Wednesday, March 4, 2009
Huntington's Disease
Huntington's disease is a neurodegenerative disorder characterized by a selective degeneration of striatal projection neurons, which deal with choreic movements. Neuroprotective therapy could be achieved with the knowledge of the specific trophic requirements of these neuronal populations. Thus, the induction of endogenous trophic response or the exogenous administration of neurotrophic factors may help to prevent or stop the progression of the illness. Excitotoxicity has been implicated in the etiology of Huntington's disease, because intrastriatal injection of glutamate receptor agonists reproduces some of the neuropathological features of this disorder. Activation of glutamate receptors in the striatum differentially regulates the expression of neurotrophins, glial cell line-derived neurotrophic factor (GDNF), neurturin, and their receptors in the striatum and in its connections, cortex, and substantia nigra, showing a selective trophic response against excitotoxic insults. Transplantation of cells genetically engineered to release neurotrophic factors in the striatum has been used to study the neuroprotective effects of neurotrophin and GDNF family members in the excitotoxic model of Huntington's disease. Neurotrophins (brain-derived neurotrophic factor [BDNF], neurotrophin-3, and neurotrophin-4) protected striatal projection neurons against quinolinic or kainic acid treatment. However, GDNF family members showed a more specific action. Neurturin only protected gamma-aminobutyric acid (GABA)/enkephalinergic neurons that project to the external segment of the globus pallidus, whereas GDNF exerts its effects on GABA/substance P positive neurons, which project to the substantia nigra pars compacta and the internal segment of the globus pallidus. In conclusion, the trophic requirements of each population of striatal projection neurons are due to a complex interaction between several neurotrophic factors, such as neurotrophins and GDNF family members, which can be modified, in different pathological conditions. Moreover, these neurotrophic factors may be able to provide selective protection for basal ganglia circuits, which are affected in striatonigral degenerative disorders, such as Huntington's disease or multisystem atrophy.
Soil, geography and human disease
Peter W. Abrahams
Institute of Geography and Earth Sciences, University of Wales, Aberystwyth SY23 3DB, Wales, UK
Soils have a profound impact on the causation and geographical distribution of human disease and well-being. However, because of the multifactorial causes of illnesses, the impact of soils on health needs to be considered in light of the environment in its fullest sense. Since the nineteenth century, medical cartography has served as an epidemiological tool for investigating the links between soils and human well-being. Using examples, particularly the problems of soil-transmitted helminth infections, and iodine and selenium deficiency diseases, this paper shows how maps have been used to identify problem areas, stimulate the development of aetiological hypotheses, help in the planning and management of public health problems, and assess the impact of any beneficial strategies.
Key Words: human disease • iodine deficiency disorders • medical cartography • selenium deficiency • soil geography • soil-transmitted helminths
Institute of Geography and Earth Sciences, University of Wales, Aberystwyth SY23 3DB, Wales, UK
Soils have a profound impact on the causation and geographical distribution of human disease and well-being. However, because of the multifactorial causes of illnesses, the impact of soils on health needs to be considered in light of the environment in its fullest sense. Since the nineteenth century, medical cartography has served as an epidemiological tool for investigating the links between soils and human well-being. Using examples, particularly the problems of soil-transmitted helminth infections, and iodine and selenium deficiency diseases, this paper shows how maps have been used to identify problem areas, stimulate the development of aetiological hypotheses, help in the planning and management of public health problems, and assess the impact of any beneficial strategies.
Key Words: human disease • iodine deficiency disorders • medical cartography • selenium deficiency • soil geography • soil-transmitted helminths
protein degradation and human diseases
Department of Internal Medicine B, Meir General Hospital and the Sackler School of Medicine, Tel-Aviv University, Kfar-Saba, Israel. eyalr@mit.edu
Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins.
Between the 1950s and 1980s, many scientists focused on the process by which the genetic code is translated into proteome. However, little attention was devoted to the mechanism responsible for protein degradation. When researchers discovered the organelle lysosome, they assumed that cellular proteins were degraded within it. However, several independent lines of evidence strongly suggested that intracellular proteolysis was largely nonlysosomal. The discovery of the ubiquitin proteasome system (UPS) resolved this enigma. It is now recognized that degradation of intracellular proteins by the UPS is involved in the regulation of a broad array of cellular processes, including cell-cycle division; DNA repair, growth, and differentiation; quality control; and regulation of membrane receptors and ion channels. Not surprisingly, aberrations in the system have been implicated in the pathogenesis of numerous human diseases, and it seems that pharmacologic manipulation of the UPS might alter the outcome of many diseases, especially malignant conditions and possibly neurodegenerative and chronic inflammatory diseases. These findings have led to increasing efforts to develop mechanism-based drugs that modulate UPS activity, one of which is already on the market. In the near future, one can expect to see the development of new, potent, and highly specific drugs that target the degradation pathways of a single or a few proteins without affecting other proteins.
Carbon Monoxide and Human Disease
Danielle Morse
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, MUH 628NW, 3459 Fifth Ave, Pittsburgh, PA 15213.
Jigme Sethi
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, MUH 628NW, 3459 Fifth Ave, Pittsburgh, PA 15213.
Carbon monoxide is produced endogenously in humans through the breakdown of hemoglobin by heme oxygenase. Although originally thought to be a superfluous by-product of heme catabolism, carbon monoxide is now known to play a central role in many aspects of human health and disease. The functions of carbon monoxide that have been described to date are myriad, including blood pressure regulation, maintenance of organ-specific vascular tone, neurotransmission, stress response, platelet activation, and smooth muscle relaxation. This review outlines what is known to date about carbon monoxide as it relates to human disease.
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, MUH 628NW, 3459 Fifth Ave, Pittsburgh, PA 15213.
Jigme Sethi
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, MUH 628NW, 3459 Fifth Ave, Pittsburgh, PA 15213.
Carbon monoxide is produced endogenously in humans through the breakdown of hemoglobin by heme oxygenase. Although originally thought to be a superfluous by-product of heme catabolism, carbon monoxide is now known to play a central role in many aspects of human health and disease. The functions of carbon monoxide that have been described to date are myriad, including blood pressure regulation, maintenance of organ-specific vascular tone, neurotransmission, stress response, platelet activation, and smooth muscle relaxation. This review outlines what is known to date about carbon monoxide as it relates to human disease.
Animal models of human disease
Despite the pre-eminence of the mouse in modelling human disease, several aspects of murine biology limit its routine use in large-scale genetic and therapeutic screening. Many researchers who are interested in an embryologically and genetically tractable disease model have now turned to zebrafish. Zebrafish biology allows ready access to all developmental stages, and the optical clarity of embryos and larvae allow real-time imaging of developing pathologies. Sophisticated mutagenesis and screening strategies on a large scale, and with an economy that is not possible in other vertebrate systems, have generated zebrafish models of a wide variety of human diseases. This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.
Eosinophilic Esophagitis Disease in Children from West Virginia
BACKGROUND: Eosinophilic esophagitis (EoE) is a newly established disease in adults and children. The incidence and prevalence of the disease among children from the United States are largely unknown. We examined the endoscopy reports of children who attended our gastroenterology clinic in the last 10 yr.
MATERIALS A AND METHODS: retrospective review of all diagnostic upper endoscopy procedures was executed between 1995–2004, of which a quarter (25%) per each year was randomly selected for pathological reevaluation of the number of Eos. The diagnosis of EoE was established when higher than 15 Es/hpf was detected in the esophageal biopsy; and the prevalence of EoE was calculated. The clinical symptoms, endoscopic presentation, and treatment of the patients with EoE disease were also reviewed.
RESULTS: A total of 1,424 procedures were reviewed, of which 355 esophageal samples were reevaluated. During the study period, 44 patients were diagnosed with EoE. The prevalence rate of EoE disease was 0.73/10,000 children during the study period. Similar results were found when the number of Eos was established at >20 Es/hpf. Abdominal pain (55%), vomiting (43%), and heartburn (39%) were the most common symptoms, and characteristic mucosal appearance was found in only 11% of the patients.
CONCLUSION: The rate of EoE in our pediatric patient population is low. Prospective studies are needed to establish the incident and prevalence of EoE disease in children living in the United States.
MATERIALS A AND METHODS: retrospective review of all diagnostic upper endoscopy procedures was executed between 1995–2004, of which a quarter (25%) per each year was randomly selected for pathological reevaluation of the number of Eos. The diagnosis of EoE was established when higher than 15 Es/hpf was detected in the esophageal biopsy; and the prevalence of EoE was calculated. The clinical symptoms, endoscopic presentation, and treatment of the patients with EoE disease were also reviewed.
RESULTS: A total of 1,424 procedures were reviewed, of which 355 esophageal samples were reevaluated. During the study period, 44 patients were diagnosed with EoE. The prevalence rate of EoE disease was 0.73/10,000 children during the study period. Similar results were found when the number of Eos was established at >20 Es/hpf. Abdominal pain (55%), vomiting (43%), and heartburn (39%) were the most common symptoms, and characteristic mucosal appearance was found in only 11% of the patients.
CONCLUSION: The rate of EoE in our pediatric patient population is low. Prospective studies are needed to establish the incident and prevalence of EoE disease in children living in the United States.
Occupational performance challenges for children with congenital heart disease
Backround. Paediatric specialists have advocated for exercise training programs for children with congenital heart disease without addressing other common deficits, such as behavioural and psychological problems. Despite evidence of the role of occupational therapy in rehabilitation for adults with cardiac disease, there has been little published about occupational therapy for children with congenital heart disease. Purpose. This literature review on the outcomes of congenital heart disease, guided by the Canadian Model of Occupational Performance, highlights the comprehensive needs of these children. Results. The findings of the review are that congenital heart disease can have ...
ASPIRIN LINKED TO CHILDREN'S DISEASE
There is growing concern in the medical profession about a link between aspirin and a rare but sometimes deadly children's disease called Reye's Syndrome.
In the last six years, Government agencies have released studies and issued guarded warnings, hoping to alert the public to the potential danger without causing undue alarm. But as each new case of Reye's Syndrome is recorded, the pressure builds on Government agencies to take stronger action.
The American Academy of Pediatricians has now decided to issue its own warning to its 23,000 members. Its June issue of Pediatrics, the academy's technical journal, will advise members not to prescribe aspirin or aspirin compounds to children suffering influenza symptoms or chicken pox. The recommendation, similar to those issued by the Centers for Disease Control in Atlanta, is based on evidence linking 137 cases of Reye's Syndrome to children who were administered aspirin in previous bouts with flu or chicken pox.
Ralph Nader's Health Research Group and the American Public Health Association have expressed concern with the way the Food and Drug Administration is exercising its regulatory authority. The two groups have individually petitioned the F.D.A. to require warning labels on children's aspirin, and both have threatened legal action if the agency does not respond by Friday.
In the last six years, Government agencies have released studies and issued guarded warnings, hoping to alert the public to the potential danger without causing undue alarm. But as each new case of Reye's Syndrome is recorded, the pressure builds on Government agencies to take stronger action.
The American Academy of Pediatricians has now decided to issue its own warning to its 23,000 members. Its June issue of Pediatrics, the academy's technical journal, will advise members not to prescribe aspirin or aspirin compounds to children suffering influenza symptoms or chicken pox. The recommendation, similar to those issued by the Centers for Disease Control in Atlanta, is based on evidence linking 137 cases of Reye's Syndrome to children who were administered aspirin in previous bouts with flu or chicken pox.
Ralph Nader's Health Research Group and the American Public Health Association have expressed concern with the way the Food and Drug Administration is exercising its regulatory authority. The two groups have individually petitioned the F.D.A. to require warning labels on children's aspirin, and both have threatened legal action if the agency does not respond by Friday.
Children's and young people's experiences of chronic renal disease
The aims of this paper were to review and critique existing research literature on children's and young people's experiences of chronic renal disease and to propose alternative approaches that may be more fruitful in addressing existing research shortcomings. Background.
Chronic renal disease, which results in approximately 1·6–4 new cases per year per million population in the 0–15 years age group, is a serious illness that causes severe and irreversible reduction in kidney function. Despite modern medical advances, its significance and implications for the lives of the children and young people concerned are profound. Method.
Salient literature for this review was obtained using the major health and social science electronic databases such as Medline, CINAHL, Psyclit and Sociofile. Manual searching of relevant books, journals and `grey literature', combined with the genealogy approach, extended and strengthened the search. Conclusions.
Research in this area focuses mainly on two areas, namely psychological adjustment and adaptation to end-stage renal disease. This research is grounded within a framework of empirical psychology that values objectivity, measurement and quantification. This predominantly psychometric approach is critiqued for simplifying the complex experience of end-stage renal disease and for pathologizing children and young people with this disease. We identify a significant gap in the research literature, namely the lack of research that takes into account these children's and young peoples'own perspectives of their experiences. Relevance to clinical practice.
Chronic renal disease has a significant impact on children's and young people's lives. Understanding the experiences of these children is important for the provision of effective healthcare. Conducting child-centred qualitative research in this area would allow us to explore vital questions of meaning, perception and understanding. If health and social care organizations claim to provide `consumer-focused' services, it behoves us to develop first a clearer understanding of the lives and experiences of children and families who seek our help and to use this knowledge and understanding to plan and provide more grounded and responsive services.
Chronic renal disease, which results in approximately 1·6–4 new cases per year per million population in the 0–15 years age group, is a serious illness that causes severe and irreversible reduction in kidney function. Despite modern medical advances, its significance and implications for the lives of the children and young people concerned are profound. Method.
Salient literature for this review was obtained using the major health and social science electronic databases such as Medline, CINAHL, Psyclit and Sociofile. Manual searching of relevant books, journals and `grey literature', combined with the genealogy approach, extended and strengthened the search. Conclusions.
Research in this area focuses mainly on two areas, namely psychological adjustment and adaptation to end-stage renal disease. This research is grounded within a framework of empirical psychology that values objectivity, measurement and quantification. This predominantly psychometric approach is critiqued for simplifying the complex experience of end-stage renal disease and for pathologizing children and young people with this disease. We identify a significant gap in the research literature, namely the lack of research that takes into account these children's and young peoples'own perspectives of their experiences. Relevance to clinical practice.
Chronic renal disease has a significant impact on children's and young people's lives. Understanding the experiences of these children is important for the provision of effective healthcare. Conducting child-centred qualitative research in this area would allow us to explore vital questions of meaning, perception and understanding. If health and social care organizations claim to provide `consumer-focused' services, it behoves us to develop first a clearer understanding of the lives and experiences of children and families who seek our help and to use this knowledge and understanding to plan and provide more grounded and responsive services.
A Personal Touch On ... Celiac Disease
Edited by Peter R. Berlin and Jerry Stone; 341 pages. From the book cover: "The #1 Misdiagnosed Intestinal Disorder. Millions have it and don't know it. Could you be one of them? Learn from others' experiences."
Like sitting in a support group or reading messages on online bulletin boards -- where, in fact, many of these stories originated -- reading this book involves listening to the voices of those affected by Celiac Disease as they tell their stories, share their
* Sometimes moving, sometimes humorous, always personal stories
* Perspectives from children, teens, parents, adults and seniors
* Easy-to-read book filled with short essays and poems
* If you or a loved one have Celiac Disease, this book will make you feel less alone
* If you're undiagnosed but suspicious, this book will spur you to get tested
Cons
* Not much really hard information on Celiac Disease or gluten-free diets
* Quite a bit of repetition from one story to another
* You could save the cost of the book and read most of this on online message boards
* Does have good information for parents, but majority of stories are of adults with celiac
Description
* Chapter 1: Finding Out What's Wrong
* Chapter 2: Celiac: An Inherited Disease
* Chapter 3: My New Life
Chapter 4: Living with Celiac
* Chapter 5: My Child Has Celiac
* Chapter 6: Making It Easier for Our Children
* Chapter 7: Being a Teen with Celiac
* Chapter 8: Senior Celiacs
Chapter 9: Success with Celiac
* Chapter 10: Travel Tales
* Chapter 11: Recipes for Success
* Chapter 12: Tips, Tricks and Smiles
Like sitting in a support group or reading messages on online bulletin boards -- where, in fact, many of these stories originated -- reading this book involves listening to the voices of those affected by Celiac Disease as they tell their stories, share their
* Sometimes moving, sometimes humorous, always personal stories
* Perspectives from children, teens, parents, adults and seniors
* Easy-to-read book filled with short essays and poems
* If you or a loved one have Celiac Disease, this book will make you feel less alone
* If you're undiagnosed but suspicious, this book will spur you to get tested
Cons
* Not much really hard information on Celiac Disease or gluten-free diets
* Quite a bit of repetition from one story to another
* You could save the cost of the book and read most of this on online message boards
* Does have good information for parents, but majority of stories are of adults with celiac
Description
* Chapter 1: Finding Out What's Wrong
* Chapter 2: Celiac: An Inherited Disease
* Chapter 3: My New Life
Chapter 4: Living with Celiac
* Chapter 5: My Child Has Celiac
* Chapter 6: Making It Easier for Our Children
* Chapter 7: Being a Teen with Celiac
* Chapter 8: Senior Celiacs
Chapter 9: Success with Celiac
* Chapter 10: Travel Tales
* Chapter 11: Recipes for Success
* Chapter 12: Tips, Tricks and Smiles
Parental Smoking and Middle Ear Disease in Children
This report presents a detailed review of the available epidemiological evidence concerning the prevalence of middle ear infections in children in relation to their exposure to smoking by their parents or other household members and is based on English-language papers covering the period 1979-1998. Fifty-eight studies are included in the review, with the most widely used index of exposure being parental smoking. Smoking by all household members, by either parent separately and by the mother during pregnancy were also considered in some of the studies. Only 3 studies attempted to quantify exposure objectively, using measurements of cotinine and nicotine in hair, saliva and pericardial fluid. Tables listing unadjusted and adjusted relative risk estimates were constructed for both postnatal exposure to tobacco smoke and for maternal smoking during pregnancy. The results for postnatal exposure were separated into five disease categories. The overall data suggested some association of postnatal exposure to tobacco smoke with three categories; recurrent otitis media, otitis media with effusion and unspecified middle ear disease, with risk tending to increase with increasing exposure, but no association with acute otitis media or with persistent otitis media with effusion. However, reported associations were generally quite weak, with relative risks typically below 1.5. Problems in interpreting the data arise from the difficulty of distinguishing possible effects of environmental tobacco smoke and of maternal smoking during pregnancy (for which the data also suggest an association), the possibility that the underlying cause of middle ear disease is in fact an infection, and from the various possibilities of bias inherent in epidemiological studies of a weak association, particularly due to inadequate control of confounding. Though it is prudent for parents not to expose their children to high doses of environmental tobacco smoke for long periods, the overall epidemiological evidence does not convincingly demonstrate that exposure to environmental tobacco smoke increases the incidence of middle ear diseases in children.
Meningococcal disease and its management in children
Meningococcal disease produces a considerable global burden of disease. In this clinical review we focus mainly on meningococcal disease in the United Kingdom, but we also acknowledge the wider issues across the world. Meningococcal disease, which may present clinically as septicaemia, as meningitis, or with a mixed picture, is caused by infection with Neisseria meningitidis or meningococcus.
Recent advances include greater knowledge about the pathogenesis of meningococcal disease, work to facilitate its early diagnosis, and some evidence of improved outcomes after meningococcal disease. Despite these advances, valid evidence from large controlled studies is scarce, so most recommendations are based on consensus or tradition rather than on firm scientific evidence.
Description of the disease only as "meningitis" is inaccurate and misleading to patients and professionals. Septicaemia is the more dangerous clinical syndrome,1 which needs urgent treatment; meningitis also needs rapid treatment but is more likely to lead to neurodevelopmental sequelae. In . . .
Recent advances include greater knowledge about the pathogenesis of meningococcal disease, work to facilitate its early diagnosis, and some evidence of improved outcomes after meningococcal disease. Despite these advances, valid evidence from large controlled studies is scarce, so most recommendations are based on consensus or tradition rather than on firm scientific evidence.
Description of the disease only as "meningitis" is inaccurate and misleading to patients and professionals. Septicaemia is the more dangerous clinical syndrome,1 which needs urgent treatment; meningitis also needs rapid treatment but is more likely to lead to neurodevelopmental sequelae. In . . .
Growth hormone for children with chronic kidney disease
Dushyanthi Vimalachandra2, Elisabeth M Hodson1, Narelle S Willis3, Jonathan C Craig1, Christopher T Cowell4, John F Knight5
1Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia. 2Kids Health, The Children's Hospital at Westmead, Westmead, Australia. 3Cochrane Renal Group, The Children's Hospital at Westmead, Westmead, Australia. 4Institute of Endocrinology, Children's Hospital at Westmead, Westmead, Australia. 5Regional Head, Benefit Risk Management Asia Pacific, Johnson & Johnson Pharmaceutical Research & Development, North Ryde, Australia
Contact address: Elisabeth M Hodson, Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. Elisah@chw.edu.au. (Editorial group: Cochrane Renal Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD003264.pub2
This version first published online: 19 July 2006 in Issue 3, 2006. Re-published online with edits: 21 January 2009 in Issue 1, 2009. Last assessed as up-to-date: 21 May 2006. (Help document - Dates and Statuses explained).
This record should be cited as: Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell CT, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003264. DOI: 10.1002/14651858.CD003264.pub2.
1Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia. 2Kids Health, The Children's Hospital at Westmead, Westmead, Australia. 3Cochrane Renal Group, The Children's Hospital at Westmead, Westmead, Australia. 4Institute of Endocrinology, Children's Hospital at Westmead, Westmead, Australia. 5Regional Head, Benefit Risk Management Asia Pacific, Johnson & Johnson Pharmaceutical Research & Development, North Ryde, Australia
Contact address: Elisabeth M Hodson, Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. Elisah@chw.edu.au. (Editorial group: Cochrane Renal Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD003264.pub2
This version first published online: 19 July 2006 in Issue 3, 2006. Re-published online with edits: 21 January 2009 in Issue 1, 2009. Last assessed as up-to-date: 21 May 2006. (Help document - Dates and Statuses explained).
This record should be cited as: Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell CT, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003264. DOI: 10.1002/14651858.CD003264.pub2.
Growth hormone for children with chronic kidney disease
Dushyanthi Vimalachandra2, Elisabeth M Hodson1, Narelle S Willis3, Jonathan C Craig1, Christopher T Cowell4, John F Knight5
1Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia. 2Kids Health, The Children's Hospital at Westmead, Westmead, Australia. 3Cochrane Renal Group, The Children's Hospital at Westmead, Westmead, Australia. 4Institute of Endocrinology, Children's Hospital at Westmead, Westmead, Australia. 5Regional Head, Benefit Risk Management Asia Pacific, Johnson & Johnson Pharmaceutical Research & Development, North Ryde, Australia
Contact address: Elisabeth M Hodson, Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. Elisah@chw.edu.au. (Editorial group: Cochrane Renal Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD003264.pub2
This version first published online: 19 July 2006 in Issue 3, 2006. Re-published online with edits: 21 January 2009 in Issue 1, 2009. Last assessed as up-to-date: 21 May 2006. (Help document - Dates and Statuses explained).
This record should be cited as: Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell CT, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003264. DOI: 10.1002/14651858.CD003264.pub2.
1Centre for Kidney Research, The Children's Hospital at Westmead, Westmead, Australia. 2Kids Health, The Children's Hospital at Westmead, Westmead, Australia. 3Cochrane Renal Group, The Children's Hospital at Westmead, Westmead, Australia. 4Institute of Endocrinology, Children's Hospital at Westmead, Westmead, Australia. 5Regional Head, Benefit Risk Management Asia Pacific, Johnson & Johnson Pharmaceutical Research & Development, North Ryde, Australia
Contact address: Elisabeth M Hodson, Centre for Kidney Research, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia. Elisah@chw.edu.au. (Editorial group: Cochrane Renal Group.)
Cochrane Database of Systematic Reviews, Issue 1, 2009 (Status in this issue: Edited)
Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DOI: 10.1002/14651858.CD003264.pub2
This version first published online: 19 July 2006 in Issue 3, 2006. Re-published online with edits: 21 January 2009 in Issue 1, 2009. Last assessed as up-to-date: 21 May 2006. (Help document - Dates and Statuses explained).
This record should be cited as: Vimalachandra D, Hodson EM, Willis NS, Craig JC, Cowell CT, Knight JF. Growth hormone for children with chronic kidney disease. Cochrane Database of Systematic Reviews 2006, Issue 3. Art. No.: CD003264. DOI: 10.1002/14651858.CD003264.pub2.
Trace Amounts of Gluten Acceptable in the Treatment of Celiac Disease
Alimentary Pharmacology & Therapeutics, Volume 19 Issue 12 Page 1277 - June 2004
Celiac.com 06/28/2004 – According to celiac disease researchers gluten contamination in gluten-free products cannot be totally avoided. With this in mind they set out to determine the safe threshold of gluten in the diets of those with celiac disease. To determine this level they measured the gluten content of 59 naturally gluten-free and 24 Codex quality wheat starch-based gluten-free products using the enzyme-linked immunosorbent assay test. The daily intake of flours was calculated in 76 adults on gluten-free diets and was then compared with their biopsies (mucosal histology). The researchers found that 13 of the 59 naturally gluten-free products and 11 of 24 Codex quality wheat starch-based gluten-free products contained gluten in the amount of 20 to 200 ppm (=mg/kg). The average flour intake for the group was 80g, and this ranged between 10g at the low end, and 300g on the high end.
The researchers conclude that the threshold for gluten in the diets of those with celiac disease can safely be set at 100 ppm. Even those in the study who consumed flour at the high end--300g per day with a gluten level of 100 ppm--only consumed 30mg of gluten per day. The researchers determined that this level was safe when correlated to their histology in both clinical and challenge studies. Last, this level can be achieved by the food industry, will not make the diet too cumbersome, and will have the additional benefit of encouraging additional food companies to get into the gluten-free food market.
Celiac.com 06/28/2004 – According to celiac disease researchers gluten contamination in gluten-free products cannot be totally avoided. With this in mind they set out to determine the safe threshold of gluten in the diets of those with celiac disease. To determine this level they measured the gluten content of 59 naturally gluten-free and 24 Codex quality wheat starch-based gluten-free products using the enzyme-linked immunosorbent assay test. The daily intake of flours was calculated in 76 adults on gluten-free diets and was then compared with their biopsies (mucosal histology). The researchers found that 13 of the 59 naturally gluten-free products and 11 of 24 Codex quality wheat starch-based gluten-free products contained gluten in the amount of 20 to 200 ppm (=mg/kg). The average flour intake for the group was 80g, and this ranged between 10g at the low end, and 300g on the high end.
The researchers conclude that the threshold for gluten in the diets of those with celiac disease can safely be set at 100 ppm. Even those in the study who consumed flour at the high end--300g per day with a gluten level of 100 ppm--only consumed 30mg of gluten per day. The researchers determined that this level was safe when correlated to their histology in both clinical and challenge studies. Last, this level can be achieved by the food industry, will not make the diet too cumbersome, and will have the additional benefit of encouraging additional food companies to get into the gluten-free food market.
Commercial Tissue Transglutaminase (tTG) Lab Screenings May Miss Many Cases of Celiac Disease
Celiac.com 12/12/2004 - A new study that was presented on November 1, 2004 by Julian Abrams, MD, and colleagues from Columbia University Medical Center in New York City at the American College of Gastroenterology (ACG) 69th Annual Scientific Meeting indicates that using only antibody to tissue transglutaminase (tTG) to diagnose celiac disease will likely result in missed diagnoses—and the accuracy of the tTG results depends on which lab conducts the test. Many clinical studies during the past few years have indicated that tTG testing is as accurate as endomyosial antibody (EMA), which has caused many labs to use tTG rather than EMA, and even the recent National Institutes of Health Consensus Conference on Celiac Disease advocated the use of tTG over EMA.
In the study the researchers evaluated the effectiveness of tTG in a general referral practice medical setting by reviewing 137 patients who had duodenal biopsy and tTG testing for celiac disease, out of which 117 were biopsy confirmed. serum from these individuals was sent to four different commercial laboratories for analysis, and the results from these labs were compared. The average tTG sensitivity overall was 71% with a specificity of 67%. In patients with total villous atrophy sensitivity was as high as 92%, and in those with only partial villous atrophy it was as low as 38%. One of the four laboratories tested samples from 48 of the patients and their sensitivity was only 51%, while the specificity was 100%.
According to these results it appears that tTG testing—at least outside of the clinical study setting—may not be accurate, and its accuracy depends heavily on which lab is used. Unfortunately the researchers did not reveal the names of the commercial laboratories used in their study, but we hope they will do so when the study is published.
In the study the researchers evaluated the effectiveness of tTG in a general referral practice medical setting by reviewing 137 patients who had duodenal biopsy and tTG testing for celiac disease, out of which 117 were biopsy confirmed. serum from these individuals was sent to four different commercial laboratories for analysis, and the results from these labs were compared. The average tTG sensitivity overall was 71% with a specificity of 67%. In patients with total villous atrophy sensitivity was as high as 92%, and in those with only partial villous atrophy it was as low as 38%. One of the four laboratories tested samples from 48 of the patients and their sensitivity was only 51%, while the specificity was 100%.
According to these results it appears that tTG testing—at least outside of the clinical study setting—may not be accurate, and its accuracy depends heavily on which lab is used. Unfortunately the researchers did not reveal the names of the commercial laboratories used in their study, but we hope they will do so when the study is published.
Anti-Tissue Transglutaminase (tTG) Antibodies Also Found in Inflammatory Bowel Disease
Celiac.com 01/22/2005 - A study by Italian researchers has found that anti-tissue transglutaminase (tTG) antibodies, once considered to be identical to anti-endomysial antibodies (EMA) in celiac disease, can also be found in patients with inflammatory bowel disease. The researchers looked at serum and intestinal tTG levels in 49 patients with Crohns disease, 29 patients with ulcerative colitis, 45 patients with celiac disease, 85 autoimmune patients as disease controls, and 58 volunteers as healthy controls. Additionally, immunoglobulin A (IgA) anti-recombinant human tissue transglutaminase and anti-endomysial antibody detection in sera and fecal supernatants, along with adsorption of positive sera with recombinant human tissue transglutaminase, were performed on all patients.
The researchers detected an increase in tTG concentration in all patients with celiac disease, and also low positive values in those with Crohns disease and ulcerative colitis, however the EMA were only detected in those with celiac disease. According to the researchers, the "Data highlight that both circulating and intestinal anti-tissue transglutaminases are detectable in inflammatory bowel disease, and that they are related to disease activity. These features underline that, in addition to anti-tissue transglutaminase, an anti-endomysial antibody test is necessary in the diagnostic work-up of celiac sprue, especially in patients with known inflammatory bowel disease."
This study supports others that have found that the sole use of tTG to diagnose celiac disease may lead to misdiagnoses, and EMA testing must be performed to make an accurate celiac disease diagnosis.
The researchers detected an increase in tTG concentration in all patients with celiac disease, and also low positive values in those with Crohns disease and ulcerative colitis, however the EMA were only detected in those with celiac disease. According to the researchers, the "Data highlight that both circulating and intestinal anti-tissue transglutaminases are detectable in inflammatory bowel disease, and that they are related to disease activity. These features underline that, in addition to anti-tissue transglutaminase, an anti-endomysial antibody test is necessary in the diagnostic work-up of celiac sprue, especially in patients with known inflammatory bowel disease."
This study supports others that have found that the sole use of tTG to diagnose celiac disease may lead to misdiagnoses, and EMA testing must be performed to make an accurate celiac disease diagnosis.
Saliva and Fecal Antibody Testing in Celiac Disease
Celiac.com 02/09/2005 – The following abstract supports the use of fecal scIgA AGA combined with fecal IgA AGA, IgG AGA and IgM AGA to diagnose celiac disease, as they may be detected there even before they can be in the blood of celiac patients. This research adds support for the use of fecal testing as an early diagnostic tool, and perhaps also supports the work that has been done in this area by doctors like Kenneth Fine.
Clin Lab. 2004;50(9-10):551-7.
Comparison of different salivary and fecal antibodies for the diagnosis of celiac disease. Halblaub JM, Renno J, Kempf A, Bartel J, Schmidt-Gayk H.
Clin Lab. 2004;50(9-10):551-7.
ABSTRACT: To investigate the detectability and expressiveness of salivary and fecal anti-gliadin (AGA), anti-endomysium (EMA) and anti-tissue-transglutaminase (ATA) antibodies, 127 salivary and 160 fecal samples of healthy volunteers and salivary and fecal samples of 17 patients with histologically proven and 9 patients with suggested celiac disease were investigated in this study. With all salivary parameters and fecal IgA AGA, IgM AGA, IgA EMA and IgG EMA, healthy volunteers and patients showed partially overlapping results. The most promising results in our study with higher concentrations in patients with celiac disease were obtained by fecal scIgA AGA and a combined determination of fecal IgA AGA, IgG AGA and IgM AGA. Further investigations should be performed with fecal IgA EMA and scIgA ATA based on human recombinant tissue-transglutaminase. One patient with histologically proven celiac disease had normal serological but high fecal scIgA AGA and scIgA ATA values. This patient emphasizes the importance of fecal antibody determination for the diagnosis of celiac disease, at least in patients with suggested celiac disease and negative serum antibodies.
Clin Lab. 2004;50(9-10):551-7.
Comparison of different salivary and fecal antibodies for the diagnosis of celiac disease. Halblaub JM, Renno J, Kempf A, Bartel J, Schmidt-Gayk H.
Clin Lab. 2004;50(9-10):551-7.
ABSTRACT: To investigate the detectability and expressiveness of salivary and fecal anti-gliadin (AGA), anti-endomysium (EMA) and anti-tissue-transglutaminase (ATA) antibodies, 127 salivary and 160 fecal samples of healthy volunteers and salivary and fecal samples of 17 patients with histologically proven and 9 patients with suggested celiac disease were investigated in this study. With all salivary parameters and fecal IgA AGA, IgM AGA, IgA EMA and IgG EMA, healthy volunteers and patients showed partially overlapping results. The most promising results in our study with higher concentrations in patients with celiac disease were obtained by fecal scIgA AGA and a combined determination of fecal IgA AGA, IgG AGA and IgM AGA. Further investigations should be performed with fecal IgA EMA and scIgA ATA based on human recombinant tissue-transglutaminase. One patient with histologically proven celiac disease had normal serological but high fecal scIgA AGA and scIgA ATA values. This patient emphasizes the importance of fecal antibody determination for the diagnosis of celiac disease, at least in patients with suggested celiac disease and negative serum antibodies.
Tissue Transglutaminase Antibody Screening May Replace the Biopsy in the Diagnosis of Celiac Disease
Pediatrics 2005;115:1341-1346.
Celiac.com 05/31/2005 – According to Canadian researchers, the use of Tissue transglutaminase antibody (tTG) Screening may soon replace the use of the small bowel biopsy to diagnose celiac disease in children. The researchers reviewed the charts of 103 children who were screened for celiac disease using both small bowel biopsy and tTG. Fifty-eight of the children were found to have positive biopsy results, and out of these, 48 had very high tTG levels (over 100 U), 7 had middle tTG levels (20-100 U), and 3 had low levels (less than 20 U). Out of the 49 children with the highest tTG levels, all but one of them had a positive biopsy result. There were 3 biopsy-positive children who had low tTG levels, two who were found to be IgA negative, and one who had a duodenal ulcer.
According to the researchers, using tTG values of greater than 100 U and less than 20 U, and knowing the patients IgA status, tTG testing was "98% sensitive and 97% specific in detecting celiac disease." The researchers also point out that the cost of diagnosis could be cut by 30% by utilizing tTG screening. The researchers conclude that children with high tTG titers can proceed straight to a gluten-free diet--if they respond well then their diagnosis is confirmed—if not they can proceed to a biopsy.
Although the authors dont address this issue specifically, this method would likely lead to an increase in the diagnosis rate of celiac disease, as many people are unwilling to undergo a biopsy--or have their children undergo one.
Celiac.com 05/31/2005 – According to Canadian researchers, the use of Tissue transglutaminase antibody (tTG) Screening may soon replace the use of the small bowel biopsy to diagnose celiac disease in children. The researchers reviewed the charts of 103 children who were screened for celiac disease using both small bowel biopsy and tTG. Fifty-eight of the children were found to have positive biopsy results, and out of these, 48 had very high tTG levels (over 100 U), 7 had middle tTG levels (20-100 U), and 3 had low levels (less than 20 U). Out of the 49 children with the highest tTG levels, all but one of them had a positive biopsy result. There were 3 biopsy-positive children who had low tTG levels, two who were found to be IgA negative, and one who had a duodenal ulcer.
According to the researchers, using tTG values of greater than 100 U and less than 20 U, and knowing the patients IgA status, tTG testing was "98% sensitive and 97% specific in detecting celiac disease." The researchers also point out that the cost of diagnosis could be cut by 30% by utilizing tTG screening. The researchers conclude that children with high tTG titers can proceed straight to a gluten-free diet--if they respond well then their diagnosis is confirmed—if not they can proceed to a biopsy.
Although the authors dont address this issue specifically, this method would likely lead to an increase in the diagnosis rate of celiac disease, as many people are unwilling to undergo a biopsy--or have their children undergo one.
Distal Duodenum and Jejunum Biopsies: Does the Test Site Affect Accuracy in Diagnosing Celiac Disease?
Am J Gastroenterol. 2005 Jan;100(1):177-85
Celiac.com 06/30/2005 – In order to determine whether celiac disease mucosal lesions may have a patchy distribution that would require more than one biopsy sample to make an accurate celiac disease diagnosis, Italian researchers closely examined the detailed biopsies taken from 112 consecutively diagnosed children. All of the children in the study had positive anti-endomysium (EMA) or anti-tissue transglutaminase (tTGA) antibodies, and each underwent an upper GI endoscopy in which 4-5 biopsies were taken from Treitz and/or distal duodenum, intermediate duodenum, proximal duodenum, and the duodenal bulb. All biopsies were then classified according to the Marsh criteria. The researchers diagnosed 110 or the 112 patients with celiac disease, and none of the biopsies taken from these children appeared normal. All those diagnosed were positive for HLA-DQ2 or DQ8 genetic markers.
The researchers conclude that: “Mucosal atrophy is present in 85% of patients with celiac disease and total villous atrophy is significantly more frequent in distal duodenum or proximal jejunum. Fifty percent of patients have identical villous atrophy throughout the duodenum and no duodenal areas are histologically normal. In genetically susceptible children with positive serology, a diagnosis of celiac disease can reliably be made even if biopsies are not taken from the distal duodenum or jejunum.”
Celiac.com 06/30/2005 – In order to determine whether celiac disease mucosal lesions may have a patchy distribution that would require more than one biopsy sample to make an accurate celiac disease diagnosis, Italian researchers closely examined the detailed biopsies taken from 112 consecutively diagnosed children. All of the children in the study had positive anti-endomysium (EMA) or anti-tissue transglutaminase (tTGA) antibodies, and each underwent an upper GI endoscopy in which 4-5 biopsies were taken from Treitz and/or distal duodenum, intermediate duodenum, proximal duodenum, and the duodenal bulb. All biopsies were then classified according to the Marsh criteria. The researchers diagnosed 110 or the 112 patients with celiac disease, and none of the biopsies taken from these children appeared normal. All those diagnosed were positive for HLA-DQ2 or DQ8 genetic markers.
The researchers conclude that: “Mucosal atrophy is present in 85% of patients with celiac disease and total villous atrophy is significantly more frequent in distal duodenum or proximal jejunum. Fifty percent of patients have identical villous atrophy throughout the duodenum and no duodenal areas are histologically normal. In genetically susceptible children with positive serology, a diagnosis of celiac disease can reliably be made even if biopsies are not taken from the distal duodenum or jejunum.”
Finger-Stick Rapid Test Kit for Celiac Disease and Gluten Intolerance Now Available
Celiac.com 11/08/2005 - Today a team of scientists at Alba Therapeutics Corporation (Alba) and the University of Maryland School of Medicine reported a direct link between gluten-induced intestinal permeability and zonulin in tissues from patients with celiac disease. The investigators were able to successfully prevent gluten-induced intestinal tissue leak with the administration of the zonulin antagonist FZI/0 (AT-1001). AT-1001 is an orally administered peptide currently under development for the treatment of celiac disease.
Published in the November issue of the Scandinavian Journal of Gastroenterology, these results describe the role that leaky gut plays in celiac disease and the role that zonulin plays in establishing the leak. These results are another milestone towards understanding the role of zonulin in celiac disease, says Alessio Fasano, M.D., lead author of the paper, professor of pediatrics, medicine and physiology at the University of Maryland School of Medicine and director of its Center for Celiac Research.
These results reinforce our conviction that AT-1001 has great therapeutic potential and we look forward to confirming these observations in celiac patients soon, stated Alba CEO Dr. Blake M. Paterson.
About Zonulin
Zonulin is a signaling protein that transiently and reversibly opens the tight junctions (tj) between the cells of epithelial and endothelial tissues such as the intestinal mucosa, blood brain barrier and pulmonary epithelia. Zonulin appears to be involved in many diseases in which leakage occurs via paracellular transport across epithelial and endothelial tight junctions (tj),
and thus may play an important potential role in the treatment of autoimmune diseases.
About Celiac Disease
Celiac disease is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. According to the National Institutes of Health, celiac disease affects approximately 3 million Americans, although the diagnosis is rarely made. The only treatment for celiac disease is complete elimination of gluten from the diet, which results in remission for some patients.
About Alba
Alba Therapeutics Corporation is a privately held biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Albas lead molecule, AT-1001, is targeted towards the treatment of celiac disease and other auto-immune illnesses.
Contact: Dr. Blake Paterson
Alba Therapeutics Corporation
(410) 522-8708
Published in the November issue of the Scandinavian Journal of Gastroenterology, these results describe the role that leaky gut plays in celiac disease and the role that zonulin plays in establishing the leak. These results are another milestone towards understanding the role of zonulin in celiac disease, says Alessio Fasano, M.D., lead author of the paper, professor of pediatrics, medicine and physiology at the University of Maryland School of Medicine and director of its Center for Celiac Research.
These results reinforce our conviction that AT-1001 has great therapeutic potential and we look forward to confirming these observations in celiac patients soon, stated Alba CEO Dr. Blake M. Paterson.
About Zonulin
Zonulin is a signaling protein that transiently and reversibly opens the tight junctions (tj) between the cells of epithelial and endothelial tissues such as the intestinal mucosa, blood brain barrier and pulmonary epithelia. Zonulin appears to be involved in many diseases in which leakage occurs via paracellular transport across epithelial and endothelial tight junctions (tj),
and thus may play an important potential role in the treatment of autoimmune diseases.
About Celiac Disease
Celiac disease is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. According to the National Institutes of Health, celiac disease affects approximately 3 million Americans, although the diagnosis is rarely made. The only treatment for celiac disease is complete elimination of gluten from the diet, which results in remission for some patients.
About Alba
Alba Therapeutics Corporation is a privately held biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Albas lead molecule, AT-1001, is targeted towards the treatment of celiac disease and other auto-immune illnesses.
Contact: Dr. Blake Paterson
Alba Therapeutics Corporation
(410) 522-8708
FDA Approves Clinical Trial of BioBalance Corporation's Probactrix for Possible Celiac Disease Treatment
Celiac.com 12/27/2005 - The BioBalance Corp. (BioBalance), a wholly owned subsidiary of New York Health Care (OTC BB: BBAL), announced today that it has received approval to begin a small-scale clinical trial of its proprietary biotherapeutic agent, Probactrix, in the dietary management of patients with celiac disease, a chronic disorder of the gastrointestinal (GI) tract.
The Company also announced that it has responded to the U.S. Food and Drug Administration (FDA) regarding questions received earlier this year on the Companys Investigational New Drug (IND) application for Probactrix as a prescription drug for pouchitis, a frequent complication following bowel surgery.
The pilot study for celiac will take place at Rambam Medical Center in Haifa, Israel. Dr. Rami Eliakim, the Centers Director of Gastroenterology, is the principal investigator. The study will be conducted in approximately 38 celiac patients to demonstrate the ability of a medical food formulation of Probactrix to modify the bacterial flora in the GI tract and improve quality of life. Probactrix has been proven to displace pathogenic bacteria in the GI tract and prevent their re-colonization, restoring and maintaining a healthy balance of intestinal flora without the potential negative consequences of antibiotic use.
We are very excited to have approval to initiate this celiac study and to have provided a comprehensive response to FDA questions on our pouchitis IND, said Dennis ODonnell, BioBalances President and CEO.
Celiac disease is an inherited condition where gluten proteins found in grains trigger an immune system attack on the lining of the small intestine. While celiac disease is rarely life threatening, it is a life altering disorder with symptoms such as diarrhea, fatigue, nausea and weight loss. Celiac is also linked to other autoimmune disorders and is now believed to lead to osteoporosis, anemia, infertility and cancer if left untreated. Diagnosis is often difficult because of the range of GI symptoms. A 2001 survey found that celiac patients in the U.S. suffer for 11 years on average before they are successfully diagnosed. Estimates from the NIH indicate that as many as one in 100 Americans have celiac disease, with significantly higher levels found in Finland, Italy, Ireland and Israel.
Dr. Robert Hoerr, BioBalances Vice President of Medical & Regulatory Affairs, commented, Recent studies have identified a potential link between the overgrowth of pathogenic bacteria in the gastrointestinal tract and the symptoms of celiac disease. We are pleased to participate in this study, which will test the use of Probactrix as a means of modifying the bacterial flora in the GI tract and its impact on quality of life for these individuals.
Contacts:
Dennis ODonnell
CEO
The BioBalance Corp
Tel: (212) 679-7778
Fax: (212) 679-7774
Stanley Wunderlich
CEO
Consulting For Strategic Growth
Tel: (800) 625-2236
Fax: (212)337-8089
The Company also announced that it has responded to the U.S. Food and Drug Administration (FDA) regarding questions received earlier this year on the Companys Investigational New Drug (IND) application for Probactrix as a prescription drug for pouchitis, a frequent complication following bowel surgery.
The pilot study for celiac will take place at Rambam Medical Center in Haifa, Israel. Dr. Rami Eliakim, the Centers Director of Gastroenterology, is the principal investigator. The study will be conducted in approximately 38 celiac patients to demonstrate the ability of a medical food formulation of Probactrix to modify the bacterial flora in the GI tract and improve quality of life. Probactrix has been proven to displace pathogenic bacteria in the GI tract and prevent their re-colonization, restoring and maintaining a healthy balance of intestinal flora without the potential negative consequences of antibiotic use.
We are very excited to have approval to initiate this celiac study and to have provided a comprehensive response to FDA questions on our pouchitis IND, said Dennis ODonnell, BioBalances President and CEO.
Celiac disease is an inherited condition where gluten proteins found in grains trigger an immune system attack on the lining of the small intestine. While celiac disease is rarely life threatening, it is a life altering disorder with symptoms such as diarrhea, fatigue, nausea and weight loss. Celiac is also linked to other autoimmune disorders and is now believed to lead to osteoporosis, anemia, infertility and cancer if left untreated. Diagnosis is often difficult because of the range of GI symptoms. A 2001 survey found that celiac patients in the U.S. suffer for 11 years on average before they are successfully diagnosed. Estimates from the NIH indicate that as many as one in 100 Americans have celiac disease, with significantly higher levels found in Finland, Italy, Ireland and Israel.
Dr. Robert Hoerr, BioBalances Vice President of Medical & Regulatory Affairs, commented, Recent studies have identified a potential link between the overgrowth of pathogenic bacteria in the gastrointestinal tract and the symptoms of celiac disease. We are pleased to participate in this study, which will test the use of Probactrix as a means of modifying the bacterial flora in the GI tract and its impact on quality of life for these individuals.
Contacts:
Dennis ODonnell
CEO
The BioBalance Corp
Tel: (212) 679-7778
Fax: (212) 679-7774
Stanley Wunderlich
CEO
Consulting For Strategic Growth
Tel: (800) 625-2236
Fax: (212)337-8089
Effectiveness of Stool Testing in the Diagnosis of Celiac Disease in Children: With Comments by Dr. Kenneth Fine
Celiac.com 02/27/2006 - Kappler M, Krauss-Etschmann S, Diehl V, Zeilhofer H, Koletzko S. Detection of secretory IgA antibodies against gliadin and human tissue transglutaminase in stool to screen for celiac disease in children: validation study. BMJ. 2006 January 28; 332(7535): 213-14.
Study Abstract:
Objective: To evaluate two commercial stool tests for detection of secretory IgA antibodies against gliadin and human tissue transglutaminase for diagnosis of celiac disease in children with symptoms.
Setting: Tertiary care childrens hospital.
Participants: Coded stool samples from 20 children with newly diagnosed celiac disease and 64 controls. Six children with celiac disease had stool tests every two weeks for three months after starting a gluten-free diet.
Main Outcome Measures: Secretory IgA antibodies against gliadin and human tissue transglutaminase in stool samples, determined in duplicate by using recommended cut-off limits.
Results: Sensitivity of fecal antibodies against human tissue transglutaminase was 10% (95% confidence interval 1% to 32%), and specificity was 98% (91% to 100%). For antibodies against gliadin, sensitivity was 6% (0% to 29%) and specificity was 97% (89% to 100%). Optimisation of cut-off limits by receiver operating characteristic analysis and use of results of both tests increased sensitivity to 82%, but specificity decreased to 58%. All follow-up stool tests remained negative, except for two positive anti-gliadin results in one patient, six and 10 weeks after the gluten-free diet was started.
Conclusions: Neither stool test was suitable for screening for celiac disease in children with symptoms.
Dr. Kenneth Fine Comments on this Study:
Dont Throw the Baby Out With the Bath Water!
Letter to the Editor BMJ
Kamran Rostami, M.D., Ph.D. Department of Medicine, Gloucestershire Royal Hospital Gloucester, UK
Kenneth Fine, M.D. The intestinal Health Institute, Dallas, Texas, USA
We have read with interest the article by Kappler et al recently published in your journal (1) and feel several issues deserve mention. This article is very timely in light of the growing worldwide awareness of immunologic sensitivity to dietary gluten and celiac disease, as well as appreciation of its high prevalence; these facts are driving the need for more widely available, low cost, non-invasive screening tests. Stool testing for these disorders holds great promise for screening because it does not require any invasion of body tissues, is of relatively low cost, and could be widely available combining medical care delivery of such tests with home testing.
While our first criticism of this study is its small cohort size (20 patients), the results are intriguing, but in our opinion have been misinterpreted by the authors. First, there is a potential methodological flaw in this study whereby a serologic method was apparently transferred intact to analyze stool. The aspects of a serologic ELISA method possibly requiring modification for use in stool include but are not limited to: degree to which the sample is diluted prior to analysis; technique and amount of washing of plates during ELISA analysis (because of greater solid contaminant of fecal fluid vs. serum); mathematical conversion of detected optical density to a Unit; and how that calculated Unit is interpreted relative to a normal vs. abnormal cutoff. Utilizing fecal antigliadin and antitissuetransglutaminase IgA antibody testing in this way were reported to be very insensitive (6-10%) but highly specific (97-98%) for celiac disease. Such results should be interpreted as possibly possessing either a misassigned cutoff value (i.e., one that was too high), or possibly introduction of an artificial element that drove fecal antibody concentrations down (such as over-diluting the stool, improper handling or storage of specimens allowing ex vivo destruction of antibody, or centrifuging the stool at the wrong speed driving antibody into the pellet; the authors mentioned destruction of antibody during transit within the GI tract, but antibody is very stable within the GI tract, and has been detected in stool by many authors). Nevertheless, as performed in this study, such a highly specific stool test for celiac disease could be used as a pre-screening test of sorts, able to specifically and non-invasively detect celiac disease, perhaps with a home collected stool specimen. At the worst, 6-10% of celiac patients could be identified even before presenting to a medical institution.
The authors went on to correct a potential cutoff error, using optimization of cut-off limits by receiver operating characteristic analysis, and found that resetting the cut-off value and combining the tests could possess an 82% sensitivity and 58% specificity. Again the authors discounted these findings, in our opinion failing to grasp their importance. Although they did not report the corrected accuracy results of antigliadin test alone, their stool test may have outperformed serum antigliadin antibody, the serologic test in longest use in screening for celiac disease. Many investigators have lost confidence in the presumed lack of specificity of antigliadin antibody alone as a screening test for celiac disease because of the paradigm within which it has been applied, that is, villous atrophic celiac disease. It is also known that its sensitivity is highly dependent on the degree of small intestinal villous atrophy present (2). Most importantly today however, in our opinion, with the wealth of expanding knowledge on the broadening clinical spectrum of gluten-sensitive disorders (3), it should at least have been considered and/or discussed by Kappler et al that in their optimized cut-off analysis, a positive fecal antigliadin antibody may have been a true sign of immunologic sensitivity to gluten either in an evolutionary phase before the onset of villous atrophic celiac disease (4), or in gluten sensitive individuals who may never develop classic celiac disease but who suffer symptoms and associated autoimmune disorders nevertheless. When interpreted in this context, the authors results may have been clinically important. We feel further study of this method with improved attention to methodological issues pertaining to stool, and broader clinical application beyond classic celiac disease is warranted.
References:
1. Kappler M, Krauss-Etschmann S, Diehl V, Zeilhofer H, Koletzko S. Detection of secretory IgA antibodies against gliadin and human tissue transglutaminase in stool to screen for celiac disease in children: validation study. BMJ. 2006 January 28; 332(7535): 213-14.
2. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol. 1999 Apr;94(4):888-94.
3. Ferguson A, Arranz E, OMahony S. Clinical and pathological spectrum of celiac disease--active, silent, latent, potential. Gut. 1993 Feb;34(2):150-1.
4. Arranz E, Ferguson A. jejunal fluid antibodies and mucosal gamma/delta IEL in latent and potential celiac disease. Adv Exp Med Biol. 1995;371B:1345-8.
Study Abstract:
Objective: To evaluate two commercial stool tests for detection of secretory IgA antibodies against gliadin and human tissue transglutaminase for diagnosis of celiac disease in children with symptoms.
Setting: Tertiary care childrens hospital.
Participants: Coded stool samples from 20 children with newly diagnosed celiac disease and 64 controls. Six children with celiac disease had stool tests every two weeks for three months after starting a gluten-free diet.
Main Outcome Measures: Secretory IgA antibodies against gliadin and human tissue transglutaminase in stool samples, determined in duplicate by using recommended cut-off limits.
Results: Sensitivity of fecal antibodies against human tissue transglutaminase was 10% (95% confidence interval 1% to 32%), and specificity was 98% (91% to 100%). For antibodies against gliadin, sensitivity was 6% (0% to 29%) and specificity was 97% (89% to 100%). Optimisation of cut-off limits by receiver operating characteristic analysis and use of results of both tests increased sensitivity to 82%, but specificity decreased to 58%. All follow-up stool tests remained negative, except for two positive anti-gliadin results in one patient, six and 10 weeks after the gluten-free diet was started.
Conclusions: Neither stool test was suitable for screening for celiac disease in children with symptoms.
Dr. Kenneth Fine Comments on this Study:
Dont Throw the Baby Out With the Bath Water!
Letter to the Editor BMJ
Kamran Rostami, M.D., Ph.D. Department of Medicine, Gloucestershire Royal Hospital Gloucester, UK
Kenneth Fine, M.D. The intestinal Health Institute, Dallas, Texas, USA
We have read with interest the article by Kappler et al recently published in your journal (1) and feel several issues deserve mention. This article is very timely in light of the growing worldwide awareness of immunologic sensitivity to dietary gluten and celiac disease, as well as appreciation of its high prevalence; these facts are driving the need for more widely available, low cost, non-invasive screening tests. Stool testing for these disorders holds great promise for screening because it does not require any invasion of body tissues, is of relatively low cost, and could be widely available combining medical care delivery of such tests with home testing.
While our first criticism of this study is its small cohort size (20 patients), the results are intriguing, but in our opinion have been misinterpreted by the authors. First, there is a potential methodological flaw in this study whereby a serologic method was apparently transferred intact to analyze stool. The aspects of a serologic ELISA method possibly requiring modification for use in stool include but are not limited to: degree to which the sample is diluted prior to analysis; technique and amount of washing of plates during ELISA analysis (because of greater solid contaminant of fecal fluid vs. serum); mathematical conversion of detected optical density to a Unit; and how that calculated Unit is interpreted relative to a normal vs. abnormal cutoff. Utilizing fecal antigliadin and antitissuetransglutaminase IgA antibody testing in this way were reported to be very insensitive (6-10%) but highly specific (97-98%) for celiac disease. Such results should be interpreted as possibly possessing either a misassigned cutoff value (i.e., one that was too high), or possibly introduction of an artificial element that drove fecal antibody concentrations down (such as over-diluting the stool, improper handling or storage of specimens allowing ex vivo destruction of antibody, or centrifuging the stool at the wrong speed driving antibody into the pellet; the authors mentioned destruction of antibody during transit within the GI tract, but antibody is very stable within the GI tract, and has been detected in stool by many authors). Nevertheless, as performed in this study, such a highly specific stool test for celiac disease could be used as a pre-screening test of sorts, able to specifically and non-invasively detect celiac disease, perhaps with a home collected stool specimen. At the worst, 6-10% of celiac patients could be identified even before presenting to a medical institution.
The authors went on to correct a potential cutoff error, using optimization of cut-off limits by receiver operating characteristic analysis, and found that resetting the cut-off value and combining the tests could possess an 82% sensitivity and 58% specificity. Again the authors discounted these findings, in our opinion failing to grasp their importance. Although they did not report the corrected accuracy results of antigliadin test alone, their stool test may have outperformed serum antigliadin antibody, the serologic test in longest use in screening for celiac disease. Many investigators have lost confidence in the presumed lack of specificity of antigliadin antibody alone as a screening test for celiac disease because of the paradigm within which it has been applied, that is, villous atrophic celiac disease. It is also known that its sensitivity is highly dependent on the degree of small intestinal villous atrophy present (2). Most importantly today however, in our opinion, with the wealth of expanding knowledge on the broadening clinical spectrum of gluten-sensitive disorders (3), it should at least have been considered and/or discussed by Kappler et al that in their optimized cut-off analysis, a positive fecal antigliadin antibody may have been a true sign of immunologic sensitivity to gluten either in an evolutionary phase before the onset of villous atrophic celiac disease (4), or in gluten sensitive individuals who may never develop classic celiac disease but who suffer symptoms and associated autoimmune disorders nevertheless. When interpreted in this context, the authors results may have been clinically important. We feel further study of this method with improved attention to methodological issues pertaining to stool, and broader clinical application beyond classic celiac disease is warranted.
References:
1. Kappler M, Krauss-Etschmann S, Diehl V, Zeilhofer H, Koletzko S. Detection of secretory IgA antibodies against gliadin and human tissue transglutaminase in stool to screen for celiac disease in children: validation study. BMJ. 2006 January 28; 332(7535): 213-14.
2. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol. 1999 Apr;94(4):888-94.
3. Ferguson A, Arranz E, OMahony S. Clinical and pathological spectrum of celiac disease--active, silent, latent, potential. Gut. 1993 Feb;34(2):150-1.
4. Arranz E, Ferguson A. jejunal fluid antibodies and mucosal gamma/delta IEL in latent and potential celiac disease. Adv Exp Med Biol. 1995;371B:1345-8.
Alba Therapeutics Announces Positive Celiac Disease Trial Results
Celiac.com 03/14/2006 - Alba Therapeutics Corporation announced today successful completion of Phase Ib proof-of-concept studies for its lead compound, AT1001. In a 21-patient cohort of celiac disease sufferers, the oral administration of AT1001 versus placebo control induced a significantly positive result in the trials primary target endpoint.
"We anticipated a strong signal, however, the magnitude of the response surpassed our expectations," stated Blake Paterson, M.D., President and CEO of Alba. "We are particularly excited, as to the best of our knowledge this is the first demonstration of a desired and systemic immunological effect resulting from a physiological event at a mucosal surface."
AT1001 is an antagonist to the zonulin system -- a signaling pathway discovered by Alessio Fasano, M.D., Professor of Pediatrics, Medicine and Physiology at the University of Maryland School of Medicine, and the basis of Albas extensive intellectual property portfolio.
About Zonulin
Zonulin is a signaling protein that transiently and reversibly opens the tight junctions ("tj") between the cells of epithelial and endothelial tissues such as the intestinal mucosa, blood brain barrier and pulmonary epithelia. Zonulin appears to be involved in many diseases in which leakage occurs via paracellular transport across epithelial and endothelial tight junctions (tj), and thus may play an important potential role in the treatment of autoimmune diseases.
About Celiac Disease
Celiac disease (CD) is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. According to the National Institutes of Health, celiac disease affects approximately 3 million Americans, although the diagnosis is rarely made. The only current treatment for celiac disease is complete elimination of gluten from the diet, which results in remission for some patients.
About Alba
Alba Therapeutics Corporation is a privately held biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Albas lead molecule, AT-1001, is targeted towards the treatment of celiac disease and other auto-immune illnesses.
"We anticipated a strong signal, however, the magnitude of the response surpassed our expectations," stated Blake Paterson, M.D., President and CEO of Alba. "We are particularly excited, as to the best of our knowledge this is the first demonstration of a desired and systemic immunological effect resulting from a physiological event at a mucosal surface."
AT1001 is an antagonist to the zonulin system -- a signaling pathway discovered by Alessio Fasano, M.D., Professor of Pediatrics, Medicine and Physiology at the University of Maryland School of Medicine, and the basis of Albas extensive intellectual property portfolio.
About Zonulin
Zonulin is a signaling protein that transiently and reversibly opens the tight junctions ("tj") between the cells of epithelial and endothelial tissues such as the intestinal mucosa, blood brain barrier and pulmonary epithelia. Zonulin appears to be involved in many diseases in which leakage occurs via paracellular transport across epithelial and endothelial tight junctions (tj), and thus may play an important potential role in the treatment of autoimmune diseases.
About Celiac Disease
Celiac disease (CD) is a T-cell mediated auto-immune disease that occurs in genetically susceptible individuals and is characterized by small intestinal inflammation, injury and intolerance to gluten. According to the National Institutes of Health, celiac disease affects approximately 3 million Americans, although the diagnosis is rarely made. The only current treatment for celiac disease is complete elimination of gluten from the diet, which results in remission for some patients.
About Alba
Alba Therapeutics Corporation is a privately held biopharmaceutical company based in Baltimore, Maryland. Alba is dedicated to commercializing disease-modifying therapeutics and drug delivery adjuvants based on the zonulin pathway. Albas lead molecule, AT-1001, is targeted towards the treatment of celiac disease and other auto-immune illnesses.
New Therapy May Mean Less Dietary Restrictions for Celiac Disease Sufferers
Celiac.com 07/01/2006 - Scientists have discovered what may be a successful non-dietary therapy for celiac sprue, an inherited inflammatory disorder of the small intestine that impacts an estimated 1 in 200 people around the world. Two research studies, published in the June issue of Chemistry and Biology, pave the way for clinical testing with an oral enzyme therapy that may prevent the many symptoms and complications of this widespread disease.
People with celiac sprue, also called celiac disease, cannot tolerate the protein gluten in their diet. Gluten is present in grains like wheat, barley, and rye. When gluten is ingested by a celiac patient, it sets off an inflammatory reaction that damages the small intestine, leading to malabsorption, an autoimmune-like response, and many other complications. The only effective therapy for celiac disease is complete dietary exclusion of gluten. However, the ubiquitous nature of gluten poses a constant threat to celiacs, and a majority of celiac patients who adopt a restrictive diet still exhibit structural and functional gut abnormalities.
"Non-dietary therapies that allow celiac patients to safely incorporate low-to-moderate levels of gluten into their daily diet would be of considerable benefit," explains study leader Dr. Chaitan Khosla, from Stanford University and Celiac Sprue Research Foundation. "Having demonstrated earlier that certain types of enzymes can detoxify gluten, our laboratory set out to devise an optimal oral enzyme therapy for celiac sprue by borrowing from nature. In germinating barley seed, gluten serves as a nutritious storage protein that is efficiently digested by enzymes. One enzyme, EP-B2, plays a crucial role in this process by breaking gluten proteins after glutamine residues, which comprise one-third of all amino acid residues in gluten."
Dr. Khoslas group used recombinant bacteria to produce a form of EP-B2 that only activates under acidic conditions similar to the conditions found in the human stomach. The researchers demonstrated that EP-B2 efficiently digested gluten protein under gastric conditions and, importantly, EP-B2 was most specific for those parts of gluten that are known to trigger celiac pathogenesis. In a second study, the researchers went on to devise an even more potent double enzyme therapy for detoxifying gluten.
EP-B2 was tested in combination with another well-characterized enzyme called PEP that breaks gluten protein after proline residues. Like glutamine, proline is also abundant in inflammatory gluten peptides. At very high gluten loads, where neither PEP nor EP-B2 alone could detoxify gluten quickly enough to prevent inflammation, a PEP and EP-B2 combination completely abolished gluten immunotoxicity within ten minutes under simulated gastric and duodenal conditions.
In this tag-team therapy, EP-B2 first cleaved gluten into small pieces under gastric conditions that were then easier for PEP to fully detoxify under duodenal conditions. "Our results suggest that recombinant EP-B2 should be effective as supportive therapy to help celiacs cope with the hidden gluten in everyday life, and that a two-enzyme cocktail containing PEP and EP-B2 may even allow celiacs to resume a more normal diet in the future," offers Dr. Khosla.
References:
Seigel et al.
The researchers include Matthew Siegel, Michael T. Bethune, Jiang Xia, Alexandre Johannsen, Tor B. Stuge, and Peter P. Lee of Stanford University in Stanford, CA; Jonathan Gass, Jennifer Ehren, Gary M. Gray, and Chaitan Khosla of Stanford University in Stanford, CA and Celiac Sprue Research Foundation in Palo Alto, CA. This research was supported by a grant from the National Institutes of Health (R01 DK63158 to C.K. and Mary Hewitt Loveless, MD Pilot-Project Grant to P.P.L.).
Siegel et al.: "Rational Design of Combination Enzyme Therapy for Celiac Sprue." Publishing in Chemistry & Biology 13, 649–658, June 2006 DOI 10.1016/j.chembiol.2006.04.009 www.chembiol.com
Bethune et al.
The researchers include Michael T. Bethune, Yinyan Tang, and Chaitan Khosla of Stanford University in Stanford, CA; Pavel Strop of Howard Hughes Medical Institute and Stanford University in Stanford, CA; Ludvig M. Sollid of University of Oslo and Rikshospitalet University Hospital in Oslo, Norway. This research was supported by R01 DK063158 to C.K. M.T.B. is a recipient of a National Institutes of Health Cellular and molecular Biology Training Grant through Stanford University.
Bethune et al.: "Heterologous Expression, Purification, Refolding, and Structural-Functional Characterization of EP-B2, a Self-Activating Barley Cysteine Endoprotease." Publishing in Chemistry & Biology 13, 637–647, June 2006 DOI 10.1016/j.chembiol.2006.04.008
People with celiac sprue, also called celiac disease, cannot tolerate the protein gluten in their diet. Gluten is present in grains like wheat, barley, and rye. When gluten is ingested by a celiac patient, it sets off an inflammatory reaction that damages the small intestine, leading to malabsorption, an autoimmune-like response, and many other complications. The only effective therapy for celiac disease is complete dietary exclusion of gluten. However, the ubiquitous nature of gluten poses a constant threat to celiacs, and a majority of celiac patients who adopt a restrictive diet still exhibit structural and functional gut abnormalities.
"Non-dietary therapies that allow celiac patients to safely incorporate low-to-moderate levels of gluten into their daily diet would be of considerable benefit," explains study leader Dr. Chaitan Khosla, from Stanford University and Celiac Sprue Research Foundation. "Having demonstrated earlier that certain types of enzymes can detoxify gluten, our laboratory set out to devise an optimal oral enzyme therapy for celiac sprue by borrowing from nature. In germinating barley seed, gluten serves as a nutritious storage protein that is efficiently digested by enzymes. One enzyme, EP-B2, plays a crucial role in this process by breaking gluten proteins after glutamine residues, which comprise one-third of all amino acid residues in gluten."
Dr. Khoslas group used recombinant bacteria to produce a form of EP-B2 that only activates under acidic conditions similar to the conditions found in the human stomach. The researchers demonstrated that EP-B2 efficiently digested gluten protein under gastric conditions and, importantly, EP-B2 was most specific for those parts of gluten that are known to trigger celiac pathogenesis. In a second study, the researchers went on to devise an even more potent double enzyme therapy for detoxifying gluten.
EP-B2 was tested in combination with another well-characterized enzyme called PEP that breaks gluten protein after proline residues. Like glutamine, proline is also abundant in inflammatory gluten peptides. At very high gluten loads, where neither PEP nor EP-B2 alone could detoxify gluten quickly enough to prevent inflammation, a PEP and EP-B2 combination completely abolished gluten immunotoxicity within ten minutes under simulated gastric and duodenal conditions.
In this tag-team therapy, EP-B2 first cleaved gluten into small pieces under gastric conditions that were then easier for PEP to fully detoxify under duodenal conditions. "Our results suggest that recombinant EP-B2 should be effective as supportive therapy to help celiacs cope with the hidden gluten in everyday life, and that a two-enzyme cocktail containing PEP and EP-B2 may even allow celiacs to resume a more normal diet in the future," offers Dr. Khosla.
References:
Seigel et al.
The researchers include Matthew Siegel, Michael T. Bethune, Jiang Xia, Alexandre Johannsen, Tor B. Stuge, and Peter P. Lee of Stanford University in Stanford, CA; Jonathan Gass, Jennifer Ehren, Gary M. Gray, and Chaitan Khosla of Stanford University in Stanford, CA and Celiac Sprue Research Foundation in Palo Alto, CA. This research was supported by a grant from the National Institutes of Health (R01 DK63158 to C.K. and Mary Hewitt Loveless, MD Pilot-Project Grant to P.P.L.).
Siegel et al.: "Rational Design of Combination Enzyme Therapy for Celiac Sprue." Publishing in Chemistry & Biology 13, 649–658, June 2006 DOI 10.1016/j.chembiol.2006.04.009 www.chembiol.com
Bethune et al.
The researchers include Michael T. Bethune, Yinyan Tang, and Chaitan Khosla of Stanford University in Stanford, CA; Pavel Strop of Howard Hughes Medical Institute and Stanford University in Stanford, CA; Ludvig M. Sollid of University of Oslo and Rikshospitalet University Hospital in Oslo, Norway. This research was supported by R01 DK063158 to C.K. M.T.B. is a recipient of a National Institutes of Health Cellular and molecular Biology Training Grant through Stanford University.
Bethune et al.: "Heterologous Expression, Purification, Refolding, and Structural-Functional Characterization of EP-B2, a Self-Activating Barley Cysteine Endoprotease." Publishing in Chemistry & Biology 13, 637–647, June 2006 DOI 10.1016/j.chembiol.2006.04.008
Positive Antigliadin Antibody (AGA) is a Poor Marker for Celiac Disease
Eur J Gastroenterol Hepatol 2006;18:503-506.
Celiac.com 08/14/2006 – A team of German researchers led by Dr. Martin W. Laass of the Childrens Hospital in Dresden have determined that antigliadin antibody (AGA) positivity disappears in over 50% of cases, and is therefore a poor marker for celiac disease. The researchers did follow up AGA testing on 69 adults and 47 children who participated in a much larger study conducted four years ago and found that only 26 of the adults and 21 of the children still had detectable levels of AGA in their blood samples, and none of them were positive for IgA-class anti-endomysial antibodies. Additionally no correlation was found in the subjects between their serum and fecal AGA.
The researchers conclude that the appearance of AGA should be interpreted as a non-specific “immunomodulation phenomenon” that has low specificity as a diagnostic marker for celiac disease. The researchers emphasize that it is still unknown why the AGA markers are transient, but various conditions might account for it, including a change in the sensitivity of the test that was used in the original study conducted four years ago versus the one used in this study
Celiac.com 08/14/2006 – A team of German researchers led by Dr. Martin W. Laass of the Childrens Hospital in Dresden have determined that antigliadin antibody (AGA) positivity disappears in over 50% of cases, and is therefore a poor marker for celiac disease. The researchers did follow up AGA testing on 69 adults and 47 children who participated in a much larger study conducted four years ago and found that only 26 of the adults and 21 of the children still had detectable levels of AGA in their blood samples, and none of them were positive for IgA-class anti-endomysial antibodies. Additionally no correlation was found in the subjects between their serum and fecal AGA.
The researchers conclude that the appearance of AGA should be interpreted as a non-specific “immunomodulation phenomenon” that has low specificity as a diagnostic marker for celiac disease. The researchers emphasize that it is still unknown why the AGA markers are transient, but various conditions might account for it, including a change in the sensitivity of the test that was used in the original study conducted four years ago versus the one used in this study
Two Rapid Commercial Celiac Disease Test Kits Found to be Accurate
Am J Gastroenterol. 2006;101(7):1597-1600.
Celiac.com 08/14/2006 – In an effort to increase the diagnosis rate of celiac disease, researchers in Italy conducted a study to determine the accuracy of two of the new "at home" type rapid commercial celiac disease test kits--both of which require only one drop of whole blood to gain results. Both of the kits detect IgA-IgG anti-human-transglutaminase antibodies (anti-h-tTG) in serum and IgA anti-h-tTG antibody in a single drop of whole blood. The researchers analyzed the serum samples of 114 biopsy-confirmed celiacs, 120 healthy controls, 20 first-degree relatives of celiacs, and 75 diseased controls, and compared them to the standard enzyme-linked immunosorbent assay testing method. Whole blood samples were taken in 51 of the biopsy-confirmed celiacs and 100 controls.
The serum-based test was found to be positive in all 114 celiac patients, or 100% sensitivity, and among the controls which included three with celiac disease there was 94.9% sensitivity. The accuracy of the blood drop-based assay testing was positive in 46 of the 51 celiacs tested, which equals 90.2% sensitivity. The accuracy, however, is actually higher because five of the patients who tested negative had total IgA deficiency, so the real sensitivity level is actually 95.8%. All 100 controls tested negative which equals 100% specificity.
Given the high degree of accuracy of the two commercial test kits that were evaluated the researchers conclude that general practitioners should utilize these low cost kits during standard office visits whenever celiac disease is suspected.
Celiac.com 08/14/2006 – In an effort to increase the diagnosis rate of celiac disease, researchers in Italy conducted a study to determine the accuracy of two of the new "at home" type rapid commercial celiac disease test kits--both of which require only one drop of whole blood to gain results. Both of the kits detect IgA-IgG anti-human-transglutaminase antibodies (anti-h-tTG) in serum and IgA anti-h-tTG antibody in a single drop of whole blood. The researchers analyzed the serum samples of 114 biopsy-confirmed celiacs, 120 healthy controls, 20 first-degree relatives of celiacs, and 75 diseased controls, and compared them to the standard enzyme-linked immunosorbent assay testing method. Whole blood samples were taken in 51 of the biopsy-confirmed celiacs and 100 controls.
The serum-based test was found to be positive in all 114 celiac patients, or 100% sensitivity, and among the controls which included three with celiac disease there was 94.9% sensitivity. The accuracy of the blood drop-based assay testing was positive in 46 of the 51 celiacs tested, which equals 90.2% sensitivity. The accuracy, however, is actually higher because five of the patients who tested negative had total IgA deficiency, so the real sensitivity level is actually 95.8%. All 100 controls tested negative which equals 100% specificity.
Given the high degree of accuracy of the two commercial test kits that were evaluated the researchers conclude that general practitioners should utilize these low cost kits during standard office visits whenever celiac disease is suspected.
Alvine Pharmaceuticals Closes a $21 Million Series A Financing for Research into Celiac Disease Treatment
Celiac.com 09/29/2006 - Alvine Pharmaceuticals, Inc., a biopharmaceutical company focused on developing pharmaceutical products for the treatment of celiac sprue, today announced the closing of a $21 million Series A financing. Sofinnova Ventures led the investment round with strong support from Prospect Venture Partners and InterWest Partners. Cargill Ventures and Flagship Ventures also participated in the financing.
"This financing brings together a premier group of investors committed to advancing the companys lead product candidate ALV001 into human clinical and safety trials," said Stanford Professor Chaitan Khosla, Ph.D., who co-founded the company. "Celiac sprue is a serious yet common immune disease that is triggered by gluten, a component of cereal grains found in most foods sold in the U.S. While under-diagnosed, as many as one in one hundred individuals suffer from celiac sprue, yet there is no drug therapy available. Alvines mission is to provide innovative drug therapies for this disease and to change the lives of its many patients," he continued.
"Sofinnova has known Chaitan since the early 90s when we worked together on behalf of Kosan Biosciences. Were thrilled to be working with him again on his current venture," commented Sofinnova Ventures General Partner Nicola Campbell, Ph.D. "Alvines lead products will be beneficial to the celiac market for the treatment of a neglected patient population. ALV001 has proven to be uniquely safe for patients with celiac sprue, an actuality that the management team and investors alike are proud of."
Joining Khosla in this venture are Alvine co-founders Blair Stewart, President and Kevin Kaster, Vice President of Corporate Development.
Alvines platform is based on over six years of research, and an extensive intellectual property portfolio licensed from Stanford University and acquired from the Celiac Sprue Research Foundation.
The Alvine Board of Directors consists of: Nicola Campbell, Ph.D., General Partner, Sofinnova Ventures; Ilan Zipkin, Ph.D., Partner, Prospect Venture Partners; Nina Kjellson, Partner, InterWest Partners; and Chaitan Khosla, Wells H. Rauser and Harold M. Petiprin Professor in the School of Engineering; Professor of Chemical Engineering, Chemistry, and Biochemistry, by courtesy, of Stanford University.
About Alvine:
Alvine Pharmaceuticals, Inc., is a Palo Alto-based biopharmaceutical company dedicated to developing and commercializing therapeutics for the treatment of Celiac sprue. Alvines lead molecule, ALV001, is a protease designed to be consumed with food to detoxify the gluten that triggers the autoimmune response in celiac patients. Celiac sprue is believed to affect as many as two million people in the United States alone, many of whom have suffered the symptoms of the disease but have not yet been diagnosed.
"This financing brings together a premier group of investors committed to advancing the companys lead product candidate ALV001 into human clinical and safety trials," said Stanford Professor Chaitan Khosla, Ph.D., who co-founded the company. "Celiac sprue is a serious yet common immune disease that is triggered by gluten, a component of cereal grains found in most foods sold in the U.S. While under-diagnosed, as many as one in one hundred individuals suffer from celiac sprue, yet there is no drug therapy available. Alvines mission is to provide innovative drug therapies for this disease and to change the lives of its many patients," he continued.
"Sofinnova has known Chaitan since the early 90s when we worked together on behalf of Kosan Biosciences. Were thrilled to be working with him again on his current venture," commented Sofinnova Ventures General Partner Nicola Campbell, Ph.D. "Alvines lead products will be beneficial to the celiac market for the treatment of a neglected patient population. ALV001 has proven to be uniquely safe for patients with celiac sprue, an actuality that the management team and investors alike are proud of."
Joining Khosla in this venture are Alvine co-founders Blair Stewart, President and Kevin Kaster, Vice President of Corporate Development.
Alvines platform is based on over six years of research, and an extensive intellectual property portfolio licensed from Stanford University and acquired from the Celiac Sprue Research Foundation.
The Alvine Board of Directors consists of: Nicola Campbell, Ph.D., General Partner, Sofinnova Ventures; Ilan Zipkin, Ph.D., Partner, Prospect Venture Partners; Nina Kjellson, Partner, InterWest Partners; and Chaitan Khosla, Wells H. Rauser and Harold M. Petiprin Professor in the School of Engineering; Professor of Chemical Engineering, Chemistry, and Biochemistry, by courtesy, of Stanford University.
About Alvine:
Alvine Pharmaceuticals, Inc., is a Palo Alto-based biopharmaceutical company dedicated to developing and commercializing therapeutics for the treatment of Celiac sprue. Alvines lead molecule, ALV001, is a protease designed to be consumed with food to detoxify the gluten that triggers the autoimmune response in celiac patients. Celiac sprue is believed to affect as many as two million people in the United States alone, many of whom have suffered the symptoms of the disease but have not yet been diagnosed.
Confocal Laser Endomicroscopy and Celiac Disease by Roy Jamron
Celiac.com 11/07/2006 – We should be hearing more about this in the news soon. A confocal laser endomicroscopy device developed by Optiscan, an Australian company, permits endoscopists to make an accurate real-time diagnosis of celiac disease, bypassing the need to take and prepare and evaluate biopsy specimens in a laboratory. This technique would allow the endoscopist to view and evaluate as many samples as needed to make a correct diagnosis and immediately give the results to the patient. This should reduce diagnostic errors. A paper on Confocal Laser Endomicroscopy in the diagnosis of Celiac disease by R. Leong et al. will be presented in Adelaide, Australia this Saturday, Oct. 14.
Australian Gastroenterology Week (AGW) 2006
Hosted by the Gastroenterological Society of Australia (GESA)
Adelaide Convention Centre, Adelaide, South Australia
11-14th October 2006.
To be presented Oct. 14, 2006:
Confocal Laser Endomicroscopy in the diagnosis of Celiac disease R Leong
Optiscans unique and patented technology has miniaturized the microscopes scanning head, so that it is now so small it can fit inside the body. Once the miniaturized scanner is integrated into an endoscope to create an endomicroscope, doctors can for the first time safely and instantly get high quality images of tissue at a cellular level from their patients. This gives doctors new levels of information providing a highly magnified view of living tissue that is entirely consistent with the macroscopic views that they are used to seeing from their endoscopes. This breakthrough technology creates a vast array of new applications, both medical and industrial. Optiscans primary focus is in the medical arena, where it can provide a virtual biopsy, potentially revolutionizing current pathology and histology practices.
Australian Gastroenterology Week (AGW) 2006
Hosted by the Gastroenterological Society of Australia (GESA)
Adelaide Convention Centre, Adelaide, South Australia
11-14th October 2006.
To be presented Oct. 14, 2006:
Confocal Laser Endomicroscopy in the diagnosis of Celiac disease R Leong
Optiscans unique and patented technology has miniaturized the microscopes scanning head, so that it is now so small it can fit inside the body. Once the miniaturized scanner is integrated into an endoscope to create an endomicroscope, doctors can for the first time safely and instantly get high quality images of tissue at a cellular level from their patients. This gives doctors new levels of information providing a highly magnified view of living tissue that is entirely consistent with the macroscopic views that they are used to seeing from their endoscopes. This breakthrough technology creates a vast array of new applications, both medical and industrial. Optiscans primary focus is in the medical arena, where it can provide a virtual biopsy, potentially revolutionizing current pathology and histology practices.
Celiac Disease Genetic Testing Awareness Campaign Launched by Kimball Genetics
If you would like to learn more about celiac disease genetic testing, or read about my personal experience with Kimball Genetics, be sure to read the following two related articles:Celiac.com 11/29/2006 - Kimball Genetics, Inc. announces its participation this week at the XII International Celiac Disease Symposium in New York City and its support of the Celiac Disease Center at Columbia University. Kimball Genetics has a strong commitment to celiac disease education and genetic testing for this common, chronic, autoimmune disorder. Celiac disease affects approximately 1% of the U.S. population but is highly underdiagnosed, with less than 10% of cases currently detected. In genetically susceptible individuals with the specific markers HLA-DQ2 and HLA-DQ8, ingestion of gluten-containing grains causes inflammation of the small intestine and leads to malabsorption. Symptoms may be gastrointestinal and/or a wide range of other multi-systemic manifestations such as iron-deficiency anemia, chronic fatigue, osteoporosis, dermatitis herpetiformis, and attention-deficit/hyperactivity disorder. Early diagnosis and lifelong treatment with a gluten-free diet is critical to relieve inflammation and symptoms and to reduce the risk for development of secondary autoimmune disorders such as type 1 diabetes. Silent celiac disease, involving inflammation without symptoms, is also important to detect and treat.
Kimball Genetics offers the Celiac Disease DNA Test, a genetic test with increasingly recognized importance in the diagnostic work-up of celiac disease. The test is valuable because it excludes the diagnosis of celiac disease in patients with a negative result, detects family members at risk for the disorder, and is accurate even when the patient is on a gluten-free diet. Both antibody testing and small bowel biopsy require going off a gluten-free diet to gain reliable results if the patient initiated the diet before diagnosis.
Kimball Genetics is the only laboratory presently offering celiac disease DNA testing on cheek cell specimens with results available in one day. Dr. Peter Green of the Celiac Disease Center at Columbia University says "Cheek cell testing at Kimball Genetics is convenient and tremendously popular with my patients since it eliminates the need for blood draw. The one-day turnaround time and expert genetic counseling provided with Kimballs service are much appreciated." The Celiac Disease Foundation also recommends Kimball Genetics Celiac Disease DNA test due to these unique features of its service.
In concurrence with the National Institute of Healths "Celiac Disease Campaign for Health Care Providers and Public," Kimball Genetics, Inc. conducts ongoing educational efforts including presentations to gastroenterologists, family practitioners, nautropaths, chiropractors, and nutritionists, and assists national celiac support groups. Dr. Annette Taylor and genetic counselors from Kimball have written an in depth review about celiac disease, co-authored by Dr. Peter Green, soon to be published in GeneReviews online. In addition, Kimball Genetics is collaborating with Drs. Xavier Castellanos and Dominick Auciello from New York University Child Study Center and Dr. Peter Green from Columbia University on an exciting new research study to determine the incidence of celiac disease in children with attention-deficit/hyperactivity disorder (ADHD) or learning disabilities.
About Kimball Genetics, Inc.
Founded in 1994 by Annette K. Taylor, M.S., Ph.D., Kimball Genetics is a national DNA diagnostic laboratory specializing in testing for common genetic disorders that are preventable or can be treated. Known for its unparalleled turnaround time and distinctive focus on genetic counseling and education, the company has a major focus on celiac disease and is at the forefront of education and testing for this disorder. Other major areas of testing currently include inherited hypercoagulability, hemochromatosis, cystic fibrosis, and fragile X syndrome. Soon Kimball will be expanding into pharmocogenomic testing which allows for the personal customization of drug therapy.
Kimball Genetics offers the Celiac Disease DNA Test, a genetic test with increasingly recognized importance in the diagnostic work-up of celiac disease. The test is valuable because it excludes the diagnosis of celiac disease in patients with a negative result, detects family members at risk for the disorder, and is accurate even when the patient is on a gluten-free diet. Both antibody testing and small bowel biopsy require going off a gluten-free diet to gain reliable results if the patient initiated the diet before diagnosis.
Kimball Genetics is the only laboratory presently offering celiac disease DNA testing on cheek cell specimens with results available in one day. Dr. Peter Green of the Celiac Disease Center at Columbia University says "Cheek cell testing at Kimball Genetics is convenient and tremendously popular with my patients since it eliminates the need for blood draw. The one-day turnaround time and expert genetic counseling provided with Kimballs service are much appreciated." The Celiac Disease Foundation also recommends Kimball Genetics Celiac Disease DNA test due to these unique features of its service.
In concurrence with the National Institute of Healths "Celiac Disease Campaign for Health Care Providers and Public," Kimball Genetics, Inc. conducts ongoing educational efforts including presentations to gastroenterologists, family practitioners, nautropaths, chiropractors, and nutritionists, and assists national celiac support groups. Dr. Annette Taylor and genetic counselors from Kimball have written an in depth review about celiac disease, co-authored by Dr. Peter Green, soon to be published in GeneReviews online. In addition, Kimball Genetics is collaborating with Drs. Xavier Castellanos and Dominick Auciello from New York University Child Study Center and Dr. Peter Green from Columbia University on an exciting new research study to determine the incidence of celiac disease in children with attention-deficit/hyperactivity disorder (ADHD) or learning disabilities.
About Kimball Genetics, Inc.
Founded in 1994 by Annette K. Taylor, M.S., Ph.D., Kimball Genetics is a national DNA diagnostic laboratory specializing in testing for common genetic disorders that are preventable or can be treated. Known for its unparalleled turnaround time and distinctive focus on genetic counseling and education, the company has a major focus on celiac disease and is at the forefront of education and testing for this disorder. Other major areas of testing currently include inherited hypercoagulability, hemochromatosis, cystic fibrosis, and fragile X syndrome. Soon Kimball will be expanding into pharmocogenomic testing which allows for the personal customization of drug therapy.
Celiac Disease Diagnosis using Intestinal Endomysial Autoantibodies (EmA) in Serum EmA-negative Patients
Celiac.com 01/11/2007 – Researchers in Finland have determined that many patients with untreated celiac disease show the presence of intestinal endomysial autoantibodies (EmA), even in the 10-20% of cases where their serum EmA is negative. The researchers also believe that the negative serum EmA test in these cases is an indication of more advanced and long-standing celiac disease. Normally positive serum EmA is close to 100% accurate, however there is a subset of around 10-20% of patients where the test is negative even though they do have the disease. Dr. Katri Kaukinen and colleagues at the University of Tampere looked at 177 celiac disease patients and found that 22 were serum EmA-negative. A common theme among the 22 serum EmA-negative patients was that they were older and had more abdominal symptoms and other complications that indicated a more advanced stage of celiac disease than their serum EmA-positive counterparts. The research team found that even though the EmA antibodies could not be detected in the blood of these 22 patients, they could be detected in the small bowel mucosa in all of them, and none were detected in 20 control patients. Dr. Kaukinen and colleagues believe that the use of intestinal EmA antibody detection should be used in seronegative individuals who are suspected to have celiac disease.
This study further supports Dr. Kenneth Fines use of IgA antigliadin antibodies in the stool to detect gluten sensitivity, and one has to wonder if the EmA antibodies, if detectable in the small bowel mucosa, would not also be detectable in the patient’s stool, and if so would that not be a much better and more cost-effective way to perform such a screening?
Gut 2006;55:1746-1753.
This study further supports Dr. Kenneth Fines use of IgA antigliadin antibodies in the stool to detect gluten sensitivity, and one has to wonder if the EmA antibodies, if detectable in the small bowel mucosa, would not also be detectable in the patient’s stool, and if so would that not be a much better and more cost-effective way to perform such a screening?
Gut 2006;55:1746-1753.
Refractory Celiac Disease Responds to Stem Cell Transplant
Celiac.com 04/10/2007 - Patients suffering from refractory celiac disease with aberrant T cells seem to benefit from high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation. Refractory celiac disease with aberrant T cells has generally proven resistant to known celiac therapies, and patients are at high risk for developing enteropathy associated T-cell lymphoma. The small pilot trial was conducted by Dr. Abdulbaqi Al-toma and colleagues from VU University Medical Center, Amsterdam.
The study followed seven patients whose mean average age was 52.5 years old at the time of the procedure, and followed them for an average of 15.5 months (the lowest follow-up time was 7 months, the longest was 30 months). According to the study, there was no transplantation-related mortality, and only mild cases of transplantation-related toxicity. A one-month post-procedure follow-up showed remarkable clinical improvement all patients, including disappearance of abdominal pain, normalization of stool frequency, and improvement of biochemical markers.
The research team also noted that post-transplant histology of the small intestine revealed marked regeneration coupled with a disappearance of erosions and ulcerations. Furthermore, at 3 to 4 months, post-transplantation tests showed a decline in aberrant T cells from a mean of 63% at baseline to 38%. Additionally, at 2 years, tests for the first hematopoietic stem cell transplant patient showed continuing declines in aberrant T cells (to 3%).
It should be noted that one subject of the study showed no declines in aberrant T cell percentages, histology examination or CD8+ cells, and that the patient died 8 months after the stem-cell transplant.
The research team concluded that the promising short-term results enjoyed by this small test group warrants a longer-term follow-up to properly assess the significance of the findings.
Blood 2007;109:2243-2249.
The study followed seven patients whose mean average age was 52.5 years old at the time of the procedure, and followed them for an average of 15.5 months (the lowest follow-up time was 7 months, the longest was 30 months). According to the study, there was no transplantation-related mortality, and only mild cases of transplantation-related toxicity. A one-month post-procedure follow-up showed remarkable clinical improvement all patients, including disappearance of abdominal pain, normalization of stool frequency, and improvement of biochemical markers.
The research team also noted that post-transplant histology of the small intestine revealed marked regeneration coupled with a disappearance of erosions and ulcerations. Furthermore, at 3 to 4 months, post-transplantation tests showed a decline in aberrant T cells from a mean of 63% at baseline to 38%. Additionally, at 2 years, tests for the first hematopoietic stem cell transplant patient showed continuing declines in aberrant T cells (to 3%).
It should be noted that one subject of the study showed no declines in aberrant T cell percentages, histology examination or CD8+ cells, and that the patient died 8 months after the stem-cell transplant.
The research team concluded that the promising short-term results enjoyed by this small test group warrants a longer-term follow-up to properly assess the significance of the findings.
Blood 2007;109:2243-2249.
Vitamin D Deficiency May be Affecting Celiacs' Immune Systems by Laura Wesson
This article appeared in the Winter 2007 edition of Celiac.coms Scott-Free Newsletter.
Celiac.com 04/26/2007 - My fingernails were shredding and I was a bit out of it mentally, missing obvious things. I’ve had to stop eating many foods because I have intolerances to almost everything I used to eat before I went gluten-free, and I wondered if I had dropped some essential nutrients when I cleared all of those foods out of my diet. So I checked my diet for nutrient deficiencies, using the USDA nutrients database at www.nal.usda.gov/fnic/foodcomp/search. I’m sure there’s software that works with this database but I wrote a little computer program to analyze my diet. I have an electronic food scale, so weighing food is easy.
The most important thing I found is that I’m low on vitamin D. You can get vitamin D from food, or from a supplement, and from the ultraviolet B in sunlight; many of us, like me, may get almost none from any of those sources. And—this is important for a lot of us—vitamin D deficiency can cause a lot of symptoms including immune system problems! I went looking on Medline and it was mentioned as having anti-inflammatory properties, as preventing cancers such as colon cancer and lymphoma; preventing infections, and helping with autoimmune diseases. Gluten intolerance is less common in the middle east and more common in northern Europe. I’ve seen this explained as the result of evolution, since wheat has been used for longer in the Middle East. But I wonder if people in the north are also more likely to be gluten intolerant (an autoimmune disease) because they don’t get as much vitamin D. It may also explain why people get more colds during the winter season when there’s less sunlight. Vitamin D deficiency is best known for causing rickets in children and osteomalacia (softened bones, muscle weakness and pain, tender sternum) in adults. Osteomalacia is often misdiagnosed as fibromyalgia, because the symptoms are similar. Rickets is increasing in the U.S., especially among black children. Most post-menopausal bone loss in women occurs during the winter. It can take months of increased vitamin D intake to correct the health problems caused by deficiency.
There are only a few significant dietary sources of vitamin D. In the U.S., almost all milk is fortified with vitamin D to 100 IU per cup, so you should get the recommended daily intake of 400 IU if you drink 4 cups of milk per day. However, milk often doesn’t have as much vitamin D as is claimed on the label. Some cereals, like Kellogg’s Cornflakes, have small amounts of added vitamin D. Typically, 10 cups of fortified cereal would give you the RDI. The government encourages fortification of milk and cereal so that fewer children will develop rickets. Otherwise—you would get the RDI from nine oysters, or about 4 ounces of fatty fish like salmon or tuna, or a teaspoon of cod liver oil. Many other kinds of fish have only small amounts. You’d have to eat 2 pounds of cod to get the RDI. The only natural vegan source of vitamin D is Shiitake mushrooms. Just like people, mushrooms make vitamin D when they’re exposed to ultraviolet. About 13 sun-dried shiitake mushrooms contain the RDI. And that’s it. Many of us on gluten-free diets are also not eating dairy or fortified cereals, so unless we have a passionate love-affair with fish or oysters or shiitake, we would be getting almost no vitamin D from food.
You can get vitamin D the natural way, from the sun. It takes exposure to sunlight outside (not under glass) on your hands and feet for about fifteen minutes a day. I was not sure what was meant by “direct sunlight”. I read someplace that ultraviolet is scattered over the whole sky. Unlike visible light, the whole sky shines with ultraviolet. Clouds would filter out some of it. People with dark skin require more time in the sun, so many black people develop a deficiency. Using even low-SPF sunscreen prevents your body from making vitamin D. The farther from the equator you live, the less UVB there is in the winter sunlight, because the sun is closer to the horizon in the winter and the sunlight filters through more atmosphere before it gets to you. At the latitude of Boston, and near sea level, there isn’t enough UVB radiation between November and February for one’s body to make vitamin D.
You have probably heard the public health advice to wear sunscreen—the same ultraviolet B that generates vitamin D in your body also causes skin cancer and ages skin. The small amount of exposure to sunlight required is probably only a very small cancer risk and would cause little photo-aging of the skin. Unfortunately I wasn’t able to find quantitative information about how carcinogenic fifteen minutes’ daily sun exposure would be. There are also vitamin D lights, which are probably also a healthful choice.
I have severe immune system problems. I tested positive for 53 inhalant allergies—my body had developed allergies to almost all the allergens around. I get sick for days if I eat almost any of the foods that I ate while I was eating gluten. I even get sick from a couple of foods that, so far as I can remember, I only started eating on a gluten-free diet. So I live on an exotic-foods diet. I’ve had a hellish time trying to get allergy shots. At a concentration of 1 part in 10 million they make me sick for a couple of days while the normal starting concentration for allergy shots is 1 in 100,000. I’m plagued by bladder infections. With cranberries being one of my intolerances, I can’t even use them to help prevent the infections.
I’ve certainly been short of vitamin D. I live in the north, and I’m always careful to use high-SPF sunscreen when I go outdoors. I can’t eat milk, fish, shellfish or mushrooms, so I can’t get a significant amount of vitamin D from food. I haven’t been taking any vitamin supplements, because almost all have traces of protein from some food that makes me sick. It would be lovely if vitamin D deficiency turned out to be part of the cause of my very burdensome immune problems. I’m skeptical because I was getting vitamin D from a supplement and/or from my diet up until 2 years ago, when I found I had a vast number of hidden food intolerances, and I started having reactions to vitamin pills. Fortunately there is a vitamin D supplement that I can take—vitamin D3 made by Pure Encapsulations. The ingredients in the capsule are made from wool and pine trees. I’ll find out if it helps over the next few months.
Vitamin D causes disease when taken in large amounts, so if you think you are deficient, don’t take too much to make up for it. Vitamin D is a hormone—it’s not something to take in mega-doses, any more than, hopefully, one would take a mega-dose of estrogen or testosterone. If your doctor recommends a high dose, they should do regular blood tests to keep track of your vitamin D level. It’s pretty safe to take up to 2000 IU per day on your own. Dr. Michael Holick, a vitamin D researcher at Boston University and author of The UV Advantage, believes that people need about 1000 IU per day. I asked a family doctor, who said they suggest 400-800 IU per day for middle-aged women. However, it might be a good idea for gluten intolerant people to take more, about 1000 - 2000 IU per day, since we may have difficulties absorbing vitamins and celiac disease is an autoimmune disease.
Vitamin D is very important, just as all the vitamins are. But we are conditioned by the media, and tend to think more about vitamins C and E, which get a lot of attention because they’re antioxidants. Vitamin D was the absolutely last one I looked at. Then I found that it was my most serious deficiency! And nutrient deficiencies are not a trendy topic, so the possibility of developing deficiencies is something people tend to forget while trying to improve their diets. Many people who avoid gluten also have other food intolerances, or are on some other kind of special diet, and it would be an excellent idea to go to the USDA database and find out whether their new diet is giving them enough vitamins and minerals. It certainly helped me. I feel more cheerful and alert, like my mind woke up on a sunny day.
It’s best to get as much as possible from one’s diet, too. Whole foods have a lot in them that’s good for the body that research hasn’t yet identified, and if your diet gives you the RDA of all the vitamins and minerals, it will also be giving you other healthful nutrients that will do you a lot of good. This might also be true of vitamin D. Maybe it’s better to get a small amount of ultraviolet, like an iguana sitting under a UV lamp, instead of taking pills. UVB might be healthy in ways we don’t yet know about.
Vitamin D is a bit like stored-up sunlight. You can catch it for yourself from the sun when it’s high in the sky, you can eat the sunlight the fish have gathered for you, or you can take a supplement and keep packed sunlight on your shelf.
Celiac.com 04/26/2007 - My fingernails were shredding and I was a bit out of it mentally, missing obvious things. I’ve had to stop eating many foods because I have intolerances to almost everything I used to eat before I went gluten-free, and I wondered if I had dropped some essential nutrients when I cleared all of those foods out of my diet. So I checked my diet for nutrient deficiencies, using the USDA nutrients database at www.nal.usda.gov/fnic/foodcomp/search. I’m sure there’s software that works with this database but I wrote a little computer program to analyze my diet. I have an electronic food scale, so weighing food is easy.
The most important thing I found is that I’m low on vitamin D. You can get vitamin D from food, or from a supplement, and from the ultraviolet B in sunlight; many of us, like me, may get almost none from any of those sources. And—this is important for a lot of us—vitamin D deficiency can cause a lot of symptoms including immune system problems! I went looking on Medline and it was mentioned as having anti-inflammatory properties, as preventing cancers such as colon cancer and lymphoma; preventing infections, and helping with autoimmune diseases. Gluten intolerance is less common in the middle east and more common in northern Europe. I’ve seen this explained as the result of evolution, since wheat has been used for longer in the Middle East. But I wonder if people in the north are also more likely to be gluten intolerant (an autoimmune disease) because they don’t get as much vitamin D. It may also explain why people get more colds during the winter season when there’s less sunlight. Vitamin D deficiency is best known for causing rickets in children and osteomalacia (softened bones, muscle weakness and pain, tender sternum) in adults. Osteomalacia is often misdiagnosed as fibromyalgia, because the symptoms are similar. Rickets is increasing in the U.S., especially among black children. Most post-menopausal bone loss in women occurs during the winter. It can take months of increased vitamin D intake to correct the health problems caused by deficiency.
There are only a few significant dietary sources of vitamin D. In the U.S., almost all milk is fortified with vitamin D to 100 IU per cup, so you should get the recommended daily intake of 400 IU if you drink 4 cups of milk per day. However, milk often doesn’t have as much vitamin D as is claimed on the label. Some cereals, like Kellogg’s Cornflakes, have small amounts of added vitamin D. Typically, 10 cups of fortified cereal would give you the RDI. The government encourages fortification of milk and cereal so that fewer children will develop rickets. Otherwise—you would get the RDI from nine oysters, or about 4 ounces of fatty fish like salmon or tuna, or a teaspoon of cod liver oil. Many other kinds of fish have only small amounts. You’d have to eat 2 pounds of cod to get the RDI. The only natural vegan source of vitamin D is Shiitake mushrooms. Just like people, mushrooms make vitamin D when they’re exposed to ultraviolet. About 13 sun-dried shiitake mushrooms contain the RDI. And that’s it. Many of us on gluten-free diets are also not eating dairy or fortified cereals, so unless we have a passionate love-affair with fish or oysters or shiitake, we would be getting almost no vitamin D from food.
You can get vitamin D the natural way, from the sun. It takes exposure to sunlight outside (not under glass) on your hands and feet for about fifteen minutes a day. I was not sure what was meant by “direct sunlight”. I read someplace that ultraviolet is scattered over the whole sky. Unlike visible light, the whole sky shines with ultraviolet. Clouds would filter out some of it. People with dark skin require more time in the sun, so many black people develop a deficiency. Using even low-SPF sunscreen prevents your body from making vitamin D. The farther from the equator you live, the less UVB there is in the winter sunlight, because the sun is closer to the horizon in the winter and the sunlight filters through more atmosphere before it gets to you. At the latitude of Boston, and near sea level, there isn’t enough UVB radiation between November and February for one’s body to make vitamin D.
You have probably heard the public health advice to wear sunscreen—the same ultraviolet B that generates vitamin D in your body also causes skin cancer and ages skin. The small amount of exposure to sunlight required is probably only a very small cancer risk and would cause little photo-aging of the skin. Unfortunately I wasn’t able to find quantitative information about how carcinogenic fifteen minutes’ daily sun exposure would be. There are also vitamin D lights, which are probably also a healthful choice.
I have severe immune system problems. I tested positive for 53 inhalant allergies—my body had developed allergies to almost all the allergens around. I get sick for days if I eat almost any of the foods that I ate while I was eating gluten. I even get sick from a couple of foods that, so far as I can remember, I only started eating on a gluten-free diet. So I live on an exotic-foods diet. I’ve had a hellish time trying to get allergy shots. At a concentration of 1 part in 10 million they make me sick for a couple of days while the normal starting concentration for allergy shots is 1 in 100,000. I’m plagued by bladder infections. With cranberries being one of my intolerances, I can’t even use them to help prevent the infections.
I’ve certainly been short of vitamin D. I live in the north, and I’m always careful to use high-SPF sunscreen when I go outdoors. I can’t eat milk, fish, shellfish or mushrooms, so I can’t get a significant amount of vitamin D from food. I haven’t been taking any vitamin supplements, because almost all have traces of protein from some food that makes me sick. It would be lovely if vitamin D deficiency turned out to be part of the cause of my very burdensome immune problems. I’m skeptical because I was getting vitamin D from a supplement and/or from my diet up until 2 years ago, when I found I had a vast number of hidden food intolerances, and I started having reactions to vitamin pills. Fortunately there is a vitamin D supplement that I can take—vitamin D3 made by Pure Encapsulations. The ingredients in the capsule are made from wool and pine trees. I’ll find out if it helps over the next few months.
Vitamin D causes disease when taken in large amounts, so if you think you are deficient, don’t take too much to make up for it. Vitamin D is a hormone—it’s not something to take in mega-doses, any more than, hopefully, one would take a mega-dose of estrogen or testosterone. If your doctor recommends a high dose, they should do regular blood tests to keep track of your vitamin D level. It’s pretty safe to take up to 2000 IU per day on your own. Dr. Michael Holick, a vitamin D researcher at Boston University and author of The UV Advantage, believes that people need about 1000 IU per day. I asked a family doctor, who said they suggest 400-800 IU per day for middle-aged women. However, it might be a good idea for gluten intolerant people to take more, about 1000 - 2000 IU per day, since we may have difficulties absorbing vitamins and celiac disease is an autoimmune disease.
Vitamin D is very important, just as all the vitamins are. But we are conditioned by the media, and tend to think more about vitamins C and E, which get a lot of attention because they’re antioxidants. Vitamin D was the absolutely last one I looked at. Then I found that it was my most serious deficiency! And nutrient deficiencies are not a trendy topic, so the possibility of developing deficiencies is something people tend to forget while trying to improve their diets. Many people who avoid gluten also have other food intolerances, or are on some other kind of special diet, and it would be an excellent idea to go to the USDA database and find out whether their new diet is giving them enough vitamins and minerals. It certainly helped me. I feel more cheerful and alert, like my mind woke up on a sunny day.
It’s best to get as much as possible from one’s diet, too. Whole foods have a lot in them that’s good for the body that research hasn’t yet identified, and if your diet gives you the RDA of all the vitamins and minerals, it will also be giving you other healthful nutrients that will do you a lot of good. This might also be true of vitamin D. Maybe it’s better to get a small amount of ultraviolet, like an iguana sitting under a UV lamp, instead of taking pills. UVB might be healthy in ways we don’t yet know about.
Vitamin D is a bit like stored-up sunlight. You can catch it for yourself from the sun when it’s high in the sky, you can eat the sunlight the fish have gathered for you, or you can take a supplement and keep packed sunlight on your shelf.
Lesser Degrees of Villous Atrophy Correspond to a Greater Frequency of Seronegative Celiac Disease
Celiac.com 05/08/2007 - A recent study published in the journal Digestive Diseases and Sciences indicates that lesser degrees of villous atrophy correspond to seronegative celiac disease.
The study was conducted by researchers J.A. Abrams, B. Diamond, H. Rotterdam, and P.H. Green, of the Department of Medicine, Columbia University College of Physicians and Surgeons in New York City. The research team set out to assess the effectiveness of various serologic tests used to diagnose celiac disease in patients with differing degrees of villous atrophy. The team evaluated 115 adult patients with biopsy-proven celiac disease. All participants met strict criteria, including serologic testing at the time of diagnosis and response to a gluten-free diet,
71% of participants showed total villous atrophy and 29% showed partial villous atrophy. Of those with total villous atrophy, 77% tested positive for endomysial antibody, compared to 33% with partial villous atrophy (P < 0.001). No difference in sensitivity was found between those who classical presentation of celiac disease versus those with silent presentation.
Also, patients who were endomysial positive and patients who were endomysial negative showed no difference with respect to age at diagnosis, duration of symptoms, mode of presentation, or family history of celiac disease. Endomysial antibody positivity correlated not with the mode of presentation of celiac disease, but rather, with more severe villous atrophy.
Lastly, the study showed that, in clinical practice, serologic tests lack the sensitivity reported in the literature.
Digestive Diseases and Sciences, 2004 Apr; 49(4):546-50.
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
The study was conducted by researchers J.A. Abrams, B. Diamond, H. Rotterdam, and P.H. Green, of the Department of Medicine, Columbia University College of Physicians and Surgeons in New York City. The research team set out to assess the effectiveness of various serologic tests used to diagnose celiac disease in patients with differing degrees of villous atrophy. The team evaluated 115 adult patients with biopsy-proven celiac disease. All participants met strict criteria, including serologic testing at the time of diagnosis and response to a gluten-free diet,
71% of participants showed total villous atrophy and 29% showed partial villous atrophy. Of those with total villous atrophy, 77% tested positive for endomysial antibody, compared to 33% with partial villous atrophy (P < 0.001). No difference in sensitivity was found between those who classical presentation of celiac disease versus those with silent presentation.
Also, patients who were endomysial positive and patients who were endomysial negative showed no difference with respect to age at diagnosis, duration of symptoms, mode of presentation, or family history of celiac disease. Endomysial antibody positivity correlated not with the mode of presentation of celiac disease, but rather, with more severe villous atrophy.
Lastly, the study showed that, in clinical practice, serologic tests lack the sensitivity reported in the literature.
Digestive Diseases and Sciences, 2004 Apr; 49(4):546-50.
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
Prolyl Endoprotease Enzyme May Allow Patients with Celiac Disease to Safely Eat Gluten on Occasion
Celiac.com 05/23/2007 - The results of a study recently published in the journal Gut suggest that the enzyme prolyl endoprotease from Aspergillus niger (AN-PEP) taken along with meals might allow patients with celiac disease to safely consume gluten on occasion.
The negative effects of celiac disease are due in large part to an immune response to gluten.
Because proline-rich gluten proteins resist the digestive enzymes of the gastro-intestinal tract, they are very likely suspects in the generation of this immune response.
A team of doctors in the Netherlands set out to assess the abilities of a post-proline cutting enzyme, prolyl endoprotease from Aspergillus niger (AN-PEP) in breaking down gluten. The research team was made up of doctors Cristina Mitea (1), Robert Havenaar (2), Jan Wouter Drijfhout (1), Luppo Edens (3), Liesbeth Dekking (1)* and Frits Koning (1).
The study was not performed on actual celiac patients, but used a dynamic system that mimics the human gastrointestinal tract (TIM system). Using the TIM system, the team performed two experiments. The first used the TIM-system to process a slice of bread with and without the presence of AN-PEP. The second experiment used the TIM-system to process standard fast food items, again both with and without the presence of AN-PEP.
Samples of the digesting food were taken from the TIM systems stomach, duodenum, jejunum and ileum compartments from zero to four hours after the beginning of the experiment. These samples were evaluated for levels of immunogenic peptides from gliadins and glutenins by monoclonal antibody based competition assays, Western blot analysis and proliferation T-cell assays.
Results of both experiments showed that AN-PEP broke down gluten in the stomach so effectively that almost no gluten reached the duodenum compartment. Because these results show that AN-PEP is capable of speeding the breakdown of gluten in a gastrointestinal system that closely mimics live digestion, the team concluded that AN-PEP might offer celiac patients an opportunity to stray from their strict gluten free diets from time to time.
Participating Institutions:
1 Dept of Immunohematology and Blood Transfusion,
Leiden University Medical Center, Leiden, Netherlands.
2 TNO Quality of Life, Zeist, Netherlands
3 DSM Food Specialties, Delft, Netherlands
Gut. Published Online First: 9 May 2007. doi:10.1136/gut.2006.111609
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
The negative effects of celiac disease are due in large part to an immune response to gluten.
Because proline-rich gluten proteins resist the digestive enzymes of the gastro-intestinal tract, they are very likely suspects in the generation of this immune response.
A team of doctors in the Netherlands set out to assess the abilities of a post-proline cutting enzyme, prolyl endoprotease from Aspergillus niger (AN-PEP) in breaking down gluten. The research team was made up of doctors Cristina Mitea (1), Robert Havenaar (2), Jan Wouter Drijfhout (1), Luppo Edens (3), Liesbeth Dekking (1)* and Frits Koning (1).
The study was not performed on actual celiac patients, but used a dynamic system that mimics the human gastrointestinal tract (TIM system). Using the TIM system, the team performed two experiments. The first used the TIM-system to process a slice of bread with and without the presence of AN-PEP. The second experiment used the TIM-system to process standard fast food items, again both with and without the presence of AN-PEP.
Samples of the digesting food were taken from the TIM systems stomach, duodenum, jejunum and ileum compartments from zero to four hours after the beginning of the experiment. These samples were evaluated for levels of immunogenic peptides from gliadins and glutenins by monoclonal antibody based competition assays, Western blot analysis and proliferation T-cell assays.
Results of both experiments showed that AN-PEP broke down gluten in the stomach so effectively that almost no gluten reached the duodenum compartment. Because these results show that AN-PEP is capable of speeding the breakdown of gluten in a gastrointestinal system that closely mimics live digestion, the team concluded that AN-PEP might offer celiac patients an opportunity to stray from their strict gluten free diets from time to time.
Participating Institutions:
1 Dept of Immunohematology and Blood Transfusion,
Leiden University Medical Center, Leiden, Netherlands.
2 TNO Quality of Life, Zeist, Netherlands
3 DSM Food Specialties, Delft, Netherlands
Gut. Published Online First: 9 May 2007. doi:10.1136/gut.2006.111609
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
Discovery of Key Genetic Risk Factor for Disease Diagnosis and Treatment
The results of a study recently published in the online science journal Nature Genetics have revealed a previously unknown genetic risk factor for celiac disease. An international team of researchers set out to study the genetic causes of intestinal inflammatory disorders.
When the study began, it was well known that individuals with celiac disease have specific tissue types that identify wheat proteins. Why healthy individuals with the same tissue type failed to develop celiac symptoms or celiac disease remained unknown, and was a key question the team set out to answer. The team was led David van Heel, Professor of gastrointestinal Genetics at Queen Mary, University of London. The Human Genome Project and the Hap Map Project played key support roles in the study.
The results show that a protective DNA sequence in a specific gene segment, generally found in healthy individuals are missing in people with celiac disease. The research team evaluated genome data of 778 individuals with celiac disease and 1,422 controls non-celiacs within the British, Irish and Dutch populations.
Key DNA Sequence Missing in Celiacs
Researchers discovered that, compared to people with celiac disease, healthy people more commonly have a DNA sequence in the interleukin-2 and interleukin-21 gene region that protects against celiac disease. Interleukin-2 and interleukin-21 are cytokine proteins that are secreted by white blood cells, and which control inflammation. In people with celiac disease, the protective DNA sequence most likely leads to lesser amounts of these cytokines being produced, which weakens the defense against intestinal inflammation.
Breakthrough in Better Understanding Risk Factors for Development of Celiac Disease
About 1 in 133 people develop the disease, but, so far, predicting those at risk to develop the disease has been haphazard at best. Present methods of genetic testing can only narrow down the search to about 30% of the general population. These results give doctors a means to discover what further genetic risk factors leave people vulnerable to developing celiac disease.
Queen Mary, University of London Press Release - Public release date: 10-Jun-2007
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
When the study began, it was well known that individuals with celiac disease have specific tissue types that identify wheat proteins. Why healthy individuals with the same tissue type failed to develop celiac symptoms or celiac disease remained unknown, and was a key question the team set out to answer. The team was led David van Heel, Professor of gastrointestinal Genetics at Queen Mary, University of London. The Human Genome Project and the Hap Map Project played key support roles in the study.
The results show that a protective DNA sequence in a specific gene segment, generally found in healthy individuals are missing in people with celiac disease. The research team evaluated genome data of 778 individuals with celiac disease and 1,422 controls non-celiacs within the British, Irish and Dutch populations.
Key DNA Sequence Missing in Celiacs
Researchers discovered that, compared to people with celiac disease, healthy people more commonly have a DNA sequence in the interleukin-2 and interleukin-21 gene region that protects against celiac disease. Interleukin-2 and interleukin-21 are cytokine proteins that are secreted by white blood cells, and which control inflammation. In people with celiac disease, the protective DNA sequence most likely leads to lesser amounts of these cytokines being produced, which weakens the defense against intestinal inflammation.
Breakthrough in Better Understanding Risk Factors for Development of Celiac Disease
About 1 in 133 people develop the disease, but, so far, predicting those at risk to develop the disease has been haphazard at best. Present methods of genetic testing can only narrow down the search to about 30% of the general population. These results give doctors a means to discover what further genetic risk factors leave people vulnerable to developing celiac disease.
Queen Mary, University of London Press Release - Public release date: 10-Jun-2007
health writer who lives in San Francisco and is a frequent author of articles for Celiac.com.
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