Succinylation of Park 7 Activates a Protective Metabolic Response to Acute Kidney Injury.

Acute Kidney Injury (AKI) is extremely prevalent among hospitalizations and presents a significant risk for the development of chronic kidney disease and increased mortality. Ischemia caused by shock, trauma, and transplant are common causes of AKI. To attenuate ischemic AKI therapeutically, we need a better understanding of the physiological and cellular mechanisms underlying damage. Instances of ischemia are most damaging in Proximal Tubule Epithelial Cells (PTECs) where hypoxic signaling cascades, and perhaps more rapidly, posttranslational modifications (PTMs), act in concert to change cellular metabolism. Here we focus on the effects of the understudied PTM, lysine succinylation. We have previously shown a protective effect of protein hypersuccinylation on PTECs after depletion of the desuccinylase Sirtuin 5. General trends in the results suggested that hypersuccinylation led to upregulation of peroxisomal activity and was protective against kidney injury. Included in the list of changes was the Parkinson's-related deglycase Park7. There is little known about any links between peroxisome activity and Park7. In this study we show in vitro and in vivo that Park7 has a crucial role in protection from AKI, and upregulated peroxisome activity. These data in combination with published results of Park7's protective role in cardiovascular damage and chronic kidney disease lead us to hypothesize that succinylation of Park7 may ameliorate oxidative damage resulting from AKI and prevent disease progression. This novel mechanism provides a potential therapeutic mechanism that can be targeted.

Hydrophobic residues in S1 modulate enzymatic function and voltage sensing in voltage-sensing phosphatase.

The voltage-sensing domain (VSD) is a four-helix modular protein domain that converts electrical signals into conformational changes, leading to open pores and active enzymes. In most voltage-sensing proteins, the VSDs do not interact with one another, and the S1-S3 helices are considered mainly scaffolding, except in the voltage-sensing phosphatase (VSP) and the proton channel (Hv). To investigate its contribution to VSP function, we mutated four hydrophobic amino acids in S1 to alanine (F127, I131, I134, and L137), individually or in combination. Most of these mutations shifted the voltage dependence of activity to higher voltages; however, not all substrate reactions were the same. The kinetics of enzymatic activity were also altered, with some mutations significantly slowing down dephosphorylation. The voltage dependence of VSD motions was consistently shifted to lower voltages and indicated a second voltage-dependent motion. Additionally, none of the mutations broke the VSP dimer, indicating that the S1 impact could stem from intra- and/or intersubunit interactions. Lastly, when the same mutations were introduced into a genetically encoded voltage indicator, they dramatically altered the optical readings, making some of the kinetics faster and shifting the voltage dependence. These results indicate that the S1 helix in VSP plays a critical role in tuning the enzyme's conformational response to membrane potential transients and influencing the function of the VSD.

S1 hydrophobic residues modulate voltage sensing phosphatase enzymatic function and voltage sensing.

The voltage sensing domain (VSD) is a four-helix modular protein domain that converts electrical signals into conformational changes, leading to open pores and active enzymes. In most voltage sensing proteins, the VSDs do not interact with one another and the S1-S3 helices are considered mainly as scaffolding. The two exceptions are the voltage sensing phosphatase (VSP) and the proton channel (Hv). VSP is a voltage-regulated enzyme and Hvs are channels that only have VSDs. To investigate the S1 contribution to VSP function, we individually mutated four hydrophobic amino acids in S1 to alanine (F127, I131, I134 and L137). We also combined these mutations to generate quadruple mutation designated S1-Q. Most of these mutations shifted the voltage dependence of activity to higher voltages though interestingly, not all substrate reactions were the same. The kinetics of enzymatic activity were also altered with some mutations significantly slowing down dephosphorylation. The voltage dependence of VSD motions were consistently shifted to lower voltages and indicated a second voltage dependent motion. Co-immunoprecipitation demonstrated that none of the mutations broke the VSP dimer indicating that the S1 impact could stem from intrasubunit and/or intersubunit interactions. Lastly, when the same alanine mutations were introduced into a genetically encoded voltage indicator, they dramatically altered the optical readings, making some of the kinetics faster and shifting the voltage dependence. These results indicate that the S1 helix in VSP plays a critical role in tuning the enzymes conformational response to membrane potential transients and influencing the function of the VSD.

Dicarboxylic Acid Dietary Supplementation Protects against AKI.

SIGNIFICANCE STATEMENT: In this study, we demonstrate that a common, low-cost compound known as octanedioic acid (DC 8 ) can protect mice from kidney damage typically caused by ischemia-reperfusion injury or the chemotherapy drug cisplatin. This compound seems to enhance peroxisomal activity, which is responsible for breaking down fats, without adversely affecting mitochondrial function. DC 8 is not only affordable and easy to administer but also effective. These encouraging findings suggest that DC 8 could potentially be used to assist patients who are at risk of experiencing this type of kidney damage. BACKGROUND: Proximal tubules are rich in peroxisomes, which are damaged during AKI. Previous studies demonstrated that increasing peroxisomal fatty acid oxidation (FAO) is renoprotective, but no therapy has emerged to leverage this mechanism. METHODS: Mice were fed with either a control diet or a diet enriched with dicarboxylic acids, which are peroxisome-specific FAO substrates, then subjected to either ischemia-reperfusion injury-AKI or cisplatin-AKI models. Biochemical, histologic, genetic, and proteomic analyses were performed. RESULTS: Both octanedioic acid (DC 8 ) and dodecanedioic acid (DC 12 ) prevented the rise of AKI markers in mice that were exposed to renal injury. Proteomics analysis demonstrated that DC 8 preserved the peroxisomal and mitochondrial proteomes while inducing extensive remodeling of the lysine succinylome. This latter finding indicates that DC 8 is chain shortened to the anaplerotic substrate succinate and that peroxisomal FAO was increased by DC 8 . CONCLUSIONS: DC 8 supplementation protects kidney mitochondria and peroxisomes and increases peroxisomal FAO, thereby protecting against AKI.

ATP1A1-linked diseases require a malfunctioning protein product from one allele.

Heterozygous germline variants in ATP1A1, the gene encoding the α1 subunit of the Na+/K+-ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT). ATP1A1 variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αß) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na+ and K+ that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-null ATP1A1 variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous Atp1a1+/- knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that Atp1a1+/- mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of known ATP1A1-related diseases despite carrying a plasma-membrane protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction by ATP1A1 variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.

A Na pump with reduced stoichiometry is up-regulated by brine shrimp in extreme salinities.

Brine shrimp (Artemia) are the only animals to thrive at sodium concentrations above 4 M. Salt excretion is powered by the Na+,K+-ATPase (NKA), a heterodimeric (αß) pump that usually exports 3Na+ in exchange for 2 K+ per hydrolyzed ATP. Artemia express several NKA catalytic α-subunit subtypes. High-salinity adaptation increases abundance of α2KK, an isoform that contains two lysines (Lys308 and Lys758 in transmembrane segments TM4 and TM5, respectively) at positions where canonical NKAs have asparagines (Xenopus α1's Asn333 and Asn785). Using de novo transcriptome assembly and qPCR, we found that Artemia express two salinity-independent canonical α subunits (α1NN and α3NN), as well as two ß variants, in addition to the salinity-controlled α2KK. These ß subunits permitted heterologous expression of the α2KK pump and determination of its CryoEM structure in a closed, ion-free conformation, showing Lys758 residing within the ion-binding cavity. We used electrophysiology to characterize the function of α2KK pumps and compared it to that of Xenopus α1 (and its α2KK-mimicking single- and double-lysine substitutions). The double substitution N333K/N785K confers α2KK-like characteristics to Xenopus α1, and mutant cycle analysis reveals energetic coupling between these two residues, illustrating how α2KK's Lys308 helps to maintain high affinity for external K+ when Lys758 occupies an ion-binding site. By measuring uptake under voltage clamp of the K+-congener 86Rb+, we prove that double-lysine-substituted pumps transport 2Na+ and 1 K+ per catalytic cycle. Our results show how the two lysines contribute to generate a pump with reduced stoichiometry allowing Artemia to maintain steeper Na+ gradients in hypersaline environments.

Magnetic resonance neurography techniques in the pediatric population.

The use of magnetic resonance imaging (MRI) in the evaluation of the central extracranial nervous system, namely the brachial and lumbosacral plexuses, is well established and has been performed for many years. Only recently after numerous advances in MRI, has image quality been sufficient to properly visualize small structures, such as nerves in the extremities. Despite the advances, peripheral MR Neurography remains a complex and difficult examination to perform, especially in the pediatric patient population, in which the risk for motion artifact and compliance is always of concern. Thus, technical aspects of the MR imaging protocol must be flexible but robust, to balance image quality with scan time, in a patient population of varying sizes. An additional important step for reliably performing a successful MR Neurography examination is the non-technical pre-imaging preparation, which includes patient/family education and open communication with referring teams. This paper will discuss in detail the individual technical and non-technical/operational aspects of peripheral MR Neurography, to help guide in building a successful program in the pediatric population.

Reduced Left Atrial Rotational Flow Is Independently Associated With Embolic Brain Infarcts.

BACKGROUND: Up to 25% of embolic strokes occur in individuals without atrial fibrillation (AF) or other identifiable mechanisms. OBJECTIVES: This study aims to assess whether left atrial (LA) blood flow characteristics are associated with embolic brain infarcts, independently of AF. METHODS: The authors recruited 134 patients: 44 with a history of ischemic stroke and 90 with no history of stroke but CHA2DS2VASc score ≥1. Cardiac magnetic resonance (CMR) evaluated cardiac function and LA 4-dimensional flow parameters, including velocity and vorticity (a measure of rotational flow), and brain magnetic resonance imaging (MRI) was performed to detect large noncortical or cortical infarcts (LNCCIs) (likely embolic), or nonembolic lacunar infarcts. RESULTS: Patients (41% female; age 70 ± 9 years) had moderate stroke risk (median CHA2DS2VASc = 3, Q1-Q3: 2-4). Sixty-eight (51%) had diagnosed AF, of whom 58 (43%) were in AF during CMR. Thirty-nine (29%) had ≥1 LNCCI, 20 (15%) had ≥1 lacunar infarct without LNCCI, and 75 (56%) had no infarct. Lower LA vorticity was significantly associated with prevalent LNCCIs after adjustment for AF during CMR, history of AF, CHA2DS2VASc score, LA emptying fraction, LA indexed maximum volume, left ventricular ejection fraction, and indexed left ventricular mass (OR: 2.06 [95% CI: 1.08-3.92 per SD]; P = 0.027). By contrast, LA flow peak velocity was not significantly associated with LNCCIs (P = 0.21). No LA parameter was associated with lacunar infarcts (all P > 0.05). CONCLUSIONS: Reduced LA flow vorticity is significantly and independently associated with embolic brain infarcts. Imaging LA flow characteristics may aid identification of individuals who would benefit from anticoagulation for embolic stroke prevention, regardless of heart rhythm.

ATP1A1 -linked diseases require a malfunctioning protein product from one allele.

Heterozygous germline variants in ATP1A1 , the gene encoding the α1 subunit of the Na + /K + -ATPase (NKA), have been linked to diseases including primary hyperaldosteronism and the peripheral neuropathy Charcot-Marie-Tooth disease (CMT). ATP1A1 variants that cause CMT induce loss-of-function of NKA. This heterodimeric (αß) enzyme hydrolyzes ATP to establish transmembrane electrochemical gradients of Na + and K + that are essential for electrical signaling and cell survival. Of the 4 catalytic subunit isoforms, α1 is ubiquitously expressed and is the predominant paralog in peripheral axons. Human population sequencing datasets indicate strong negative selection against both missense and protein-null ATP1A1 variants. To test whether haploinsufficiency generated by heterozygous protein-null alleles are sufficient to cause disease, we tested the neuromuscular characteristics of heterozygous Atp1a1 +/- knockout mice and their wildtype littermates, while also evaluating if exercise increased CMT penetrance. We found that Atp1a1 +/- mice were phenotypically normal up to 18 months of age. Consistent with the observations in mice, we report clinical phenotyping of a healthy adult human who lacks any clinical features of known ATP1A1 -related diseases despite carrying a protein-null early truncation variant, p.Y148*. Taken together, these results suggest that a malfunctioning gene product is required for disease induction by ATP1A1 variants and that if any pathology is associated with protein-null variants, they may display low penetrance or high age of onset.

Storying survival: An approach to radical healing for the Black community.

Anti-Black racism (ABR) contributes to racial trauma and to the disproportionate negative mental, physical, and social outcomes faced by Black populations (Hargons et al., 2017; Wun, 2016a). The previous literature demonstrates that storytelling and other narrative interventions are often used to promote collective healing among Black people (Banks-Wallace, 2002; Moors, 2019). Storying survival (i.e., the utilization of stories to promote liberation from racial trauma) is one such narrative intervention (Mosley et al., 2021); however, little is known about the processes by which Black people utilize storying survival to promote radical healing. Using an intersectional framework and thematic analysis from a phenomenological perspective (Braun & Clarke, 2006), the present study analyzed interviews from 12 racial justice activists in order to understand how these activists engage in storying survival to foster Black survival and healing. Results show that storying survival includes five interconnected components: storying influences, mechanisms of storying survival, content of storying survival, context of storying survival, and impact of storying survival. Each of these categories and subcategories are detailed herein and are supported with quotations. The findings and related discussion explore the concept of storying survival and its contributions to critical consciousness, radical hope, strength and resistance, cultural self-knowledge, and collectivism among participants and their communities. This study therefore provides important and practical information about how Black people and the counseling psychologists who aim to serve them can utilize storying survival to resist and heal from ABR. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Update on Pediatric Interventional Radiology.

The field of pediatric interventional radiology encompasses the treatment of a broad range of patients. Whether treating a premature infant who weighs less than 1 kg or treating an adult-sized teenager who weighs more than 100 kg, the innovative skills of the interventional radiologist are required to adapt equipment designed for adult patients, to meet the needs of children. Moreover, children cannot be treated simply as small adults owing to a number of factors, including differences in physiology, disease processes, and treatment techniques between pediatric and adult patients. In this article, the unique medical needs of children are highlighted, noting specific areas the interventional radiologist should be aware of when treating patients of all ages. Specific focus is placed on the unique considerations related to children in terms of their periprocedural needs and the procedural modifications required for routine pediatric procedures, with specific diseases of the liver, chest, and musculoskeletal system highlighted. The broader topic of vascular anomalies, although an important part of pediatric interventional radiology, was intentionally excluded to highlight some of the lesser-known procedures performed. ©RSNA, 2022.

Structure and function of H+/K+ pump mutants reveal Na+/K+ pump mechanisms.

Ion-transport mechanisms evolve by changing ion-selectivity, such as switching from Na+ to H+ selectivity in secondary-active transporters or P-type-ATPases. Here we study primary-active transport via P-type ATPases using functional and structural analyses to demonstrate that four simultaneous residue substitutions transform the non-gastric H+/K+ pump, a strict H+-dependent electroneutral P-type ATPase, into a bona fide Na+-dependent electrogenic Na+/K+ pump. Conversion of a H+-dependent primary-active transporter into a Na+-dependent one provides a prototype for similar studies of ion-transport proteins. Moreover, we solve the structures of the wild-type non-gastric H+/K+ pump, a suitable drug target to treat cystic fibrosis, and of its Na+/K+ pump-mimicking mutant in two major conformations, providing insight on how Na+ binding drives a concerted mechanism leading to Na+/K+ pump phosphorylation.

Association between feline hyperthyroidism and thoracic radiographic evaluation of cardiomegaly and pulmonary hyperinflation.

OBJECTIVES: Hyperthyroidism frequently affects middle-to-older-aged cats that can present with cardiorespiratory signs. The effects of hyperthyroidism on cardiac size and function have been previously documented. Anecdotally, pulmonary hyperinflation identified on thoracic radiographs may also be associated with hyperthyroidism; however, there is no literature to support this claim. The goal of this study was to determine any association between hyperthyroidism, pulmonary hyperinflation and cardiomegaly with the following hypotheses: (1) hyperthyroid cats would not have evidence of radiographic pulmonary hyperinflation compared with control cats; and (2) hyperthyroid cats were more likely to have evidence of radiographic cardiomegaly than control cats. METHODS: In this retrospective case-control study, the thoracic radiographs of 52 hyperthyroid cats and 46 non-hyperthyroid cats were evaluated for subjective and objective measurements of pulmonary hyperinflation and cardiomegaly. RESULTS: There were no statistically significant differences between hyperthyroid and non-hyperthyroid cats for any variable indicative of pulmonary hyperinflation. The mean ± SD vertebral heart score on lateral views for hyperthyroid cats was 7.75 ± 0.53 and for control cats was 7.55 ± 0.54, which was significantly different (P = 0.05). Among all cats, a more severe total elevation in thyroxine (T4) was correlated with a larger vertebral heart score on lateral views (Spearman's correlation coefficient = 0.23, P = 0.02). CONCLUSIONS AND RELEVANCE: While the results of this study suggest that hyperthyroid cats are more likely to have a larger vertebral heart score on lateral views than control cats, the clinical relevance of this finding is unclear given the large degree of overlap between hyperthyroid and non-hyperthyroid cats. In addition, among all cats, a greater total T4 elevation was weakly correlated with a larger vertebral heart score. Hyperthyroidism is not associated with radiographic pulmonary hyperinflation and is an unlikely differential for this radiographic finding.

Role of a conserved ion-binding site tyrosine in ion selectivity of the Na+/K+ pump.

The essential transmembrane Na+ and K+ gradients in animal cells are established by the Na+/K+ pump, a P-type ATPase that exports three Na+ and imports two K+ per ATP hydrolyzed. The mechanism by which the Na+/K+ pump distinguishes between Na+ and K+ at the two membrane sides is poorly understood. Crystal structures identify two sites (sites I and II) that bind Na+ or K+ and a third (site III) specific for Na+. The side chain of a conserved tyrosine at site III of the catalytic α-subunit (Xenopus-α1 Y780) has been proposed to contribute to Na+ binding by cation-π interaction. We substituted Y780 with natural and unnatural amino acids, expressed the mutants in Xenopus oocytes and COS-1 cells, and used electrophysiology and biochemistry to evaluate their function. Substitutions disrupting H-bonds impaired Na+ interaction, while Y780Q strengthened it, likely by H-bond formation. Utilizing the non-sense suppression method previously used to incorporate unnatural derivatives in ion channels, we were able to analyze Na+/K+ pumps with fluorinated tyrosine or phenylalanine derivatives inserted at position 780 to diminish cation-π interaction strength. In line with the results of the analysis of mutants with natural amino acid substitutions, the results with the fluorinated derivatives indicate that Na+-π interaction with the phenol ring at position 780 contributes minimally, if at all, to the binding of Na+. All Y780 substitutions decreased K+ apparent affinity, highlighting that a state-dependent H-bond network is essential for the selectivity switch at sites I and II when the pump changes conformational state.

Evaluation and management of biliary complications after pediatric liver transplantation: pearls and pitfalls for percutaneous techniques.

In pediatric liver transplantation, bile duct complications occur with a greater incidence than vascular anastomotic dysfunction and represent a major source of morbidity and mortality. While surgical re-anastomosis can reduce the need for retransplantation, interventional radiology offers minimally invasive and graft-saving therapies. The combination of small patient size and prevailing Roux-en-Y biliary enteric anastomotic techniques makes endoscopic retrograde cholangiopancreatography difficult if not impossible. Expertise in percutaneous management is therefore imperative. This article describes post-surgical anatomy, pathophysiology and noninvasive imaging of biliary complications. We review percutaneous techniques, focusing heavily on biliary access and interventions for reduced liver grafts. Subsequently we review the results and adverse events of these procedures and describe conditions that masquerade as biliary obstruction.

Zero echo time pediatric musculoskeletal magnetic resonance imaging: initial experience.

BACKGROUND: Projection radiography (XR) is often supplemented by both CT (to evaluate osseous structures with ionizing radiation) and MRI (for marrow and soft-tissue assessment). Zero echo time (ZTE) MR imaging produces a "CT-like" osseous contrast that might obviate CT. OBJECTIVE: This study investigated our institution's initial experience in implementing an isotropic ZTE MR imaging sequence for pediatric musculoskeletal examinations. MATERIALS AND METHODS: Pediatric patients referred for extremity MRI at 3 tesla (T) underwent ZTE MR imaging to yield images with contrast similar to that of CT. A radiograph-like image was also created with ray-sum image processing. We assessed ZTE-CT/XR anatomical image quality (Sanat) from 0 (nondiagnostic) to 5 (outstanding). Further, we made image comparisons on a 5-point scale (Scomp) (range of -2 = conventional CT/XR greater anatomical delineation to +2 = ZTE-CT/XR greater anatomical delineation; 0=same) for three cohorts: (1) ZTE-XR to conventional radiography, (2) ZTE-CT to conventional CT and (3) pathological lesion assessment on ZTE-XR to conventional radiography. We measured cortical thickness of ZTE-XR and ZTE-CT and compared these with conventional imaging. We calculated confidence interval of proportions, Wilcoxon rank sum test and intraclass correlation coefficients for inter-reader agreement. RESULTS: Cohorts 1, 2 and 3 consisted of 40, 20 and 35 cases, respectively (age range 0.6-23.0 years). ZTE-CT versus CT and ZTE-XR versus radiography of cortical thicknesses were not significantly different (P=0.55 and P=0.31, respectively). Cortical delineation was rated diagnostic or better (score of 3, 4 or 5) in all cases (confidence interval of proportions = 100%) for ZTE-CT/XR. Similarly, intramedullary cavity delineation was rated diagnostic or better in all cases for ZTE-CT, and ZTE-XR was at least diagnostic in 58-63% of cases. For cohort 2, cortex and intramedullary cavity Scomp for ZTE-CT was comparable to those of conventional CT, with confidence interval of proportion (sum of score of -1 to +2) of 93-100% and 95%, respectively. Pathology visualized on ZTE-CT/XR was comparable; Scomp confidence interval of proportions was 95%/97-100%, with improved delineation of non-displaced fractures on ZTE-XR. Readers had moderate to near-perfect intraclass correlation coefficient (range=0.60-0.93). CONCLUSION: Implementation of a diagnostic-quality ZTE MRI sequence in the pediatric population is feasible and can be performed as a complementary pulse sequence to enhance musculoskeletal MRI studies. Compared to conventional CT, ZTE has comparable cortical delineation, intramedullary cavity and pathology visualization. While not intended as a replacement for conventional radiography, ZTE-XR provides similar visualization of pathology.

Is there need for routine CT colonography after CT-verified uncomplicated diverticulitis of the sigmoid colon?

BACKGROUND: Following an episode of acute diverticulitis, surgical guidelines commonly advise routine colonic follow-up to rule out underlying malignancy. However, as a CT of the abdomen is frequently performed during clinical work-up, the routine need for colonic follow-up has become debated. PURPOSE: To evaluate the need for routine CT colonography after an episode of CT-verified uncomplicated sigmoid diverticulitis to rule out underlying colorectal malignancy. MATERIAL AND METHODS: This study retrospectively evaluated 312 patients routinely referred to colonic evaluation by CT colonography following an episode of acute diverticulitis. Patients were excluded if lacking diagnostic CT of the abdomen at time of diagnosis, if presenting with atypical colonic involvement, or if CT findings were suggestive of complicated disease (e.g., abscess or perforation). CT colonography exams were routinely reviewed by experienced abdominal radiology consultants on the day of the procedure. If significant polyps were detected, or if colorectal malignancy could not be excluded, patients were referred to same-day optical colonoscopy. For these patients, medical records were reviewed for optical colonoscopy results and histology reports if applicable. RESULTS: Among 223 patients with CT-verified uncomplicated sigmoid diverticulitis, no patients were found to have underlying colorectal malignancy. 27 patients were referred to optical colonoscopy based on CT colonography findings. 18 patients consequently underwent polypectomy, all with either hyperplastic or adenomatous histology. CONCLUSIONS: This study indicates that routine colonic evaluation by CT colonography following an episode of CT-verified uncomplicated sigmoid diverticulitis may be unwarranted, and should arguably be reserved for patients with protracted or atypical clinical course.

Displacement of the Na+/K+ pump's transmembrane domains demonstrates conserved conformational changes in P-type 2 ATPases.

Cellular survival requires the ion gradients built by the Na+/K+ pump, an ATPase that alternates between two major conformations (E1 and E2). Here we use state-specific engineered-disulfide cross-linking to demonstrate that transmembrane segment 2 (M2) of the pump's α-subunit moves in directions that are inconsistent with distances observed in existing crystal structures of the Na+/K+ pump in E1 and E2. We characterize this movement with voltage-clamp fluorometry in single-cysteine mutants. Most mutants in the M1-M2 loop produced state-dependent fluorescence changes upon labeling with tetramethylrhodamine-6-maleimide (TMRM), which were due to quenching by multiple endogenous tryptophans. To avoid complications arising from multiple potential quenchers, we analyzed quenching of TMRM conjugated to R977C (in the static M9-M10 loop) by tryptophans introduced, one at a time, in M1-M2. This approach showed that tryptophans introduced in M2 quench TMRM only in E2, with D126W and L130W on the same helix producing the largest fluorescence changes. These observations indicate that M2 moves outward as Na+ is deoccluded from the E1 conformation, a mechanism consistent with cross-linking results and with proposals for other P-type 2 ATPases.

Aneurysms of the communicating segment of the internal carotid artery with posterior communicating artery agenesis are associated with perforator infarction after embolization.

BACKGROUND: While anatomic features associated with the risk of posterior communicating artery (PcoA) occlusion after embolization of aneurysms of the PcoA segment of the internal carotid artery (ICA) are well known, the link between perforator origin and perforator infarction has only been reported following neurosurgical clipping. The aim of this study was to determine the origin of anterior thalamic perforators and correlate it with risk of perforator infarction after embolization of PcoA segment aneurysms. METHODS: One-hundred-and-ninety consecutive patients treated for PcoA segment aneurysms between 2017 and 2019 were included. PcoA and anterior thalamic perforator origin anatomy was assessed with computed tomography (CT) angiography, digital subtracted angiography, and high-resolution three-dimensional rotational cone-beam CT angiography (CBCT-A) by two independent interventional neuroradiologists. The presence of perforator infarction after embolization was ascertained from the patient's notes and follow-up imaging. RESULTS: CBCT-A was superior in demonstrating the origin of perforators (P<0.001). The prevalence of perforator origin was estimated at 86% (95% CI 81%-92%) for PcoA, 8% (95% CI 4%-13%) for aneurysm wall, and 5% (95% CI 2%-9%) for ICA. The aneurysm wall origin was exclusively associated with PcoA agenesis, as well as higher risk of perforator infarction after aneurysm coiling compared with other variants (OR=14, 95% CI 2-88, P=0.006). CONCLUSIONS: Our study suggests that anterior thalamic perforators may arise from aneurysm wall when there is no PcoA. Anatomic association between PcoA agenesis and perforator arising from ICA could underlie such findings, and careful consideration is essential before aneurysm repair to anticipate the risk of thalamic infarction in such cases.

Near-Silent and Distortion-Free Diffusion MRI in Pediatric Musculoskeletal Disorders: Comparison With Echo Planar Imaging Diffusion.

BACKGROUND: Diffusion-weighted imaging (DWI) is common for evaluating pediatric musculoskeletal lesions, but suffers from geometric distortion and intense acoustic noise. PURPOSE: To investigate the performance of a near-silent and distortion-free DWI sequence (DW-SD) relative to standard echo-planar DWI (DW-EPI) in pediatric extremity MRI. STUDY TYPE: Prospective validation study. SUBJECTS: Thirty-nine children referred for extremity MRI. FIELD STRENGTH/SEQUENCE: DW-EPI and DW-SD, based on a rotating ultrafast sequence modified with sinusoidal diffusion preparation gradients, at 3T. ASSESSMENT: DW-SD image quality (Sanat ) was assessed from 0 (nondiagnostic) to 5 (outstanding) and comparative image quality (Scomp ) (from -2 = DW-EPI more delineated to +2 = DW-SD more delineated, 0 = same). ADC measured by DW-SD and DW-EPI were compared in bone marrow, muscle, and lesions. STATISTICAL TESTS: Wilcoxon rank-sum test and confidence interval of proportions (CIOP) were calculated for Scomp , Student's t-test, coefficient of variation (COV), and Bland-Altman analysis for ADC values, and intraclass correlation coefficient (ICC) for interreader agreement. RESULTS: DW-SD and DW-EPI ADC values for bone marrow, muscle, and lesions were not significantly different (P = 0.3, P = 0.2, and P = 0.27, respectively) and had an overall ADC COV of 14.8% (95% confidence interval: 12.3%, 16.9%) and no significant proportional bias on Bland-Altman analysis. Sanat CIOP was rated diagnostic or better (score of 3, 4, or 5) in 72-98% of cases for bone marrow, muscle, and soft tissues. DW-SD was equivalent to or preferred over DW-EPI in muscles and soft tissues, with CIOP 86-93% and 93%, respectively. Lesions were equally visualized on DW-SD and DW-EPI in 40-51%, with DW-SD preferred in 44-56% of cases. DW-SD was rated significantly better than DW-EPI across all comparative variables that included bone marrow, muscle, soft tissue, cartilage, and lesions (P < 0.05). Readers had moderate to near-perfect (ICC range = 0.45-0.85). DATA CONCLUSION: DW-SD of the extremities provided similar ADC values and improved image quality compared with conventional DW-EPI. Level of Evidence 2 Technical Efficacy Stage 2 J. MAGN. RESON. IMAGING 2021;53:504-513.