503 results on '"Todd, Alexander"'
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2. Duration of and time to response in oncology clinical trials from the perspective of the estimand framework
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Weber, Hans-Jochen, Corson, Stephen, Li, Jiang, Mercier, Francois, Roychoudhury, Satrajit, Sailer, Martin Oliver, Sun, Stephen, Todd, Alexander, and Yung, Godwin
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Statistics - Methodology - Abstract
Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early-stage clinical studies in oncology when efficacy is assessed by the best overall response (BOR) and presented as the overall response rate (ORR). Despite common use of DOR and TTR in particular in single-arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols.
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- 2022
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3. Disruption of the c‐terminal serine protease domain of Fam111a does not alter calcium homeostasis in mice
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Rebecca Siu Ga Tan, Christy Hui Lin Lee, Wanling Pan, Serene Wohlgemuth, Michael R. Doschak, and R. Todd Alexander
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calcium ,FAM111A ,Kenney–Caffey syndrome ,Osteocraniostenosis ,Physiology ,QP1-981 - Abstract
Abstract FAM111A gene mutations cause Kenney–Caffey syndrome (KCS) and Osteocraniostenosis (OCS), conditions characterized by short stature, low serum ionized calcium (Ca2+), low parathyroid hormone (PTH), and bony abnormalities. The molecular mechanism mediating this phenotype is unknown. The c‐terminal domain of FAM111A harbors all the known disease‐causing variations and encodes a domain with high homology to serine proteases. However, whether this serine protease domain contributes to the maintenance of Ca2+ homeostasis is not known. We hypothesized the disruption of the serine protease domain of FAM111A would disrupt Ca2+ homeostasis. To test this hypothesis, we generated with CRISPR/Cas9, mice with a frameshift insertion (c.1450insA) or large deletion (c.1253‐1464del) mutation in the Fam111a serine protease domain. Serum‐ionized Ca2+ and PTH levels were not significantly different between wild type, heterozygous, or homozygous Fam111a mutant mice. Additionally, there were no significant differences in fecal or urine Ca2+ excretion, intestinal Ca2+ absorption or overall Ca2+ balance. Only female homozygous (c.1450insA), but not heterozygous mice displayed differences in bone microarchitecture and mineral density compared to wild‐type animals. We conclude that frameshift mutations that disrupt the c‐terminal serine protease domain do not induce a KCS or OCS phenotype in mice nor alter Ca2+ homeostasis.
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- 2024
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4. Galaxy Zoo: 3D -- Crowd-sourced Bar, Spiral and Foreground Star Masks for MaNGA Target Galaxies
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Masters, Karen L., Krawczyk, Coleman, Shamsi, Shoaib, Todd, Alexander, Finnegan, Daniel, Bershady, Matthew, Bundy, Kevin, Cherinka, Brian, Fraser-McKelvie, Amelia, Krishnarao, Dhanesh, Kruk, Sandor, Lane, Richard R., Law, David, Lintott, Chris, Merrifield, Michael, Simmons, Brooke, Weijmans, Anne-Marie, and Yan, Renbin
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Astrophysics - Astrophysics of Galaxies - Abstract
The challenge of consistent identification of internal structure in galaxies - in particular disc galaxy components like spiral arms, bars, and bulges - has hindered our ability to study the physical impact of such structure across large samples. In this paper we present Galaxy Zoo: 3D (GZ: 3D) a crowdsourcing project built on the Zooniverse platform which we used to create spatial pixel (spaxel) maps that identify galaxy centres, foreground stars, galactic bars and spiral arms for 29831 galaxies which were potential targets of the MaNGA survey (Mapping Nearby Galaxies at Apache Point Observatory, part of the fourth phase of the Sloan Digital Sky Surveys or SDSS-IV), including nearly all of the 10,010 galaxies ultimately observed. Our crowd-sourced visual identification of asymmetric, internal structures provides valuable insight on the evolutionary role of non-axisymmetric processes that is otherwise lost when MaNGA data cubes are azimuthally averaged. We present the publicly available GZ:3D catalog alongside validation tests and example use cases. These data may in the future provide a useful training set for automated identification of spiral arm features. As an illustration, we use the spiral masks in a sample of 825 galaxies to measure the enhancement of star formation spatially linked to spiral arms, which we measure to be a factor of three over the background disc, and how this enhancement increases with radius., Comment: 13 pages, 9 figures. MNRAS accepted
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- 2021
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5. Candidate mechanisms of acquired resistance to first-line osimertinib in EGFR-mutated advanced non-small cell lung cancer
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Chmielecki, Juliann, Gray, Jhanelle E., Cheng, Ying, Ohe, Yuichiro, Imamura, Fumio, Cho, Byoung Chul, Lin, Meng-Chih, Majem, Margarita, Shah, Riyaz, Rukazenkov, Yuri, Todd, Alexander, Markovets, Aleksandra, Barrett, J. Carl, Hartmaier, Ryan J., and Ramalingam, Suresh S.
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- 2023
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6. Longitudinal Analyses of Circulating Tumor DNA for the Detection of EGFR Mutation-Positive Advanced NSCLC Progression During Treatment: Data From FLAURA and AURA3
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Gray, Jhanelle E., Markovets, Aleksandra, Reungwetwattana, Thanyanan, Majem, Margarita, Nogami, Naoyuki, Peled, Nir, Lee, Jong-Seok, Cho, Byoung Chul, Chewaskulyong, Busayamas, John, Tom, Han, Ji-Youn, Sebastian, Martin, Todd, Alexander, Rukazenkov, Yuri, Barrett, Carl, Chmielecki, Juliann, Lee, Siow Ming, Ramalingam, Suresh S., and Hartmaier, Ryan
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- 2024
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7. Expression of the kidney anion exchanger 1 affects WNK4 and SPAK phosphorylation and results in claudin-4 phosphorylation
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Rawad Lashhab, Grace Essuman, Maria Chavez-Canales, R. Todd Alexander, and Emmanuelle Cordat
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Kidney ,Claudin ,Transporters ,Membrane protein ,Epithelium ,Tight junctions ,Science (General) ,Q1-390 ,Social sciences (General) ,H1-99 - Abstract
In the renal collecting ducts, chloride reabsorption occurs through both transcellular and paracellular pathways. Recent literature highlights a functional interplay between both pathways. We recently showed that in polarized inner medullary collecting duct cells, expression of the basolateral kidney anion exchanger 1 (kAE1) results in a decreased transepithelial electrical resistance (TEER), in a claudin-4 dependent pathway. Claudin-4 is a paracellular sodium blocker and chloride pore. Here, we show that kAE1 expression in mouse inner medullary collecting duct cells triggers WNK4, SPAK and claudin-4 phosphorylation. Expression of a functionally dead kAE1 E681Q mutant has no effect on phosphorylation of these proteins. Expression of a catalytically inactive WNK4 D321A or chloride-insensitive WNK4 L319F mutant abolishes kAE1 effect on TEER, supporting a contribution of WNK4 to the process. We propose that variations of the cytosolic pH and chloride concentration upon kAE1 expression alter WNK4 kinase activity and tight junction properties.
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- 2023
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8. Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes
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Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud, and Michael Zappitelli
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: Acute kidney injury (AKI) in critically ill children is associated with increased risk for short- and long-term adverse outcomes. Currently, there is no systematic follow-up for children who develop AKI in intensive care unit (ICU). Objective: This study aimed to assess variation regarding management, perceived importance, and follow-up of AKI in the ICU setting within and between healthcare professional (HCP) groups. Design: Anonymous, cross-sectional, web-based surveys were administered nationally to Canadian pediatric nephrologists, pediatric intensive care unit (PICU) physicians, and PICU nurses, via professional listservs. Setting: All Canadian pediatric nephrologists, PICU physicians, and nurses treating children in the ICU were eligible for the survey. Patients: N/A. Measurements: Surveys included multiple choice and Likert scale questions on current practice related to AKI management and long-term follow-up, including institutional and personal practice approaches, and perceived importance of AKI severity with different outcomes. Methods: Descriptive statistics were performed. Categorical responses were compared using Chi-square or Fisher’s exact tests; Likert scale results were compared using Mann-Whitney and Kruskal-Wallis tests. Results: Surveys were completed by 34/64 (53%) pediatric nephrologists, 46/113 (41%) PICU physicians, and 82 PICU nurses (response rate unknown). Over 65% of providers reported hemodialysis to be prescribed by nephrology; a mix of nephrology, ICU, or a shared nephrology-ICU model was reported responsible for peritoneal dialysis and continuous renal replacement therapy (CRRT). Severe hyperkalemia was the most important renal replacement therapy (RRT) indication for both nephrologists and PICU physicians (Likert scale from 0 [not important] to 10 [most important]; median = 10, 10, respectively). Nephrologists reported a lower threshold of AKI for increased mortality risk; 38% believed stage 2 AKI was the minimum compared to 17% of PICU physicians and 14% of nurses. Nephrologists were more likely than PICU physicians and nurses to recommend long-term follow-up for patients who develop any AKI during ICU stay (Likert scale from 0 [none] to 10 [all patients]; mean=6.0, 3.8, 3.7, respectively) ( P < .05). Limitations: Responses from all eligible HCPs in the country could not obtained. There may be differences in opinions between HCPs that completed the survey compared to those that did not. Additionally, the cross-sectional design of our study may not adequately reflect changes in guidelines and knowledge since survey completion, although no specific guidelines have been released in Canada since survey dissemination. Conclusions: Canadian HCP groups have variable perspectives on pediatric AKI management and follow-up. Understanding practice patterns and perspectives will help optimize pediatric AKI follow-up guideline implementation.
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- 2023
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9. Developmental Changes in Phosphate Homeostasis
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MacDonald, Tate, Saurette, Matthew, Beggs, Megan R., Todd Alexander, R., Pedersen, Stine Helene Falsig, Editor-in-Chief, Barber, Diane L., Series Editor, Cordat, Emmanuelle, Series Editor, Kajimura, Mayumi, Series Editor, Leipziger, Jens G., Series Editor, O'Donnell, Martha E., Series Editor, Pardo, Luis A., Series Editor, Schmitt, Nicole, Series Editor, and Stock, Christian, Series Editor
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- 2021
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10. Advancing Discovery Research in Nephrology in Canada: A Conference Report From the 2021 Molecules and Mechanisms Mediating Kidney Health and Disease (M3K) Scientific Meeting and Investigator Summit
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Dylan Burger, Amira Abdelrasoul, R. Todd Alexander, Barbara Ballermann, Darren Bridgewater, John S. D. Chan, Joanna Cunanan, Andrey V. Cybulsky, Casimiro Gerarduzzi, Lakshman Gunaratnam, Sunny Hartwig, Andras Kapus, Christopher R. J. Kennedy, Caroline Lamarche, Robert L. Myette, Ifeanyi Kennedy Nmecha, Leanne Stalker, Katalin Szaszi, Elena Torban, Shao Ling Zhang, and Tomoko Takano
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Purpose of conference: New discoveries arising from investigations into fundamental aspects of kidney development and function in health and disease are critical to advancing kidney care. Scientific meetings focused specifically on fundamental biology of the kidney can facilitate interactions, support the development of collaborative groups, and accelerate translation of key findings. The Canadian fundamental kidney researcher community has lacked such a forum. On December 3 to 4, 2021, the first Molecules and Mechanisms Mediating Kidney Health and Disease (M3K) Scientific Meeting and Investigator Summit was held to address this gap with the goal of advancing fundamental kidney research nationally. The meeting was held virtually and was supported by a planning and dissemination grant from the Canadian Institutes of Health Research. Attendees included PhD scientists, nephrology clinician scientists, engineers, industry representatives, graduate students, medical residents, and fellows. Sources of information: This report was prepared from the scientific program, registration numbers, and details obtained from the online platform WHOVA, and summaries written by organizers and participants of the 2021 meeting. Methods: A 21-person team, consisting of the organizing committee members and participants from the meeting, was assembled. Key highlights of the meeting and future directions were identified and the team jointly assembled this report. Key findings: Participation in the meeting was strong, with more than 140 attendees across a range of disciplines. The program featured state-of-the-art presentations on diabetic nephropathy, the immune system, kidney development, and fibrosis, and was heavily focused on trainee presentations. The moderated “Investigator Summit” identified key barriers to research advancement and discussed strategies for overcoming them. These included establishment of a pan-Canadian fundamental kidney research network, development of key resources, cross-pollination with clinical nephrology, better reintegration into the Canadian Society of Nephrology, and further establishment of identity and knowledge translation. Limitations and implications: The 2021 M3K meeting represented a key first step in uniting fundamental kidney researchers in Canada. However, it was universally agreed that regular meetings were necessary to sustain this momentum. The proceedings of this meeting and future actions to sustain the M3K Scientific Meeting and Investigator Summit are presented in this article.
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- 2022
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11. Involving Patient Partners in the KRESCENT Peer Review: Intent, Process, Challenges, and Opportunities
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Elisabeth A. Fowler, Karin Bell, Kevin Burns, Angela Chiazzese, Sacha A. DeSerres, Bethany J. Foster, Sunny Hartwig, Gwen Herrington, Matthew T. James, Victor Jensen, Nina Jones, Sandi Kidston, Serge Lemay, Adeera Levin, Anne MacPhee, Shanda McCutcheon, Pietro Ravani, Susan Samuel, James Scholey, Tomoko Takano, Navdeep Tangri, Nancy Verdin, R. Todd Alexander, and Catherine M. Clase
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Purpose of review: The Kidney Research Scientist Core Education and National Training (KRESCENT) is a national Canadian training program for kidney scientists, funded by the Kidney Foundation of Canada (KFOC), the Canadian Institutes of Health Research (CIHR), and the Canadian Society of Nephrology (CSN). We describe our first year of incorporating patient partners into a scientific peer-review committee, the 2017 committee to select senior research trainees and early-career kidney researchers for funding and training, in the hope that it will be helpful to others who wish to integrate the perspective of people with lived experience into the peer-review process. Sources of information: Other peer-review committees, websites, journal articles, patient partners, Kidney Foundation of Canada Research Council, Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD) Patient Council, participants in the 2017 Kidney Foundation of Canada KRESCENT peer-review panel. Methods: We describe our motivation, rationale, guiding principles, plans, feedback, implementation, and response. Key findings: We disseminated a “call for patient partners” 8 weeks before the meeting, seeking patients or their care givers to partner with the KRESCENT peer-review panel; we defined these people with lived experience of kidney disease as patient partners. Eight patient partners came forward and all participated as reviewers. Patient partners first participated in a webinar to learn about the function, structure, and processes of a peer-review committee. They practiced reviewing plain language summaries and giving feedback. In a subsequent teleconference, they shared and discussed their reviews. Plain language summaries were scored, overall, on the same 0-5 quality scale used by scientific reviewers. Three patient reviewers participated in some or all of the 6-hour meeting, which was conducted as usual, for this panel, by teleconference (initially audio only; from 2020 onwards by videoconference). In the meeting, the 2 assigned scientific reviewers first gave their scores, followed by the patient reviewers giving their scores, and discussion (mostly scientific, and conducted in usual scientific language). Scientific reviewers then negotiated a consensus score based on their initial scores, the discussion, patient reviewers’ scores and statements, and the scientific officer’s notes. Patient reviewers, scientific reviewers, and the Kidney Foundation of Canada (KFOC) were generally positive about the process. The increased length of the meeting (estimated at 1 hour) was generally thought to be acceptable. Patient reviewers also provided feedback on the methods used to incorporate patients into the research under review. These comments were concrete, insightful, and helpful. The patients did not uniformly recommend that basic scientists involve patients in their work. We did not detect bias against preclinical science, work that did not involve patients, or rarer diseases. Some patients found participation inspiring and enlightening. All participants appreciated the idea of patient partners as community witnesses to a group process committed to fairness and supportiveness. We discussed assigning formal meaningful weight to patient reviewers’ assessments. Most, but not all, patients thought that the scientific reviewers were ultimately the best judges of the allocation of scarce research resources. Limitations: Patient participants tended to be Caucasian, middle class, and well educated. Because of the difficulties of travel for some people living with or supporting those living with kidney disease, our findings may not generalize fully to peer-review meetings that are conducted face to face. This is explicitly a supportive panel, committed to reviewing junior scientists with kindness as well as rigor; our findings may not generalize to panels conducted differently. We did not use formal qualitative methodology. Implications: Inclusion of patient partners as patient reviewers for the KRESCENT program peer-review panel was feasible, added value for scientific and patient reviewers, and for the funding stakeholders (CIHR, KFOC, and CSN). We were glad that we had taken this step and continue to refine the process with each successive competition.
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- 2022
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12. Mutations in Are Not a Common Cause of Pediatric Idiopathic Hypercalciuria in Canada
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Emma H. Ulrich, Elizabeth Harvey, Catherine J. Morgan, Maury Pinsk, Robin Erickson, Lisa A. Robinson, and R. Todd Alexander
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: Hypercalciuria is the most common risk factor for kidney stone formation, including in pediatric patients. However, the etiology is often unknown and children are frequently diagnosed with idiopathic hypercalciuria. Nearly 50% of children with hypercalciuria have a first-degree relative with kidney stones, suggesting a strong genetic basis for this disease. A failure of calcium reabsorption from the proximal nephron is implicated in the pathogenesis of hypercalciuria. Claudin-2 is a tight junction protein abundantly expressed in the proximal tubule. It confers paracellular permeability to calcium that is essential for transport across the proximal tubule where the majority of filtered calcium is reabsorbed. Objective: Our objective was to examine the frequency of coding variations in CLDN2 in a cohort of children with idiopathic hypercalciuria. Design: Mixed method including retrospective chart review and patient interview, followed by genetic sequencing. Setting: Three tertiary care centers in Canada. Patients: Children (age 1-18 years) with idiopathic hypercalciuria. Patients with other causes of hypercalciuria were excluded. Methods: Data were collected from 40 patients with idiopathic hypercalciuria. Informed consent to collect DNA was obtained from 13 patients, and the final and only coding exon of CLDN2 was sequenced. Results: The majority of patients were male, white, and had a positive family history of kidney stones. Parathyroid hormone levels were significantly lower than the reference range ( P < .001). The levels of 1,25-dihydroxyvitamin D were also significantly higher in our patient cohort, relative to the reference range ( P < .001). Sequence analysis of CLDN2 did not identify any coding variations. Limitations: Sequencing analysis was limited to the final coding exon and small sample size. Conclusions: CLDN2 coding variations are not a common cause of idiopathic hypercalciuria in Canadian children. Further study is needed to determine the causes of hypercalciuria in pediatric patients and develop targeted therapies.
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- 2022
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13. Differential parathyroid and kidney Ca2+-sensing receptor activation in autosomal dominant hypocalcemia 1
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Wouter H. van Megen, Rebecca Siu Ga Tan, R. Todd Alexander, and Henrik Dimke
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Hypercalciuria ,CaSR ,Kidney ,Claudin-14 ,ADH1 case report ,Medicine ,Medicine (General) ,R5-920 - Abstract
Summary: Background: Parathyroid Ca2+-sensing receptor (CaSR) activation inhibits parathyroid hormone (PTH) release, while activation of renal CaSRs attenuates Ca2+ transport and increases expression of the pore-blocking claudin-14. Patients with autosomal dominant hypocalcemia 1 (ADH1), due to activating CASR mutations, exhibit hypocalcemia but not always hypercalciuria (elevated Ca2+ in urine). The latter promotes nephrocalcinosis and renal insufficiency. Although CaSRs throughout the body including the kidney harbor activating CASR mutations, it is not understood why only some ADH1 patients display hypercalciuria. Methods: Activation of the CaSR was studied in mouse models and a ADH1 patient. In vitro CaSR activation was studied in HEK293 cells. Findings: Cldn14 showed blood Ca2+ concentration-dependent regulation, which was absent in mice with kidney-specific Casr deletion, indicating Cldn14 is a suitable marker for chronic CaSR activation in the kidney. Mice with a gain-of-function mutation in the Casr (Nuf) were hypocalcemic with low plasma PTH levels. However, renal CaSRs were not activated at baseline but only after normalizing blood Ca2+ levels. Similarly, significant hypercalciuria was not observed in a ADH1 patient until blood Ca2+ was normalized. In vitro experiments indicate that increased CaSR expression in the parathyroid relative to the kidney could contribute to tissue-specific CaSR activation thresholds. Interpretation: Our findings suggest that parathyroid CaSR overactivity can reduce plasma Ca2+ to levels insufficient to activate renal CaSRs, even when an activating mutation is present. These findings identify a conceptually new mechanism of CaSR-dependent Ca2+ balance regulation that aid in explaining the spectrum of hypercalciuria in ADH1 patients. Funding: Erasmus+ 2018/E+/4458087, the Canadian Institutes for Health research, the Novo Nordisk Foundation, the Beckett Foundation, the Carlsberg Foundation and Independent Research Fund Denmark.
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- 2022
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14. What causes the spread of model projections of ocean dynamic sea-level change in response to greenhouse gas forcing?
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Couldrey, Matthew P., Gregory, Jonathan M., Boeira Dias, Fabio, Dobrohotoff, Peter, Domingues, Catia M., Garuba, Oluwayemi, Griffies, Stephen M., Haak, Helmuth, Hu, Aixue, Ishii, Masayoshi, Jungclaus, Johann, Köhl, Armin, Marsland, Simon J., Ojha, Sayantani, Saenko, Oleg A., Savita, Abhishek, Shao, Andrew, Stammer, Detlef, Suzuki, Tatsuo, Todd, Alexander, and Zanna, Laure
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- 2021
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15. Use of the FebriDx® host-response point-of-care test may reduce antibiotic use for respiratory tract infections in primary care: a mixed-methods feasibility study.
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Wilcox, Christopher R, Odeh, Nour, Clark, Tristan W, Muller, Ingrid, Becque, Taeko, Todd, Alexander, Islam, Nazrul, Little, Paul, Davies, Firoza, McGavin, John, and Francis, Nick
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RESPIRATORY infections ,PRIMARY care ,POINT-of-care testing ,INFECTION ,FEASIBILITY studies - Abstract
Introduction FebriDx
® is a CE-marked, single-use point-of-care test with markers for bacterial [C-reactive protein (CRP)] and viral [myxovirus resistance protein A (MxA)] infection, using finger-prick blood samples. Results are available after 10–12 min. We explored the usability and potential impact of FebriDx® in reducing antibiotic prescriptions for lower respiratory tract infection (LRTI) in primary care, and the feasibility of conducting a randomized controlled trial (RCT). Methods Patients (aged ≥1 year) with LRTI deemed likely to receive antibiotic prescription were recruited at nine general practices and underwent FebriDx® testing. Data collection included FebriDx® results, antibiotic prescribing plan (before and after testing) and re-consultation rates. Staff completed System Usability Scale questionnaires. Results From 31 January 2023 to 9 June 2023, 162 participants participated (median age 57 years), with a median symptom duration of 7 days (IQR 5–14). A valid FebriDx® result was obtained in 97% (157/162). Of 155 patients with available results, 103 (66%) had no detectable CRP or MxA, 28 (18%) had CRP only, 5 (3%) had MxA only, and 19 (12%) had both CRP and MxA. The clinicians' stated management plan was to prescribe antibiotics for 86% (134/155) before testing and 45% (69/155) after testing, meaning a 41% (95% CI: 31%, 51%) difference after testing, without evidence of increased re-consultation rates. Ease-of-use questionnaires showed 'good' user-friendliness. Conclusions Use of FebriDx® to guide antibiotic prescribing for LRTI in primary care was associated with a substantial reduction in prescribing intentions. These results support a fully powered RCT to confirm its impact and safety. [ABSTRACT FROM AUTHOR]- Published
- 2024
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16. Rituximab Use for the Treatment of Childhood Nephrotic Syndrome by Canadian Pediatric Nephrologists: A National Survey
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Cory Meeuwisse, Catherine J. Morgan, Susan Samuel, R Todd Alexander, and Sara Rodriguez-Lopez
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: There is known practice variation in the treatment of frequently relapsing, steroid-dependent, and steroid-resistant nephrotic syndrome in children. Rituximab is an emerging therapy for difficult-to-treat nephrotic syndrome; however, there are no clear treatment guidelines. We therefore hypothesized that a wide variety of approaches to this therapy exist. Objective: To evaluate when and how rituximab is used for the treatment of childhood nephrotic syndrome in Canada. Design and setting: An online survey was used. Participants: Canadian pediatric nephrologists. Methods: A cross-sectional survey was distributed across Canada through the Canadian Association of Pediatric Nephrologists (CAPN) to evaluate rituximab treatment practices. Results: Of a total of 20 responses, 19 (95%) use rituximab in the treatment of nephrotic syndrome, usually as a third or fourth agent. For the number of rituximab doses, the majority (68%) uses 2 doses each time they use it. Eighteen respondents (90%) measure B cells when using this medication, mostly monthly (50%) or every 3 months (39%). Respondents administered additional doses of rituximab prophylactically (74%) or at first relapse (47%). Long-term drug safety and drug funding were identified as the main barriers to rituximab use. Limitations: This survey represents the practice styles of physicians in a single country, and there is a nonresponse bias of 63%. Also, associations were not calculated. Conclusions: Among Canadian pediatric nephrologists, rituximab use for nephrotic syndrome appears to be increasing, but significant practice variations remain, including approaches to B-cell monitoring. It is reserved mostly for second-line and third-line use due to cost, funding issues, and residual uncertainty regarding long-term safety. Understanding these critical areas of practice uncertainty is a first step to optimize treatment of nephrotic syndrome in children.
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- 2022
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17. Training Programs for Fundamental and Clinician-Scientists: Balanced Outcomes for Graduates by Gender
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Christie Rampersad, Todd Alexander, Elisabeth Fowler, Sunny Hartwig, Adeera Levin, Norman D. Rosenblum, Susan Samuel, Chris Wiebe, and Julie Ho
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Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: Women scientists are less likely to obtain Assistant Professorship and achieve promotion, and obtain less grant funding than men. Scientist/clinician-scientist training programs which provide salary awards as well as training and mentorship are a potential intervention to improve outcomes among women scientists. We hypothesized whether a programmatic approach to scientist/clinician-scientist training is associated with improved outcomes for women scientists in Canada when compared with salary awards alone. Trainees within the Kidney Research Scientist Core Education and National Training Program (KRESCENT), Canadian Child Health Clinician Scientist Program (CCHCSP), and the Canadian Institutes of Health Research (CIHR) salary award programs were evaluated. Objective: To examine whether the structured KRESCENT training program with salary support improves academic success for women scientists relative to salary awards alone. Design: Retrospective cohort study. Setting: Canadian national research scientist and clinician-scientist training programs and salary awards. Participants: KRESCENT cohort (n = 59, 2005-2017), CCHCSP cohort (n = 58, 2002-2015), and CIHR (n = 571, 2005-2015) Salary Awardees for postdoctoral fellows (PDF) and new investigators (NI). Measurements: National operating grant funding success, achieving an academic position as an Assistant Professor for PDF, or achieving promotion to Associate Professor for NI. Methods: The gender distribution of each cohort was determined using first name and NamepediA and was examined for PDF and NI, followed by a description of trainee outcomes by gender and training level. Results: KRESCENT and CIHR PDF were balanced (12/27, 44% men and 55/116, 47% women) while CCHCSP had a higher proportion of women (13/20, 65%). KRESCENT and CCHCSP NI retained women scientists (19/32, 59% and 22/38, 58% women), whereas CIHR NI had fewer women (165/455, 36% women vs 290/455, 64% men, P = 0.01). There was a high rate of NI operating grant success (91%-95%) with no gender differences in each cohort. There was a high proportion of CCHCSP PDF who achieved an Assistant Professorship (18/20, 90%) that may be due in part to a longer follow-up period (9.3 ± 3 years) compared with KRESCENT PDF (7/27, 26%, 0.88 ± 4.5 years), and these data were not available for CIHR PDF. Women KRESCENT NI showed increased promotion to Associate Professor ( P = 0.02, 0.25 ± 3.2 years follow-up) and CCHCSP NI had high promotion rates (37/38, 97%, 6.9 ± 3.6 years follow-up) irrespective of gender. There was an overall trend toward more men pursuing biomedical research. Limitations: KRESCENT and CCHCSP training program cohort size and heterogeneity; assigning gender by first name may result in misclassification; lack of data on the respective applicant pools; and inability to examine intersectionality with gender, ethnicity, and sexual orientation. Conclusion: Overall trainee performance across programs is remarkable by community standards regardless of gender. KRESCENT and CCHCSP training programs demonstrated balanced success in their PDF and NI, whereas the CIHR awardees had reduced representation of women scientists from PDF to NI. This exploratory study highlights the utility of programmatic training approaches like the KRESCENT program as potential tools to support and retain women scientists in the academic pipeline during the challenging PDF to NI transition period.
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- 2021
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18. Duration of and time to response in oncology clinical trials from the perspective of the estimand framework.
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Weber, Hans‐Jochen, Corson, Stephen, Li, Jiang, Mercier, François, Roychoudhury, Satrajit, Sailer, Martin Oliver, Sun, Steven, Todd, Alexander, and Yung, Godwin
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MANTLE cell lymphoma ,CLINICAL trials ,ONCOLOGY ,RESEARCH protocols ,MEDICAL protocols - Abstract
Duration of response (DOR) and time to response (TTR) are typically evaluated as secondary endpoints in early‐stage clinical studies in oncology when efficacy is assessed by the best overall response and presented as the overall response rate. Despite common use of DOR and TTR in particular in single‐arm studies, the definition of these endpoints and the questions they are intended to answer remain unclear. Motivated by the estimand framework, we present relevant scientific questions of interest for DOR and TTR and propose corresponding estimand definitions. We elaborate on how to deal with relevant intercurrent events which should follow the same considerations as implemented for the primary response estimand. A case study in mantle cell lymphoma illustrates the implementation of relevant estimands of DOR and TTR. We close the paper with practical recommendations to implement DOR and TTR in clinical study protocols. [ABSTRACT FROM AUTHOR]
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- 2024
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19. The impact of a uniform ocean warming on the West African monsoon
- Author
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Mutton, Harry, primary, Chadwick, Robin, additional, Collins, Matthew, additional, Lambert, F. Hugo, additional, Taylor, Christopher M., additional, Geen, Ruth, additional, and Todd, Alexander, additional
- Published
- 2023
- Full Text
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20. Ces1d deficiency protects against high-sucrose diet-induced hepatic triacylglycerol accumulation[S]
- Author
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Jihong Lian, Russell Watts, Ariel D. Quiroga, Megan R. Beggs, R. Todd Alexander, and Richard Lehner
- Subjects
carboxylesterase 1d ,liver ,nonalcoholic fatty liver disease ,lipogenesis ,Biochemistry ,QD415-436 - Abstract
Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. Triacylglycerol accumulation in the liver is a hallmark of NAFLD. Metabolic studies have confirmed that increased hepatic de novo lipogenesis (DNL) in humans contributes to fat accumulation in the liver and to NAFLD progression. Mice deficient in carboxylesterase (Ces)1d expression are protected from high-fat diet-induced hepatic steatosis. To investigate whether loss of Ces1d can also mitigate steatosis induced by over-activated DNL, WT and Ces1d-deficient mice were fed a lipogenic high-sucrose diet (HSD). We found that Ces1d-deficient mice were protected from HSD-induced hepatic lipid accumulation. Mechanistically, Ces1d deficiency leads to activation of AMP-activated protein kinase and inhibitory phosphorylation of acetyl-CoA carboxylase. Together with our previous demonstration that Ces1d deficiency attenuated high-fat diet-induced steatosis, this study suggests that inhibition of CES1 (the human ortholog of Ces1d) might represent a novel pharmacological target for prevention and treatment of NAFLD.
- Published
- 2019
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21. TRPV6 and Cav1.3 Mediate Distal Small Intestine Calcium Absorption Before WeaningSummary
- Author
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Megan R. Beggs, Justin J. Lee, Kai Busch, Ahsan Raza, Henrik Dimke, Petra Weissgerber, Jutta Engel, Veit Flockerzi, and R. Todd Alexander
- Subjects
Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Background & Aims: Intestinal Ca2+ absorption early in life is vital to achieving optimal bone mineralization. The molecular details of intestinal Ca2+ absorption have been defined in adults after peak bone mass is obtained, but they are largely unexplored during development. We sought to delineate the molecular details of transcellular Ca2+ absorption during this critical period. Methods: Expression of small intestinal and renal calcium transport genes was assessed by using quantitative polymerase chain reaction. Net calcium flux across small intestinal segments was measured in Ussing chambers, including after pharmacologic inhibition or genetic manipulation of TRPV6 or Cav1.3 calcium channels. Femurs were analyzed by using micro–computed tomography and histology. Results: Net TRPV6-mediated Ca2+ flux across the duodenum was absent in pre-weaned (P14) mice but present after weaning. In contrast, we found significant transcellular Ca2+ absorption in the jejunum at 2 weeks but not 2 months of age. Net jejunal Ca2+ absorption observed at P14 was not present in either Trpv6 mutant (D541A) mice or Cav1.3 knockout mice. We observed significant nifedipine-sensitive transcellular absorption across the ileum at P14 but not 2 months. Cav1.3 knockout pups exhibited delayed bone mineral accrual, compensatory nifedipine-insensitive Ca2+ absorption in the ileum, and increased expression of renal Ca2+ reabsorption mediators at P14. Moreover, weaning pups at 2 weeks reduced jejunal and ileal Cav1.3 expression. Conclusions: We have detailed novel pathways contributing to transcellular Ca2+ transport across the distal small intestine of mice during development, highlighting the complexity of the multiple mechanisms involved in achieving a positive Ca2+ balance early in life. Keywords: Calcium Channel, Pediatric, Bone, Development
- Published
- 2019
- Full Text
- View/download PDF
22. Diagnosing ENSO and Global Warming Tropical Precipitation Shifts Using Surface Relative Humidity and Temperature
- Author
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Todd, Alexander, Collins, Matthew, Lambert, F. Hugo, and Chadwick, Robin
- Published
- 2018
23. Developmental Changes in Phosphate Homeostasis
- Author
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MacDonald, Tate, primary, Saurette, Matthew, additional, Beggs, Megan R., additional, and Todd Alexander, R., additional
- Published
- 2020
- Full Text
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24. Capillary Flow-Driven Microfluidics Combined with a Paper Device for Fast User-Friendly Detection of Heavy Metals in Water
- Author
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Prakash Aryal, Eric Brack, Todd Alexander, and Charles S. Henry
- Subjects
Analytical Chemistry - Published
- 2023
25. Molecular mechanisms underlying paracellular calcium and magnesium reabsorption in the proximal tubule and thick ascending limb
- Author
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R. Todd Alexander and Henrik Dimke
- Subjects
Calcium, Dietary ,History and Philosophy of Science ,Cations, Divalent ,General Neuroscience ,Claudins ,Loop of Henle ,Humans ,Magnesium ,Calcium ,General Biochemistry, Genetics and Molecular Biology - Abstract
Calcium and magnesium are the most abundant divalent cations in the body. The plasma level is controlled by coordinated interaction between intestinal absorption, reabsorption in the kidney, and, for calcium at least, bone storage and exchange. The kidney adjusts urinary excretion of these ions in response to alterations in their systemic concentration. Free ionized and anion-complexed calcium and magnesium are filtered at the glomerulus. The majority (i.e.,85%) of filtered divalent cations are reabsorbed via paracellular pathways from the proximal tubule and thick ascending limb (TAL) of the loop of Henle. Interestingly, the largest fraction of filtered calcium is reabsorbed from the proximal tubule (65%), while the largest fraction of filtered magnesium is reclaimed from the TAL (60%). The paracellular pathways mediating these fluxes are composed of tight junctional pores formed by claudins. In the proximal tubule, claudin-2 and claudin-12 confer calcium permeability, while the exact identity of the magnesium pore remains to be determined. Claudin-16 and claudin-19 contribute to the calcium and magnesium permeable pathway in the TAL. In this review, we discuss the data supporting these conclusions and speculate as to why there is greater fractional calcium reabsorption from the proximal tubule and greater fractional magnesium reabsorption from the TAL.
- Published
- 2022
26. Canadian Society of Nephrology Commentary on the Kidney Disease Improving Global Outcomes 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder
- Author
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Rachel M. Holden, Reem A. Mustafa, R. Todd Alexander, Marisa Battistella, Micheli U. Bevilacqua, Greg Knoll, Fabrice Mac-Way, Martina Reslerova, Ron Wald, Philip D. Acott, Patrick Feltmate, Allan Grill, Kailash K. Jindal, Meena Karsanji, Bryce A. Kiberd, Sara Mahdavi, Kailee McCarron, Amber O. Molnar, Maury Pinsk, Celia Rodd, Steven D. Soroka, Amanda J. Vinson, Deborah Zimmerman, and Catherine M. Clase
- Subjects
Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Purpose of review: (1) To provide commentary on the 2017 update to the Kidney Disease Improving Global Outcomes (KDIGO) 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD); (2) to apply the evidence-based guideline update for implementation within the Canadian health care system; (3) to provide comment on the care of children with chronic kidney disease (CKD); and (4) to identify research priorities for Canadian patients. Sources of information: The KDIGO 2017 Clinical Practice Guideline Update for the Diagnosis, Evaluation, Prevention, and Treatment of CKD-MBD. Methods: The commentary committee co-chairs selected potential members based on their knowledge of the Canadian kidney community, aiming for wide representation from relevant disciplines, academic and community centers, and different geographical regions. Key findings: We agreed with many of the recommendations in the clinical practice guideline on the diagnosis, evaluation, prevention, and treatment of CKD-MBD. However, based on the uncommon occurrence of abnormalities in calcium and phosphate and the low likelihood of severe abnormalities in parathyroid hormone (PTH), we recommend against screening and monitoring levels of calcium, phosphate, PTH, and alkaline phosphatase in adults with CKD G3. We suggest and recommend monitoring these parameters in adults with CKD G4 and G5, respectively. In children, we agree that monitoring for CKD-MBD should begin in CKD G2, but we suggest measuring ionized calcium, rather than total calcium or calcium adjusted for albumin. With regard to vitamin D, we suggest against routine screening for vitamin D deficiency in adults with CKD G3-G5 and G1T-G5T and suggest following population health recommendations for adequate vitamin D intake. We recommend that the measurement and management of bone mineral density (BMD) be according to general population guidelines in CKD G3 and G3T, but we suggest against routine BMD testing in CKD G4-G5, CKD G4T-5T, and in children with CKD. Based on insufficient data, we also recommend against routine bone biopsy in clinical practice for adults with CKD or CKD-T, or in children with CKD, although we consider it an important research tool. Limitations: The committee relied on the evidence summaries produced by KDIGO. The CSN committee did not replicate or update the systematic reviews.
- Published
- 2020
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27. Abstract LB294: Baseline and on-treatment plasma-based genomics as a predictor of outcome in SAVANNAH: Savolitinib + osimertinib in EGFRm MET overexpressed/amplified NSCLC post-osimertinib
- Author
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Hartmaier, Ryan James, primary, Markovets, Aleksandra, additional, Xu, Wanning, additional, Baczynska, Agata, additional, Todd, Alexander, additional, and Ahn, Myung-Ju, additional
- Published
- 2023
- Full Text
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28. Differential impacts of pregnancy and lactation on maternal calcium homeostasis: a mathematical modeling analysis
- Author
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Melissa Stadt, Todd Alexander, and Anita Layton
- Subjects
Physiology - Abstract
The maternal physiological adaptations during pregnancy and lactation impact almost all tissues and organs, including those involved in calcium homeostasis. Despite having a similar additional calcium demand, maternal adaptations in pregnancy and lactation are different. During pregnancy, the mother’s body increases intestinal absorption of calcium. However, during lactation, intestinal absorption returns to normal levels and the calcium needs of breastmilk are met by increased bone resorption and renal calcium reabsorption. Existing mathematical models of calcium homeostasis do not consider these unique physiological states. Given this observation, the goal of this project is to develop the first pregnancy- and lactation-specific mathematical models of calcium regulation. The resulting models represent how a female body adapts to support the excess demands brought on by pregnancy and lactation. Our computational models reveal how both differential adaptations support calcium delivery to the fetus and breastmilk while maintaining normal calcium ranges in the maternal body. This work is supported by the Canada 150 Research Chair program and by the Natural Sciences and Engineering Research Council of Canada. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
- Published
- 2023
29. Investigating vitamin D insufficiency in claudin-2 and claudin-12 knockout mice
- Author
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Kennedi Young and R. Todd Alexander
- Subjects
Physiology - Abstract
Infants and children require a net positive calcium (Ca2+) balance to achieve optimal bone mineral density by early adulthood. Active vitamin D (calcitriol) increases blood Ca2+ levels by increasing intestinal absorption and renal reabsorption of Ca2+ as well as bone remodelling. In both the kidney and intestine, Ca2+ is absorbed both paracellularly, through claudin proteins that make up the tight junction, and transcellularly, through Ca2+ specific transporters and channels. Claudins-2 and -12 are tight junction proteins that mediate Ca2+ permeability across renal and intestinal cell culture epithelial layers. Claudin-2 and claudin-12 double knockout (DKO) mice have a perturbed Ca2+ balance resulting in hypocalcemia, hypercalciuria and decreased bone mineralization. Interestingly, DKO mice did not have increased calcitriol levels or upregulation of Cyp27b1 (the key enzyme regulating serum calcitriol levels), despite a significant increase in serum parathyroid hormone (PTH) levels and decreased serum Ca2+ compared to wild-type mice. We hypothesize therefore that claudin-2 and/or claudin-12 are necessary for optimal PTHR1 signalling to increase Cyp27b1 expression, and thus calcitriol production in the proximal tubule (PT). To address this, we first administered wild-type and double knockout mice calcitriol and found that they could increase their blood calcium levels, though not to the same extent as WT, consistent with the DKO animals not having vitamin D resistance. Next we put wild-type and DKO animals on a low calcium diet. The DKO mice were able to increase their serum calcitriol levels and Cyp27b1 expression under these conditions, consistent with attenuated regulation and not abolition of PTHR1 signalling. Next we examined PTHR1 signaling in HEK-293 cells and a CYP27B1 reporter construct. We found that in HEK cells, PTH treatment results in increased expression of the CYP27B1 promoter construct, and that claudin-2 expression alone, increased promoter expression to the same extent as PTH. Additionally, calcitriol suppressed CYP27B1 promoter expression, however this suppression was abolished when claudin-2, but not claudin-12, was expressed. In primary mouse proximal tubule cells, PTH significantly increased Cyp27b1 mRNA expression compared to controls. In future experiments we will investigate the effects of claudin-2 and/or claudin-12 on PTH-induced Cyp27b1 mRNA expression using primary proximal tubule cells from claudin-2, claudin-12 or claudin-2/12 DKO mice. This work will tease out the role of the proximal tubule tight junction proteins claudin-2 and -12 in regulating calcitriol levels. Funding: Alberta Innovates, NSERC and CIHR This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
- Published
- 2023
30. Cldn2-Trpv6 double knockout mice have hypocalcaemia and reduced bone mineral density
- Author
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Harneet Bhullar and Todd Alexander
- Subjects
Physiology - Abstract
Central to calcium homeostasis and bone health is adequate intestinal calcium absorption. This occurs via either a transcellular or a paracellular pathway. In cases of low dietary calcium availability, a transcellular pathway that relies at least in part on the apical calcium channel Trpv6 predominates. However, when calcium is abundant in the diet, paracellular calcium absorption occurs through tight junction proteins, including claudin-2 (Cldn2). This tight junction protein also plays a role in calcium reabsorption from the renal proximal tubule. Despite this, Cldn2 knockout mice only display mildly altered calcium homeostasis characterized by hypercalciuria without evidence of altered bone mineral density (BMD), plasma calcium or calciotropic hormone levels. Similarly, mice expressing non-functional mutant Trpv6 (TRPV6D541A/D541A) channels have reduced intestinal calcium absorption without altered urine or plasma calcium levels, and only when fed a low calcium diet. We hypothesized that the lack of a more pronounced phenotype in these single functional knockout mice was due to the compensation of one pathway in the absence of the other. To test this hypothesis, we crossed claudin-2 knockout mice with mice expressing the mutant Trpv6, generating a functional double knockout (dko, Trpv6mut/mut/Cldn2-/- mice). Metabolic cage studies revealed hypocalcaemia (Male WT: 1.07 ± 0.02 mM, Male DKO: 0.97 ± 0.02 mM, p-value=0.0065, Female WT: 1.07 ± 0.02 mM, Female dko: 0.96 ± 0.03 mM , p-value= 0.0050) and hypercalciuria (Male WT Ca2+/Creatinine: 0.51 ± 0.05, Male dko:1.93 ± 0.18, p-value < 0.0001 Female WT Ca2+/Creatinine: 1.10 ± 0.13, Female dko: 3.56 ± 0.28 , p-value < 0.0001) in the dko mice. In contrast to the single claudin-2 KO mice and Trpv6 mutant animals the dko mice had elevated plasma calcitriol and parathyroid hormone. Moreover, BMD was reduced in the dko animals (Cortical BMD WT: 1.36 ± 0.02 g/cm3 vs dko: 1.29 ± 0.02g/cm3 ). RT-qPCR of intestinal segments and whole kidney revealed increased calbindin-D9k expression in the proximal colon (but not duodenum) and calbindin-D28k in the kidneys, consistent with compensatory increased transcellular absorption from these intestinal segments. Together these results are consistent with the paracellular pathway compensating for the loss of transcellular calcium absorption from the intestine. Funding: Alberta Innovates Graduate Studentship, NSERC, CIHR This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
- Published
- 2023
31. Kidney stones, hypercalciuria, and recent insights into proximal tubule calcium reabsorption
- Author
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R. Todd Alexander
- Subjects
Nephrology ,Internal Medicine - Published
- 2023
32. Lightweight micro-cellular plastics from polylactide/polyolefin hybrids
- Author
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Xu, Yuewen, Delgado, Paula, Todd, Alexander D., Loi, Jesse, Saba, Stacey A., McEneany, Ryan J., Tower, Ted, Topolkaraev, Vasily, Macosko, Christopher W., and Hillmyer, Marc A.
- Published
- 2016
- Full Text
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33. El Niño–Southern Oscillation complexity
- Author
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Timmermann, Axel, An, Soon-Il, Kug, Jong-Seong, Jin, Fei-Fei, Cai, Wenju, Capotondi, Antonietta, Cobb, Kim M., Lengaigne, Matthieu, McPhaden, Michael J., Stuecker, Malte F., Stein, Karl, Wittenberg, Andrew T., Yun, Kyung-Sook, Bayr, Tobias, Chen, Han-Ching, Chikamoto, Yoshimitsu, Dewitte, Boris, Dommenget, Dietmar, Grothe, Pamela, Guilyardi, Eric, Ham, Yoo-Geun, Hayashi, Michiya, Ineson, Sarah, Kang, Daehyun, Kim, Sunyong, Kim, WonMoo, Lee, June-Yi, Li, Tim, Luo, Jing-Jia, McGregor, Shayne, Planton, Yann, Power, Scott, Rashid, Harun, Ren, Hong-Li, Santoso, Agus, Takahashi, Ken, Todd, Alexander, Wang, Guomin, Wang, Guojian, Xie, Ruihuang, Yang, Woo-Hyun, Yeh, Sang-Wook, Yoon, Jinho, Zeller, Elke, and Zhang, Xuebin
- Published
- 2018
- Full Text
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34. Creating the American Newspaper Boy: Middle-Class Route Service and Juvenile Salesmanship in the Great Depression
- Author
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Postol, Todd Alexander
- Published
- 1997
35. Proteasomal degradation competes with Mia40-mediated import into mitochondria
- Author
-
Eva Zöller, R. Todd Alexander, and Johannes M. Herrmann
- Subjects
Biology (General) ,QH301-705.5 - Abstract
Abstract Tandem fluorescent protein timers are elegant tools to determine proteolytic stabilities of cytosolic proteins with high spatial and temporal resolution. In a new study published in BMC Biology, Kowalski et al. fused timers to precursors of proteins of the mitochondrial intermembrane space and found that they are under surveillance of the ubiquitin-proteasome system. Ubiquitination at lysine residues of these precursors directly inhibits their translocation into the intermembrane space and targets them for proteasomal degradation.
- Published
- 2018
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36. Increased FoxO3a expression prevents osteoblast differentiation and matrix calcification
- Author
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Kathy C. Tang, Wanling Pan, Michael R. Doschak, and R. Todd Alexander
- Subjects
Diseases of the musculoskeletal system ,RC925-935 - Abstract
Forkhead Box O transcription factors play important roles in bone metabolism by defending against oxidative stress and apoptosis. FoxO3a is of special interest as it is the predominant isoform expressed in bone. In osteoblasts, the administration of 1,25 dihydroxyvitamin D3 (1,25D3) increases FoxO3a expression, and alters calcium handling. We therefore queried whether FoxO3a participates in vitamin D-mediated regulation of calcium transport pathways or matrix calcification, independent of reactive oxygen species (ROS) formation. To examine this possibility, we differentiated MC3T3-E1 cells into mature osteoblast-like cells over 7 days. This coincided with an increased ability to mineralize extracellular matrix. FoxO3a expression increased throughout differentiation. 1,25D3 enhanced both FoxO3a mRNA and protein expression. Immunofluorescence microscopy found increased FoxO3a nuclear localization with differentiation and after treatment with 1,25D3. Live cell ratiometric imaging with Fura-2AM identified significant L-type calcium channel mediated calcium uptake that was enhanced by 1,25D3. We observed expression of both Cav1.2 and Cav1.3, although expression decreased throughout differentiation and was not altered by 1,25D3 treatment. FoxO3a overexpression reduced calcium uptake and calcium deposition. FoxO3a overexpression also prevented alterations in calcium channel expression and the cell differentiation associated decrease in expression of Runx2 and increased expression of osteocalcin, findings consistent with a failure for the cells to differentiate. Based on both our expression and functional data, we suggest that high levels of FoxO3a prevent osteoblast differentiation and matrix calcification. Keywords: Forkhead Box O3, Osteoblast differentiation, Osteoblast mineralization, Matrix calcification, Calcium deposition, MC3T3-E1 cells
- Published
- 2019
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37. Effects of parathyroid hormone on renal tubular calcium and phosphate handling
- Author
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R. Todd Alexander and Henrik Dimke
- Subjects
Physiology - Published
- 2023
38. Werkzeugtechnologie
- Author
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Klassen, Andreas, Bistron, Marcus, Dellinger, Philip, Schaup, Jörg, Deißer, Todd Alexander, Behrens, Leif, Köhler, Jens, Bouguecha, Anas, Möhwald, Kai, Denkena, Berend, Behrens, Bernd-Arno, Bach, Friedrich-Wilhelm, editor, and Kerber, Kai, editor
- Published
- 2014
- Full Text
- View/download PDF
39. Effects of phospho- and calciotropic hormones on electrolyte transport in the proximal tubule [version 1; referees: 2 approved]
- Author
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Justin J. Lee, Allein Plain, Megan R. Beggs, Henrik Dimke, and R. Todd Alexander
- Subjects
Review ,Articles ,Animal Genetics ,Cell Signaling ,Endocrine & Metabolic Pharmacology ,Endocrinology ,Medical Genetics ,Parathyroid hormone ,fibroblast growth factor 23 ,phosphotropic hormomes ,calciotropic hormones - Abstract
Calcium and phosphate are critical for a myriad of physiological and cellular processes within the organism. Consequently, plasma levels of calcium and phosphate are tightly regulated. This occurs through the combined effects of the phospho- and calciotropic hormones, parathyroid hormone (PTH), active vitamin D 3, and fibroblast growth factor 23 (FGF23). The organs central to this are the kidneys, intestine, and bone. In the kidney, the proximal tubule reabsorbs the majority of filtered calcium and phosphate, which amounts to more than 60% and 90%, respectively. The basic molecular mechanisms responsible for phosphate reclamation are well described, and emerging work is delineating the molecular identity of the paracellular shunt wherein calcium permeates the proximal tubular epithelium. Significant experimental work has delineated the molecular effects of PTH and FGF23 on these processes as well as their regulation of active vitamin D 3 synthesis in this nephron segment. The integrative effects of both phospho- and calciotropic hormones on proximal tubular solute transport and subsequently whole body calcium-phosphate balance thus have been further complicated. Here, we first review the molecular mechanisms of calcium and phosphate reabsorption from the proximal tubule and how they are influenced by the phospho- and calciotropic hormones acting on this segment and then consider the implications on both renal calcium and phosphate handling as well as whole body mineral balance.
- Published
- 2017
- Full Text
- View/download PDF
40. Cognitive Enhancement in Infants Associated with Increased Maternal Fruit Intake During Pregnancy: Results from a Birth Cohort Study with Validation in an Animal Model
- Author
-
Francois V. Bolduc, Amanda Lau, Cory S. Rosenfelt, Steven Langer, Nan Wang, Lisa Smithson, Diana Lefebvre, R. Todd Alexander, Clayton T. Dickson, Liang Li, Allan B. Becker, Padmaja Subbarao, Stuart E. Turvey, Jacqueline Pei, Malcolm R. Sears, and Piush J. Mandhane
- Subjects
Gestational diet ,Fruit ,Birth cohort ,Drosophila learning ,Medicine ,Medicine (General) ,R5-920 - Abstract
In-utero nutrition is an under-studied aspect of cognitive development. Fruit has been an important dietary constituent for early hominins and humans. Among 808 eligible CHILD-Edmonton sub-cohort subjects, 688 (85%) had 1-year cognitive outcome data. We found that each maternal daily serving of fruit (sum of fruit plus 100% fruit juice) consumed during pregnancy was associated with a 2.38 point increase in 1-year cognitive development (95% CI 0.39, 4.37; p
- Published
- 2016
- Full Text
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41. ODP124 Sickle Cell Bone Disease and Response to Intravenous Bisphosphonates in Children
- Author
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Todd Alexander, R, primary, Grimbly, Chelsey, additional, Ward, Leanne M, additional, Escagedo, Patricia Diaz, additional, Jaremko, Jacob L, additional, Bruce, Aisha, additional, Alos, Nathalie, additional, Robinson, Marie-Eve, additional, Konji, Victor N, additional, Page, Marika, additional, Simpson, Ewurabena, additional, Pastore, Yves D, additional, and Girgis, Rose, additional
- Published
- 2022
- Full Text
- View/download PDF
42. NHA2 is expressed in distal nephron and regulated by dietary sodium
- Author
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Kondapalli, Kalyan C., Todd Alexander, R., Pluznick, Jennifer L, and Rao, Rajini
- Published
- 2017
- Full Text
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43. Claudin-12 Knockout Mice Demonstrate Reduced Proximal Tubule Calcium Permeability
- Author
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Allein Plain, Wanling Pan, Deborah O’Neill, Megan Ure, Megan R. Beggs, Maikel Farhan, Henrik Dimke, Emmanuelle Cordat, and R. Todd Alexander
- Subjects
proximal tubule ,calcium permeability ,claudin-12 ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
The renal proximal tubule (PT) is responsible for the reabsorption of approximately 65% of filtered calcium, primarily via a paracellular pathway. However, which protein(s) contribute this paracellular calcium pore is not known. The claudin family of tight junction proteins confers permeability properties to an epithelium. Claudin-12 is expressed in the kidney and when overexpressed in cell culture contributes paracellular calcium permeability (PCa). We therefore examined claudin-12 renal localization and its contribution to tubular paracellular calcium permeability. Claudin-12 null mice (KO) were generated by replacing the single coding exon with β-galactosidase from Escherichia coli. X-gal staining revealed that claudin-12 promoter activity colocalized with aquaporin-1, consistent with the expression in the PT. PTs were microperfused ex vivo and PCa was measured. PCa in PTs from KO mice was significantly reduced compared with WT mice. However, urinary calcium excretion was not different between genotypes, including those on different calcium containing diets. To assess downstream compensation, we examined renal mRNA expression. Claudin-14 expression, a blocker of PCa in the thick ascending limb (TAL), was reduced in the kidney of KO animals. Thus, claudin-12 is expressed in the PT, where it confers paracellular calcium permeability. In the absence of claudin-12, reduced claudin-14 expression in the TAL may compensate for reduced PT calcium reabsorption.
- Published
- 2020
- Full Text
- View/download PDF
44. Thiazide Diuretic Dose and Risk of Kidney Stones in Older Adults: A Retrospective Cohort Study
- Author
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R. Todd Alexander, Eric McArthur, Racquel Jandoc, Blayne Welk, Daniel G. Fuster, Amit X. Garg, and Robert R. Quinn
- Subjects
Diseases of the genitourinary system. Urology ,RC870-923 - Abstract
Background: Thiazide diuretics are commonly prescribed to prevent kidney stones. However, it is unclear whether higher doses confer greater benefit. Objective: To determine whether lower doses of thiazide diuretics confer a similar protective effect against kidney stone events as higher doses. Design: Population-based cohort study. Setting: Linked health administrative databases in Ontario, Canada. Patients: Older adults newly prescribed a thiazide diuretic between 2003 and 2014 were separated into 2 groups based on daily dose: low dose (⩽12.5 mg hydrochlorothiazide/chlorthalidone, or ⩽1.25 mg indapamide) or high dose. Measurements: The primary outcome was time to a kidney stone event, using diagnosis and procedure codes. A secondary outcome was kidney stone surgery. Methods: An association between thiazide diuretic dose and a kidney stone event was estimated using Cox proportional hazards regression. Results: A total of 536 of 105 239 patients (0.51%) experienced a kidney stone event. We did not detect a difference in kidney stone risk in the high-dose relative to the low-dose group (adjusted hazard ratio, 1.10; 95% confidence interval, 0.93-1.31). Results were similar when analysis was restricted to the more specific outcome of kidney stone surgery. Neither a history of prior kidney stones nor the type of thiazide diuretic modified the effect of diuretic dose on outcome. Limitations: Patients were >65 years old and we were unable to adjust for some potential confounders such as dietary factors. Conclusions: Lower dose thiazide diuretics appear to confer a similar protective effect as higher dose thiazides against the development of kidney stones.
- Published
- 2018
- Full Text
- View/download PDF
45. Deficiency of Carbonic Anhydrase II Results in a Urinary Concentrating Defect
- Author
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Devishree Krishnan, Wanling Pan, Megan R. Beggs, Francesco Trepiccione, Régine Chambrey, Dominique Eladari, Emmanuelle Cordat, Henrik Dimke, and R. Todd Alexander
- Subjects
carbonic anhydrase II ,polyuria ,urine concentration ,aquaporin-1 ,metabolic ,Physiology ,QP1-981 - Abstract
Carbonic anhydrase II (CAII) is expressed along the nephron where it interacts with a number of transport proteins augmenting their activity. Aquaporin-1 (AQP1) interacts with CAII to increase water flux through the water channel. Both CAII and aquaporin-1 are expressed in the thin descending limb (TDL); however, the physiological role of a CAII-AQP1 interaction in this nephron segment is not known. To determine if CAII was required for urinary concentration, we studied water handling in CAII-deficient mice. CAII-deficient mice demonstrate polyuria and polydipsia as well as an alkaline urine and bicarbonaturia, consistent with a type III renal tubular acidosis. Natriuresis and hypercalciuria cause polyuria, however, CAII-deficient mice did not have increased urinary sodium nor calcium excretion. Further examination revealed dilute urine in the CAII-deficient mice. Urinary concentration remained reduced in CAII-deficient mice relative to wild-type animals even after water deprivation. The renal expression and localization by light microscopy of NKCC2 and aquaporin-2 was not altered. However, CAII-deficient mice had increased renal AQP1 expression. CAII associates with and increases water flux through aquaporin-1. Water flux through aquaporin-1 in the TDL of the loop of Henle is essential to the concentration of urine, as this is required to generate a concentrated medullary interstitium. We therefore measured cortical and medullary interstitial concentration in wild-type and CAII-deficient mice. Mice lacking CAII had equivalent cortical interstitial osmolarity to wild-type mice: however, they had reduced medullary interstitial osmolarity. We propose therefore that reduced water flux through aquaporin-1 in the TDL in the absence of CAII prevents the generation of a maximally concentrated medullary interstitium. This, in turn, limits urinary concentration in CAII deficient mice.
- Published
- 2018
- Full Text
- View/download PDF
46. Do Thiazides Reduce the Risk of Kidney-Stone Recurrence?
- Author
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R. Todd Alexander
- Subjects
General Medicine - Published
- 2023
47. Renal claudin-14 expression is not required for regulating Mg2+ balance in mice
- Author
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Wouter H van Megen, Christy Hui Lin Lee, Per Svenningsen, Rebecca Siu Ga Tan, Patrícia G Ferreira, R. Todd Alexander, and Henrik Dimke
- Subjects
inorganic chemicals ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Kidney ,Claudin-14 ,Excretion ,Ca2+-sensing receptor ,03 medical and health sciences ,Downregulation and upregulation ,Internal medicine ,medicine ,Extracellular ,Magnesium ,Receptor ,Tight junctions ,030102 biochemistry & molecular biology ,Chemistry ,Reabsorption ,medicine.disease ,Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Hypermagnesemia ,Homeostasis - Abstract
Item does not contain fulltext The kidneys play a crucial role in maintaining Ca(2+) and Mg(2+) homeostasis by regulating these minerals' reabsorption. In the thick ascending limb of Henle's loop (TAL), Ca(2+) and Mg(2+) are reabsorbed through the tight junctions by a shared paracellular pathway formed by claudin-16 and claudin-19. Hypercalcemia activates the Ca(2+)-sensing receptor (CaSR) in the TAL, causing upregulation of pore-blocking claudin-14 (CLDN14), which reduces Ca(2+) and Mg(2+) reabsorption from this segment. In addition, a high-Mg(2+) diet is known to increase both urinary Mg(2+) and Ca(2+) excretion. Since Mg(2+) may also activate CaSR, we aimed to investigate whether CaSR-dependent increases in CLDN14 expression also regulate urinary Mg(2+) excretion in response to hypermagnesemia. Here, we show that a Mg(2+)-enriched diet increased urinary Mg(2+) and Ca(2+) excretion in mice; however, this occurred without detectable changes in renal CLDN14 expression. The administration of a high-Mg(2+) diet to Cldn14(-/-) mice did not cause more pronounced hypermagnesemia or significantly alter urinary Mg(2+) excretion. Finally, in vitro evaluation of CaSR-driven Cldn14 promoter activity in response to increasing Mg(2+) concentrations revealed that Cldn14 expression only increases at supraphysiological extracellular Mg(2+) levels. Together, these results suggest that CLDN14 is not involved in regulating extracellular Mg(2+) balance following high dietary Mg(2+) intake.NEW & NOTEWORTHY Using transgenic models and in vitro assays, this study examined the effect of Mg(2+) on regulating urinary excretion of Ca(2+) and Mg(2+) via activation of the Ca(2+)-sensing receptor-claudin 14 (CLDN14) pathway. The study suggests that CLDN14 is unlikely to play a significant role in the compensatory response to hypermagnesemia.
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- 2021
48. Molecular mechanisms altering tubular calcium reabsorption
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R. Todd Alexander and Mallory L. Downie
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medicine.medical_specialty ,Sodium-calcium exchanger ,urogenital system ,business.industry ,Reabsorption ,Calcium channel ,030232 urology & nephrology ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Calcium ,medicine.disease ,Urinary calcium ,Connecting tubule ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,medicine.anatomical_structure ,chemistry ,Nephrology ,Internal medicine ,Paracellular transport ,Pediatrics, Perinatology and Child Health ,medicine ,Hypercalciuria ,business - Abstract
The majority of calcium filtered by the glomerulus is reabsorbed along the nephron. Most is reabsorbed from the proximal tubule (> 60%) via a paracellular pathway composed of the tight junction proteins claudins-2 and -12, a process driven by sodium and consequently water reabsorption. The thick ascending limb reabsorbs the next greatest amount of calcium (20-25%), also by a paracellular pathway composed of claudins-16 and -19. This pathway is regulated by the CaSR, whose activity increases the expression of claudin-14, a protein that blocks paracellular calcium reabsorption. The fine tuning of urinary calcium excretion occurs in the distal convoluted and connecting tubule by a transcellular pathway composed of the apical calcium channel TRPV5, the calcium shuttling protein calbindin-D28K and the basolateral proteins PMCA1b and the sodium calcium exchanger, NCX. Not surprisingly, mutations in a subset of these genes cause monogenic disorders with hypercalciuria as a part of the phenotype. More commonly, "idiopathic" hypercalciuria is encountered clinically with genetic variations in CLDN14, the CASR and TRPV5 associating with kidney stones and increased urinary calcium excretion. An understanding of the molecular pathways conferring kidney tubular calcium reabsorption is employed in this review to help explain how dietary and medical interventions for this disorder lower urinary calcium excretion.
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- 2021
49. Proteasomal degradation competes with Mia40-mediated import into mitochondria
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Zöller, Eva, Todd Alexander, R., and Herrmann, Johannes M.
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- 2018
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50. ODP124 Sickle Cell Bone Disease and Response to Intravenous Bisphosphonates in Children
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R Todd Alexander, Chelsey Grimbly, Leanne M Ward, Patricia Diaz Escagedo, Jacob L Jaremko, Aisha Bruce, Nathalie Alos, Marie-Eve Robinson, Victor N Konji, Marika Page, Ewurabena Simpson, Yves D Pastore, and Rose Girgis
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Endocrinology, Diabetes and Metabolism - Abstract
Purpose To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with Sickle Cell Disease (SCD). Methods We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). Results Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises or stroke attributed to IV bisphosphonate therapy. Bone mineral apparent density Z-score increased at the lumbar spine (N=14, mean change +0.6, SD 0.4) and total body less head (N=14, mean change +0.5, SD 0.4) after IV bisphosphonate therapy (mean 1.5 years, SD 0.8). Conclusion Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. Presentation: No date and time listed
- Published
- 2022
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