RESUMO
Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.
RESUMO
BACKGROUND: During pregnancy, urinary infections are an important cause of maternofetal morbidity and mortality and may lead to several complications. OBJECTIVE: To verify whether the use of antibiotic therapy in a single dose when compared with multiple doses in lower tract urinary infections during pregnancy is effective to obtain microbiologic cure. SEARCH STRATEGY: Online databases were searched. Keywords used were "single-drug dose", "antibiotic", "fosfomycin", "amoxicillin", "trimethoprim", "pregnancy", and "urinary tract infection". SELECTION CRITERIA: Studies were included if they were randomized controlled trials, the population was pregnant woman, microbiologic cure was attained, and one of the treatment groups received single-dose antibiotic therapy. DATA COLLECTION AND ANALYSIS: Preselected studies have been independently read by pairs, and data were extracted according to a predetermined sheet. The Cochrane tool was used for the risk of bias. MAIN RESULTS: A total of 1063 women from nine studies were included. The primary outcome was the microbiologic cure attested by urine culture. When compared with the multiple-day use of antibiotics, the single-dose treatment has shown statistically similar results in reaching culture cure (odds ratio 1.02, 95% confidence interval 0.73-1.44). CONCLUSION: The current study has shown that the use of single-dose treatment for lower tract urinary infections during pregnancy can be recommended, especially using fosfomycin. SYSTEMATIC REVIEW REGISTRATION: This review has not been registered.