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Biomedical subjects

Raanan Shamir

Publications and source records attributed to Raanan Shamir.

At least 19 recordsLinked to original sources
PubMed2025

RELA Haploinsufficiency Manifesting as an Atypical Phenotype of Crohn's Disease.

BACKGROUND: Mutations in RELA, a key component of NF-κB signaling, are associated with dysregulated immune responses and inflammatory disorders. While immunodeficiency phenotypes associated with RELA haploinsufficiency have been reported, gastrointestinal manifestations remain poorly described. This study aimed to characterize the clinical, genomic, and immunological features of a patient presenting with an atypical Crohn's-like phenotype driven by RELA haploinsufficiency. METHODS: Whole-exome sequencing was performed, and results were confirmed by Sanger sequencing. Protein modeling, Western blotting, immunofluorescence, and nuclear extract-based NF-κB activation assays were conducted to assess the functional impact of the identified variant. Immune profiling was performed using mass cytometry time of flight (CyTOF) and single-cell RNA sequencing (scRNA-seq) and compared to controls. RESULTS: We studied a 17-year-old male diagnosed with pan-enteric Crohn's disease (CD), perianal fistulas, chronic mucocutaneous candidiasis, and chronic lymphopenia. Sequencing identified a heterozygous missense variant in RELA (c.587T>C, p.V196A) that potentially impairs RelA (p65) protein stability, confirmed by reduced activity and diminished protein expression. CyTOF analysis revealed decreased circulating T regulatory cells (Tregs), absence of mucosal Tregs, high apoptotic rates, and elevated IFN-γ induced levels, while scRNA-seq demonstrated a robust type I/II interferon signature in multiple immune subsets. Dysregulated mucosal-associated invariant T (MAIT) and cytotoxic CD4+ T cells exhibited upregulation of IL23R and ADAM12, further linking RELA dysfunction to enhanced pro-inflammatory T cell response and tissue inflammation. CONCLUSION: This study links RELA haploinsufficiency with CD-like features, Th1/Th17 polarization, and interferon-driven inflammation, emphasizing the importance of genetic evaluation in patients with atypical or refractory IBD.

Humans↗
PubMed2006

Impaired gastric myolectrical activity in patients with cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF) is frequently associated with gastrointestinal complaints that can be due to gastrointestinal dysmotility. Electrogastrography (EGG) is an attractive, non-invasive procedure to assess gastric electric activity. The aims of our study were to investigate EGG abnormalities in pancreatic sufficient and pancreatic insufficient CF patients, and to examine whether EGG correlates with gastric emptying as assessed by scintigraphy. METHODS: EGG was performed in 23 CF patients (12 pancreatic sufficient patients, 11 pancreatic insuffficient) by using cutaneous recording pre- and postprandialy. Pre- and postpostprandial EGG indexes were compared to 19 healthy control patients. Gastric emptying was assessed simultaneously by gastric scintigraphy in 11 of the 23 CF patients. Six patients underwent a repeated scintigraphy recording following a month of treatment with cisapride. RESULTS: Abnormal patterns of EGG were found in 78.3% of CF patients compared to 31.3% of controls during fasting (p<or=0.003) and in 56.5% of CF patients compared to 15.7% in healthy controls postprandially (p<or=0.018). In the CF patients, dysmotility consisted mostly of bradygastria during both fasting (16 of 18 with abnormal EGG) and postprandially (12 of 13 [92.3%]). Gastric emptying results on scintigraphy were in agreement with EGG results in 9 of 11 (two normal and seven pathological). Five of the six patients treated with cisapride (83.3%) showed significant improvement in EGG indexes. CONCLUSIONS: Our results suggest that EGG abnormalities are frequently found in CF patients. The similar rate of EGG and gastric scintigraphy abnormalities suggests that EGG may be a useful clinical tool in CF patients.

Adolescent↗
PubMed2006

Soy protein infant formulae and follow-on formulae: a commentary by the ESPGHAN Committee on Nutrition.

This comment by the European Society for Paediatric Gastroenterology Hepatology and Nutrition (ESPGHAN) Committee on Nutrition summarizes available information on the composition and use of soy protein formulae as substitutes for breastfeeding and cows' milk protein formulae as well as on their suitability and safety for supporting adequate growth and development in infants. Soy is a source of protein that is inferior to cows' milk, with a lower digestibility and bioavailability as well as a lower methionine content. For soy protein infant formulae, only protein isolates can be used, and minimum protein content required in the current European Union legislation is higher than that of cows' milk protein infant formulae (2.25 g/100 kcal vs. 1.8 g/100kcal). Soy protein formulae can be used for feeding term infants, but they have no nutritional advantage over cows' milk protein formulae and contain high concentrations of phytate, aluminum, and phytoestrogens (isoflavones), which might have untoward effects. There are no data to support the use of soy protein formulae in preterm infants. Indications for soy protein formulae include severe persistent lactose intolerance, galactosemia, and ethical considerations (e.g., vegan concepts). Soy protein formulae have no role in the prevention of allergic diseases and should not be used in infants with food allergy during the first 6 months of life. If soy protein formulae are considered for therapeutic use in food allergy after the age of 6 months because of their lower cost and better acceptance, tolerance to soy protein should first be established byclinical challenge. There is no evidence supporting the use of soy protein formulae for the prevention or management of infantile colic, regurgitation, or prolonged crying.

Colic↗
PubMed2006

Feeding preterm infants after hospital discharge: a commentary by the ESPGHAN Committee on Nutrition.

Survival of small premature infants has markedly improved during the last few decades. These infants are discharged from hospital care with body weight below the usual birth weight of healthy term infants. Early nutrition support of preterm infants influences long-term health outcomes. Therefore, the ESPGHAN Committee on Nutrition has reviewed available evidence on feeding preterm infants after hospital discharge. Close monitoring of growth during hospital stay and after discharge is recommended to enable the provision of adequate nutrition support. Measurements of length and head circumference, in addition to weight, must be used to identify those preterm infants with poor growth that may need additional nutrition support. Infants with an appropriate weight for postconceptional age at discharge should be breast-fed when possible. When formula-fed, such infants should be fed regular infant formula with provision of long-chain polyunsaturated fatty acids. Infants discharged with a subnormal weight for postconceptional age are at increased risk of long-term growth failure, and the human milk they consume should be supplemented, for example, with a human milk fortifier to provide an adequate nutrient supply. If formula-fed, such infants should receive special postdischarge formula with high contents of protein, minerals and trace elements as well as an long-chain polyunsaturated fatty acid supply, at least until a postconceptional age of 40 weeks, but possibly until about 52 weeks postconceptional age. Continued growth monitoring is required to adapt feeding choices to the needs of individual infants and to avoid underfeeding or overfeeding.

Anthropometry↗
PubMed2006

Gastrointestinal tract as a target organ for orally administered insulin.

The intestine is not considered to be a classic target tissue for insulin. Recent in vitro and in vivo experiments suggest that intestinal as well as systemic effects are observed following oral administration of insulin. Local effects include enhancement of intestinal growth, cell maturation, enzyme expression, gut adaptation after intestinal resection and reduction of intestinal permeability. Systemic effects, at least in animal models, include favorable effects on blood glucose and lipid profile and on the prevention of autoimmunity and attenuating the atherosclerotic process.

Administration, Oral↗
PubMed2006

Long-term lamivudine therapy for chronic hepatitis B infection in children unresponsive to interferon.

OBJECTIVES: Prolonged lamivudine treatment in adults has been shown to improve hepatitis B e (HBe) seroconversion rates in patients with chronic hepatitis B. This prospective open study reports the results of prolonged lamivudine treatment in a group of children with chronic hepatitis B. PATIENTS AND METHODS: Twenty-two children and adolescents age 13.2 years (range, 9.5-18 years), who have been treated with lamivudine for 1 year, continued treatment with lamivudine (3 mg/kg/day, up to 100 mg/d) as long as there was evidence of continued biochemical and virological benefit compared with baseline. We evaluated virological and biochemical responses, the occurrence of YMDD mutants and adverse effects during 4 years of follow-up. RESULTS: After 4 years on lamivudine, only 4 patients (18%) underwent HBe seroconversion. In addition, in 3 patients (13%), the treatment was stopped when lamivudine's lack of efficacy became evident. During the 4-year study period, we recorded a continuing decline in the participants' number, mostly because of lack of compliance with treatment (9/22, 41%). Only 5 children were still receiving lamivudine and showing benefit after 4 years. In 2 children, treatment termination and YMDD mutant emergence were associated with hepatitis flare. Besides subclinical elevation of creatine phosphokinase, no other adverse events were recorded during the study period. CONCLUSIONS: Four years after starting lamivudine treatment, most children from this study were off lamivudine, mainly because of lack of compliance and poor HBe seroconversion. These findings suggest that continuing treatment with lamivudine for undefined periods is hard to implement and does not improve HBe seroconversion.

Adolescent↗
PubMed2006

Fat intolerance in developmentally impaired children with severe feeding intolerance.

Children with a variety of genetic, metabolic, and neurologic disorders can suffer from severe feeding intolerance that is unresponsive to medical, surgical, and nutritional therapy. Developmentally disabled tube-fed children with severe upper gastrointestinal symptoms that persisted after fundoplication who were unresponsive to all medical, surgical, and nutritional interventions underwent a thorough gastrointestinal evaluation, including gastroscopy, pH-metry, upper gastrointestinal barium series, and gastric emptying studies. They were placed on a low-fat diet, and the symptoms before and after the diet were compared. The patients were then rechallenged with incremental increases in fat until the symptoms recurred or the patients reached their former fat concentration. Six children meeting the study criteria were evaluated. Four of these patients had a significant improvement in symptoms, oral intake and feeding tolerance with a decrease in fat intake, and relapse of symptoms when fat calories were increased. Improvement occurred in children who had been intolerant to duodenal feeding. We were subsequently able to wean two children from tube feeding. Dietary fat can provoke upper gastrointestinal symptoms in children with gastric and intestinal dysmotility. Short-term manipulation of dietary fat intake can improve tolerance to feeding.

Child, Preschool↗
PubMed2006

Parenteral nutrition in neonatology--to standardize or individualize?

Premature very low birth weight (< 1500 g) infants comprise one of the largest groups receiving parenteral nutrition. PN should be optimized to answer their high nutritional requirements and suit their metabolic status, but should also be validated pharmaceutically. PN can be provided as a standard, usually commercial, formulation, representing the average needs of a large group of patients. Alternatively, an individualized PN compound adapted to the patient's needs can be prescribed and prepared, usually on a daily basis. The main advantage of individually prescribed PN is that it is tailored to suit a specific patient, thereby assuring the best possible nutrition and biochemical control. Batch-produced standardized PN bags can be readily available as ward stocks in neonatal intensive care units, enabling initiation of early PN immediately after the delivery of a premature infant. Moreover, standard PN solutions incorporate expert nutritional knowledge and support. A combination of standardized PN bags, prepared under strict standardization criteria, for most neonates, with a small number of specifically tailored individualized PN formulations for those in need for them, could reduce pharmacy workload and costs and increase safety, while maintaining the desired clinical flexibility. For those in need of the individualized PN formulations, a computerized ordering system can save time, decrease prescription and compounding errors, and improve quality of nutritional care.

Clinical Pharmacy Information Systems↗
PubMed2006

[The significance of IL-13 gene +2044G/A mutation in patients with inflammatory bowel disease].

BACKGROUND: Inflammatory bowel disease (IBD) is caused by a combination of genetic, immunological and environmental factors. Despite recent advances in the study of IBD pathogenesis, including the discovery of the NOD2/CARD15 mutation in 40% of Crohn's Disease (CD) patients, in most IBD patients no known mutations have yet been discovered. The interleukin (IL)-13 gene is located near the IBD5 locus on chromosome 5q31, known to be in linkage disequilibrium with CD. IL-13 has a role in the pathogenesis of several chronic inflammatory diseases including IBD. The +2044G/A mutation, which encodes an IL-13 protein with glutamine instead of arginine, has been associated with various inflammatory conditions. However, its role in IBD has not been defined. AIM: This is a study of the role of the IL-13 gene +2044G/A mutation in the susceptibility to and phenotype of IBD. METHODS: Two hundred and eighty-five patients with CD and 111 cases of ulcerative colitis (UC) were enrolled in the study. Mutation frequency was determined using restriction fragment length polymorphism study in IBD patients and 178 healthy ethnically matched controls. The mutated allele frequency was determined in various clinical sub-groups of IBD patients. Statistical significance of the differences in allele frequency in CD and UC patients and healthy controls was determined. RESULTS: The +2044G/A allele frequency was similar in CD, UC and healthy controls (23.3%, 19.4%, 19.6%, respectively, p = 0.294). There was no significant association of +2044G/A mutation carriage with specific phenotypes of CD and UC. CONCLUSION: The IL-13 gene +2044G/A mutation has no significant role in susceptibility to and phenotype of IBD.

Colitis, Ulcerative↗
PubMed2005

Paraoxonases (PONs) 1, 2, and 3 are expressed in human and mouse gastrointestinal tract and in Caco-2 cell line: selective secretion of PON1 and PON2.

The paraoxonase (PON) family contains three genes (PON1/2/3) that are believed to be involved in the protection against oxidative stress. PON1 and PON3 are circulating in serum attached to high-density lipoprotein fraction (HDL), whereas PON2 is ubiquitously expressed. The intestine is the second major organ that synthesizes lipoproteins; therefore, we examined PON mRNA expression and protein levels in gastrointestinal biopsies from humans, from C57BL6 mice, and from Caco-2 cells, a colon carcinoma-derived cell line that exhibits properties of intestinal epithelium at differentiation. PON 1/2/3 mRNA and proteins were present in human biopsies with variable expression among different gastrointestinal segments. Only PON2 and PON3 were present in mice. All PON mRNA, proteins, and enzymatic activities were present in Caco-2 cells. Oxidation of CaCo-2 cells with ferrum ascorbate had no significant effect on PON mRNA expression, but it increased paraoxonase and lactonase activity, whereas statinase activity was decreased. We showed polarized secretion of PON1 (basolateral) and PON2 (apical) into Caco-2 culture medium, raising the possibility that intestine is capable of producing and releasing PON1 and PON3 to the circulation, whereas PON2 is released at the brush-border membrane to intestinal lumen where it may perform another yet unclear function.

Animals↗
PubMed2005

Intestinal and systemic effects of oral insulin supplementation in rats after weaning.

Oral insulin has intestinal trophic effects in suckling animals. In mice, lower glucose and lipid levels may be seen when oral insulin is given after the weaning period. The purpose of the present study is to examine local and systemic effects of oral insulin supplementation in rats in the postweaning period. Immediately after weaning, Sprague-Dawley rats received either drinking water (controls) or oral insulin in their drinking water (1 U/ml) for either 1 week or 6 weeks. Intestinal mucosal parameters (bowel and mucosal weight, mucosal DNA and protein) and histological changes were examined in all study groups. Glucose levels were monitored weekly, and at the end of the study, blood levels of glucose, lipids, and insulin were measured in the fasting state. After 1 week of insulin supplementation, mucosal weight in duodenum and jejunum as well as jejunal DNA content were significantly higher in insulin-supplemented rats compared to controls. Duodenal circumference and villus height in jejunum were significantly higher in insulin-supplemented rats compared to controls on both day 7 and day 42. Total cholesterol levels were significantly lower in the study group compared with the controls. We conclude that oral insulin supplementation exerts intestinal trophic effects, as well as systemic effects in the postweaning period in rats.

Administration, Oral↗
PubMed2005

Oral insulin enhances intestinal regrowth following massive small bowel resection in rat.

Experimental studies have suggested that insulin (INS) plays an important role in small intestinal growth and development. In the present study we investigated the effect of oral INS on structural intestinal adaptation and enterocyte proliferation and loss via apoptosis in a rat model of short bowel syndrome (SBS). Male Sprague-Dawley rats were divided into three experimental groups: sham rats underwent bowel transection, SBS rats underwent 75% small bowel resection, and SBS-INS rats underwent bowel resection and were treated with oral INS given in the drinking water from the 3rd to the 15th postoperative day. Parameters of intestinal adaptation (bowel and mucosal weight, mucosal DNA and protein, villous height, and crypt depth), enterocyte proliferation, and apoptosis were determined on day 15. SBS-INS rats demonstrated a significant increase (vs SBS rats) in jejunal and ileal overall bowel and mucosal weight, ileal mucosal DNA and protein, ileal villous height, and crypt depth. SBS-INS rats also showed an increased cell proliferation index in jejunum and ileum and decreased apoptotic index in jejunum compared to SBS animals. In conclusion, in a rat model of SBS, oral INS strongly enhances intestinal adaptation. Possible mechanisms may include increased cell proliferation and decreased enterocyte loss via apoptosis.

Adaptation, Physiological↗
PubMed2005

Beneficial effects of oral insulin on intestinal recovery following ischemia-reperfusion injury in rat.

BACKGROUND: It has been reported that oral insulin has a trophic effect on intestinal mucosa, but the precise mechanism of its action is still unclear. The purpose of the present study was to investigate the effect of oral insulin on ischemia-reperfusion (IR) intestinal mucosal injury in rat. MATERIALS AND METHODS: Male Sprague-Dawley rats underwent laparotomy (Sham) or IR-intestinal damage by clamping both the superior mesenteric artery and the portal vein for 30 min followed by 24 h reperfusion. IR-INS rats were treated with oral insulin given in drinking water (1U/ml) 48 h before and after IR. Intestinal structural changes, enterocyte proliferation, and enterocyte apoptosis were determined 24 h after IR. Park's score was used for the quantitative assessment of histological change. A non-parametric Kruskal-Wallis ANOVA test was used for statistical analysis with P less than 0.05 considered statistically significant. RESULTS: IR-injury resulted in a significant decrease in bowel weight in jejunum, mucosal weight in jejunum and ileum, villus height in jejunum and ileum, cell proliferation index in jejunum, and ileum compared to sham animals. IR-INS animals demonstrated greater duodenal and jejunal bowel weight, duodenal, jejunal and ileal mucosal weight, jejunal mucosal DNA, jejunal and ileal mucosal protein, jejunal and ileal villus height and crypt depth, jejunal and ileal proliferation index compared to IR-animals. Oral insulin administration induced also a significant decrease in apoptotic index in ileum (1.2 +/- 0.4 versus 2.8 +/- 0.7 TUNEL positive cells/10 villi, P < 0.05) compared to IR-untreated animals. CONCLUSIONS: Oral insulin improves intestinal recovery after IR- injury in rat.

Administration, Oral↗
PubMed2005

Evaluation of a diet containing probiotics and zinc for the treatment of mild diarrheal illness in children younger than one year of age.

OBJECTIVES: Supplementation of probiotics and supplementation of zinc during acute gastroenteritis in children have been shown to exert positive effects on diarrhea duration and severity. Our aim was to evaluate a new diet enriched with zinc and probiotic bacteria in the treatment of acute gastroenteritis in young children. METHODS: In a double blind prospective study, 65 children aged 6-12 months were randomized to receive 6 x 10(9) colony forming units of Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus (2 x 10(9) of each strain), 10 mg of zinc/day, and 0.3 grams of fructo-oligosaccharides in the supplemented group (n = 33) or placebo (n = 32), given in a soy protein based rice cereal. For each child, age, sex, weight, degree of dehydration, the presence of fever or vomiting, stool frequency and consistency were recorded daily until diarrhea resolution. RESULTS: Diarrhea resolution occurred after 1.43 +/- 0.71 days in the supplemented group vs. 1.96 +/- 1.24 in the control group (p = 0.017). In the subset of children who presented with vomiting, time to vomiting resolution was 0.27 +/- 0.59 vs. 0.81 +/- 0.91 days in the supplemented and control groups, respectively (p = 0.06). On day 3, there was only 1 child with watery stools in the supplemented group versus 10 children in the control group (p = 0.02). CONCLUSIONS: In our series, the feeding of a cereal containing Streptococcus thermophilus, Bifidobacterium lactis, Lactobacillus acidophilus and zinc, reduced the severity and duration of acute gastroenteritis in young children. However, whether this combination is better than either the addition of probiotics or zinc alone is yet to be determined.

Acute Disease↗