Search

Your search keyword '"Hena R. Ramay"' showing total 180 results
Start Over Author "Hena R. Ramay"
180 results on '"Hena R. Ramay"'

1. Divergent maturational patterns of the infant bacterial and fungal gut microbiome in the first year of life are associated with inter-kingdom community dynamics and infant nutrition

Author

Emily M. Mercer, Hena R. Ramay, Shirin Moossavi, Isabelle Laforest-Lapointe, Myrtha E. Reyna, Allan B. Becker, Elinor Simons, Piush J. Mandhane, Stuart E. Turvey, Theo J. Moraes, Malcolm R. Sears, Padmaja Subbarao, Meghan B. Azad, and Marie-Claire Arrieta

Subjects
Gut microbiome, Gut mycobiome, Alpha diversity, Early life, Microbial succession, Microbiome maturation, Microbial ecology, QR100-130
Abstract

Abstract Background The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. Results We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40% of infants, which were characterized by differences in community composition, inter-kingdom dynamics, and microbe-derived metabolites in urine, suggestive of alterations in the timing of ecosystem transitions. Known microbiome-modifying factors, such as formula feeding and delivery by C-section, were associated with atypical bacterial, but not fungal, microbiome maturation patterns. Instead, fungal microbiome maturation was influenced by prenatal exposure to artificially sweetened beverages and the bacterial microbiome, emphasizing the importance of inter-kingdom dynamics in early-life colonization patterns. Conclusions These findings highlight the ecological and environmental factors underlying atypical patterns of microbiome maturation in infants, and the need to incorporate multi-kingdom and individual-level perspectives in microbiome research to improve our understandings of gut microbiome maturation patterns in early life and how they relate to host health. Video Abstract

Published
2024
Full Text
View/download PDF

2. Isha yoga practices, vegan diet, and participation in Samyama meditation retreat: impact on the gut microbiome & metabolome – a non-randomized trial

Author

Maitreyi Raman, Ramana Vishnubhotla, Hena R. Ramay, Maria C. B. Gonçalves, Andrea S. Shin, Dhanashri Pawale, Balachundhar Subramaniam, and Senthilkumar Sadhasivam

Subjects
Meditation, Yoga, Vegan diet, Microbiome, Brain-gut axis, Other systems of medicine, RZ201-999
Abstract

Abstract Background Growing evidence suggests a role for gut bacteria and their metabolites in host-signaling responses along the gut-brain axis which may impact mental health. Meditation is increasingly utilized to combat stress, anxiety, and depression symptoms. However, its impact on the microbiome remains unclear. This study observes the effects of preparation and participation in an advanced meditation program (Samyama) implemented with a vegan diet including 50% raw foods, on gut microbiome and metabolites profiles. Methods There were 288 subjects for this study. Stool samples were collected at 3-time points for meditators and household controls. Meditators prepared for 2 months for the Samyama, incorporating daily yoga and meditation practices with a vegan diet including 50% raw foods. Subjects were requested to submit stool samples for 3 time points – 2 months before Samyama (T1), right before Samyama (T2), and 3 months following Samyama (T3). 16 s rRNA sequencing was used to study participants' microbiome. Alpha and beta diversities along with short-chain fatty acid (SCFA) were assessed. Metabolomics were performed on a mass spectrometer coupled to a UHLPC system and analyzed by El-MAVEN software. Results Alpha diversity showed no significant differences between meditators and controls, while beta diversity showed significant changes (padj = 0.001) after Samyama in meditators’ microbiota composition. After the preparation phase, changes in branched short-chain fatty acids, higher levels of iso-valerate (padj = 0.02) and iso-buytrate (padj = 0.019) were observed at T2 in meditators. Other metabolites were also observed to have changed in meditators at timepoint T2. Conclusion This study examined the impact of an advanced meditation program combined with a vegan diet on the gut microbiome. There was an increase in beneficial bacteria even three months after the completion of the Samyama program. Further study is warranted to validate current observations and investigate the significance and mechanisms of action related to diet, meditation, and microbial composition and function, on psychological processes, including mood. Trial registration Registration number: NCT04366544 ; Registered on 29/04/2020.

Published
2023
Full Text
View/download PDF

3. Sequence characterisation and novel insights into bovine mastitis-associated Streptococcus uberis in dairy herds

Author

Ben Vezina, Hulayyil Al-harbi, Hena R. Ramay, Martin Soust, Robert J. Moore, Timothy W. J. Olchowy, and John I. Alawneh

Subjects
Medicine, Science
Abstract

Abstract Streptococcus uberis is one of the most frequent mastitis-causing pathogens isolated from dairy cows. Further understanding of S. uberis genetics may help elucidate the disease pathogenesis. We compared the genomes of S. uberis isolates cultured from dairy cows located in distinctly different geographic regions of Australia. All isolates had novel multi locus sequence types (MLST) indicating a highly diverse population of S. uberis. Global clonal complexes (GCC) were more conserved. GCC ST86 and GCC ST143 represented 30% of the total isolates (n = 27) and were clustered within different geographic regions. Core genome phylogeny revealed low phylogenetic clustering by region, isolation source, and MLST. Identification of putative sortase (srtA) substrates and generation of a custom putative virulence factor database revealed genes which may explain the affinity of S. uberis for mammary tissue, evasion of antimicrobial efforts and disease pathogenesis. Of 27 isolates, four contained antibiotic resistance genes including an antimicrobial resistance cluster containing mel/mef(A), mrsE, vatD, lnuD, and transposon-mediated lnuC was also identified. These are novel genes for S. uberis, which suggests interspecies lateral gene transfer. The presence of resistance genes across the two geographic regions tested within one country supports the need for a careful, tailored, implementation and monitoring of antimicrobial stewardship.

Published
2021
Full Text
View/download PDF

4. Intestinal fungi are causally implicated in microbiome assembly and immune development in mice

Author

Erik van Tilburg Bernardes, Veronika Kuchařová Pettersen, Mackenzie W. Gutierrez, Isabelle Laforest-Lapointe, Nicholas G. Jendzjowsky, Jean-Baptiste Cavin, Fernando A. Vicentini, Catherine M. Keenan, Hena R. Ramay, Jumana Samara, Wallace K. MacNaughton, Richard J. A. Wilson, Margaret M. Kelly, Kathy D. McCoy, Keith A. Sharkey, and Marie-Claire Arrieta

Subjects
Science
Abstract

The immunomodulatory role of commensal gut fungi and interactions with bacteria remain unclear. Here, using germ-free mice colonized with defined species of bacteria and fungi, the authors find that fungal colonization induces changes in bacterial microbiome ecology while having an independent effect on innate and adaptive immunity in mice.

Published
2020
Full Text
View/download PDF

5. Survey and Sequence Characterization of Bovine Mastitis-Associated Escherichia coli in Dairy Herds

Author

John I. Alawneh, Ben Vezina, Hena R. Ramay, Hulayyil Al-Harbi, Ameh S. James, Martin Soust, Robert J. Moore, and Timothy W. J. Olchowy

Subjects
cattle, genomics, virulence, plasmid, comparative genomics, antibiotic resistance, Veterinary medicine, SF600-1100
Abstract

Escherichia coli is frequently associated with mastitis in cattle. “Pathogenic” and “commensal” isolates appear to be genetically similar. With a few exceptions, no notable genotypic differences have been found between commensal and mastitis-associated E. coli. In this study, 24 E. coli strains were isolated from dairy cows with clinical mastitis in three geographic regions of Australia (North Queensland, South Queensland, and Victoria), sequenced, then genomically surveyed. There was no observed relationship between sequence type (ST) and region (p = 0.51). The most common Multi Locus Sequence Type was ST10 (38%), then ST4429 (13%). Pangenomic analysis revealed a soft-core genome of 3,463 genes, including genes associated with antibiotic resistance, chemotaxis, motility, adhesion, biofilm formation, and pili. A total of 36 different plasmids were identified and generally found to have local distributions (p = 0.02). Only 2 plasmids contained antibiotic resistance genes, a p1303_5-like plasmid encoding multidrug-resistance (trimethoprim, quaternary ammonium, beta-lactam, streptomycin, sulfonamide, and kanamycin) from two North Queensland isolates on the same farm, while three Victorian isolates from the same farm contained a pCFSAN004177P_01-like plasmid encoding tetracycline-resistance. This pattern is consistent with a local spread of antibiotic resistance through plasmids of bovine mastitis cases. Notably, co-occurrence of plasmids containing virulence factors/antibiotic resistance with putative mobilization was rare, though the multidrug resistant p1303_5-like plasmid was predicted to be conjugative and is of some concern. This survey has provided greater understanding of antibiotic resistance within E. coli-associated bovine mastitis which will allow greater prediction and improved decision making in disease management.

Published
2020
Full Text
View/download PDF

6. Weighted Gene Co-Expression Network Analysis Identifies a Functional Guild and Metabolite Cluster Mediating the Relationship between Mucosal Inflammation and Adherence to the Mediterranean Diet in Ulcerative Colitis

Author

Jaclyn C. Strauss, Natasha Haskey, Hena R. Ramay, Tarini Shankar Ghosh, Lorian M. Taylor, Munazza Yousuf, Christina Ohland, Kathy D. McCoy, Richard J. M. Ingram, Subrata Ghosh, Remo Panaccione, and Maitreyi Raman

Subjects
Inorganic Chemistry, Organic Chemistry, General Medicine, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Catalysis, inflammatory bowel disease, ulcerative colitis, diet, microbiome, metabolomics, weighted gene co-expression analysis (WGCNA), Computer Science Applications
Abstract

Diet influences the pathogenesis and clinical course of inflammatory bowel disease (IBD). The Mediterranean diet (MD) is linked to reductions in inflammatory biomarkers and alterations in microbial taxa and metabolites associated with health. We aimed to identify features of the gut microbiome that mediate the relationship between the MD and fecal calprotectin (FCP) in ulcerative colitis (UC). Weighted gene co-expression network analysis (WGCNA) was used to identify modules of co-abundant microbial taxa and metabolites correlated with the MD and FCP. The features considered were gut microbial taxa, serum metabolites, dietary components, short-chain fatty acid and bile acid profiles in participants that experienced an increase (n = 13) or decrease in FCP (n = 16) over eight weeks. WGCNA revealed ten modules containing sixteen key features that acted as key mediators between the MD and FCP. Three taxa (Faecalibacterium prausnitzii, Dorea longicatena, Roseburia inulinivorans) and a cluster of four metabolites (benzyl alcohol, 3-hydroxyphenylacetate, 3-4-hydroxyphenylacetate and phenylacetate) demonstrated a strong mediating effect (ACME: −1.23, p = 0.004). This study identified a novel association between diet, inflammation and the gut microbiome, providing new insights into the underlying mechanisms of how a MD may influence IBD. See clinicaltrials.gov (NCT04474561).

Published
2023

7. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy

Author

Marco Gallo, Ryan A. Groves, Nicola Pett, Kathy D. McCoy, Seungil Paik, Noah C. A. Cooke, Hena R. Ramay, Kirsty Brown, Ian A. Lewis, Lukas F. Mager, John Stagg, Regula Burkhard, and Markus B. Geuking

Subjects
Male, Skin Neoplasms, Receptor, Adenosine A2A, T-Lymphocytes, medicine.medical_treatment, T cell, Adenosine A2A receptor, Antibodies, B7-H1 Antigen, Mice, 03 medical and health sciences, 0302 clinical medicine, Immune system, Intestinal Neoplasms, medicine, Animals, CTLA-4 Antigen, Microbiome, Inosine, Melanoma, Lactobacillus johnsonii, 030304 developmental biology, 0303 health sciences, Multidisciplinary, biology, Chemistry, Neoplasms, Experimental, Immunotherapy, biology.organism_classification, Gastrointestinal Microbiome, 3. Good health, Mice, Inbred C57BL, medicine.anatomical_structure, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Cancer research, Female, Bifidobacterium, Checkpoint Blockade Immunotherapy, medicine.drug
Abstract

Inosine modulates antitumor immunity Checkpoint blockade immunotherapy harnesses the immune system to kill cancer cells and has been used with great success to treat certain tumors, but not all cancer patients respond. The efficacy of checkpoint blockade immunotherapy has been shown to depend on the presence of distinct, beneficial bacteria residing in the gut of patients, but how the microbiome mediates such beneficial effects is unclear. Mager et al. found that specific bacteria produce a metabolite called inosine that enhances the effect of checkpoint blockade immunotherapy (see the Perspective by Shaikh and Sears). In mouse models, inosine, together with proinflammatory stimuli and immunotherapy, strongly enhanced the antitumor capacities of T cells in multiple tumor types, including colorectal cancer, bladder cancer, and melanoma. Science , this issue p. 1481 ; see also p. 1427

Published
2020

8. Effect of a functional fibre supplement on glycemic control when added to a year-long medically supervised weight management program in adults with type 2 diabetes

Author

Raylene A. Reimer, Michael Lyon, Timothy J. Green, Priya Manjoo, Hena R. Ramay, Roland J. Gahler, Simon Wood, and Sean Wharton

Subjects
Adult, Blood Glucose, Dietary Fiber, 0301 basic medicine, medicine.medical_specialty, Medicine (miscellaneous), Blood lipids, 030209 endocrinology & metabolism, Glycemic Control, Type 2 diabetes, Overweight, Placebo, 03 medical and health sciences, 0302 clinical medicine, Double-Blind Method, Weight loss, Internal medicine, Weight management, medicine, Humans, Obesity, Glycemic, 030109 nutrition & dietetics, Nutrition and Dietetics, business.industry, medicine.disease, Weight Reduction Programs, Diabetes Mellitus, Type 2, medicine.symptom, business
Abstract

Soluble fibre beneficially affects metabolism but whether it can augment the reductions in glycemia induced through intensive weight management has not been extensively studied. Our objective was to examine the adjunct effect of the soluble viscous fibre PGX® on glycemic control in adults with type 2 diabetes (T2D) enrolled in a year-long medically supervised weight management program. In a placebo-controlled, double-blind study, 290 adults with overweight/obesity and T2D were randomized to receive PGX (15–20 g/day) or isocaloric placebo (rice flour, 6.4–8.6 g/day) as an adjunct to intensive weight management for 52 weeks. The primary outcome was change in glycemic control (HbA1c). Other outcome measures included weight loss, blood lipids, blood pressure, cytokines and fecal microbiota. Compared to baseline HbA1c in PGX (7.2 ± 1.1%) and placebo (7.0 ± 0.9%) groups, there was a significant reduction at 16 and 26 weeks, however, only PGX showed a significant absolute reduction of 0.23% at 52 weeks; there were no between-group differences in HbA1c. At 52 weeks, only PGX significantly decreased body weight compared to baseline and reduced waist circumference at all time points. Compared to baseline, only PGX showed a significant reduction in LDL cholesterol at 16 and 26 weeks. PGX significantly increased the relative abundance of Collinsella, Parabacteroides and Roseburia. Adding PGX to a weight management program for individuals with T2D provides a sustained reduction in HbA1c compared to placebo. Improvements in other metabolic outcomes suggest that PGX may be a promising adjunct to weight loss programs in patients with T2D. This trial was registered at ClinicalTrials.gov as NCT01644201.

Published
2020

9. Small Intestinal Resident Eosinophils Maintain Gut Homeostasis Following Microbial Colonisation

Author

Nicholas C. Wong, Kathleen Shah, Regula Burkhard, Mati Moyat, Aline Ignacio, Nicola L. Harris, Kathy D. McCoy, Carolyn A. Thomson, Antoine Dufour, Petrova T, Köller Y, Gillian Coakley, Hamelin R, Bernier-Latmani J, Armand F, and Hena R. Ramay

Subjects
Extracellular matrix, medicine.anatomical_structure, Immune system, Eosinophil activation, medicine, Motility, Eosinophil, Biology, Epithelium, Homeostasis, Small intestine, Cell biology
Abstract

SUMMARYIntestinal homeostasis following postnatal microbial colonization requires the coordination of multiple processes including the activation of immune cells, cell-cell communication, the controlled deposition of extracellular matrix, and epithelial cell turnover and differentiation. The intestine harbors the largest frequency of resident eosinophils of all homeostatic organs, yet the functional significance of eosinophil recruitment to this organ has long remained enigmatic. Eosinophils are equipped to both respond to, and modify, their local tissue environment and thus are able to regulate the adaption of tissues to environmental changes. We report a critical role for eosinophils in regulating villous structure, barrier integrity and motility in the small intestine. Notably, the microbiota was identified as a key driver of small intestinal eosinophil activation and function. Collectively our findings demonstrate a critical role for eosinophils in facilitating mutualistic interactions between host and microbiota and provide a rationale for the functional significance of their early life recruitment in the small intestine.HIGHLIGHTSThe microbiota is a critical regulator of eosinophil activation and turnoverEosinophils uphold intestinal barrier integrity following microbial colonizationLoss of eosinophils at steady-state results in increased villous blunting and altered intestinal motility

Published
2021

11. Sequence characterisation and novel insights into bovine mastitis-associated Streptococcus uberis in dairy herds

Author

Hulayyil Al-harbi, Ben Vezina, John I. Alawneh, Hena R. Ramay, Martin Soust, Robert J. Moore, and Timothy W. J. Olchowy

Subjects
0301 basic medicine, Genotype, Bioinformatics, Epidemiology, Science, 030106 microbiology, Locus (genetics), Biology, Genome, Article, Genomic analysis, 03 medical and health sciences, Antibiotic resistance, Sortase, Streptococcal Infections, Drug Resistance, Bacterial, Genetics research, Animals, Humans, Clinical microbiology, Gene, Mastitis, Bovine, Streptococcus uberis, Genetics, Molecular Epidemiology, Multidisciplinary, Australia, Streptococcus, biology.organism_classification, Anti-Bacterial Agents, 030104 developmental biology, Horizontal gene transfer, Multilocus sequence typing, Medicine, Cattle, Female, Dairy Products, Pathogens, Multilocus Sequence Typing
Abstract

Streptococcus uberis is one of the most frequent mastitis-causing pathogens isolated from dairy cows. Further understanding of S. uberis genetics may help elucidate the disease pathogenesis. We compared the genomes of S. uberis isolates cultured from dairy cows located in distinctly different geographic regions of Australia. All isolates had novel multi locus sequence types (MLST) indicating a highly diverse population of S. uberis. Global clonal complexes (GCC) were more conserved. GCC ST86 and GCC ST143 represented 30% of the total isolates (n = 27) and were clustered within different geographic regions. Core genome phylogeny revealed low phylogenetic clustering by region, isolation source, and MLST. Identification of putative sortase (srtA) substrates and generation of a custom putative virulence factor database revealed genes which may explain the affinity of S. uberis for mammary tissue, evasion of antimicrobial efforts and disease pathogenesis. Of 27 isolates, four contained antibiotic resistance genes including an antimicrobial resistance cluster containing mel/mef(A), mrsE, vatD, lnuD, and transposon-mediated lnuC was also identified. These are novel genes for S. uberis, which suggests interspecies lateral gene transfer. The presence of resistance genes across the two geographic regions tested within one country supports the need for a careful, tailored, implementation and monitoring of antimicrobial stewardship.

Published
2020

12. Immunotherapy efficacy in colorectal cancer is dependent on activation of a microbial-metabolite-immune circuit

Author

Kirsty Brown, Noah C. A. Cooke, Hena R. Ramay, John Stagg, Ryan Grooves, Ian A. Lewis, Regula Burkhard, Marco Gallo, Lukas F. Mager, Seungil Paik, Markus B. Geuking, and Kathy D. McCoy

Subjects
010405 organic chemistry, business.industry, Colorectal cancer, medicine.medical_treatment, Cancer, Immunotherapy, 010402 general chemistry, medicine.disease, 01 natural sciences, Immune checkpoint, 3. Good health, 0104 chemical sciences, Blockade, Immune system, Cancer research, medicine, Cell activation, business, Inosine, medicine.drug
Abstract

SummaryCancer is a leading cause of death globally. Checkpoint blockade therapies offer a promising treatment for many cancers, but have been ineffective for colorectal cancers. Previous studies have shown a dependency of immunotherapies on the microbiota. Consequently, we hypothesized that specific gut bacteria promote immunotherapy for colorectal cancer. We identify three commensal bacteria and a microbial metabolite, inosine, that enhance the efficacy of immune checkpoint blockade therapy in colorectal cancer. We show that inosine interacts with the adenosine A2A receptor on T cells resulting in intestinal Th1 cell differentiation. Decreased gut barrier function induced by immunotherapy increased the translocation of bacterial metabolites and promoted cancer protective Th1 cell activation. This microbial-metabolite-immune circuit provides a mechanism for a new class of bacteria-enhanced checkpoint blockade therapies. The efficacy of this mechanism differs among colorectal cancer subtypes and highlights the strengths as well as potential limitations of this novel bacterial co-therapy for cancer.

Published
2020

13. Intestinal fungi are causally implicated in microbiome assembly and immune development in mice

Author

Jean-Baptiste Cavin, Jumana Samara, Nicholas G. Jendzjowsky, Marie-Claire Arrieta, Margaret M. Kelly, Veronika Kuchařová Pettersen, Richard J. A. Wilson, Wallace K. MacNaughton, Catherine M. Keenan, Erik van Tilburg Bernardes, Fernando A. Vicentini, Keith A. Sharkey, Kathy D. McCoy, Mackenzie W. Gutierrez, Isabelle Laforest-Lapointe, and Hena R. Ramay

Subjects
0301 basic medicine, Ovalbumin, Science, 030106 microbiology, General Physics and Astronomy, Inflammation, Bacterial Physiological Phenomena, General Biochemistry, Genetics and Molecular Biology, Article, Microbiology, 03 medical and health sciences, Feces, Immune system, Microbial ecology, medicine, Metabolome, Animals, Germ-Free Life, Humans, VDP::Medisinske Fag: 700, Microbiome, Colitis, lcsh:Science, Multidisciplinary, biology, Dextran Sulfate, Fungi, General Chemistry, biology.organism_classification, medicine.disease, Gastrointestinal Microbiome, Intestines, Mice, Inbred C57BL, VDP::Medical disciplines: 700, 030104 developmental biology, Immune System, lcsh:Q, Female, medicine.symptom, Bacteria
Abstract

The gut microbiome consists of a multi-kingdom microbial community. Whilst the role of bacteria as causal contributors governing host physiological development is well established, the role of fungi remains to be determined. Here, we use germ-free mice colonized with defined species of bacteria, fungi, or both to differentiate the causal role of fungi on microbiome assembly, immune development, susceptibility to colitis, and airway inflammation. Fungal colonization promotes major shifts in bacterial microbiome ecology, and has an independent effect on innate and adaptive immune development in young mice. While exclusive fungal colonization is insufficient to elicit overt dextran sulfate sodium-induced colitis, bacterial and fungal co-colonization increase colonic inflammation. Ovalbumin-induced airway inflammation reveals that bacterial, but not fungal colonization is necessary to decrease airway inflammation, yet fungi selectively promotes macrophage infiltration in the airway. Together, our findings demonstrate a causal role for fungi in microbial ecology and host immune functionality, and therefore prompt the inclusion of fungi in therapeutic approaches aimed at modulating early life microbiomes., The immunomodulatory role of commensal gut fungi and interactions with bacteria remain unclear. Here, using germ-free mice colonized with defined species of bacteria and fungi, the authors find that fungal colonization induces changes in bacterial microbiome ecology while having an independent effect on innate and adaptive immunity in mice.

Published
2020

14. Iron Sequestration in Microbiota Biofilms As A Novel Strategy for Treating Inflammatory Bowel Disease

Author

Ryan A. Groves, Jean-Paul Motta, Andre G. Buret, Luke E Green-Harrison, Paul L. Beck, Thibault Allain, Hena R. Ramay, Ian A. Lewis, Troy D Feener, and John L. Wallace

Subjects
0301 basic medicine, Purine, Adult, Male, colitis, Iron, 030106 microbiology, Original Basic Science Articles, hydrogen sulfide, Virulence, medicine.disease_cause, Bacterial Physiological Phenomena, Inflammatory bowel disease, digestive system, mesalamine, Microbiology, 03 medical and health sciences, chemistry.chemical_compound, Mice, inflammatory bowel disease, medicine, Immunology and Allergy, Animals, Homeostasis, Humans, Secretion, Microbiome, microbiota biofilms, biology, Gastroenterology, Biofilm, Pathogenic bacteria, Middle Aged, biology.organism_classification, medicine.disease, Inflammatory Bowel Diseases, 3. Good health, Gastrointestinal Microbiome, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, chemistry, Biofilms, Case-Control Studies, Dysbiosis, Female, Bacteria
Abstract

Significant alterations of intestinal microbiota and anemia are hallmarks of inflammatory bowel disease (IBD). It is widely accepted that iron is a key nutrient for pathogenic bacteria, but little is known about its impact on microbiota associated with IBD. We used a model device to grow human mucosa-associated microbiota in its physiological anaerobic biofilm phenotype. Compared to microbiota from healthy donors, microbiota from IBD patients generate biofilms ex vivo that were larger in size and cell numbers, contained higher intracellular iron concentrations, and exhibited heightened virulence in a model of human intestinal epithelia in vitro and in the nematode Caenorhabditis elegans. We also describe an unexpected iron-scavenging property for an experimental hydrogen sulfide-releasing derivative of mesalamine. The findings demonstrate that this new drug reduces the virulence of IBD microbiota biofilms through a direct reduction of microbial iron intake and without affecting bacteria survival or species composition within the microbiota. Metabolomic analyses indicate that this drug reduces the intake of purine nucleosides (guanosine), increases the secretion of metabolite markers of purine catabolism (urate and hypoxanthine), and reduces the secretion of uracil (a pyrimidine nucleobase) in complex multispecies human biofilms. These findings demonstrate a new pathogenic mechanism for dysbiotic microbiota in IBD and characterize a novel mode of action for a class of mesalamine derivatives. Together, these observations pave the way towards a new therapeutic strategy for treatment of patients with IBD.

Published
2018

15. Contribution of fungal microbiome to intestinal physiology, early-life immune development and mucosal inflammation in mice

Author

van Tilburg Bernardes E, Fernando A. Vicentini, Keith A. Sharkey, Veronika Kuchařová Pettersen, Wilson Rja, Mackenzie W. Gutierrez, Hena R. Ramay, Samara J, Catherine M. Keenan, Margaret M. Kelly, Wallace K. MacNaughton, Isabelle Laforest-Lapointe, Kathy D. McCoy, Marie-Claire Arrieta, Nicholas G. Jendzjowsky, and Jean-Baptiste Cavin

Subjects
2. Zero hunger, 0303 health sciences, 030306 microbiology, Host (biology), Ecology (disciplines), Human microbiome, Biology, medicine.disease, biology.organism_classification, Microbiology, 03 medical and health sciences, Immune system, medicine, Metabolome, Microbiome, Colitis, Bacteria, 030304 developmental biology
Abstract

Gut microbiomes make major contributions to the physiological and immunological development of the host, but the relative importance of their bacterial and fungal components, and how they interact, remain largely unknown. We applied carefully controlled experiments in gnotobiotic mice colonized with defined communities of bacteria, fungi, or both to differentiate the direct role of fungi on microbiome assembly, host development, and susceptibility to colitis and airway inflammation. Our results revealed that fungal colonization alone was insufficient to promote the intestinal anatomic and physiological changes seen in mice colonized by bacteria, and had limited impact on the fecal metabolome. However, fungal colonization promoted major shifts in bacterial microbiome ecology, and had an independent effect on the innate and adaptive immune development in young mice. Fungi further exacerbated some aspects of the inflammatory effects of the bacterial community during OVA-induced airway inflammation by promoting macrophage infiltration in the airway. Our results demonstrate a dominant ecological and physiological role of bacteria in gut microbiomes, but highlight fungi as an ecological factor shaping the assembly of the bacterial community and a direct capacity to impact immune system and modulate disease susceptibility. These findings demonstrate that studies focused on bacteria alone provide an incomplete portrayal on microbiome ecology and functionality, and prompt for the inclusion of fungi in human microbiome studies.

Published
2019
Full Text
View/download PDF

16. Maternal low-dose aspartame and stevia consumption with an obesogenic diet alters metabolism, gut microbiota and mesolimbic reward system in rat dams and their offspring

Author

Faye Chleilat, Leah A Johnston, Alissa C. Nicolucci, Jodi E. Nettleton, Nicole A. Cho, Erin W. Noye Tuplin, Stephanie L. Borgland, Raylene A Reimer, Hena R. Ramay, Kathy D. McCoy, Jane Shearer, Shyamchand Mayengbam, Teja Klancic, and Carolyn A. Thomson

Subjects
0301 basic medicine, medicine.medical_specialty, obesity, Offspring, glucose metabolism, Gut flora, Diet, High-Fat, Impaired glucose tolerance, 03 medical and health sciences, Mice, Pregnancy, Internal medicine, Lactation, Glucose Intolerance, energy metabolism, medicine, Weaning, Animals, Stevia, Gut Microbiota, Aspartame, Adiposity, 2. Zero hunger, 030109 nutrition & dietetics, biology, Body Weight, Gastroenterology, Fecal Microbiota Transplantation, medicine.disease, biology.organism_classification, Obesity, Gastrointestinal Microbiome, Rats, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Glucose, Animals, Newborn, Prenatal Exposure Delayed Effects, Sweetening Agents, Female, intestinal bacteria, medicine.symptom, diet, Weight gain
Abstract

ObjectiveWe examined the impact of maternal low-dose aspartame and stevia consumption on adiposity, glucose tolerance, gut microbiota and mesolimbic pathway in obese dams and their offspring.DesignFollowing obesity induction, female Sprague-Dawley rats were allocated during pregnancy and lactation to: (1) high fat/sucrose diet (HFS) +water (obese-WTR); (2) HFS +aspartame (obese-APM; 5–7 mg/kg/day); (3) HFS +stevia (obese-STV; 2–3 mg/kg/day). Offspring were weaned onto control diet and water and followed until 18 weeks. Gut microbiota and metabolic outcomes were measured in dams and offspring. Cecal matter from offspring at weaning was used for faecal microbiota transplant (FMT) into germ-free (GF) mice.ResultsMaternal APM and STV intake with a HFS diet increased body fat in offspring at weaning and body weight long-term with APM. Maternal APM/HFS consumption impaired glucose tolerance in male offspring at age 8 weeks and both APM and STV altered faecal microbiota in dams and offspring. Maternal obesity/HFS diet affected offspring adiposity and glucose tolerance more so than maternal LCS consumption at age 12 and 18 weeks. APM and STV altered expression of genes in the mesolimbic reward system that may promote consumption of a palatable diet. GF mice receiving an FMT from obese-APM and obese-STV offspring had greater weight gain and body fat and impaired glucose tolerance compared with obese-WTR.ConclusionMaternal low-calorie sweetener consumption alongside HFS may disrupt weight regulation, glucose control and gut microbiota in dams and their offspring most notably in early life despite no direct low-calorie sweetener consumption by offspring.

Published
2018

17. Histological improvement of non-alcoholic steatohepatitis with a prebiotic: a pilot clinical trial

Author

Saumya Jayakumar, Chris Probert, Marc R. Bomhof, Raylene A. Reimer, Hena R. Ramay, Maitreyi Raman, Kevin P. Rioux, Pam Crotty, and Jill A. Parnell

Subjects
0301 basic medicine, Male, medicine.medical_specialty, medicine.medical_treatment, Medicine (miscellaneous), Oligosaccharides, 030209 endocrinology & metabolism, Pilot Projects, Gut flora, digestive system, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Weight loss, Non-alcoholic Fatty Liver Disease, Internal medicine, Diabetes mellitus, medicine, Humans, 030109 nutrition & dietetics, Nutrition and Dietetics, medicine.diagnostic_test, biology, business.industry, Prebiotic, Fatty liver, Middle Aged, medicine.disease, biology.organism_classification, 3. Good health, Prebiotics, Treatment Outcome, Liver biopsy, Female, Steatosis, medicine.symptom, Steatohepatitis, business
Abstract

In obesity and diabetes the liver is highly susceptible to abnormal uptake and storage of fat. In certain individuals hepatic steatosis predisposes to the development of non-alcoholic steatohepatitis (NASH), a disease marked by hepatic inflammation and fibrosis. Although the precise pathophysiology of NASH is unknown, it is believed that the gut microbiota-liver axis influences the development of this disease. With few treatment strategies available for NASH, exploration of gut microbiota-targeted interventions is warranted. We investigated the therapeutic potential of a prebiotic supplement to improve histological parameters of NASH. In a placebo-controlled, randomized pilot trial, 14 individuals with liver-biopsy-confirmed NASH [non-alcoholic fatty liver activity score (NAS) ≥ 5] were randomized to receive oligofructose (8 g/day for 12 weeks followed by 16 g/day for 24 weeks) or isocaloric placebo for 9 months. The primary outcome measure was the change in liver biopsy NAS score and the secondary outcomes included changes in body weight, body composition, glucose tolerance, inflammatory markers, and gut microbiota. Independent of weight loss, oligofructose improved liver steatosis relative to placebo and improved overall NAS score (P = 0.016). Bifidobacterium was enhanced by oligofructose, whereas bacteria within Clostridium cluster XI and I were reduced with oligofructose (P

Published
2018

18. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors

Author

Denarda Dangaj, Jaikumar Duraiswamy, Mauro Delorenzi, David Barras, Lana E. Kandalaft, Donald G. Jackson, Melita Irving, Catherine Ronet, Andrea Facciabene, Kathleen T. Montone, Alizée J. Grimm, Janos L. Tanyi, Sylvie Rusakiewicz, Priyanka Duttagupta, Lin Zhang, George Coukos, Evripidis Lanitis, Hena R. Ramay, Periklis G. Foukas, Stephen Hodi, Phyllis A. Gimotty, Fabian Benencia, Jeffrey S. Weber, Jose R. Conejo-Garcia, Marine Bruand, Daniel J. Powell, and Scott J. Rodig

Subjects
0301 basic medicine, Cancer Research, Chemokine, Myeloid, Lymphocyte, CD8-Positive T-Lymphocytes, Lymphocyte Activation, CXCR3, Chemokine CXCL9, Epigenesis, Genetic, Antineoplastic Agents, Immunological, 0302 clinical medicine, Chemokine CCL5, Ovarian Neoplasms, biology, virus diseases, hemic and immune systems, Gene Expression Regulation, Neoplastic, Chemotaxis, Leukocyte, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, DNA methylation, Cytokines, Female, Immunotherapy, Signal Transduction, Receptors, CXCR3, T cell, Article, CCL5, Interferon-gamma, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, Immune system, stomatognathic system, Cell Line, Tumor, Paracrine Communication, parasitic diseases, medicine, Animals, Humans, Macrophages, Dendritic Cells, DNA Methylation, Coculture Techniques, Mice, Inbred C57BL, stomatognathic diseases, 030104 developmental biology, biology.protein, Cancer research
Abstract

Summary We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors.

Published
2019

19. Differential sensitivity of Ca2+wave and Ca2+spark events to ruthenium red in isolated permeabilised rabbit cardiomyocytes

Author

Hena R. Ramay, Niall Macquaide, Godfrey L. Smith, and E. A Sobie

Subjects
Calcium metabolism, Ruthenium red, Physiology, Ryanodine receptor, Confocal, Cardiac muscle, Anatomy, musculoskeletal system, EGTA, chemistry.chemical_compound, medicine.anatomical_structure, chemistry, cardiovascular system, medicine, Biophysics, Myocyte, tissues, Perfusion
Abstract

Spontaneous Ca2+ waves in cardiac muscle cells are thought to arise from the sequential firing of local Ca2+ sparks via a fire–diffuse–fire mechanism. This study compares the ability of the ryanodine receptor (RyR) blocker ruthenium red (RuR) to inhibit these two types of Ca2+ release in permeabilised rabbit ventricular cardiomyocytes. Perfusing with 600 nm Ca2+ (50 μm EGTA) caused regular spontaneous Ca2+ waves that were imaged with the fluorescence from Fluo-5F using a laser-scanning confocal microscope. Addition of 4 μm RuR caused complete inhibition of Ca2+ waves in 50% of cardiomyocytes by 2 min and in 100% by 4 min. Separate experiments used 350 μm EGTA (600 nm Ca2+) to limit Ca2+ diffusion but allow the underlying Ca2+ sparks to be imaged. The time course of RuR-induced inhibition did not match that of waves. After 2 min of RuR, none of the characteristics of the Ca2+ sparks were altered, and after 4 min Ca2+ spark frequency was reduced ∼40%; no sparks could be detected after 10 min. Measurements of Ca2+ within the SR lumen using Fluo-5N showed an increase in intra-SR Ca2+ during the initial 2–4 min of perfusion with RuR in both wave and spark conditions. Computational modelling suggests that the sensitivity of Ca2+ waves to RuR block depends on the number of RyRs per cluster. Therefore inhibition of Ca2+ waves without affecting Ca2+ sparks may be explained by block of small, non-spark producing clusters of RyRs that are important to the process of Ca2+ wave propagation.

Published
2010

20. Excitation-contraction coupling gain in ventricular myocytes: insights from a parsimonious model

Author

Hena R. Ramay and Eric A. Sobie

Subjects
Coupling (electronics), Physics, Physiology, Excitation–contraction coupling, Spark (mathematics), Model parameters, Ventricular myocytes, Biological system
Abstract

We present a minimal mathematical model of Ca2+ spark triggering under voltage-clamp conditions in ventricular myocytes. The model predicts changes in excitation–contraction coupling ‘gain’ that result from diverse experimental interventions. We compare model results to several sets of data, and, in so doing, place apparent constraints on physiologically relevant model parameters. Specifically, the analysis suggests that many L-type Ca2+ channel openings can potentially trigger each Ca2+ spark, but the probability that an individual opening will trigger a spark is low. This procedure helps to reconcile contradictory results obtained in recent studies; moreover, this new model should be a useful tool for understanding changes in gain that occur physiologically and in disease.

Published
2009

21. Diffusion Restrictions Surrounding Mitochondria: A Mathematical Model of Heart Muscle Fibers

Author

Marko Vendelin and Hena R. Ramay

Subjects
ATPase, Cell Respiration, Pyruvate Kinase, Biophysics, Mitochondrion, Models, Biological, Mitochondria, Heart, Permeability, Diffusion, Phosphoenolpyruvate, 03 medical and health sciences, 0302 clinical medicine, Adenosine Triphosphate, Imaging, Three-Dimensional, Animals, Diffusion (business), Cytoskeleton, Heart metabolism, 030304 developmental biology, 0303 health sciences, Microscopy, Confocal, biology, Biophysical Systems and Multicellular Dynamics, Endoplasmic reticulum, Myocardium, Heart, Cell biology, Rats, Adenosine Diphosphate, Cytosol, Cytoskeletal Proteins, Microscopy, Electron, Sarcoplasmic Reticulum, Permeability (electromagnetism), biology.protein, 030217 neurology & neurosurgery
Abstract

Several experiments on permeabilized heart muscle fibers suggest the existence of diffusion restrictions grouping mitochondria and surrounding ATPases. The specific causes of these restrictions are not known, but intracellular structures are speculated to act as diffusion barriers. In this work, we assume that diffusion restrictions are induced by sarcoplasmic reticulum (SR), cytoskeleton proteins localized near SR, and crowding of cytosolic proteins. The aim of this work was to test whether such localization of diffusion restrictions would be consistent with the available experimental data and evaluate the extent of the restrictions. For that, a three-dimensional finite-element model was composed with the geometry based on mitochondrial and SR structural organization. Diffusion restrictions induced by SR and cytoskeleton proteins were varied with other model parameters to fit the set of experimental data obtained on permeabilized rat heart muscle fibers. There are many sets of model parameters that were able to reproduce all experiments considered in this work. However, in all the sets

Published
2009

22. The Consensus Molecular Subtypes of Colorectal Cancer

Author

David Barras, Sarah Gerster, Sabine Tejpar, Krisztian Homicsko, Xingwu Wang, Rodrigo Dienstmann, Hena R. Ramay, Lodewyk F. A. Wessels, Mauro Delorenzi, Felipe De Sousa E Melo, Gift Nyamundanda, Louis Vermeulen, Iris Simon, Douglas Hanahan, Charlotte Soneson, Edoardo Missiaglia, Bradley M. Broom, Justin Guinney, Joe W. Gray, Aurélien de Reyniès, Anguraj Sadanandam, Brian M. Bot, Paul Roepman, Jeffrey S. Morris, René Bernards, Evelyn Fessler, Andreas Schlicker, Ted Laderas, Scott Kopetz, Dipen M. Maru, Pierre Laurent-Puig, Beatriz Perez-Villamil, Josep Tabernero, Stephen H. Friend, Valérie Boige, Ganiraju C. Manyam, Ramon Salazar, Laetitia Marisa, Jan Paul Medema, Paolo Angelino, Center of Experimental and Molecular Medicine, CCA -Cancer Center Amsterdam, Radiotherapy, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Universitat de Barcelona

Subjects
Classificació de tumors, Oncologia, Angiogenesis, Colorectal cancer, Genes, myc, Disease, Bioinformatics, Transforming Growth Factor beta, Medicine, Non-U.S. Gov't, Wnt Signaling Pathway, biology, Neovascularization, Pathologic, Research Support, Non-U.S. Gov't, Wnt signaling pathway, General Medicine, Prognosis, Phenotype, 3. Good health, Gene Expression Regulation, Neoplastic, Oncology, Microsatellite Instability, Colorectal Neoplasms, Proto-Oncogene Proteins B-raf, Consensus, DNA Copy Number Variations, Research Support, General Biochemistry, Genetics and Molecular Biology, Article, N.I.H, Proto-Oncogene Proteins p21(ras), Research Support, N.I.H., Extramural, Càncer colorectal, Proto-Oncogene Proteins, Journal Article, Humans, business.industry, Information Dissemination, Tumors classification, Gene Expression Profiling, Carcinoma, Extramural, Microsatellite instability, Transforming growth factor beta, DNA Methylation, medicine.disease, Gene expression profiling, Mutation, biology.protein, Cancer research, ras Proteins, CpG Islands, business
Abstract

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use -- https://www.nature.com/authors/policies/license.html#terms Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMS) with distinguishing features: CMS1 (MSI Immune, 14%), hypermutated, microsatellite unstable, strong immune activation; CMS2 (Canonical, 37%), epithelial, chromosomally unstable, marked WNT and MYC signaling activation; CMS3 (Metabolic, 13%), epithelial, evident metabolic dysregulation; and CMS4 (Mesenchymal, 23%), prominent transforming growth factor β activation, stromal invasion, and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intra-tumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC - with clear biological interpretability - and the basis for future clinical stratification and subtype-based targeted interventions.

Published
2015

23. An Il-lumen-ating look at ryanodine receptor modulation by disruption in triadin and calsequestrin interactions in cardiac myocytes

Author

Onika Noel, Hena R. Ramay, Amrita X. Sarkar, and Frank Fabris

Subjects
medicine.medical_specialty, Physiology, Lipid Bilayers, Muscle Proteins, chemistry.chemical_element, Calcium, Calsequestrin, Ryanodine receptor 2, Internal medicine, medicine, Animals, Myocyte, Myocytes, Cardiac, Cells, Cultured, Chemistry, Ryanodine receptor, Endoplasmic reticulum, Cardiac muscle, Ryanodine Receptor Calcium Release Channel, musculoskeletal system, Rats, Cell biology, Sarcoplasmic Reticulum, Endocrinology, medicine.anatomical_structure, Triadin, cardiovascular system, Cellular, Carrier Proteins, tissues
Abstract

In cardiac muscle, intracellular Ca2+ release is controlled by a number of proteins including the ryanodine receptor (RyR2), calsequestrin (CASQ2), triadin-1 (Trd) and junctin (Jn) which form a complex in the junctional sarcoplasmic reticulum (SR) membrane. Within this complex, Trd appears to link CASQ2 to RyR2 although the functional significance of this interaction is unclear. In this study, we explored the functional importance of Trd–CASQ2 interactions for intracellular Ca2+ handling in rat ventricular myocytes. A peptide encompassing the homologous CASQ2 binding domain of Trd (residues 206–230 in the rat; TrdPt) was expressed in the lumen of the SR to disrupt Trd–CASQ2 interactions. Myocytes expressing TrdPt exhibited increased responsiveness of SR Ca2+ release to activation by ICa as manifested by flattened and broadened voltage dependency of the amplitude of cytosolic Ca2+ transients. Rhythmically paced, TrdPt-expressing myocytes exhibited spontaneous arrhythmogenic oscillations of intracellular Ca2+ and membrane potential that was not seen in control cells. In addition, the frequency of spontaneous Ca2+ sparks and Ca2+ waves was significantly increased in TrdPt-expressing, permeabilized myocytes. These alterations in SR Ca2+ release were accompanied by a significant decrease in basal free intra-SR[Ca2+] and total SR Ca2+ content in TrdPt-expressing cells. At the same time a synthetic peptide corresponding to the CASQ2 binding domain of Trd produced no direct effects on the activity of single RyR2 channels incorporated into lipid bilayers while interfering with the ability of CASQ2 to inhibit the RyR2 channel. These results suggest that CASQ2 stabilizes SR Ca2+ release by inhibiting the RyR2 channel through interaction with Trd. They also show that intracellular Ca2+ cycling in the heart relies on coordinated interactions between proteins of the RyR2 channel complex and that disruption of these interactions may represent a molecular mechanism for cardiac disease.

Published
2008

24. Recovery of cardiac calcium release is controlled by sarcoplasmic reticulum refilling and ryanodine receptor sensitivity

Author

Eric A. Sobie, Hena R. Ramay, and Ona Liu

Subjects
Male, medicine.medical_specialty, Physiology, Refractory period, chemistry.chemical_element, Stimulation, Gating, Calcium, Calsequestrin, Sarcoplasmic Reticulum Calcium-Transporting ATPases, chemistry.chemical_compound, Physiology (medical), Internal medicine, medicine, Animals, Computer Simulation, Ryanodine receptor, Ryanodine, Endoplasmic reticulum, Myocardium, Isoproterenol, Ryanodine Receptor Calcium Release Channel, Original Articles, musculoskeletal system, Rats, Sarcoplasmic Reticulum, Endocrinology, chemistry, cardiovascular system, Cardiology and Cardiovascular Medicine, Caffeine, tissues
Abstract

Aims In heart cells, the mechanisms underlying refractoriness of the elementary units of sarcoplasmic reticulum (SR) Ca2+ release, Ca2+ sparks, remain unclear. We investigated local recovery of SR Ca2+ release using experimental measurements and mathematical modelling. Methods and results Repeated Ca2+ sparks were induced from individual clusters of ryanodine receptors (RyRs) in quiescent rat ventricular myocytes, and we examined how changes in RyR gating influenced the time-dependent recovery of Ca2+ spark amplitude and triggering probability. Repeated Ca2+ sparks from individual sites were analysed in the presence of 50 nM ryanodine with: (i) no additional agents (control); (ii) 50 µM caffeine to sensitize RyRs; (iii) 50 µM tetracaine to inhibit RyRs; or (iv) 100 nM isoproterenol to activate β-adrenergic receptors. Sensitization and inhibition of RyR clusters shortened and lengthened, respectively, the median interval between consecutive Ca2+ sparks (caffeine 239 ms; control 280 ms; tetracaine 453 ms). Recovery of Ca2+ spark amplitude, however, was exponential with a time constant of ∼100 ms in all cases. Isoproterenol both accelerated the recovery of Ca2+ spark amplitude (τ = 58 ms) and shortened the median interval between Ca2+ sparks (192 ms). The results were recapitulated by a mathematical model in which SR [Ca2+] depletion terminates Ca2+ sparks, but not by an alternative model based on limited depletion and Ca2+-dependent inactivation of RyRs. Conclusion Together, the results strongly suggest that: (i) local SR refilling controls Ca2+ spark amplitude recovery; (ii) Ca2+ spark triggering depends on both refilling and RyR sensitivity; and (iii) β-adrenergic stimulation influences both processes.

Published
2011

25. Predicting local SR Ca(2+) dynamics during Ca(2+) wave propagation in ventricular myocytes

Author

W. Jonathan Lederer, Hena R. Ramay, M. Saleet Jafri, and Eric A. Sobie

Subjects
medicine.medical_specialty, Cytoplasm, Wave propagation, Heart Ventricles, Biophysics, chemistry.chemical_element, 030204 cardiovascular system & hematology, Calcium, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Diffusion, 03 medical and health sciences, 0302 clinical medicine, Cytosol, Internal medicine, medicine, Myocyte, Animals, Cellular Biophysics and Electrophysiology, Computer Simulation, Myocytes, Cardiac, Ventricular myocytes, 030304 developmental biology, 0303 health sciences, Ryanodine receptor, Chemistry, Endoplasmic reticulum, Models, Cardiovascular, Ryanodine Receptor Calcium Release Channel, Partial inhibition, Kinetics, Sarcoplasmic Reticulum, Endocrinology, Algorithms
Abstract

Of the many ongoing controversies regarding the workings of the sarcoplasmic reticulum (SR) in cardiac myocytes, two unresolved and interconnected topics are 1), mechanisms of calcium (Ca(2+)) wave propagation, and 2), speed of Ca(2+) diffusion within the SR. Ca(2+) waves are initiated when a spontaneous local SR Ca(2+) release event triggers additional release from neighboring clusters of SR release channels (ryanodine receptors (RyRs)). A lack of consensus regarding the effective Ca(2+) diffusion constant in the SR (D(Ca,SR)) severely complicates our understanding of whether dynamic local changes in SR [Ca(2+)] can influence wave propagation. To address this problem, we have implemented a computational model of cytosolic and SR [Ca(2+)] during Ca(2+) waves. Simulations have investigated how dynamic local changes in SR [Ca(2+)] are influenced by 1), D(Ca,SR); 2), the distance between RyR clusters; 3), partial inhibition or stimulation of SR Ca(2+) pumps; 4), SR Ca(2+) pump dependence on cytosolic [Ca(2+)]; and 5), the rate of transfer between network and junctional SR. Of these factors, D(Ca,SR) is the primary determinant of how release from one RyR cluster alters SR [Ca(2+)] in nearby regions. Specifically, our results show that local increases in SR [Ca(2+)] ahead of the wave can potentially facilitate Ca(2+) wave propagation, but only if SR diffusion is relatively slow. These simulations help to delineate what changes in [Ca(2+)] are possible during SR Ca(2+)release, and they broaden our understanding of the regulatory role played by dynamic changes in [Ca(2+)](SR).

Published
2009

26. Endocraniosis

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

27. Early Onset Severe Retinal Dystrophy

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

28. Essential Myoclonus

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

29. Eosinophilic Pneumonia

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

30. Eosinophilic Granuloma (Single-Organ Involvement)

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

31. Extrinsic Allergic Alveolitis

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

32. Eczema-Thrombocytopenia-Immunodeficiency Syndrome

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

33. Erythroderma of Brocq

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

34. Episkopi Blindness

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

35. Enteropathy, Autoimmune, with Hemolytic Anemia and Polyendocrinopathy

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

36. Elbow Tendinosis

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

37. Essential Hereditary Myoclonus

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

38. Epidermolytic Hyperkeratosis

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

39. Emery-Dreifuss Muscular Dystrophy

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

40. Erythrogenesis Imperfecta

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

41. Epidermolytic Palmoplantar Keratoderma

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

42. Erythrokeratodermia Variabilis

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

43. Embryonic Common Atrium

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

44. Exomphalos-Macroglossia-Gigantism Syndrome

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

45. Efferent Loop Syndrome

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

46. Endostosis Crani

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

47. Estrogen Resistance

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

48. Ectrodactyly, Ectodermal Dysplasia, and Clefting Syndrome

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

49. Erythema Neonatorum Allergicum

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

50. Endothelial Dysfunction

Author

Kei Inai, Alexander K. C. Leung, Jouni Uitto, Gerhard-Paul Diller, Michael A. Gatzoulis, John-John B. Schnog, Victor E. A. Gerdes, M. Cristina Digilio, Bruno Marino, Bruno Dallapiccola, Christian A. Koch, Angela Vincent, Ravi Bhargava, Norma Leonard, Siobhan D. Ma, Patrick T. S. Ma, Dirk Westermann, Carsten Tschöpe, Timothy Watson, Gregory Y. H. Lip, Klaus Pfeffer, Colin R. MacKenzie, Walter Däubener, Reginald S. Sauve, Andrew L. Wong, Leonard O’Sullivan, Stefan Beissert, Silke Hofmann, Leena Bruckner-Tuderman, Rolf Schröder, Iris Unterberger, Rüdiger Köhling, Holger Lerche, Fabienne Picard, Andreas Hahn, Bernd A. Neubauer, Carla Marini, Renzo Guerrini, Frederico Zara, Fernando Cendes, Iscia Lopes-Cendes, Heinz Beck, Christian Elger, Tracey D. Graves, Michael G. Hanna, Werner J. Heppt, Rainer Weber, Walter Lisch, Andreas Janecke, Berthold Seitz, Cord Sunderkötter, Mosaad Megahed, Akmal Hassan, Sonja Ständer, Heiko Traupe, William Jeffcoate, Marcus Schmitt, Thomas Frieling, Nirmal S. Mann, Michaela Luconi, Vincenzo Rochira, Rossana Mineri, Valeria Tiranti, Seda Sancak, Ralf Paschke, Eric A. Sobie, and Hena R. Ramay

Published
2009

Catalog

Books, media, physical & digital resources
See catalog results