Publications by authors named "Victoria Wong"

118 Publications

Evaluation of Meibomian Gland Dysfunction Among Ophthalmic Healthcare Workers.

Clin Ophthalmol 2021 19;15:1201-1206. Epub 2021 Mar 19.

Hong Kong Eye Hospital, Kowloon, Hong Kong.

Purpose: To evaluate the prevalence of meibomian gland dysfunction (MGD) among ophthalmic healthcare workers.

Setting: A tertiary ophthalmic center.

Design: Prospective, observational study.

Methods: Forty-four volunteer ophthalmologists and ophthalmic nurses were recruited. Information including demographics, contact lens wear, history of refractive surgery and symptom score based on Standardized Patient Evaluation of Eye Dryness (SPEED) II Questionnaire for Dry Eye Disease/Ocular Surface Disease were recorded. Lipid layer thickness (LLT), meibomian glands dropout and dilation grades, and proportion of partial blinking were evaluated using an ocular surface interferometer with dynamic meibomian imaging (LipiView, Johnson & Johnson). Based on the chance of MGD, meibomian gland dropout and dilation, selected subjects also underwent treatment with a thermal pulsation system (LipiFlow, Johnson & Johnson) in one or both eyes.

Results: Eighty-eight eyes of 44 volunteers were evaluated during the study period. The mean LLT was 60.0nm. Twenty-seven (61.4%) subjects had a 90% or high chance of MGD and their mean lower lid meibomian gland dropout and dilation grades were 1.2 and 1.7, respectively. Twenty-eight eyes of 16 volunteers received treatment with the thermal pulsation system. Following treatment, the mean LLT improved from 50.3nm to 61.0nm (Wilcoxon's signed rank test, p=0.001).

Conclusion: Despite being more knowledgeable to MGD and more accessible to treatment, MGD is a highly prevalent condition among ophthalmic healthcare workers, with a 61.4% prevalence among the recruited subjects. This is similar to reported prevalence in Asian populations of up to 74.5%. Targeted therapy based on dynamic meibomian imaging is effective in improving both objective and subjective measures of MGD.
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http://dx.doi.org/10.2147/OPTH.S299338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989054PMC
March 2021

Metastatic Melanoma With Leptomeningeal Disease.

J Adv Pract Oncol 2021 Jan-Feb;12(1):79-83. Epub 2021 Jan 1.

Fox Chase Cancer Center, Philadelphia, Pennsylvania.

Leptomeningeal disease in patients with melanoma historically portends a grim prognosis, with median survival measured in weeks to months. The advent of effective immunotherapy and targeted agents may modify the outcome of such patients. This case report describes a 43-year-old patient diagnosed with stage IIIa -positive cutaneous melanoma in 2012 who subsequently developed leptomeningeal involvement as her sole site of melanotic metastasis. She received multiple systemic therapies and radiotherapy and survived 2.5 years after her diagnosis with central nervous system involvement. This case report highlights the importance of a multidisciplinary team and the advent of effective agents, which offers the potential for significantly improved outcomes for patients with metastatic melanoma involving the central nervous system.
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http://dx.doi.org/10.6004/jadpro.2021.12.1.6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844196PMC
January 2021

Ophthalmology in the time of COVID-19: experience from Hong Kong Eye Hospital.

Int J Ophthalmol 2020 18;13(6):851-859. Epub 2020 Jun 18.

Department of Ophthalmology and Visual Sciences, the Chinese University of Hong Kong, Hong Kong SAR, China.

Aim: To review international guidelines and to share our infection control experience during the coronavirus disease 2019 (COVID-19) pandemic at a tertiary eye centre in Hong Kong.

Methods: Infection control guidelines and recommendations from international ophthalmological bodies are reviewed and discussed. The measures at our hospital were drawn up as per international and local health authorities' guidelines and implemented with the collaboration of doctors, nurses and administrative staff.

Results: The aims of our infection control measures are to 1) minimize cross-infection within the hospital; 2) protect and support hospital staff; 3) ensure environmental control. To minimize the risk of cross-infection, outpatient attendance and elective surgery have been reduced by 40%, and general anesthesia procedures were reduced by 90%. Patients entering the hospital are screened for fever, travel history, contact and cluster history, and COVID-19 related symptoms. To protect and support hospital staff, we ensure provision of adequate personal protective equipment (PPE) and provide clear guidelines on the level of PPE needed, depending on the clinical situation. Other protective measures include provision of work uniforms, easy access to alcohol-based hand rub, opening new lunch areas, implementation of self-monitoring and self-reporting systems, and communication online education and updates. Finally, environmental control is achieved by ensuring regular disinfection of the hospital premise, enhancing ventilation, and usage of disposable ophthalmic instruments.

Conclusion: Our multi-pronged approach to infection control is, so far, successful in minimizing infection risks, while allowing the maintenance of essential ophthalmic services.
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http://dx.doi.org/10.18240/ijo.2020.06.01DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7270264PMC
June 2020

Natural history of the social millipede Wood, 1864.

Biodivers Data J 2020 3;8:e50770. Epub 2020 Apr 3.

Virginia Tech, Blacksburg, United States of America Virginia Tech Blacksburg United States of America.

The millipede Wood, 1864 is a fungivorous social millipede known for paternal care of eggs and forming multi-generational aggregations. We investigated the life history, paternal care, chemical defence, feeding and social behaviour of and provided morphological and anatomical descriptions, using light and scanning electron microscopy. Based on observations of from 13 locations throughout its distribution, we report the following natural history aspects. The oviposition period of lasted from mid-April to late June and the incubation period lasted 3-4 weeks. Only males cared for the eggs and subsequent care of juveniles was not observed. In one case, the clutches of two males became combined and they were later cared for by only one of the males. The defensive compound of is stored in large glands occupying a third of the paranotal volume and were observed only in stadia II millipedes and older. We observed feeding on fungi of the order Polyporales and describe a cuticular structure on the tip of the labrum that may relate to fungivory. We found that their stellate-shaped aggregations (pinwheels) do not form in the absence of fungus and suggest the aggregation is associated with feeding. We describe and illustrate a previously undescribed comb-like structure on the tibia and tarsi of the six anterior-most leg-pairs and measure the colour and spectral reflectance of the exoskeleton.
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http://dx.doi.org/10.3897/BDJ.8.e50770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148388PMC
April 2020

The millipede family Conotylidae in northwestern North America, with a complete bibliography of the family (Diplopoda, Chordeumatida, Heterochordeumatidea, Conotyloidea).

Zootaxa 2020 Mar 19;4753(1):zootaxa.4753.1.1. Epub 2020 Mar 19.

Professor Emeritus, Hampden-Sydney College, Hampden-Sydney, VA 23943, present address: 1950 Price Drive, Farmville, VA 23901..

The center of diversity for the chordeumatidan millipede family Conotylidae is northwestern North America, where five of six subfamilies and ten of fourteen previously described genera occur; in this paper, seven additional new genera and 33 new species from the region are described. New species in the genus Taiyutyla Chamberlin, 1952 are: Taiyutyla tillamook, Taiyutyla acuphora, and Taiyutyla amicitia; in the genus Bollmanella Chamberlin, 1941: Bollmanella bombus, Bollmanella washingtonensis and Bollmanella leonardi; in the genus Brunsonia Loomis Schmitt, 1971: Brunsonia pulchra, Brunsonia digitata, Brunsonia wenatchee, Brunsonia chelanoparva, Brunsonia chelanomagna, Brunsonia selwayana and Brunsonia benewah. Vancouvereuma n. gen. is described with the type species Taiyutyla shawi Shear 2004. Calityla n. gen. includes the new species Calityla siskiyou, Calityla ubicki, Calityla trinitaria, Calityla essigi, and Calityla humboldtensis. Ovaskella, n. gen. includes the new species Ovaskella ovaskae and Ovaskella sinuosa. Karagama, n. gen. includes the new species Karagama ladybird. Complicatella, n. gen. includes the new species Complicatella pectenifera and Complicatella neili. Bifurcatella n. gen. includes the new species Bifurcatella olympiana, Bifurcatella hoh, Bifurcatella angulata, Bifurcatella pacifica, Bifurcatella germania, Bifurcatella uniclada, Bifurcatella inflata and Bifurcatella hobo. Loomisiella, n. gen. includes the new species Loomisiella evergreen and Loomisiella pylei. New distribution records are provided for numerous previously described species of conotylids. A complete bibliography of the family Conotylidae of the world is also included.
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http://dx.doi.org/10.11646/zootaxa.4753.1.1DOI Listing
March 2020

Incidentally discovered primary mediastinal germ cell tumor.

JAAPA 2020 Apr;33(4):35-37

Victoria Wong practices at Fox Chase Cancer Center in Philadelphia, Pa. Daniel M. Geynisman is an assistant professor of medical oncology at Fox Chase Cancer Center. The authors have disclosed no potential conflicts of interest, financial or otherwise.

Most germ cell tumors arise from the testicles and often are self-diagnosed. Extragonadal germ cell tumors are rare and vary greatly in their clinical presentations. This case report describes a 24-year-old man with an unusual presentation for an extragonadal germ cell tumor.
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http://dx.doi.org/10.1097/01.JAA.0000657172.30545.a3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534393PMC
April 2020

A drug discovery platform to identify compounds that inhibit EGFR triple mutants.

Nat Chem Biol 2020 05 24;16(5):577-586. Epub 2020 Feb 24.

Donnelly Centre, University of Toronto, Toronto, Ontario, Canada.

Receptor tyrosine kinases (RTKs) are transmembrane receptors of great clinical interest due to their role in disease. Historically, therapeutics targeting RTKs have been identified using in vitro kinase assays. Due to frequent development of drug resistance, however, there is a need to identify more diverse compounds that inhibit mutated but not wild-type RTKs. Here, we describe MaMTH-DS (mammalian membrane two-hybrid drug screening), a live-cell platform for high-throughput identification of small molecules targeting functional protein-protein interactions of RTKs. We applied MaMTH-DS to an oncogenic epidermal growth factor receptor (EGFR) mutant resistant to the latest generation of clinically approved tyrosine kinase inhibitors (TKIs). We identified four mutant-specific compounds, including two that would not have been detected by conventional in vitro kinase assays. One of these targets mutant EGFR via a new mechanism of action, distinct from classical TKI inhibition. Our results demonstrate how MaMTH-DS is a powerful complement to traditional drug screening approaches.
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http://dx.doi.org/10.1038/s41589-020-0484-2DOI Listing
May 2020

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects.

Nat Commun 2020 02 19;11(1):965. Epub 2020 Feb 19.

Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G1M1, Canada.

The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.
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http://dx.doi.org/10.1038/s41467-019-14143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031342PMC
February 2020

Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming levels of KRAS.

Nat Commun 2020 01 24;11(1):499. Epub 2020 Jan 24.

Systems Biology Ireland, University College Dublin, Dublin, Ireland.

Protein-protein-interaction networks (PPINs) organize fundamental biological processes, but how oncogenic mutations impact these interactions and their functions at a network-level scale is poorly understood. Here, we analyze how a common oncogenic KRAS mutation (KRAS) affects PPIN structure and function of the Epidermal Growth Factor Receptor (EGFR) network in colorectal cancer (CRC) cells. Mapping >6000 PPIs shows that this network is extensively rewired in cells expressing transforming levels of KRAS (mtKRAS). The factors driving PPIN rewiring are multifactorial including changes in protein expression and phosphorylation. Mathematical modelling also suggests that the binding dynamics of low and high affinity KRAS interactors contribute to rewiring. PPIN rewiring substantially alters the composition of protein complexes, signal flow, transcriptional regulation, and cellular phenotype. These changes are validated by targeted and global experimental analysis. Importantly, genetic alterations in the most extensively rewired PPIN nodes occur frequently in CRC and are prognostic of poor patient outcomes.
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http://dx.doi.org/10.1038/s41467-019-14224-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981206PMC
January 2020

Structure and pigment make the eyed elater's eyespots black.

PeerJ 2020 13;8:e8161. Epub 2020 Jan 13.

Department of Entomology, Virginia Polytechnic Institute and State University (Virginia Tech), Blacksburg, VA, United States of America.

Surface structures that trap light leading to near complete structural absorption creates an appearance of "super black." Well known in the natural world from bird feathers and butterfly scales, super black has evolved independently from various anatomical structures. Due to an exceptional ability to reduce specular reflection, these biological materials have garnered interest from optical industries. Here we describe the false eyes of the eyed elater click beetle, which, while not classified as super black, still attains near complete absorption of light partly due to an array of vertically-aligned microtubules. These cone-shaped microtubules are modified hairs (setae) that are localized to eyespots on the dorsum of the beetle, and absorb 96.1% of incident light (at a 24.8° collection angle) in the spectrum between 300-700 nm. Filled with melanin, the setae combine structure and pigment to generate multiple reflections and refractions causing light to travel a greater distance. This light-capturing architecture leaves little light available to receivers and the false eyes appear as deep black making them appear more conspicuous to predators.
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http://dx.doi.org/10.7717/peerj.8161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964691PMC
January 2020

Diversity and function of fungi associated with the fungivorous millipede, .

Fungal Ecol 2019 Oct 9;41:187-197. Epub 2019 Jul 9.

Division of Plant and Soil Sciences, West Virginia University, Morgantown, WV, 26506, USA.

Fungivorous millipedes (subterclass Colobognatha) likely represent some of the earliest known mycophagous terrestrial arthropods, yet their fungal partners remain elusive. Here we describe relationships between fungi and the fungivorous millipede, . Their fungal community is surprisingly diverse, including 176 genera, 39 orders, four phyla, and several undescribed species. Of particular interest are twelve genera conserved across wood substrates and millipede clades that comprise the core fungal community of . Wood decay fungi, long speculated to serve as the primary food source for species, were absent from this core assemblage and proved lethal to millipedes in pathogenicity assays while entomopathogenic Hypocreales were more common in the core but had little effect on millipede health. This study represents the first survey of fungal communities associated with any colobognath millipede, and these results offer a glimpse into the complexity of millipede fungal communities.
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http://dx.doi.org/10.1016/j.funeco.2019.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6927558PMC
October 2019

Shape partitioning interacts with global shape integration.

Vision Res 2020 01 5;166:20-32. Epub 2019 Dec 5.

School of Psychological Science, 35 Stirling Highway, The University of Western Australia, Crawley, Perth, WA, Australia. Electronic address:

Objects are often identified by the shape of their profiles but complex objects are often comprised of multiple articulated components. It has been proposed that complex objects are decomposed and recognized by their component parts. This study exploits the proposition that the visual system decomposes objects at matched deep concavities on their boundaries. Rapid decreases in thresholds for detection of sinusoidal deformation of a circle's radius with number of cycles of modulation shows that shape information is integrated around radial frequency (RF) patterns. Here we merge RF patterns to form composite patterns with concavities and show that integration around the RF patterns is disrupted if the concavities are shallow but preserved if they are deep, consistent with their decomposition at matched deep concavities. Geon theory identifies complex patterns through a structural description of viewpoint invariant primitives known as geons. Geons are defined by properties on their boundaries that co-occur in a non-accidental manner across viewpoint changes rather than by reconciling metric properties such as curvature with viewpoint specific templates. Similarly, shapes of RF patterns are defined by the positions of curvature features on their boundaries. We argue that RF patterns provide flexible stimuli that might be used to study geons.
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http://dx.doi.org/10.1016/j.visres.2019.11.005DOI Listing
January 2020

Measuring Proliferation of Vascular Smooth Muscle Cells Using Click Chemistry.

J Vis Exp 2019 10 30(152). Epub 2019 Oct 30.

Department of Neuroscience, Cell Biology, and Physiology, Wright State University; Department of Surgery, Boonshoft School of Medicine, Wright State University;

The ability of a cell to proliferate is integral to the normal function of most cells, and dysregulation of proliferation is at the heart of many disease processes. For these reasons, measuring proliferation is a common tool used to assess cell function. Cell proliferation can be measured simply by counting; however, this is an indirect means of measuring proliferation. One common means of directly detecting cells preparing to divide is by incorporation of labeled nucleoside analogs. These include the radioactive nucleoside analog H-thymidine plus non-radioactive nucleoside analogs such as 5-bromo-2' deoxyuridine (BrdU) and 5-ethynyl-2'-deoxyuridine (EdU). Incorporation of EdU is detected by click chemistry, which has several advantages when compared to BrdU. In this report, we provide a protocol for measuring proliferation by the incorporation of EdU. This protocol includes options for various readouts, along with the advantages and disadvantages of each. We also discuss places where the protocol can be optimized or altered to meet the specific needs of the experiment planned. Finally, we touch on the ways that this basic protocol can be modified for measuring other cell metabolites.
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http://dx.doi.org/10.3791/59930DOI Listing
October 2019

Highly Combinatorial Genetic Interaction Analysis Reveals a Multi-Drug Transporter Influence Network.

Cell Syst 2020 01 23;10(1):25-38.e10. Epub 2019 Oct 23.

Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Many traits are complex, depending non-additively on variant combinations. Even in model systems, such as the yeast S. cerevisiae, carrying out the high-order variant-combination testing needed to dissect complex traits remains a daunting challenge. Here, we describe "X-gene" genetic analysis (XGA), a strategy for engineering and profiling highly combinatorial gene perturbations. We demonstrate XGA on yeast ABC transporters by engineering 5,353 strains, each deleted for a random subset of 16 transporters, and profiling each strain's resistance to 16 compounds. XGA yielded 85,648 genotype-to-resistance observations, revealing high-order genetic interactions for 13 of the 16 transporters studied. Neural networks yielded intuitive functional models and guided exploration of fluconazole resistance, which was influenced non-additively by five genes. Together, our results showed that highly combinatorial genetic perturbation can functionally dissect complex traits, supporting pursuit of analogous strategies in human cells and other model systems.
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http://dx.doi.org/10.1016/j.cels.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6989212PMC
January 2020

Marijuana use among patients with epilepsy at a tertiary care center.

Epilepsy Behav 2019 08 25;97:144-148. Epub 2019 Jun 25.

Oregon Health and Science University, Department of Neurology, 3181 SW Sam Jackson Park Rd, Portland, OR 97239, United States of America. Electronic address:

The expansion of medical and recreational marijuana legalization facilitates patient access to cannabis, and many patients with epilepsy pursue marijuana as a treatment for seizures. We administered a nine-item survey on marijuana use to patients seen in an epilepsy clinic over a 9 month period at a tertiary care center in Oregon where recreational use was legalized in 2015. The majority of respondents (n = 39) reported cannabis use for the purpose of treating epilepsy (87.2%, n = 34), and strongly agreed (53.8%, n = 21) or agreed (28.2%, n = 11) that cannabis use improved seizure control. The most commonly selected cannabis strains were high cannabidiol (CBD) (30.8%, n = 12) or multiple types (30.8%, n = 12), with administration methods of smoking (66.7%, n = 26), edibles (48.7%, n = 19), and concentrates (43.6%, n = 17). More participants reported using marijuana with primarily CBD than primarily tetrahydrocannabinol (THC) or equal CBD:THC content, and very few women reported using marijuana with primarily THC compared with men (10% of female versus 47% of male respondents). Only 2 of 39 participants were able to give an exact dosage used in milligrams. Medical and recreational dispensaries were the most common cannabis sources, followed by homegrown and friends/family members. Although pharmaceutical CBD extract is now Food and Drug Administration (FDA)-approved for certain epilepsy types, access remains limited. Further research is needed to understand recreational cannabis use among patients with epilepsy while clinical research for pharmaceutical cannabis products continues.
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http://dx.doi.org/10.1016/j.yebeh.2019.05.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608609PMC
August 2019

A Multireporter Bacterial 2-Hybrid Assay for the High-Throughput and Dynamic Assay of PDZ Domain-Peptide Interactions.

ACS Synth Biol 2019 05 18;8(5):918-928. Epub 2019 Apr 18.

Department of Biochemistry Molecular Pharmacology and Institute for Systems Genetics , NYU Langone Health , New York , New York 10016 , United States.

The accurate determination of protein-protein interactions has been an important focus of molecular biology toward which much progress has been made due to the continuous development of existing and new technologies. However, current methods can have limitations, including scale and restriction to high affinity interactions, limiting our understanding of a large subset of these interactions. Here, we describe a modified bacterial-hybrid assay that employs combined selectable and scalable reporters that enable the sensitive screening of large peptide libraries followed by the sorting of positive interactions by the level of reporter output. We have applied this tool to characterize a set of human and E. coli PDZ domains. Our results are consistent with prior characterization of these proteins, and the improved sensitivity increases our ability to predict known and novel in vivo binding partners. This approach allows for the recovery of a wide range of affinities with a high throughput method that does not sacrifice the scale of the screen.
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http://dx.doi.org/10.1021/acssynbio.8b00499DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818413PMC
May 2019

Seizure and epilepsy publication in nonneurology journals.

Epilepsy Behav 2019 04 16;93:7-11. Epub 2019 Feb 16.

Department of Neurology, University of Arkansas for Medical Sciences, Little Rock, AR, United States of America; Minnesota Epilepsy Group, P.A., St. Paul, MN, United States of America.

Purpose: The prevalence and characteristics of seizure and epilepsy research published in nonneurology journals are unknown. Characterizing this published research allows for insight into the relevance of seizures and epilepsy in other specialties and may increase opportunity for cross-specialty collaboration.

Methods: In this observational study, we reviewed the top five highly cited clinical journals within eleven specialties in the InCites Journal Citation Reports (JCR) database (2016). For each specialty, we collected 2013-2017 PubMed data on publications with MeSH Major Topic of "seizures," "epilepsy," or "status epilepticus." Medical subject headings (MeSH) in PubMed are standardized terms assigned by subject analysts. MeSH Major Topic identifies articles in which a specified topic is the major focus of the article. We also retrieved author country and medical specialty affiliations. We analyzed whether author specialty affiliation was 1) concordant with journal medical specialty, 2) neurology-related, or 3) other.

Results: Articles on "seizures," "epilepsy," or "status epilepticus" had the following prevalence in specialty clinical journals: cardiac and cardiovascular systems (0.01%); clinical neurology (5.34%); critical care medicine (0.20%); emergency medicine (0.47%); general and internal medicine (0.44%); neuroimaging (2.05%); neurosurgery (2.23%); obstetrics and gynecology (0.16%); oncology (0.01%); pediatrics (0.69%); and psychiatry (0.23%). Within general and internal medicine, neuroimaging, and pediatrics, seizure-related articles are more likely to be first-authored by someone with a neurology-related affiliation. Within critical care medicine, emergency medicine, neurosurgery, and obstetrics and gynecology, seizure-related articles were more likely to be first-authored by someone whose affiliation is within the field.

Conclusions: Our study characterizes seizure and epilepsy research published in nonneurology journals. We found that there is a paucity of such research published in nonneurology journals, whether authored by neurologists or other specialists. This is not ideal since nonneurologists are often first-line providers for recognizing, diagnosing, or managing seizures prior to assessment by a neurologist. Cross-specialty collaboration should be strongly encouraged in clinical research.
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http://dx.doi.org/10.1016/j.yebeh.2019.01.032DOI Listing
April 2019

Industry payments to physician journal editors.

PLoS One 2019 7;14(2):e0211495. Epub 2019 Feb 7.

University of California, San Francisco, California, United States of America.

Background: Open Payments is a United States federal program mandating reporting of medical industry payments to physicians, increasing transparency of physician conflicts of interest (COI). Study objectives were to assess industry payments to physician-editors, and to compare their financial COI rate to all physicians within the specialty.

Methods And Findings: We performed a retrospective analysis of prospectively collected data, reviewing Open Payments from August 1, 2013 to December 31, 2016. We reviewed general payments ("… not made in connection with a research agreement") and research funding to "top tier" physician-editors of highly-cited medical journals. We compared payments to physician-editors and physicians-by-specialty. In 35 journals, 333 (74.5%) of 447 "top tier" US-based editors met inclusion criteria. Of these, 212 (63.7%) received industry-associated payments in the study period. In an average year, 141 (42.3%) of physician-editors received any direct payments to themselves including general payments and research payments, 66 (19.8%) received direct payments >$5,000 (National Institutes of Health threshold for a Significant Financial Interest) and 51 (15.3%) received >$10,000. Mean annual general payments to physician-editors was $55,157 (median 3,512, standard deviation 561,885, range 10-10,981,153). Median general payments to physician-editors were mostly higher compared to all physicians within their specialty. Mean annual direct research payment to the physician-editor was $14,558 (median 4,000, range 15-174,440). Mean annual indirect research funding to the physician-editor's institution (highly valued by academic leaders such as departmental chairs and deans) was $175,282 (median 49,107, range 0.18-5,000,000). The main study limitation was difficulty identifying physician-editors primarily responsible for making manuscript decisions.

Conclusions: A substantial minority of physician-editors receive payments from industry within any given year, sometimes quite large. Most editors received payment of some kind during the four-year study period. Given the extent of editors' influences on the medical literature, more robust and accessible editor financial COI declarations are recommended.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211495PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6366761PMC
November 2019

Melatonin receptors limit dopamine reuptake by regulating dopamine transporter cell-surface exposure.

Cell Mol Life Sci 2018 Dec 24;75(23):4357-4370. Epub 2018 Jul 24.

Inserm, U1016, Institut Cochin, 22 Rue Mechain, 75014, Paris, France.

Melatonin, a neuro-hormone released by the pineal gland, has multiple effects in the central nervous system including the regulation of dopamine (DA) levels, but how melatonin accomplishes this task is not clear. Here, we show that melatonin MT and MT receptors co-immunoprecipitate with the DA transporter (DAT) in mouse striatal synaptosomes. Increased DA re-uptake and decreased amphetamine-induced locomotor activity were observed in the striatum of mice with targeted deletion of MT or MT receptors. In vitro experiments confirmed the interactions and recapitulated the inhibitory effect of melatonin receptors on DA re-uptake. Melatonin receptors retained DAT in the endoplasmic reticulum in its immature non-glycosylated form. In conclusion, we reveal one of the first molecular complexes between G protein-coupled receptors (MT and MT) and transporters (DAT) in which melatonin receptors regulate the availability of DAT at the plasma membrane, thus limiting the striatal DA re-uptake capacity in mice.
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http://dx.doi.org/10.1007/s00018-018-2876-yDOI Listing
December 2018

Emergency department neuroimaging for epileptic seizures.

Epilepsia 2018 09 18;59(9):1676-1683. Epub 2018 Jul 18.

Department of Neurology, Oregon Health & Science University, Portland, Oregon.

Objective: To determine the frequency and yield of neuroimaging in patients with known seizure disorders presenting to the emergency department (ED) with recurrent (nonindex) seizures.

Methods: We reviewed 822 consecutive ED visits for nonindex seizures at the Oregon Health & Science University and the VA Portland Health Care System. For each visit, we abstracted details of the clinical presentation, whether neuroimaging was obtained, the results of neuroimaging, and the results of previous neuroimaging studies, when available. We determined whether ED neuroimaging led to an acute change in patient management (yield). Clinical factors associated with obtaining ED neuroimaging, and with the yield of neuroimaging, were evaluated by multivariate logistic regression.

Results: A majority (78%) of ED seizure visits were for nonindex seizures. Neuroimaging was obtained in 381 of 822 nonindex seizure visits (46%). Of these, 11 imaging studies (3%) led to an acute change in patient management, 8 (2%) after excluding false-positive scans. Acute head trauma, prolonged alteration of consciousness, and a focal neurologic examination at presentation were associated with an increased yield of ED neuroimaging. Absent any of these 3 clinical factors the true positive yield of neuroimaging was zero.

Significance: ED neuroimaging was performed in nearly half of all patients presenting with nonindex seizures. A more conservative use of ED neuroimaging for nonindex seizures, based on clinical factors at presentation, could decrease imaging frequency with minimal loss of yield.
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http://dx.doi.org/10.1111/epi.14518DOI Listing
September 2018

Mentored peer review of standardized manuscripts as a teaching tool for residents: a pilot randomized controlled multi-center study.

Res Integr Peer Rev 2017 5;2. Epub 2017 Jun 5.

3Department of Neurology, Columbia University College of Physicians and Surgeons, 630 W 168th St, New York, NY 10032 USA.

Background: There is increasing need for peer reviewers as the scientific literature grows. Formal education in biostatistics and research methodology during residency training is lacking. In this pilot study, we addressed these issues by evaluating a novel method of teaching residents about biostatistics and research methodology using peer review of standardized manuscripts. We hypothesized that mentored peer review would improve resident knowledge and perception of these concepts more than non-mentored peer review, while improving review quality.

Methods: A partially blinded, randomized, controlled multi-center study was performed. Seventy-eight neurology residents from nine US neurology programs were randomized to receive mentoring from a local faculty member or not. Within a year, residents reviewed a baseline manuscript and four subsequent manuscripts, all with introduced errors designed to teach fundamental review concepts. In the mentored group, mentors discussed completed reviews with residents. Primary outcome measure was change in knowledge score between pre- and post-tests, measuring epidemiology and biostatistics knowledge. Secondary outcome measures included level of confidence in the use and interpretation of statistical concepts before and after intervention, and RQI score for baseline and final manuscripts.

Results: Sixty-four residents (82%) completed initial review with gradual decline in completion on subsequent reviews. Change in primary outcome, the difference between pre- and post-test knowledge scores, did not differ between mentored (-8.5%) and non-mentored (-13.9%) residents ( = 0.48). Significant differences in secondary outcomes (using 5-point Likert scale, 5 = strongly agree) included mentored residents reporting enhanced understanding of research methodology (3.69 vs 2.61;  = 0.001), understanding of manuscripts (3.73 vs 2.87;  = 0.006), and application of study results to clinical practice (3.65 vs 2.78;  = 0.005) compared to non-mentored residents. There was no difference between groups in level of interest in peer review (3.00 vs 3.09;  = 0.72) or the quality of manuscript review assessed by the Review Quality Instrument (RQI) (3.25 vs 3.06;  = 0.50).

Conclusions: We used mentored peer review of standardized manuscripts to teach biostatistics and research methodology and introduce the peer review process to residents. Though knowledge level did not change, mentored residents had enhanced perception in their abilities to understand research methodology and manuscripts and apply study results to clinical practice.
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http://dx.doi.org/10.1186/s41073-017-0032-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5803578PMC
June 2017

NDFIP allows NEDD4/NEDD4L-induced AQP2 ubiquitination and degradation.

PLoS One 2017 20;12(9):e0183774. Epub 2017 Sep 20.

Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.

Regulation of our water homeostasis is fine-tuned by dynamic translocation of Aquaporin-2 (AQP2)-bearing vesicles to and from the plasma membrane of renal principal cells. Whereas binding of vasopressin to its type-2 receptor initiates a cAMP-protein kinase A cascade and AQP2 translocation to the apical membrane, this is counteracted by protein kinase C-activating hormones, resulting in ubiquitination-dependent internalization of AQP2. The proteins targeting AQP2 for ubiquitin-mediated degradation are unknown. In collecting duct mpkCCD cells, siRNA knockdown of NEDD4 and NEDD4L E3 ligases yielded increased AQP2 abundance, but they did not bind AQP2. Membrane Yeast Two-Hybrid assays using full-length AQP2 as bait, identified NEDD4 family interacting protein 2 (NDFIP2) to bind AQP2. NDFIP2 and its homologue NDFIP1 have PY motifs by which they bind NEDD4 family members and bring them close to target proteins. In HEK293 cells, NDFIP1 and NDFIP2 bound AQP2 and were essential for NEDD4/NEDD4L-mediated ubiquitination and degradation of AQP2, an effect not observed with PY-lacking NDFIP1/2 proteins. In mpkCCD cells, downregulation of NDFIP1, NEDD4 and NEDD4L, but not NDFIP2, increased AQP2 abundance. In mouse kidney, Ndfip1 and Ndfip2 mRNA distribution was similar and high in proximal tubules and collecting ducts, which was also found for NDFIP1 proteins. Our results reveal that NEDD4/NEDD4L mediate ubiquitination and degradation of AQP2, but that NDFIP proteins are needed to connect NEDD4/NEDD4L to AQP2. As NDFIP1/2 bind many NEDD4 family E3 ligases, which are implicated in several cellular processes, NDFIP1/2 may be the missing link for AQP2 ubiquitination and degradation from different subcellular locations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0183774PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606929PMC
October 2017

Systematic protein-protein interaction mapping for clinically relevant human GPCRs.

Mol Syst Biol 2017 03 15;13(3):918. Epub 2017 Mar 15.

Donnelly Centre, University of Toronto, Toronto, ON, Canada

G-protein-coupled receptors (GPCRs) are the largest family of integral membrane receptors with key roles in regulating signaling pathways targeted by therapeutics, but are difficult to study using existing proteomics technologies due to their complex biochemical features. To obtain a global view of GPCR-mediated signaling and to identify novel components of their pathways, we used a modified membrane yeast two-hybrid (MYTH) approach and identified interacting partners for 48 selected full-length human ligand-unoccupied GPCRs in their native membrane environment. The resulting GPCR interactome connects 686 proteins by 987 unique interactions, including 299 membrane proteins involved in a diverse range of cellular functions. To demonstrate the biological relevance of the GPCR interactome, we validated novel interactions of the GPR37, serotonin 5-HT4d, and adenosine ADORA2A receptors. Our data represent the first large-scale interactome mapping for human GPCRs and provide a valuable resource for the analysis of signaling pathways involving this druggable family of integral membrane proteins.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5371730PMC
http://dx.doi.org/10.15252/msb.20167430DOI Listing
March 2017

Teaching Neuro: A spiritual visual hallucination from a right parieto-occipital seizure: Ictal guardian angel.

Neurology 2017 03;88(11):e101-e102

From the Department of Neurology, Oregon Health & Science University, Portland. Dr. Wong is currently affiliated with The Queen's Medical Center Neuroscience Institute, Honolulu, HI.

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http://dx.doi.org/10.1212/WNL.0000000000003709DOI Listing
March 2017

A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.

Mol Cell 2017 Jan 5;65(2):347-360. Epub 2017 Jan 5.

Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address:

Receptor tyrosine kinases (RTKs) and protein phosphatases comprise protein families that play crucial roles in cell signaling. We used two protein-protein interaction (PPI) approaches, the membrane yeast two-hybrid (MYTH) and the mammalian membrane two-hybrid (MaMTH), to map the PPIs between human RTKs and phosphatases. The resulting RTK-phosphatase interactome reveals a considerable number of previously unidentified interactions and suggests specific roles for different phosphatase families. Additionally, the differential PPIs of some protein tyrosine phosphatases (PTPs) and their mutants suggest diverse mechanisms of these PTPs in the regulation of RTK signaling. We further found that PTPRH and PTPRB directly dephosphorylate EGFR and repress its downstream signaling. By contrast, PTPRA plays a dual role in EGFR signaling: besides facilitating EGFR dephosphorylation, it enhances downstream ERK signaling by activating SRC. This comprehensive RTK-phosphatase interactome study provides a broad and deep view of RTK signaling.
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http://dx.doi.org/10.1016/j.molcel.2016.12.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5663465PMC
January 2017

Trends and Determinants of Familial Consent for Corneal Donation in Chinese.

Cornea 2017 Mar;36(3):295-299

*Hong Kong Eye Hospital, Hong Kong SAR, China; †School of Public Health, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong SAR, China; and ‡Hospital Authority Eye Bank, Hong Kong SAR, China.

Purpose: Corneal transplantation is the treatment of choice for many corneal diseases. At present, there is a global shortage of corneal transplant tissues, and failure to obtain consent from families of potential donors is a major limiting factor in tissue procurement.

Methods: All family members of potential donors after cardiac death approached by the local eye bank staff members from January 2008 to December 2014 in Hong Kong were included. Reasons for consent or refusal and sociodemographic details of the deceased and the family members approached were reviewed. Trends in consent rates from 2008 to 2014 were examined. Multivariable logistic regression was performed to examine determinants of donation among cases from 2013 to 2014.

Results: A total of 1740 cases were identified. The overall consent rate was 36.8%, and the consent rate did not change significantly over the 7-year study period (P = 0.24). The most common reason for consent by family members was "the wish to help others" (86.0%), and the most common reason for refusal was "traditional Chinese culture to keep the body intact after death" (42.7%). From the multivariable analysis in the subset of cases from 2013 to 2014 (n = 628), family members were more likely to consent when the deceased was female (adjusted odds ratio 1.45, P = 0.03), with a do-not-resuscitate order (adjusted odds ratio 2.27, P < 0.001).

Conclusions: The consent rate for eye donation did not change significantly from 2008 to 2014. Our findings suggest that health education and promotion campaigns need to address cultural barriers to organ donation.
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http://dx.doi.org/10.1097/ICO.0000000000001091DOI Listing
March 2017

Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring.

Epilepsia 2016 09 11;57(9):1495-502. Epub 2016 Jul 11.

University of Virginia, Charlottesville, Virginia, U.S.A.

Objective: Previous studies reporting circadian patterns of epileptiform activity and seizures are limited by (1) short-term recording in an epilepsy monitoring unit (EMU) with altered antiepileptic drugs (AEDs) and sleep, or (2) subjective seizure diary reports. We studied circadian patterns using long-term ambulatory intracranial recordings captured by the NeuroPace RNS System.

Methods: Retrospective study of RNS System trial participants with stable detection parameters over a continuous 84-day period. We analyzed all detections and long device-detected epileptiform events (long episodes) and defined a subset of subjects in whom long episodes represented electrographic seizures (LE-SZ). Spectrum resampling determined the dominant frequency periodicity and cosinor analysis identified significant circadian peaks in detected activity. Chi-square analysis was used to compare subjects grouped by region of seizure onset.

Results: In the 134 subjects, detections showed a strongly circadian and uniform pattern irrespective of region of onset that peaked during normal sleep hours. In contrast, long episodes and LE-SZ patterns varied by region. Neocortical regions had a monophasic, nocturnally dominant rhythm, whereas limbic regions showed a more complex pattern and diurnal peak. Rhythms in some individual limbic subjects were best fit by a dual oscillator (circadian + ultradian) model.

Significance: Epileptiform activity has a strong 24 h periodicity with peak nocturnal occurrence. Limbic and neocortical epilepsy show divergent circadian influences. These findings confirm that circadian patterns of epileptiform activity vary by seizure-onset zone, with implications for treatment and safety, including SUDEP.
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http://dx.doi.org/10.1111/epi.13455DOI Listing
September 2016

Outcomes of cataract operations in extreme high axial myopia.

Graefes Arch Clin Exp Ophthalmol 2016 Sep 16;254(9):1811-7. Epub 2016 Jun 16.

Hong Kong Eye Hospital, 147K Argyle street, Kowloon, Hong Kong.

Purpose: To analyse the outcomes of phacoemulsification in extreme axial myopia

Methods: Consecutive cases of phacoemulsification in eyes with axial length ≥ 30.0 mm from January 1, 2010 to Dec 31, 2013 in a tertiary referral eye hospital were retrospectively reviewed. A single intraocular lens (IOL) type was used for all cases. Main outcome measures included perioperative complications and refractive outcome.

Results: Two hundred and twenty-one eyes were identified. Intraoperatively, two eyes (0.9 %) had unstable capsular bag and three (1.4 %) had posterior capsular rupture. At a mean follow-up duration was 27.4 ± 14.6 months, three eyes (1.5 % of 198 eyes with no history of retinal detachment or macular hole) developed retinal detachment. There was an overall hyperopic shift with a mean biometry error of 0.45 ± 1.21 D in all eyes. The mean absolute biometry prediction error was 0.98 ± 0.83 D in all eyes, 1.11 ± 0.86 D and 0.85 ± 0.82 D in eyes receiving negative- and positive-power IOL, respectively (p = 0.042). A total of 61.2 % of eyes had refractive outcome within ± 1.0 D of target spherical equivalent. Regression analysis showed low IOL power as an independent predictor for greater postoperative absolute biometry error (p = 0.014).

Conclusions: We showed no increase in perioperative complications in eyes with extreme high axial myopia. In eyes with long axial length, implantation of IOL with lower power was associated with more hyperopic shift, which was more pronounced with negative-power IOL.
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http://dx.doi.org/10.1007/s00417-016-3414-yDOI Listing
September 2016

Novel regulation of equlibrative nucleoside transporter 1 (ENT1) by receptor-stimulated Ca2+-dependent calmodulin binding.

Am J Physiol Cell Physiol 2016 05 23;310(10):C808-20. Epub 2016 Mar 23.

Department of Biology, York University, Toronto, Canada; Department of Chemistry and Biology, Ryerson University, Toronto, Canada;

Equilibrative nucleoside transporters (ENTs) facilitate the flux of nucleosides, such as adenosine, and nucleoside analog (NA) drugs across cell membranes. A correlation between adenosine flux and calcium-dependent signaling has been previously reported; however, the mechanistic basis of these observations is not known. Here we report the identification of the calcium signaling transducer calmodulin (CaM) as an ENT1-interacting protein, via a conserved classic 1-5-10 motif in ENT1. Calcium-dependent human ENT1-CaM protein interactions were confirmed in human cell lines (HEK293, RT4, U-87 MG) using biochemical assays (HEK293) and the functional assays (HEK293, RT4), which confirmed modified nucleoside uptake that occurred in the presence of pharmacological manipulations of calcium levels and CaM function. Nucleoside and NA drug uptake was significantly decreased (∼12% and ∼39%, respectively) by chelating calcium (EGTA, 50 μM; BAPTA-AM, 25 μM), whereas increasing intracellular calcium (thapsigargin, 1.5 μM) led to increased nucleoside uptake (∼26%). Activation of N-methyl-d-aspartate (NMDA) receptors (in U-87 MG) by glutamate (1 mM) and glycine (100 μM) significantly increased nucleoside uptake (∼38%) except in the presence of the NMDA receptor antagonist, MK-801 (50 μM), or CaM antagonist, W7 (50 μM). These data support the existence of a previously unidentified novel receptor-dependent regulatory mechanism, whereby intracellular calcium modulates nucleoside and NA drug uptake via CaM-dependent interaction of ENT1. These findings suggest that ENT1 is regulated via receptor-dependent calcium-linked pathways resulting in an alteration of purine flux, which may modulate purinergic signaling and influence NA drug efficacy.
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http://dx.doi.org/10.1152/ajpcell.00243.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4895448PMC
May 2016

No teeth, no nails and not enough tears.

Postgrad Med J 2016 Aug 3;92(1090):485-6. Epub 2016 Mar 3.

Hong Kong Eye Hospital, Hong Kong SAR, Hong Kong Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong SAR, Hong Kong.

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http://dx.doi.org/10.1136/postgradmedj-2015-133491DOI Listing
August 2016