Tularemia From Veterinary Occupational Exposure.

Tularemia is a disease caused by Francisella tularensis, a highly infectious bacteria that can be transmitted to humans by direct contact with infected animals. Because of the potential for zoonotic transmission of F. tularensis, veterinary occupational risk is a concern. Here, we report on a human case of tularemia in a veterinarian after an accidental needlestick injury during abscess drainage in a sick dog. The veterinarian developed ulceroglandular tularemia requiring hospitalization but fully recovered after abscess drainage and a course of effective antibiotics. To systematically assess veterinary occupational transmission risk of F. tularensis, we conducted a survey of veterinary clinical staff after occupational exposure to animals with confirmed tularemia. We defined a high-risk exposure as direct contact to the infected animal's body fluids or potential aerosol inhalation without use of standard personal protective equipment (PPE). Survey data included information on 20 veterinary occupational exposures to animals with F. tularensis in 4 states. Veterinarians were the clinical staff most often exposed (40%), followed by veterinarian technicians and assistants (30% and 20%, respectively). Exposures to infected cats were most common (80%). Standard PPE was not used during 80% of exposures; a total of 7 exposures were categorized as high risk. Transmission of F. tularensis in the veterinary clinical setting is possible but overall risk is likely low. Veterinary clinical staff should use standard PPE and employ environmental precautions when handling sick animals to minimize risk of tularemia and other zoonotic infections; postexposure prophylaxis should be considered after high-risk exposures to animals with suspected or confirmed F. tularensis infection to prevent tularemia.

Analytical Unreliability of 25 Hydroxy Vitamin D Measurements in Pre-Term Neonates.

BACKGROUND: Vitamin D supplementation is common practice for neonates and infants due to limited stores of vitamin D at birth. Although not commonly encountered, vitamin D toxicity can occur due to over-supplementation. However, toxic concentrations are often not included in method validation experiments, and assays often are not validated in the neonatal population. METHODS: We compared serial 25 hydroxy vitamin D [25(OH)D] measurements in pre-term neonates receiving 25(OH)D supplementation and identified 12 patients wherein concentrations of 25(OH)D were above 50 ng/mL (125 nM) that required additional investigations as the 25(OH)D results did not match the clinical picture. Available samples were compared across 4 immunoassay platforms (LIAISON XL, Roche Cobas e602, Abbott Alinity i, and Siemens Centaur XP) and LC-MS/MS. RESULTS: Concentrations of 25(OH)D observed on one individual immunoassay platform (LIAISON XL) fluctuated substantially between subsequent blood draws in select neonates with elevated concentrations. Serum samples from these patients showed variable agreement between LC-MS/MS and other immunoassay platforms. These fluctuations were not explained by the presence of 3-epimer-25(OH)D or 24,25(OH)2D. CONCLUSIONS: Although we were unable to identify a cause for the variable elevated results, our findings suggest that neonatal 25(OH)D measurements alone should not be used for assessment of nutritional monitoring, and that clinical correlation and other laboratory parameters including ionized calcium should be considered.

Pediatric Reference Value Profiling of Essential Trace and Toxic Elements in Healthy Children and Adolescents Using High-Resolution and Triple Quadrupole Inductively Coupled Plasma Mass Spectrometry.

BACKGROUND: Assessment of trace and toxic element status is important for the diagnosis and monitoring of several pediatric conditions. Elemental deficiency and toxicity have serious implications, particularly in pediatrics wherein risk is higher. Pediatric reference intervals (RIs) for trace elements and normal exposure limits for toxic elements are lacking on modern analytical systems. Herein, reference values were established for 13 plasma and 22 whole blood trace elements in the Canadian Laboratory Initiative on Pediatric Reference Intervals (CALIPER) cohort of healthy children and adolescents. METHODS: Approximately 320 healthy children and adolescents were recruited with informed consent. Trace elements were measured in whole blood and plasma samples using 2 technologies: (a) triple quadrupole inductively coupled plasma tandem mass spectrometry (ICP-MS/MS) (n = 172) and (b) high-resolution sector field ICPMS (HR-SF-ICPMS) (n =161). RIs and normal exposure limits were then established according to Clinical and Laboratory Standards Institute guidelines. RESULTS: Of all elements assessed, none required sex partitioning and 8 required age partitioning (e.g., copper, manganese, and cadmium). Reference value distributions determined via ICP-MS/MS and HR-SF-ICPMS demonstrated excellent concordance, with few exceptions (e.g., molybdenum, cobalt, and nickel). CONCLUSIONS: These data represent the first study wherein pediatric RIs and normal exposure limits were derived simultaneously on 2 different clinically validated MS platforms which provide urgently needed data to inform clinical decision-making for trace elements in pediatrics. Study findings suggest some trace elements require age-specific consideration for appropriate interpretation. Highly concordant observations across the 2 analytical methods also demonstrate the comparability and reliability of results obtained on both platforms.

Highly sensitive tandem mass spectrometric measurement of serum estradiol without derivatization and pediatric reference intervals in children and adolescents.

OBJECTIVES: Monitoring estradiol (E2) is important for determining the onset of pubertal development as well as in the evaluation of girls with precocious puberty. However, E2 measurement remains an analytical challenge in children, who have lower circulating levels. We developed and evaluated a simple and sensitive LC-MS/MS procedure for serum E2 quantification in pediatric populations and established age- and sex-specific pediatric reference intervals. METHODS: Residual patient serum samples were used to evaluate the analytical performance of our in-house LC-MS/MS E2 assay. The evaluation included accuracy, precision, linearity, functional sensitivity (LLoQ), and method comparison. Age- and sex-specific pediatric E2 reference intervals were also established from a cohort of 405 healthy children (birth to 18 years) recruited with informed consent. Age- and sex-specific differences were assessed, and outliers were removed. Reference intervals were established using the robust method. RESULTS: The assay imprecision was <5.3 %. Assay linearity ranged from 13.7 to 1923.3 pmol/L. The LLoQ corresponding to a CV of 20 % was determined to be 8.9 pmol/L. Bland-Altman analysis revealed a mean bias of 29.3 pmol/L or 9.1 % between our LC-MS/MS E2 assay and an external reference laboratory measuring E2 by LC-MS/MS. CONCLUSIONS: Our LC-MS/MS E2 assay shows acceptable accuracy, precision, functional sensitivity (LLoQ), and linearity for E2 quantification. Our LC-MS/MS E2 assay also showed good agreement with an external reference laboratory measuring E2 by LC-MS/MS. In addition, using CALIPER samples, we established robust age- and sex-specific pediatric E2 reference intervals to improve accuracy of test result interpretation and clinical decision making.

Structured sampling of olfactory input by the fly mushroom body.

Associative memory formation and recall in the fruit fly Drosophila melanogaster is subserved by the mushroom body (MB). Upon arrival in the MB, sensory information undergoes a profound transformation from broadly tuned and stereotyped odorant responses in the olfactory projection neuron (PN) layer to narrowly tuned and nonstereotyped responses in the Kenyon cells (KCs). Theory and experiment suggest that this transformation is implemented by random connectivity between KCs and PNs. However, this hypothesis has been challenging to test, given the difficulty of mapping synaptic connections between large numbers of brain-spanning neurons. Here, we used a recent whole-brain electron microscopy volume of the adult fruit fly to map PN-to-KC connectivity at synaptic resolution. The PN-KC connectome revealed unexpected structure, with preponderantly food-responsive PN types converging at above-chance levels on downstream KCs. Axons of the overconvergent PN types tended to arborize near one another in the MB main calyx, making local KC dendrites more likely to receive input from those types. Overconvergent PN types preferentially co-arborize and connect with dendrites of αß and α'ß' KC subtypes. Computational simulation of the observed network showed degraded discrimination performance compared with a random network, except when all signal flowed through the overconvergent, primarily food-responsive PN types. Additional theory and experiment will be needed to fully characterize the impact of the observed non-random network structure on associative memory formation and recall.

Iron in airway macrophages and infective exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Excess pulmonary iron has been implicated in the pathogenesis of lung disease, including asthma and COPD. An association between higher iron content in sputum macrophages and infective exacerbations of COPD has previously been demonstrated. OBJECTIVES: To assess the mechanisms of pulmonary macrophage iron sequestration, test the effect of macrophage iron-loading on cellular immune function, and prospectively determine if sputum hemosiderin index can predict infectious exacerbations of COPD. METHODS: Intra- and extracellular iron was measured in cell-line-derived and in freshly isolated sputum macrophages under various experimental conditions including treatment with exogenous IL-6 and hepcidin. Bacterial uptake and killing were compared in the presence or absence of iron-loading. A prospective cohort of COPD patients with defined sputum hemosiderin indices were monitored to determine the annual rate of severe infectious exacerbations. RESULTS: Gene expression studies suggest that airway macrophages have the requisite apparatus of the hepcidin-ferroportin axis. IL-6 and hepcidin play roles in pulmonary iron sequestration, though IL-6 appears to exert its effect via a hepcidin-independent mechanism. Iron-loaded macrophages had reduced uptake of COPD-relevant organisms and were associated with higher growth rates. Infectious exacerbations were predicted by sputum hemosiderin index (ß = 0.035, p = 0.035). CONCLUSIONS: We demonstrate in-vitro and population-level evidence that excess iron in pulmonary macrophages may contribute to recurrent airway infection in COPD. Specifically, IL-6-dependent iron sequestration by sputum macrophages may result in immune cell dysfunction and ultimately lead to increased frequency of infective exacerbation.

A Diagnostic Dilemma from a Presentation of Shortness of Breath and Chest Pain.

INTRODUCTION: A patient presented to hospital with chest pain and shortness of breath on 2 occasions 4 weeks apart. Clinical examination revealed an elevated jugular venous pressure consistent with heart failure or elevated filling pressures. METHODS: The patient was investigated through various modalities including electrocardiogram (ECG), transthoracic echocardiogram, coronary angiography, MRI, cardiac catheterization, positron emission tomography, and an extensive laboratory workup. RESULTS: Serial hs TnI measurements consistently revealed grossly elevated troponin I (>10 000 ng/L). In-lab investigation of increased high sensitivity troponin I (hsTnI) showed evidence of falsely increased troponin due to the presence of heterophilic antibodies. DISCUSSION: This case demonstrates a complex patient presentation and the value of involving the laboratory medicine team when dealing with potentially discrepant results. This is a rare report of grossly elevated troponin due to heterophilic antibodies for high-sensitivity troponin Abbott assay.

Trends in Incidence and Mortality Rates of Uterine Cancer in Kentucky.

OBJECTIVES: The objective of this analysis was to gauge how the incidence and mortality of uterine cancer in Kentucky have changed from 1995 through 2017. An assessment of the trends in incidence and mortality across different geographic areas and between different races was also performed. METHODS: Age-adjusted annual incidence and mortality rates for uterine cancer were obtained from the Kentucky Cancer Registry. A meta-regression framework was used to assess changes in incidence and mortality rates during the time frame and to determine differences in these rates between rural versus urban counties, Appalachian versus non-Appalachian counties, and Black versus White women. RESULTS: The incidence of uterine cancer has significantly increased throughout the state of Kentucky since 1995. Uterine cancer incidence was 10% and 22% higher in rural and Appalachian counties, respectively, compared with urban and non-Appalachian counties (P < 0.0001) from 1995 through 2017. In contrast, urban and non-Appalachian women had higher or equivalent age-adjusted mortality from uterine cancer, compared with rural and Appalachian women, respectively. The incidence of uterine cancer was significantly higher in White women compared with Black women from 1995 through 2006, but since 2007, there has been no significant difference in uterine cancer incidence based on race. Black women had higher age-adjusted mortality than White women throughout the entire time period examined. CONCLUSIONS: The incidence of uterine cancer is higher in rural and Appalachian Kentucky, without a corresponding geographic trend in mortality. Uterine cancer mortality is significantly higher in Black women.

Precision test of statistical dynamics with state-to-state ultracold chemistry.

Chemical reactions represent a class of quantum problems that challenge both the current theoretical understanding and computational capabilities1. Reactions that occur at ultralow temperatures provide an ideal testing ground for quantum chemistry and scattering theories, because they can be experimentally studied with unprecedented control2, yet display dynamics that are highly complex3. Here we report the full product state distribution for the reaction 2KRb → K2 + Rb2. Ultracold preparation of the reactants allows us complete control over their initial quantum degrees of freedom, whereas state-resolved, coincident detection of both products enables the probability of scattering into each of the 57 allowed rotational state-pairs to be measured. Our results show an overall agreement with a state-counting model based on statistical theory4-6, but also reveal several deviating state-pairs. In particular, we observe a strong suppression of population in the state-pair closest to the exoergicity limit as a result of the long-range potential inhibiting the escape of products. The completeness of our measurements provides a benchmark for quantum dynamics calculations beyond the current state of the art.

Nuclear spin conservation enables state-to-state control of ultracold molecular reactions.

Quantum-state control of reactive systems has enabled microscopic probes of underlying interaction potentials and the alteration of reaction rates using quantum statistics. However, extending such control to the quantum states of reaction outcomes remains challenging. Here, we realize this goal by utilizing the conservation of nuclear spins throughout the reaction. Using resonance-enhanced multiphoton ionization spectroscopy to investigate the products formed in bimolecular reactions between ultracold KRb molecules we find that the system retains a near-perfect memory of the reactants' nuclear spins, manifested as a strong parity preference for the rotational states of the products. We leverage this effect to alter the occupation of these product states by changing the coherent superposition of initial nuclear spin states with an external magnetic field. In this way, we are able to control both the inputs and outputs of a reaction with quantum-state resolution. The techniques demonstrated here open up the possibilities to study quantum entanglement between reaction products and ultracold reaction dynamics at the state-to-state level.

Reoccurrence of Stroke in a Patient With Peri-Device Leak of WATCHMAN Device.

Atrial fibrillation is the leading cause of cardioembolic stroke, with emboli most commonly originating from the left atrial appendage. We report the case of a 71-year-old male with left atrial appendage closure via implantation of the WATCHMAN device, due to possible anticoagulation therapy failure and increased bleeding risk, following a stroke. Following a new stroke over a year later, a 1.8-mm peri-device leak was observed. Surgical records noted a minimal (<5 mm jet flow) peri-device leak after the installation, which was considered successful WATCHMAN implantation per protocol. This case highlights the persistent risk of cardioembolic stroke in patients with nonvalvular atrial fibrillation despite device implantation and questions the significance of peri-device leak and further management with anticoagulation for recurrent stroke.

Neuronal mitochondrial calcium uniporter deficiency exacerbates axonal injury and suppresses remyelination in mice subjected to experimental autoimmune encephalomyelitis.

High-capacity mitochondrial calcium (Ca2+) uptake by the mitochondrial Ca2+ uniporter (MCU) is strategically positioned to support the survival and remyelination of axons in multiple sclerosis (MS) by undocking mitochondria, buffering Ca2+ and elevating adenosine triphosphate (ATP) synthesis at metabolically stressed sites. Respiratory chain deficits in MS are proposed to metabolically compromise axon survival and remyelination by suppressing MCU activity. In support of this hypothesis, clinical scores, mitochondrial dysfunction, myelin loss, axon damage and inflammation were elevated while remyelination was blocked in neuronal MCU deficient (Thy1-MCU Def) mice relative to Thy1 controls subjected to experimental autoimmune encephalomyelitis (EAE). At the first sign of walking deficits, mitochondria in EAE/Thy1 axons showed signs of activation. By contrast, cytoskeletal damage, fragmented mitochondria and large autophagosomes were seen in EAE/Thy1-MCU Def axons. As EAE severity increased, EAE/Thy1 axons were filled with massively swollen mitochondria with damaged cristae while EAE/Thy1-MCU Def axons were riddled with late autophagosomes. ATP concentrations and mitochondrial gene expression were suppressed while calpain activity, autophagy-related gene mRNA levels and autophagosome marker (LC3) co-localization in Thy1-expressing neurons were elevated in the spinal cords of EAE/Thy1-MCU Def compared to EAE/Thy1 mice. These findings suggest that MCU inhibition contributes to axonal damage that drives MS progression.

Cervical cancer incidence and mortality rates in Kentucky.

OBJECTIVES: The goal of this study was to assess how the incidence and mortality of cervical cancer in Kentucky has changed from 1995 through 2017. Additionally, trends in incidence and mortality across different geographic areas and between different races were evaluated. METHODS: Age-adjusted annual incidence and mortality rates for cervical cancer were collected from the Kentucky Cancer Registry (KCR). A quadratic fit model was used to evaluate changes in the incidence and mortality over time and to compare differences in cervical cancer incidence and mortality by: 1) rural versus urban counties, 2) Appalachian versus non-Appalachian counties, and 3) black versus white women. RESULTS: Overall, the incidence of cervical cancer has significantly decreased throughout Kentucky since 1995. When comparing different geographic regions, the incidence was 14% and 23% higher in rural and Appalachian counties, respectively, compared to urban and non-Appalachian counties (p < 0.0001) throughout the study period. The incidence of cervical cancer was significantly higher in black women compared to white women from 1995 through 2007, but since 2008 there has been no significant difference in cervical cancer incidence based on race. Similar to incidence rates, mortality from cervical cancer was 29% higher in Appalachia (p = 0.0004) throughout the studied time period. Black women had higher age-adjusted mortality than white women until 2012, but since that time there has not been a significant difference in cervical cancer mortality based on race. CONCLUSIONS: Women residing in rural and Appalachian Kentucky have higher cervical cancer incidence and mortality rates.

The cell-permeable mitochondrial calcium uniporter inhibitor Ru265 preserves cortical neuron respiration after lethal oxygen glucose deprivation and reduces hypoxic/ischemic brain injury.

The mitochondrial calcium (Ca2+) uniporter (MCU) mediates high-capacity mitochondrial Ca2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency and duration of seizure-like behaviours. Ru265 is proposed to promote convulsions by reducing Ca2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the therapeutic potential of MCU inhibition in the treatment of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265.

Experimental autoimmune encephalomyelitis accelerates remyelination after lysophosphatidylcholine-induced demyelination in the corpus callosum.

Experimental autoimmune encephalomyelitis (EAE) and lysophosphatidylcholine (LPC)-induced demyelination were combined to study remyelination in a pro-inflammatory context. Two groups of female C57BL/6 mice were subjected either to EAE (EAE mice) or injected with just complete Freund's adjuvant (CFA) and pertussis toxin (PTX) followed by bilateral LPC and phosphate buffered saline injections in the corpus callosum on day 7 (CFA controls). Relative to CFA controls, EAE accelerated remyelination and increased innate immune cell activation, lymphocyte infiltration and cytokine gene expression in the LPC lesions. However, compared to CFA mice, remyelination was reduced (day 14) suggesting this aggressive immune response also compromised myelin repair in EAE mice.

Early progression of Krabbe disease in patients with symptom onset between 0 and 5 months.

BACKGROUND: Krabbe disease is a rare neurological disorder caused by a deficiency in the lysosomal enzyme, ß-galactocerebrosidase, resulting in demyelination of the central and peripheral nervous systems. If left without treatment, Krabbe disease results in progressive neurodegeneration with reduced quality of life and early death. The purpose of this prospective study was to describe the natural progression of early onset Krabbe disease in a large cohort of patients. METHODS: Patients with early onset Krabbe disease were prospectively evaluated between 1999 and 2018. Data sources included diagnostic testing, parent questionnaires, standardized multidisciplinary neurodevelopmental assessments, and neuroradiological and neurophysiological tests. RESULTS: We evaluated 88 children with onset between 0 and 5 months. Median age of symptom onset was 4 months; median time to diagnosis after onset was 3 months. The most common initial symptoms were irritability, feeding difficulties, appendicular spasticity, and developmental delay. Other prevalent symptoms included axial hypotonia, abnormal deep tendon reflexes, constipation, abnormal pupillary response, scoliosis, loss of head control, and dysautonomia. Results of nerve conduction studies showed that 100% of patients developed peripheral neuropathy by 6 months of age. Median galactocerebrosidase enzyme activity was 0.05 nmol/h/mg protein. The median survival was 2 years. CONCLUSIONS: This is the largest prospective natural history study of Krabbe disease. It provides a comprehensive description of the disease during the first 2 years of life. With recent inclusion of state mandated newborn screening programs and promising therapeutic interventions, enhancing our understanding of disease progression in early onset Krabbe disease will be critical for developing treatments, designing clinical trials, and evaluating outcomes.

Spin transport in a Mott insulator of ultracold fermions.

Strongly correlated materials are expected to feature unconventional transport properties, such that charge, spin, and heat conduction are potentially independent probes of the dynamics. In contrast to charge transport, the measurement of spin transport in such materials is highly challenging. We observed spin conduction and diffusion in a system of ultracold fermionic atoms that realizes the half-filled Fermi-Hubbard model. For strong interactions, spin diffusion is driven by super-exchange and doublon-hole-assisted tunneling, and strongly violates the quantum limit of charge diffusion. The technique developed in this work can be extended to finite doping, which can shed light on the complex interplay between spin and charge in the Hubbard model.

Trypanosoma cruzi in a Mexican Free-Tailed Bat ( Tadarida brasiliensis) in Oklahoma, USA.

Trypanosoma cruzi is a vector-borne protozoan parasite that infects seven million individuals in Central and South America and is the etiologic agent of Chagas disease. There are increasing reports of endemic transmission within the southern US. Trypanosoma cruzi occurs in wild raccoons and dogs in Oklahoma, but its endemicity in the state is poorly studied. We suspected Mexican free-tailed bats ( Tadarida brasiliensis) contributed to the endemicity of T. cruzi in Oklahoma due to their annual migration from Central America to their North American maternity roosts. During the summer of 2017, we sampled 361 Mexican free-tailed bats for T. cruzi at three maternity roosts in Oklahoma. We collected wing tissues, extracted T. cruzi DNA, amplified target DNA by PCR using the primers TCZ1/TCZ2, and observed amplification by gel electrophoresis. One juvenile Mexican free-tailed bat was positive for T. cruzi resulting in a 0.27% prevalence in the 361 sampled bats. Our finding of a wild bat naturally infected with T. cruzi in Oklahoma provided insight on the endemicity of T. cruzi in underrepresented endemic areas. The positive sample was sequenced, confirmed as T. cruzi, and uploaded to GenBank (no. MG869732). Future research will focus on monitoring T. cruzi prevalence in wild bats and insect vectors to better understand the enzootic emergence of this neglected tropical parasite.

A Complete Electron Microscopy Volume of the Brain of Adult Drosophila melanogaster.

Drosophila melanogaster has a rich repertoire of innate and learned behaviors. Its 100,000-neuron brain is a large but tractable target for comprehensive neural circuit mapping. Only electron microscopy (EM) enables complete, unbiased mapping of synaptic connectivity; however, the fly brain is too large for conventional EM. We developed a custom high-throughput EM platform and imaged the entire brain of an adult female fly at synaptic resolution. To validate the dataset, we traced brain-spanning circuitry involving the mushroom body (MB), which has been extensively studied for its role in learning. All inputs to Kenyon cells (KCs), the intrinsic neurons of the MB, were mapped, revealing a previously unknown cell type, postsynaptic partners of KC dendrites, and unexpected clustering of olfactory projection neurons. These reconstructions show that this freely available EM volume supports mapping of brain-spanning circuits, which will significantly accelerate Drosophila neuroscience. VIDEO ABSTRACT.

Tamoxifen-induced knockdown of the mitochondrial calcium uniporter in Thy1-expressing neurons protects mice from hypoxic/ischemic brain injury.

The mitochondrial calcium uniporter (MCU) mediates high-capacity mitochondrial calcium uptake that stimulates energy production. However, excessive MCU activity can cause ischemic heart injury. To examine if the MCU is also involved in hypoxic/ischemic (HI) brain injury, we have generated conditional MCU knockout mice by tamoxifen (TMX) administration to adult MCU-floxed (MCUfl/fl) mice expressing a construct encoding Thy1-cre/ERT2-eYFP. Relative to TMX/Thy1-cre/ERT2-eYFP controls, HI-induced sensorimotor deficits, forebrain neuron loss and mitochondrial damage were decreased for conditional MCU knockout mice. MCU knockdown by siRNA-induced silencing in cortical neuron cultures also reduced cell death and mitochondrial respiratory deficits following oxygen-glucose deprivation. Furthermore, MCU silencing did not produce metabolic abnormalities in cortical neurons observed previously for global MCU nulls that increased reliance on glycolysis for energy production. Based on these findings, we propose that brain-penetrant MCU inhibitors have strong potential to be well-tolerated and highly-efficacious neuroprotectants for the acute management of ischemic stroke.