Opioid analgesics are currently known as the best analgesics. However， toxicity and side effects such as constipation， tolerance and addiction severely limit their clinical application. With the in-depth understanding of the signal transduction mechanism of opioid receptors and the continuous advancement of drug design technology， researchers have managed to develop many promising new methods to get low-toxic and more efficient opioid analgesics， which are different from the traditional morphine skeleton structure modifications. This article focuses on three new research strategies of G-protein biased activation，“ one drug-multiple targets” and peripheral activation. The basic principles of relative separation of analgesic activity and adverse drug reaction by each strategy are introduced， and the latest research progress of representative drugs is briefly reviewed. Among them， the recently approved novel opioid analgesics oliceridine and tegileridine are G-protein biased μ-opioid receptor agonists， Cebranopadol is a typical “one drug-multiple targets” analgesic， and NFEPP is a representative drug of peripheral opioid receptor agonists. The above several strategies complement each other and provide reference for the development of new opioid analgesic drugs.

Neuroendocrine neoplasm (NEN) is a type of heterogeneous tumor that originates from peptidergic neurons and neuroendocrine cells. The presence of over-expressed somatostatin receptors (SSTR) on the surface of NEN tumor cells has led to the administration of radiolabeled somatostatin analogs (SSA) in combination with over-expressed SSTR, which is called peptide receptor radionuclide therapy (PRRT). The 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacceticacid- D-Phe1-Tyr3-Thr8-octreotide (DOTATATE)-based α/β radionuclide therapy is one of the representative therapeutic methods of PRRT. This article reviews the progress of research on α/β radionuclide therapy based on DOTATATE and its related combination therapy, drug toxicity and safety, as well as expectation for modalities with clinical value for NEN treatment.

Objective:To explore the effect of post-pyloric feeding by spiral nasoenteric tubes on the prognosis of critically ill patients with acute gastrointestinal injury (AGI) grade Ⅱ.Methods:A retrospective study was performed to analyze the clinical data of critically ill adult patients with AGI grade Ⅱ, who were enrolled in three randomized controlled trials conducted by Guangdong Provincial People's Hospital for post-pyloric tube placement between April 2012 and May 2019. Data including demographic characteristics, serological indicators of nutrition, the tube tip position confirmed by abdominal X-ray 24 h after tube insertion, and intensive care unit (ICU), 28-day and hospital mortality were collected. Patients were divided into the post-pyloric feeding group and gastric feeding group according to the tube tip position. Propensity score matching method was used to perform 1:1 matching, and the differences of each index between the two groups were compared after matching. Then the influencing factors of P<0.1 were included in multivariate logistic regression analysis to investigate the potential ICU mortality risk factors of critically ill patients with AGI gradeⅡ. Factors with 0.1 level of significance from the univariate analysis were considered in the multivariate analysis. Results:There were 90 patients in post-pyloric feeding group and 90 patients in the gastric feeding group. Demographics and clinical characteristics of study population were well balanced between the two groups after matching. ICU, 28-day and hospital mortality in the post-pyloric feeding group were significantly lower than those in the gastric feeding group (4.4% vs 15.6%, 14.4% vs 27.8%, 6.7% vs 17.8%, all P < 0.05). Multivariate logistic regression analysis indicated that post-pyloric feeding was an independent protective factor [odds ratio ( OR)=0.295, 95% confidence internal (95% CI): 0.091-0.959, P=0.042] and APACHEⅡ score was an independent risk factor ( OR=1.111, 95% CI: 1.025-1.203, P=0.010) for ICU mortality of critically ill patients with AGI gradeⅡ. Conclusions:Post-pyloric feeding for critically ill patients with AGI grade Ⅱ could decrease ICU mortality and is an independent protective factor against mortality.

To explore the effect of post-pyloric feeding by spiral nasoenteric tubes on ventilator-associated pneumonia (VAP) in neurocritical care patients. Methods A retrospective study was performed to analyze the clinical data of 175 neurocritical care adult patients with mechanical ventilation (MV) more than 48 hours, who were enrolled in three randomized controlled trials (RCT) conducted by Guangdong Provincial People's Hospital for post-pyloric tube placement between April 2012 to March 2019. The following patient clinical data were collected when patients were enrolled: gender, age, neurologic diagnosis, comorbidities, medication, endotracheal reintubation, bronchoscope treatment, the distal site of nasoenteric tubes, and acute physiology and chronic health evaluation Ⅱ(APACHEⅡ) score, sequential organ failure assessment (SOFA) score, Glasgow coma scale (GCS) score, and acute gastrointestinal injury (AGI) grade assessed. Patients were divided into VAP group and non-VAP group according to the occurrence of VAP, and the differences of each index between the two groups were compared. Then the influencing factors of P < 0.1 were included in multivariate Logistic regression analysis to identify the potential risk factors affecting the incidence of VAP. Furthermore, patients were divided into gastric feeding group and post-pyloric feeding group according to the distal site of nasoenteric tubes, and subgroup analysis was performed to evaluate the variety of VAP in patients with different tube sites and status. Results ① Forty-two patients occurred VAP in 175 MV patients, and the incidence of VAP was 24.0%. ② Univariate analysis showed the P value of post-pyloric feeding, APACHE Ⅱscore, GCS score and bronchoscope treatment were less than 0.1, and post-pyloric feeding and GCS score in VAP group were significantly lower than those in non-VAP group [post-pyloric feeding: 19.0% (8/42) vs. 36.8% (49/133), GCS:5 (3, 7) vs. 6 (4, 9), both P < 0.05]. Multivariate Logistic regression analysis indicated that post-pyloric feeding was independent protective factor [odds ratio (OR) = 0.360, 95% confidence internal (95%CI) = 0.151-0.857, P = 0.021] and bronchoscope treatment was the independent risk factor (OR = 2.210, 95%CI = 1.051-4.647, P = 0.036) for VAP. ③ The incidence of VAP was 28.8% (34/118), 0% (0/4), 8.3% (1/12), 26.7% (4/15), 22.2% (2/9) and 5.9% (1/17) respectively when tube tip in stomach, D1, D2, D3, D4 and jejunum confirmed by abdominal radiography. Post-pyloric feeding in each proportion seemed to present lower VAP rate compared with gastric feeding, however, no significant difference was found (all P > 0.05). ④ The incidence of VAP in post-pyloric feeding group was significantly lower than that in gastric feeding group [14.0% (8/57) vs. 28.8% (34/118), OR = 0.403, 95%CI = 0.173-0.941, P = 0.032]. Lower VAP rate appeared on patients with SOFA < 12 (OR = 0.392, 95%CI = 0.154-0.995, P = 0.044) and AGI grade ≥Ⅱ (OR =0.086, 95%CI = 0.011-0.705, P = 0.006) fed by post-pyloric route according to the result of subgroup analysis stratified by age, gender, APACHEⅡ score, SOFA score and AGI grade. Conclusion Post-pyloric feeding would decrease the incidence of VAP in neurocritical care patients on MV.

Objective In this study,Protosappanin A,Caesalpinia Sappan L extract and Cisplatin were combined with radiotherapy in gastric cancer cell SGC-7901 to investigate whether the Protosappanin A could in-crease radiosensitivity( SER) in gastric cancer SGC-7901 cells. This will be medication to create new areas of in-novation in the future. Methods The cell proliferation of SGC-7901 cells was detected by MTT assay. The rela-tionship between the effect of the Protosappanin A on cell proliferation and the time of action was determined. Caesalpinia Sappan L extract and Cisplatin were as controls. The fitted cell survival curve and clonal formation as-says were used to determine the SER to analyze the sensitizative effect of Protosappanin A. Results Protosappa-nin A could inhibit the growth of SGC-7901 cells,and its inhibitory effect is relatively weak. Its cytotoxicity has a time-and concentration-dependent manner. Cellular morphological changes were observed accompanying with increased concentrations and time treatments of Protosappanin A. Clonal formation experiment showed that the Protosappanin A significantly increased the radiosensitivity of SGC-7901 cells when compared to the radioactive group. They showed a statistically difference. Conclusion The inhibitory effect of the Protosappanin A on SGC-7901 cells in a concentration and time-dependent manner. Protosappanin A combined radiotherapy can improve the radiosensitization of cells,both of which may have synergistic anti-tumor effect.

A new approach based on online coupled liquid chromatography-gas chromatography-mass spectrometry ( LC-GC / MS ) was developed for the rapid determination of 4-( methylnitrosamino )-1-( 3-pyridyl)-1-butanone (NNK) in mainstream cigarette smoke, in which a switching valve was employed to online switching between two-dimensional chromatography. The online LC-GC / MS system used in this study was built by using online gel permeation chromatography-gas chromatography-mass spectrometry except that the micro gel column was replaced by micro alkaline alumina column which was prepared by ourselves before. The NNK in mainstream cigarette smoke was collected by a Cambridge filter pad, then the pad was extracted with dichloromethane, and the extract was quantitatively analyzed by online LC-GC / MS with D4-NNK as an internal standard. Online LC-GC / MS allowed online pretreatment purification, and the sample was subjected to online LC-GC / MS without any prior purification, which reduced human error in analysis process. The injection volume of the present online LC-GC / MS could reach 40 μL, which was 20 times of that of the conventional GC / MS (2. 0 μL of injection volume), and thus significantly improved the sensitivity. Under the optimum conditions, good linearity ( r = 0. 9998) was obtained over the range of 1. 2 - 120 ng / mL. The recoveries at three spiked levels ranged from 93. 9% to 96. 0% , and the limits of detection for qualitative and quantitative detection were 0. 25 ng / mL and 0. 9 ng / mL, respectively. All the results obtained by the present method are comparable to those of standard method recommend by China National Tobacco Company.

OBJECTIVE: The prior functional MRI studies have demonstrated significantly abnormal activity in the bilateral superior temporal gyrus (STG) of anxiety patients. The purpose of the current investigation was to determine whether the abnormal activity in these regions was related to a loss of functional connectivity between these regions. MATERIALS AND METHODS: Ten healthy controls and 10 anxiety patients underwent noninvasive fMRI while actively listening to emotionally neutral words alternated by silence (Task 1) or threat-related words (Task 2). The participants were instructed to silently make a judgment of each word's valence (i.e., unpleasant, pleasant, or neutral). A coherence analysis was applied to the functional MRI data to examine the functional connectivity between the left and the right STG, which was selected as the primary region of interest on the basis of our prior results. RESULTS: The data demonstrated that the anxiety patients exhibited significantly increased activation in the bilateral STG than the normal controls. The functional connectivity analysis indicated that the patient group showed significantly decreased degree of connectivity between the bilateral STG during processing Task 2 compared to Task 1 (t = 2.588, p = 0.029). In addition, a significantly decreased connectivity was also observed in the patient group compared to the control group during processing Task 2 (t = 2.810, p = 0.012). CONCLUSION: Anxiety patients may exhibit increased activity of the STG but decreased functional connectivity between the left and right STG, which may reflect the underlying neural abnormality of anxiety disorder, and this will provide new insights into this disease.
Adult ; Anxiety Disorders/pathology/*physiopathology ; Case-Control Studies ; Emotions/physiology ; Female ; Humans ; Magnetic Resonance Imaging/*methods ; Male ; Middle Aged ; Temporal Lobe/pathology/*physiopathology

The Rad1 gene is evolutionarily conserved from yeast to human. The fission yeast Schizosaccharomyces pombe Rad1 ortholog promotes cell survival against DNA damage and is required for G(2)/M checkpoint activation. In this study, mouse embryonic stem (ES) cells with a targeted deletion of Mrad1, the mouse ortholog of this gene, were created to evaluate its function in mammalian cells. Mrad1 (-/-) ES cells were highly sensitive to ultraviolet-light (UV light), hydroxyurea (HU) and gamma rays, and were defective in G(2)/M as well as S/M checkpoints. These data indicate that Mrad1 is required for repairing DNA lesions induced by UV-light, HU and gamma rays, and for mediating G(2)/M and S/M checkpoint controls. We further demonstrated that Mrad1 plays an important role in homologous recombination repair (HRR) in ES cells, but a minor HRR role in differentiated mouse cells.
Animals ; Cell Division ; Cell Proliferation ; DNA Damage ; DNA Repair ; Embryonic Stem Cells ; metabolism ; Exonucleases ; genetics ; metabolism ; physiology ; G2 Phase ; Gamma Rays ; Gene Deletion ; Hydroxyurea ; pharmacology ; Mice ; Ultraviolet Rays

Objective To assess the reliability and validity of the Somatic Self-rating Scale(SSS). Methods The sample consisted of 589 outpatients and 64 inpatients, which all the patients completed Zung's Scales at the same time to test criterion validity of the SSS. And 24 inpatients were selected randomly to take a retest after two weeks without antidepressant treatment. Result The test-retest reliability of the SSS was 0.96 and the Cronbach' s αcoefficients was 0.89. The correlation coefficients of the four factors with the total scale score ranged from 0.76 to 0.88, the correlation coefficients of the four factors ranged from 0. 56 to 0.70. The confirmatory factor analysis showed that the fit index for GFI, NFI, NNFI, CFI, IFI were all approaching 0.9, REMEA = 0. 064,x2/df = 3.67. The factor loadings ranged from 0. 427 to 0.732. Correlations with Zung's Scales were in range of 0.74to 0. 80 while the four factors were in range of 0.55 to 0.74. Drawing the ROC curve and the area under the curve was 0.841. Conclusion The SSS has a high reliability and a good validity and can be used in general hospital.

OBJECTIVETo explore the impact of depressive symptoms on psychological and physical outcomes among elderly living in the residential areas.

METHODSA five years follow-up survey of health outcome was carried out among people aged 55 years or above in community without dementia. The outcome measurements included CES-D (center for epidemiological survey, depression scale), MMSE (mini-mental state examination), ADL (activity of daily living), LSIA (life satisfaction index A), index of physical disease and self-rated health questionnaire. A multiple regression analysis was administered to explore the correlation between depressive symptoms and indices of psychological and physical outcomes.

RESULTS(1) Data from 2 927 subjects having completed two surveys were analyzed. Baseline data showed significant distribution difference of MMSE, ADL, gender and education among the four CES-D score levels. (2) No significant correlation between CES-D score at baseline and MMSE, ADL, LSIA score at five-year follow up was found after controlling the age, gender, educational level and baseline score of MMSE and ADL. (3) Self-rated general health and memory change were significantly correlated to baseline CESD score under controlling the effects of other baseline variables. (4) The score of CESD was found to be a significant predictor for risks of physical disease and mortality by logistic regression model. The odds ratios were 1.52 (95% CI: 1.19 - 1.95) and 2.68 (95% CI: 1.41 - 5.06) respectively.

CONCLUSIONDepressive symptoms play an important role on both psychological and physical health outcomes among elderly living in the community.

Aged ; Aged, 80 and over ; Depression ; physiopathology ; psychology ; Female ; Follow-Up Studies ; Health ; Humans ; Logistic Models ; Male ; Middle Aged