This page has only limited features, please log in for full access.

Unclaimed
Roger Pamphlett
Discipline of Pathology and Department of Neuropathology, Brain and Mind Centre, The University of Sydney, Sydney, Australia

Honors and Awards

The user has no records in this section


Career Timeline

The user has no records in this section.


Short Biography

The user biography is not available.
Following
Followers
Co Authors
The list of users this user is following is empty.
Following: 0 users

Feed

Journal article
Published: 18 August 2021 in Scientific Reports
Reads 0
Downloads 0

Successful aging is likely to involve both genetic and environmental factors, but environmental toxicants that accelerate aging are not known. Human exposure to mercury is common, and mercury has genotoxic, autoimmune, and free radical effects which could contribute to age-related disorders. The presence of inorganic mercury was therefore assessed in the organs of 170 people aged 1–104 years to determine the prevalence of mercury in human tissues at different ages. Mercury was found commonly in cells of the brain, kidney, thyroid, anterior pituitary, adrenal medulla and pancreas. The prevalence of mercury in these organs increased during aging but decreased in people aged over 80 years. People with mercury in one organ usually also had mercury in several others. In conclusion, the prevalence of inorganic mercury in human organs increases with age. The relative lack of tissue mercury in the very old could account for the flattened mortality rate and reduced incidence of cancer in this advanced age group. Since mercury may accelerate aging, efforts to reduce atmospheric mercury pollution could improve the chances of future successful aging.

ACS Style

Roger Pamphlett. The prevalence of inorganic mercury in human cells increases during aging but decreases in the very old. Scientific Reports 2021, 11, 1 .

AMA Style

Roger Pamphlett. The prevalence of inorganic mercury in human cells increases during aging but decreases in the very old. Scientific Reports. 2021; 11 ():1.

Chicago/Turabian Style

Roger Pamphlett. 2021. "The prevalence of inorganic mercury in human cells increases during aging but decreases in the very old." Scientific Reports 11, no. : 1.

Journal article
Published: 27 April 2021 in European Journal of Human Genetics
Reads 0
Downloads 0

Amyotrophic Lateral Sclerosis (ALS) is recognised to be a complex neurodegenerative disease involving both genetic and non-genetic risk factors. The underlying causes and risk factors for the majority of cases remain unknown; however, ever-larger genetic data studies and methodologies promise an enhanced understanding. Recent analyses using published summary statistics from the largest ALS genome-wide association study (GWAS) (20,806 ALS cases and 59,804 healthy controls) identified that schizophrenia (SCZ), cognitive performance (CP) and educational attainment (EA) related traits were genetically correlated with ALS. To provide additional evidence for these correlations, we built single and multi-trait genetic predictors using GWAS summary statistics for ALS and these traits, (SCZ, CP, EA) in an independent Australian cohort (846 ALS cases and 665 healthy controls). We compared methods for generating the risk predictors and found that the combination of traits improved the prediction (Nagelkerke-R2) of the case–control logistic regression. The combination of ALS, SCZ, CP, and EA, using the SBayesR predictor method gave the highest prediction (Nagelkerke-R2) of 0.027 (P value = 4.6 × 10−8), with the odds-ratio for estimated disease risk between the highest and lowest deciles of individuals being 3.15 (95% CI 1.96–5.05). These results support the genetic correlation between ALS, SCZ, CP and EA providing a better understanding of the complexity of ALS.

ACS Style

Restuadi Restuadi; Fleur C. Garton; Beben Benyamin; Tian Lin; Kelly L. Williams; Anna Vinkhuyzen; Wouter van Rheenen; Zhihong Zhu; Nigel G. Laing; Karen A. Mather; Perminder S. Sachdev; Shyuan T. Ngo; Frederik J. Steyn; Leanne Wallace; Anjali K. Henders; Peter M. Visscher; Merrilee Needham; Susan Mathers; Garth Nicholson; Dominic B. Rowe; Robert D. Henderson; Pamela A. McCombe; Roger Pamphlett; Ian P. Blair; Naomi R. Wray; Allan F. McRae. Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia. European Journal of Human Genetics 2021, 1 -8.

AMA Style

Restuadi Restuadi, Fleur C. Garton, Beben Benyamin, Tian Lin, Kelly L. Williams, Anna Vinkhuyzen, Wouter van Rheenen, Zhihong Zhu, Nigel G. Laing, Karen A. Mather, Perminder S. Sachdev, Shyuan T. Ngo, Frederik J. Steyn, Leanne Wallace, Anjali K. Henders, Peter M. Visscher, Merrilee Needham, Susan Mathers, Garth Nicholson, Dominic B. Rowe, Robert D. Henderson, Pamela A. McCombe, Roger Pamphlett, Ian P. Blair, Naomi R. Wray, Allan F. McRae. Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia. European Journal of Human Genetics. 2021; ():1-8.

Chicago/Turabian Style

Restuadi Restuadi; Fleur C. Garton; Beben Benyamin; Tian Lin; Kelly L. Williams; Anna Vinkhuyzen; Wouter van Rheenen; Zhihong Zhu; Nigel G. Laing; Karen A. Mather; Perminder S. Sachdev; Shyuan T. Ngo; Frederik J. Steyn; Leanne Wallace; Anjali K. Henders; Peter M. Visscher; Merrilee Needham; Susan Mathers; Garth Nicholson; Dominic B. Rowe; Robert D. Henderson; Pamela A. McCombe; Roger Pamphlett; Ian P. Blair; Naomi R. Wray; Allan F. McRae. 2021. "Polygenic risk score analysis for amyotrophic lateral sclerosis leveraging cognitive performance, educational attainment and schizophrenia." European Journal of Human Genetics , no. : 1-8.

Preprint content
Published: 24 March 2021
Reads 0
Downloads 0

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability of around 50%. DNA methylation patterns can serve as biomarkers of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study (EWAS) meta-analysis in 10,462 samples (7,344 ALS patients and 3,118 controls), representing the largest case-control study of DNA methylation for any disease to date. We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We show that DNA-methylation-based proxies for HDL-cholesterol, BMI, white blood cell (WBC) proportions and alcohol intake were independently associated with ALS. Integration of these results with our latest GWAS showed that cholesterol biosynthesis was causally related to ALS. Finally, we found that DNA methylation levels at several DMPs and blood cell proportion estimates derived from DNA methylation data, are associated with survival rate in patients, and could represent indicators of underlying disease processes.

ACS Style

Paul J. Hop; Ramona A.J. Zwamborn; Eilis Hannon; Gemma L. Shireby; Marta F. Nabais; Emma M. Walker; Wouter van Rheenen; Joke J.F.A. van Vugt; Annelot M. Dekker; Henk-Jan Westeneng; Gijs H.P. Tazelaar; Kristel R. van Eijk; Matthieu Moisse; Denis Baird; Ahmad Al Khleifat; Alfredo Iacoangeli; Nicola Ticozzi; Antonia Ratti; Jonathan Cooper-Knock; Karen E. Morrison; Pamela J. Shaw; A. Nazli Basak; Adriano Chiò; Andrea Calvo; Cristina Moglia; Antonio Canosa; Maura Brunetti; Maurizio Grassano; Marc Gotkine; Yossef Lerner; Michal Zabari; Patrick Vourc’H; Philippe Corcia; Philippe Couratier; Jesus S. Mora Pardina; Teresa Salas; Patrick Dion; Jay P. Ross; Robert D. Henderson; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Garth Nicholson; Dominic B. Rowe; Roger Pamphlett; Karen A. Mather; Perminder S. Sachdev; Sarah Furlong; Fleur C. Garton; Anjali K. Henders; Tian Lin; Shyuan T. Ngo; Frederik J. Steyn; Leanne Wallace; Kelly L. Williams; Miguel Mitne Neto; Ruben J. Cauchi; Ian P. Blair; Matthew C. Kiernan; Vivian Drory; Monica Povedano; Mamede de Carvalho; Susana Pinto; Markus Weber; Guy Rouleau; Vincenzo Silani; John E. Landers; Christopher E. Shaw; Peter M. Andersen; Allan F. McRae; Michael A. van Es; R. Jeroen Pasterkamp; Naomi R. Wray; Russell L. McLaughlin; Orla Hardiman; Kevin P. Kenna; Ellen Tsai; Heiko Runz; Ammar Al-Chalabi; Leonard H. Van Den Berg; Philip Van Damme; Jonathan Mill; Jan H. Veldink; BIOS Consortium; Brain MEND Consortium. Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways. 2021, 1 .

AMA Style

Paul J. Hop, Ramona A.J. Zwamborn, Eilis Hannon, Gemma L. Shireby, Marta F. Nabais, Emma M. Walker, Wouter van Rheenen, Joke J.F.A. van Vugt, Annelot M. Dekker, Henk-Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Matthieu Moisse, Denis Baird, Ahmad Al Khleifat, Alfredo Iacoangeli, Nicola Ticozzi, Antonia Ratti, Jonathan Cooper-Knock, Karen E. Morrison, Pamela J. Shaw, A. Nazli Basak, Adriano Chiò, Andrea Calvo, Cristina Moglia, Antonio Canosa, Maura Brunetti, Maurizio Grassano, Marc Gotkine, Yossef Lerner, Michal Zabari, Patrick Vourc’H, Philippe Corcia, Philippe Couratier, Jesus S. Mora Pardina, Teresa Salas, Patrick Dion, Jay P. Ross, Robert D. Henderson, Susan Mathers, Pamela A. McCombe, Merrilee Needham, Garth Nicholson, Dominic B. Rowe, Roger Pamphlett, Karen A. Mather, Perminder S. Sachdev, Sarah Furlong, Fleur C. Garton, Anjali K. Henders, Tian Lin, Shyuan T. Ngo, Frederik J. Steyn, Leanne Wallace, Kelly L. Williams, Miguel Mitne Neto, Ruben J. Cauchi, Ian P. Blair, Matthew C. Kiernan, Vivian Drory, Monica Povedano, Mamede de Carvalho, Susana Pinto, Markus Weber, Guy Rouleau, Vincenzo Silani, John E. Landers, Christopher E. Shaw, Peter M. Andersen, Allan F. McRae, Michael A. van Es, R. Jeroen Pasterkamp, Naomi R. Wray, Russell L. McLaughlin, Orla Hardiman, Kevin P. Kenna, Ellen Tsai, Heiko Runz, Ammar Al-Chalabi, Leonard H. Van Den Berg, Philip Van Damme, Jonathan Mill, Jan H. Veldink, BIOS Consortium, Brain MEND Consortium. Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways. . 2021; ():1.

Chicago/Turabian Style

Paul J. Hop; Ramona A.J. Zwamborn; Eilis Hannon; Gemma L. Shireby; Marta F. Nabais; Emma M. Walker; Wouter van Rheenen; Joke J.F.A. van Vugt; Annelot M. Dekker; Henk-Jan Westeneng; Gijs H.P. Tazelaar; Kristel R. van Eijk; Matthieu Moisse; Denis Baird; Ahmad Al Khleifat; Alfredo Iacoangeli; Nicola Ticozzi; Antonia Ratti; Jonathan Cooper-Knock; Karen E. Morrison; Pamela J. Shaw; A. Nazli Basak; Adriano Chiò; Andrea Calvo; Cristina Moglia; Antonio Canosa; Maura Brunetti; Maurizio Grassano; Marc Gotkine; Yossef Lerner; Michal Zabari; Patrick Vourc’H; Philippe Corcia; Philippe Couratier; Jesus S. Mora Pardina; Teresa Salas; Patrick Dion; Jay P. Ross; Robert D. Henderson; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Garth Nicholson; Dominic B. Rowe; Roger Pamphlett; Karen A. Mather; Perminder S. Sachdev; Sarah Furlong; Fleur C. Garton; Anjali K. Henders; Tian Lin; Shyuan T. Ngo; Frederik J. Steyn; Leanne Wallace; Kelly L. Williams; Miguel Mitne Neto; Ruben J. Cauchi; Ian P. Blair; Matthew C. Kiernan; Vivian Drory; Monica Povedano; Mamede de Carvalho; Susana Pinto; Markus Weber; Guy Rouleau; Vincenzo Silani; John E. Landers; Christopher E. Shaw; Peter M. Andersen; Allan F. McRae; Michael A. van Es; R. Jeroen Pasterkamp; Naomi R. Wray; Russell L. McLaughlin; Orla Hardiman; Kevin P. Kenna; Ellen Tsai; Heiko Runz; Ammar Al-Chalabi; Leonard H. Van Den Berg; Philip Van Damme; Jonathan Mill; Jan H. Veldink; BIOS Consortium; Brain MEND Consortium. 2021. "Genome-wide study of DNA methylation in Amyotrophic Lateral Sclerosis identifies differentially methylated loci and implicates metabolic, inflammatory and cholesterol pathways." , no. : 1.

Journal article
Published: 21 March 2021 in Toxics
Reads 0
Downloads 0

The kidney plays a dominant role in the pathogenesis of essential hypertension, but the initial pathogenic events in the kidney leading to hypertension are not known. Exposure to mercury has been linked to many diseases including hypertension in epidemiological and experimental studies, so we studied the distribution and prevalence of mercury in the human kidney. Paraffin sections of kidneys were available from 129 people ranging in age from 1 to 104 years who had forensic/coronial autopsies. One individual had injected himself with metallic mercury, the other 128 were from varied clinicopathological backgrounds without known exposure to mercury. Sections were stained for inorganic mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was used on six samples to confirm the presence of autometallography-detected mercury and to look for other toxic metals. In the 128 people without known mercury exposure, mercury was found in: (1) proximal tubules of the cortex and Henle thin loops of the medulla, in 25% of kidneys (and also in the man who injected himself with mercury), (2) proximal tubules only in 16% of kidneys, and (3) Henle thin loops only in 23% of kidneys. The age-related proportion of people who had any mercury in their kidney was 0% at 1–20 years, 66% at 21–40 years, 77% at 41–60 years, 84% at 61–80 years, and 64% at 81–104 years. LA-ICP-MS confirmed the presence of mercury in samples staining with autometallography and showed cadmium, lead, iron, nickel, and silver in some kidneys. In conclusion, mercury is found commonly in the adult human kidney, where it appears to accumulate in proximal tubules and Henle thin loops until an advanced age. Dysfunctions of both these cortical and medullary regions have been implicated in the pathogenesis of essential hypertension, so these findings suggest that further studies of the effects of mercury on blood pressure are warranted.

ACS Style

Roger Pamphlett; Philip Doble; David Bishop. The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension. Toxics 2021, 9, 67 .

AMA Style

Roger Pamphlett, Philip Doble, David Bishop. The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension. Toxics. 2021; 9 (3):67.

Chicago/Turabian Style

Roger Pamphlett; Philip Doble; David Bishop. 2021. "The Prevalence of Inorganic Mercury in Human Kidneys Suggests a Role for Toxic Metals in Essential Hypertension." Toxics 9, no. 3: 67.

Preprint content
Published: 18 March 2021
Reads 0
Downloads 0

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Of the environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

ACS Style

Wouter van Rheenen; Rick van der Spek; Mark Bakker; Leonard Van Den Berg; Jan Veldink; Joke van Vugt; Paul Hop; Ramona Zwamborn; Niek de Klein; Harm-Jan Westra; Olivier Bakker; Patrick Deelen; Gemma Shireby; Eilis Hannon; Matthieu Moisse; Denis Baird; Restuadi Restuadi; Egor Dolzhenko; Annelot Dekker; Klara Gawor; Henk-Jan Westeneng; Gijs Tazelaar; Kristel van Eijk; Maarten Kooyman; Ross Byrne; Mark Doherty; Mark Heverin; Ahmad Al Khleifat; Alfredo Iacoangeli; Aleksey Shatunov; Nicola Ticozzi; Johnathan Cooper-Knock; Bradley Smith; Marta Gromicho; Siddharthan Chandran; Suvankar Pal; Karen Morrison; Pamela Shaw; John Hardy; Richard Orrell; Michael Sendtner; Thomas Meyer; Nazli Basak; Anneke van der Kooi; Antonia Ratti; Isabella Fogh; Cinzia Gellera; Guiseppe Lauria Pinter; Stefania Corti; Cristina Cereda; Daisy Sproviero; Sandra D'Alfonso; Gianni Soraru; Gabriele Siciliano; Massimiliano Filosto; Alessandro Padovani; Adriano Chio; Andrea Calvo; Cristina Moglia; Maura Brunetti; Antonio Canosa; Maurizio Grassano; Ettore Beghi; Elisabetta Pupillo; Giancarlo Logroscino; Beatrice Nefussy; Alma Osmanovic; Angelica Nordin; Yossef Lerner; Michal Zabari; Marc Gotkine; Robert Baloh; Shaugn Bell; Patrick Vourc'H; Philippe Corcia; Philippe Couratier; Stephanie Millecamps; Vincent Meininger; Francois Salachas; Jesus Mora Pardina; Abdelilah Assialioui; Ricardo Rojas-García; Patrick Dion; Jay Ross; Albert Ludolph; Jochen Weishaupt; David Brenner; Axel Freischmidt; Gilbert Bensimon; Alexis Brice; Alexandra Durr; Christine Payan; Safa Saker-Delye; Nicholas Wood; Simon Topp; Rosa Rademakers; Lukas Tittmann; Wolfgang Lieb; Andre Franke; Stephan Ripke; Alice Braun; Julia Kraft; David Whiteman; Catherine Olsen; André Uitterlinden; Albert Hofman; Marcella Rietschel; Sven Cichon; Markus Nöthen; Philippe Amouyel; Bryan Traynor; Andrew Singleton; Miguel Mitne Neto; Ruben Cauchi; Roel Ophoff; Martina Wiedau-Pazos; Catherine Lomen-Hoerth; Vivianna Van Deerlin; Julian Grosskreutz; Annekathrin Rödiger; Alexander Jörk; Tabea Barthel; Erik Theele; Berjamin Ilse; Beatrice Stubendorff; Otto Witte; Robert Steinbach; Christian Hübner; Caroline Graff; Lev Brylev; Vera Fominykh; Vera Demeshonok; Anastasia Ataulina; Boris Rogelj; Blaž Koritnik; Janez Zidar; Metka Ravnik-Glavač; Damjan Glavač; Zorica Stević; Vivian Drory; Mónica Povedano; Ian Blair; Matthew Kiernan; Beben Benyamin; Robert Henderson; Sarah Furlong; Susan Mathers; Pamela McCombe; Merrilee Needham; Shyuan Ngo; Garth Nicholson; Roger Pamphlett; Dominic Rowe; Frederik Steyn; Kelly Williams; Karen Mather; Perminder Sachdev; Anjali Henders; Leanne Wallace; Mamede de Carvalho; Susana Pinto; Susanne Petri; Markus Weber; Guy Rouleau; Vincenzo Silani; Charles Curtis; Gerome Breen; Jonathan Glass; Robert Brown; John Landers; Christopher Shaw; Peter Andersen; Ewout Groen; Michael van Es; Jeroen Pasterkamp; Dongsheng Fan; Fleur Garton; Allan McRae; George Davey Smith; Tom Gaunt; Michael Eberle; Jonathan Mill; Russell McLaughlin; Orla Hardiman; Kevin Kenna; Naomi Wray; Ellen Tsai; Heiko Runz; Lude Franke; Ammar Al-Chalabi; Philip Van Damme; Nayana Gaur. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. 2021, 1 .

AMA Style

Wouter van Rheenen, Rick van der Spek, Mark Bakker, Leonard Van Den Berg, Jan Veldink, Joke van Vugt, Paul Hop, Ramona Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs Tazelaar, Kristel van Eijk, Maarten Kooyman, Ross Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen Morrison, Pamela Shaw, John Hardy, Richard Orrell, Michael Sendtner, Thomas Meyer, Nazli Basak, Anneke van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Guiseppe Lauria Pinter, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D'Alfonso, Gianni Soraru, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chio, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert Baloh, Shaugn Bell, Patrick Vourc'H, Philippe Corcia, Philippe Couratier, Stephanie Millecamps, Vincent Meininger, Francois Salachas, Jesus Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick Dion, Jay Ross, Albert Ludolph, Jochen Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Durr, Christine Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David Whiteman, Catherine Olsen, André Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus Nöthen, Philippe Amouyel, Bryan Traynor, Andrew Singleton, Miguel Mitne Neto, Ruben Cauchi, Roel Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna Van Deerlin, Julian Grosskreutz, Annekathrin Rödiger, Alexander Jörk, Tabea Barthel, Erik Theele, Berjamin Ilse, Beatrice Stubendorff, Otto Witte, Robert Steinbach, Christian Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Mónica Povedano, Ian Blair, Matthew Kiernan, Beben Benyamin, Robert Henderson, Sarah Furlong, Susan Mathers, Pamela McCombe, Merrilee Needham, Shyuan Ngo, Garth Nicholson, Roger Pamphlett, Dominic Rowe, Frederik Steyn, Kelly Williams, Karen Mather, Perminder Sachdev, Anjali Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan Glass, Robert Brown, John Landers, Christopher Shaw, Peter Andersen, Ewout Groen, Michael van Es, Jeroen Pasterkamp, Dongsheng Fan, Fleur Garton, Allan McRae, George Davey Smith, Tom Gaunt, Michael Eberle, Jonathan Mill, Russell McLaughlin, Orla Hardiman, Kevin Kenna, Naomi Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip Van Damme, Nayana Gaur. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. . 2021; ():1.

Chicago/Turabian Style

Wouter van Rheenen; Rick van der Spek; Mark Bakker; Leonard Van Den Berg; Jan Veldink; Joke van Vugt; Paul Hop; Ramona Zwamborn; Niek de Klein; Harm-Jan Westra; Olivier Bakker; Patrick Deelen; Gemma Shireby; Eilis Hannon; Matthieu Moisse; Denis Baird; Restuadi Restuadi; Egor Dolzhenko; Annelot Dekker; Klara Gawor; Henk-Jan Westeneng; Gijs Tazelaar; Kristel van Eijk; Maarten Kooyman; Ross Byrne; Mark Doherty; Mark Heverin; Ahmad Al Khleifat; Alfredo Iacoangeli; Aleksey Shatunov; Nicola Ticozzi; Johnathan Cooper-Knock; Bradley Smith; Marta Gromicho; Siddharthan Chandran; Suvankar Pal; Karen Morrison; Pamela Shaw; John Hardy; Richard Orrell; Michael Sendtner; Thomas Meyer; Nazli Basak; Anneke van der Kooi; Antonia Ratti; Isabella Fogh; Cinzia Gellera; Guiseppe Lauria Pinter; Stefania Corti; Cristina Cereda; Daisy Sproviero; Sandra D'Alfonso; Gianni Soraru; Gabriele Siciliano; Massimiliano Filosto; Alessandro Padovani; Adriano Chio; Andrea Calvo; Cristina Moglia; Maura Brunetti; Antonio Canosa; Maurizio Grassano; Ettore Beghi; Elisabetta Pupillo; Giancarlo Logroscino; Beatrice Nefussy; Alma Osmanovic; Angelica Nordin; Yossef Lerner; Michal Zabari; Marc Gotkine; Robert Baloh; Shaugn Bell; Patrick Vourc'H; Philippe Corcia; Philippe Couratier; Stephanie Millecamps; Vincent Meininger; Francois Salachas; Jesus Mora Pardina; Abdelilah Assialioui; Ricardo Rojas-García; Patrick Dion; Jay Ross; Albert Ludolph; Jochen Weishaupt; David Brenner; Axel Freischmidt; Gilbert Bensimon; Alexis Brice; Alexandra Durr; Christine Payan; Safa Saker-Delye; Nicholas Wood; Simon Topp; Rosa Rademakers; Lukas Tittmann; Wolfgang Lieb; Andre Franke; Stephan Ripke; Alice Braun; Julia Kraft; David Whiteman; Catherine Olsen; André Uitterlinden; Albert Hofman; Marcella Rietschel; Sven Cichon; Markus Nöthen; Philippe Amouyel; Bryan Traynor; Andrew Singleton; Miguel Mitne Neto; Ruben Cauchi; Roel Ophoff; Martina Wiedau-Pazos; Catherine Lomen-Hoerth; Vivianna Van Deerlin; Julian Grosskreutz; Annekathrin Rödiger; Alexander Jörk; Tabea Barthel; Erik Theele; Berjamin Ilse; Beatrice Stubendorff; Otto Witte; Robert Steinbach; Christian Hübner; Caroline Graff; Lev Brylev; Vera Fominykh; Vera Demeshonok; Anastasia Ataulina; Boris Rogelj; Blaž Koritnik; Janez Zidar; Metka Ravnik-Glavač; Damjan Glavač; Zorica Stević; Vivian Drory; Mónica Povedano; Ian Blair; Matthew Kiernan; Beben Benyamin; Robert Henderson; Sarah Furlong; Susan Mathers; Pamela McCombe; Merrilee Needham; Shyuan Ngo; Garth Nicholson; Roger Pamphlett; Dominic Rowe; Frederik Steyn; Kelly Williams; Karen Mather; Perminder Sachdev; Anjali Henders; Leanne Wallace; Mamede de Carvalho; Susana Pinto; Susanne Petri; Markus Weber; Guy Rouleau; Vincenzo Silani; Charles Curtis; Gerome Breen; Jonathan Glass; Robert Brown; John Landers; Christopher Shaw; Peter Andersen; Ewout Groen; Michael van Es; Jeroen Pasterkamp; Dongsheng Fan; Fleur Garton; Allan McRae; George Davey Smith; Tom Gaunt; Michael Eberle; Jonathan Mill; Russell McLaughlin; Orla Hardiman; Kevin Kenna; Naomi Wray; Ellen Tsai; Heiko Runz; Lude Franke; Ammar Al-Chalabi; Philip Van Damme; Nayana Gaur. 2021. "Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology." , no. : 1.

Preprint content
Published: 15 March 2021
Reads 0
Downloads 0

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a life-time risk of 1 in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry GWAS in ALS including 29,612 ALS patients and 122,656 controls which identified 15 risk loci in ALS. When combined with 8,953 whole-genome sequenced individuals (6,538 ALS patients, 2,415 controls) and the largest cortex-derived eQTL dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, repeat expansions or regulatory effects. ALS associated risk loci were shared with multiple traits within the neurodegenerative spectrum, but with distinct enrichment patterns across brain regions and cell-types. Across environmental and life-style risk factors obtained from literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. All ALS associated signals combined reveal a role for perturbations in vesicle mediated transport and autophagy, and provide evidence for cell-autonomous disease initiation in glutamatergic neurons.

ACS Style

Wouter van Rheenen; Rick A.A. van der Spek; Mark K. Bakker; Joke J.F.A. van Vugt; Paul J. Hop; Ramona A.J. Zwamborn; Niek de Klein; Harm-Jan Westra; Olivier B. Bakker; Patrick Deelen; Gemma Shireby; Eilis Hannon; Matthieu Moisse; Denis Baird; Restuadi Restuadi; Egor Dolzhenko; Annelot M. Dekker; Klara Gawor; Henk-Jan Westeneng; Gijs H.P. Tazelaar; Kristel R. van Eijk; Maarten Kooyman; Ross P. Byrne; Mark Doherty; Mark Heverin; Ahmad Al Khleifat; Alfredo Iacoangeli; Aleksey Shatunov; Nicola Ticozzi; Johnathan Cooper-Knock; Bradley N. Smith; Marta Gromicho; Siddharthan Chandran; Suvankar Pal; Karen E. Morrison; Pamela J. Shaw; John Hardy; Richard W. Orrell; Michael Sendtner; Thomas Meyer; Nazli Başak; Anneke J. van der Kooi; Antonia Ratti; Isabella Fogh; Cinzia Gellera; Giuseppe Lauria Pinter; Stefania Corti; Cristina Cereda; Daisy Sproviero; Sandra D’Alfonso; Gianni Sorarù; Gabriele Siciliano; Massimiliano Filosto; Alessandro Padovani; Adriano Chiò; Andrea Calvo; Cristina Moglia; Maura Brunetti; Antonio Canosa; Maurizio Grassano; Ettore Beghi; Elisabetta Pupillo; Giancarlo Logroscino; Beatrice Nefussy; Alma Osmanovic; Angelica Nordin; Yossef Lerner; Michal Zabari; Marc Gotkine; Robert H. Baloh; Shaughn Bell; Patrick Vourc’H; Philippe Corcia; Philippe Couratier; Stéphanie Millecamps; Vincent Meininger; François Salachas; Jesus S. Mora Pardina; Abdelilah Assialioui; Ricardo Rojas-García; Patrick Dion; Jay P. Ross; Albert C. Ludolph; Jochen H. Weishaupt; David Brenner; Axel Freischmidt; Gilbert Bensimon; Alexis Brice; Alexandra Dürr; Christine A.M. Payan; Safa Saker-Delye; Nicholas Wood; Simon Topp; Rosa Rademakers; Lukas Tittmann; Wolfgang Lieb; Andre Franke; Stephan Ripke; Alice Braun; Julia Kraft; David C. Whiteman; Catherine M. Olsen; Andre G. Uitterlinden; Albert Hofman; Marcella Rietschel; Sven Cichon; Markus M. Nöthen; Philippe Amouyel; Bryan Traynor; Adrew B. Singleton; Miguel Mitne Neto; Ruben J. Cauchi; Roel A. Ophoff; Martina Wiedau-Pazos; Catherine Lomen-Hoerth; Vivianna M. van Deerlin; Julian Grosskreutz; Annekathrin Rödiger; Nayana Gaur; Alexander Jörk; Tabea Barthel; Erik Theele; Benjamin Ilse; Beatrice Stubendorff; Otto W. Witte; Robert Steinbach; Christian A. Hübner; Caroline Graff; Lev Brylev; Vera Fominykh; Vera Demeshonok; Anastasia Ataulina; Boris Rogelj; Blaž Koritnik; Janez Zidar; Metka Ravnik-Glavač; Damjan Glavač; Zorica Stević; Vivian Drory; Monica Povedano; Ian P. Blair; Matthew C. Kiernan; Beben Benyamin; Robert D. Henderson; Sarah Furlong; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Shyuan T. Ngo; Garth A. Nicholson; Roger Pamphlett; Dominic B. Rowe; Frederik J. Steyn; Kelly L. Williams; Karen Mather; Perminder S. Sachdev; Anjali K. Henders; Leanne Wallace; Mamede de Carvalho; Susana Pinto; Susanne Petri; Markus Weber; Guy A. Rouleau; Vincenzo Silani; Charles Curtis; Gerome Breen; Jonathan Glass; Robert H. Brown; John E. Landers; Christopher E. Shaw; Peter M. Andersen; Ewout J.N. Groen; Michael A. van Es; R. Jeroen Pasterkamp; Dongsheng Fan; Fleur C. Garton; Allan F. McRae; George Davey Smith; Tom R. Gaunt; Michael A. Eberle; Jonathan Mill; Russell L. McLaughlin; Orla Hardiman; Kevin P. Kenna; Naomi R. Wray; Ellen Tsai; Heiko Runz; Lude Franke; Ammar Al-Chalabi; Philip Van Damme; Leonard H. Van Den Berg; Jan H. Veldink; SLALOM Consortium; PARALS Consortium; SLAGEN Consortium; SLAP Consortium. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. 2021, 1 .

AMA Style

Wouter van Rheenen, Rick A.A. van der Spek, Mark K. Bakker, Joke J.F.A. van Vugt, Paul J. Hop, Ramona A.J. Zwamborn, Niek de Klein, Harm-Jan Westra, Olivier B. Bakker, Patrick Deelen, Gemma Shireby, Eilis Hannon, Matthieu Moisse, Denis Baird, Restuadi Restuadi, Egor Dolzhenko, Annelot M. Dekker, Klara Gawor, Henk-Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Maarten Kooyman, Ross P. Byrne, Mark Doherty, Mark Heverin, Ahmad Al Khleifat, Alfredo Iacoangeli, Aleksey Shatunov, Nicola Ticozzi, Johnathan Cooper-Knock, Bradley N. Smith, Marta Gromicho, Siddharthan Chandran, Suvankar Pal, Karen E. Morrison, Pamela J. Shaw, John Hardy, Richard W. Orrell, Michael Sendtner, Thomas Meyer, Nazli Başak, Anneke J. van der Kooi, Antonia Ratti, Isabella Fogh, Cinzia Gellera, Giuseppe Lauria Pinter, Stefania Corti, Cristina Cereda, Daisy Sproviero, Sandra D’Alfonso, Gianni Sorarù, Gabriele Siciliano, Massimiliano Filosto, Alessandro Padovani, Adriano Chiò, Andrea Calvo, Cristina Moglia, Maura Brunetti, Antonio Canosa, Maurizio Grassano, Ettore Beghi, Elisabetta Pupillo, Giancarlo Logroscino, Beatrice Nefussy, Alma Osmanovic, Angelica Nordin, Yossef Lerner, Michal Zabari, Marc Gotkine, Robert H. Baloh, Shaughn Bell, Patrick Vourc’H, Philippe Corcia, Philippe Couratier, Stéphanie Millecamps, Vincent Meininger, François Salachas, Jesus S. Mora Pardina, Abdelilah Assialioui, Ricardo Rojas-García, Patrick Dion, Jay P. Ross, Albert C. Ludolph, Jochen H. Weishaupt, David Brenner, Axel Freischmidt, Gilbert Bensimon, Alexis Brice, Alexandra Dürr, Christine A.M. Payan, Safa Saker-Delye, Nicholas Wood, Simon Topp, Rosa Rademakers, Lukas Tittmann, Wolfgang Lieb, Andre Franke, Stephan Ripke, Alice Braun, Julia Kraft, David C. Whiteman, Catherine M. Olsen, Andre G. Uitterlinden, Albert Hofman, Marcella Rietschel, Sven Cichon, Markus M. Nöthen, Philippe Amouyel, Bryan Traynor, Adrew B. Singleton, Miguel Mitne Neto, Ruben J. Cauchi, Roel A. Ophoff, Martina Wiedau-Pazos, Catherine Lomen-Hoerth, Vivianna M. van Deerlin, Julian Grosskreutz, Annekathrin Rödiger, Nayana Gaur, Alexander Jörk, Tabea Barthel, Erik Theele, Benjamin Ilse, Beatrice Stubendorff, Otto W. Witte, Robert Steinbach, Christian A. Hübner, Caroline Graff, Lev Brylev, Vera Fominykh, Vera Demeshonok, Anastasia Ataulina, Boris Rogelj, Blaž Koritnik, Janez Zidar, Metka Ravnik-Glavač, Damjan Glavač, Zorica Stević, Vivian Drory, Monica Povedano, Ian P. Blair, Matthew C. Kiernan, Beben Benyamin, Robert D. Henderson, Sarah Furlong, Susan Mathers, Pamela A. McCombe, Merrilee Needham, Shyuan T. Ngo, Garth A. Nicholson, Roger Pamphlett, Dominic B. Rowe, Frederik J. Steyn, Kelly L. Williams, Karen Mather, Perminder S. Sachdev, Anjali K. Henders, Leanne Wallace, Mamede de Carvalho, Susana Pinto, Susanne Petri, Markus Weber, Guy A. Rouleau, Vincenzo Silani, Charles Curtis, Gerome Breen, Jonathan Glass, Robert H. Brown, John E. Landers, Christopher E. Shaw, Peter M. Andersen, Ewout J.N. Groen, Michael A. van Es, R. Jeroen Pasterkamp, Dongsheng Fan, Fleur C. Garton, Allan F. McRae, George Davey Smith, Tom R. Gaunt, Michael A. Eberle, Jonathan Mill, Russell L. McLaughlin, Orla Hardiman, Kevin P. Kenna, Naomi R. Wray, Ellen Tsai, Heiko Runz, Lude Franke, Ammar Al-Chalabi, Philip Van Damme, Leonard H. Van Den Berg, Jan H. Veldink, SLALOM Consortium, PARALS Consortium, SLAGEN Consortium, SLAP Consortium. Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology. . 2021; ():1.

Chicago/Turabian Style

Wouter van Rheenen; Rick A.A. van der Spek; Mark K. Bakker; Joke J.F.A. van Vugt; Paul J. Hop; Ramona A.J. Zwamborn; Niek de Klein; Harm-Jan Westra; Olivier B. Bakker; Patrick Deelen; Gemma Shireby; Eilis Hannon; Matthieu Moisse; Denis Baird; Restuadi Restuadi; Egor Dolzhenko; Annelot M. Dekker; Klara Gawor; Henk-Jan Westeneng; Gijs H.P. Tazelaar; Kristel R. van Eijk; Maarten Kooyman; Ross P. Byrne; Mark Doherty; Mark Heverin; Ahmad Al Khleifat; Alfredo Iacoangeli; Aleksey Shatunov; Nicola Ticozzi; Johnathan Cooper-Knock; Bradley N. Smith; Marta Gromicho; Siddharthan Chandran; Suvankar Pal; Karen E. Morrison; Pamela J. Shaw; John Hardy; Richard W. Orrell; Michael Sendtner; Thomas Meyer; Nazli Başak; Anneke J. van der Kooi; Antonia Ratti; Isabella Fogh; Cinzia Gellera; Giuseppe Lauria Pinter; Stefania Corti; Cristina Cereda; Daisy Sproviero; Sandra D’Alfonso; Gianni Sorarù; Gabriele Siciliano; Massimiliano Filosto; Alessandro Padovani; Adriano Chiò; Andrea Calvo; Cristina Moglia; Maura Brunetti; Antonio Canosa; Maurizio Grassano; Ettore Beghi; Elisabetta Pupillo; Giancarlo Logroscino; Beatrice Nefussy; Alma Osmanovic; Angelica Nordin; Yossef Lerner; Michal Zabari; Marc Gotkine; Robert H. Baloh; Shaughn Bell; Patrick Vourc’H; Philippe Corcia; Philippe Couratier; Stéphanie Millecamps; Vincent Meininger; François Salachas; Jesus S. Mora Pardina; Abdelilah Assialioui; Ricardo Rojas-García; Patrick Dion; Jay P. Ross; Albert C. Ludolph; Jochen H. Weishaupt; David Brenner; Axel Freischmidt; Gilbert Bensimon; Alexis Brice; Alexandra Dürr; Christine A.M. Payan; Safa Saker-Delye; Nicholas Wood; Simon Topp; Rosa Rademakers; Lukas Tittmann; Wolfgang Lieb; Andre Franke; Stephan Ripke; Alice Braun; Julia Kraft; David C. Whiteman; Catherine M. Olsen; Andre G. Uitterlinden; Albert Hofman; Marcella Rietschel; Sven Cichon; Markus M. Nöthen; Philippe Amouyel; Bryan Traynor; Adrew B. Singleton; Miguel Mitne Neto; Ruben J. Cauchi; Roel A. Ophoff; Martina Wiedau-Pazos; Catherine Lomen-Hoerth; Vivianna M. van Deerlin; Julian Grosskreutz; Annekathrin Rödiger; Nayana Gaur; Alexander Jörk; Tabea Barthel; Erik Theele; Benjamin Ilse; Beatrice Stubendorff; Otto W. Witte; Robert Steinbach; Christian A. Hübner; Caroline Graff; Lev Brylev; Vera Fominykh; Vera Demeshonok; Anastasia Ataulina; Boris Rogelj; Blaž Koritnik; Janez Zidar; Metka Ravnik-Glavač; Damjan Glavač; Zorica Stević; Vivian Drory; Monica Povedano; Ian P. Blair; Matthew C. Kiernan; Beben Benyamin; Robert D. Henderson; Sarah Furlong; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Shyuan T. Ngo; Garth A. Nicholson; Roger Pamphlett; Dominic B. Rowe; Frederik J. Steyn; Kelly L. Williams; Karen Mather; Perminder S. Sachdev; Anjali K. Henders; Leanne Wallace; Mamede de Carvalho; Susana Pinto; Susanne Petri; Markus Weber; Guy A. Rouleau; Vincenzo Silani; Charles Curtis; Gerome Breen; Jonathan Glass; Robert H. Brown; John E. Landers; Christopher E. Shaw; Peter M. Andersen; Ewout J.N. Groen; Michael A. van Es; R. Jeroen Pasterkamp; Dongsheng Fan; Fleur C. Garton; Allan F. McRae; George Davey Smith; Tom R. Gaunt; Michael A. Eberle; Jonathan Mill; Russell L. McLaughlin; Orla Hardiman; Kevin P. Kenna; Naomi R. Wray; Ellen Tsai; Heiko Runz; Lude Franke; Ammar Al-Chalabi; Philip Van Damme; Leonard H. Van Den Berg; Jan H. Veldink; SLALOM Consortium; PARALS Consortium; SLAGEN Consortium; SLAP Consortium. 2021. "Common and rare variant association analyses in Amyotrophic Lateral Sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology." , no. : 1.

Research article
Published: 09 February 2021 in PLOS ONE
Reads 0
Downloads 0

Objective Mercury and other toxic metals have been suggested to be involved in thyroid disorders, but the distribution and prevalence of mercury in the human thyroid gland is not known. We therefore used two elemental bio-imaging techniques to look at the distribution of mercury and other toxic metals in the thyroid glands of people over a wide range of ages. Materials and methods Formalin-fixed paraffin-embedded thyroid tissue blocks were obtained from 115 people aged 1–104 years old, with varied clinicopathological conditions, who had thyroid samples removed during forensic/coronial autopsies. Seven-micron sections from these tissue blocks were used to detect intracellular inorganic mercury using autometallography. The presence of mercury was confirmed using laser ablation-inductively coupled plasma-mass spectrometry which can detect multiple elements. Results Mercury was found on autometallography in the thyroid follicular cells of 4% of people aged 1–29 years, 9% aged 30–59 years, and 38% aged 60–104 years. Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in samples staining with autometallography, and detected cadmium, lead, iron, nickel and silver in selected samples. Conclusions The proportion of people with mercury in their thyroid follicular cells increases with age, until it is present in over one-third of people aged 60 years and over. Other toxic metals in thyroid cells could enhance mercury toxicity. Mercury can trigger genotoxicity, autoimmune reactions, and oxidative damage, which raises the possibility that mercury could play a role in the pathogenesis of thyroid cancers, autoimmune thyroiditis, and hypothyroidism.

ACS Style

Roger Pamphlett; Philip A. Doble; David P. Bishop. Mercury in the human thyroid gland: Potential implications for thyroid cancer, autoimmune thyroiditis, and hypothyroidism. PLOS ONE 2021, 16, e0246748 .

AMA Style

Roger Pamphlett, Philip A. Doble, David P. Bishop. Mercury in the human thyroid gland: Potential implications for thyroid cancer, autoimmune thyroiditis, and hypothyroidism. PLOS ONE. 2021; 16 (2):e0246748.

Chicago/Turabian Style

Roger Pamphlett; Philip A. Doble; David P. Bishop. 2021. "Mercury in the human thyroid gland: Potential implications for thyroid cancer, autoimmune thyroiditis, and hypothyroidism." PLOS ONE 16, no. 2: e0246748.

Journal article
Published: 03 February 2021 in Scientific Reports
Reads 0
Downloads 0

Plasma noradrenaline levels increase with aging, and this could contribute to the sympathetic overactivity that is associated with essential hypertension and the metabolic syndrome. The underlying cause of this rise in noradrenaline is unknown, but a clue may be that mercury increases noradrenaline output from the adrenal medulla of experimental animals. We therefore determined the proportion of people from 2 to 104 years of age who had mercury in their adrenal medulla. Mercury was detected in paraffin sections of autopsied adrenal glands using two methods of elemental bioimaging, autometallography and laser ablation-inductively coupled plasma-mass spectrometry. Mercury first appeared in cells of the adrenal medulla in the 21–40 years group, where it was present in 52% of samples, and increased progressively in frequency in older age groups, until it was detected in 90% of samples from people aged over 80 years. In conclusion, the proportion of people having mercury in their adrenal medulla increases with aging. Mercury could alter the metabolism of catecholamines in the adrenal medulla that leads to the raised levels of plasma noradrenaline in aging. This retrospective autopsy study was not able to provide a definitive link between adrenal mercury, noradrenaline levels and hypertension, but future functional human and experimental studies could provide further evidence for these associations.

ACS Style

Roger Pamphlett; Stephen Kum Jew; Philip A. Doble; David P. Bishop. Mercury in the human adrenal medulla could contribute to increased plasma noradrenaline in aging. Scientific Reports 2021, 11, 1 -14.

AMA Style

Roger Pamphlett, Stephen Kum Jew, Philip A. Doble, David P. Bishop. Mercury in the human adrenal medulla could contribute to increased plasma noradrenaline in aging. Scientific Reports. 2021; 11 (1):1-14.

Chicago/Turabian Style

Roger Pamphlett; Stephen Kum Jew; Philip A. Doble; David P. Bishop. 2021. "Mercury in the human adrenal medulla could contribute to increased plasma noradrenaline in aging." Scientific Reports 11, no. 1: 1-14.

Short communication
Published: 16 January 2021 in Neurobiology of Aging
Reads 0
Downloads 0

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by the progressive degeneration of motor neurons. Recently, genetic variants in GLT8D1 and ARPP21 were associated with ALS in a cohort of European descent. A synergistic relationship was proposed between ALS associated variants in GLT8D1 and ARPP21. We aimed to determine the prevalence of genetic variation in GLT8D1 and ARPP21 in an Australian cohort of familial (n=81) and sporadic ALS (n= 618) cases using whole-exome and whole-genome sequencing data. No novel mutations were identified in either gene, nor was there significant enrichment of protein-altering sequence variation among ALS cases. GLT8D1 and ARPP21 mutations are not a common cause of ALS in Australian familial and sporadic cohorts.

ACS Style

Sandrine Chan Moi Fat; Emily P. McCann; Kelly L. Williams; Lyndal Henden; Natalie A. Twine; Denis C. Bauer; Roger Pamphlett; Matthew C. Kiernan; Dominic B. Rowe; Garth A. Nicholson; Jennifer A. Fifita; Ian P. Blair. Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis. Neurobiology of Aging 2021, 101, 297.e9 -297.e11.

AMA Style

Sandrine Chan Moi Fat, Emily P. McCann, Kelly L. Williams, Lyndal Henden, Natalie A. Twine, Denis C. Bauer, Roger Pamphlett, Matthew C. Kiernan, Dominic B. Rowe, Garth A. Nicholson, Jennifer A. Fifita, Ian P. Blair. Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis. Neurobiology of Aging. 2021; 101 ():297.e9-297.e11.

Chicago/Turabian Style

Sandrine Chan Moi Fat; Emily P. McCann; Kelly L. Williams; Lyndal Henden; Natalie A. Twine; Denis C. Bauer; Roger Pamphlett; Matthew C. Kiernan; Dominic B. Rowe; Garth A. Nicholson; Jennifer A. Fifita; Ian P. Blair. 2021. "Genetic analysis of GLT8D1 and ARPP21 in Australian familial and sporadic amyotrophic lateral sclerosis." Neurobiology of Aging 101, no. : 297.e9-297.e11.

Brief communication
Published: 22 December 2020 in Internal Medicine Journal
Reads 0
Downloads 0

Hydroxychloroquine is being used for COVID‐19 symptoms and in clinical trials, but can cause a toxic myopathy that leads to muscle weakness. A review of skeletal muscle biopsies from patients with hydroxychloroquine myopathy gives pointers of steps that can be taken to diagnose this toxic myopathy early and help differentiate it from COVID‐19‐related muscle weakness.

ACS Style

Roger Pamphlett; Min‐Xia Wang; Renee Cf Chan. Challenges in diagnosing hydroxychloroquine myopathy during the COVID ‐19 pandemic. Internal Medicine Journal 2020, 50, 1559 -1562.

AMA Style

Roger Pamphlett, Min‐Xia Wang, Renee Cf Chan. Challenges in diagnosing hydroxychloroquine myopathy during the COVID ‐19 pandemic. Internal Medicine Journal. 2020; 50 (12):1559-1562.

Chicago/Turabian Style

Roger Pamphlett; Min‐Xia Wang; Renee Cf Chan. 2020. "Challenges in diagnosing hydroxychloroquine myopathy during the COVID ‐19 pandemic." Internal Medicine Journal 50, no. 12: 1559-1562.

Journal article
Published: 02 December 2020 in International Journal of Environmental Research and Public Health
Reads 0
Downloads 0

Toxic metals have been implicated in the pathogenesis of pancreatic cancer. Human exposure to mercury is widespread, but it is not known how often mercury is present in the human pancreas and which cells might contain mercury. We therefore aimed to determine, in people with and without pancreatic cancer, the distribution and prevalence of mercury in pancreatic cells. Paraffin-embedded sections of normal pancreatic tissue were obtained from pancreatectomy samples of 45 people who had pancreatic adenocarcinoma, and from autopsy samples of 38 people without pancreatic cancer. Mercury was identified using two methods of elemental bio-imaging: (1) With autometallography, inorganic mercury was seen in islet cells in 14 of 30 males (47%) with pancreatic cancer compared to two of 17 males (12%) without pancreatic cancer (p = 0.024), and in 10 of 15 females (67%) with pancreatic cancer compared to four of 21 females (19%) without pancreatic cancer (p = 0.006). Autometallographic mercury was present in acinar cells in 24% and in periductal cells in 11% of people with pancreatic cancer, but not in those without pancreatic cancer. (2) Laser ablation-inductively coupled plasma-mass spectrometry confirmed the presence of mercury in islets that stained with autometallography and detected cadmium, lead, chromium, iron, nickel and aluminium in some samples. In conclusion, the genotoxic metal mercury is found in normal pancreatic cells in more people with, than without, pancreatic cancer. These findings support the hypothesis that toxic metals such as mercury contribute to the pathogenesis of pancreatic cancer.

ACS Style

Roger Pamphlett; Andrew J. Colebatch; Philip A. Doble; David P. Bishop. Mercury in Pancreatic Cells of People with and without Pancreatic Cancer. International Journal of Environmental Research and Public Health 2020, 17, 8990 .

AMA Style

Roger Pamphlett, Andrew J. Colebatch, Philip A. Doble, David P. Bishop. Mercury in Pancreatic Cells of People with and without Pancreatic Cancer. International Journal of Environmental Research and Public Health. 2020; 17 (23):8990.

Chicago/Turabian Style

Roger Pamphlett; Andrew J. Colebatch; Philip A. Doble; David P. Bishop. 2020. "Mercury in Pancreatic Cells of People with and without Pancreatic Cancer." International Journal of Environmental Research and Public Health 17, no. 23: 8990.

Research article
Published: 29 October 2020 in PLoS ONE
Reads 0
Downloads 0

Toxic metals are suspected to play a role in the pathogenesis of age-related macular degeneration. However, difficulties in detecting the presence of multiple toxic metals within the intact human retina, and in separating primary metal toxicity from the secondary uptake of metals in damaged tissue, have hindered progress in this field. We therefore looked for the presence of several toxic metals in the posterior segment of normal adult eyes using elemental bioimaging. Paraffin sections of the posterior segment of the eye from seven tissue donors (age range 54–74 years) to an eye bank were examined for toxic metals in situ using laser ablation-inductively coupled plasma-mass spectrometry, a technique that detects multiple elements in tissues, as well as the histochemical technique of autometallography that demonstrates inorganic mercury, silver, and bismuth. No donor had a visual impairment, and no significant retinal abnormalities were seen on post mortem fundoscopy and histology. Metals found by laser ablation-inductively coupled plasma-mass spectrometry in the retinal pigment epithelium and choriocapillaris were lead (n = 7), nickel (n = 7), iron (n = 7), cadmium (n = 6), mercury (n = 6), bismuth (n = 5), aluminium (n = 3), and silver (n = 1). In the neural retina, mercury was present in six samples, and iron in one. Metals detected in the optic nerve head were iron (N = 7), mercury (N = 7), nickel (N = 4), and aluminium (N = 1). No gold or chromium was seen. Autometallography demonstrated probable inorganic mercury in the retinal pigment epithelium of one donor. Several toxic metals are taken up by the human retina and optic nerve head. Injury to the retinal pigment epithelium from toxic metals could damage the neuroprotective functions of the retinal pigment epithelium and allow toxic metals to enter the outer neural retina. These findings support the hypothesis that accumulations of toxic metals in the retina could contribute to the pathogenesis of age-related macular degeneration.

ACS Style

Roger Pamphlett; Svetlana Cherepanoff; Lay Khoon Too; Stephen Kum Jew; Philip A. Doble; David P. Bishop. The distribution of toxic metals in the human retina and optic nerve head: Implications for age-related macular degeneration. PLoS ONE 2020, 15, e0241054 .

AMA Style

Roger Pamphlett, Svetlana Cherepanoff, Lay Khoon Too, Stephen Kum Jew, Philip A. Doble, David P. Bishop. The distribution of toxic metals in the human retina and optic nerve head: Implications for age-related macular degeneration. PLoS ONE. 2020; 15 (10):e0241054.

Chicago/Turabian Style

Roger Pamphlett; Svetlana Cherepanoff; Lay Khoon Too; Stephen Kum Jew; Philip A. Doble; David P. Bishop. 2020. "The distribution of toxic metals in the human retina and optic nerve head: Implications for age-related macular degeneration." PLoS ONE 15, no. 10: e0241054.

Journal article
Published: 01 October 2020 in Cell Reports
Reads 0
Downloads 0

Summary We meta-analyze amyotrophic lateral sclerosis (ALS) genome-wide association study (GWAS) data of European and Chinese populations (84,694 individuals). We find an additional significant association between rs58854276 spanning ACSL5-ZDHHC6 with ALS (p = 8.3 × 10−9), with replication in an independent Australian cohort (1,502 individuals; p = 0.037). Moreover, B4GALNT1, G2E3-SCFD1, and TRIP11-ATXN3 are identified using a gene-based analysis. ACSL5 has been associated with rapid weight loss, as has another ALS-associated gene, GPX3. Weight loss is frequent in ALS patients and is associated with shorter survival. We investigate the effect of the ACSL5 and GPX3 single-nucleotide polymorphisms (SNPs), using longitudinal body composition and weight data of 77 patients and 77 controls. In patients' fat-free mass, although not significant, we observe an effect in the expected direction (rs58854276: −2.1 ± 1.3 kg/A allele, p = 0.053; rs3828599: −1.0 ± 1.3 kg/A allele, p = 0.22). No effect was observed in controls. Our findings support the increasing interest in lipid metabolism in ALS and link the disease genetics to weight loss in patients.

ACS Style

Alfredo Iacoangeli; Tian Lin; Ahmad Al Khleifat; Ashley R. Jones; Sarah Opie-Martin; Jonathan R.I. Coleman; Aleksey Shatunov; William Sproviero; Kelly L. Williams; Fleur Garton; Restuadi Restuadi; Anjali K. Henders; Karen A. Mather; Merilee Needham; Susan Mathers; Garth A. Nicholson; Dominic B. Rowe; Robert Henderson; Pamela A. McCombe; Roger Pamphlett; Ian P. Blair; David Schultz; Perminder S. Sachdev; Stephen J. Newhouse; Petroula Proitsi; Isabella Fogh; Shyuan T. Ngo; Richard J.B. Dobson; Naomi R. Wray; Frederik J. Steyn; Ammar Al-Chalabi. Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics. Cell Reports 2020, 33, 108323 .

AMA Style

Alfredo Iacoangeli, Tian Lin, Ahmad Al Khleifat, Ashley R. Jones, Sarah Opie-Martin, Jonathan R.I. Coleman, Aleksey Shatunov, William Sproviero, Kelly L. Williams, Fleur Garton, Restuadi Restuadi, Anjali K. Henders, Karen A. Mather, Merilee Needham, Susan Mathers, Garth A. Nicholson, Dominic B. Rowe, Robert Henderson, Pamela A. McCombe, Roger Pamphlett, Ian P. Blair, David Schultz, Perminder S. Sachdev, Stephen J. Newhouse, Petroula Proitsi, Isabella Fogh, Shyuan T. Ngo, Richard J.B. Dobson, Naomi R. Wray, Frederik J. Steyn, Ammar Al-Chalabi. Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics. Cell Reports. 2020; 33 (4):108323.

Chicago/Turabian Style

Alfredo Iacoangeli; Tian Lin; Ahmad Al Khleifat; Ashley R. Jones; Sarah Opie-Martin; Jonathan R.I. Coleman; Aleksey Shatunov; William Sproviero; Kelly L. Williams; Fleur Garton; Restuadi Restuadi; Anjali K. Henders; Karen A. Mather; Merilee Needham; Susan Mathers; Garth A. Nicholson; Dominic B. Rowe; Robert Henderson; Pamela A. McCombe; Roger Pamphlett; Ian P. Blair; David Schultz; Perminder S. Sachdev; Stephen J. Newhouse; Petroula Proitsi; Isabella Fogh; Shyuan T. Ngo; Richard J.B. Dobson; Naomi R. Wray; Frederik J. Steyn; Ammar Al-Chalabi. 2020. "Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics." Cell Reports 33, no. 4: 108323.

Research article
Published: 19 May 2020 in PLOS ONE
Reads 0
Downloads 0

Damage to locus ceruleus neurons could play a part in the pathogenesis of neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis because of impairment of the blood-brain barrier and enhanced neuroinflammation. The locus ceruleus has connections throughout the brain and spinal cord, so the characteristic widespread multifocal pathology in these disorders could be due to damage to different subsets of locus ceruleus neurons. Previous studies have shown that only certain locus ceruleus neurons accumulate the neurotoxic metal mercury. To find out if concentrations of other toxic metals or of essential trace elements also vary between individual locus ceruleus neurons, we used synchrotron X-ray fluorescence microscopy on frozen sections of locus ceruleus neurons taken from people with multiple sclerosis, in whom the locus ceruleus is structurally intact. Paraffin embedded sections containing the locus ceruleus from seven people with multiple sclerosis were stained with autometallography that demonstrates accumulations of mercury, silver and bismuth. These were compared to maps of multiple elements obtained from frozen sections of locus ceruleus neurons from the same people using X-ray fluorescence microscopy. Neurons in the anterior pons from three of these donors were used as internal controls. Autometallography staining was observed in scattered locus ceruleus neurons from three of the seven donors. X-ray fluorescence microscopy showed variations among individual locus ceruleus neurons in levels of mercury, selenium, iron, copper, lead, bromine, and rubidium. Variations between donors of locus ceruleus neuronal average levels of mercury, iron, copper, and bromine were also detected. Anterior pons neurons contained no mercury, had varied levels of iron, and had lower copper levels than locus ceruleus neurons. Individual human locus ceruleus neurons contain varying levels of toxic metals and essential trace elements. In contrast, most toxic metals are absent or at low levels in nearby anterior pons neurons. The locus ceruleus plays a role in numerous central nervous system functions, including maintaining the blood-brain-barrier and limiting neuroinflammation. Toxic metals, or alterations in essential trace metals within individual locus ceruleus neurons, could be one factor determining the non-random destruction of locus ceruleus neurons in normal aging and neurodegenerative diseases, and subsequently the sites of the widespread multifocal central nervous system pathology in these disorders.

ACS Style

Roger Pamphlett; Rachel Mak; Joonsup Lee; Michael E. Buckland; Antony J. Harding; Stephen Kum Jew; David J. Paterson; Michael Jones; Peter A. Lay. Concentrations of toxic metals and essential trace elements vary among individual neurons in the human locus ceruleus. PLOS ONE 2020, 15, e0233300 .

AMA Style

Roger Pamphlett, Rachel Mak, Joonsup Lee, Michael E. Buckland, Antony J. Harding, Stephen Kum Jew, David J. Paterson, Michael Jones, Peter A. Lay. Concentrations of toxic metals and essential trace elements vary among individual neurons in the human locus ceruleus. PLOS ONE. 2020; 15 (5):e0233300.

Chicago/Turabian Style

Roger Pamphlett; Rachel Mak; Joonsup Lee; Michael E. Buckland; Antony J. Harding; Stephen Kum Jew; David J. Paterson; Michael Jones; Peter A. Lay. 2020. "Concentrations of toxic metals and essential trace elements vary among individual neurons in the human locus ceruleus." PLOS ONE 15, no. 5: e0233300.

Neurogenetics
Published: 14 May 2020 in Journal of Medical Genetics
Reads 0
Downloads 0

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with phenotypic and genetic heterogeneity. Approximately 10% of cases are familial, while remaining cases are classified as sporadic. To date, >30 genes and several hundred genetic variants have been implicated in ALS.MethodsSeven hundred and fifty-seven sporadic ALS cases were recruited from Australian neurology clinics. Detailed clinical data and whole genome sequencing (WGS) data were available from 567 and 616 cases, respectively, of which 426 cases had both datasets available. As part of a comprehensive genetic analysis, 853 genetic variants previously reported as ALS-linked mutations or disease-associated alleles were interrogated in sporadic ALS WGS data. Statistical analyses were performed to identify correlation between clinical variables, and between phenotype and the number of ALS-implicated variants carried by an individual. Relatedness between individuals carrying identical variants was assessed using identity-by-descent analysis.ResultsForty-three ALS-implicated variants from 18 genes, including C9orf72, ATXN2, TARDBP, SOD1, SQSTM1 and SETX, were identified in Australian sporadic ALS cases. One-third of cases carried at least one variant and 6.82% carried two or more variants, implicating a potential oligogenic or polygenic basis of ALS. Relatedness was detected between two sporadic ALS cases carrying a SOD1 p.I114T mutation, and among three cases carrying a SQSTM1 p.K238E mutation. Oligogenic/polygenic sporadic ALS cases showed earlier age of onset than those with no reported variant.ConclusionWe confirm phenotypic associations among ALS cases, and highlight the contribution of genetic variation to all forms of ALS.

ACS Style

Emily P McCann; Lyndal Henden; Jennifer A Fifita; Katharine Y Zhang; Natalie Grima; Denis C Bauer; Sandrine Chan Moi Fat; Natalie A Twine; Roger Pamphlett; Matthew C Kiernan; Dominic B Rowe; Kelly L Williams; Ian P Blair. Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis. Journal of Medical Genetics 2020, 58, 87 -95.

AMA Style

Emily P McCann, Lyndal Henden, Jennifer A Fifita, Katharine Y Zhang, Natalie Grima, Denis C Bauer, Sandrine Chan Moi Fat, Natalie A Twine, Roger Pamphlett, Matthew C Kiernan, Dominic B Rowe, Kelly L Williams, Ian P Blair. Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis. Journal of Medical Genetics. 2020; 58 (2):87-95.

Chicago/Turabian Style

Emily P McCann; Lyndal Henden; Jennifer A Fifita; Katharine Y Zhang; Natalie Grima; Denis C Bauer; Sandrine Chan Moi Fat; Natalie A Twine; Roger Pamphlett; Matthew C Kiernan; Dominic B Rowe; Kelly L Williams; Ian P Blair. 2020. "Evidence for polygenic and oligogenic basis of Australian sporadic amyotrophic lateral sclerosis." Journal of Medical Genetics 58, no. 2: 87-95.

Research article
Published: 22 April 2020 in PLOS ONE
Reads 0
Downloads 0

Interference with the transmission of sensory signals along visual and auditory pathways has been implicated in the pathogenesis of hallucinations. The relay centres for vision (the lateral geniculate nucleus) and hearing (the medial geniculate nucleus) appear to be susceptible to the uptake of circulating mercury. We therefore investigated the distribution of mercury in cells of both these geniculate nuclei. Paraffin-embedded tissue sections containing the lateral geniculate nucleus were obtained from 50 adults (age range 20–104 years) who at autopsy had a variety of clinicopathological conditions, including neurological and psychiatric disorders. The medial geniculate nucleus was present in seven sections. Sections were stained for mercury using autometallography. Laser ablation-inductively coupled plasma-mass spectrometry was used to confirm the presence of mercury. Ten people had mercury in cells of the lateral geniculate nucleus, and in the medial geniculate nucleus of three of these. Medical diagnoses in these individuals were: none (3), Parkinson disease (3), and one each of depression, bipolar disorder, multiple sclerosis, and mercury self-injection. Mercury was distributed in different groups of geniculate capillary endothelial cells, neurons, oligodendrocytes, and astrocytes. Mass spectrometry confirmed the presence of mercury. Mercury is present in different combinations of cell types in the lateral and medial geniculate nuclei in a proportion of people from varied backgrounds. This raises the possibility that mercury-induced impairment of the function of the geniculate nuclei could play a part in the genesis of visual and auditory hallucinations. Although these findings do not provide a direct link between mercury in geniculate cells and hallucinations, they suggest that further investigations into the possibility of toxicant-induced hallucinations are warranted.

ACS Style

Roger Pamphlett; Stephen Kum Jew; Philip A. Doble; David Bishop. Elemental imaging shows mercury in cells of the human lateral and medial geniculate nuclei. PLOS ONE 2020, 15, e0231870 .

AMA Style

Roger Pamphlett, Stephen Kum Jew, Philip A. Doble, David Bishop. Elemental imaging shows mercury in cells of the human lateral and medial geniculate nuclei. PLOS ONE. 2020; 15 (4):e0231870.

Chicago/Turabian Style

Roger Pamphlett; Stephen Kum Jew; Philip A. Doble; David Bishop. 2020. "Elemental imaging shows mercury in cells of the human lateral and medial geniculate nuclei." PLOS ONE 15, no. 4: e0231870.

Journal article
Published: 06 March 2020 in Molecular Brain
Reads 0
Downloads 0

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.

ACS Style

Robin N. Stringer; Bohumila Jurkovicova-Tarabova; Sun Huang; Omid Haji-Ghassemi; Romane Idoux; Anna Liashenko; Ivana A. Souza; Yuriy Rzhepetskyy; Lubica Lacinova; Filip Van Petegem; Gerald W. Zamponi; Roger Pamphlett; Norbert Weiss. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity. Molecular Brain 2020, 13, 1 -11.

AMA Style

Robin N. Stringer, Bohumila Jurkovicova-Tarabova, Sun Huang, Omid Haji-Ghassemi, Romane Idoux, Anna Liashenko, Ivana A. Souza, Yuriy Rzhepetskyy, Lubica Lacinova, Filip Van Petegem, Gerald W. Zamponi, Roger Pamphlett, Norbert Weiss. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity. Molecular Brain. 2020; 13 (1):1-11.

Chicago/Turabian Style

Robin N. Stringer; Bohumila Jurkovicova-Tarabova; Sun Huang; Omid Haji-Ghassemi; Romane Idoux; Anna Liashenko; Ivana A. Souza; Yuriy Rzhepetskyy; Lubica Lacinova; Filip Van Petegem; Gerald W. Zamponi; Roger Pamphlett; Norbert Weiss. 2020. "A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity." Molecular Brain 13, no. 1: 1-11.

Research article
Published: 31 January 2020 in PLOS ONE
Reads 0
Downloads 0

Exposure to toxic metals such as mercury has been proposed to be a risk factor for the development of breast cancer since some metals can promote genetic mutations and epigenetic changes. We sought to find what toxic metals are present in normal breast tissue and in the tumours of women who had mastectomies for invasive ductal breast carcinoma. Formalin-fixed paraffin-embedded blocks from mastectomies for breast carcinoma were examined from 50 women aged 34–69 years. Paraffin blocks selected for elemental analysis were from breast tissue not involved by carcinoma and from the carcinoma itself. Seven micrometer-thick sections were stained with autometallography to demonstrate the presence of mercury, and subjected to laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) to confirm the presence of mercury and to detect other toxic metals. Autometallography-detected mercury was seen in intraductal secretions and some luminal epithelial cells of normal breast lobules in 26 (55%) of the 47 samples where lobules were present, and in 10 (23%) of carcinomas from the 44 samples where carcinoma was present. In eight samples ductal carcinoma in situ was present and one of these contained mercury. LA-ICP-MS confirmed the presence of mercury in samples that stained with autometallography, and detected lead, iron, nickel, aluminium, chromium and cadmium in some samples. Mercury was present in normal breast lobules in more than half of mastectomy samples that contained an invasive carcinoma, and in a smaller proportion of carcinomas and ductal carcinomas in situ. Other toxic metals that may interact synergistically with mercury could be detected in some samples. These findings do not provide direct evidence that toxic metals such as mercury play a role in the pathogenesis of breast cancer, but suggest that future molecular biological investigations on the role of toxic metals in breast cancer are warranted.

ACS Style

Roger Pamphlett; Laveniya Satgunaseelan; Stephen Kum Jew; Philip A. Doble; David Bishop. Elemental bioimaging shows mercury and other toxic metals in normal breast tissue and in breast cancers. PLOS ONE 2020, 15, e0228226 .

AMA Style

Roger Pamphlett, Laveniya Satgunaseelan, Stephen Kum Jew, Philip A. Doble, David Bishop. Elemental bioimaging shows mercury and other toxic metals in normal breast tissue and in breast cancers. PLOS ONE. 2020; 15 (1):e0228226.

Chicago/Turabian Style

Roger Pamphlett; Laveniya Satgunaseelan; Stephen Kum Jew; Philip A. Doble; David Bishop. 2020. "Elemental bioimaging shows mercury and other toxic metals in normal breast tissue and in breast cancers." PLOS ONE 15, no. 1: e0228226.

Research article
Published: 07 August 2019 in PLOS ONE
Reads 0
Downloads 0

Damage to the retina and optic nerve is found in some neurodegenerative disorders, but it is unclear whether the optic pathway and central nervous system (CNS) are affected by the same injurious agent, or whether optic pathway damage is due to retrograde degeneration following the CNS damage. Finding an environmental agent that could be responsible for the optic pathway damage would support the hypothesis that this environmental toxicant also triggers the CNS lesions. Toxic metals have been implicated in neurodegenerative disorders, and mercury has been found in the retina and optic nerve of experimentally-exposed animals. Therefore, to see if mercury exposure in the prenatal period could be one link between optic pathway damage and human CNS disorders of later life, we examined the retina and optic nerve of neonatal mice that had been exposed prenatally to mercury vapor, using a technique, autometallography, that detects the presence of mercury within cells. Pregnant mice were exposed to a non-toxic dose of mercury vapor for four hours a day for five days in late gestation, when the mouse placenta most closely resembles the human placenta. The neonatal offspring were sacrificed one day after birth and gapless serial sections of formalin-fixed paraffin-embedded blocks containing the eyes were stained with silver nitrate autometallography to detect inorganic mercury. Mercury was seen in the nuclear membranes of retinal ganglion cells and endothelial cells. A smaller amount of mercury was present in the retinal inner plexiform and inner nuclear layers. Mercury was conspicuous in the peripapillary retinal pigment epithelium. In the optic nerve, mercury was seen in the nuclear membranes and processes of glia and in endothelial cells. Optic pathway and CNS endothelial cells contained mercury. In conclusion, mercury is taken up preferentially by fetal retinal ganglion cells, optic nerve glial cells, the retinal pigment epithelium, and endothelial cells. Mercury induces free radical formation, autoimmunity, and genetic and epigenetic changes, so these findings raise the possibility that mercury plays a part in the pathogenesis of degenerative CNS disorders that also affect the retina and optic nerve.

ACS Style

Roger Pamphlett; Stephen Kum Jew; Svetlana Cherepanoff. Mercury in the retina and optic nerve following prenatal exposure to mercury vapor. PLOS ONE 2019, 14, e0220859 .

AMA Style

Roger Pamphlett, Stephen Kum Jew, Svetlana Cherepanoff. Mercury in the retina and optic nerve following prenatal exposure to mercury vapor. PLOS ONE. 2019; 14 (8):e0220859.

Chicago/Turabian Style

Roger Pamphlett; Stephen Kum Jew; Svetlana Cherepanoff. 2019. "Mercury in the retina and optic nerve following prenatal exposure to mercury vapor." PLOS ONE 14, no. 8: e0220859.

Original research article
Published: 19 July 2019 in Frontiers in Medicine
Reads 0
Downloads 0

Background: The causes of most arthropathies, osteoarthritis, and connective tissue disorders remain unknown, but exposure to toxic metals could play a part in their pathogenesis. Human exposure to mercury is common, so to determine whether mercury could be affecting joints, bones, and connective tissues we used a histochemical method to determine the cellular uptake of mercury in mice. Whole neonatal mice were examined since this allowed histological assessment of mercury in joint, bone, and connective tissue cells. Materials and Methods: Pregnant mice were exposed to a non-toxic dose of 0.5 mg/m3 of mercury vapor for 4 h a day on gestational days 14–18. Neonates were sacrificed at postnatal day 1, fixed in formalin, and transverse blocks of the body were processed for paraffin embedding. Seven micrometer sections were stained for inorganic mercury using silver nitrate autometallography, either alone or combined with CD44 immunostaining to detect progenitor cells. Control neonates were not exposed to mercury during gestation. Results: Uptake of mercury was marked in synovial cells, articular chondrocytes, and periosteal and tracheal cartilage cells. Mercury was seen in fibroblasts in the dermis, aorta, esophagus and striated muscle, some of which were CD44-positive progenitor cells, and in the endothelial cells of small blood vessels. Mercury was also present in renal tubules and liver periportal cells. Conclusions: Mercury is taken up selectively by cells that are predominantly affected in rheumatoid arthritis and osteoarthritis. In addition, fibroblasts in several organs often involved in multisystem connective tissue disorders take up mercury. Mercury provokes the autoimmune, inflammatory, genetic, and epigenetic changes that have been described in a range of arthropathies and bone and connective tissue disorders. These findings support the hypothesis that mercury exposure could trigger some of these disorders, particularly in people with a genetic susceptibility to autoimmunity.

ACS Style

Roger Pamphlett; Stephen Kum Jew. Mercury Is Taken Up Selectively by Cells Involved in Joint, Bone, and Connective Tissue Disorders. Frontiers in Medicine 2019, 6, 168 .

AMA Style

Roger Pamphlett, Stephen Kum Jew. Mercury Is Taken Up Selectively by Cells Involved in Joint, Bone, and Connective Tissue Disorders. Frontiers in Medicine. 2019; 6 ():168.

Chicago/Turabian Style

Roger Pamphlett; Stephen Kum Jew. 2019. "Mercury Is Taken Up Selectively by Cells Involved in Joint, Bone, and Connective Tissue Disorders." Frontiers in Medicine 6, no. : 168.