BackgroundRecently, the safety of repeated and lengthy anesthesia administration has been called into question, a subset of these animal studies demonstrated that anesthetics induced blood-brain barrier (BBB) dysfunction. The BBB is critical in protecting the brain parenchyma from the surrounding micro-vasculature. BBB breakdown and dysfunction has been observed in several neurodegenerative diseases and may contribute to both the initiation and the progression of the disease. In this study we utilize a human induced pluripotent stem cell (iPSC) derived-BBB model, exhibiting near in vivo properties, to evaluate the effects of anesthetics on critical barrier properties.MethodsiPSC-derived brain microvascular endothelial cells (BMECs) expressed near in vivo barrier tightness assessed by trans-endothelial electrical resistance and para-cellular permeability. Efflux transporter activity was determined by substrate transport in the presence of specific inhibitors. Trans-cellular transport was measured utilizing large fluorescently tagged dextran. Tight junction localization in BMECs was evaluated with fluorescent microscopy. The anesthetic, propofol was exposed to BMECs at varying durations and concentrations and BBB properties were monitored post-exposure.ResultsFollowing propofol exposure, BMECs displayed reduced resistance and increased permeability indicative of a leaky barrier. Reduced barrier tightness and the dysregulation of occludin, a tight junction protein, were partly the result of an elevation in matrix metalloproteinase (MMP) levels. Efflux transporter activity and trans-cellular transport were unaffected by propofol exposure. Propofol induced barrier dysfunction was partially restored following matrix metalloproteinase inhibition.ConclusionFor the first time, we have demonstrated that propofol alters BBB integrity utilizing a human in vitro BBB model that displays key in vivo characteristics. A leaky BBB enables otherwise impermeable molecules such as pathogens and toxins the ability to reach vulnerable cell types of the brain parenchyma. A robust human in vitro BBB model will allow for the evaluation of several anesthetics at fluctuating clinical scenarios and to elucidate mechanisms with the goal of ultimately improving anesthesia safety.
Skeletal fluorosis is a long-term bone disease that develops when prolonged fluoride toxicity leads to osteosclerosis and bone deformities that result in crippling pain and debility. The disease is endemic to many countries due to environmental or industrial exposures. However, rare cases in the United States have been reported from various causes including heavy toothpaste ingestion, excessive tea consumption, voriconazole use, and inhalant abuse. Here, we present a case of a 41-year-old man who presented for weight loss and severe joint pains due to bony sclerotic lesions found on X-rays. Social history revealed that he had been recreationally inhaling compressed air dusters used for cleaning electronics. Owing to concern for malignancy, he underwent an extensive work-up which led to a diagnosis of colon cancer, but positron emission tomography/computed tomography (PET/CT) and bone biopsy were unexpectedly negative for metastatic bone disease. Further characterization of his lesions by skeletal survey led to a diagnosis of skeletal fluorosis secondary to inhalant abuse. As in this patient, the disease can be difficult for clinicians to recognize as it can be mistaken for various boney diseases such as metastatic cancer. However, once there is clinical suspicion for skeletal fluorosis, various tests to help confirm the diagnosis can include serum and urine fluoride levels, skeletal survey, and bone ash fluoride concentration. Treatment of skeletal fluorosis primarily involves cessation of fluoride exposure, and recovery can take years. Ultimately, further study is required to develop recommendations and guidelines for diagnosis, management, and prognosis of the disease in the United States.
Introduction/Objective The initial months of the SARS-CoV-2 pandemic entailed unprecedented changes to the way lives are lived worldwide, resulting in new means of social and economic engagement. For instance, stay-at-home orders led to youths (and staff) attending school virtually. Likewise, entire sectors of the workforce were blocked from their offices and jobs went online. The aim of these public health policies was to reduce the transmission of SARS- CoV-2; however, less attention has been given to how these policies have impacted the spread of other communicable illnesses. As such, we hypothesized that stay-at-home orders, in conjunction with increased hygiene surveillance and other public health guidelines, altered the transmission cycles of communicable gastrointestinal parasites. We anticipated that when plotted against time, a decrease in positive cases would occur concomitantly with known periods of lockdown; similarly, an increase in positive cases would follow efforts to re-open society. Methods/Case Report To probe this hypothesis, the laboratory information system was queried for positive and negative cases of Giardia and Cryptosporidium identified within the Indiana University Health System based on the Surve-Vue Signature™ Crypto/Giardia assay (Fisher Healthcare, Waltham, MA). Results (if a Case Study enter NA) Results were categorized by patient age: 0 to 18-years-old and 19-110-years-old. Initial review of the pediatric data set reflected that pandemic-related public health measures did not meaningfully alter the incidence of positive test results for these two parasites, though notable observations suggested patterns buried more deeply within the data. Conclusion The findings of this study have broad implications regarding the perceived and actual communicability of Giardia and Cryptosporidium (as well as other gastrointestinal parasites) in both normal and pandemic-times.
Background and Hypothesis: Propofol is an anesthetic commonly used to induce general anesthesia for a myriad of medical procedures. However, a growing corpus of evidence suggests that propofol-induced increases in VEGF may contribute to blood-brain barrier (BBB) leakiness in varying animal models. The BBB is a neurovascular structure which protects the central nervous system from pathogens, toxins, and other deleterious metabolites; therefore, considerations regarding BBB integrity in humans are indispensable to the practice of anesthesia. We hypothesize that propofol-induced BBB dysfunction in human models is partially mediated by an increase in VEGF expression. Methods: We utilized human induced pluripotent stem cells (hiPSC) to derive brain microvascular endothelial cells (BMECs)—the barrier forming cell type of the BBB. BMECs were then subjected to clinically relevant doses of propofol for 3 hours, and barrier integrity was monitored via transendothelial electrical resistance (TEER) and para-cellular permeability for up to 72 hours. Propofol-induced VEGF levels were determined with an ELISA assay. Axitinib, a VEGF receptor blocker, was further utilized to assess the role of VEGF in propofol-induced BBB breakdown. Results: Prior works, including this study, have shown that propofol induces BBB damage, as demonstrated by decreases in TEER; here, preliminary work with ELISA assays further suggest that BMECs treated with propofol demonstrate an upregulation of VEGF. Pretreatment of BMECs with Axitinib before the addition of propofol partially rescues TEER and thus attenuates the propofol-mediated diminution of TEER. These observations thereby implicate VEGF as a damage mediator after propofol treatment. Conclusion and Potential Impact: This study utilized an in vitro model to demonstrate that propofol may mediate, in part, damage to blood- brain barrier endothelium via a VEGF dependent mechanism; thus, this work may guide future investigations to facilitate the development of safer anesthetic alternatives, or towards additional pharmacologic interventions that counteract propofol-mediated damage during anesthetic induction.
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