Comparison of pediatric and adult antibiotic-associated diarrhea and Clostridium difficile infections

Antibiotic-associated diarrhea(AAD) and Clostridum difficile infections(CDI) have been well studied for adult cases, but not as well in the pediatric population. Whether the disease process or response to treatments differs between pediatric and adult patients is an important clinical concern when following global guidelines based largely on adult patients. A systematic review of the literature using databases Pub Med(June 3, 1978-2015) was conducted to compare AAD and CDI in pediatric and adult populations and determine significant differences and similarities that might impact clinical decisions. In general, pediatric AAD and CDI have a more rapid onset of symptoms, a shorter duration of disease and fewer CDI complications(required surgeries and extended hospitalizations) than in adults. Children experience more community-associated CDI and are associated with smaller outbreaks than adult cases of CDI. The ribotype NAP1/027/BI is more common in adults than children. Children and adults share some similar risk factors, but adults have more complex risk factor profiles associated with more co-morbidities, types of disruptive factors and a wider range of exposures to C. difficile in the healthcare environment. The treatment of pediatric and adult AAD is similar(discontinuing or switching the inciting antibiotic), but other treatment strategies for AAD have not been established. Pediatric CDI responds better to metronidazole, while adult CDI responds better to vancomycin. Recurrent CDI is not commonly reported for children. Prevention for both pediatric and adult AAD and CDI relies upon integrated infection control programs, antibiotic stewardship and may include the use of adjunctive probiotics. Clinical presentation of pediatric AAD and CDI are different than adult AAD and CDI symptoms. These differences should be taken into account when rating severity of disease and prescribing antibiotics.

Combining Genome Wide Association Studies and Differential Gene Expression Data Analyses Identifies Candidate Genes Affecting Mastitis Caused by Two Different Pathogens in the Dairy Cow

Mastitis is a costly disease which hampers the dairy industry. Inflammation of the mammary gland is commonly caused by bacterial infection, mainly Escherichia coli, Streptococcus uberis and Staphylococcus aureus. As more bacteria become multi-drug resistant, one potential approach to reduce the disease incidence rate is to breed selectively for the most appropriate and potentially protective innate immune response. The genetic contribution to effective disease resistance is, however, difficult to identify due to the complex interactions that occur. In the present study two published datasets were searched for common differentially expressed genes (DEGs) with similar changes in expression in mammary tissue following intra-mammary challenge with either E. coli or S. uberis. Additionally, the results of seven published genome-wide association studies (GWAS) on different dairy cow populations were used to compile a list of SNPs associated with somatic cell count. All genes located within 2 Mbp of significant SNPs were retrieved from the Ensembl database, based on the UMD3.1 assembly. A final list of 48 candidate genes with a role in the innate immune response identified from both the DEG and GWAS studies was further analyzed using Ingenuity Pathway Analysis. The main signalling pathways highlighted in the response of the bovine mammary gland to both bacterial infections were 1) granulocyte adhesion and diapedesis, 2) ephrin receptor signalling, 3) RhoA signalling and 4) LPS/IL1 mediated inhibition of RXR function. These pathways comprised a network regulating the activity of leukocytes, especially neutrophils, during mammary gland inflammation. The timely and properly controlled movement of leukocytes to infection loci seems particularly important in achieving a good balance between pathogen elimination and excessive tissue damage. These results suggest that polymorphisms in key genes in these pathways such as SELP, SELL, BCAR1, ACTR3, CXCL2, CXCL6, CXCL8 and FABP may influence the ability of dairy cows to resist mastitis.

Rationally designed mariner vectors for functional genomic analysis of Actinobacillus pleuropneumoniae and other Pasteurellaceae species by transposon-directed insertion-site sequencing (TraDIS)

Comprehensive identification of conditionally essential genes requires efficient tools for generating high-density transposon libraries that, ideally, can be analysed using next-generation sequencing methods such as Transposon Directed Insertion-site Sequencing (TraDIS). The Himar1 (mariner) transposon is ideal for generating near-saturating mutant libraries, especially in AT-rich chromosomes, as the requirement for integration is a TA dinucleotide, and this transposon has been used for mutagenesis of a wide variety of bacteria. However, plasmids for mariner delivery do not necessarily work well in all bacteria. In particular, there are limited tools for functional genomic analysis of Pasteurellaceae species of major veterinary importance, such as swine and cattle pathogens, Actinobacillus pleuropneumoniae and Pasteurella multocida, respectively. Here, we developed plasmids, pTsodCPC9 and pTlacPC9 (differing only in the promoter driving expression of the transposase gene), that allow delivery of mariner into both these pathogens, but which should also be applicable to a wider range of bacteria. Using the pTlacPC9 vector, we have generated, for the first time, saturating mariner mutant libraries in both A. pleuropneumoniae and P. multocida that showed a near random distribution of insertions around the respective chromosomes as detected by TraDIS. A preliminary screen of 5000 mutants each identified 8 and 14 genes, respectively, that are required for growth under anaerobic conditions. Future high-throughput screening of the generated libraries will facilitate identification of mutants required for growth under different conditions, including in vivo, highlighting key virulence factors and pathways that can be exploited for development of novel therapeutics and vaccines.

Preventing pediatric antibiotic-associated diarrhea and Clostridium difficile infections with probiotics: A metaanalysis

AIM: To assess the efficacy and safety of probiotics for preventing pediatric:(1) antibiotic associated diarrhea and(2) Clostridium difficile(C. difficile) infections.METHODS: On June 3, 2013, we searched Pub Med(1960-2013), EMBASE(1974-2013), Cochrane Database of Systematic Reviews(1990-2013), CINAHL(1981-2013), AMED(1985-2013), and ISI Web of Science(2000-2013). Additionally, we conducted an extensive grey literature search including contact with National Institutes of Health Clinical Trials Registry, abstracts from annual infectious disease and gastroenterology meetings, experts in the field and correspondence with authors. The primary outcomes were the incidence of antibiotic-associated diarrhea(AAD) and C. difficile infections(CDI). Dichotomous outcomes(e.g., incidence of AAD or CDI) were pooled using a random-effects model to calculate the relative risk and corresponding 95% confidence interval(95%CI) and weighted on study quality. To explore possible explanations for heterogeneity, a priori subgroup analysis were conducted on probiotic strain type, daily dose, quality of study and safety of probiotics. The overall quality of the evidence supporting each outcome was assessed using the grading of recommendations, assessment, development and evaluation criteria.RESULTS: A total of 1329 studies were identified with 22 trials(23 treatment arms and 4155 participants) meeting eligibility requirements for our review of prevention of AAD and 5 trials(1211 participants) for the prevention of CDI. Trials in adult populations, trials of uncertain antibiotic exposure or studies which did not provide incidence of AAD were excluded. We found 12 trials testing a single strain of probiotic and 10 trials testing a mixture of probiotic strains. Probiotics(all strains combined) significantly reduced the incidence of pediatric AAD(pooled RR = 0.42, 95%CI: 0.33-0.53) and significantly reduced pediatric CDI(pooled RR = 0.35, 95%CI: 0.13-0.92). Of the two strains with multiple trials, both significantly reduced pediatric AAD: Saccharomyces boulardii lyo(pooled RR = 0.43, 95%CI: 0.32-0.60) and Lactobacillus rhamnosus GG(pooled RR = 0.36, 95%CI: 0.19-0.69). There was no significant effect by type of antibiotic, or by duration or dose of probiotic. No adverse events associated were found in the 22 controlled trials relating to the use of probiotics.CONCLUSION: This meta-analysis found that probiotics significantly prevented pediatric antibiotic associated diarrhea and pediatric CDI, but the efficacy varies significantly by the strain of the probiotic.

Can we switch production of toxic Aβ oligomers to neuroprotective Aβ monomers to allow synapse regeneration?

Alzheimer＇s disease （AD） is a complex neurological disor- der characterized by a progressive dementia. The amyloid hypothesis states that pathogenesis is driven by the accumu- lation of amyloid β（Aβ） peptides within the brain （Hardy and Higgins, 1992）, which have multiple effects including activation of glial cells and synapse degeneration. For many years therapeutic strategies were based upon the discovery of compounds that reduced the production of Aβ in vitro and in vivo. However, the amyloid hypothesis is not universally accepted; critics pointed out poor correlations between con- centrations of Aβ in the brain and clinical disease and that, although numerous compounds reduced the production of Aβ in animal models, few had any clinical benefit in AD pa- tients. The failure of Aβ-1owering therapies in translational research has resulted in important modifications of the amy- loid hypothesis.

Enhanced neuronal degradation of amyloid-β oligomers allows synapse regeneration

The amyloid hypothesis of Alzheimer＇s disease （AD） pathogen- esis maintains that the key event is the production of specific C-terminal amyloid-β （Aβ） peptides following the abnormal proteolytic cleavage of the amyloid precursor protein （Vassar and Citron, 2000）.