A Neural Circuit for Spirituality and Religiosity Derived From Patients With Brain Lesions.

BACKGROUND: Over 80% of the global population consider themselves religious, with even more identifying as spiritual, but the neural substrates of spirituality and religiosity remain unresolved. METHODS: In two independent brain lesion datasets (N1 = 88; N2 = 105), we applied lesion network mapping to test whether lesion locations associated with spiritual and religious belief map to a specific human brain circuit. RESULTS: We found that brain lesions associated with self-reported spirituality map to a brain circuit centered on the periaqueductal gray. Intersection of lesion locations with this same circuit aligned with self-reported religiosity in an independent dataset and previous reports of lesions associated with hyper-religiosity. Lesion locations causing delusions and alien limb syndrome also intersected this circuit. CONCLUSIONS: These findings suggest that spirituality and religiosity map to a common brain circuit centered on the periaqueductal gray, a brainstem region previously implicated in fear conditioning, pain modulation, and altruistic behavior.

Fluid Restriction Contributes to Poor Nutritional Adequacy in Patients With Congenital Heart Disease Receiving Renal Replacement Therapy.

OBJECTIVES: Critically ill patients receiving renal replacement therapy (RRT) in the pediatric cardiac intensive care unit (CICU) are at high risk for inadequate nutrition delivery. The objective of this study is to evaluate barriers to adequate energy and protein delivery in critically ill patients with congenital heart disease receiving RRT. METHODS: This is a single-center retrospective cohort study of patients receiving RRT in the CICU from 2011 to 2019. Energy and protein adequacy was recorded over the first 7 days of RRT. Adequacy was defined as delivery of >80% of the energy and protein targets during this time period. Patients who achieved adequacy were compared to those who did not. Multivariable logistic regression models were constructed to determine factors independently associated with energy and protein adequacy while receiving RRT. RESULTS: Sixty patients were included for analysis. Fifty-five patients (92%) achieved energy adequacy and 37 patients (62%) achieved protein adequacy. A higher weight-for-age z-score (WAZ) on admission to the CICU was the only independent predictor of inadequate energy intake (odds ratio 0.07, 95% confidence interval 0.01-0.58, P = .014); median WAZ was -1.17 versus +1.24 for those with adequate versus inadequate energy intake, respectively. Fluid restriction to <80% of maintenance fluid at the time of RRT initiation was more likely in patients with higher WAZ. Fluid restriction was the only independent predictor of inadequate protein intake (odds ratio 0.13, 95% confidence interval 0.02-0.7, P = .018); 5% versus 30% were fluid restricted in those with adequate versus inadequate protein intake, respectively. Azotemia was not associated with inadequate protein intake. Initiation of RRT did not allow for liberalization of fluid intake over the time period evaluated. CONCLUSIONS: Protein delivery was inadequate in 38% of children undergoing RRT in the CICU. Fluid restriction was associated with inadequate protein intake and higher WAZ was associated with inadequate energy intake.

Setting Our Sights on Infectious Diseases.

In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learnings.

Preclinical candidate for the treatment of visceral leishmaniasis that acts through proteasome inhibition.

Visceral leishmaniasis (VL), caused by the protozoan parasites Leishmania donovani and Leishmania infantum, is one of the major parasitic diseases worldwide. There is an urgent need for new drugs to treat VL, because current therapies are unfit for purpose in a resource-poor setting. Here, we describe the development of a preclinical drug candidate, GSK3494245/DDD01305143/compound 8, with potential to treat this neglected tropical disease. The compound series was discovered by repurposing hits from a screen against the related parasite Trypanosoma cruzi Subsequent optimization of the chemical series resulted in the development of a potent cidal compound with activity against a range of clinically relevant L. donovani and L. infantum isolates. Compound 8 demonstrates promising pharmacokinetic properties and impressive in vivo efficacy in our mouse model of infection comparable with those of the current oral antileishmanial miltefosine. Detailed mode of action studies confirm that this compound acts principally by inhibition of the chymotrypsin-like activity catalyzed by the ß5 subunit of the L. donovani proteasome. High-resolution cryo-EM structures of apo and compound 8-bound Leishmania tarentolae 20S proteasome reveal a previously undiscovered inhibitor site that lies between the ß4 and ß5 proteasome subunits. This induced pocket exploits ß4 residues that are divergent between humans and kinetoplastid parasites and is consistent with all of our experimental and mutagenesis data. As a result of these comprehensive studies and due to a favorable developability and safety profile, compound 8 is being advanced toward human clinical trials.

Reward, salience, and attentional networks are activated by religious experience in devout Mormons.

High-level cognitive and emotional experience arises from brain activity, but the specific brain substrates for religious and spiritual euphoria remain unclear. We demonstrate using functional magnetic resonance imaging scans in 19 devout Mormons that a recognizable feeling central to their devotional practice was reproducibly associated with activation in nucleus accumbens, ventromedial prefrontal cortex, and frontal attentional regions. Nucleus accumbens activation preceded peak spiritual feelings by 1-3 s and was replicated in four separate tasks. Attentional activation in the anterior cingulate and frontal eye fields was greater in the right hemisphere. The association of abstract ideas and brain reward circuitry may interact with frontal attentional and emotive salience processing, suggesting a mechanism whereby doctrinal concepts may come to be intrinsically rewarding and motivate behavior in religious individuals.

Increased platelet mitochondrial respiration after cardiac arrest and resuscitation as a potential peripheral biosignature of cerebral bioenergetic dysfunction.

UNLABELLED: Cardiac arrest (CA) results in a sepsis-like syndrome with activation of the innate immune system and increased mitochondrial bioenergetics. OBJECTIVE: To determine if platelet mitochondrial respiration increases following CA in a porcine pediatric model of asphyxia-associated ventricular fibrillation (VF) CA, and if this readily obtained biomarker is associated with decreased brain mitochondrial respiration. CA protocol: 7 min of asphyxia, followed by VF, protocolized titration of compression depth to systolic blood pressure of 90 mmHg and vasopressor administration to a coronary perfusion pressure greater than 20 mmHg. PRIMARY OUTCOME: platelet integrated mitochondrial electron transport system (ETS) function evaluated pre- and post-CA/ROSC four hours after return of spontaneous circulation (ROSC). Secondary outcome: correlation of platelet mitochondrial bioenergetics to cerebral bioenergetic function. Platelet maximal oxidative phosphorylation (OXPHOSCI+CII), P < 0.02, and maximal respiratory capacity (ETSCI+CII), P < 0.04, were both significantly increased compared to pre-arrest values. This was primarily due to a significant increase in succinate-supported respiration through Complex II (OXPHOSCII, P < 0.02 and ETSCII, P < 0.03). Higher respiration was not due to uncoupling, as the LEAKCI + CII respiration (mitochondrial respiration independent of ATP-production) was unchanged after CA/ROSC. Larger increases in platelet mitochondrial respiratory control ratio (RCR) compared to pre-CA RCR were significantly correlated with lower RCRs in the cortex (P < 0.03) and hippocampus (P < 0.04) compared to sham respiration. Platelet mitochondrial respiration is significantly increased four hours after ROSC. Future studies will identify mechanistic relationships between this serum biomarker and altered cerebral bioenergetics function following cardiac arrest.

Coronary artery aneurysm and thrombosis following chronic ephedra use.

Ephedra, also known as Ma Huang, was commonly used to enhance athletic performance, "fat burning", and weight loss before its removal from the United States in April 2004 due to acute adverse health reactions including lethal arrhythmias, stroke, vasoconstriction, and myocardial infarction. We report the case of a 29-year-old patient with acute myocardial infarction, secondary to coronary artery aneurysms and thrombosis who reported use of Ma Huang, Xenadrine(r)RFA, and Hydroxycut at recommended dosages for a combined total of approximately 2 years. Other causes of coronary artery aneurysm and hypercoagulability were ruled out. Our case exemplifies the long-term (as opposed to acute) danger of ephedrine products and the first case of coronary artery aneurysm associated with its use.

STEMI in a 24-year-old man after use of a synephrine-containing dietary supplement: a case report and review of the literature.

Billions of dollars are spent annually in the United States in the largely unregulated market of dietary supplements. Many of these supplements are marketed as weight-loss and athletic-performance-enhancement products. The association of various ephedra-containing products with adverse cardiovascular events has led to a ban on the sale of these products by the U.S. Food and Drug Administration. The result has been the emergence of new formulations marketed for weight loss and athletic-performance enhancement that are "ephedra-free" but contain other sympathomimetic substances, the safety of which has not been established. We present the case of a previously healthy 24-year-old man who presented with an ST-segment-elevation myocardial infarction (STEMI) within hours of taking the ephedra-free product Nutrex Lipo-6x. Emergent coronary angiography revealed the presence of extensive, diffuse thrombus in the left anterior descending coronary artery. The patient had no risk factors for coronary artery disease or myocardial infarction; this includes the absence of a hypercoagulable state and the absence of a history of illicit drug use. This case of STEMI--associated as it is with the use of a synephrine-containing product by a person without risk factors for coronary artery disease--is to our knowledge the 1st reported in the literature. We discuss the patient's evaluation and clinical course, and we review the literature with respect to synephrine-containing dietary supplements. On the basis of synephrine's chemical composition and mechanism of action, we propose a direct association between this patient's use of Nutrex Lipo-6x and his STEMI.

Biomarkers of acute kidney injury.

Acute kidney injury (AKI) is a common condition with a high risk of death. The standard metrics used to define and monitor the progression of AKI, such as serum creatinine and blood urea nitrogen levels, are insensitive, nonspecific, and change significantly only after significant kidney injury and then with a substantial time delay. This delay in diagnosis not only prevents timely patient management decisions, including administration of putative therapeutic agents, but also significantly affects the preclinical evaluation of toxicity thereby allowing potentially nephrotoxic drug candidates to pass the preclinical safety criteria only to be found to be clinically nephrotoxic with great human costs. Studies to establish effective therapies for AKI will be greatly facilitated by two factors: (a) development of sensitive, specific, and reliable biomarkers for early diagnosis/prognosis of AKI in preclinical and clinical studies, and (b) development and validation of high-throughput innovative technologies that allow rapid multiplexed detection of multiple markers at the bedside.

The identification of isoprenoids that bind in the intersubunit cavity of Escherichia coli 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase by complementary biophysical methods.

The discovery of a distinct metabolic pathway, the non-mevalonate or 1-deoxy-D-xylulose-5-phosphate (DOXP) pathway for isoprenoid precursor biosynthesis, in eubacteria and apicomplexan parasites has revealed a new set of potential drug targets. The emphasis of research on this pathway has been on delineating the intermediates and the biochemical and structural characterization of component enzymes. Two new monoclinic crystal forms of recombinant Escherichia coli 2C-methyl-D-erythritol-2,4-cyclodiphosphate (MECP) synthase cocrystallized with (i) CMP and (ii) CMP and MECP show well defined electron density at the subunit interface suggestive of an isoprenoid-like ligand. 31P NMR analysis of the recombinant protein sample indicates the presence of bound diphosphate species and electrospray mass spectrometry identifies a mixture of isopentenyl diphosphate (and/or dimethylallyl diphosphate), geranyl diphosphate and farnesyl diphosphate in an approximate ratio of 1:4:2. The most prevalent species, geranyl diphosphate, was successfully modelled into the electron density, revealing the important protein-ligand interactions that stabilize binding of the isoprenoid. The observation that MECP synthase binds three metabolites that are produced by enzymes two, three and four stages downstream in isoprenoid biosynthesis suggests that feedback regulation of the non-mevalonate pathway is possible.