Baruch Yerushalmi

Age-related efficacy of Shigella O-specific polysaccharide conjugates in 1–4-year-old Israeli children

BACKGROUND Despite its high worldwide morbidity and mortality, there is yet no licensed vaccine for shigellosis. We reported the safety and immunogenicity of Shigella O-specific polysaccharide-protein conjugates in adults and young children and efficacy of Shigella sonnei conjugate in young adults. METHODS A double-blinded, randomized and vaccine-controlled Phase 3 evaluation of S. sonnei and Shigella flexneri 2a O-SP-rEPA conjugates, 25 microg, injected IM twice, 6 weeks apart, into healthy 1-4 years old, is reported. The children were followed for 2 years by telephone every other week and stool cultures were obtained for each episode of acute diarrhea (> or =3 loose stools/day or a bloody/mucous stool). Sera were taken randomly from 10% of the participants for IgG anti-LPS and anti-carrier levels. RESULTS Of the 2799 enrollees, 1433 received S. sonnei and 1366 S. flexneri 2a conjugates; 2699 (96.4%) completed the 2-year follow-up. Local reactions occurred in approximately 5% and approximately 4% had temperatures > or =38.0 degrees C lasting 1-2 days. There were no serious adverse events attributable to the vaccines. Of the 3295 stool cultures obtained, 125 yielded S. sonnei and 21 S. flexneri 2a. Immunogenicity and efficacy were age-related. The overall efficacy of the S. sonnei conjugate was 27.5%; 71.1% (P=0.043) in the 3-4 years old. The numbers for S. flexneri 2a were too few for meaningful analysis. Cross-protection by S. flexneri 2a for non-vaccine S. flexneri types was found, but the numbers were too few for statistical significance. There was an age-related rise of vaccine-specific IgG anti-LPS in both groups, peaking at about 10 weeks and declining thereafter, but remaining > or =4-fold higher than in the controls 2 years after the second dose. CONCLUSIONS Shigella conjugates are safe and immunogenic in 1-4 years old. The S. sonnei conjugate elicited 71.1% efficacy in the 3-4 years old and can be predicted to be efficacious in individuals older than 3 years of age. These results urge studies with our improved conjugates.

Maternal Worries about Child Underweight Mediate and Moderate the Relationship Between Child Feeding Disorders and Mother–Child Feeding Interactions

OBJECTIVE To examine the role of maternal worries about child underweight and undereating in mother-child feeding interactions with children having a feeding disorder (FD). METHOD Participants were 27 children diagnosed with nonorganic-based FD and 28 children without FD. Mothers were interviewed about their worries about child underweight and undereating. Mother-child interactions were videotaped during feeding. RESULTS Maternal child weight-related worries acted as both a mediator and a moderator. The more negative mother-child interactions found in the FD group, compared to the control group, were explained by greater maternal worry regarding child underweight. Furthermore, mother-child interactions within the FD group were not at risk per se, but only when coupled with high maternal worries about childrens underweight. CONCLUSION Worry about child underweight partially explains the development of negative feeding interactions when having children with FD, signifying clinical implications for the treatment of FD.

Comparison of two dosing methods for induction of response and remission with oral budesonide in active pediatric Crohn's disease: A randomized placebo-controlled trial†

Background: Oral budesonide has been found to be comparable to systemic corticosteroids in mild to moderately active Crohns disease (CD). Remission rates in pediatric studies to date have been suboptimal (47%–55%), even though patients with colonic involvement were excluded in some studies. In addition, the optimal pediatric dosing regimen has never been evaluated before. Methods: This was a randomized, controlled, double‐blind study in 70 children with mild or moderately active CD randomized to 1 of 2 groups: Group 1: Standard dose budesonide (9 mg/day) for 7 weeks followed by 6 mg budesonide daily for an additional 3 weeks. Group 2: Induction with 12 mg/day for the first month followed by the same regimen as Group 1. Outcome measures included a decrease in Pediatric Crohns Disease Activity Index and remission rates. Patients with colonic disease were not excluded. Results: At week 7 a clinical response was obtained in 51.4% in Group 1 versus 74.3% in Group 2. A significant decrease in C‐reactive protein was seen only in Group 2. At the end of treatment, remission was obtained in 42.9% in Group 1 versus 65.7% in Group 2 (P = 0.054). There was no significant difference in adverse events or serum cortisol. Conclusions: Use of an induction dose of budesonide followed by a budesonide taper resulted in a trend to higher rates of clinical remission and a decrease in inflammation, without an increase in steroid‐associated side effects. Budesonide was also useful for patients with ileocolonic disease.

Hyperchlorhidrosis Caused by Homozygous Mutation in CA12, Encoding Carbonic Anhydrase XII

Excessive chloride secretion in sweat (hyperchlorhidrosis), leading to a positive sweat test, is most commonly indicative of cystic fibrosis yet is found also in conjunction with various metabolic, endocrine, and dermatological disorders. There is conflicting evidence regarding the existence of autosomal-recessive hyperchlorhidrosis. We now describe a consanguineous Israeli Bedouin kindred with autosomal-recessive hyperchlohidrosis whose sole symptoms are visible salt precipitates after sweating, a preponderance to hyponatremic dehydration, and poor feeding and slow weight gain at infancy. Through genome-wide linkage analysis, we demonstrate that the phenotype is due to a homozygous mutation in CA12, encoding carbonic anhydrase XII. The mutant (c.427G>A [p.Glu143Lys]) protein showed 71% activity of the wild-type enzyme for catalyzing the CO₂ hydration to bicarbonate and H(+), and it bound the clinically used sulfonamide inhibitor acetazolamide with high affinity (K(I) of 10 nM). Unlike the wild-type enzyme, which is not inhibited by chloride, bromide, or iodide (K(I)s of 73-215 mM), the mutant is inhibited in the submicromolar range by these anions (K(I)s of 0.37-0.73 mM).

Idiopathic pancreatitis preceding the diagnosis of inflammatory bowel disease is more frequent in pediatric patients.

Background and Objectives:Acute pancreatitis (AP) can be a rare extraintestinal manifestation of inflammatory bowel disease (IBD). There are only a few reports of AP presenting before the diagnosis of IBD. We aimed to characterize the demographic, clinical, and laboratory data of patients with IBD in whom AP preceded disease onset and compare the presentation of AP between children and adults. Patients and Methods:Pediatric and adult patients presenting with AP as the first symptom of IBD were retrospectively identified (10 years, 7 university hospitals). Demographic and clinical data, IBD type, disease extension, and laboratory data were extracted from the charts. Imaging methods, number of AP episodes, and lag time between onset of first pancreatitis episode and onset of IBD were recorded. Results:AP preceding the diagnosis of IBD was found in 10 in 460 pediatric patients with IBD (2.17%), compared with only 2 in 3500 adults (0.06%). Eight children had colonic disease (4 Crohn disease, 4 ulcerative colitis [3 pancolitis]). Mean amylase level was 1419 and range 100 to 1370. Three children (30%) had mildly elevated transaminases. Median time between onset of first episode of AP in relation to onset of IBD was 24 (range 1–156) weeks. AP most commonly presented with abdominal pain. Conclusions:IBD presenting as AP was more frequent among the pediatric population with IBD in comparison to adults. It was more common in patients with colitis than in those with ileal disease, suggesting that patients with idiopathic AP should be observed carefully for a possible diagnosis of IBD.

Genetic and electrophysiological characteristics of recurrent acute pancreatitis.

Objectives: The aim was to present the workup of patients with acute recurrent pancreatitis (ARP) for genetic analysis and electrophysiological testing. Methods: Patients with ARP with unknown etiology were referred for genetic testing and evaluation of cystic fibrosis transmembrane conductor regulator (CFTR) function by nasal potential difference (NPD) testing. Results: A total of 67 patients were evaluated. The mean age was 23 ± 17 years (median 17.0 years, range 1.5–72 years); 90% were Jewish and 10% Arab. Ten (15%) patients carried PRSS1 gene mutation (K23R(7), R122H(2), and D21A(1)). One patient had K172E/− (chymotrypsin C [CTRC]) mutation, 1 had I42M (serine protease inhibitor Kazal type 1 [SPINK1])/V235I (CTRC) together with &Dgr;F508/5T, 1 patient had R67H (SPINK1)/V235I (CTRC), and 1 patient had V235I (CTRC)/−. Ten of 67 (15%) patients submitted for CFTR gene testing carried mutations (&Dgr;F508/L997F, &Dgr;F508/5T(11TG), W1282/5T(12TG), W1282X/Y1014C, &Dgr;F508/R31C, R117H/−, R117H/Y1014C, D1152H/−, 5T(11TG)/−, and L997F/−). Fifty-four (80%) patients underwent sweat testing. Of these, 5 had sweat chloride ≥60 mEq/L, and 22 patients had sweat chloride from 40 to 60 mEq/L. Of the 56 (83%) patients had nasal potential difference testing, 4 (6%) with abnormal results. Conclusions: One-third (34%) of patients with ARP carry mutations for hereditary pancreatitis including rare mutations (K23R), and 12.5% have evidence of cftr mutations and 10% had CFTR dysfunction underscoring the importance of genetic and functional workup of these patients.

Mealtime Dynamics in Child Feeding Disorder: The Role of Child Temperament, Parental Sense of Competence, and Paternal Involvement

OBJECTIVE We examined how child temperament, parental sense of competence, and paternal involvement predicted observed mealtime dynamics. METHOD 97 families of children with feeding disorder (FD), sleep problems (SP), and typically developing (TD) children participated in the study. Data were collected during home visits, where mother-child and father-child mealtime dynamics were videotaped and parents completed questionnaires. RESULTS More mother-child and father-child conflict and control was observed during mealtimes in the FD than SP and TD groups. Among the FD group, maternal sense of competence was negatively correlated with mother-child conflict and control, and child temperament was linked to father-child conflict and control, but only for families in which fathers were highly involved. These correlations were not significant among the SP and TD groups. CONCLUSION Different patterns of results were seen for mothers and fathers and among the FD and control groups. Clinical implications for the treatment of FD are discussed.

Natural History and Clinical Manifestations of Hyponatremia and Hyperchlorhidrosis due to Carbonic Anhydrase XII Deficiency

Introduction: We identified patients of Bedouin origin with a mutation in carbonic anhydrase XII (CA XII) leading to hyponatremia due to excessive salt loss via sweat. Methods: The medical records of patients were reviewed for clinical and laboratory data. Results: A total of 11 subjects were identified; 7 symptomatic patients presented with hyponatremic dehydration in infancy. Screening of the entire kindred identified 4 asymptomatic individuals with elevated sweat chloride. All symptomatic patients had failure to thrive and moderate-severe hyponatremia (106-124 mmol·l-1); 6 had hypochloremia (79-94 mmol·l-1). All asymptomatic subjects had normal or near-normal serum sodium and chloride concentrations. Both symptomatic and asymptomatic subjects had normal renal functions and normal cortisol response on low-dose ACTH test. All symptomatic patients were treated by dietary salt, which prevents episodes of hyponatremic dehydration and promotes growth. At follow-up, the chief complaints remained heat intolerance, accumulation of salt precipitates on the face and hyperhidrosis. No evidence for chronic renal, respiratory, gastrointestinal or fertility abnormalities was found. Conclusion: Recognizing this newly described entity and differentiating it from cystic fibrosis and pseudohypoaldosteronism are important. Patients with CA XII mutations should be followed even after early childhood, especially in hot temperatures and intense physical activity.

Continuous 13C-methacetin breath test differentiates biliary atresia from other causes of neonatal cholestasis.

Background and Aim: Distinguishing biliary atresia (BA) from other causes of neonatal cholestasis (NC) is challenging. Continuous BreathID 13C-methacetin breath test (MBT) is a novel method that determines liver function. Methacetin is metabolized uniquely by the liver and 13CO2 is measured passively, through a nasal cannula in the exhaled breath. The aim of this study was to assess the ability of MBT to differentiate BA from other causes of NC. Methods: MBT was performed in infants with NC before any invasive procedure. Percent dose recovered (PDR) peak and time to peak (TTPP) of 13C recovered were correlated with blood test results and degree of fibrosis on liver biopsy. Results: Fifteen infants were enrolled in the study. Eight were eventually diagnosed as having BA. MBT showed that infants with NC from various causes reached the PDR peak after 44.5 ± 6.7 minutes, whereas infants with BA reached the PDR peak value after 54.7 ± 4.3 minutes (P < 0.005). This suggested low cytochrome P450 1A2 activity in the BA group. The area under the curve (AUC) was 0.95 (95% confidence interval [CI] 0.83–1), sensitivity of 88%, and specificity of 100%. Conclusions: This pilot study shows that MBT can differentiate between BA and other causes of NC by time to peak of methacetin metabolism. The results suggest that MBT may be used as part of the diagnostic algorithm in infants with liver disease. Larger-scale studies should be conducted to confirm these initial observations.

Once- Versus Twice-daily Mesalazine to Induce Remission in Paediatric Ulcerative Colitis: A Randomised Controlled Trial.

Background Trials in adults suggested that, in ulcerative colitis [UC], once-daily [OD] dosing of 5-ASA [5-amino salicylic acid] may be as or more effective than twice-daily [BD] dosing. In this induction of remission, investigator-blinded, randomised controlled-trial, we aimed to compare effectiveness and safety of once- versus twice-daily mesalazine in paediatric UC. Methods Children, aged 4-18 years with a PUCAI [Paediatric Ulcerative Colitis Activity Index] of 10-55 points at inclusion, were randomised in blocks of six with blinded allocation to OD or BD mesalazine, using a weight-based dosing table. The primary outcome was mean PUCAI score at Week 6. Results A total of 83/86 randomised children were eligible and analysed: 43 in the OD group and 40 in the BD group (mean age 14 ± 2.7 years, 43 [52%] males, 51 [62%] extensive colitis). The groups did not differ with regard to disease activity or any other parameter at baseline. There was no difference in median PUCAI score between the OD group and BD group at Week 6: 15 ( interquartile range [IQR] 5-40) versus 10 [0-40]; p = 0.48]. Response was seen in 25 [60%] OD versus 25 [63%] BD dosing [p = 0.78]. Proportion of children in remission [PUCAI < 10] at Week 6 was 13 [30%] OD versus 16 [40%] BD; p = 0.35]. Most adverse events were related to disease aggravation; the rates of serious adverse events were similar [p > 0.2]. Conclusions In this first randomised controlled trial in children, no differences were found between OD and BD dosing for any clinical outcome. Remission was achieved in 35% of children treated with mesalazine for active UC.