[Analysis of complications and learning curve effects related to deep brain stimulation surgery in 822 Parkinson's disesase patients with the same surgeon].

Objective: To analyze the complications related to deep brain stimulation(DBS) surgery in Parkinson's disease(PD) patients and to determine whether there is a learning curve effect in terms of complications. Methods: Retrospective analysis of the DBS surgical data of 822 PD patients performed by the same surgeon at the First Affiliated Hospital of the University of Science and Technology of China (Anhui Provincial Hospital) from December 2012 to December 2022. The complications related to DBS were evaluated and analyzed the complications of every 100 DBS surgery were further analyzed. Results: A total of 822 PD patients, 453 males and 369 females, aged 31-80 years old, were included. The minimum follow-up period after DBS surgery is 6 months. Surgical related complications occurred in 55 patients (6.69%), including 5 patients (0.61%) with slight bleeding around the electrode, 1 patient (0.12%) with cerebral infarction, 4 patients (0.49%) with postoperative epilepsy, 42 patients (5.11%) with postoperative delirium, 2 patients (0.24%) with respiratory distress, and 1 patient (0.12%) with acute cardiac insufficiency. There were 16 cases (1.94%) of hardware related complications in DBS, of which 4 cases (0.48%) had infection, 1 case (0.12%) had a broken angle at the connection between the pulse generator and the extension wire, 8 cases (0.97%) had an excessively tight extension wire, and 3 cases (0.36%) had an IPG bag hematoma. In the infected cases, 2 patients removed IPG and extension wires. There were 7 cases (0.85%) of stimulus related complications, including 4 cases (0.61%) with programmed sensory abnormalities, 1 case (0.12%) with postoperative abnormal movements and dance like movements, and 2 cases (0.24%) with psychiatric symptoms. A comprehensive analysis was conducted on the above complications, among which 8 cases (0.97%) were relatively serious complications. After active treatment, satisfactory results were achieved, and none of them affected the patient's DBS treatment effect and no patients died. For every 100 cases of DBS surgery complications were analyzed, the percentage of complications decreased significantly from 14.50% (58 cases) in the first 400 cases to 4.73% (20 cases) in the last 400 cases (P<0.001). Conclusion: DBS surgery is safe and has an acceptable low incidence of complications. The incidence of complications also decreases with the accumulation of experience, showing a learning curve effect.

Neural inhibition by c-Jun as a synergizing factor in bone morphogenetic protein 4 signaling.

The transcription factor, activator protein 1 (AP-1) complexes (c-Jun and c-Fos heterodimers) has been shown to interact with transforming growth factor beta signaling in mammalian cells and Drosophila embryo. Here we show that c-Jun alone is involved in the anti-neuralizing activity of bone morphogenetic protein 4, a transforming growth factor beta superfamily member, in Xenopus neurogenesis. Co-injection of mRNAs encoding c-jun and a dominant negative bone morphogenetic protein receptor completely inhibits dominant negative bone morphogenetic protein receptor-induced neuralization and reverses the epidermal fate in the animal cap. Surprisingly, a dominant negative c-Jun does not induce neural tissue in the animal cap, but it synergizes with dominant negative bone morphogenetic protein receptor for neural induction. Temporal analysis using a dexamethasone-inducible c-Jun shows that exogenous c-Jun activity must be turned on before or at stage 11 to fulfill the anti-neuralizing effect. Neural inhibition by c-Jun does not occur until stage 13 suggesting that c-Jun probably acts by suppressing neural maintenance rather than neural initiation. This is also supported by the fact that c-Jun does not inhibit expression of the neural-initializing gene Zic-r1 but the neural cofactor Sox2, and that ectopic expression of Sox2 attenuates the anti-neuralizing effect of c-Jun. Finally, we display that the c-Jun effect is enhanced by an auto-regulatory loop between c-Jun and bone morphogenetic protein. These studies suggest that c-Jun/AP-1 is a converging point in both the fibroblast growth factor and transforming growth factor beta signaling pathways. Based on our findings, we propose that c-Jun synergizes with bone morphogenetic protein 4 signaling to inhibit neural development in Xenopus ectoderm.

Proline oxidase, encoded by p53-induced gene-6, catalyzes the generation of proline-dependent reactive oxygen species.

The p53-dependent initiation of apoptosis is accompanied by the induction of proline oxidase (POX), a mitochondrial enzyme catalyzing the conversion of proline to pyrroline-5-carboxylate with the concomitant transfer of electrons to cytochrome c. However, the contribution of increased POX activity to apoptosis, if any, remains unknown. Using Adriamycin to initiate p53-dependent apoptosis, we showed that the expression of POX is up-regulated in a time- and dose-dependent manner in a human colon cancer cell line (LoVo). In cells expressing POX, the addition of proline increases reactive oxygen species (ROS) generation in a concentration-dependent manner; glutamate, a downstream product of proline oxidation, had no effect. Induction of POX was dependent on the p53 status of the cell. In the conditionally immortalized murine colonic epithelial cell line YAMC, where the p53 phenotype can be modulated by temperature, proline oxidase expression and ROS production could only be induced when the cells were phenotypically p53-positive. To confirm that the observed ROS production was not secondary to some other effect of p53, we also conditionally expressed POX in a p53-negative colon cancer line. Again, we found a proline-dependent ROS increase with POX expression. We hypothesize that proline oxidation supports the generation of ROS by donating reducing potential to an electron transport chain altered either by p53-dependent mechanisms or by overexpression of POX.

Differential formation of beta-catenin/lymphoid enhancer factor-1 DNA binding complex induced by nitric oxide in mouse colonic epithelial cells differing in adenomatous polyposis coli (Apc) genotype.

Increased cytoplasmic beta-catenin levels and the associated nuclear beta-catenin/T-cell factor (Tcf)-lymphoid enhancer factor (LEF) complex formation have been frequently found in colon cancer. In this context, overproduction of nitric oxide (NO) attributable to inflammatory stimuli in diseases such as ulcerative colitis and Crohn's disease may-contribute to colonic carcinogenesis. Therefore, we examined the modulation by NO of cytoplasmic beta-catenin levels and the formation of the nuclear beta-catenin/LEF-1 DNA binding complex in conditionally immortalized mouse colonic epithelial cells that differed in adenomatous polyposis coli (Apc) genotype, namely young adult mouse colon (YAMC; Apc+/+) and immortal mouse colon epithelium (IMCE; ApcMin/+). Unlike most colon cancer cell lines, this pair of cell lines has either nondetectable or low basal level of beta-catenin when they are cultured under nonpermissive and nonproliferative conditions. Using electrophoretic mobility shift assays, we found that NO-releasing agents (E)-methyl-2-[(E)-hydroxyimino]-5-nitro-6-methoxy-3-hexeneamide and S-nitroso-N-acetylpenicillamine greatly enhanced the formation of beta-catenin/LEF-1 DNA binding complex in a concentration- and time-dependent fashion in YAMC and IMCE cells. Significantly, IMCE cells showed a markedly greater amount of nuclear beta-catenin/LEF-1 DNA binding complex in response to NO. Super shift by anti-beta-catenin antibody confirmed the presence of beta-catenin in the complex. Western blot analysis of the soluble cytoplasmic fractions demonstrated that these NO donors caused differential accumulation of cytoplasmic beta-catenin in YAMC and IMCE. In conclusion, this study indicates that the defective beta-catenin degradation machinery attributable to ApcMin/+ mutation in IMCE cells not only affects basal levels but also contributes to NO-induced dysregulation of cytoplasmic beta-catenin and nuclear beta-catenin/LEF-1 DNA binding complex formation.

Expression of prostaglandin endoperoxide H synthase-2 induced by nitric oxide in conditionally immortalized murine colonic epithelial cells.

Increased expression of prostaglandin endoperoxide H synthase-2 (PGHS-2) has been implicated in pathological conditions such as inflammatory bowel diseases and colon cancer. Recently, it has been demonstrated that inducible nitric oxide synthase (NOS II) expression and nitric oxide (NO) production are up-regulated in these diseases as well. However, the apparent link between PGHS-2 and NOS II has not been thoroughly investigated in nontransformed and nontumorigenic colonic epithelial cells. In the present study, we examined the concomitant expression of PGHS-2 and NOS II as well as the production of prostaglandin E2 (PGE2) and NO in conditionally immortalized mouse colonic epithelial cells, namely YAMC (Apc(+/+)). We found that the induction of PGHS-2 and generation of PGE2 in these cells by IFN-gamma and lipopolysaccharide (LPS) were greatly reduced by two selective NOS II inhibitors, L-NIL and SMT. To ascertain the effect of NO on PGHS-2 overexpression, we tested NO-releasing compounds, NOR-1 and SNAP, and found that they caused PGHS-2 expression and PGE2 production. This effect was abolished by hemoglobin, a NO scavenger. Using electrophoretic mobility shift assays, we found that both NOR-1 and SNAP caused beta-catenin/LEF-1 DNA complex formation. Super-shift by anti-beta-catenin antibody confirmed the presence of beta-catenin in the complex. Cell fractionation studies indicated that NO donors caused an increase in free soluble cytoplasmic beta-catenin. This is further corroborated by the immunocytochemistry data showing the redistribution of beta-catenin from the predominantly membrane localization into the cytoplasm and nucleus after treatment with NO donors. To further explore the possible connection between PGHS-2 expression and beta-catenin/LEF-1 DNA complex formation, we studied IMCE (Apc(Min/+)) cells, a sister cell line of YAMC with similar genetic background but differing in Apc genotype and, consequently, their beta-catenin levels. We found that IMCE cells, in comparison with YAMC cells, had markedly higher beta-catenin/LEF-1 DNA complex formation under both resting conditions as well as after induction with NO. In parallel fashion, IMCE cells expressed significantly higher levels of PGHS-2 mRNA and protein, and generated more PGE2. Overall, this study suggests that NO may be involved in PGHS-2 overexpression in conditionally immortalized mouse colonic epithelial cells. Although the molecular mechanism of the link is still under investigation, this effect of NO appears directly or indirectly to be a result of the increase in free soluble beta-catenin and the formation of nuclear beta-catenin/LEF-1 DNA complex.

Effects of MCI-154, a calcium sensitizer, on cardiac function in endotoxemic rabbits.

AIM: To observe the effects of MCI-154, a calcium sensitizer, on cardiac function after endotoxic shock. METHODS: The rabbits were intravenously injected with MCI-154 0.1 mg.kg-1 at 10 h after the administration of endotoxin 1.0 mg.kg-1, followed by a continuous infusion of normal saline (NS) 50 mL.kg-1 + MCI-154 0.1 mg.kg-1. During this process, the parameters of cardiac function were measured. RESULTS: Ten hours after the endotoxin injection, heart rate (HR) increased noticeably while the mean arterial blood pressure (MAP), left ventricular systolic pressure (LVSP), isovolumetric pressure (IP), myocardial contractility (MC), and the area of p-dp/dtmax vector loop (Lo) were all markedly decreased. Treatment with NS 50 mL.kg-1 alone had slight effects on these parameters. LVSP, IP, MC, and Lo were all markedly increased while HR did not obviously change and left ventricular end-diastolic pressure (LVEDP) was reduced markedly following MCI-154 administration in endotoxic shock rabbits. The parameters of MC were improved nearly to the same values as in sham shock group and were markedly higher than in NS treated group. CONCLUSION: MCI-154 exerts remarkable therapeutic effects on cardiac dysfunction after endotoxic shock.

Effect of MCI-154, a calcium sensitizer, on calcium sensitivity of myocardial contractile system in endotoxemic rats.

AIM: To investigate the effect of MCI-154 on calcium sensitivity of myocardial contractile system in endotoxemic rats. METHODS: Skinned right ventricular papillary muscles from endotoxemic rats were prepared by saponin 500 mg/L. Forces of the skinned muscles were recorded when they were activated sequentially by different concentrations of Ca2+ with or without cardiotonic agents. The tension-pCa relationship and pCa50 of the skinned fibers were taken as the index of Ca2+ sensitivity of myocardial contractile system. RESULTS: The maximal Ca(2+)-activated tension (Tmax) was lower, and pCa50 was reduced in endotoxemia group as compared with those in sham control group. Milrinone 50 mumol/L could not counteract the above abnormalities. However, after MCI-154 10 mumol/L was added, the Tmax and pCa50 were increased to an extent similar to that of sham control group and significantly higher than those of endotoxemia group and endotoxemia + milrinone group. Furthermore, such effects of MCI-154 were concentration-dependent. CONCLUSION: The Ca2+ sensitivity of cardiac contractile system in endotoxemic rats is decreased. MCI-154 can reverse the decreased sensitivity and increase Tmax of myocardial muscles from endotoxemic rats.

Differential expression of prostaglandin endoperoxide H synthase-2 and formation of activated beta-catenin-LEF-1 transcription complex in mouse colonic epithelial cells contrasting in Apc.

Mutations in Apc underlie the intestinal lesions in familial adenomatous polyposis and are found in >85% of sporadic colon cancers. They are frequently associated with overexpression of prostaglandin endoperoxide H synthase-2 (PGHS-2) in colonic adenomas. It has been suggested that Apc mutations are linked mechanistically to increased PGHS-2 expression by elevated nuclear accumulation of beta-catenin-Tcf-LEF transcription complex. In the present study, we show that PGHS-2 is differentially expressed in mouse colonic epithelial cells with distinct Apc status. Cells with a mutated Apc expressed markedly higher levels of PGHS-2 mRNA and protein and produced significantly more prostaglandin E2 than cells with normal Apc. Using electrophoretic mobility shift assays, we demonstrate that DNA-beta-catenin-LEF-1 complex formation is differentially induced in these two cell lines in an Apc-dependent manner. Our data indicate that the differential induction of beta-catenin-LEF-1 complex correlates closely with differential expression of PGHS-2. These findings support the hypothesis that the differential expression of PGHS-2 is mediated through the proposed beta-catenin/Tcf-LEF signaling pathway.

Identification of Staphylococcus aureus virulence genes in a murine model of bacteraemia using signature-tagged mutagenesis.

Signature-tagged mutagenesis with transposon Tn917 was used to identify genes of Staphylococcus aureus required for virulence in a murine model of bacteraemia. Screening 1248 mutant strains in pools of 96 resulted in the provisional identification of 50 mutants attenuated in virulence. Subsequent individual analysis of many of these mutants confirmed that they are attenuated in virulence. DNA sequence analysis of regions flanking their transposon insertion points revealed that approximately half of them represent genes with unknown function, while most of the remainder are involved in nutrient biosynthesis and cell surface metabolism. Three mutants were found with transposon insertions in different positions in femA, and one mutant had an insertion in femB. Both femA and femB are involved in the formation of cell wall peptidoglycan pentaglycine cross-bridges. A further mutation occurred in a previously unknown gene that shares significant similarity to femB. Mutations were also obtained in recA and lsp (encoding the S. aureus prolipoprotein signal peptidase). On the basis of sequence similarities to proteins of known function, the products of other genes are probably involved in the synthesis of diaminopimelic acid (a component of peptidoglycan), maintenance of surface adhesins and cell surface membrane transport, showing that many components of the S. aureus cell surface are critical for the survival and replication of this pathogen in blood.

Involvement of nitric oxide in the deregulation of cytosolic calcium in cerebellar neurons during combined glucose-oxygen deprivation.

Nitric oxide (NO) has been proposed as a neuronal messenger molecule in hypoxic/ischemic cell injury (Nowicki et al., 1991; Trifiletti, 1992). We conducted studies in a model of combined glucose-oxygen deprivation using cultured rat cerebellar granule cells. Experiments were designed to test the hypothesis that sustained elevation of cytosolic calcium ([Ca2+]i) and NO generation act in concert to trigger neuronal injury after anoxic insult. A hypoxic state was achieved by perfusing the cells with medium pre-equilibrated with argon gas. [Ca2+]i was monitored using digital-imaging fluorescence microscopy in cells loaded with fura-2 AM. Under short-term hypoxic conditions, cells displayed a progressive and sustained, moderate increase of [Ca2+]i, which returned to near basal levels on restoration of O2-containing medium. Prolonged hypoxic conditions (> 60 min) caused irreversible elevation of [Ca2+]i followed by disruption of cell membrane integrity, as indicated by severe swelling, loss of regular cell shape and processes, leakage of dye fura-2, and propidium iodide uptake ("point of no return"). Pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, 100 microM), a specific NO synthase inhibitor, markedly delayed the onset of intensity of the rise of [Ca2+]i. The hypoxia-induced elevation of [Ca2+]i was also greatly attenuated if L-NAME (100 microM) was added to the argon-perfused medium before the cells demonstrated signs of irreversible injury. Prolonged or repeated hypoxic conditions, however, caused a rapid and intense increase of [Ca2+]i, which could not be blocked by inhibition of NO synthase (NOS). In addition, reoxygenation after the "point of no return," as characterized above, greatly potentiated [Ca2+]i overload and facilitated the process of cell injury. The potentiation and facilitation of cell damage, as demonstrated by rapid massive increase of [Ca2+]i and subsequent cell death, was not blocked by NOS inhibitor, L-NAME.

Effects of small-volume infusion of 7.5% hypertonic saline/6% dextran-70 on the cardiovascular function of traumatic-hemorrhagic shock rats at high altitude.

This study was designed to evaluate the effects of small-volume infusion of 7.5% hypertonic saline/6% dextran-70 (HSD) on the cardiovascular function of traumatic-hemorrhagic shock rats at simulated high altitude. 32 rats were randomly divided into four groups: 1) normal saline (NS)-treated group, 2) .9% NaCl/6% dextran-70 (Dex)-treated group, 3) 7.5% hypertonic saline (HS)-treated group, and 4) 7.5% hypertonic saline/6% dextran-70 (HSD)-treated group. The rats were exposed to a simulated high altitude of 4,000 m in a hypobaric hypoxic chamber, and traumatic-hemorrhagic shock was inflicted through fracture of the shaft of the left femur and bleeding from femoral vein to reduce mean arterial pressure (MAP) to 6.00 +/- .67 kPa within 5 min. The MAP was kept at this level for 1 h, and then a bolus intravenous injection of 4 mL/kg NS, Dex, HS, or HSD were given to the rats, respectively. In the 5 h period after treatment, it was found that MAP, left ventricular systolic pressure, maximal rate of left ventricular pressure rise and drop (+/- dp/dtmax) were significantly higher in HSD group than in the NS, Dex and HS groups. It can be concluded that 1) HSD can improve the cardiovascular function and hemodynamics of traumatic-hemorrhagic shock rats at simulated high altitude and 2) HSD is more effective than HS.