Assessing Univentricular Function in Adult Fontan Using 3D Echocardiography

Objective: To determine the accuracy of assessing univentricular function in adult Fontan patients using three-dimensional (3D) volumetric echocardiography. Design: A prospective observational study in an adult Fontan patient cohort. Setting: University Hospitals Birmingham, NHS Foundation Trust. Patients: 26 patients were enrolled in the study all aged over 18 years, possessing the Fontan anatomy, with no contraindications to Cardiac Magnetic Resonance (CMR) imaging and in sinus rhythm. Intervention: All patients underwent transthoracic echocardiography using a Philips EPIQ 7 and X5-1 transducer. End diastolic volume (EDV), end systolic volume (ESV), stroke volume (SV) and ejection fraction (EF) were obtained using two dimensional (2D) and 3D acquisitions. CMR was performed within 3 months according to standard protocols. Outcome Measures: The agreement and correlation between 2D, 3D and CMR derived parameters were determined by Bland and Altman analysis and Pearson’s correlation coefficient method. The inter-observer variability was also assessed for all three modalities. Results: 3D volumetric acquisitions of the single ventricle were feasible in 18/26 (69%) patients. 3D volumes strongly correlated with CMR but with a systematic bias to underestimation: EDV r = 0.66, bias = –47.1 (–109.6 to 15.2); ESV r = 0.82, bias = – 19.4 (–59.9 to 21.1); EF r = 0.73, –1.56 (–18.8 to 15.7) and SV r = 0.32, –27.7 (– 70.2 to 14.7). Inter-observer variability was lowest with CMR, when compared to echocardiographic techniques. The inter-observer variability for 3D when compared with 2D echocardiography was lower across all parameters except EDV. Conclusions: 3D volumes correlate strongly with CMR and may be used for serial assessment of univentricular function. However, 3D volumes on echo are not interchangeable with CMR due to systematic underestimation of volume.     

A pro‐inflammatory signalome is constitutively activated by C33Y mutant TNF receptor 1 in TNF receptor‐associated periodic syndrome (TRAPS)

Mutations in TNFRSF1A encoding TNF receptor 1 (TNFR1) cause the autosomal dominant TNF receptor‐associated periodic syndrome (TRAPS): a systemic autoinflammatory disorder. Misfolding, intracellular aggregation, and ligand‐independent signaling by mutant TNFR1 are central to disease pathophysiology. Our aim was to understand the extent of signaling pathway perturbation in TRAPS. A prototypic mutant TNFR1 (C33Y), and wild‐type TNFR1 (WT), were expressed at near physiological levels in an SK‐Hep‐1 cell model. TNFR1‐associated signaling pathway intermediates were examined in this model, and in PBMCs from C33Y TRAPS patients and healthy controls. In C33Y‐TNFR1‐expressing SK‐Hep‐1 cells and TRAPS patients’ PBMCs, a subtle, constitutive upregulation of a wide spectrum of signaling intermediates and their phosphorylated forms was observed; these were associated with a proinflammatory/antiapoptotic phenotype. In TRAPS patients’ PBMCs, this upregulation of proinflammatory signaling pathways was observed irrespective of concurrent treatment with glucocorticoids, anakinra or etanercept, and the absence of overt clinical symptoms at the time that the blood samples were taken. This study reveals the pleiotropic effect of a TRAPS‐associated mutant form of TNFR1 on inflammatory signaling pathways (a proinflammatory signalome), which is consistent with the variable and limited efficacy of cytokine‐blocking therapies in TRAPS. It highlights new potential target pathways for therapeutic intervention.     

Integration of vestibular and gastrointestinal inputs by cerebellar fastigial nucleus neurons: multisensory influences on motion sickness

Previous studies demonstrated that ingestion of the emetic compound copper sulfate (CuSO₄) alters the responses to vestibular stimulation of a large fraction of neurons in brainstem regions that mediate nausea and vomiting, thereby affecting motion sickness susceptibility. Other studies suggested that the processing of vestibular inputs by cerebellar neurons plays a critical role in generating motion sickness and that neurons in the cerebellar fastigial nucleus receive visceral inputs. These findings raised the hypothesis that stimulation of gastrointestinal receptors by a nauseogenic compound affects the processing of labyrinthine signals by fastigial nucleus neurons. We tested this hypothesis in decerebrate cats by determining the effects of intragastric injection of CuSO₄ on the responses of rostral fastigial nucleus to whole-body rotations that activate labyrinthine receptors. Responses to vestibular stimulation of fastigial nucleus neurons were more complex in decerebrate cats than reported previously in conscious felines. In particular, spatiotemporal convergence responses, which reflect the convergence of vestibular inputs with different spatial and temporal properties, were more common in decerebrate than in conscious felines. The firing rate of a small percentage of fastigial nucleus neurons (15 %) was altered over 50 % by the administration of CuSO₄; the firing rate of the majority of these cells decreased. The responses to vestibular stimulation of a majority of these cells were attenuated after the compound was provided. Although these data support our hypothesis, the low fraction of fastigial nucleus neurons whose firing rate and responses to vestibular stimulation were affected by the administration of CuSO₄ casts doubt on the notion that nauseogenic visceral inputs modulate motion sickness susceptibility principally through neural pathways that include the cerebellar fastigial nucleus. Instead, it appears that convergence of gastrointestinal and vestibular inputs occurs mainly in the brainstem.     

Skin and Adhesive Issues With Continuous Glucose Monitors: A Sticky Situation

Background:The purpose of this article is to describe challenges associated with successful use of continuous glucose monitoring (CGM) by young children with type 1 diabetes (T1D) and to detail the techniques and products used to improve the duration of sensor wear.Methods:The DirecNet Study Group conducted 2 studies in 169 children with T1D between the ages of 1 and 9 years who were instructed to wear a CGM device daily. Problems related to skin irritation and sensor adhesiveness in these young children presented challenges to daily use of the CGM. Study coordinators instituted a variety of techniques using commercially available products to attempt to overcome these problems.Results:Three primary factors that contributed to reduced CGM use were identified: the limited body surface area in smaller children, ambient temperature and humidity, as well as the type and duration of physical activity. Using supplemental products to minimize the impact of these factors resulted in improved adherence and reduced skin irritation.Conclusion:Achieving satisfactory adhesion of the CGM sensor and transmitter may involve finding the right supplemental product or combination of products through trial and error. Optimizing adhesion and minimizing skin irritation can significantly improve duration of use and tolerability of CGM devices by young children.     

Investigating the Use of Protein Saver Cards for Storage and Subsequent Detection of Bovine Anti-Brucella abortus Smooth Lipopolysaccharide Antibodies and Gamma Interferon

Brucella abortus, a smooth strain of the genus Brucella, is the causative agent of bovine brucellosis. To support the ongoing development of diagnostic tests for bovine brucellosis, the use of Protein Saver cards (Whatman) for bovine blood serum and plasma sample collection has been evaluated. These cards offer significant logistical and safety alternatives to transporting and storing liquid samples and may aid in diagnostic programs and validation studies. To evaluate the utility of these cards, 204 bovine blood serum samples from Brucella-infected and noninfected animals were stored on and eluted from the Protein Saver cards. Anti-Brucella smooth lipopolysaccharide (sLPS) antibody titers for the serum eluates were compared to those of the unprocessed original serum samples by indirect enzyme-linked immunosorbent assay (ELISA). The results showed a highly significant correlation between titers from the serum eluates and the unprocessed sera. Therefore, under these circumstances, serum eluates and unprocessed serum samples may be used interchangeably. Blood plasma from 113 mitogen-stimulated whole-blood samples was added to and eluted from the Protein Saver cards. The gamma interferon (IFN-γ) titers in the plasma eluates were compared to those of the unprocessed plasma samples obtained by IFN-γ ELISA. The results showed a significant correlation between the plasma eluates and the unprocessed plasma samples. To derive a signal in the plasma eluate, it was necessary to develop a novel and highly sensitive ELISA for the detection of IFN-γ. The serum samples stored on cards at room temperature over a 10-day period showed little variation in antibody titers. However, the plasma eluates showed a progressive loss of IFN-γ recovery over 10 days when stored at room temperature.