DGAT1 mutation is linked to a congenital diarrheal disorder.

Congenital diarrheal disorders (CDDs) are a collection of rare, heterogeneous enteropathies with early onset and often severe outcomes. Here, we report a family of Ashkenazi Jewish descent, with 2 out of 3 children affected by CDD. Both affected children presented 3 days after birth with severe, intractable diarrhea. One child died from complications at age 17 months. The second child showed marked improvement, with resolution of most symptoms at 10 to 12 months of age. Using exome sequencing, we identified a rare splice site mutation in the DGAT1 gene and found that both affected children were homozygous carriers. Molecular analysis of the mutant allele indicated a total loss of function, with no detectable DGAT1 protein or activity produced. The precise cause of diarrhea is unknown, but we speculate that it relates to abnormal fat absorption and buildup of DGAT substrates in the intestinal mucosa. Our results identify DGAT1 loss-of-function mutations as a rare cause of CDDs. These findings prompt concern for DGAT1 inhibition in humans, which is being assessed for treating metabolic and other diseases.

New insights in celiac disease.

Celiac disease (CD) is an autoimmune disorder occurring in genetically susceptible subjects. The incidence of CD is around 1%, and it is much more common in first-degree relatives of CD patients, 10%-18%. However, the pattern of the genetic inheritance is still obscure. Environmental factors are undoubtedly affecting the disease's clinical presentation, time at presentation, and may have an effect on the characteristics of the disease. The clinical presentation of CD has shifted during the previous decades from the classical presentation in which the toddler suffers from diarrhea, constipation, vomiting, failure to thrive, abdominal distension, etc., to the child with a monosymptomatic presentation, such as anemia, as well as an enlarged list of extra-intestinal disorders. The diagnosis of CD is being established by symptoms consistent with CD and positive serology. The ultimate diagnosis should be made upon histological evaluation of the small bowel mucosa. The treatment of CD is a lifelong, strict gluten-free diet (GFD). Compliance with a GFD is quite difficult. Therefore, new strategies for prevention and treatment modalities other than GFD are greatly needed. Recently several promising therapeutic modalities have been developed; these include resuming traditional baking techniques. Another methodology is using probiotic-driven prolylendopeptidase. Another pathway to tackle the therapeutic option in CD is by down-regulation of the activity of zonulin-the active pump enabling gluten to enter the enterocytes. We are facing an era where other modalities beyond a GFD might allow CD patients to be able to tolerate occasionally a small amount of gluten in their diet.

Prevalence of celiac disease in an adult Jewish population in Israel.

BACKGROUND: In the last decade the frequency of celiac disease diagnosis has increased in adults. OBJECTIVES: To determine disease prevalence (including silent and potential disease) in this population group. METHODS: We performed serologic screening of celiac disease in a representative and homogenous sample of a young adult general population in Israel, namely, 18 year old military conscripts, in 2003. Serologic screening was performed on serum samples randomly obtained from 850 healthy recruits (male/female = 1.1). Immunoglobulin A anti-tissue transglutaminase was determined by enzyme-linked immunosorbent assay. In cases of IgA deficiency, lgG anti-endomysial antibodies were determined. A small intestinal biopsy was offered to all patients with positive serology. RESULTS: The prevalence of overt CD diagnosed prior to recruitment was 0.12% (0.1% in men and 0.14% in women). The overall prevalence based on positive serology was 1.1%. Six of nine subjects with positive serology agreed to undergo endoscopy and intestinal biopsies. In all cases, biopsies were compatible with celiac disease (five biopsies were graded as Marsh 3a and one as Marsh 3b). One subject previously reporting irritable bowel-like symptoms was diagnosed with overt atypical CD. The prevalence of overt CD diagnosed by screening was 0.12%. The ratio, of overt to silent CD was 1:8. No cases of potential CD were encountered. CONCLUSIONS: Our findings suggest that CD is highly prevalent in the young adult population in Israel. Serologic screening for CD is a reliable and simple method for diagnosing this disease before symptoms or complications develop.

Prolidase deficiency: it looks like systemic lupus erythematosus but it is not.

Three siblings with recalcitrant leg ulceration, splenomegaly, photosensitive rash, and autoantibodies were suspected of having prolidase deficiency. Urine was checked for iminodipeptiduria, fibroblasts were cultured and analyzed for prolidase activity, and DNA was extracted for identifying the causative mutation. Glycyl proline was found as the dominant dipeptide in the urine. The activity of proline dipeptidase in fibroblasts was 2.5% of control fibroblasts. Sequence analysis of the PEPD gene revealed a homozygous nonsense C-->G transition at nucleotide 768. In conclusion, prolidase deficiency was diagnosed in siblings with skin ulceration autoantibodies and a lupus-like disease. A novel nonsense mutation was found, associated with the severe outcome of our patients.

The fear of necrotizing enterocolitis versus achieving optimal growth in preterm infants--an opinion.

UNLABELLED: Very-low-birthweight (VLBW) infants suffer marked growth delay despite well-intentioned efforts at combining enteral and parenteral nutrition. Fear of necrotizing enterocolitis (NEC) has traditionally influenced neonatologists toward delaying and progressing slowly with enteral feeding, while supporting the infant with parenteral nutrition. Current evidence suggests significant benefits of enteral feeding that is started early and advanced at rates of 20-35 ml/kg/d. CONCLUSION: We conclude that fear of inadequate growth should replace the fear of NEC in guiding nutritional strategies for these infants.

Leukocyte aggregation-related pseudoleukopenia in pediatrics: a sporadic event or a systematic error?

OBJECTIVE: To determine whether electronic counter-related pseudoleukopenia is a rare phenomenon or a systematic underestimation in children with acute infection/inflammation. METHODS: We have used a simple slide test and image analysis to reveal the number of white blood cells and their degree of aggregation. The number of leukocytes counted by an electronic cell analyzer was divided by the number of cells counted on the slides creating an electronic cell-to-slide leukocyte count ratio. RESULTS: A significant (P < 0.0005) negative (r = -0.314) correlation between the above mentioned ratios and the percent of aggregated leukocytes in the peripheral blood was found in a group of 239 children with various acute infections. Thus elevated leukocyte aggregation is associated with a relatively lower electronic analyzer cell count. CONCLUSIONS: The appearance of aggregated leukocytes in the peripheral blood during acute infections might be associated with pseudoleukopenia. This phenomenon has been extensively described in the adult population and seems to exist in children as well.

Automatic 3-dimensional visualization of peripheral blood slides: a new approach for the detection of infection/inflammation at the point of care.

CONTEXT: The identification and quantitation of the intensity of the acute-phase response at the point of care might be of clinical relevance. OBJECTIVE: To report the possibility of automatic screening of unstained peripheral blood slides by using a 3-dimensional image analysis system. DESIGN: Peripheral venous blood was obtained from children with acute inflammation/infection and examined by an automatic 3-dimensional image analyzer to detect the number of white blood cells as well as to reveal the degree of erythrocyte aggregation, a marker of the humoral phase response. RESULTS: We included 66 children with acute bacterial infections and 59 with nonbacterial inflammation/infection; mean ages of the 2 groups were 4.3 +/- 3.9 years and 4.2 +/- 3.7 years, respectively (P = .91). The percentages of correct classifications based on discriminant analysis in predicting between bacterial and nonbacterial inflammation/infection were 61.3% by using the white blood cell count, 64.5% by using the percentage of granulocytes, 61.6% by using the degree of erythrocyte aggregation, and 59.2% by using the number of leukocytes counted on the unstained slides. The results of the receiver-operated characteristic curve analysis yielded an area under the curve of 0.714 (P < .001) for the number of granulocytes, 0.699 (P < .001) for the white blood cell count, 0.685 (P < .001) for the number of leukocytes on the slides, and 0.685 (P = .001) for the degree of erythrocyte aggregation. The correlation between the number of leukocytes by the electronic cell analyzer and the number of cells counted on the slides was highly significant (r = 0.85, P < .001). CONCLUSIONS: It is feasible to use an automatic 3-dimensional image analyzer to reveal the different intensities of the acute-phase response between a group of children with an acute bacterial infection and another with nonbacterial inflammation/infection. These findings might be relevant for potential application at the point of care.

Sludge ball, pseudolithiasis, cholelithiasis and choledocholithiasis from intrauterine life to 2 years: a 13-year follow-up.

OBJECTIVE: Evaluation and follow-up of infants with cholelithiasis and pseudolithiasis in a pediatric ward. PATIENTS & METHODS: Prospective study from April 1990 to October 2003 identified hospitalized infants younger than 2 years with ultrasonographic findings of cholelithiasis, choledocholithiasis or pseudolithiasis. Associated abnormalities or contributory factors were recorded and patients were followed for from 6 months to 13 years (mean, 4 years). RESULTS: Thirty-four patients were diagnosed between the age of 3 weeks and 24 months. Thirteen (38%) had been treated with third-generation cephalosporins. Other associated factors were dehydration in 10 (29%), urinary tract infection in two (6%) and one each for cholestatic liver disease, total parenteral nutrition, immunoglobulin A deficiency and prematurity. Six infants (17%) had no known risk factor. Six additional patients were diagnosed by antenatal ultrasound. CONCLUSIONS: Cholelithiasis in infants hospitalized for a variety of common pediatric conditions is not rare. Dehydration and treatment with third-generation cephalosporins are important associated factors. The classic risk factors of hemolysis and previous gastrointestinal surgery, were not found in our group. The overall prognosis was good. Pseudolithiasis disappeared in all infants. Of the 21 infants with cholelithiasis, only two developed cholecystitis. In nine infants, spontaneous resolution occurred. In the absence of other clinical or imaging evidence of biliary tract disease, conservative management is advised.

Inhibition of IL-1beta and TNF-alpha secretion from resting and activated human immunocytes by the homeopathic medication Traumeel S.

Traumeel S (Traumeel), a mixture of highly diluted (10(-1)-10(-9)) extracts from medicinal plants and minerals is widely used in humans to relieve trauma, inflammation and degenerative processes. However, little is known about its possible effects on the behavior of immune cells. The effects of Traumeel were examined in vitro on the ability of resting and PHA-, PMA- or TNF-alpha-activated human T cells, monocytes, and gut epithelial cells to secrete the prototypic pro-inflammatory mediators IL-1beta, TNF-alpha and IL-8 over a period of 24-72 h. Traumeel inhibited the secretion of all three agents in resting, as well as activated immune cells. IL-beta secretion was reduced by up to 70% in both resting and activated cells; TNF-alpha secretion was reduced by up to 65 and 54%, respectively, and IL-8 secretion was reduced by 50% in both resting and activated cells (P < 0.01 for all cells). Interestingly, the effect appeared to be inversely dose-related; maximal inhibition (usually 30-60% inhibition; P < 0.01) was seen with dilutions of 10(-3)-10(-6) of the Traumeel stock material. This finding suggests that Traumeel does not inhibit immune cells functions by exerting a toxic effect. Indeed, Traumeel did not affect T cell and monocyte proliferation. Although additional studies are needed to clarify the mode of action of Traumeel and to demonstrate causative relationship between the inhibition of cytokine/chemokine secretion in cell culture and the reported clinical effects of the preparation, our in vitro results offer a mechanism for the anti-inflammatory effects of Traumeel observed in clinical use.

[Changing the therapeutic approach to acute otitis media in children].

Acute Otitis Media (AOM) is the most common reason for pediatrician's visits and for antibiotic prescription in childhood. A significant rise in bacterial resistance to antibiotic treatment has been detected in recent years. Accordingly, the attitude towards antibiotic treatment for AOM has been re-evaluated. Due to various difficulties in ear examination, physicians overdiagnosis Otitis Media with Effusion (OME) as AOM, leading to unnecessary prescription of antibiotics. The natural history of AOM shows spontaneous improvement without complications. Studies that have examined antibiotic treatment versus placebo in AOM have shown only minimal advantage for the antibiotic therapy in symptom reduction. Critical appraisal of the literature according to Evidence-based Medicine (EBM) criteria has led to several meta-analyses that showed only a minor advantage for antibiotics over placebo in AOM. In the Netherlands, the approach to AOM is that of delayed prescribing: symptomatic therapy is given for the first 24-72 hours and an antibiotic drug is prescribed only if symptoms persist after this initial period. This review examines the difficulties in reaching an accurate diagnosis of AOM and describes the natural history of AOM and evaluates the studies and meta-analyses comparing antibiotics to placebo. The Dutch approach to AOM will be discussed as an option and a recommended basis for reduction in antibiotic prescriptions for AOM.

Attitude of medical students to the introduction of complementary medicine into the medical curriculum in Israel.

BACKGROUND: Complementary medicine is gaining in public popularity, yet medical school curricula usually ignore it. OBJECTIVES: To determine whether senior medical students are interested in learning principles of complementary or alternative medicine, to check their degree of familiarity with it, and to suggest a format for such studies in the medical curriculum. METHODS: Senior medical students (n = 117) were surveyed by an anonymous questionnaire. RESULTS: Seventy-nine percent of the senior medical students were interested in studying complementary or alternative medicine in medical school, and 65% were interested in applying these techniques to treat patients. Eighty-seven percent of students were familiar with some techniques of complementary medicine. CONCLUSIONS: Senior medical students are interested in studying complementary and alternative medicine in medical school and in applying these techniques in practice.

Helicobacter pylori genotypes in Israeli children: the significance of geography.

BACKGROUND: There is substantial genetic variation among different isolates of Helicobacter pylori, which may affect the clinical outcome. The aims of this study were to find the common H. pylori genotypes in Israeli children and to look for a possible genotype-phenotype correlation. METHODS: Ninety-eight H. pylori cultures were isolated from antral biopsy specimens of symptomatic Israeli children and were analyzed for vacA and iceA genotype and cagA and cagE status by polymerase chain reaction. RESULTS: cagA and cagE genes were present in only 25.5% and 24.5%, respectively. The common vacA genotype was s2m2, which was found in 65%. Eleven specimens (11%) contained multiple vacA genotypes. iceA1 was found in 37% and iceA2 in 52% of cases. Both iceA alleles were found in 11%. Increased prevalence of iceA1 and cagE were observed in children with duodenal disease, although it did not reach significance. CONCLUSIONS: The low prevalence of cagA and the high prevalence of vacA genotype s2m2 in Israeli pediatric patients are different from the genotype prevalence reported globally. However, similar findings have been reported in Egypt, indicating a possible geographic influence. There is a possible correlation between duodenal ulcer and cag E and ice A1 genotype, but the power of the study was too low to prove it.