Publications by authors named "Joseph Choi"

44 Publications

The asymmetric Pitx2 gene regulates gut muscular-lacteal development and protects against fatty liver disease.

Cell Rep 2021 Nov;37(8):110030

Department of Molecular Medicine, College of Veterinary Medicine, Cornell, Ithaca, NY 14853, USA. Electronic address:

Intestinal lacteals are essential lymphatic channels for absorption and transport of dietary lipids and drive the pathogenesis of debilitating metabolic diseases. However, organ-specific mechanisms linking lymphatic dysfunction to disease etiology remain largely unknown. In this study, we uncover an intestinal lymphatic program that is linked to the left-right (LR) asymmetric transcription factor Pitx2. We show that deletion of the asymmetric Pitx2 enhancer ASE alters normal lacteal development through the lacteal-associated contractile smooth muscle lineage. ASE deletion leads to abnormal muscle morphogenesis induced by oxidative stress, resulting in impaired lacteal extension and defective lymphatic system-dependent lipid transport. Surprisingly, activation of lymphatic system-independent trafficking directs dietary lipids from the gut directly to the liver, causing diet-induced fatty liver disease. Our study reveals the molecular mechanism linking gut lymphatic function to the earliest symmetry-breaking Pitx2 and highlights the important relationship between intestinal lymphangiogenesis and the gut-liver axis.
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http://dx.doi.org/10.1016/j.celrep.2021.110030DOI Listing
November 2021

Functional loss of ketogenesis in odontocete cetaceans.

J Exp Biol 2021 Nov 28;224(21). Epub 2021 Oct 28.

Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Odontocete cetaceans exhibit genomic mutations in key ketogenesis genes. In order to validate an inferred lack of ketogenesis made by observations from genome sequencing, we biochemically analyzed tissues from several odontocete cetacean species and demonstrate that they indeed do not exhibit appreciable hepatic β-hydroxybutyrate (βHB) or its carnitine ester. Furthermore, liver tissue exhibited significantly lower long chain acylcarnitines and increased odd chain acylcarnitines indicative of a decreased reliance on hepatic long chain fatty acid oxidation in these carnivorous mammals. Finally, we performed single molecule, real-time next generation sequencing of liver and brain RNA of Tursiops truncatus and demonstrate that the succinyl-CoA transferase required for acetoacetate catabolism is expressed in the nervous system. These data show that odontocete cetaceans have lost the ability to perform ketogenesis and suggest a hepatocentric coenzyme A recycling function rather than a predominantly systemic-bioenergetic role for ketogenesis in other ketogenic competent mammals such as humans.
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http://dx.doi.org/10.1242/jeb.243062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601715PMC
November 2021

Recurrent acute pancreatitis during a ketogenic diet-a case report and literature review.

Int J Emerg Med 2021 Sep 15;14(1):52. Epub 2021 Sep 15.

Emergency Department, University Health Network, 200 Elizabeth Street, RFE - Ground Floor, 480, Toronto, Ontario, M5G 2C4, Canada.

Background: The ketogenic ("keto") diet has been gaining more attention lately in the medical literature and the lay media as a potentially effective method for weight control and management of type 2 diabetes. Though rare, there have been case reports of serious side effects. Here, we present a peculiar case of pancreatitis presumably associated with the ketogenic diet.

Case Presentation: A 35-year-old man on a calorie-restricted ketogenic diet presented to the emergency department with weekly abdominal pain on Monday mornings, each time after dietary indiscretions ("cheat days") on the weekend. It was found that he had a clinical presentation consistent with acute pancreatitis with no associated alcohol use, hypertriglyceridemia, pancreatic obstruction, or other anatomic abnormalities. The patient's symptoms resolved with conservative management and progressive reintroduction of a standard diet.

Conclusion: This case indicates that the ketogenic diet could lower the threshold for acute pancreatitis, and that an episodic stressor may trigger an acute attack in the absence of traditional risk factors.
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http://dx.doi.org/10.1186/s12245-021-00374-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8444592PMC
September 2021

Addressing the role of edaravone in the management of amyotrophic lateral sclerosis and gaps in care and access: expert panel recommendations.

Am J Manag Care 2021 08;27(12 Suppl):S231-S237

Magellan Rx Management, Middletown, RI. Email:

A virtual key opinion leader (KOL) and payer discussion was held on December 5, 2020. In attendance were 2 KOLs, both specialists in amyotrophic lateral sclerosis (ALS) at leading clinics in the United States, and 6 managed care executives from US regional health plans. The objective of this panel was to share opinions, ideas, and information around the treatment of ALS with edaravone, gaps in management and guidelines, and potential solutions. The panel concluded that coverage criteria for edaravone may need to be reassessed and treatment guidelines could be revisited to include a determination of place in therapy for edaravone.
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http://dx.doi.org/10.37765/ajmc.2021.88732DOI Listing
August 2021

An effective in-hospital chaplaincy-led care program for nurses: Tea for the soul a qualitative investigation.

J Health Care Chaplain 2021 Jun 24:1-14. Epub 2021 Jun 24.

Saint Jude Medical Center, Orange, CA, USA.

Tea for the Soul (TFS) is an understudied care model, addressing bereavement and other emotional needs of nurses related to impactful patient care experiences. Nurses are at high risk for compassion fatigue, moral distress, and burnout. Facilitated by a Chaplain, the TFS program provides participants a venue to express their feelings and explore ways of adapting effectively with the death of a patient, and other traumatic workplace experiences. In this qualitative grounded theory study, hospital nurses ( = 7) who participated in TFS were interviewed. IRB approval was obtained. Questions were constructed within the context of the medical center research council and asked if TFS: (a) was personally beneficial, (b) helped nurses feel better about their work, and (c) affected job satisfaction. Four core themes emerged: (a) Nurses' Self-Care, (b) Professional Practice, (c) Community, and (d) Improved Patient Care Outcomes. The Roy Adaptation Model, Group Identity Mode was applied to the content analysis. Overarching themes were Compassionate Service, Ministry of Presence, Reflective Practice, and Sacred Encounters. Nurses reported that TFS facilitated a spiritual respite and a sense of enhanced community and was a source of strength and coping, thus may aid in the promotion of nurse well-being and the amelioration of moral distress, compassion fatigue, and burnout.
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http://dx.doi.org/10.1080/08854726.2021.1932134DOI Listing
June 2021

Production and Characterization of High Value Prebiotics From Biorefinery-Relevant Feedstocks.

Front Microbiol 2021 29;12:675314. Epub 2021 Apr 29.

Center for Renewable Carbon, The University of Tennessee Institute of Agriculture, Knoxville, TN, United States.

Hemicellulose, a structural polysaccharide and often underutilized co-product stream of biorefineries, could be used to produce prebiotic ingredients with novel functionalities. Since hot water pre-extraction is a cost-effective strategy for integrated biorefineries to partially fractionate hemicellulose and improve feedstock quality and performance for downstream operations, the approach was applied to process switchgrass (SG), hybrid poplar (HP), and southern pine (SP) biomass at 160°C for 60 min. As a result, different hemicellulose-rich fractions were generated and the chemical characterization studies showed that they were composed of 76-91% of glucan, xylan, galactan, arabinan, and mannan oligosaccharides. The hot water extracts also contained minor concentrations of monomeric sugars (≤18%), phenolic components (≤1%), and other degradation products (≤3%), but were tested for probiotic activity without any purification. When subjected to batch fermentations by individual cultures of , , and , the hemicellulosic hydrolysates elicited varied responses. SG hydrolysates induced the highest cell count in at 8.6 log cells/ml, whereas the highest cell counts for and were obtained with southern pine (5.8 log cells/ml) and HP hydrolysates (6.4 log cells/ml), respectively. The observed differences were attributed to the preferential consumption of mannooligosaccharides in SP hydrolysates by . preferentially consumed xylooligosaccharides in the switchgrass and southern pine hydrolysates, whereas consumed galactose in the hybrid poplar hydrolysates. Thus, this study (1) reveals the potential to produce prebiotic ingredients from biorefinery-relevant lignocellulosic biomass, and (2) demonstrates how the chemical composition of hemicellulose-derived sources could regulate the viability and selective proliferation of probiotic microorganisms.
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http://dx.doi.org/10.3389/fmicb.2021.675314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116503PMC
April 2021

Orthopaedic Manifestations of Transverse Myelitis in Children.

J Pediatr Orthop 2021 May 13. Epub 2021 May 13.

Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE Seton Hall Orthopaedics, St. Joseph's University Medical Center, Paterson, NJ Icahn School of Medicine at Mount Sinai, New York, NY Department of Orthopaedic Surgery, Nemours Children's Specialty Care, Jacksonville, FL.

Background: Transverse myelitis (TM) is a rare inflammatory disorder of the spinal cord. It can have a heterogeneous presentation with sensory, motor, and autonomic dysfunction. Neurological sequelae of TM include autonomic dysfunction, motor weakness, and/or spasticity. Studies describing orthopaedic deformities and treatments associated with TM are nonexistent. This purpose of this study was to describe the orthopaedic manifestations of TM in children.

Methods: A multicenter retrospective review was conducted of patients, 0 to 21 years of age, with TM presenting over a 15-year period at 4 academic children's hospitals. Those with confirmed diagnosis of TM and referred to an orthopaedic surgeon were included. Demographics, orthopaedic manifestations, operative/nonoperative treatments, and complications were recorded. Descriptive statistics were used for data reporting.

Results: Of 119 patients identified with TM, 37 saw an orthopaedic surgeon. By etiology, 23 were idiopathic (62%), 10 infectious (27%), 3 (8%) inflammatory/autoimmune, and 1 (3%) vascular. The mean age at diagnosis was 6.7 (SD: 5.5) years and at orthopaedic presentation was 8.4 (SD: 5.2) years. Orthopaedic manifestations included scoliosis in 13 (35%), gait abnormalities in 7 (19%), foot deformities in 7 (19%), upper extremity issues in 7 (19%), symptomatic spasticity in 6 (16%), lower extremity muscle contractures in 6 (16%), fractures in 6 (16%), hip displacement in 3 (8%), pain in 2 (5%), and limb length discrepancy in 2 (5%) patients. Seven children (19%) were seen for establishment of care. In all, 14 (38%) underwent operative intervention, mainly for soft-tissue and scoliosis management. Four patients had baclofen pump placement for spasticity management. Postoperative complications occurred in 36% of cases, most commonly because of infection. Neither topographic pattern nor location of lesion had a significant relationship with need for hip or spine surgery.

Conclusions: This report describes the orthopaedic manifestations associated with TM in children, nearly 40% of whom required operative intervention(s). Understanding the breadth of musculoskeletal burden incurred in TM can help develop surveillance programs to identify and treat these deformities in a timely manner.

Level Of Evidence: Level IV.
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http://dx.doi.org/10.1097/BPO.0000000000001845DOI Listing
May 2021

Electrodiagnostic Testing for Disorders of Peripheral Nerves.

Clin Geriatr Med 2021 05 23;37(2):209-221. Epub 2021 Mar 23.

Department of Neurology, MedStar Georgetown University Hospital, 3800 Reservoir Road, PHC 7th Floor, Washington, DC 20007, USA.

Nerve conduction studies and electromyography are useful diagnostic tools that neurologists use to diagnose diseases of the peripheral nerves, neuromuscular junction, and muscles. These tests are considered an extension of clinical history and examination, and their results should always be interpreted with the clinical context. Neuromuscular diseases are common and affect a large proportion of the elderly population. With an aging population in expansion, these diseases are expected to become even more prevalent. It is important to highlight the basics of electrophysiology and provide a reference for providers who are planning to send their patients to electromyographers for these studies.V.
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http://dx.doi.org/10.1016/j.cger.2021.01.010DOI Listing
May 2021

Intubator Performance and Contamination with the Use of Barrier Enclosure Devices: Results from a Simulated COVID-19 Resuscitation.

Ann Work Expo Health 2021 07;65(6):732-737

Division of Emergency Medicine, Faculty of Medicine, University of Toronto, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.

Introduction: Medical institutions are using barrier enclosure devices during intubation procedures and other aerosol-generating medical procedures without evidence of their effectiveness or usability, potentially compromising patient care, and provider safety. Our objective was to determine the degree of protection offered by these devices and explore other usability factors for two popular barrier systems.

Methods: A simulated trial comparing an intubation box, a frame and plastic tarp system, and unprotected intubation was performed in an academic emergency department. Ten emergency physicians were recruited to participate. Our primary outcome was the degree of contamination from secretions measured by average surface area exposed to phosphorescent material. Secondary outcomes included: laryngoscopy time and time to barrier application, unsuccessful intubation attempts, and usability ratings for each system. Descriptive statistics were reported for all variables of interest and a linear mixed model was used to analyze contamination and laryngoscopy time. Usability was captured through electronic questionnaires using a five-point Likert scale.

Results: Contamination was more prevalent with the box, compared to the frame and tarp, and no device, however, this did not achieve statistical significance (13.2% versus 8.1% versus 12.2%, P = 0.17). A barrier system delayed intubation when compared to using no system (no system = 24.4 s [95% CI 17.3-27.5], frame = 54.4 s [95% CI 13.8-95.0], box = 33.8 s [95% CI 21.4-46.1], P = 0.02). In assessing usability, 30% of users preferred the use of a box barrier, 40% of users preferred the frame, and 30% would not use either in future intubation.

Conclusions: Compared to no barrier protection, an intubation box enclosure offers limited additional protection. A frame and tarp system reduces exposure at the expense of visibility and operator comfort. Finally, barrier systems do not appear to have a clinically significant impact on airway management.
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http://dx.doi.org/10.1093/annweh/wxaa144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929446PMC
July 2021

Discordant hepatic fatty acid oxidation and triglyceride hydrolysis leads to liver disease.

JCI Insight 2021 01 25;6(2). Epub 2021 Jan 25.

Department of Biological Chemistry and.

To extract energy from stored lipids, fatty acids must first be liberated from triglyceride before their β-oxidation in mitochondria in a coordinated and stepwise manner. To determine the independent and interdependent roles of hepatic triglyceride hydrolysis and fatty acid oxidation, mice were generated with a liver-specific defect in triglyceride hydrolysis (AtglL-/-), fatty acid oxidation (Cpt2L-/-), or both (double knockout). The loss of either gene resulted in the compensatory increase in the other, demonstrating their coordination. The loss of individual components of fatty acid catabolism (carnitine palmitoyl transferase 2 [Cpt2], adipose triglyceride lipase [Atgl], and Pparα) resulted in largely independent effects on hepatocyte morphology, intermediary metabolism, and gene expression in response to fasting. However, high-fat feeding revealed the interdependent role of Atgl and Cpt2, as the loss of only one of the genes resulted in steatosis (fatty liver) but the loss of both components resulted in significant steatohepatitis (inflammation and fibrosis). Lipolysis and β-oxidation are intimately linked within a continuous pathway, and disruption of their coordination leads to unique cellular and molecular phenotypes that ultimately result in liver disease.
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http://dx.doi.org/10.1172/jci.insight.135626DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934875PMC
January 2021

Barrier enclosure use during aerosol-generating medical procedures: A scoping review.

Am J Emerg Med 2021 Mar 6;41:209-218. Epub 2020 Nov 6.

Division of Emergency Medicine, Faculty of Medicine, University of Toronto, Toronto, ON, Canada; Toronto General Hospital - Emergency Department, University Health Network, Toronto, ON, Canada. Electronic address:

Introduction: Barrier enclosure devices were introduced to protect against infectious disease transmission during aerosol generating medical procedures (AGMP). Recent discussion in the medical community has led to new designs and adoption despite limited evidence. A scoping review was conducted to characterize devices being used and their performance.

Methods: We conducted a scoping review of formal databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews, CENTRAL, Scopus), grey literature, and hand-searched relevant journals. Forward and reverse citation searching was completed on included articles. Article/full-text screening and data extraction was performed by two independent reviewers. Studies were categorized by publication type, device category, intended medical use, and outcomes (efficacy - ability to contain particles; efficiency - time to complete AGMP; and usability - user experience).

Results: Searches identified 6489 studies and 123 met criteria for inclusion (k = 0.81 title/abstract, k = 0.77 full-text). Most articles were published in 2020 (98%, n = 120) as letters/commentaries (58%, n = 71). Box systems represented 42% (n = 52) of systems described, while plastic sheet systems accounted for 54% (n = 66). The majority were used for airway management (67%, n = 83). Only half of articles described outcome measures (54%, n = 67); 82% (n = 55) reporting efficacy, 39% (n = 26) on usability, and 15% (n = 10) on efficiency. Efficacy of devices in containing aerosols was limited and frequently dependent on use of suction devices.

Conclusions: While use of various barrier enclosure devices has become widespread during this pandemic, objective data of efficacy, efficiency, and usability is limited. Further controlled studies are required before adoption into routine clinical practice.
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http://dx.doi.org/10.1016/j.ajem.2020.10.071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7837026PMC
March 2021

Systemic osteoprotegerin does not improve peri-implant bone volume or osseointegration in rabbits.

J Orthop Res 2021 Aug 27;39(8):1611-1621. Epub 2020 Oct 27.

Hospital for Special Surgery, New York, New York, USA.

Anti-RANKL (receptor activator of nuclear factor kappa-B ligand) agents function by blocking the differentiation of osteoclasts, thereby proving useful in the clinical management of postmenopausal osteoporosis. The effects of such agents on osseointegration is less well understood. The purpose of the current study was to investigate whether osteoprotegerin (OPG), an osteoclast inhibitor, enhances the known anabolic effects of mechanical loading (VEH) and intermittent PTH (iPTH) using a well-established rabbit model of osseointegration. In the first set of experiments, OPG was administered either alone or combined with iPTH to study its effects on measured bone mass. The second set of experiments was conducted using a higher dosage of OPG (10 mg/kg) to explore its early impact at the cellular and molecular levels. All subjects had mechanical load applied to the implant on one extremity, and no load applied on the contralateral side. In the first set of experiments, OPG alone decreased peri-implant bone mass compared to the mechanical loading group, whereas OPG + iPTH increased peri-implant bone mass compared to the OPG group. In the second set of experiments, high-dose OPG significantly decreased osteoclast number (-74.3%) at 1 week. However, this effect was not sustained as osteoclast number returned to baseline by 2 weeks. These results suggest that systemic administration of OPG does not enhance osseointegration, but rather has a detrimental effect.
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http://dx.doi.org/10.1002/jor.24884DOI Listing
August 2021

Deep learning for synthetic microstructure generation in a materials-by-design framework for heterogeneous energetic materials.

Sci Rep 2020 Aug 6;10(1):13307. Epub 2020 Aug 6.

Department of Industrial and Systems Engineering, University of Iowa, Iowa City, IA, 52242, USA.

The sensitivity of heterogeneous energetic (HE) materials (propellants, explosives, and pyrotechnics) is critically dependent on their microstructure. Initiation of chemical reactions occurs at hot spots due to energy localization at sites of porosities and other defects. Emerging multi-scale predictive models of HE response to loads account for the physics at the meso-scale, i.e. at the scale of statistically representative clusters of particles and other features in the microstructure. Meso-scale physics is infused in machine-learned closure models informed by resolved meso-scale simulations. Since microstructures are stochastic, ensembles of meso-scale simulations are required to quantify hot spot ignition and growth and to develop models for microstructure-dependent energy deposition rates. We propose utilizing generative adversarial networks (GAN) to spawn ensembles of synthetic heterogeneous energetic material microstructures. The method generates qualitatively and quantitatively realistic microstructures by learning from images of HE microstructures. We show that the proposed GAN method also permits the generation of new morphologies, where the porosity distribution can be controlled and spatially manipulated. Such control paves the way for the design of novel microstructures to engineer HE materials for targeted performance in a materials-by-design framework.
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http://dx.doi.org/10.1038/s41598-020-70149-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413342PMC
August 2020

Optimising after-hours workflow of computed tomography orders in the emergency department.

BMJ Open Qual 2020 07;9(3)

Emergency Medicine, University Health Network, Toronto, Ontario, Canada.

Ordering and protocolling CT scans after-hours from the emergency department (ED) at our institution previously required discussion between the ED physician and radiology resident, which led to workflow inefficiency. Our intervention consisted of creating an electronic list of CT requests that radiology residents would monitor. Radiology protocolled straightforward requests and contacted the ordering physician for more details when required. We aimed to improve workflow efficiency, increase provider satisfaction and reduce CT turnaround time without significantly affecting CT utilisation. Plan-do-study-act cycles were used to plan and evaluate the intervention. The intervention was initiated on weekday evenings and then expanded to weekend hours after an interim analysis. Qualitative outcomes were measured via electronic survey, and quantitative outcomes were collected from administrative data and analysed via control charts and other statistical methods. Survey response was high from ED physicians (76%, n=82/108) and radiology residents (79%, n=30/38). After the intervention, the majority of ED staff and radiology residents perceived improved workflow efficiency (96.3%, 73.3%), radiology residents noted a subjective decrease in disruptions (83.3%) and most ED staff felt that scans were performed more quickly (84.1%). Radiology residents received fewer pages per shift, adjusted for scan volume. There was a reduction in time from order entry to protocol on weekday shifts only, with no statistically significant effect on time from order entry to scan. Segmented regression analysis demonstrated a background increase in utilisation over time (0.7-2.0 CT/100 ED visits/year, p<0.0005), but the intervention itself did not contribute to an overall increase in CT utilisation. In conclusion, our intervention led to improved perceived workflow efficiency and reduced pages. Scans were protocoled more quickly on weekdays, but turnaround times were otherwise not significantly affected by the intervention. Background CT utilisation increased over time, but this increase was not attributable to our intervention.
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http://dx.doi.org/10.1136/bmjoq-2020-000969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365424PMC
July 2020

Determining the Bioenergetic Capacity for Fatty Acid Oxidation in the Mammalian Nervous System.

Mol Cell Biol 2020 04 28;40(10). Epub 2020 Apr 28.

Department of Biological Chemistry, Johns Hopkins School of Medicine, Baltimore, Maryland, USA

The metabolic state of the brain can greatly impact neurologic function. Evidence of this includes the therapeutic benefit of a ketogenic diet in neurologic diseases, including epilepsy. However, brain lipid bioenergetics remain largely uncharacterized. The existence, capacity, and relevance of mitochondrial fatty acid β-oxidation (FAO) in the brain are highly controversial, with few genetic tools available to evaluate the question. We have provided evidence for the capacity of brain FAO using a pan-brain-specific conditional knockout (KO) mouse incapable of FAO due to the loss of carnitine palmitoyltransferase 2, the product of an obligate gene for FAO (CPT2). Loss of central nervous system (CNS) FAO did not result in gross neuroanatomical changes or systemic differences in metabolism. Loss of CPT2 in the brain did not result in robustly impaired behavior. We demonstrate by unbiased and targeted metabolomics that the mammalian brain oxidizes a substantial quantity of long-chain fatty acids and Loss of CNS FAO results in robust accumulation of long-chain acylcarnitines in the brain, suggesting that the mammalian brain mobilizes fatty acids for their oxidation, irrespective of diet or metabolic state. Together, these data demonstrate that the mammalian brain oxidizes fatty acids under normal circumstances with little influence from or on peripheral tissues.
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http://dx.doi.org/10.1128/MCB.00037-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189099PMC
April 2020

Endometriosis of the appendix causing small bowel obstruction in a virgin abdomen.

BMJ Case Rep 2019 Jul 22;12(7). Epub 2019 Jul 22.

Department of Surgery, Norwest Private Hospital, Sydney, New South Wales, Australia.

A 29-year-old, otherwise well, nulligravid woman presented to the emergency department with 1-day history of generalised abdominal pain and vomiting. She had similar symptoms 6 months prior following recent menstruations, which resolved conservatively. She had no prior history of abdominal surgery or endometriosis. CT scan demonstrated distal small bowel obstruction. A congenital band adhesion was suspected, and she underwent prompt surgical intervention. During laparoscopy, a thickened appendix was adhered to a segment of distal ileum. There was blood in the pelvis. Laparoscopic adhesiolysis and appendicectomy were performed. Histopathology demonstrated multiple foci of endometriosis of the appendix with endometrial glands surrounded by endometrial stroma. Oestrogen receptor and CD10 immunostains highlighted the endometriotic foci. The patient made a good recovery and was referred to a gynaecologist for further management.
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http://dx.doi.org/10.1136/bcr-2019-230496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6663186PMC
July 2019

Pathological outcomes of HER2-positive non-metastatic breast cancer patients treated with neoadjuvant dual anti-HER2 therapy and taxane: An Australian experience.

Asia Pac J Clin Oncol 2020 Jun 19;16(3):103-107. Epub 2019 Jun 19.

Division of Surgery, Sydney Adventist Hospital, Sydney, New South Wales, Australia.

Aims: Internationally, there has recently been growing interest in the use of neoadjuvant pertuzumab and trastuzumab in patients with non-metastatic HER-2 positive breast cancer following the NEOSPHERE trial in 2012. However, pertuzumab is currently not funded by the Pharmaceutical Benefits Scheme (PBS) in Australia for use in this setting. The authors sought to assess the clinical and pathological response rates at the time of surgery in patients who received neoadjuvant dual anti-HER2 and taxane therapy in a multidisciplinary breast cancer unit.

Methods: A retrospective case series of all patients treated with the neoadjuvant therapy, and who had definitive surgery was conducted. Demographic data, size, grade, tumor type, receptor status prior to neoadjuvant treatment, pathological complete response (pCR) rates, and adverse effects were analyzed.

Results: Nineteen patients were included in the study. Sixty-eight percent of all patients achieved pCR, of which 54% further demonstrated no residual ductal carcinoma in situ. Eight patients (42%) had N1 disease pretreatment, of these 88% demonstrated total pCR in the axilla and the breast. Most adverse effects to treatment were manageable grade 1-2 side effects.

Conclusion: This is the first reported Australian experience using neoadjuvant dual anti-HER2 and taxane therapy for HER-2 positive nonmetastatic breast cancer. The authors have demonstrated favorable pCR rates for invasive disease compared to the NEOSPHERE trial (68% vs 46%), with reasonable patient tolerability. Larger collaborative data sets are required to fully evaluate correlation of pCR with survival outcomes, and cost-effectiveness. National funding models need to be considered.
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http://dx.doi.org/10.1111/ajco.13178DOI Listing
June 2020

Gastric band tubing causing cecal volvulus.

Surg Obes Relat Dis 2018 Dec 16;14(12):1914-1915. Epub 2018 Aug 16.

Department of General Surgery and Associated Subspecialties, Sydney Adventist Hospital (SAH), Wahroonga, Sydney, Australia.

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http://dx.doi.org/10.1016/j.soard.2018.08.011DOI Listing
December 2018

Path of least resistance: how computerised provider order entry can lead to (and reduce) wasteful practices.

BMJ Open Qual 2018 9;7(2):e000345. Epub 2018 Apr 9.

Division of Emergency Medicine, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Background: Computerised provider order entry (CPOE) is rapidly becoming the mainstay in clinical care and has the potential to improve provider efficiency and accuracy. However, this hinges on careful planning and implementation. Poorly planned CPOE order sets can lead to undetected errors and waste. In our emergency department (ED), lactate dehydrogenase (LDH) was bundled into various blood work panels but had little clinical value.

Objectives: This quality improvement initiative aimed to reduce unnecessary LDH testing in the ED.

Methods: A group of ED physicians reviewed CPOE blood work panels and uncoupled LDH in conditions where it was deemed not to provide any clinically useful information. We measured the daily number of LDH tests performed before and after its removal. We tracked the frequency of other serum tests as controls. We also analysed the number of add-on LDH (ie, to add LDH to samples already sent to the lab) as a balancing measure, since this can disrupt work flow and delay care.

Results: Through this intervention, we reduced the number of LDH tests performed by 69%, from an average of 75.1 tests per day to 23.2 (P<0.0005). The baseline controls did not differ after the intervention (eg, a complete blood count was performed 197.7 and 196.1 times per day preintervention and postintervention, respectively (P=0.7663)). There was less than one add-on LDH per day on average.

Conclusions: CPOE care templates can be powerful in shaping behaviours and reducing variability. However, close oversight of these panels is necessary to prevent errors and waste.
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http://dx.doi.org/10.1136/bmjoq-2018-000345DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5905735PMC
April 2018

Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing.

Mol Metab 2018 01 11;7:45-56. Epub 2017 Nov 11.

Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore MD 21205, USA. Electronic address:

Objective: To determine the role of fatty acid oxidation on the cellular, molecular, and physiologic response of brown adipose tissue to disparate paradigms of chronic thermogenic stimulation.

Methods: Mice with an adipose-specific loss of Carnitine Palmitoyltransferase 2 (Cpt2), that lack mitochondrial long chain fatty acid β-oxidation, were subjected to environmental and pharmacologic interventions known to promote thermogenic programming in adipose tissue.

Results: Chronic administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists induced a loss of BAT morphology and UCP1 expression in Cpt2 mice. Fatty acid oxidation was also required for the browning of white adipose tissue (WAT) and the induction of UCP1 in WAT. In contrast, chronic cold (15 °C) stimulation induced UCP1 and thermogenic programming in both control and Cpt2 adipose tissue albeit to a lesser extent in Cpt2 mice. However, thermoneutral housing also induced the loss of UCP1 and BAT morphology in Cpt2 mice. Therefore, adipose fatty acid oxidation is required for both the acute agonist-induced activation of BAT and the maintenance of quiescent BAT. Consistent with this data, Cpt2 BAT exhibited increased macrophage infiltration, inflammation and fibrosis irrespective of BAT activation. Finally, obese Cpt2 mice housed at thermoneutrality exhibited a loss of interscapular BAT and were refractory to β3-adrenergic-induced energy expenditure and weight loss.

Conclusion: Mitochondrial long chain fatty acid β-oxidation is critical for the maintenance of the brown adipocyte phenotype both during times of activation and quiescence.
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http://dx.doi.org/10.1016/j.molmet.2017.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5784326PMC
January 2018

Loss of Hepatic Mitochondrial Long-Chain Fatty Acid Oxidation Confers Resistance to Diet-Induced Obesity and Glucose Intolerance.

Cell Rep 2017 07;20(3):655-667

Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

The liver has a large capacity for mitochondrial fatty acid β-oxidation, which is critical for systemic metabolic adaptations such as gluconeogenesis and ketogenesis. To understand the role of hepatic fatty acid oxidation in response to a chronic high-fat diet (HFD), we generated mice with a liver-specific deficiency of mitochondrial long-chain fatty acid β-oxidation (Cpt2 mice). Paradoxically, Cpt2 mice were resistant to HFD-induced obesity and glucose intolerance with an absence of liver damage, although they exhibited serum dyslipidemia, hepatic oxidative stress, and systemic carnitine deficiency. Feeding an HFD induced hepatokines in mice, with a loss of hepatic fatty acid oxidation that enhanced systemic energy expenditure and suppressed adiposity. Additionally, the suppression in hepatic gluconeogenesis was sufficient to improve HFD-induced glucose intolerance. These data show that inhibiting hepatic fatty acid oxidation results in a systemic hormetic response that protects mice from HFD-induced obesity and glucose intolerance.
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http://dx.doi.org/10.1016/j.celrep.2017.06.080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5546239PMC
July 2017

Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction.

Am J Physiol Endocrinol Metab 2017 05 21;312(5):E381-E393. Epub 2017 Feb 21.

Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, Maryland; and

Fatty acid oxidation in macrophages has been suggested to play a causative role in high-fat diet-induced metabolic dysfunction, particularly in the etiology of adipose-driven insulin resistance. To understand the contribution of macrophage fatty acid oxidation directly to metabolic dysfunction in high-fat diet-induced obesity, we generated mice with a myeloid-specific knockout of carnitine palmitoyltransferase II (CPT2 Mϕ-KO), an obligate step in mitochondrial long-chain fatty acid oxidation. While fatty acid oxidation was clearly induced upon IL-4 stimulation, fatty acid oxidation-deficient CPT2 Mϕ-KO bone marrow-derived macrophages displayed canonical markers of M2 polarization following IL-4 stimulation in vitro. In addition, loss of macrophage fatty acid oxidation in vivo did not alter the progression of high-fat diet-induced obesity, inflammation, macrophage polarization, oxidative stress, or glucose intolerance. These data suggest that although IL-4-stimulated alternatively activated macrophages upregulate fatty acid oxidation, fatty acid oxidation is dispensable for macrophage polarization and high-fat diet-induced metabolic dysfunction. Macrophage fatty acid oxidation likely plays a correlative, rather than causative, role in systemic metabolic dysfunction.
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http://dx.doi.org/10.1152/ajpendo.00408.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5451524PMC
May 2017

A Quality Improvement Initiative to Decrease the Rate of Solitary Blood Cultures in the Emergency Department.

Acad Emerg Med 2017 09 17;24(9):1080-1087. Epub 2017 Mar 17.

Department of Emergency Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Objectives: Best practice guidelines recommend that at least two sets of blood cultures (BCs) be sent when blood cultures are required. However, high rates of solitary BCs are still common in the emergency department (ED). The aim of this study was to evaluate the efficacy of different quality improvement initiatives aimed at reducing the rate of solitary blood cultures being sent to the laboratory on patients ultimately discharged from our ED.

Methods: This was a multicenter, multiphase, prospective study evaluating a comprehensive education-based intervention and a second intervention that combined a computerized forcing function (FF) along with a brief education-based intervention. The results were analyzed using segmented regression analysis, as well as statistical process control charts.

Results: The baseline rate of solitary sets of BCs was 41.1%. The education intervention reduced this rate to 30.3%. The introduction of a FF with a brief educational intervention further reduced the rate to 11.6%. This represents an absolute reduction of 29.5% from baseline (relative reduction of 71.8%). According to segmental regression analyses, the education intervention alone did not produce a statistically significant change when factoring possible background time-related trends (p = 0.071). However, the FF produced a statistically significant improvement (p < 0.0005), which was maintained for 6 months.

Conclusion: The combination of a brief education-based intervention and a computerized FF was more effective than education alone in reducing solitary BC collection in our ED in this time series study. FFs can be a powerful tool in modifying behaviors and processes in the clinical setting.
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http://dx.doi.org/10.1111/acem.13161DOI Listing
September 2017

Quantifying the competing relationship between adduction range of motion and baseplate micromotion with lateralization of reverse total shoulder arthroplasty.

J Biomech 2017 02 29;52:24-30. Epub 2016 Nov 29.

Department of Mechanical Engineering, Thomas J. Watson School of Engineering and Applied Science, State University of New York at Binghamton, Binghamton, NY, USA. Electronic address:

Lateralizing the center of rotation (COR) of reverse total shoulder arthroplasty (rTSA) could improve functional outcomes and mitigate scapular notching, a commonly occurring complication of the procedure. However, resulting increases in torque at the bone-implant interface may negatively affect initial fixation of the glenoid-side component, especially if only two fixation screws can be placed. Shoulder-specific finite element (FE) models of four fresh-frozen cadaveric shoulders were constructed. Scapular geometry and material property distributions were derived from CT data. Generic baseplates with two and four fixation screws were virtually implanted, after which superiorly-oriented shear loads, accompanied by a compressive load, were applied incrementally further from the glenoid surface to simulate lateralization of the COR. Relationships between lateralization, adduction range of motion (ROM), the number of fixation screws and micromotion of the baseplate (initial implant fixation) were characterized. Lateralization significantly increases micromotion (p=0.015) and adduction ROM (p=0.001). Using two, versus four, baseplate fixation screws significantly increases micromotion (p=0.008). The effect of lateralization and the number of screws on adduction ROM and baseplate fixation is variable on a shoulder-specific basis. Trade-offs exist between functional outcomes, namely adduction ROM, and initial implant fixation and the negative effect of lateralization on implant fixation is amplified when only two fixation screws are used. The possibility of lateralizing the COR in order to improve functional outcomes of the procedure should be considered on a patient-specific basis accounting for factors such as availability and quality of bone stock.
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http://dx.doi.org/10.1016/j.jbiomech.2016.11.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5309173PMC
February 2017

Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation.

Cell Rep 2016 06 16;16(1):201-212. Epub 2016 Jun 16.

Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2(L-/-)), an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2(L-/-) mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2(L-/-) mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.
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http://dx.doi.org/10.1016/j.celrep.2016.05.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4927362PMC
June 2016

Loss of Adipose Fatty Acid Oxidation Does Not Potentiate Obesity at Thermoneutrality.

Cell Rep 2016 Feb 4;14(6):1308-1316. Epub 2016 Feb 4.

Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address:

Ambient temperature affects energy intake and expenditure to maintain homeostasis in a continuously fluctuating environment. Here, mice with an adipose-specific defect in fatty acid oxidation (Cpt2(A-/-)) were subjected to varying temperatures to determine the role of adipose bioenergetics in environmental adaptation and body weight regulation. Microarray analysis of mice acclimatized to thermoneutrality revealed that Cpt2(A-/-) interscapular brown adipose tissue (BAT) failed to induce the expression of thermogenic genes such as Ucp1 and Pgc1α in response to adrenergic stimulation, and increasing ambient temperature exacerbated these defects. Furthermore, thermoneutral housing induced mtDNA stress in Cpt2(A-/-) BAT and ultimately resulted in a loss of interscapular BAT. Although the loss of adipose fatty acid oxidation resulted in clear molecular, cellular, and physiologic deficits in BAT, body weight gain and glucose tolerance were similar in control and Cpt2(A-/-) mice in response to a high-fat diet, even when mice were housed at thermoneutrality.
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http://dx.doi.org/10.1016/j.celrep.2016.01.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758873PMC
February 2016

Neurometabolic roles of ApoE and Ldl-R in mouse brain.

J Bioenerg Biomembr 2016 Feb 21;48(1):13-21. Epub 2015 Dec 21.

Department of Biological Chemistry, Center for Metabolism and Obesity Research, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Polymorphisms in ApoE are highly correlated with the progression of neurodegenerative disease, in particular Alzheimer's disease. Little is known, however, about the role of ApoE or cholesterol metabolism on brain neurochemistry in general. To better understand the role of lipoprotein and cholesterol metabolism in the brain, we profiled 6 and 12-week old Apoe KO and Ldlr KO mouse models via unbiased metabolomics to determine which metabolites were affected at an early age to identify those that may play a role in triggering pathology later in life. Steady-state metabolomics revealed only subtle differences among Apoe KO, Ldlr KO and WT mouse brains. Ldlr KO mice exhibited alterations in metabolites involved in neurotransmitter, amino acid and cholesterol metabolism. In contrast, Apoe KO mice only showed subtle changes in amino acid and neurotransmitter metabolism. These subtle changes in a broad range of metabolites indicate that ApoE and Ldl-R alone may not play a significant role in these mouse models at an early age, but instead require the cumulative effect from different pathways that lead to dysfunction at a much later stage of life.
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http://dx.doi.org/10.1007/s10863-015-9636-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4733629PMC
February 2016

Physical and Biological Characterization of the Gamma-Irradiated Human Cornea.

Cornea 2015 Oct;34(10):1287-94

*Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Ophthalmology, Johns Hopkins University, Baltimore, MD; and †Wilmer Eye Institute, Johns Hopkins University, Baltimore, MD.

Purpose: To compare the physical and biological characteristics of commercial gamma-irradiated corneas with those of fresh human corneas and to determine suitability for transplantation.

Methods: The physical properties of gamma-irradiated and fresh corneas were evaluated with respect to light transmittance, hydration (swelling ratio), elastic modulus (compressive modulus by the indentation method), matrix organization (differential scanning calorimetry), and morphology (light and transmission electron microscopy). The biological properties of the gamma-irradiated cornea, including residual cell content and cellular biocompatibility, were evaluated by quantifying DNA content and measuring the proliferation rate of human corneal epithelial cells, respectively.

Results: The hydration, light transmittance, elastic modulus, and proliferation rate of human corneal epithelial cells were not significantly different between fresh and gamma-irradiated corneas. However, differences were observed in tissue morphology, DNA content, and thermal properties. The density of collagen fibrils of the gamma-irradiated corneal sample (160.6 ± 33.2 fibrils/μm) was significantly lower than that of the fresh corneal sample (310.0 ± 44.7 fibrils/μm). Additionally, in the gamma-irradiated corneas, cell fragments-but not viable cells-were observed, supported by lower DNA content of the gamma-irradiated cornea (1.0 ± 0.1 μg/mg) than in fresh corneas (1.9 μg/mg). Moreover, the denaturation temperature of gamma-irradiated corneas (61.8 ± 1.1 °C) was significantly lower than that of fresh corneas (66.1 ± 1.9 °C).

Conclusions: Despite structural changes due to irradiation, the physical and biological properties of the gamma-irradiated cornea remain similar to the fresh cornea. These factors, combined with a decreased risk of rejection and longer shelf life, make the gamma-irradiated tissue a viable and clinically desired option in various ophthalmic procedures.
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http://dx.doi.org/10.1097/ICO.0000000000000555DOI Listing
October 2015

Paraxial full-field cloaking.

Opt Express 2015 Jun;23(12):15857-62

We complete the 'paraxial' (small-angle) ray optics cloaking formalism presented previously [Opt. Express 22, 29465 (2014)], by extending it to the full-field of light. Omnidirectionality is then the only relaxed parameter of what may be considered an ideal, broadband, field cloak. We show that an isotropic plate of uniform thickness, with appropriately designed refractive index and dispersion, can match the phase over the whole visible spectrum. Our results support the fundamental limits on cloaking for broadband vs. omnidirectionality, and provide insights into when anisotropy may be required.
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http://dx.doi.org/10.1364/OE.23.015857DOI Listing
June 2015

Paraxial ray optics cloaking.

Opt Express 2014 Dec;22(24):29465-78

Despite much interest and progress in optical spatial cloaking, a three-dimensional (3D), transmitting, continuously multidirectional cloak in the visible regime has not yet been demonstrated. Here we experimentally demonstrate such a cloak using ray optics, albeit with some edge effects. Our device requires no new materials, uses isotropic off-the-shelf optics, scales easily to cloak arbitrarily large objects, and is as broadband as the choice of optical material, all of which have been challenges for current cloaking schemes. In addition, we provide a concise formalism that quantifies and produces perfect optical cloaks in the small-angle ('paraxial') limit.
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http://dx.doi.org/10.1364/OE.22.029465DOI Listing
December 2014
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