In recent years, the prevalence of Alzheimer's disease (AD) has increased, which places a great burden on society and families and creates considerable challenges for medical services. N6-methyladenine (m6A) deoxyribonucleic acid (DNA) adenine methylation is a novel biomarker and is abundant in the brain, but less common in AD. We support to analyze the relationship between DNA m6A and cognition in patients with AD and normal controls (NCs) in China.To analyze the relationship between the novel m6A DNA and cognition in patients with AD and NCs in China.A total of 179 AD patients (mean age 71.60 ± 9.89 years; males: 91; females: 88) and 147 NCs (mean age 69.59 ± 11.22 years; males: 77; females: 70) who were age- and sex-matched were included in our study. All subjects underwent neuropsychological scale assessment and magnetic resonance imaging examination. Apolipoprotein E (APOE) genotypes were measured through agarose gel electrophoresis. Global m6A levels were evaluated by a MethylFlash m6A DNA Methylation ELISA Kit (colorimetric). Global m6A levels in total DNA from ten AD patients with 18F-AV-45 (florbetapir) positron emission tomography (PET) positivity and ten NCs with PET negativity were analyzed by dot blotting to determine the results.Our ELISA results showed that the global m6A DNA levels in peripheral blood were different between patients with AD and NCs (P = 0.002; < 0.05). And ten AD patients who were PET positive and ten NCs who were PET negative also showed the same results through dot blotting. There were significant differences between the two groups, which indicated that the leukocyte m6A DNA levels were different (P = 0.005; < 0.05). The m6A level was approximately 8.33% lower in AD patients than in NCs (mean 0.011 ± 0.006 vs 0.012 ± 0.005). A significant correlation was found between the Montreal Cognitive Assessment score and the peripheral blood m6A level in the tested population (r = 0.143, P = 0.01; < 0.05). However, no relationship was found with APOE ε4 (P = 0.633, > 0.05). Further studies should be performed to validate these findings.Our results show that reduced global m6A DNA methylation levels are significantly lower in AD patients than in NCs by approximately 8.33% in China.
The lack of understanding of molecular pathologies of the solitary functioning kidney makes improving and strengthening the continuity of care between pediatric and adult nephrological patients difficult. Copy number variations (CNVs) account for a molecular cause of solitary functioning kidney, but characterization of the pathogenic genes remains challenging.In our prospective cohort study, 99 fetuses clinically diagnosed with a solitary functioning kidney were enrolled and evaluated using chromosomal microarray analysis (CMA). The genetic drivers for the pathogenic CNVs were analyzed. We characterized QPRT localization in fetal kidneys using immunohistochemistry and its expression in adult kidneys using quantitative RT-PCR. Further, QPRT was knocked down using siRNA in human embryonic kidney (HEK293T) cells, and the cell cycle and proliferation were tested.Besides one Triple X syndrome and one Down syndrome, we identified a total of 45 CNVs out of 34 subjects. Among the 14 pathogenic CNVs, CNV 16p11.2 reached the highest number of records with the phenotype of kidney anomalies in the Decipher database. Among the 26 genes within the 16p11.2 region, as a key enzyme for nicotinamide adenine dinucleotide (NAD+) biosynthesis, QPRT was distinctly localized in renal tubules but was barely observed in renal interstitial and glomeruli in fetal kidneys. The loss of QPRT prevented cells' efficient transition into S phase, affected cell-cycle progression, and abrogated proliferation of human embryonic kidney cells.Our data suggest that QPRT is a candidate gene associated with susceptibility for solitary functioning kidney. The CNVs discovered in our study exhibit great potential for future applications in genetic counseling and pregnancy management.
Backgroud Human epithelial growth factor receptor 2 (HER2) amplification is an important mechanism of acquired resistance to anti-epidermal growth factor receptor (EGFR) therapy in non-small cell lung cancer (NSCLC) patients. For patients with both EGFR mutation and HER2 amplification, there is currently no unified standard treatment, and further exploration is needed on how to choose the therapy. Methods and results A female NSCLC patient developed bone and brain metastases 14 and 42 months after radical surgery, respectively. The second genetic sequencing detected EGFR L858R mutation and HER2 amplification, and therefore initiated treatment with almonertinib and pyrotinib. The patient achieved partial remission and did not show any further progression during the follow-up period. Conclusion For NSCLC patients with both EGFR mutation and HER2 amplification, the combination of almonertinib and pyrotinib is a valuable therapy that can continuously reduce tumor burden and achieve long-term survival.
Abstract The education programs for transesophageal echocardiography (TEE), which plays significant roles in various surgical procedures, in China is currently limited to stimulation system and in-hospital patients. Although, existing TEE simulators have become increasingly sophisticated, the use of animal models retains significant advantages in terms of enabling dynamic cardiac monitoring. The aim of this study is to develop a better teaching and training program for TEE and establish baseline values for the porcine animal model. The thorough TEE examinations were conducted in 10 domestic porcine weighing 45-60kg according to ASA guideline for TEE. All the recommended views were explored and saved. The depth and angles of each view were recorded. Additionally, hemodynamic measurements were performed and recorded. All parameters were compared with human reference values. The porcine model is feasible to initiate a teaching model, and TEE baseline values were acquired for more development in the experimental porcine model.
To clarify the clinical feature, diagnosis and therapy of the pulmonary cryptococcosis (PC).A retrospective study of cases with PC who were diagnosed by pathological examinations between January 1996 and December 2010 was conducted. Eighty-one cases were enrolled in the study (58 male and 23 female patients; mean age of (51±11) years). Forty-one cases were asymptomatic at the time of diagnosis. There were single pulmonary lesions in 50 cases, and multiple lesions in 31 cases. Fourteen lesions (17.3%) were located in left upper lobe, 27 (33.3%) in left lower lobe, 21 (25.9%) in right upper lobe, 3 (3.7%) in right middle lobe, 28 (34.6%) in right lower lobe, and 3 (3.7%) diffusely involved bilateral lungs. The tumors ranged from 0.8 to 10.0 cm in diameter with a mean of (2.9±1.8) cm. All the cases were misdiagnosis prior to the surgical resection, and histologically confirmed by postoperative pathological specimens.All the cases received surgical treatment including complete resection in 69 cases, and palliative resection in 12 cases. Resections were performed by means of video-assisted thoracoscopy in 31 cases and thoracotomy in 50 cases. Surgical resections included pulmonary wedge excisions in 42 cases, and lobectomies in 39 cases. After histological confirmation, 63 cases (77.8%) were treated with antifungal agents, which consisted of fluconazole in 38 cases, itraconazole in 18 cases, amphotericin B in 6 cases, and flucytosine in 4 cases. There were no intraoperative death, but two cases died for cryptococcal meningoencephalitis in the postoperative period. Operative morbidity occurred in 7 (8.6%) cases. The median follow-up was 42.5 months (6 to 84 months). There were 2 local relapses of PC, and 9 cases with complications of anti-fungal agents.The clinical manifestations of PC are mild and non-specific, with no characteristic radiographic manifestations. Surgical resection is usually indicated for definite diagnosis and treatment. Antifungal drug therapy is indispensable even after complete resection.
Detecting plasma tau biomarkers used to be impossible due to their low concentrations in blood samples. Currently, new high-sensitivity assays made it a reality. We performed a systematic review and meta-analysis in order to test the accuracy of plasma tau protein in diagnosing Alzheimer's disease (AD) or mild cognitive impairment (MCI).We searched PubMed, Cochrane, Embase and Web of Science databases, and conducted correlation subgroup analysis, sensitivity analysis and publication bias analysis using R Programming Language.A total of 56 studies were included. Blood t-tau and p-tau levels increased from controls to MCI to AD patients, and showed significant changes in pairwise comparisons of AD, MCI and normal cognition. P-tau217 was more sensitive than p-tau181 and p-tau231 in different cognition periods. In addition, ultrasensitive analytical platforms, immunomagnetic reduction (IMR), increased the diagnostic value of tau proteins, especially the diagnostic value of t-tau.Both t-tau and p-tau are suitable AD blood biomarkers, and p-tau217 is more sensitive than other tau biomarkers to differentiate MCI and AD. Detection techniques also have an impact on biomarkers' results. New ultrasensitive analytical platforms of IMR increase the diagnostic value of both t-tau and p-tau biomarkers.https://www.crd.york.ac.uk/PROSPERO/, registration number: CRD42021264701.
To investigate the association between atrial fibrillation and the single nucleotide polymorphism (SNP) of slow delayed rectifier K(+) channel (I(Ks)) genes in Han nationality Chinese.Three hundred and eighty of Han nationality Chinese (142 atrial fibrillation, 120 in-hospital and 118 out-hospital control) were enrolled in this study. Asian specific non-synonymous SNPs of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N were genotyped by restriction fragment length polymorphism analysis. A newly cloned KCNE4 gene was also screened for any possible SNP.The minor allele frequency of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N in out-hospital subjects was 0.079, 0, 0.042, 0.317 and 0.004, respectively. None of these SNPs was relationed with any atrial fibrillation phenotype. A KCNE4 E145D was discovered and proven statistically to relation significantly to atrial fibrillation by logistic regression analysis (OR = 1.66, P = 0.044). The minor allele frequency of KCNE4 E145D was as high as 0.271 in out-hospital subjects.None of the SNPs of KCNQ1 P448R, KCNQ1 R519H, KCNQ1 G643S, KCNE1 G38S and KCNE1 D85N was associated with atrial fibrillation phenotype, but KCNE4 E145D may relation to atrial fibrillation. The effect of KCNE4 E145D variation on the function of I(Ks) channel is to be determined.
Objectives: Dementia is a clinical syndrome caused by multiple etiologies, usually manifests with progressive and diffuse brain dysfunction. The activity of the human glymphatic system was evaluated in cases of dementia by the diffusion tensor image analysis along the perivascular space (DTI-ALPS). Methods: We recruited 28 healthy subjects and 77 patients, including 38 with Alzheimer’s disease (AD),18 with mild cognitive impairment (MCI), 28 with normal controls (NC) and 21 with vascular cognitive impairment (VCI). All participants underwent DTI scanning. Diffusivities in the X, Y and Z axes were obtained in the lateral ventricle body plane of all subjects. We assessed the diffusivity along the perivascular spaces, as well as projection fibers and association fibers, respectively, in order to acquire an DTI-ALPS-index and correlated them with mini mental state examination (MMSE) and montreal cognitive assessment (MOCA) scores using partial correlation which the influence of age was controlled. Results: The AD, MCI, and VCI patients showed significantly lower DTI-ALPS-index (p < 0.001) compared to the NC. Besides, the VCI group had significantly higher DTI-ALPS-index than the AD group (p = 0.007). There was a significant positive correlation between DTI-ALPS-index and MMSE and MOCA scores (the effect of age was controlled), showing that lower water diffusivity along the perivascular spaces associated with dementia.The higher Dzassoc led to the reduced DTI-ALPS-index in VCI, while lower Dxassoc contributed to the decrease of DTI-ALPS-index in AD. Conclusion: The evaluation of DTI-ALPS demonstrates impairment of the glymphatic system in dementia patients by decreased DTI-ALPS-index. Different from AD, the VCI patients show glymphatic drainage disorder rather than glymphatic system impairment. Advances in knowledge: This article comprehensively covers several types of dementia and performs the comparison of VCI, AD and MCI in glymphatic system dysfunction.
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