dynamics during TB treatment.
A variety of stressors induce endothelial cells (ECs) to produce excessive oxygen radicals, triggering vascular inflammation, cellular stress and apoptotic activation which may have deleterious effects on vascular function and contribute to the pathophysiology of hypertension during preeclampsia. Although the benefits of AICAR on ischemic‐reperfusion (I/R) injury in the myocardium are well established, the role of AICAR on specifically on vascular ECs is much less clear. Thus, we hypothesized AICAR would promote cytoprotective pathways in ECs, reducing stress and attenuating apoptotic activity under hypoxic stress. To model vascular ischemia as might be found in the preeclamptic placenta, human umbilical vascular endothelial cells (HUVECs) were cultured at physiologic normoxic (8% O2) or hypoxic (1% O2) conditions and treated with AICAR (0.2, and 2mM). Cell protein and media were collected for further analysis. AICAR increased (p<0.05) pAMPKα/AMPKα in hypoxic conditions, but not in normoxia. AICAR pretreatment (2mM, 1hr) and subsequent exposure to hypoxia (24hr) showed decreased (p<0.05) BiP expression and cell‐adhesion molecule ICAM‐1 compared to normoxic control. AICAR reduced (p<0.05) cellular metabolic activity measured by MTT assay in both 8 and 1% O2. Further, ET‐1 secretion was reduced (p<0.05) following AICAR treatment (434 ±14 vs. *179 ±1pg/mL). Endothelial permeability was increased (p<0.05) with AICAR at 12 (869%) and 24 hours (315%) compared to the control. HUVEC adhesion was reduced (p<0.05) following AICAR treatment (‐91.57%), and CC blocked this effect. These data suggest by slowing cellular metabolic activity, reducing cell stress and apoptotic activity, AICAR could be a novel cytoprotective factor for improvement of vascular endothelial function in preeclampsia as well as other types of cardiovascular disease. Grant Funding Source : Supported by National Institute of Health RO1HL114096 and AHA 10SDG2600040
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