A transgene consisting of an upstream glucokinase (GK) promoter fragment linked to coding sequenc... more A transgene consisting of an upstream glucokinase (GK) promoter fragment linked to coding sequences of the human growth hormone gene was expressed in certain neuroendocrine cells of the pancreas, pituitary, brain, gut, thyroid, and lungs of mice. In pancreas, the transgene was expressed in a nonuniform manner among beta cells and in a variable but substantial fraction of the other islet cell types. In pituitary, it was expressed in corticotropes, and in brain, it was expressed in cells of the medial hypothalamus. Within the gut transgene expression was detected in a subset of enteroendocrine cells of the stomach and duodenal epithelium, some of which also exhibited glucagon-like polypeptide-1 immunoreactivity. In thyroid, transgene expression was observed in C cells of neonatal animals, whereas in the lung, it was expressed among rare endocrine cells of the bronchopulmonary mucosa. RNA polymerase chain reaction analysis of human growth hormone mRNA corroborated the tissue-specific transgene expression pattern. Prompted by the finding of transgene expression in specific neuroendocrine cells, we sought to determine whether GK mRNA and GK itself was also expressed in the brain and gut, tissues not previously associated with the expression of this enzyme. Using rat tissues, GK mRNA was detected by RNA polymerase chain reaction in both the brain and intestine and was localized to specific cells in the hypothalamus and enteric mucosa by in situ hybridization. A high Km glucose phosphorylating activity was detected from isolated rat jejunal enterocytes that displayed a chromatographic elution profile identical to hepatic GK. GK immunoreactivity was detected in cells of the medial hypothalamus with many of the same cells also displaying GLUT2 immunoreactivity. Together, these studies provide evidence for upstream GK promoter activity, GK mRNA, and GK itself in certain neuroendocrine cells outside the pancreatic islet and lead us to suggest that GK may play a broader role in glucose sensing by neuroendocrine cells than was thought previously.
Lysosomal acid lipase deficiency (LAL-D), or cholesterol ester storage disease, is a rare inherit... more Lysosomal acid lipase deficiency (LAL-D), or cholesterol ester storage disease, is a rare inherited lipid metabolism disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. The case of a 9 year old patient with growth retardation and hepatosplenomegaly had a confirmed diagnosis of LAL-D. The initial response to the recommended Sebelipase alfa enzyme replacement therapy in a biweekly infusion regimen was suboptimal; elevated lipid levels and transaminase elevations continued. After dose escalation by increasing the dose per infusion from 2.2mg/kg to 2.5mg/kg and change from a biweekly to a weekly infusion regimen resulted in significant improvement in the total cholesterol, triglycerides, low density lipoprotein and transaminases. To our knowledge this is the first report in the US on dose escalation and infusion frequency increase in a patient of this age, which resulted in improved short term outcome.
Objectives Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testi... more Objectives Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testing since the 1990s. In patients, short ePFT assesses acinar function, unlike the longer version for ductal function in adults. The present study summarizes characteristics of 1913 short ePFTs (S-ePFT) performed at 2 centers since 2001. Methods The main indications in patients presenting at ages infancy to 24.3 years, for the S-ePFT were failure to thrive, weight loss, diarrhea, and abdominal pain with bloating. Secretin was administered as bolus, and 4 aliquots of fluid were collected between 4 and 10 minutes after administration. Amylase, lipase, trypsin, and chymotrypsin activities were measured in the laboratory. Results The pH of consecutive samples increased by 0.3 to 0.7. Overall, 36.7% had abnormal S-ePFT with selective amylase deficiency (9.5%) and generalized enzyme deficiency (8.9%) being the most frequent. Retest reproducibility, repeatability, and clinical validity were high. By adding S-ePFT to endoscopy for the suspicion of malabsorption, the abnormal findings increased by 36.9%. Conclusions Short ePFT assesses pancreatic acinar function in a reliable and clinically meaningful way in patients. Diagnostic yield of endoscopy increased substantially albeit with increased sedation time. By S-ePFT ductal function, cytokines and proteomics can also be assessed.
Journal of Pediatric Gastroenterology & Nutrition, 2020
Objectives: The gold standard diagnostic procedure for food proteininduced proctocolitis (FPIP) r... more Objectives: The gold standard diagnostic procedure for food proteininduced proctocolitis (FPIP) requires flexible sigmoidoscopy (FS). To date there is no validated, noninvasive test to confirm FPIP diagnosis. Eosinophilderived neurotoxin (EDN), a product of eosinophil (EOS) degranulation, has been shown to correlate with eosinophil infiltration in other tissues. Our objective was to compare EDN concentrations in rectal epithelial samples from infants with FPIP with those from a control population. Methods: Children who underwent routine FS at Arnold Palmer Hospital for Children were enrolled in an IRB-approved, prospective, open-label pilot study between July 2017 and May 2019. We obtained rectal epithelial samples via: rectal swab, cytology brushing through FS, and rectal biopsy through FS. We then measured EDN levels in the samples and compared levels found in infants with FPIP against levels found in the control group. FPIP was defined as more than 60 EOS per 10 high-power fields (HPF) in rectal epithelial tissue obtained via rectosigmoid biopsy. Results: Twenty-four patients were enrolled. The control group (n ¼ 13) included patients with normal histopathology (84% boys, mean age 19 months, SD 6 months) and the FPIP group (n ¼ 11) included patients with FPIP confirmed via biopsy (45% boys, mean age 6.9 months, SD 9 months). EDN concentration was significantly higher in the FPIP group than in the control group, for 2 sampling methods: rectal biopsy (183.6 AE 114.6 vs 76.6 AE 71.0 mg/ mL; P ¼ 0.010) and rectal swab (66.2 AE 64.8 vs 20.4 AE 22.2 mg/mL; P ¼ 0.025). Conclusions: EDN concentrations measured from rectal swab and rectal biopsy samples is elevated and may be a useful tool to screen for FPIP in children.
Journal of Pediatric Gastroenterology and Nutrition, 2004
Methods: 56 celiac patients diagnosed after a large screening conducted recently in the US, accep... more Methods: 56 celiac patients diagnosed after a large screening conducted recently in the US, accepted to be retested for celiac related antibodies (h-tTG= human tissue transglutaminase, AEA= antiendomysium antibodies), diabetes related auto-antibodies (IA-2= tyrosine ...
Introduction: Feeding problems are common in early childhood with up to 40% of toddlers and young... more Introduction: Feeding problems are common in early childhood with up to 40% of toddlers and young children displaying some difficulty with meals. Usually these behaviors eventually resolve, however 3% to 10% of children develop chronic feeding disorders, with texture aversion and sensory problems. This in turn may impact their developmental and/or medical outcome. Studies have demonstrated the efficacy of inpatient and outpatient childhood feeding programs. Few have reported underlying gastrointestinal (GI) etiologies uncovered during investigative evaluations prior to enrollment in such programs. We present our experience at our outpatient feeding center. Methods: We retrospectively reviewed medical records of 52 patients that completed a 4-week intense feeding program for feeding difficulties. Children enrolled in the program displayed total food refusal, texture aversion, or food selectivity to the extent of being nutritionally compromised. Our program is supervised by two pediatric gastroenterologists, and involves dietitians, occupational, behavioral, and speech therapists. Patients underwent a multidisciplinary evaluation and thorough pertinent investigation for underlying etiologies, including endoscopies, laboratory studies, allergy testing, gastric emptying scan, pH impedance study, oropharyngeal motility studies, and radiographic imaging. We report underlying GI conditions found in this cohort. Results: The majority of enrolled patients were males (79%). Average age was 4.78 ±2.83years. Thirty-nine children underwent esophagogastroduodenoscopy. Half (20) of them showed abnormal esophageal pathology with the majority showing changes suggestive of esophagitis and 2 (5%) had eosinophilic esophagitis. Gastric pathology was abnormal in 7/39, mainly with findings of inactive chronic gastritis. Duodenal biopsies were normal in 92% of the cases. Lactase deficiency was present in 17/39. Microbial overgrowth was found in 17 of 22 who had duodenal culture. Gastric emptying scan was done in 28 patients with 5 showing gastroparesis and 1 dumping syndrome. Eighty percent of the patients had constipation at enrollment. Forty underwent ImmunoCap testing and 21 were abnormal. Fourteen were on allergy medications. pH/impedance studies were done in 18 children and 13 showed abnormal reflux patterns (acidic and/or volume). Proton pump inhibitors were prescribed in 33 (63%) and H 2-blockers in 16 (30%). A prokinetic agent was used in 23 (44%) children. Conclusion: Gastrointestinal organic etiologies are common in children with feeding difficulty and should always be considered prior to enrollment into an intense feeding program.
... for coeliac disease in the USA. Neri E, Not T, Horvath K, Kryszak D, Drago S, Di Pierro MR, T... more ... for coeliac disease in the USA. Neri E, Not T, Horvath K, Kryszak D, Drago S, Di Pierro MR, Tommasini A, Ventura A, Fasano A. Center for Celiac Research, University of Maryland at Baltimore, USA. [email protected] PMID ...
Journal of Pediatric Gastroenterology and Nutrition, 1994
Dans une Classification des climats tropicaux, il faut considerer: 1) la latitude qui determine l... more Dans une Classification des climats tropicaux, il faut considerer: 1) la latitude qui determine les variations de la temperature, les differentes longueurs des jours, les Saisons et, de lä, le climat de la zone; 2) la temperature moyenne annuelle d'apres laquelle on distingue les «climats d'altitude» (tierra helada, päramo, tierra fria, templada, caliente); 3) l'humidite qui conduit ä une nouvelle subdivision parmi les climats d'altitude en type aride, semi¬ aride, semi-humide, humide et perhumide. Le Systeme compte ainsi 25 types ou regions climatiques. Dans les tropiques de l'Amerique du sud, ce sont les facteurs de pluviosite qui ont fait leurs preuves, car 1) la zone climatique est donnee, 2) on utilise le denominateur (tem¬ perature T) pour determiner les zones d'altitudes, 3) le quotient (N:T) donne l'humidite ä l'interieur des zones d'altitude. Par contre, les facteurs de pluviosite ne sont d'aucune utilite lorsque le quotient seul est utilise, parce que dans ce cas, le climat d'altitude n'est pas fixe. * Referat, gehalten in der Sektion «Geographie und Kartographie» an der SNG-Tagung in Basel am 23. September 1956.
Journal of Pediatric Gastroenterology and Nutrition, 2005
Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in g... more Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion.
Methods: Fourteen American celiac families (14 CD patients and 38 first degree relatives, includi... more Methods: Fourteen American celiac families (14 CD patients and 38 first degree relatives, including both parents) and 14 Italian celiac families (14 CD patients and 45 first degree relatives, including both parents) were included in this study. DNA was extracted from whole blood samples. ...
A transgene consisting of an upstream glucokinase (GK) promoter fragment linked to coding sequenc... more A transgene consisting of an upstream glucokinase (GK) promoter fragment linked to coding sequences of the human growth hormone gene was expressed in certain neuroendocrine cells of the pancreas, pituitary, brain, gut, thyroid, and lungs of mice. In pancreas, the transgene was expressed in a nonuniform manner among beta cells and in a variable but substantial fraction of the other islet cell types. In pituitary, it was expressed in corticotropes, and in brain, it was expressed in cells of the medial hypothalamus. Within the gut transgene expression was detected in a subset of enteroendocrine cells of the stomach and duodenal epithelium, some of which also exhibited glucagon-like polypeptide-1 immunoreactivity. In thyroid, transgene expression was observed in C cells of neonatal animals, whereas in the lung, it was expressed among rare endocrine cells of the bronchopulmonary mucosa. RNA polymerase chain reaction analysis of human growth hormone mRNA corroborated the tissue-specific transgene expression pattern. Prompted by the finding of transgene expression in specific neuroendocrine cells, we sought to determine whether GK mRNA and GK itself was also expressed in the brain and gut, tissues not previously associated with the expression of this enzyme. Using rat tissues, GK mRNA was detected by RNA polymerase chain reaction in both the brain and intestine and was localized to specific cells in the hypothalamus and enteric mucosa by in situ hybridization. A high Km glucose phosphorylating activity was detected from isolated rat jejunal enterocytes that displayed a chromatographic elution profile identical to hepatic GK. GK immunoreactivity was detected in cells of the medial hypothalamus with many of the same cells also displaying GLUT2 immunoreactivity. Together, these studies provide evidence for upstream GK promoter activity, GK mRNA, and GK itself in certain neuroendocrine cells outside the pancreatic islet and lead us to suggest that GK may play a broader role in glucose sensing by neuroendocrine cells than was thought previously.
Lysosomal acid lipase deficiency (LAL-D), or cholesterol ester storage disease, is a rare inherit... more Lysosomal acid lipase deficiency (LAL-D), or cholesterol ester storage disease, is a rare inherited lipid metabolism disorder affecting the breakdown of cholesterol esters and triglycerides within lysosomes. The case of a 9 year old patient with growth retardation and hepatosplenomegaly had a confirmed diagnosis of LAL-D. The initial response to the recommended Sebelipase alfa enzyme replacement therapy in a biweekly infusion regimen was suboptimal; elevated lipid levels and transaminase elevations continued. After dose escalation by increasing the dose per infusion from 2.2mg/kg to 2.5mg/kg and change from a biweekly to a weekly infusion regimen resulted in significant improvement in the total cholesterol, triglycerides, low density lipoprotein and transaminases. To our knowledge this is the first report in the US on dose escalation and infusion frequency increase in a patient of this age, which resulted in improved short term outcome.
Objectives Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testi... more Objectives Endoscopic pancreatic function test (ePFT) has been in use for exocrine function testing since the 1990s. In patients, short ePFT assesses acinar function, unlike the longer version for ductal function in adults. The present study summarizes characteristics of 1913 short ePFTs (S-ePFT) performed at 2 centers since 2001. Methods The main indications in patients presenting at ages infancy to 24.3 years, for the S-ePFT were failure to thrive, weight loss, diarrhea, and abdominal pain with bloating. Secretin was administered as bolus, and 4 aliquots of fluid were collected between 4 and 10 minutes after administration. Amylase, lipase, trypsin, and chymotrypsin activities were measured in the laboratory. Results The pH of consecutive samples increased by 0.3 to 0.7. Overall, 36.7% had abnormal S-ePFT with selective amylase deficiency (9.5%) and generalized enzyme deficiency (8.9%) being the most frequent. Retest reproducibility, repeatability, and clinical validity were high. By adding S-ePFT to endoscopy for the suspicion of malabsorption, the abnormal findings increased by 36.9%. Conclusions Short ePFT assesses pancreatic acinar function in a reliable and clinically meaningful way in patients. Diagnostic yield of endoscopy increased substantially albeit with increased sedation time. By S-ePFT ductal function, cytokines and proteomics can also be assessed.
Journal of Pediatric Gastroenterology & Nutrition, 2020
Objectives: The gold standard diagnostic procedure for food proteininduced proctocolitis (FPIP) r... more Objectives: The gold standard diagnostic procedure for food proteininduced proctocolitis (FPIP) requires flexible sigmoidoscopy (FS). To date there is no validated, noninvasive test to confirm FPIP diagnosis. Eosinophilderived neurotoxin (EDN), a product of eosinophil (EOS) degranulation, has been shown to correlate with eosinophil infiltration in other tissues. Our objective was to compare EDN concentrations in rectal epithelial samples from infants with FPIP with those from a control population. Methods: Children who underwent routine FS at Arnold Palmer Hospital for Children were enrolled in an IRB-approved, prospective, open-label pilot study between July 2017 and May 2019. We obtained rectal epithelial samples via: rectal swab, cytology brushing through FS, and rectal biopsy through FS. We then measured EDN levels in the samples and compared levels found in infants with FPIP against levels found in the control group. FPIP was defined as more than 60 EOS per 10 high-power fields (HPF) in rectal epithelial tissue obtained via rectosigmoid biopsy. Results: Twenty-four patients were enrolled. The control group (n ¼ 13) included patients with normal histopathology (84% boys, mean age 19 months, SD 6 months) and the FPIP group (n ¼ 11) included patients with FPIP confirmed via biopsy (45% boys, mean age 6.9 months, SD 9 months). EDN concentration was significantly higher in the FPIP group than in the control group, for 2 sampling methods: rectal biopsy (183.6 AE 114.6 vs 76.6 AE 71.0 mg/ mL; P ¼ 0.010) and rectal swab (66.2 AE 64.8 vs 20.4 AE 22.2 mg/mL; P ¼ 0.025). Conclusions: EDN concentrations measured from rectal swab and rectal biopsy samples is elevated and may be a useful tool to screen for FPIP in children.
Journal of Pediatric Gastroenterology and Nutrition, 2004
Methods: 56 celiac patients diagnosed after a large screening conducted recently in the US, accep... more Methods: 56 celiac patients diagnosed after a large screening conducted recently in the US, accepted to be retested for celiac related antibodies (h-tTG= human tissue transglutaminase, AEA= antiendomysium antibodies), diabetes related auto-antibodies (IA-2= tyrosine ...
Introduction: Feeding problems are common in early childhood with up to 40% of toddlers and young... more Introduction: Feeding problems are common in early childhood with up to 40% of toddlers and young children displaying some difficulty with meals. Usually these behaviors eventually resolve, however 3% to 10% of children develop chronic feeding disorders, with texture aversion and sensory problems. This in turn may impact their developmental and/or medical outcome. Studies have demonstrated the efficacy of inpatient and outpatient childhood feeding programs. Few have reported underlying gastrointestinal (GI) etiologies uncovered during investigative evaluations prior to enrollment in such programs. We present our experience at our outpatient feeding center. Methods: We retrospectively reviewed medical records of 52 patients that completed a 4-week intense feeding program for feeding difficulties. Children enrolled in the program displayed total food refusal, texture aversion, or food selectivity to the extent of being nutritionally compromised. Our program is supervised by two pediatric gastroenterologists, and involves dietitians, occupational, behavioral, and speech therapists. Patients underwent a multidisciplinary evaluation and thorough pertinent investigation for underlying etiologies, including endoscopies, laboratory studies, allergy testing, gastric emptying scan, pH impedance study, oropharyngeal motility studies, and radiographic imaging. We report underlying GI conditions found in this cohort. Results: The majority of enrolled patients were males (79%). Average age was 4.78 ±2.83years. Thirty-nine children underwent esophagogastroduodenoscopy. Half (20) of them showed abnormal esophageal pathology with the majority showing changes suggestive of esophagitis and 2 (5%) had eosinophilic esophagitis. Gastric pathology was abnormal in 7/39, mainly with findings of inactive chronic gastritis. Duodenal biopsies were normal in 92% of the cases. Lactase deficiency was present in 17/39. Microbial overgrowth was found in 17 of 22 who had duodenal culture. Gastric emptying scan was done in 28 patients with 5 showing gastroparesis and 1 dumping syndrome. Eighty percent of the patients had constipation at enrollment. Forty underwent ImmunoCap testing and 21 were abnormal. Fourteen were on allergy medications. pH/impedance studies were done in 18 children and 13 showed abnormal reflux patterns (acidic and/or volume). Proton pump inhibitors were prescribed in 33 (63%) and H 2-blockers in 16 (30%). A prokinetic agent was used in 23 (44%) children. Conclusion: Gastrointestinal organic etiologies are common in children with feeding difficulty and should always be considered prior to enrollment into an intense feeding program.
... for coeliac disease in the USA. Neri E, Not T, Horvath K, Kryszak D, Drago S, Di Pierro MR, T... more ... for coeliac disease in the USA. Neri E, Not T, Horvath K, Kryszak D, Drago S, Di Pierro MR, Tommasini A, Ventura A, Fasano A. Center for Celiac Research, University of Maryland at Baltimore, USA. [email protected] PMID ...
Journal of Pediatric Gastroenterology and Nutrition, 1994
Dans une Classification des climats tropicaux, il faut considerer: 1) la latitude qui determine l... more Dans une Classification des climats tropicaux, il faut considerer: 1) la latitude qui determine les variations de la temperature, les differentes longueurs des jours, les Saisons et, de lä, le climat de la zone; 2) la temperature moyenne annuelle d'apres laquelle on distingue les «climats d'altitude» (tierra helada, päramo, tierra fria, templada, caliente); 3) l'humidite qui conduit ä une nouvelle subdivision parmi les climats d'altitude en type aride, semi¬ aride, semi-humide, humide et perhumide. Le Systeme compte ainsi 25 types ou regions climatiques. Dans les tropiques de l'Amerique du sud, ce sont les facteurs de pluviosite qui ont fait leurs preuves, car 1) la zone climatique est donnee, 2) on utilise le denominateur (tem¬ perature T) pour determiner les zones d'altitudes, 3) le quotient (N:T) donne l'humidite ä l'interieur des zones d'altitude. Par contre, les facteurs de pluviosite ne sont d'aucune utilite lorsque le quotient seul est utilise, parce que dans ce cas, le climat d'altitude n'est pas fixe. * Referat, gehalten in der Sektion «Geographie und Kartographie» an der SNG-Tagung in Basel am 23. September 1956.
Journal of Pediatric Gastroenterology and Nutrition, 2005
Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in g... more Celiac disease is an immune-mediated enteropathy caused by a permanent sensitivity to gluten in genetically susceptible individuals. It occurs in children and adolescents with gastrointestinal symptoms, dermatitis herpetiformis, dental enamel defects, osteoporosis, short stature, delayed puberty and persistent iron deficiency anemia and in asymptomatic individuals with type 1 diabetes, Down syndrome, Turner syndrome, Williams syndrome, selective immunoglobulin (Ig)A deficiency and first degree relatives of individuals with celiac disease. The Celiac Disease Guideline Committee of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has formulated a clinical practice guideline for the diagnosis and treatment of pediatric celiac disease based on an integration of a systematic review of the medical literature combined with expert opinion.
Methods: Fourteen American celiac families (14 CD patients and 38 first degree relatives, includi... more Methods: Fourteen American celiac families (14 CD patients and 38 first degree relatives, including both parents) and 14 Italian celiac families (14 CD patients and 45 first degree relatives, including both parents) were included in this study. DNA was extracted from whole blood samples. ...
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Papers by Karoly Horvath