Clinical utility of stimulated cholescintigraphy using a standardized Ensure-Plus fatty meal protocol in patients with suspected functional gallbladder disorder: a retrospective study of seven-years clinical experience.

BACKGROUND: The clinical utility of fatty meal stimulated cholescintigraphy particularly using a standardized formulation in patients with suspected functional gallbladder disorder has not been extensively studied. We present our seven-year clinical experience using an Ensure plus protocol. METHODS: A retrospective study was performed on patients undergoing stimulated cholescintigraphy using Ensure Plus for evaluation of suspected functional gallbladder disorder. A gallbladder ejection fraction (GBEF) of <33% was considered abnormal. RESULTS: Of the 173 patients evaluated, 57 (33%) had an abnormal GBEF, 112 (65%) had a normal GBEF and 4 (2%) had no gallbladder visualization. Of the 57 patients with an abnormal GBEF, symptom improvement occurred in 30/31 (97%) who underwent cholecystectomy and in 17/26 (65%) who were managed conservatively (p = 0.003). Of the 112 patients with a normal GBEF, symptom improvement occurred in 8/10 (80%) who underwent cholecystectomy and 74/102 (73%) who were managed conservatively (p = 1.000). In the subgroup of 102 patients with a normal GBEF managed conservatively, those without symptomatic improvement had lower GBEFs compared to those with symptomatic improvement (median GBEF 46% versus 57%, p = 0.019). CONCLUSION: Our retrospective results support a clinical role for stimulated cholescintigraphy using Ensure Plus in the evaluation of patients with suspected functional gallbladder disorder. While an abnormal GBEF predicts good surgical outcome, our results suggest that using an absolute GBEF cut off value of <33% may not apply to all patients and hence GBEF results should only be used as an adjunct in the surgical decision-making process.

Use of a radiopharmaceutical multidose dispenser for positron emission tomography: Risk assessment and mitigation measures for infection prevention.

Positron emission tomography (PET) imaging necessitates the use of multidose vials for radiopharmaceutical delivery to patients. Conventional practices involve manual extraction of radiopharmaceuticals from a multidose vial prior to each PET procedure, which exposes the technologist to increasing levels of radiation and poses a potential infection risk to patients with frequent handling and access of the vial. New technologies for automated dosing and infusion delivery are available, however these incorporate both a multidose vial and a multi-patient infusion set. There is an absence of guidance for infection prevention (IP) units regarding the safety and acceptability of these devices. This paper describes the process of risk assessment and the mitigation measures for training, workflows, and documentation which led to the safe introduction of an automated PET infusion device in a large tertiary public healthcare facility.

Predictive performance of different kidney function estimation equations in lung transplant patients.

BACKGROUND: There has been limited examination of the performance of glomerular filtration rate estimation (eGFR) equations in lung transplant populations. This study aimed to compare the performance of serum creatinine and cystatin C based eGFR equations with Tc-99m diethylenetriaminepentaacetic acid (DTPA) GFR measurements in individuals with end-stage lung disease, either prior to, or following, lung transplantation. METHODS: In this prospective observational study, participants underwent GFR measurements with Tc-99m Pentetate. Measured results were compared with GFR estimates derived from estimation equations [4-variable Modification of Diet in Renal Disease, Cockcroft-Gault, Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine, cystatin C and creatinine-cystatin C combined equations]. RESULTS: Ninety-seven individuals were studied (77 post- and 20 wait-listed for transplantation). Median (range) radionucleotide GFR was 56.7ml/min/1.73m2 (22.8-109.2ml/min/1.73m2). In the study cohort as a whole, the CKD-EPI creatinine-cystatin C combined equation showed the highest performance, but was only slightly superior to the CKD-EPI creatinine equation. However, in individuals with cystic fibrosis, low arm muscle mass and/or low body mass index, all of the creatinine-based equations showed unacceptable performance. In these subgroups, improved GFR estimation was seen with the CKD-EPI cystatin C equation, and predictions were better still using the CKD-EPI creatinine-cystatin C combined equation. CONCLUSIONS: This study shows adequate predictive ability of CKD-EPI creatinine in the cohort as a whole, but unacceptable performance in patients with cystic fibrosis, low arm muscle mass and/or low body mass index. Our findings demonstrate that cystatin C may be a preferable filtration marker in these subgroups.

Slc11a1 limits intracellular growth of Salmonella enterica sv. Typhimurium by promoting macrophage immune effector functions and impairing bacterial iron acquisition.

The natural resistance-associated macrophage protein 1, Slc11a1, is a phagolysosomal transporter for protons and divalent ions including iron that confers host protection against diverse intracellular pathogens including Salmonella. We investigated and compared the regulation of iron homeostasis and immune function in RAW264.7 murine phagocytes stably transfected with non-functional Slc11a1 and functional Slc11a1 controls in response to an infection with Salmonella enterica serovar Typhimurium. We report that macrophages lacking functional Slc11a1 displayed an increased expression of transferrin receptor 1, resulting in enhanced acquisition of transferrin-bound iron. In contrast, cellular iron release mediated via ferroportin 1 was significantly lower in Salmonella-infected Slc11a1-negative macrophages in comparison with phagocytes bearing Slc11a1. Lack of Slc11a1 led to intracellular persistence of S. enterica serovar Typhimurium within macrophages, which was paralleled by a reduced formation of nitric oxide, tumour necrosis factor-alpha and interleukin-6 in Slc11a1-negative macrophages following Salmonella infection, whereas interleukin-10 production was increased. Moreover, Slc11a1-negative phagocytes exhibited higher cellular iron content, resulting in increased iron acquisition by intracellular Salmonella. Our observations indicate a bifunctional role for Slc11a1 within phagocytes. Slc11a restricts iron availability, which first augments pro-inflammatory macrophage effector functions and second concomitantly limits microbial iron access.

Nramp1-functionality increases iNOS expression via repression of IL-10 formation.

In mice, resistance to certain intracellular microbes depends on the expression of a late phagosomal protein termed natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1). Nramp1-functionality is associated with alterations of cellular iron homeostasis and a sustained pro-inflammatory immune response, including the formation of the antimicrobial effector molecule NO. To investigate the underlying mechanism we used RAW-264.7 murine macrophage cells stably transfected with a functional Nramp1 allele (RAW-37) or Nramp1 non-functional controls (RAW-21). We found that the production of and signalling by the anti-inflammatory cytokine IL-10 was significantly enhanced in macrophages lacking functional Nramp1. Upon infection of macrophages with Salmonella typhimurium pathogen survival was significantly better in RAW-21 than in RAW-37, which inversely correlated to NO and TNF-alpha formation. Addition of a neutralising anti-IL-10 antibody to RAW-21 cells led to a significantly reduced survival of S. typhimurium within these cells and enhanced formation of NO and TNF-alpha reaching levels comparable to that observed in cells bearing functional Nramp1. Oppositely, supplementation of iron to RAW-21 cells further increased IL-10 formation.Thus, Nramp1 mediates effective host defence in part via suppression of excessive IL-10 production which may relate to Nramp1-mediated reduction of cellular iron pools, thus strengthening antimicrobial effector mechanisms.

Modulation of macrophage iron transport by Nramp1 (Slc11a1).

In mice, the expression of the phagolysosomal protein natural-resistance associated macrophage protein 1 (Nramp1, Slc11a1) is associated with host resistance to various intracellular pathogens. Nramp1 acts as a transporter for protons, iron, and other divalent cations, and Nramp1 functionality is associated with an enhanced activity of pro-inflammatory immune pathways, including the formation of nitric oxide (NO) via transcriptional stimulation of inducible nitric oxide synthase (iNOS) expression. As iron availability also strongly influences iNOS expression, we studied the effects of Nramp1 functionality on iron homeostasis in the RAW264.7 macrophage cell line stably transfected with functional or non-functional Nramp1. We found that macrophages lacking functional Nramp1 exhibited a significantly higher iron uptake via transferrin receptor 1 and, as a consequence of this, an increased iron release which is mediated via the iron export protein ferroportin-1. RNA-bandshift experiments for determination of iron regulatory protein activity showed that, as a net effect of the altered expression of iron transporters, the overall cellular iron content was lower in macrophages bearing functional Nramp1. Since low intracellular iron availability enhances iNOS transcription, Nramp1 could exert its effect on NO formation and other pro-inflammatory immune pathways via modulation of iron homeostasis.

Nramp1 functionality increases inducible nitric oxide synthase transcription via stimulation of IFN regulatory factor 1 expression.

Natural-resistance associated macrophage protein 1 (Nramp1) encodes a transmembrane phagolysosomal protein exerting resistance toward infections with intracellular pathogens by a mechanism not fully elucidated so far. We used the murine macrophage cell line RAW264.7, stably transfected with functional (RAW-37) or nonfunctional (RAW-21) Nramp1, to study for differences in the expression of NO, a central antimicrobial effector molecule of macrophages. Following stimulation with IFN-gamma and LPS, Nramp1-expressing cells exhibit higher enzymatic activity of inducible NO synthase (iNOS) and increased cytoplasmic iNOS mRNA levels than RAW-21 cells. Time-course experiments showed that iNOS-mRNA levels remain increased in RAW-37 cells after prolonged cytokine stimulation while they decrease in RAW-21 cells. Reporter gene assays with iNOS-promoter luciferase constructs demonstrated an increased and prolonged promoter activity in Nramp1-resistant vs susceptible cells. This was paralleled by increased IFN regulatory factor 1 (IRF-1) expression and binding affinity to the iNOS promoter in RAW-37 cells, which may be related to enhanced STAT-1 binding affinity in these cells. A point mutation within the IRF-1 binding site of the iNOS promoter abolished the differences in iNOS transcription between RAW-21 and RAW-37 cells. Cells carrying functional Nramp1 express increased amounts of NO, which may be related to STAT-1-mediated stimulation of IRF-1 expression with subsequent prolonged activation of iNOS transcription. Enhanced NO expression may partly underlie the protection against infection with intracellular pathogens by Nramp1 functionality.

Properties of the stereoscopic (cyclopean) motion aftereffect.

Across four experiments, this study investigated properties of the stereoscopic motion aftereffect (adaptation from moving retinal disparity information). The results showed that stereoscopic motion can induce an adaptation aftereffect across a wide range of conditions and observers, provided that the duration of adaptation is sufficiently long and a perceptually salient test pattern is viewed. Motion adaptation was found to transfer between the stereoscopic and luminance domains [replicating a previous report by Fox, Patterson and Lehmkuhle (1982) Investigative Ophthalmology and Visual Science (Suppl.), 22, 144], suggesting that motion perception from stereoscopic (second-order) and luminance (first-order) attributes is mediated by a common neural substrate.