Objective To compare the clinical diagnoses with autopsy findings and evaluate the frequency of misdiagnosis.Methods The findings of 356 cases who were autopsied in our department due to medical treatment dispute during the period of 1988 to 2007 were retrospectively analyzed.The clinical diagnosis and autopsy findings,sex and age of the death,length of hospitalization,the hospital department,distribution of death disease and the rank of hospital were analyzed.The concordance between diagnosis before death and at autopsy was calculated.Results In 162 cases(45.5%),the autopsy findings confirmed the clinical diagnosis.In 101 cases(28.4%),the clinical diagnosis suggested by clinicians were discordant with the autopsy findings.In 63 cases(17.7%),some diagnoses made by clinicians were proved by autopsy,and in 30 cases(8.4%),the clinical and postmortem diagnosis were beyond comparison.The most frequently misdiagnosed diseases were from cardiovascular and respiratory diseases,and among them,cardiomyopathy,aortic atherosclerosis and pneumonia were most common.Conclusion Autopsy is not only helpful for the management of medical dispute,but also beneficial to reduce the misdiagnosis in clinical practice.

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure–activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotoninorepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

Numerous psychotropic and addictive substances possess structural features similar to those of β-phenethylamine (β-PEA). In this study, we selected 29 β-PEA derivatives and determined their structure–activity relationship (SAR) to their ability to inhibit dopamine (DA) reuptake; conducted docking simulation for two selected compounds; and identified their potential functionals. The compounds were subdivided into arylethylamines, 2-(alkyl amino)-1-arylalkan-1-one derivatives and alkyl 2-phenyl-2-(piperidin-2-yl)acetate derivatives. An aromatic group, alkyl group, and alkylamine derivative were attached to the arylethylamine and 2-(alkyl amino)-1-arylalkan-1-one derivatives. The inhibitory effect of the compounds on dopamine reuptake increased in the order of the compounds substituted with phenyl, thiophenyl, and substituted phenyl groups in the aromatic position; compounds with longer alkyl groups and smaller ring-sized compounds at the alkylamine position showed stronger inhibitory activities. Docking simulation conducted for two compounds, 9 and 28, showed that the (S)-form of compound 9 was more stable than the (R)-form, with a good fit into the binding site covered by helices 1, 3, and 6 of human dopamine transporter (hDAT). In contrast, the (R, S)-configuration of compound 28 was more stable than that of other isomers and was firmly placed in the binding pocket of DAT bound to DA. DAinduced endocytosis of dopamine D2 receptors was inhibited when they were co-expressed with DAT, which lowered extracellular DA levels, and uninhibited when they were pretreated with compound 9 or 28. In summary, this study revealed critical structural features responsible for the inhibition of DA reuptake and the functional role of DA reuptake inhibitors in regulating D2 receptor function.

Among 14 subtypes of serotonin receptors (5-HTRs), 5-HT 2AR plays important roles in drug addiction and various psychiatric disorders. Agonists for 5-HT 2AR have been classified into three structural groups: phenethylamines, tryptamines, and ergolines. In this study, the structure-activity relationship (SAR) of phenethylamine and tryptamine derivatives for binding 5-HT 2AR was determined. In addition, functional and regulatory evaluation of selected compounds was conducted for extracellular signal-regulated kinases (ERKs) and receptor endocytosis. SAR studies showed that phenethylamines possessed higher affinity to 5-HT 2AR than tryptamines. In phenethylamines, two phenyl groups were attached to the carbon and nitrogen (R 3 ) atoms of ethylamine, the backbone of phenethylamines. Alkyl or halogen groups on the phenyl ring attached to the β carbon exerted positive effects on the binding affinity when they were at para positions. Oxygen-containing groups attached to R 3 exerted mixed influences depending on the position of their attachment. In tryptamine derivatives, tryptamine group was attached to the β carbon of ethylamine, and ally groups were attached to the nitrogen atom. Oxygen-containing substituents on large ring and alkyl substituents on the small ring of tryptamine groups exerted positive and negative influence on the affinity for 5-HT 2AR, respectively. Ally groups attached to the nitrogen atom of ethylamine exerted negative influences. Functional and regulatory activities of the tested compounds correlated with their affinity for 5-HT 2AR, suggesting their agonistic nature. In conclusion, this study provides information for designing novel ligands for 5-HT 2AR, which can be used to control psychiatric disorders and drug abuse.

In this study, we determined the effect of 24 different synthetic 4-benzylpiperidine carboxamides on the reuptake of serotonin, norepinephrine, and dopamine (DA), and characterized their structure–activity relationship. The compounds with a two-carbon linker inhibited DA reuptake with much higher potency than those with a three-carbon linker. Among the aromatic ring substituents, biphenyl and diphenyl groups played a critical role in determining the selectivity of the 4-benzylpiperidine carboxamides toward the serotonin transporter (SERT) and dopamine transporter (DAT), respectively. Compounds with a 2-naphthyl ring were found to exhibit a higher degree of inhibition on the norepinephrine transporter (NET) and SERT than those with a 1-naphthyl ring. A docking simulation using a triple reuptake inhibitor 8k and a serotoninorepinephrine reuptake inhibitor 7j showed that the regions spanning transmembrane domain (TM)1, TM3, and TM6 form the ligand binding pocket. The compound 8k bound tightly to the binding pocket of all three monoamine reuptake transporters; however, 7j showed poor docking with DAT. Co-expression of DAT with the dopamine D2 receptor (D2R) significantly inhibited DA-induced endocytosis of D2R probably by reuptaking DA into the cells. Pretreatment of the cells with 8f, which is one of the compounds with good inhibitory activity on DAT, blocked DAT-induced inhibition of D2R endocytosis. In summary, this study identified critical structural features contributing to the selectivity of a molecule for each of the monoamine transporters, critical residues on the compounds that bound to the transporters, and the functional role of a DA reuptake inhibitor in regulating D2R function.

Objective To study the immunoregulatory effects of emodin on macrophages during Brucella infection and to provide theoretical and experimental basis for developing new drugs to treat brucello-sis. Methods Bone marrow cells were isolated from BALB/c mice and cultured with MG-CSF to induce differentiation. Flow cytometry was used to detect the differentiation of bone marrow cells into macrophages (MΦ) by using FITC-labeled mouse anti-F4/80 antibody and PE-labeled anti-CD11b antibody. MTT meth-od was used to detect the influences of various concentrations of emodin on the survival rate of MΦ. Doxy-cycline was used as the control to compare half maximal inhibitory concentrations (IC50) of the two drugs. MΦ were cultured with Brucella at a ratio of 100 : 1 for 4 h. MΦ and Brucella were further cultured for 1, 6,12,24 and 48 h after adding emodin. Effects of emodin on the survival of MΦ were analyzed by colony counting method. ELISA was performed to detect the levels of TNF-α, IL-6 and IFN-γ in culture superna-tants. Results On day 8 of culturing,91.28% of bone marrow cells differentiated into macrophages. The IC50of emodin(608.4 μg/ml) was significantly higher than that of doxycycline(225.5 μg/ml). The logC-FU values of emodin stimulation groups (6,12,24 and 48 h) were significantly lower than those of blank control groups. Among all emodin stimulation groups, the 24 h group had the lowest logCFU value, which was also lower than that of the doxycycline treatment group. The levels of TNF-α,IL-6 and IFN-γ in 6,12 and 24 h emodin stimulations group increased significantly as compared with those of the corresponding con-trol groups. The levels of TNF-α, IL-6 and IFN-γ peaked at 24 h of culturing Brucella-infected MΦ with emodin. No significant difference in IFN-γ level was found between the 12 and 24 h emodin stimulation groups [(74.233 ±4.416) pg/ml vs (78.328 ±8.932) pg/ml]. Conclusion Emodin may enhance the ability of macrophages to kill Brucella through promoting the expression of TNF-α,IL-6 and IFN-γ.