Risk factors of mortality in septic newborns in neonatal intensive care units (NICUs) in Tbilisi, the Republic of Georgia

Butsashvili, Maia; Kourbatova, Ekaterina V.; Macharashvili, Nino; Kamkamidze, George; McNutt, Louise‐Anne; DeHovitz, Jack; Leonard, Michael

doi:10.1007/s10654-009-9360-9

Cited by 3 publications

(1 citation statement)

References 4 publications

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“…The most common newborn deaths worldwide are neonatal infections, which currently cause about 1.6 million deaths annually in developing countries [ 1 ]. Most of these deaths are caused by bacteremia and meningitis.…”

Section: Introductionmentioning

confidence: 99%

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

Bao

Peng

et al. 2015

PLoS ONE

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Neonatal sepsis and meningitis (NSM) remains a leading cause worldwide of mortality and morbidity in newborn infants despite the availability of antibiotics over the last several decades. E. coli is the most common gram-negative pathogen causing NSM. Our previous studies show that α7 nicotinic receptor (α7 nAChR), an essential regulator of inflammation, plays a detrimental role in the host defense against NSM. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat this disease. Using the in vitro/in vivo models of the blood-brain barrier (BBB) and RNA-seq, we undertook a drug repositioning study to identify unknown antimicrobial activities for known drugs. We have demonstrated for the first time that memantine (MEM), a FDA-approved drug for treatment of Alzheimer’s disease, could very efficiently block E. coli-caused bacteremia and meningitis in a mouse model of NSM in a manner dependent on α7 nAChR. MEM was able to synergistically enhance the antibacterial activity of ampicillin in HBMEC infected with E. coli K1 (E44) and in neonatal mice with E44-caused bacteremia and meningitis. Differential gene expression analysis of RNA-Seq data from mouse BMEC infected with E. coli K1 showed that several E44-increased inflammatory factors, including IL33, IL18rap, MMP10 and Irs1, were significantly reduced by MEM compared to the infected cells without drug treatment. MEM could also significantly up-regulate anti-inflammatory factors, including Tnfaip3, CISH, Ptgds and Zfp36. Most interestingly, these factors may positively and negatively contribute to regulation of NF-κB, which is a hallmark feature of bacterial meningitis. Furthermore, we have demonstrated that circulating BMEC (cBMEC) are the potential novel biomarkers for NSM. MEM could significantly reduce E44-increased blood level of cBMEC in mice. Taken together, our data suggest that memantine can efficiently block host inflammatory responses to bacterial infection through modulation of both inflammatory and anti-inflammatory pathways.

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Section: Introductionmentioning

confidence: 99%

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

Bao

Peng

et al. 2015

PLoS ONE

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Unveiling genetic signatures associated with resilience to neonatal diarrhea in lambs through two GWAS approaches

Yaman,

Kişi,

Şengül

et al. 2024

Sci Rep

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Neonatal diarrhea presents a significant global challenge due to its multifactorial etiology, resulting in high morbidity and mortality rates, and substantial economic losses. While molecular-level studies on genetic resilience/susceptibility to neonatal diarrhea in farm animals are scarce, prior observations indicate promising research directions. Thus, the present study utilizes two genome-wide association approaches, pKWmEB and MLM, to explore potential links between genetic variations in innate immunity and neonatal diarrhea in Karacabey Merino lambs. Analyzing 707 lambs, including 180 cases and 527 controls, revealed an overall prevalence rate of 25.5%. The pKWmEB analysis identified 13 significant SNPs exceeding the threshold of ≥ LOD 3. Moreover, MLM detected one SNP (s61781.1) in the SLC22A8 gene (p-value, 1.85eE-7), which was co-detected by both methods. A McNemar’s test was conducted as the final assessment to identify whether there are any major effective markers among the detected SNPs. Results indicate that four markers—oar3_OAR1_122352257, OAR17_77709936.1, oar3_OAR18_17278638, and s61781.1—have a substantial impact on neonatal diarrhea prevalence (odds ratio: 2.03 to 3.10; statistical power: 0.88 to 0.99). Therefore, we propose the annotated genes harboring three of the associated markers, TIAM1, YDJC, and SLC22A8, as candidate major genes for selective breeding against neonatal diarrhea.

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Unveiling Genetic Signatures Associated with Resilience to Neonatal Diarrhea in Lambs Through Dual GWAS Approaches

Yaman,

Kişi,

Şengül

et al. 2024

Preprint

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Neonatal diarrhea poses a particularly daunting challenge due to its multifactorial etiology, resulting in high morbidity and mortality rates and substantial economic consequences worldwide. Moreover, the zoonotic potential of neonatal diarrhea underscores its importance in public health concerns. Although no molecular-level study has evaluated genetic resistance/susceptibility to neonatal diarrhea in farm animals, previous observations suggest potential avenues for further research. The present study employs two genome-wide association approaches, namely the nonparametric multi-locus (pKWmEB) and the single-locus Mixed Linear Model (MLM), to explore potential associations between genetic variations in innate immunity and neonatal diarrhea in Karacabey Merino lambs. A total of 707 lambs, comprising 180 cases and 527 controls, were analyzed, revealing an overall prevalence rate of 25.5%. Using a multi-locus (pKWmEB) GWA analysis, 13 SNPs surpassing the threshold of ≥ LOD 3 were identified. Additionally, the single-locus MLM approach identified one SNP with an exact p-value of 1.85e-7, and this SNP (s61781.1) in the SLC22A8 gene was co-detected by both methods. Our results demonstrate that besides environmental conditions and management practices, the manifestation of neonatal diarrhea can be explained to some degree by genetic backgrounds, and marker-assisted selection can be a useful complementary tool in the struggle against neonatal diarrhea.

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Risk factors of mortality in septic newborns in neonatal intensive care units (NICUs) in Tbilisi, the Republic of Georgia

Cited by 3 publications

References 4 publications

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

Repositioning of Memantine as a Potential Novel Therapeutic Agent against Meningitic E. coli–Induced Pathogenicities through Disease-Associated Alpha7 Cholinergic Pathway and RNA Sequencing-Based Transcriptome Analysis of Host Inflammatory Responses

Unveiling genetic signatures associated with resilience to neonatal diarrhea in lambs through two GWAS approaches

Unveiling Genetic Signatures Associated with Resilience to Neonatal Diarrhea in Lambs Through Dual GWAS Approaches

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