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1.
Neuromodulation ; 2024 Feb 06.
Article in English | MEDLINE | ID: mdl-38323974

ABSTRACT

INTRODUCTION: Neuromodulation represents one of the more advanced tools in the armamentarium of pain physicians. To optimize neuromodulation patient selection and management, an institutional interdisciplinary neuromodulation committee was created at each of two academic medical centers (University of California Davis [UCD] and Stanford University). The committee aims to collaboratively optimize neuromodulation candidates, to assess and minimize medical and psychologic risks, and to select the best device given a patient's pain condition. In this study, we present the methods and outcome data of the Neuromodulation Committee at the two institutions. MATERIALS AND METHODS: After institutional review board approval, we included all adult patients who were evaluated by the Neuromodulation Committee between 2017 and 2020 at two academic pain clinics. Patients with insufficient data were excluded from the study. A retrospective chart review was completed on 385 UCD and Stanford University patient committee reviews. Data collected from the chart review included demographics (age, sex), committee meeting results (proceed with trial/implant or decline), trial success, and implant rate. RESULTS: Of the 385 patients screened, the committees recommended proceeding with an implantable device (peripheral and neuraxial) in 337 patients (87.5%). Of the 278 patients recommended for neuraxial neuromodulation, 131 underwent trials with percutaneous leads (47.1%). Trials were successful (causing a ≥50% reduction in self-reported pain or improved function) in 108 patients (82.4%). The institutions completed 87 implants of 131 trials, representing a trial-to-permanent ratio of 66.4%. CONCLUSIONS: The Neuromodulation Committee aims to identify optimal patients for neuromodulation, address procedural challenges, decrease adverse events, provide educational context for trainees, and improve patient-related outcomes. Patients who were recommended for neuromodulation and subsequently underwent intervention had high trial success rates for dorsal root ganglion stimulation and spinal cord stimulation. The findings indicate that such an approach can lead to neuromodulation success, especially at academic centers, by combining the expertise of both medical and psychologic professionals.

2.
Rofo ; 196(4): 371-380, 2024 Apr.
Article in English | MEDLINE | ID: mdl-37967821

ABSTRACT

PURPOSE: Intensive care unit (ICU) patients have a high risk of developing complications when leaving the ICU for diagnostic procedures or therapeutic interventions. Our study examined the frequency of adverse events associated with magnetic resonance imaging (MRI) of intensive care patients and the extent of changes in therapy due to the MRI scan to weigh the risks associated with the scan against the potential benefits of an MR scan, using a change in therapy as an indicator of benefit. MATERIALS AND METHODS: 4434 ICU patients (January to December 2015) were identified by Hospital Information System (SAP-R/3 IS-H, Walldorf, Germany), ICU patient data management system Metavision (iMDsoft, Israel), and Radiology Information System (Nexus.medRIS, Version 8.42, Nexus, Germany). All intensive care and medical records (HIS) and MRI reports (RIS) were matched and further evaluated in a retrospective case-to-case analysis for biometric data, mechanical ventilation, ICU requirements, planned postoperative vs. emergency diagnostic requirements, complications and impact on further diagnosis or therapy. RESULTS: Out of 4434 ICU patients, 322 ICU patients (7.3 %) underwent a total of 385 MRI examinations. 167 patients needed a total of 215 emergency scans, while 155 patients underwent 170 planned postoperative MRI exams. 158 (94.6 %) out of 167 emergency scan patients were ventilated under continuous intravenous medication and monitoring. In the planned postoperative group, only 6 (3.9 %) out of 155 were ventilated, but a total of 38 (24.5 %) were under continuous medication. 111 patients were accompanied by nurses only during MRI. Only one severe adverse event (0.3 %) was noted and was attributed to study preparation (n = 385). In 8 MRI examinations (2.1 %), the examination was interrupted or cancelled due to the patients' condition. While all MRI examinations in the planned group were completed (n = 170, 100 %) (e. g., postoperative controls), only 207 out of 215 (96.3 %) could be performed for emergency diagnostic reasons. MRI influenced the clinical course with a change in diagnosis or therapy in 74 (19.2 %) of all 385 MRI examinations performed, and in the emergency diagnostic group it was 31.2 % (n = 67/215). CONCLUSION: Nearly 20 % of MRI examinations of ICU patients resulted in a change of therapy. With only one potentially life-threatening adverse event (0.3 %) during transport and the MRI examination, the risk seems to be outweighed by the diagnostic benefit. KEY POINTS: · The risk of adverse events associated with MRI scans in ICU patients is low.. · The rate of premature termination of ICU patients' MRI scans is low.. · Almost 20 % of ICU patients' MRI scans lead to a change of therapy..


Subject(s)
Critical Care , Intensive Care Units , Humans , Retrospective Studies , Critical Care/methods , Academic Medical Centers , Magnetic Resonance Imaging
3.
Science ; 382(6671): eadf0966, 2023 11 10.
Article in English | MEDLINE | ID: mdl-37943936

ABSTRACT

Intestinal absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1) assists in the initial step of dietary cholesterol uptake, but how cholesterol moves downstream of NPC1L1 is unknown. We show that Aster-B and Aster-C are critical for nonvesicular cholesterol movement in enterocytes. Loss of NPC1L1 diminishes accessible plasma membrane (PM) cholesterol and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate PM cholesterol and show endoplasmic reticulum cholesterol depletion. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, the Aster pathway can be targeted with a small-molecule inhibitor to manipulate cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption.


Subject(s)
Cholesterol, Dietary , Enterocytes , Intestinal Absorption , Membrane Transport Proteins , Animals , Mice , Biological Transport , Cholesterol, Dietary/metabolism , Intestinal Absorption/drug effects , Intestinal Absorption/physiology , Membrane Transport Proteins/genetics , Membrane Transport Proteins/metabolism , Mice, Inbred C57BL , Enterocytes/metabolism , Liver X Receptors/metabolism , Humans , Jejunum/metabolism , Mice, Knockout
4.
Biomed Pharmacother ; 166: 115312, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37567072

ABSTRACT

Histone deacetylases (HDACs) are key epigenetic regulators and classified into four subtypes. Despite the various roles of each HDAC isoform, the lack of selective HDAC inhibitors has limited the elucidation of their roles in biological systems. HDAC11, the sole class-IV HDAC, is highly expressed in the brain, however, the role of HDAC11 in microglia is not fully understood. Based on the modification of MC1568, we developed a novel HDAC inhibitor, 5. Interestingly, 5 suppresses lipopolysaccharide-induced microglial activation by the initiation of autophagy and subsequent inhibition of nitric oxide production. Furthermore, we demonstrated that 5 significantly alleviates depression-like behavior by inhibiting microglial activation in mouse brain. Our discovery reveals that specific pharmacological regulation of HDAC11 induces autophagy and reactive nitrogen species balance in microglia for the first time, which makes HDAC11 a new therapeutic target for depressive disorder.


Subject(s)
Depression , Histone Deacetylase Inhibitors , Microglia , Animals , Mice , Brain/drug effects , Brain/metabolism , Depression/drug therapy , Depression/genetics , Depression/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , Microglia/drug effects , Microglia/metabolism
5.
bioRxiv ; 2023 Jul 10.
Article in English | MEDLINE | ID: mdl-37503112

ABSTRACT

Intestinal cholesterol absorption is an important contributor to systemic cholesterol homeostasis. Niemann-Pick C1 Like 1 (NPC1L1), the target of the drug ezetimibe (EZ), assists in the initial step of dietary cholesterol uptake. However, how cholesterol moves downstream of NPC1L1 is unknown. Here we show that Aster-B and Aster-C are critical for non-vesicular cholesterol movement in enterocytes, bridging NPC1L1 at the plasma membrane (PM) and ACAT2 in the endoplasmic reticulum (ER). Loss of NPC1L1 diminishes accessible PM cholesterol in enterocytes and abolishes Aster recruitment to the intestinal brush border. Enterocytes lacking Asters accumulate cholesterol at the PM and display evidence of ER cholesterol depletion, including decreased cholesterol ester stores and activation of the SREBP-2 transcriptional pathway. Aster-deficient mice have impaired cholesterol absorption and are protected against diet-induced hypercholesterolemia. Finally, we show that the Aster pathway can be targeted with a small molecule inhibitor to manipulate dietary cholesterol uptake. These findings identify the Aster pathway as a physiologically important and pharmacologically tractable node in dietary lipid absorption. One-Sentence Summary: Identification of a targetable pathway for regulation of dietary cholesterol absorption.

6.
J Clin Med ; 12(9)2023 Apr 28.
Article in English | MEDLINE | ID: mdl-37176616

ABSTRACT

BACKGROUND AND STUDY AIM: The incidence of wound infections after percutaneous endoscopic gastrostomy (PEG) varies widely in recent studies. The present study systematically investigates the underlying risk factors for the development of wound infections in a large cohort of patients over a long-term follow-up period. PATIENTS AND METHODS: A retrospective cohort study of patients undergoing PEG insertion using either the pull or push technique was conducted and patients followed up for 3 years. Tube-related wound infections were identified, and pathogens regularly cultured from wound swabs. Adjusted analysis was performed via univariate and multivariate logistic regression analysis. RESULTS: 616 patients were included in this study. A total of 25% percent of patients developed wound infections upon PEG tube insertion and 6.5% showed recurrent infections. Nicotine abuse (p = 0.01), previous ischemic stroke (p = 0.01) and head and neck cancer (p < 0.001) showed an increased risk for wound infection after PEG placement. Moreover, radio-chemotherapy was associated with the occurrence of wound infections (p < 0.001). Infection rates were similar between pull and push cohorts. The most common bacterial pathogen detected was Enterobacterales (19.2%). Staphylococcus aureus, Pseudomonas aeruginosa and enterococci were frequently detected in recurrent infection (14.2%, 11.4% and 9.6%, respectively). Antibiotic prophylaxis showed no effect on infection rates. CONCLUSIONS: Wound infections after PEG placement are common and occasionally occur as recurrent infections. There is potential for improvement in everyday clinical practice, particularly regarding antibiotic prophylaxis in accordance with guidelines.

8.
Cureus ; 15(3): e35868, 2023 Mar.
Article in English | MEDLINE | ID: mdl-37033549

ABSTRACT

Inhaled anesthetics account for a significant portion of the greenhouse gases generated by perioperative services within the healthcare systems. This cross-sectional study aimed to identify knowledge gaps and practice patterns related to carbon dioxide (CO2) absorbents and intraoperative delivery of fresh gas flows (FGF) for future sustainability endeavors. Secondary aims focused on differences in these knowledge gaps based on the level of training. Surveys were distributed at five large academic medical centers. In addition to site-specific CO2 absorbent use and practice volume and experience, respondents at each institution were queried about individual practice with FGF rates during anesthetic maintenance as well as the cost-effectiveness and environmental impact of different volatile anesthetics. Results were stratified and analyzed by the level of training. In total, 368 (44% physicians, 30% residents, and 26% nurse anesthetists) respondents completed surveys. Seventy-six percent of respondents were unaware or unsure about which type of CO2 absorbent was in use at their hospital. Fifty-nine percent and 48% of respondents used sevoflurane and desflurane with FGF ≥1 L/min, respectively. Most participants identified desflurane as the agent with the greatest environmental impact (89.9%) and a greater proportion of anesthesiologists correctly identified isoflurane as a cost-effective anesthetic (78.3%, p=0.02). Knowledge gaps about in-use CO2 absorbent and optimal FGF usage were identified within the anesthesia care team. Educational initiatives to increase awareness about the carbon emissions from anesthesia and newer CO2 absorbents will impact the environmental and economic cost per case and align anesthesia providers toward healthcare decarbonization.

9.
Neuromodulation ; 26(7): 1381-1386, 2023 Oct.
Article in English | MEDLINE | ID: mdl-35570148

ABSTRACT

OBJECTIVE: This study evaluates the use of a three-dimensional virtual reality spinal cord stimulator (SCS) training system to enhance trainee confidence and technical proficiency with interlaminar epidural access and SCS placement. MATERIALS AND METHODS: A total of 14 trainees comprising pain fellows and residents were recruited. Experience and confidence levels were established through pre- and postsurveys. Each trainee performed two sessions placing SCS leads using the training device. In between attempts, a standardized teaching session was performed with the simulator. Performance during each attempt was assessed through objective measures such as needle angle and an evaluation rubric Pain Procedure Rating System (PaPRS). Statistical analysis was performed through paired sample t-test to evaluate a single group between separate trials, whereas unpaired t-test was used to assess the difference between the two groups at baseline or within a single trial. RESULTS: Participants had statistically significant improvements in their ability to safely access the epidural space (57.1% improving to 100%, p < 0.01) and to effectively drive percutaneous leads to the target level (7.1% improving to 71.4%, p < 0.001). The mean confidence levels improved by 71.4% for interlaminar epidural access (p < 0.001) and 306% for SCS placement (p < 0.001). The mean procedural efficiency (total procedure time) improved by 43.2% (p < 0.001). The PaPRS total score increased by an average of 73.3% (p < 0.001). CONCLUSIONS: Virtually simulated neuromodulation training is a viable and effective method of augmenting neuromodulation education. Such didactics are options vital for neuromodulation training, given variable exposure during residency and fellowship.


Subject(s)
Internship and Residency , Virtual Reality , Humans , Spinal Cord , Pain , Computer Simulation
10.
Adv Anesth ; 41(1): 87-110, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38251624

ABSTRACT

Acute pain can have many etiologies that include surgical procedures, trauma (motor vehicle accident), musculoskeletal injuries (rib fracture) and, burns among others. Valuable components of a multimodal approach to acute pain management include both opioid and non-opioid medications, procedure specific regional anesthesia techniques (peripheral nerve blocks and neuraxial approaches), and interventional approaches (eg, peripheral nerve stimulation and cryo-neurolysis). Overall, successful acute perioperative pain management requires a multimodal, multidisciplinary approach that involves a coordinated effort between the surgical team, the anesthesia team, nursing, and pharmacy staff using Enhanced Recovery After Surgery (ERAS) protocols.


Subject(s)
Acute Pain , Anesthesia, Conduction , Transcutaneous Electric Nerve Stimulation , Humans , Pain Management , Accidents, Traffic , Acute Pain/diagnosis , Acute Pain/therapy
11.
Med Ultrason ; 24(4): 461-472, 2022 Dec 21.
Article in English | MEDLINE | ID: mdl-36191244

ABSTRACT

In this overview of vascular changes of the liver, variations in the liver vessels are discussed, in addition to congenital malformations such as Abernethy malformation, patent ductus venosus Arantii and hereditary hemorrhagic telangiectasia (OslerWeber-Rendu disease). Particular attention is paid to focal liver lesions, especially focal nodular hyperplasia (FNH), but also other solid tumours that develop as a result of altered liver vascularisation. The article focuses on the ultrasonic appearances and changes of the liver, depicted in B-mode sonography, Doppler studies and in contrast-enhanced ultrasonography (CEUS). The clinical manifestations of these conditions associated with other organ systems are also highlighted.


Subject(s)
Focal Nodular Hyperplasia , Liver Neoplasms , Humans , Contrast Media , Liver/diagnostic imaging , Liver/pathology , Ultrasonography , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/pathology , Ultrasonography, Doppler , Focal Nodular Hyperplasia/diagnostic imaging
12.
Clin Immunol ; 245: 109143, 2022 12.
Article in English | MEDLINE | ID: mdl-36191738

ABSTRACT

BACKGROUND: New therapeutic strategies for juvenile idiopathic arthritis (JIA) have evolved within the past ten years, and as a result, an update of the 2011 recommendations of the German management guidelines was initiated. METHODS: A systemic literature review was performed, overarching principles were proposed and pre-selected via an online survey followed by two multidisciplinary consensus conferences. Pharmacological and non-pharmacological treatments were discussed, statements were proposed and ultimately agreed upon by nominal group technique (NGT). RESULTS: 12 overarching therapeutic principles, as well as 9 recommendations on pharmacological and 5 on non-pharmacological treatments for JIA were agreed upon. CONCLUSION: This report summarizes the recent update of the interdisciplinary, consensus-based German guidelines on the management of JIA. The multi- and interdisciplinary participation of all caregivers was central for this patient-focused update. With these guidelines, physicians can choose an evidence-based approach, which allows better tailored treatment in this vulnerable cohort of children and adolescents.


Subject(s)
Arthritis, Juvenile , Adolescent , Child , Humans , Arthritis, Juvenile/drug therapy , Consensus , Developmental Disabilities
13.
Ecotoxicol Environ Saf ; 241: 113838, 2022 Aug.
Article in English | MEDLINE | ID: mdl-36068762

ABSTRACT

Perfluorooctane sulfonic acid (PFOS) is a ubiquitous and persistent contaminant in aquatic ecosystems. Chronic toxicity information for aquatic organisms is limited, therefore we conducted chronic PFOS toxicity tests for four model organisms commonly used for freshwater toxicology assays: Chironomus dilutus (midge), Ceriodaphnia dubia (water flea), Hyalella azteca (amphipod) and Danio rerio (zebrafish). The 16-day survival test with C. dilutus resulted in the lowest PFOS exposure concentrations to cause significant impacts, with reduced survival at 1 µg/L, a LC50 of 7.5 µg/L, and a growth EC10 of 1.5 µg/L. D. rerio was the next most sensitive species, with a 30-day LC50 of 490 µg/L and reduced growth at 260 µg/L. Effects for C. dubia and H. azteca occurred at concentrations a thousand-fold higher than for C. dilutus. H. azteca had a 42-day LC50 of 15 mg/L, an EC50 of 3.8 mg/L for reproduction (neonates per female) and an EC50 of 4.7 mg/L for growth. C. dubia was similarly tolerant of PFOS, with a 6-day LC50 of 20 mg/L for survival and an EC50 of 7 mg/L for reproduction (neonates per adult). H. azteca, C. dubia, and, to a lesser extent, D. rerio, appear tolerant of PFOS concentrations typically found in the environment. However, in agreement with previous studies, C. dilutus was particularly sensitive to PFOS exposure, with lethal and sublethal effects occurring at concentration levels present at highly contaminated sites.


Subject(s)
Amphipoda , Chironomidae , Cladocera , Water Pollutants, Chemical , Alkanesulfonic Acids , Animals , Ecosystem , Female , Fluorocarbons , Water Pollutants, Chemical/toxicity , Zebrafish
14.
Phys Rev E ; 105(5): L052501, 2022 May.
Article in English | MEDLINE | ID: mdl-35706259

ABSTRACT

Flow of viscoelastic polymer solutions in curved channels exhibits instability caused by the elastic nature of polymers even at low Reynolds numbers. However, scaling of the onset of this purely elastic instability in semidilute polymer solutions has not been previously reported. Here we experimentally investigate the flow of highly elastic polymer solutions above their overlap concentrations using pressure measurements and particle image velocimetry. We demonstrate that the onset of instability can be scaled by including shear dependent rheological properties of the polymer solutions in the nonlinear stability analysis. As a result, a universal criterion as function of normalized polymer concentration is provided for scaling the onset of purely elastic instability in the semidilute regime regardless of the type and molecular weight of the polymer.

15.
J Gastroenterol Hepatol ; 37(6): 1076-1082, 2022 Jun.
Article in English | MEDLINE | ID: mdl-35261084

ABSTRACT

BACKGROUND AND AIM: The main disadvantage of plastic stents is the high rate of stent occlusion. The usual replacement interval of biliary plastic stents is 3 months. This study aimed to investigate if a shorter interval of 6-8 weeks impacts the median premature exchange rate (mPER) in benign and malignant biliary strictures. METHODS: All cases with endoscopic retrograde cholangiopancreatography (ERCP) and plastic stent placement were retrospectively analyzed since establishing an elective replacement interval of every 6-8 weeks at our institution and mPER was determined. RESULTS: A total of 3979 ERCPs (1199 patients) were analyzed, including 1262 (31.7%) malignant and 2717 (68.3%) benign cases, respectively. The median stent patency (mSP) was 41 days (range 14-120) for scheduled stent exchanges, whereas it was 17 days (1-75) for prematurely exchanged stents. The mPER was significantly higher for malignant (28.1%, 35-50%) compared with benign strictures (15.2%, 10-28%), P < 0.0001, respectively. mSP was significantly shorter in cases with only one stent (34 days [1-87] vs 41 days [1-120]) and in cases with only a 7-Fr stent (28 days [2-79]) compared with a larger stent (34 days [1-87], P = 0.001). Correspondingly, mPER was significantly higher in cases with only one stent (23% vs 16.2%, P < 0.0001) and only a 7-Fr stent (31.3% vs 22.4%, P = 0.03). CONCLUSION: A shorter replacement interval does not seem to lead to a clinically meaningful reduction of mPER in benign and malignant strictures. Large stents and multiple stenting should be favored as possible.


Subject(s)
Cholestasis , Cholangiopancreatography, Endoscopic Retrograde , Cholestasis/diagnostic imaging , Cholestasis/etiology , Cholestasis/surgery , Constriction, Pathologic , Humans , Plastics , Retrospective Studies , Stents/adverse effects , Treatment Outcome
16.
Small ; 18(12): e2106524, 2022 03.
Article in English | MEDLINE | ID: mdl-35072348

ABSTRACT

Lipid droplets (LDs) are ubiquitous, cytoplasmic fat storage organelles that originate from the endoplasmic reticulum (ER) membrane. They are composed of a core of neutral lipids surrounded by a phospholipid monolayer. Proteins embedded into this monolayer membrane adopt a monotopic topology and are crucial for regulated lipid storage and consumption. A key question is, which collective properties of protein-intrinsic and lipid-mediated features determine spatio-temporal protein partitioning between phospholipid bilayer and LD monolayer membranes. To address this question, a freestanding phospholipid bilayer with physiological lipidic composition is produced using microfluidics and micrometer-sized LDs are dispersed around the bilayer that spontaneously insert into the bilayer. Using confocal microscopy, the 3D geometry of the reconstituted LDs is determined with high spatial resolution. The micrometer-sized bilayer-embedded LDs present a characteristic lens shape that obeys predictions from equilibrium wetting theory. Fluorescence recovery after photobleaching measurements reveals the existence of a phospholipid diffusion barrier at the monolayer-bilayer interface. Coarse-grained molecular dynamics simulation reveals lipid specific density distributions along the pore rim, which may rationalize the diffusion barrier. The lipid diffusion barrier between the LD covering monolayer and the bilayer may be a key phenomenon influencing protein partitioning between the ER membrane and LDs in living cells.


Subject(s)
Lipid Droplets , Phospholipids , Cell Membrane/metabolism , Endoplasmic Reticulum/metabolism , Lipid Droplets/metabolism , Molecular Dynamics Simulation , Phospholipids/metabolism
17.
J Biol Chem ; 298(2): 101464, 2022 02.
Article in English | MEDLINE | ID: mdl-34864059

ABSTRACT

Wall teichoic acid (WTA) polymers are covalently affixed to the Gram-positive bacterial cell wall and have important functions in cell elongation, cell morphology, biofilm formation, and ß-lactam antibiotic resistance. The first committed step in WTA biosynthesis is catalyzed by the TagA glycosyltransferase (also called TarA), a peripheral membrane protein that produces the conserved linkage unit, which joins WTA to the cell wall peptidoglycan. TagA contains a conserved GT26 core domain followed by a C-terminal polypeptide tail that is important for catalysis and membrane binding. Here, we report the crystal structure of the Thermoanaerobacter italicus TagA enzyme bound to UDP-N-acetyl-d-mannosamine, revealing the molecular basis of substrate binding. Native MS experiments support the model that only monomeric TagA is enzymatically active and that it is stabilized by membrane binding. Molecular dynamics simulations and enzyme activity measurements indicate that the C-terminal polypeptide tail facilitates catalysis by encapsulating the UDP-N-acetyl-d-mannosamine substrate, presenting three highly conserved arginine residues to the active site that are important for catalysis (R214, R221, and R224). From these data, we present a mechanistic model of catalysis that ascribes functions for these residues. This work could facilitate the development of new antimicrobial compounds that disrupt WTA biosynthesis in pathogenic bacteria.


Subject(s)
Bacterial Proteins , Glycosyltransferases , Lipoproteins , Staphylococcus aureus , Teichoic Acids , Bacterial Proteins/chemistry , Bacterial Proteins/metabolism , Cell Wall/metabolism , Glycosyltransferases/chemistry , Glycosyltransferases/metabolism , Lipoproteins/chemistry , Lipoproteins/metabolism , Staphylococcus aureus/metabolism , Substrate Specificity , Teichoic Acids/chemistry , Teichoic Acids/metabolism , Uridine Diphosphate/metabolism
18.
Chemistry ; 28(2): e202103135, 2022 Jan 10.
Article in English | MEDLINE | ID: mdl-34767667

ABSTRACT

The 4-anilino-6,7-ethylenedioxy-5-fluoroquinazoline scaffold is presented as a novel model system for the characterization of the weak NH⋅⋅⋅F hydrogen bonding (HB) interaction. In this scaffold, the aniline NH proton is forced into close proximity with the nearby fluorine (dH,F ∼2.0 Å, ∠∼138°), and a through-space interaction is observed by NMR spectroscopy with couplings (1h JNH,F ) of 19±1 Hz. A combination of experimental (NMR spectroscopy and X-ray crystallography) and theoretical methods (DFT calculations) were used for the characterization of this weak interaction. In particular, the effects of conformational rigidity and steric compression on coupling were investigated. This scaffold was used for the direct comparison of fluoride with methoxy as HB acceptors, and the susceptibility of the NH⋅⋅⋅F interaction to changes in electron distribution and resonance was probed by preparing a series of molecules with different electron-donating or -withdrawing groups in the positions para to the NH and F. The results support the idea that fluorine can act as a weak HB acceptor, and the HB strength can be modulated through additive and linear electronic substituent effects.


Subject(s)
Fluorides , Fluorine , Electronics , Hydrogen Bonding , Molecular Conformation
19.
J Clin Invest ; 132(2)2022 01 18.
Article in English | MEDLINE | ID: mdl-34813507

ABSTRACT

Various populations of cells are recruited to the heart after cardiac injury, but little is known about whether cardiomyocytes directly regulate heart repair. Using a murine model of ischemic cardiac injury, we demonstrate that cardiomyocytes play a pivotal role in heart repair by regulating nucleotide metabolism and fates of nonmyocytes. Cardiac injury induced the expression of the ectonucleotidase ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes released adenine and specific ribonucleosides that disrupted pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and induced genotoxic stress and p53-mediated cell death of cycling nonmyocytes. As nonmyocytes are critical for heart repair, we showed that rescue of pyrimidine biosynthesis by administration of uridine or by genetic targeting of the ENPP1/AMP pathway enhanced repair after cardiac injury. We identified ENPP1 inhibitors using small molecule screening and showed that systemic administration of an ENPP1 inhibitor after heart injury rescued pyrimidine biosynthesis in nonmyocyte cells and augmented cardiac repair and postinfarct heart function. These observations demonstrate that the cardiac muscle cell regulates pyrimidine metabolism in nonmuscle cells by releasing adenine and specific nucleosides after heart injury and provide insight into how intercellular regulation of pyrimidine biosynthesis can be targeted and monitored for augmenting tissue repair.


Subject(s)
Myocardium/metabolism , Myocytes, Cardiac/metabolism , Phosphoric Diester Hydrolases/metabolism , Pyrimidines/biosynthesis , Pyrophosphatases/metabolism , Regeneration , Signal Transduction , Adenosine Monophosphate/genetics , Adenosine Monophosphate/metabolism , Adenosine Triphosphate/genetics , Adenosine Triphosphate/metabolism , Animals , Heart Injuries/genetics , Heart Injuries/metabolism , Mice , Phosphoric Diester Hydrolases/genetics , Pyrophosphatases/genetics
20.
J Orthop Trauma ; 36(7): e265-e270, 2022 07 01.
Article in English | MEDLINE | ID: mdl-34924510

ABSTRACT

OBJECTIVES: To compare the interobserver and intraobserver reliability of traction radiographs with 2-dimensional computed tomography (2D CT) in distal humerus fracture classification and characterization. DESIGN: Randomized controlled radiographic review of retrospectively collected data. SETTING: Academic Level 1 trauma center. PATIENTS/PARTICIPANTS: Skeletally mature patients with intra-articular distal humerus fractures with both traction radiographs and CT scans were reviewed by 11 orthopaedists from different subspecialties and training levels. INTERVENTION: The intervention involved traction radiographs and 2D CT. MAIN OUTCOME MEASUREMENTS: The main outcome measurements included interobserver and intraobserver reliability of fracture classification by the OTA/AO and Jupiter-Mehne and determination of key fracture characteristics. RESULTS: For the OTA/AO and Jupiter-Mehne classifications, we found a moderate intraobserver agreement with both 2D CT and traction radiographs (κ = 0.70-0.75). When compared with traction radiographs, 2D CT improved the interobserver reliability of the OTA/AO classification from fair to moderate (κ = 0.3 to κ = 0.42) and the identification of a coronal fracture from slight to fair (κ = 0.2 to κ = 0.34), which was more pronounced in a subgroup analysis of less-experienced surgeons. When compared with 2D CT, traction radiographs improved the intraobserver reliability of detecting stable affected articular fragments from fair to substantial (κ = 0.4 to κ = 0.67). CONCLUSIONS: Traction radiographs provide similar diagnostic characteristics as 2D CT in distal humerus fractures. For less-experienced surgeons, 2D CT may improve the identification of coronal fracture lines and articular comminution.


Subject(s)
Fractures, Bone , Traction , Humans , Humerus , Observer Variation , Reproducibility of Results , Retrospective Studies , Tomography, X-Ray Computed/methods
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