Targeting cAMP in D1-MSNs in the nucleus accumbens, a new rapid antidepressant strategy

Studies have suggested that the nucleus accumbens (NAc) is implicated in the pathophysiology of major depression; however, the regulatory strategy that targets the NAc to achieve an exclusive and outstanding anti-depression benefit has not been elucidated. Here, we identified a specific reduction of cyclic adenosine monophosphate (cAMP) in the subset of dopamine D1 receptor medium spiny neurons (D1-MSNs) in the NAc that promoted stress susceptibility, while the stimulation of cAMP production in NAc D1-MSNs efficiently rescued depression-like behaviors. Ketamine treatment enhanced cAMP both in D1-MSNs and dopamine D2 receptor medium spiny neurons (D2-MSNs) of depressed mice, however, the rapid antidepressant effect of ketamine solely depended on elevating cAMP in NAc D1-MSNs. We discovered that a higher dose of crocin markedly increased cAMP in the NAc and consistently relieved depression 24 h after oral administration, but not a lower dose. The fast onset property of crocin was verified through multicenter studies. Moreover, crocin specifically targeted at D1-MSN cAMP signaling in the NAc to relieve depression and had no effect on D2-MSN. These findings characterize a new strategy to achieve an exclusive and outstanding anti-depression benefit by elevating cAMP in D1-MSNs in the NAc, and provide a potential rapid antidepressant drug candidate, crocin.

Changes in activity of layer 2/3 cortical neurons in isoflurane-anesthetized mice: Real-time Ultra-large-Scale High-resolution imaging platform / 中华麻醉学杂志

Objective:To observe and analyze the changes in activity of layer 2/3 cortical neurons in isoflurane-anesthetized mice by Real-time Ultra-large-Scale High-resolution (RUSH) imaging platform.Methods:Clean-grade healthy male Rasgrf2-Cre/Ai148d mice, aged 8-12 weeks, weighing 18-25 g, were studied.The mice recovered ten days after the skull replacement surgery and proceeded to the next experiment.Imaging data of calcium fluorescence signals from layer 2/3 cortical neurons were acquired by RUSH imaging platform after fixing the head of mice.The time of imaging data acquisition in the awake state, during anesthesia with 1.2% isoflurane, and after the end of anesthesia was 100, 600 and 600 s, respectively.Imaging data were analyzed using Image J and MATLAB softwares.Results:The overall trend of activity of layer 2/3 cortical neurons decreased first and then stabilized with the inhalation of 1.2% isoflurane.The cortical neural activity were gradually increased when isoflurane inhalation was stopped.The recovery rate of neural activity was different in different brain regions after isoflurane inhalation was stopped.The recovery of neural activity in the primary motor cortex was delayed obviously.During the maintenance of anesthesia, the activities of most layer 2/3 cortical neurons in the retrosplenial cortex were weakened, however, some of the neurons became more active.Conclusions:The neural activity in the 2/3 layer of cortex in isoflurane anesthetized mice is inconsistent in observation region, brain region and single cell, suggesting that different neural pathways are involved in the process of anesthesia induction and recovery from anesthesia.

Establish the urodynamic classification of male patients with benign prostatic obstruction and analysis of the effect of transurethral resection of the prostate on different classifications / 中华泌尿外科杂志

Objective:To establish the urodynamic classification of middle-aged and elderly men with benign prostatic obstruction(BPO), and to analyze the efficacy of transurethral resection of the prostate(TURP) on various types of patients.Methods:A retrospective analysis of middle-aged and elderly male patients with non-neurogenic lower urinary tract symptoms(LUTS) who underwent urodynamic tests from January 2010 to December 2018, including 793 patients with BPO. Urodynamics examination of detrusor without contraction needs to complete cystoscopy to diagnose BPO. During urodynamic examination, the detrusor uninhibited contraction induced by spontaneous or stimulation during the bladder filling period is diagnosed as overactivity of the bladder detrusor(DO), and the LinPURR chart indicates the detrusor underactivity(DU). Based on the persistence of BPO leading to DO, DU, and decreased bladder compliance, 793 male patients with BPO with LUTS were divided into four types, including type Ⅰ(BPO: n=164, 20.7%), type Ⅱ(BPO combined with DO: n=333, 42.00%), type Ⅲ(BPO combined with DU: n=267, 33.7%), type Ⅳ(BPO combined with decreased bladder compliance: n=29, 3.7%). The preoperative comparison between groups showed that the age of type Ⅰ-Ⅳ gradually increased, and the age of type Ⅰ was significantly smaller than other types [(67.3±8.2)years, (69.7±7.7)years, (71.5±7.9)years, (72.4±7.1)years, P<0.05]. Compared with other types, the type Ⅰ’s IPSS-S[(9.1±3.6)points vs.(10.4±3.1) points, (9.2±3.3) points, (10.4±3.1)points, P<0.05], IPSS-V[(13.5±3.4) points vs. (14.2±3.5)points, (14.0±3.5)points, (14.2±2.9)points, P<0.05], IPSS scores[(22.6±5.4)points, (24.7±4.9)points, (23.1±5.3)points, (24.6±4.7)points, P<0.05] were significantly lower than other groups, the maximum bladder capacity [(332.6±83.2)ml vs.(221.4±80.8)ml, (286.7±108.2)ml, (242.3±103.4)ml, P<0.05], the functional bladder capacity was significantly higher than other types[(215.2±90.0)ml, (148.5±76.0)ml, (154.9±87.2)ml, (121.2±72.9)ml, P<0.05]. Type Ⅱ’s IPSS-S[(10.4±3.1)points vs.(9.1±3.6)points, (9.2±3.3)points, P<0.05], nocturia frequency[(3.7±1.8)times vs.(3.2±1.8)times, (3.2±1.6)times, P<0.05], IPSS score[(24.7±4.9)points vs.(22.6±5.4)points, (23.1±5.3)points, P<0.05], quality of life scores [(4.9±0.9) points, (4.6±0.9)points, (4.6±0.9)points, P<0.05] was significantly higher than type Ⅰ and type Ⅲ ( P<0.05). Type Ⅲ and Ⅳ had higher residual urine than type Ⅱ[(121.3±96.4)ml, (121.3±96.4)ml vs.(71.2±73.5)ml, P<0.05]. Type Ⅳ’s IPSS-S[(10.4±3.1)points vs. (9.1±3.6)points, (9.2±3.3)points, P<0.05], IPSS-V[(14.2±2.9) points vs.(13.5±3.4)points, (14.0±3.5)points, P<0.05], the frequency of nocturia[(3.8±1.9)times vs.(3.2±1.8)times, (3.2±1.6)times, P<0.05] was significantly higher than that of type Ⅰ and type Ⅲ, and the quality of life score was higher than type Ⅰ and type Ⅲ[(4.3±0.8)points vs.(4.7±0.9)points, (4.6±0.9)points, P<0.05]. type Ⅱ and type Ⅳ’s bladder compliance[(21.4±24.2)ml/cmH 2O, (11.0±11.4)ml/cmH 2O vs.(33.9±23.7)ml/cmH 2O, (33.1±32.7)ml/cmH 2O, P<0.05], maximum bladder capacity[(221.4±80.8)ml, (242.3±103.4)ml vs.(332.6±83.2)ml, (286.7±108.2)ml, P<0.05], functional bladder capacity[(148.5±76.0)ml, (121.2±72.9)ml vs.(215.2±90.0)ml, (154.9±87.2)ml, P<0.05] were significantly less than type Ⅰ and type Ⅲ( P<0.05). From November 2016 to November 2018, 60 middle-aged and elderly male patients with confirmed BPO and TURP were selected, including type Ⅰ( n=17, 28.3%), type Ⅱ ( n=23, 38.3%), and Ⅲ type ( n=11, 18.3%), Ⅳ type( n=9, 15.1%). Type IV patients are significantly older than other types ( P<0.05), bladder compliance is significantly worse than other types( P<0.05), the maximum bladder capacity is smaller than other types( P<0.05). The follow-up started 3 months after the operation. The content of the follow-up included IPSS, IPSS-S, IPSS-V, nocturia frequency, undisturbed sleep time, nocturia quality of life score, and life quality score. Results:The IPSS scores of type Ⅰ, type Ⅱ, and type Ⅲ after TURP were significantly improved compared with preoperative(19.8±6.2 vs.3.4±1.8; 21.9±5.2 vs.4.6±2.6; 21.5±6.2 vs.5.7±4.6, P<0.05), type Ⅳ urine storage symptom score (9.1±4.1 vs.4.3±3.7), nocturia frequency(3.6±1.5vs.2.3±1.6), nocturia quality of life score (25.3±6.9 vs.31.4±13.7) Compared with preoperatively, there was no significant improvement( P>0.05). The quality of life score improvement of type Ⅳ patients was significantly lower than that of type Ⅰ, type Ⅱ, and type Ⅲ (10.9±9.1 vs.12.2±9.0, 14.4±5.7, 12.7±5.8, P<0.05). The IPSS score of type Ⅳ patients was significantly higher than that of type Ⅰ(7.0±5.8 vs.3.4±1.8), and the nocturia quality of life score was significantly lower than that of each group (31.4±13.7 vs.37.5±4.2, 38.7±3.5, 37.8±3.8, P<0.05). Conclusions:For middle-aged and elderly men with BPO, we divide them into four types based on the results of urodynamic examinations, type Ⅰ(simple BPO), type Ⅱ(BPO combined with DO), type Ⅲ(BPO combined with DU), type Ⅳ(BPO combined with bladder compliance decline). Type Ⅰ patients have the best bladder function, and TURP has the best effect; type Ⅱ has a high symptom score and poor quality of life, and can benefit after TURP; type Ⅲ bladder function is poor, and surgery should be performed as soon as possible to prevent further deterioration of bladder function; type Ⅳ bladder function is the best poor, IPSS score and quality of life score are high, TURP surgery is not effective.

Effects of CYP3A5 genetic polymorphisms on metabolism of tacrolimus in patients after kidney transplantation / 吉林大学学报(医学版)

Objective: To investigate the effects of different CYP3A5 genotypes on the concentrations of tacrolimus in blood of the patients after kidney transplantation, and to provide the valuable evidence for personalized administration in the patients after kidney transplantation. Methods: The clinical materials of 115 patients after kidney transplantation were analyzed retrospectively. The patients were divided into three groups according to the CYP3A5 genotypes: CYP3A5 ∗ 1/ ∗ 1 group (11 cases), CYP3A5 ∗ 1/ ∗ 3 group (46 cases) and CYP3A5 ∗ 3/ ∗ 3 group (58 cases). The concentration/dosage (C0/D) values of tacrolimus in blood of the patients in three groups at 7 d, 1 month, 3 months, 6 months, 1 year, and 2 years after operation were detected, respectively. Results: Thedifferences of body mass index (BMI), age composition ratios and gender composition ratios of the patients were not significant between three groups (P>0. 05). Compared with CYP3A5 ∗ 1/ ∗ 3 group, the C0/D values of tacrolimus in blood of the patients in CYP3A5 ∗ 1/ ∗ 1 group at 7 d, 3 months, 1 year and 2 years after operation were decreased (P=0. Oil, P<0.01, P=0.022, P=0.024); compared with CYP3A5 ∗ 3/∗ 3 group, the C0/D values of tacrolimus in blood of the patients in CYP3A5 ∗ 1/ ∗ 1 group and CYP3A5 ∗ 1/ ∗ 3 group at 7 d, 1 months, 3 months, 6 months, 1 year and 2 years after operation were decreased (P

Development of monoclonal antibodies against nucleoprotein of Newcastle disease virus and establishment of a quantitative double-antibody sandwich ELISA for NDV antigen / 中国人兽共患病学报

We developed the monoclonal antibodies against nucleoprotein (NP) of Newcastle disease virus (NDV),and established a double antibody sandwich ELISA method for quantitative determination of NP antigen of NDV (NDV NP ELISA).The recombination NP protein derived from strain F48E9 of NDV were prepared and used to immunize BLAB/c mice.The mouse splenic cells from immunized mice were fused with SP2/0 cells to generate monoclonal antibodies (mAb).The NDV NP specific mAbs were paired to establish a double antibody sandwich ELISA method.The performance of the NDV NP ELISA was evaluated,including specificity,sensitivity,precision,accuracy and linearity.The correlation between the ELISA and PFU virus titer was analyzed by regression analysis method.Two monoclonal antibodies 3C10 and 4E7 were selected to establish double antibody sandwich ELISA for NP antigen of NDV.The linearity and performance of the NDV NP ELISA was characterized.The detection linearity fell in the range of 0.015-0.250 μg/mL (R2 =0.997 4).The detection limit of the assay was 0.015 μg/mL.The recovery was between 88.4％ and 106.01％;the variation coefficient was below 3.4％.In testing of 50 NDV virus samples,this assay performed well and correlated comparably with PFU virus titer (R2 =0.920 9).The NDV NP ELISA for quantitative detection of NDV is a reliable quantifiable assay for detection of NDV NP protein;it provides a new approach for rapid and quantitative detection of Newcastle disease virus.

Effect of serum uric acid levels on graft function and long-term graft survival after kidney transplantation / 中华器官移植杂志

Objective To study the effect of serum uric acid (UA) levels on kidney graft function as well as long-term graft survival after renal transplantation.Methods The clinical data of 859 kidney transplant recipients from Jan.2008 to May 2014 were investigated retrospectively.The differences in clinical indexes between normal UA group and hyperuricemia group were compared based on UA levels.Cox regression model was built to analyze the effect of elevated UA on overall graft loss,death censored graft failure and death of patients,respectively.Kaplan-Meier graft survival curve was used to compare the overall graft loss,death censored graft failure and death of patients between normal UA group and hyperuricemia group.Results The average follow-up time was 38.6 ± 17.3 months for 859 kidney transplant recipients.590 (68.7％) recipients were enrolled in normal UA group and 269 (31.3％) recipients were defined as hyperuricemia patients.The average eGFR in hyperuricemia group was significantly decreased as compared with normal UA group (79.4 ± 20.93 vs.94.7 ± 20.55,P＜0.001).Cox regression model showed that if UA level increased per 10 mol/L,the risk of overall graft lost increased 1.070 times (P＜0.001) and the risk of death censored graft failure increased 1.121 times (P＜0.001) accordingly.Kaplan-Meier analysis showed the overall graft loss was dramatically decreased (P =0.009),and the death censored graft failure was significantly decreased (P＜0.0001) in hyperuricemia group as compared with that in normal UA group.The death of patients showed no significant difference between two groups (P =0.638).Conclusion Serum UA levels after kidney transplantation affect graft function as well as long-term graft survival.