Alzheimer's disease (AD) is a leading cause of dementia in the elderly. Mitogen-activated protein kinase phosphatase 1 (MKP-1) plays a neuroprotective role in AD. However, the molecular mechanisms underlying the effects of MKP-1 on AD have not been extensively studied. MicroRNAs (miRNAs) regulate gene expression at the post-transcriptional level, thereby repressing mRNA translation. Here, we reported that the microRNA-429-3p (miR-429-3p) was significantly increased in the brain of APP23/PS45 AD model mice and N2A^APP AD model cells. We further found that miR-429-3p could downregulate MKP-1 expression by directly binding to its 3'-untranslated region (3' UTR). Inhibition of miR-429-3p by its antagomir (A-miR-429) restored the expression of MKP-1 to a control level and consequently reduced the amyloidogenic processing of APP and Aβ accumulation. More importantly, intranasal administration of A-miR-429 successfully ameliorated the deficits of hippocampal CA1 long-term potentiation and spatial learning and memory in AD model mice by suppressing extracellular signal-regulated kinase (ERK1/2)-mediated GluA1 hyperphosphorylation at Ser831 site, thereby increasing the surface expression of GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). Together, these results demonstrate that inhibiting miR-429-3p to upregulate MKP-1 effectively improves cognitive and synaptic functions in AD model mice, suggesting that miR-429/MKP-1 pathway may be a novel therapeutic target for AD treatment.

Approximately 140 million people worldwide are homozygous carriers of APOE4 (ε4), a strong genetic risk factor for late onset familial and sporadic Alzheimer's disease (AD), 91% of whom will develop AD at earlier age than heterozygous carriers and noncarriers. Susceptibility to AD could be reduced by targeted editing of APOE4, but a technical basis for controlling the off-target effects of base editors is necessary to develop low-risk personalized gene therapies. Here, we first screened eight cytosine base editor variants at four injection stages (from 1- to 8-cell stage), and found that FNLS-YE1 variant in 8-cell embryos achieved the comparable base conversion rate (up to 100%) with the lowest bystander effects. In particular, 80% of AD-susceptible ε4 allele copies were converted to the AD-neutral ε3 allele in human ε4-carrying embryos. Stringent control measures combined with targeted deep sequencing, whole genome sequencing, and RNA sequencing showed no DNA or RNA off-target events in FNLS-YE1-treated human embryos or their derived stem cells. Furthermore, base editing with FNLS-YE1 showed no effects on embryo development to the blastocyst stage. Finally, we also demonstrated FNLS-YE1 could introduce known protective variants in human embryos to potentially reduce human susceptivity to systemic lupus erythematosus and familial hypercholesterolemia. Our study therefore suggests that base editing with FNLS-YE1 can efficiently and safely introduce known preventive variants in 8-cell human embryos, a potential approach for reducing human susceptibility to AD or other genetic diseases.
Humans ; Apolipoprotein E4/genetics* ; Cytosine ; Mutation ; Blastocyst ; Heterozygote ; Gene Editing ; CRISPR-Cas Systems

Objective To evaluate the optimum compatibility of nalbufine combined with ropivacaine for patient-controlled epidural analgesia (PCEA) after cesarean section.Methods A total of 100 parturients who were at full term with a singleton fetus,aged 24-35 yr,with body mass index of 29-33 kg/m2,of American society of Anesthesiologists physical status Ⅱ,scheduled for elective cesarean section under combined spinal-epidural anesthesia,were divided into 4 groups (n =25 each) using a random number table method:sufentanil 0.5 μg/ml plus 0.15％ ropivacaine group (SR group),nalbufine at final concentration of 0.2 mg/ml plus 0.15％ ropivacaine group (N1 R group),nalbufine at final concentration of 0.4 mg/ml plus 0.15％ ropivacaine group (N2R group) and nalbufine at final concentration of 0.4 mg/ml plus 0.1％ ropivacaine group (N3Rgroup).PCEA solution was prepared correspondingly after surgery,and all the drugs were diluted to 100 ml in normal saline in each group.The PCA pump was set up to deliver a 0.5 ml bolus dose with a 15-min lockout interval and background infusion at 2 ml/h.Visual analog scale scores of incisional pain and anduterine contraction pain were maintained＜4.Ramsay sedation scores were recorded at 8,12,24 and 48 h after surgery.The total pressing times of PCEA were recorded within 48 h after surgery.The development of adverse reactions such as nausea,vomiting,skin itching,numbness of lower extremity,urinary retention and respiratory depression was recorded in the analgesia period.Venous blood samples were collected before surgery and at 24 and 48 h after surgery for determination of plasma prolactin concentrations,and the time of colostrum was recorded.Neonatal nerve and adaptive capacity was assessed and scored.Results Compared with group SR,the total pressing times of PCEA were significantly reduced in N2R and N3R groups (P＜0.05),and no significant change was found in the total pressing times of PCEA in group N1R (P＞0.05).Compared with group N1R,the total pressing times of PCEA were significantly reduced in N2R and N3 R groups (P＜0.05).There was no significant difference in the total pressing times of PCEA between group N2R and group N3R (P＞0.05).The Ramsay sedation score was 2 in four groups.There was no significant difference in numbness of lower extremity,plasma prolactin concentrations or neonatal nerve and adaptive capacity scores among four groups (P＞0.05).Conclusion Nalbufine at final concentraction of 0.4 mg/ml mixed with 0.1％ ropivacaine is the optimum compatibility when used for PCEA after cesarean section.

Objective: To investigate the influential factors of efficacy of the first ¹³¹I ablation therapy for thyroid remnant in papillary thyroid microcarcinoma (PTMC) patients after thyroidectomy. Methods: Eighty-nine PTMC patients who underwent twice ¹³¹I ablation therapy and ¹³¹I whole body follow-up scan (¹³¹I-WBS) within 5 to 8 months in our department from September 2007 to October 2016 were identified and enrolled in present study. Patients were divided into complete-ablation group and uncomplete-ablation group according to whether or not radioactivity was detected at the thyroid bed in ¹³¹I-WBS. The χ² test and multi-variance Binary logistic regression were performed for the factors which might affect the therapeutic efficacy. Results: The first ¹³¹I ablation therapy was successful in 41 of 89 patients (46.07%). Residual thyroid weight was found to be associated with therapeutic efficacy (P<0.05), while gender, age, surgical method, lesions′maximum diameter, with or without LN metastasis, with or without distant metastasis, time of operation from first ¹³¹I treatment, lesions′number, thyroid stimulating hormone (TSH), thyroglobulin (Tg), the consistency of ¹³¹I-WBS and ⁹⁹Tc^m-pertechnatate, TNM stage, ATA risk, Tg/TSH ratio were not significant associated with therapeutic efficacy. Binary logistic regression analysis was performed in these respects and it indicated that residual thyroid weight and ATA risk were not statistically significant independent variable (P>0.05). Conclusions Residual thyroid weight might affect efficacy of the first ¹³¹I ablation therapy on thyroid remnant in PTMC patients after thyroidectomy, but it is not an independent factor. Multiple interrelated factors should be considered when predicting the efficacy of the first ¹³¹I ablation therapy.

Objective To quantify the workload rate of nurses at clinical departments and to clarify the current situation of clinical nursing work. Methods We randomly selected three departments respectively from the medical system and the surgery system as observation areas, and the nurses on the job as observation objects. Then we drew up the to-do-list of nursing work, and defined the concepts and activities of various items. The nurses of the department were observed and recorded every 5 minutes by uniformly-trained observers, and the data were collected and entered into the Excel software to set up the database by using the method of work sampling combined with the random starting point and other time intervals. Based on data collation and analysis of SPSS19. 0 statistical software, the improvement and control scheme was put forward. Results The average nursing workload rates of medicine and surgical systems were 93. 52％ and 92. 13％ respectively. Direct nursing in the surgical system accounted for 10. 59％, and indirect nursing accounted for 62. 89％; direct nursing for the medical system accounted for 16. 20％ and indirect nursing for 57. 32％. The proportions of nursing work belonged to operation increment were relatively large (77. 32％ and 81. 54％). Conclusions The work sampling method is more comprehensive and objective to reflect the intensity of nursing workload. To define the workload of clinical nurses and distinguish the increment and waste items of nursing process are helpful to improve the quality of nursing management and the efficiency of service.

OBJECTIVE:To provide evidence for strengthening education and training before clinical practice and employment guidance among pharmacy junior students of our university. METHODS:Anonymous questionnaire survey was conducted for our university. Questionnaire survey included student employment intention and internship units,relationship of internships with employ-ment,the tendency of employment after graduation,personal attitude about pharmaceutical professional development prospect,ex-pected monthly income in the first year of their career,etc. RESULTS:Totally 71 questionnaires were sent out,71 were effectively received. Among all respondents,74.3%(52 students)believed employment intention had great relationship with internship units;24.3%(17 students)thought employment intention had not great relationship with internship units;moreover,one student thought employment intention had no any relationship with internship units. Most students(94.3%,66 students)with good attitude on in-ternships believed it could accumulate work experience;32.9%(23 students) thought they could stay in the internship unit after practice;moreover,17.1%(12 students) believed practice had little effect on employment. Among them,94.0%(63 students) tended to be employed after graduation,and only 6.0% chose a graduate school to continue their studies. Among the students who chose employment after graduation,76.1%(51 students)tended to engage in pharmaceutical related work,while 17.9%(12 stu-dents) tended to be engaged in work nothing to do with pharmacy or self-employed. The majority (69.6%,48 students) believed that pharmaceutical major prospect was general and pharmaceutical major development varied from person to person;17.4%(12 students)thought pharmaceutical major had good prospect and was promising;13.0%(9 students)believed that pharmaceutical ma-jor had no good prospect and didn't know its prospect. Most of the students(78.2%,54 students)expected a monthly income of 2500-5000 yuan in the first year of their career;18.9%expected a monthly income more than 5000 yuan(13 students);the minor-ity expected a monthly income of 1500-2500 yuan or more than 8000 yuan. CONCLUSIONS:The view of students on internship and employment have a certain gap with the social situation. Related departments of colleges and universities need to adjust the thought of students and strengthen guidance.

Objective: To explore the diagnostic efficacy of by ¹⁸F-FDG PET-CT for hypermetabolic thyroid nodules. Methods: To retrospectively analyze the clinical data of 3 192 patients underwent ¹⁸F-FDG PET-CT in our hospital from May 2012 to October 2014. Among them, 98 patients were diagnosed with focal hypermetabolic thyroid nodules. 61 of the 98 patients were diagnosed with malignant or benign thyroid nodules using histopathological or clinical follow-up (22 malignant nodules, 39 benign nodules). The average age of these 61 patients was 61.6±12.5 years. Results: The lgSUVmax of malignant group (0.69±0.31) was significantly higher than that in benign group (0.43±0.27) (P=0.001). There was no significant difference in age, gender, nodule size, minimum diameter of nodule, lgCT, calcification, the boundary definition, density uniformity, and history of malignancy between the two groups (P>0.05). Binary Logistic regression indicated the AUC of Logistic regressive model(AUC) was 0.866±0.049 (95% CI: 0.769-0.963), and the malignant AUCs of ROC curve was 0.747±0.068 (95%CI: 0.614-0.880) which was only determined by lgSUVmax. The difference was statistically significant (P<0.01). Conclusion ¹⁸F-FDG PET-CT imaging can not only detect hypermetabolic thyroid nodules, but also have a certain clinical value for the identification of benign and malignant nodules.

Objective To explore the clinical significance of the serum brain?derived neurotrophic factor( BDNF) level in severe neonatal hyperbilirubinemia. Methods One hundred and twenty term and birth weight>2500 g infants admitted to the Neonatal Intensive Care Unit of Bethune nternational Peace Hospital of People Liberation Army were divided into severe hyperbilirubinemia group and control group according to their total bilirubin concentration. Total bilirubin( TBIL) concentration,BDNF and albumin in serum were determined in two groups. In addition, craniocerebral MRI was performed in severe neonatal hyperbilirubinemia before discharge. The correlation of the BDNF, TBIL, B/A, MRI results between severe hyperbilirubinemia group and control group were compared. Results The serum BDNF levels in severe hyperbilirubinemia group was ( 8. 84 ±3. 26) μg/L,significantly higher than that in control group((6. 24±1. 71) μg/L,t=3. 88,P<0. 05). In severe hyperbilirubinemia group,BDNF level was positively correlated with B/A level(r=0. 429,P<0. 05),but there was no correlation between BDNF and total bilirubin level(r=0. 278,P>0. 05). The serum BDNF level with craniocerebral MRI abnormal was ( 9. 53 ± 2. 77 ) μg/L, higher than that with craniocerebral MRI abnormal ((7. 81±3. 76) μg/L),but there was no statistical difference between them(t=1. 439,P>0. 05). Conclusion In severe neonatal hyperbilirubinemia, the body can secrete BDNF increasely. BDNF level is positivelycorrelated with B/ A level. As a marker of brain damage,BDNF is sensitive than craniocerebral MRI.

Objective To characterize the finals mispronunciation in Chinese-speaking children with functional articulation disorder (FAD),in order to promote the standardized diagnosis.Method A retrospective study was conducted.From January to December 2013,90 FAD children,diagnosed by Dysarthria Rating Scale and Mandarin Finals scale,were included in this study.Among them,22 were found to have finals mispronunciation;the average age was (6.56 ± 0.26) years.According to the finals classification,six different finals (simple finals,front vowel compound finals,central vowel compound finals,back vowel compound finals,anterior nasal finals,and posterior nasal finals) were defined;the produced sound samples of those subjects were analyzed.Result In all these children,22 of 90 (24％)were found having finals mispronunciation,the occurring rates of which with omission and substitution errors were:3％ (4/132) for simple finals,30％ (26/88) for front vowel compound finals,26％ (23/88) for central vowel compound finals,7％ (8/110) for back vowel compound finals,73％ (128/176) for anterior nasal finals and 73％ (112/154) for posterior nasal finals,respectively.In omission and substitution errors,the ratios of the finals above were 50％ (150/301),3％ (10/301),5％ (14/301),36％ (107/301),2％ (5/301) and 5％ (15/301),respectively.The most frequently occurred mispronunciation were omission,substitution and distortion,with rates of 37％ (273/748),4％ (28/748) and 8％ (61/748),respectively.Conclusion The FAD children have remarkable mispronunciation of finals.Omission is the main error.The nasal finals are the most commonly involved,followed by front vowel and central vowel compound finals.The simple finals and the back vowel compound finals are most commonly produced in omission and substitution.These finals production features should be considered when making and implementing rehabilitation programs.

Obgective To explore the risk factors of preterm infants with bronchopulmonary dysplasia(BPD).Methods A prospective cohort study was conducted to analyze the risk factors of preterm infants with BPD.Preterm infants (gestational age ＜ 32 weeks,and admission within 24 h since birth,and survival time more than 28 d since birth) who were sent to the Ward of Extremely Preterm Infants in Bayi Children's Hospital Affiliated to Clinical Medical College in Beijing Military General Hospital of Southern Medical University were enrolled from November 2013 to May 2014.According to the diagnostic criteria of BPD,the subjects were divided into 2 groups(BPD group and non-BPD group).Factors such as maternal information,neonatal basic information,neonatal diseases and treatments were compared between the 2 groups.Risk factors of preterm infants with BPD were analyzed by using t test,Chi-square test,Fisher's exact probability method and Logistic regression analysis.Results (1) A total of 298 cases were enrolled in this study.Among these infants,180 cases were male and 118 cases were female.The gestational age ranged from 25.6 to 31.9 weeks with the average age of (29.9 ± 1.4) weeks and the birth weights ranged from 740 to 2 300 g with the average weight of (1 428.3 ± 289.0) g.There were 19 cases of extremely low birth weight and 175 cases of very low birth weight.Sixty-nine cases of these infants were diagnosed as BPD (43 cases were mild,10 cases were moderate,16 cases were severe) with incidence of 23.2％.(2)The incidence of BPD was negatively related to gestational age and birth weight:the incidence of BPD in preterm infants with gestational age ＜ 28 weeks,28-30 weeks and ≥ 30-32 weeks were 70.4％,41.9％ and 6.2％;the incidence of BPD in preterm infants with birth weight ＜ 1 000 g,1 000-1 500 g and ≥ 1 500-1 800 g were 78.9％,29.5％ and 8.8％.(3) Multivariate Logistic regression found gestational age (OR =4.52),birth weight (OR =3.38),gender (OR =3.04),cytomegalovirus infection (OR =55.27),duration of invasive ventilation ≥ 7 d (OR =3.22),the highest concentration of inspired oxygen ≥400 mL/L (OR =4.14),patent ductus arteriosus(PDA) in need of surgical ligation (OR =7.30),and transfusion of packed red blood cells within 14 d since birth (OR =3.51) were the independent risk factors of BPD (all P ＜ 0.05).(4) Factors such as birth weight (P =0.015),duration of invasive ventilation (P =0.003),duration of inspired oxygen (P =0.000),and PDA in need of surgical ligation or not(P =0.017) were related to the severity of BPD.Conclusions BPD is a multifactorial disease.Taking effective measures to control risk factors is the key for preventing BPD.