An immunohistochemical atlas of necroptotic pathway expression.

Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators - Caspase-8, RIPK1, RIPK3 and MLKL - in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Inappropriate noise detection in Tendril family pacing leads.

INTRODUCTION: Noise oversensing encountered in patients with Abbott Tendril leads in our hospital triggered an internal investigation. METHODS: We retrospectively analyzed patients with a Tendril lead model 1688, 1788, 1888, and 2088. Most leads were connected to Abbott generators. To exclude a primary generator issue as the cause of noise oversensing, we enrolled a cohort of patients in whom Medtronic CapSureFix leads model 4076 and 5076 were prospectively connected to similar Abbott generators. RESULTS: A total of 1063 Tendril leads were implanted in 869 patients. Noise was encountered in 66 leads (6.2%) during a follow-up of 3.9 years. Most affected leads had normal impedance and only a few of these patients were symptomatic. Reprogramming was attempted in 44 of 66 (67%), and reduced oversensing in 34 of 44 (77%) of these patients. Seventeen malfunctioning leads (1.5%) were replaced, including 16 of 66 (24%) of those with noise. Of the four leads with noise extracted and returned to the manufacturer, lead to device abrasion was identified in two and inner insulation breach in one. None of the 145 Medtronic CapSureFix leads connected to Abbott generators had noise during a follow-up of 3.6 years. CONCLUSION: Noise oversensing was relatively common in Tendril leads, but was not detected in Medtronic leads despite connecting to Abbott generators. Although the majority of the affected leads did not show abnormal impedance, outer or inner insulation breach was identified in three of the four returned leads. As patients with affected leads are generally asymptomatic, most of them can be managed conservatively.