Deferoxamine mesylate improves splicing and GAA activity of the common c.-32-13T>G allele in late-onset PD patient fibroblasts

Background:Neonatal sepsis is the leading cause of newborn mortality and morbidity worldwide. The spectrum of microorganisms shows wide variation in different regions of the world and also in different hospitals of the same region. In this study we have tried to find out the common bacterial organisms causing neonatal sepsis in our region and their antibiotic susceptibility. Method: It is a hospital based observational study conducted in one of the busiest hospitals of Jorhat over a period of 18 months. Blood culture reports of all patients were traced from the hospital laboratory data. Positive culture reports for bacterial sepsis were studied and analysed statistically. Result:Total 602 blood cultures were performed during the study period out of which 46(7.6%) were bacterial culture positive. Twenty-seven(59%) were Early Onset sepsis and 19(41%) were Late onset sepsis. Male-female ratio was 1.7:1. Most common organism causing bacterial sepsis was Klebsiella Pneumoniae(28%), second was Acinetobacter baumani(22%), third was Staphylococcus aureus (20%), followed by Enterococcus (17%), E coli (9%) and finally CoNS(4%). Twenty-seven(59%) were gram positive organisms (67% caused EONS and 33% caused LONS)and 19(41%) were Gram Negative(58% caused EONS and 42% caused LONS). Levofloxacin had highest sensitivity to all the microorganisms. Conclusion:Neonatal sepsis can be treated with judicious use of antibiotics by studying the common microbial strains in the region and their antimicrobial susceptibility. Antibiotic stewardship should be stressed upon in every institution to protect patients from harm caused by unnecessary antibiotic use and combat the most dangerous threat of antibiotic resistance to the world.

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AD-linked R47H-TREM2 mutation induces disease-enhancing proinflammatory microglial states in mice and humans

10.1101/2020.07.24.218719 ◽

2020 ◽

Cited By ~ 1

Author(s):

Faten A. Sayed ◽

Lay Kodama ◽

Joe C. Udeochu ◽

Li Fan ◽

Gillian K. Carling ◽

...

Keyword(s):

Late Onset ◽

Memory Deficits ◽

Transcriptomic Analysis ◽

Specific Gene ◽

New Directions ◽

Transcriptional Changes ◽

The Common ◽

Transcriptomic Changes ◽

The Brain ◽

Shed Light

ABSTRACTThe hemizygous R47H variant of TREM2, a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). In this study, we identified a subpopulation of microglia with disease-enhancing proinflammatory signatures associated with the R47H mutation in human AD brains and tauopathy mouse brains. Using transcriptomic analysis at the single-nuclei level from AD patients with the R47H or the common variant (CV)-TREM2 with matched sex, pathology and APOE status, we found that the R47H mutation was associated with cell type- and sex-specific transcriptional changes in human AD brains, with microglia exhibiting the most robust alterations. Further characterization revealed that R47H-associated microglial subpopulations had enhanced inflammatory signatures including hyperactivation of Akt, one of the signaling pathways downstream of TREM2. In a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or CV, R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and elevation of a subset of disease-associated microglial signatures. Strikingly, pharmacological Akt inhibition largely reversed the enhanced inflammatory signatures induced by R47H in primary microglia treated with tau fibrils. By unraveling the disease-enhancing properties of the R47H mutation in mouse and human, our findings shed light on an immune-linked AD subtype and provide new directions for modulating microglial immune responses to treat AD.

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Late-onset rheumatoid arthritis in a patient with successfully treated IgA nephropathy

Terapevticheskii arkhiv ◽

10.17116/terarkh201789877-79 ◽

2017 ◽

Vol 89 (8) ◽

pp. 77-79

Author(s):

N V Chebotareva ◽

I N Bobkova ◽

S V Gulyaev

Keyword(s):

Rheumatoid Arthritis ◽

Renal Function ◽

Iga Nephropathy ◽

Clinical Case ◽

Late Onset ◽

Systemic Diseases ◽

Radiological Patterns ◽

The Common ◽

Reduced Renal Function

The paper describes a rare clinical case of rheumatoid arthritis (RA) that developed in a patient 9 years after diagnosing IgA nephropathy. Kidney disease was characterized by a stable course with moderate urinary syndrome, hypertension, and reduced renal function. Immunosuppressive therapy using glucocorticosteroids and then mycophenolic acid led to remission of nephritis and recovery of renal function. However, the absence of nephritis activity and discontinuation of immunosuppressants was responsible for articular syndrome. The diagnosis of RA is based on its characteristic radiological patterns and immunological characteristics after ruling out a number of systemic diseases and infections. The common pathogenetic components of IgA nephropathy and RA, including the role of rheumatoid factor IgA, are discussed.

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Humanized TREM2 mice reveal microglia-intrinsic and -extrinsic effects of R47H polymorphism

Journal of Experimental Medicine ◽

10.1084/jem.20171529 ◽

2018 ◽

Vol 215 (3) ◽

pp. 745-760 ◽

Cited By ~ 86

Author(s):

Wilbur M. Song ◽

Satoru Joshita ◽

Yingyue Zhou ◽

Tyler K. Ulland ◽

Susan Gilfillan ◽

...

Keyword(s):

Late Onset ◽

Association Studies ◽

Amyloid Β ◽

Genome Wide Association Studies ◽

Genome Wide ◽

Soluble Trem2 ◽

The Common ◽

Late Onset Dementia

Alzheimer’s disease (AD) is a neurodegenerative disease that causes late-onset dementia. The R47H variant of the microglial receptor TREM2 triples AD risk in genome-wide association studies. In mouse AD models, TREM2-deficient microglia fail to proliferate and cluster around the amyloid-β plaques characteristic of AD. In vitro, the common variant (CV) of TREM2 binds anionic lipids, whereas R47H mutation impairs binding. However, in vivo, the identity of TREM2 ligands and effect of the R47H variant remain unknown. We generated transgenic mice expressing human CV or R47H TREM2 and lacking endogenous TREM2 in the 5XFAD AD model. Only the CV transgene restored amyloid-β–induced microgliosis and microglial activation, indicating that R47H impairs TREM2 function in vivo. Remarkably, soluble TREM2 was found on neurons and plaques in CV- but not R47H-expressing 5XFAD brains, although in vitro CV and R47H were shed similarly via Adam17 proteolytic activity. These results demonstrate that TREM2 interacts with neurons and plaques duing amyloid-β accumulation and R47H impairs this interaction.

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