Marta Oleszczuk

Treatment of acute gastroenteritis in children: an overview of systematic reviews of interventions commonly used in developed countries

BACKGROUND Acute gastroenteritis (AGE) is an extremely common paediatric condition, which results in significant morbidity in children and is a financial burden to the society. OBJECTIVE The purpose of this overview is to critically evaluate the evidence currently available in the Cochrane Database of Systematic Reviews (CDSR) regarding the efficacy and safety of commonly considered treatment options in children with AGE. METHODS All Cochrane reviews evaluating the following treatments in children with AGE were eligible for inclusion: oral rehydration therapy, anti-emetics and probiotics. We excluded those focusing on the treatment of antibiotic associated or nosocomial diarrhoea, persistent (chronic) diarrhoea and the prevention of gastroenteritis. We focused on the following outcomes that were selected a priori as clinically important: rate of admission to the hospital; length of stay in hospital; rate of return visits; administration of intravenous (IV) therapy owing to failure of oral rehydration therapy; adverse events and dysnatremia. MAIN RESULTS Children who received oral rehydration therapy had a shorter length of stay in hospital compared with children who received IV therapy [mean difference, MD = -1.20 days (-2.38, -0.02)]; however, the result was no longer significant when an outlying study was removed. Children who received IV therapy were at increased risk of developing phlebitis [risk difference, RD= - 0.02 (-0.04, -0.01)], while paralytic ileus was more common in children receiving ORT [RD = 0.03 (confidence interval, CI 0.01-0.05)]. Children who received oral ondansetron had lower hospital admission rates to the emergency department (ED) and lower rates of IV rehydration during their ED stay compared with children receiving placebo [risk ration, RR = 0.40 (CI 0.19-0.83) and RR = 0.41 (CI 0.29-0.59), respectively]. Children receiving IV ondansetron had lower hospital admission rates to the ED than patients receiving placebo [RR = 0.21 (0.05, 0.93)]. Probiotic use amongst children hospitalized following AGE reduced the mean duration of hospitalization by 1.12 days (CI -1.16, -0.38). CONCLUSIONS Given that oral rehydration is less invasive than IV rehydration with no evidence of important clinical differences, it is the first choice for rehydration in children with AGE and mild-to-moderate dehydration. As the vast majority of children with AGE do not require IV rehydration, oral ondansetron administration to children with significant vomiting should be performed to reduce the use of IV rehydration and the need for hospital admission. In children deemed too unwell to receive oral rehydration therapy, IV ondansetron administration is an option, as its use is associated with lower hospital admission rates. Although probiotics appear to be an effective option for the treatment of AGE amongst hospitalized children, outpatient data is lacking and more studies are urgently needed to determine the optimal organism, dosing and duration of treatment.

Solution structure of the regulatory domain of human cardiac troponin C in complex with the switch region of cardiac troponin I and W7: the basis of W7 as an inhibitor of cardiac muscle contraction.

The solution structure of Ca(2+)-bound regulatory domain of cardiac troponin C (cNTnC) in complex with the switch region of troponin I (cTnI(147-163)) and the calmodulin antagonist, N-(6-aminohexyl)-5-chloro-1-naphthalenesulfinamide (W7), has been determined by NMR spectroscopy. The structure reveals that the W7 naphthalene ring interacts with the terminal methyl groups of M47, M60, and M81 as well as aliphatic and aromatic side chains of several other residues in the hydrophobic pocket of cNTnC. The H3 ring proton of W7 also contacts the methyl groups of I148 and M153 of cTnI(147-163). The N-(6-aminohexyl) tail interacts primarily with the methyl groups of V64 and M81, which are located on the C- and D-helices of cNTnC. Compared to the structure of the cNTnC*Ca(2+)*W7 complex (Hoffman, R. M. B. and Sykes, B. D. (2009) Biochemistry 48, 5541-5552), the tail of W7 reorients slightly toward the surface of cNTnC while the ring remains in the hydrophobic pocket. The positively charged -NH(3)(+) group from the tail of W7 repels the positively charged R147 of cTnI(147-163). As a result, the N-terminus of the peptide moves away from cNTnC and the helical content of cTnI(147-163) is diminished, when compared to the structure of cNTnC*Ca(2+)*cTnI(147-163) (Li, M. X., Spyracopoulos, L., and Sykes B. D. (1999) Biochemistry 38, 8289-8298). Thus the ternary structure cNTnC*Ca(2+)*W7*cTnI(147-163) reported in this study offers an explanation for the approximately 13-fold affinity reduction of cTnI(147-163) for cNTnC*Ca(2+) in the presence of W7 and provides a structural basis for the inhibitory effect of W7 in cardiac muscle contraction. This generates molecular insight into structural features that are useful for the design of cTnC-specific Ca(2+)-desensitizing drugs.

Overview of reviews in child health: evidence synthesis and the knowledge base for a specific population

BACKGROUND Overviews of reviews are an evolving form of evidence synthesis. The Cochrane Child Health Field has been producing overviews since 2006, during which time the methods that have been used have changed, both due to the development of guidance within The Cochrane Collaboration and to the decisions made by individual author teams. This paper studies the first 29 overviews published in EBCH. OBJECTIVES To describe some aspects of the approaches taken in EBCH overviews to producing evidence syntheses relevant to the healthcare needs of children; to highlight the contribution that overviews can make to the knowledge base for treatment for a particular population. METHODS Data was extracted on: whether the overview included systematic review (SR) data only, or also data from individual trials not present in the included SRs; name(s) of the Cochrane Review Group (CRG) that prepared the included SRs; topics of the overviews as compared to the topics of the included reviews; age-subgroup analyses presented in the overviews. RESULTS In 23 overviews, all published in 2012, the authors included trial data as well as SR data; two overviews addressed conditions not explicitly addressed by the included reviews; three overviews included pre-specified age-subgroup analyses. DISCUSSION The aim of clinical relevance has been achieved by means such as: drawing from reviews produced by multiple CRGs; using SR evidence to explore clinically relevant topics that may not match exactly with the topics covered by the SRs; ensuring that the evidence in overviews is as up to date as possible by redoing searches and including trials not incorporated in the included SRs; and, where permitted by the data, using age-subgroup analyses to present the data in a way which matches the stages of childhood development. CONCLUSION Overview authors are dependent on the nature of the data and methods reported in the included SRs. This suggests a need for further study about how SRs could be conducted in order to facilitate the conduct of overviews.

N-(ureidoethyl)amides of cyclic enkephalin analogs

Novel N‐(ureidoethyl)amides of cyclic enkephalin analogs have been synthesized. The p‐nitrophenyl carbamate of 1‐Boc‐1,2‐diaminoethane was coupled with 4‐methylbenzhydrylamine (MBHA) resin. The Boc group was removed by treatment with HCl/dioxane, and the peptide chain was assembled using Boc strategy. For deprotection of amino function, HCl/dioxane was used. D‐Lys or D‐Orn were incorporated in position 2, and the side chains of Lys, Orn, Dab, or Dap in position 5 were protected with Fmoc group. Side chain protection was removed by treatment with 55% piperidine in DMF, and cyclization was achieved by treatment with bis‐(4‐nitrophenyl)carbonate to form a urea bridge. The peptide was cleaved from the resin by treatment with 45% TFA in DCM. The peptides were tested in the guinea‐pig ileum (GPI) and mouse vas deferens (MVD) assays. Divers opioid activities were observed, depending on the size of the ring. In comparison with [Leu5]enkephalin, all peptides were more active in the GPI assay (between 125 and 12 times), and some of them were also more potent in the MVD assay. The conformational propensities of each peptide were determined using the EDMC method in conjunction with NMR experiments. This approach allows treating the dynamical behavior of small peptides properly. The results were compared with those obtained previously for corresponding nonsubstituted amides and are in agreement with the biologically active conformation proposed by us earlier. Copyright