Non-nitrogen-containing bisphosphonates and nitrogen-containing bisphosphonates for the treatment of atherosclerosis and vascular calcification: A meta-analysis.

BACKGROUND: The role of non-nitrogen-containing bisphosphonates (non-N-BPs) and nitrogen-containing bisphosphonates (N-BPs) in the treatment of atherosclerosis (AS) and vascular calcification (VC) is uncertain. This meta-analysis was conducted to evaluate the efficacy of non-N-BPs and N-BPs in the treatment of AS and VC. METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from their inception to July 5th, 2023. Eligible studies comparing bisphosphonates (BPs) versus no BPs in the treatment of AS and VC were included. The data were analyzed using Review Manager Version 5.3. RESULTS: Seventeen studies were included in this meta-analysis. Twelve were randomized control trials (RCTs), and 5 were nonrandomized studies. Overall, 813 patients were included in the BPs group, and 821 patients were included in the no BPs group. Compared with no BP treatment, non-N-BP or N-BP treatment did not affect serum calcium (P > .05), phosphorus (P > .05) or parathyroid hormone (PTH) levels (P > .05). Regarding the effect on serum lipids, non-N-BPs decreased the serum total cholesterol (TC) level (P < .05) and increased the serum triglyceride (TG) level (P < .01) but did not affect the serum low-density lipoprotein cholesterol (LDL-C) level (P > .05). N-BPs did not affect serum TC (P > .05), TG (P > .05) or LDL-C levels (P > .05). Regarding the effect on AS, non-N-BPs did not have a beneficial effect (P > .05). N-BPs had a beneficial effect on AS, including reducing the intima-media thickness (IMT) (P < .05) and plaque area (P < .01). For the effect on VC, non-N-BPs had a beneficial effect (P < .01), but N-BPs did not have a beneficial effect (P > .05). CONCLUSION: Non-N-BPs and N-BPs did not affect serum calcium, phosphorus or PTH levels. Non-N-BPs decreased serum TC levels and increased serum TG levels. N-BPs did not affect serum lipid levels. Non-N-BPs had a beneficial effect on VC, and N-BPs had a beneficial effect on AS.

Comparison of different anastomosis angles in radiocephalic fistula with modified functional end-to-side anastomosis.

OBJECTIVE: Functional vein end to arterial side (ETS) anastomosis uses vein side to arterial side anastomosis with distal vein ligation, which is different from traditional ETS anastomosis. To date, there are no studies concerning different anastomotic angles of fistula with functional ETS anastomosis. The purpose of the study was to analyze the clinical outcomes concerning different anastomotic angles of functional ETS anastomosis in radiocephalic fistula. METHODS: Between January 2018 and December 2020, we performed a prospective cohort study concerning functional ETS anastomosis in radiocephalic fistula. According to vascular anatomy of patients, the anastomosis angles of fistula were designed at 30 ≤ angle ≤ 50°, 50 < angle ≤ 70°, and 135° smooth obtuse angle. The end points were the primary patency rate (PPR), the secondary patency rate (SPR) and the cumulative rate of reintervention (CRR) near anastomotic venous segment. RESULTS: 124 patients with functional ETS anastomosiss were enrolled in this study. Pearson χ2 test showed that the group of 135°anastomosis angle had the maximum distance between arteries and veins, and the group of 30-50°anastomosis angle had the minimum distance between arteries and veins (P < 0.01). 30-50°anastomosis angle had the highest PPR at 12 months (P = 0.03) and the lowest CRR near anastomotic venous segment at 3 months (P = 0.04) and 12 months (P = 0.01). There were no significant differences among different anastomosis angles concerning the SPR within 12 months (P > 0.05). Kaplan-Meier and log-rank analysis showed that 30-50°anastomosis had the highest PPR (P = 0.03) and the lowest CRR near anastomotic venous segment (P = 0.01). A multivariable Cox model showed anastomotic angle was an independent factor predictive of the PPR (P = 0.04) and the CRR near anastomotic venous segment (P = 0.03). 50-70°anastomosis angle was a risk factor of decreasing PPR (P = 0.03). 50-70° (P = 0.01) and 135° (P = 0.03) anastomosis angle were both obvious risk factors of increasing CRR near anastomotic venous segment. CONCLUSION: 30-50°were the best anastomotic angles for functional ETS anastomosis, which had the highest PPR and lowest CRR near anastomotic venous segment.

Microwave ablation versus radiofrequency ablation for patients with primary and secondary hyperparathyroidism: a meta-analysis.

OBJECTIVE: Thermal ablation, including microwave ablation (MWA) and radiofrequency ablation (RFA), has been recommended for the treatment of primary hyperparathyroidism (PHPT) and refractory secondary hyperparathyroidism (SHPT). This meta-analysis was conducted to evaluate the efficacy and safety of MWA and RFA in patients with PHPT and refractory SHPT. METHODS: Databases including PubMed, EMbase, the Cochrane Library, CNKI (China National Knowledge Infrastructure), and Wanfang were searched from inception to December 5, 2022. Eligible studies comparing MWA and RFA for PHPT and refractory SHPT were included. Data were analyzed using Review Manager software, version 5.3. RESULTS: Five studies were included in the meta-analysis. Two were retrospective cohort studies, and three were RCTs. Overall, 294 patients were included in the MWA group, and 194 patients were included in the RFA group. Compared with RFA for refractory SHPT, MWA had a shorter operation time for a single lesion (P < 0.01) and a higher complete ablation rate for a single lesion ≥ 15 mm (P < 0.01) but did not show a difference in the complete ablation rate for a single lesion < 15 mm (P > 0.05). There were no significant differences between MWA and RFA for refractory SHPT concerning parathyroid hormone (P > 0.05), calcium (P > 0.05), and phosphorus levels (P > 0.05) within 12 months after ablation, except that calcium (P < 0.01) and phosphorus levels (P = 0.02) in the RFA group were lower than those in the MWA group at one month after ablation. There was no significant difference between MWA and RFA concerning the cure rate of PHPT (P > 0.05). There were no significant differences between MWA and RFA for PHPT and refractory SHPT concerning the complications of hoarseness (P > 0.05) and hypocalcaemia (P > 0.05). CONCLUSION: MWA had a shorter operation time for single lesions and a higher complete ablation rate for large lesions in patients with refractory SHPT. However, there was no significant difference in efficacy and safety between MWA and RFA in cases of both PHPT and refractory SHPT. Both MWA and RFA are effective treatment methods for PHPT and refractory SHPT.

Enhancing Wettability of Cu3P/Cu Systems through Doping with Si, Sn, and Zr Elements: Insights from First Principles Analysis.

Explaining the wetting mechanism of Cu-P brazing materials and Cu remains challenging. This fundamental research aims to reveal the wettability mechanism of Si, Sn, and Zr doping on the interfacial bond strength of the Cu3P/Cu system through the first principles study. We carried out several sets of calculations to test the validity of the result; included in the work are those used to establish the interfacial structure and to analyze the effect of doping on the wettability. Specific analysis was carried out in terms of three aspects: the work of adhesion (Wad), the charge density difference, and the density of states (DOS). The calculated results show that doping with Si, Sn, and Zr elements can effectively improve the wettability within the CuP/Cu interface with very high accuracy, and is particularly effective when doped with Zr. These results provide an insightful theoretical guide for enhancing the CuP/Cu system's wettability by adding active elements.

Efficacy and safety of tolvaptan versus placebo in the treatment of patients with autosomal dominant polycystic kidney disease: a meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and drug safety of tolvaptan with placebo for autosomal dominant polycystic kidney disease (ADPKD). METHODS: The PubMed, Embase, and Cochrane Library databases were searched from inception to September 10, 2021. Eligible studies comparing tolvaptan and placebo in the treatment of patients with ADPKD were included. Data were analysed using Review Manager Version 5.3. RESULTS: Thirteen studies involving 3575 patients were included in the meta-analysis. Compared with placebo, tolvaptan had a better effect on delaying eGFR decline (MD 1.27, 95% CI 1.24-1.29, P < 0.01) and TKV increase (MD - 3.01, 95% CI - 3.55 to - 2.47, P < 0.01) in ADPKD treatment. Additionally, tolvaptan reduced the incidence of complications such as renal pain (OR 0.71, 95% CI 0.58-0.87, P < 0.01), urinary tract infection (OR 0.69, 95% CI 0.54-0.89, P < 0.01), haematuria (OR 0.68, 95% CI 0.51-0.89, P < 0.01), and hypertension (OR 0.66, 95% CI 0.52-0.82, P < 0.01). However, tolvaptan was associated with a higher incidence rate of adverse events such as thirst (OR 8.48 95% CI 4.53-15.87, P < 0.01), polyuria (OR 4.71, 95% CI 2.17-10.24, P < 0.01), and hepatic injury (OR 4.56, 95% CI 2.51-8.29, P < 0.01). CONCLUSION: Tolvaptan can delay eGFR decline and TKV increase and reduce complications such as renal pain, urinary tract infection, haematuria, and hypertension in the treatment of ADPKD. However, tolvaptan increases the adverse effects of thirst, polyuria and hepatic injury.

Endoscopic parathyroidectomy versus open parathyroidectomy for patients with refractory secondary hyperparathyroidism: a meta-analysis.

Introduction: Endoscopic parathyroidectomy(EPTX) has been gradually introduced as a minimally invasive treatment for refractory secondary hyperparathyroidism (SHPT). However, it is uncertain about the efficacy and safety compared between EPTX and open parathyroidectomy (OPTX) for refractory SHPT. Aim: This meta-analysis was conducted to evaluate the efficacy and safety of EPTX and OPTX for secondary hyperp arathyroidism (SHPT). Material and methods: Databases including PubMed, EMbase, Cochrane Library, CNKI, and Wanfang were searched. Eligible studies comparing EPTX and OPTX for refractory SHPT were included. Results: Compared with OPTX, EPTX has the shorter hospital stay (p < 0.01) and lower incidences of hoarseness or recurrent laryngeal nerve injury (p = 0.04). There was no significant difference between EPTX and OPTX concerning operation time (p = 0.49), intraoperative blood loss (p = 0.24), postoperative parathyroid hormone levels (p = 0.22), postoperative calcium levels (p = 0.93), postoperative phosphorus levels (p = 0.37), and complications including neck ecchymosis (p = 0.87), subcutaneous haematoma (p = 0.18), and wound infection (p = 0.11). Conclusions: EPTX and OPTX are both effective methods for refractory SHPT. EPTX had the shorter hospital stay and lower incidences of hoarseness or recurrent laryngeal nerve injury.

Efficacy and safety of tacrolimus versus corticosteroid as initial monotherapy in adult-onset minimal change disease: a meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus corticosteroid as initial monotherapy in adult-onset minimal change disease (MCD) patients. METHODS: Databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from the inception to March 20, 2021. Eligible studies comparing TAC monotherapy and corticosteroid as initial monotherapy for adult-onset MCD patients were included. Data were analyzed using Review Manager Version 5.3. RESULTS: Four randomized controlled trials (RCTs) involving 196 patients were included in the meta-analysis. For initial monotherapy for adult-onset MCD, TAC and corticosteroid had similar complete remission (OR 1.06, 95% CI 0.47-2.41, P = 0.89), total remission (OR 1.30, 95% CI 0.39-4.35, P = 0.67), relapse rate (OR 0.63, 95% CI 0.28-1.42, P = 0.26). Main drug-related adverse effects of two therapeutic regimens had no difference concerning infection (OR 0.54, 95% CI 0.23-1.27, P = 0.15), glucose intolerance (OR 0.55, 95% CI 0.16-1.84, P = 0.33) and acute renal failure (OR 1.37, 95% CI 0.36-7.31, P = 0.71). CONCLUSION: TAC monotherapy is comparable with corticosteroid monotherapy in initial therapy of MCD. To further confirm the conclusion, more large multicenter RCTs are necessary.

Energy and CO2 emissions modeling for unconventional machining industry considering processing characteristics.

Unconventional machining of WEDM (Wire Electrical Discharge Machining) is playing an increasingly important role in the manufacturing industry. The processing efficiency and resource consumption of this method are research hotspots from the perspective of sustainable development. Energy and CO2 emissions modeling of process machining have been recognized as an effective and economical ways to achieve energy-saving, emission-reducing and to improve process efficiency. However, the predictive modeling of energy and CO2 emissions in unconventional machining of WEDM machining has not been thoroughly fully studied. This paper proposes a predictive model of energy consumption and CO2 emissions in WEDM process considering process characteristics. The application of the energy and CO2 emissions model proposed in this paper in an example shows that the model's energy consumption prediction accuracy for single part processing reaches 96.5%, and the energy consumption prediction accuracy for batch processing is above 99%. A new standard for cutting fluid substitution with the best machining stability and energy consumption is proposed. In the example, it is also shown that the corners in the geometric structure will reduce the processing energy consumption. The smaller the number of single folding angles, the more energy consumption will be reduced. The processing energy consumption per unit area has a greater deviation when the thickness is low, and the thickness of the workpiece will also affect the life of the electrode wire. It depends on the number of multi-layer stacks and the life of electrode wires; the quality of machine tool auxiliary materials has a greater impact on energy consumption, with a difference of up to 40% in energy consumption. The results of this research can better understand the energy consumption and CO2 emissions characteristics of the unconventional machining of WEDM.

Efficacy and safety of tacrolimus monotherapy versus tacrolimus-corticosteroid combination therapy for idiopathic membranous nephropathy: A meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus TAC-corticosteroid combination therapy in idiopathic membranous nephropathy (IMN) patients. METHODS: Databases including PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang database were searched from inception to January 10, 2021. Eligible studies comparing TAC monotherapy and TAC-corticosteroid combination therapy in IMN patients were included. Data were analysed using Review Manager Version 5.3. RESULTS: Seven studies were included in the meta-analysis. One randomized controlled trial and six cohort studies involving 372 patients were identified. Compared with TAC monotherapy, TAC-corticosteroid had a higher total remission at the sixth month (odd ratio (OR) 0.49, 95% confidence interval (CI) 0.31-0.78, P < .01). The two therapy regimens had similar complete remission rates (OR 0.79, 95% CI 0.43-1.48, P = .47) at the sixth month and similar relapse rates (OR 1.44, 95% CI 0.70-2.92, P = .32). TAC-corticosteroid combination therapy had a higher incidence of infection (OR 0.38, 95% CI 0.18-0.81, P = .01). The two therapy regimens had similar incidences of gastrointestinal symptoms (OR 0.96, 95% CI 0.34-2.70, P = .93), abnormal aminotransferase (OR 0.90, 95% CI 0.34-2.38, P = .84), and glucose intolerance (OR 0.58, 95% CI 0.32-1.07, P = .08). CONCLUSION: TAC-corticosteroid combination therapy had a higher total remission rate at the sixth month but had a higher incidence of infection than TAC monotherapy in the treatment of IMN. The two therapeutic regimens had similar relapse rates.

Efficacy and safety of tacrolimus monotherapy versus cyclophosphamide-corticosteroid combination therapy for idiopathic membranous nephropathy: A meta-analysis.

OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety of tacrolimus (TAC) monotherapy versus cyclophosphamide (CTX)-corticosteroid combination therapy in idiopathic membranous nephropathy (IMN) patients. METHODS: Databases including the PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang databases were searched from inception to October 20, 2020. Eligible studies comparing TAC monotherapy and CTX-corticosteroid combination therapy in IMN patients were included. Data were analyzed using Review Manager Version 5.3. RESULTS: Nine studies were included in the meta-analysis. One randomized controlled trial and eight cohort studies involving 442 patients were identified. Compared with CTX-corticosteroid combination therapy for IMN, TAC monotherapy had higher complete remission (CR) at month 6 (odds ratio [OR] 2.18, 95% confidence interval [CI] 1.35-3.50, P < .01). The 2 therapeutic regimens had similar partial remission (OR 0.69, 95% CI 0.45-1.04, P = .08), total remission (OR 1.38, 95% CI 0.85-2.23, P = 0.19) at month 6, and similar CR (OR 1.64, 95% CI 0.84-3.19, P = .15), partial remission (OR 0.71, 95% CI 0.37-1.38, P = 0.31), and total remission (OR 1.29, 95% CI 0.55-3.01, P = .56) after 1 year. The relapse rate of the TAC group was higher than that of the CTX group, but the difference was not statistically significant (OR 1.85, 95% CI 0.75-4.53, P = .18). There was no difference between the 2 therapeutic regimens concerning glucose intolerance (OR 1.15, 95% CI 0.61-2.14, P = .67), acute renal failure (OR 1.14, 95% CI 0.39-3.33, P = .81), or tremors (OR 4.39, 95% CI 0.75-25.67, P = .10). Incidences of gastrointestinal symptoms (OR 0.29, 95% CI 0.10-0.79, P = .02), infection (OR 0.18, 95% CI 0.08-0.39, P < 0.01), leukopenia (OR 0.14, 95% CI 0.04-0.51, P < .01), and abnormal aminotransferase (OR 0.31, 95% CI 0.13-0.77, P = .01) in the TAC group were all lower than those in the CTX group. Subgroup analysis showed that there was no significant difference between the TAC group and the CTX combined with corticosteroid 0.8 to 1 mg/kg/day group concerning CR at month 6 (P > .05). There was no significant difference between the TAC group and the CTX combined with corticosteroid 0.5 mg/kg/day group concerning abnormal aminotransferase (P > .05). CONCLUSION: TAC monotherapy is comparable to CTX-corticosteroid combination therapy for renal remission in IMN patients. TAC monotherapy had a higher CR in the early stage and had fewer drug-related adverse effects. The relapse rate of TAC monotherapy was higher than that of CTX-corticosteroid combination therapy, but the difference was not significant.

Role Overload and Work Performance: The Role of Psychological Strain and Leader-Member Exchange.

The relation between role overload and work performance remains insufficiently understood. Drawing upon conservation of resources theory, we expected role overload to negatively relate to performance through psychological strain and this relation to be buffered by leader-member exchange (LMX). Study 1 (N = 212) examined depression as a severe type of strain that mediates between role overload and in-role performance, job dedication, and voice behavior. Study 2 (N = 191) used generic, perceived strain as a mediator between role overload and in-role performance and reward recommendations. Both studies tested LMX's buffering effect, controlling for role ambiguity and conflict. A supplementary panel study (N = 99) assessed the temporal relationship between role overload and strain. Role overload triggered psychological strain, which undermined performance, and LMX acted as a buffer on role overload, but not on role ambiguity or role conflict. We discuss the implications of these findings for theory and practice.

Low-site versus traditional peritoneal dialysis catheterization: A meta-analysis.

BACKGROUND: The objective of this study was to compare the complications of low-site peritoneal dialysis (PD) catheter placement and traditional open surgery in peritoneal dialysis catheter insertion. METHODS: The following databases were searched from inception to September 6, 2019: PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, and Wanfang. Eligible studies comparing low-site PD catheter placement and traditional open surgery in peritoneal dialysis catheter insertion were included. The data were analyzed using Review Manager Version 5.3. RESULTS: Seven studies were included in the meta-analysis. A total of 504 patients were included in the low-site PD catheter placement group, and 325 patients were included in the traditional open surgery group. Compared with traditional open surgery, low-site PD catheter placement had a lower incidence rate of catheter displacement (odds ratios [OR] 0.11, 95% CI 0.05-0.22, P < .01) and noncatheter displacement dysfunction (OR 0.11, 95% CI 0.04-0.31, P < .01). However, there was no difference between the 2 catheter insertion methods concerning bleeding (OR 0.53, 95% CI 0.23-1.22, P = .13), PD fluid leakage (OR 0.40, 95% CI 0.15-1.10, P = .07), hypogastralgia (OR 0.95, 95% CI 0.32-2.80, P = .93), peritonitis (OR 0.70, 95% CI 0.32-1.54, P = .38), or exit-site and tunnel infections (OR 0.39, 95% CI 0.14-1.03, P = .06). CONCLUSION: Low-site PD catheter placement reduced the risk of catheter displacement and noncatheter displacement dysfunction and did not increase the risk of bleeding, PD fluid leakage, hypogastralgia, peritonitis, or exit site and tunnel infections. Additional large multicenter randomized controlled trials are needed to confirm these conclusions.

Paricalcitol vs. cinacalcet for secondary hyperparathyroidism in chronic kidney disease: A meta-analysis.

Paricalcitol and cinacalcet have been recommended to reduce parathyroid hormone (PTH) levels for patients with secondary hyperparathyroidism (SHPT) and chronic kidney disease (CKD), and they are able to reduce the risk of hypercalcemia and hyperphosphatemia. However, to date, it has remained uncertain which is the better drug. The aim of the present meta-analysis was to evaluate the effects on PTH, calcium and phosphorus metabolism between the two drugs. The PubMed, the Cochrane Library and Embase databases were searched from inception to June 1, 2019 and eligible studies comparing paricalcitol and cinacalcet for SHPT were included. Data were analysed using Review Manager version 5.3. A total of 7 trials from six articles, comprising 456 patients in the paricalcitol group and 412 patients in the cinacalcet group, were included in the meta-analysis. There were no differences in PTH levels [mean difference (MD): 71.82, 95% CI: -185.20-328.85, P=0.58] and phosphorus levels (standard MD: 0.59, 95% CI: -0.82-2.00, P=0.41). The calcium levels in the paricalcitol group were significantly higher than those in the cinacalcet group (MD: 1.10, 95% CI: 0.92-1.28, P<0.05). In conclusion, paricalcitol and cinacalcet exhibited no difference in their efficacy to control of PTH levels, as they were similarly effective in decreasing the PTH levels. They also had comparable efficacy in the management of phosphorus levels. However, cinacalcet produced a significantly greater reduction in serum calcium levels. More large multicentre randomized controlled trials are necessary to confirm the conclusions of the present analysis.

Thermal ablation versus parathyroidectomy for secondary hyperparathyroidism: A meta-analysis.

OBJECTIVE: Thermal ablation and parathyroidectomy (PTX) have been recommended for patients with secondary hyperparathyroidism (SHPT). However, it is uncertain which is the better method. The aim of the present meta-analysis was to evaluate the efficacy and surgical complications of the two treatment methods. METHODS: The following databases were searched from inception to December 31, 2018: PubMed, EMBASE, the Cochrane Library, CNKI, and Wanfang. Eligible studies comparing thermal ablation and PTX for SHPT were included. Data were analysed using Review Manager Version 5.3. RESULTS: Six studies were included in the meta-analysis. Four cohort studies and two randomized controlled trials involving 326 patients with SHPT were identified. There was no difference concerning parathyroid hormone (PTH) levels (MD 58.04, 95% CI -17.60-133.68, P = 0.13), calcium levels (MD -0.07, 95% CI -0.17-0.04, P = 0.21), phosphorus levels (MD 0.21, 95% CI -0.18-0.61, P = 0.29), or hoarseness (OR 0.53, 95% CI 0.24-1.16, P = 0.11) between the two surgical methods. Compared with PTX, thermal ablation reduced the risk of hypocalcaemia (OR 0.23, 95% CI 0.11-0.47, P < 0.01). However, thermal ablation increased the risk of SHPT persistence and/or recurrence compared with PTX (OR 4.24, 95% CI 1.44-15.76, P = 0.03). CONCLUSION: Thermal ablation and PTX were effective surgical approaches for SHTP. Thermal ablation reduced the risk of hypocalcaemia and increased the risk of SHPT persistence and recurrence. More large multicentre randomized controlled trials are necessary to confirm the conclusions.

Peritoneal dialysis catheter insertion using a very-low-site approach: a 5-year experience.

PURPOSE: Peritoneal dialysis (PD) catheter tip migration accounts for the majority of cases of PD catheter malfunction. In this case series, we described our experiences of using a modified PD catheter implantation approach through a site that is lower than the site that is conventionally used, to reduce catheter malfunction. METHODS: We retrospectively identified 76 patients who received PD catheter implantation at the Affiliated Wujin Hospital of Jiangsu University, among whom 39 received the traditional approach of low-site insertion and 37 received a modified approach of very-low-site insertion. All participants were followed up for at least 2 years after PD catheter implantation, and the development of catheter dysfunction or death during this period was monitored. RESULTS: We found that the survival rate of the initially inserted catheter was 75.68% among the very-low-site group. This survival rate was significantly better than that observed among the low-site group (48.72%; p = 0.029). Kaplan-Meier curves of the initial catheter survival also showed that the catheter survival was significantly higher in the patients in the very-low-site group than those in the low-site group (log rank p = 0.012). Complications, such as catheter tip migration, were not observed in the very-low-site group, while tip migration occurred in 15.38% of the patients in the low-site group (very-low-site group vs low-site group: p = 0.039). CONCLUSIONS: A safe and simple PD catheter implantation can be performed either through the low-site approach or the very-low-site approach.

Metabolism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by mitochondrion-targeted cytochrome P450 2D6: implications in Parkinson disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxic side product formed in the chemical synthesis of desmethylprodine opioid analgesic, which induces Parkinson disease. Monoamine oxidase B, present in the mitochondrial outer membrane of glial cells, catalyzes the oxidation of MPTP to the toxic 1-methyl-4-phenylpyridinium ion (MPP(+)), which then targets the dopaminergic neurons causing neuronal death. Here, we demonstrate that mitochondrion-targeted human cytochrome P450 2D6 (CYP2D6), supported by mitochondrial adrenodoxin and adrenodoxin reductase, can efficiently catalyze the metabolism of MPTP to MPP(+), as shown with purified enzymes and also in cells expressing mitochondrial CYP2D6. Neuro-2A cells stably expressing predominantly mitochondrion-targeted CYP2D6 were more sensitive to MPTP-mediated mitochondrial respiratory dysfunction and complex I inhibition than cells expressing predominantly endoplasmic reticulum-targeted CYP2D6. Mitochondrial CYP2D6 expressing Neuro-2A cells produced higher levels of reactive oxygen species and showed abnormal mitochondrial structures. MPTP treatment also induced mitochondrial translocation of an autophagic marker, Parkin, and a mitochondrial fission marker, Drp1, in differentiated neurons expressing mitochondrial CYP2D6. MPTP-mediated toxicity in primary dopaminergic neurons was attenuated by CYP2D6 inhibitor, quinidine, and also partly by monoamine oxidase B inhibitors deprenyl and pargyline. These studies show for the first time that dopaminergic neurons expressing mitochondrial CYP2D6 are fully capable of activating the pro-neurotoxin MPTP and inducing neuronal damage, which is effectively prevented by the CYP2D6 inhibitor quinidine.

Silencing of IkBß mRNA causes disruption of mitochondrial retrograde signaling and suppression of tumor growth in vivo.

A number of studies show that mitochondrial DNA (mtDNA) depletion and attendant activation of retrograde signaling induces tumor progression. We have reported previously that activation of a novel nuclear factor-Kappa B pathway is critical for the propagation of mitochondrial retrograde signaling, which induces both phenotypic and morphological changes in C2C12 myoblasts and A549 lung carcinoma cells. In this study, we investigated the role of stress-induced nuclear factor-Kappa B in tumor progression in xenotransplanted mice. We used a retroviral system for the inducible expression of small interfering RNA against IkBα and IkBß mRNAs. Expression of small interfering RNA against IkBß markedly impaired tumor growth and invasive ability of mtDNA-depleted C2C12 myoblasts and also thwarted anchorage-independent growth of the cells. Knockdown of IkBα mRNA, however, did not have any modulatory effect in this cell system. Moreover, expression of small interfering RNA against IkBß reduced the expression of marker genes for retrograde signaling and tumor growth in xenografts of mtDNA-depleted cells. Our findings demonstrate that IkBß is a master regulator of mitochondrial retrograde signaling pathway and that the retrograde signaling plays a role in tumor growth in vivo. In this regard, IkBß supports the tumorigenic potential of mtDNA-depleted C2C12 cells.

Role of calcineurin, hnRNPA2 and Akt in mitochondrial respiratory stress-mediated transcription activation of nuclear gene targets.

Pathophysiological conditions causing mitochondrial dysfunction and altered transmembrane potential (psim) initiate a mitochondrial respiratory stress response, also known as mitochondrial retrograde response, in a variety of mammalian cells. An increase in the cytosolic Ca2+ [Ca2+]c as part of this signaling cascade activates Ca2+ responsive phosphatase, calcineurin (Cn). Activation of IGF1R accompanied by increased glycolysis, invasiveness, and resistance to apoptosis is a phenotypic hallmark of C2C12 skeletal muscle cells subjected to this stress. The signaling is associated with activation and increased nuclear translocation of a number of transcription factors including a novel NFkappaB (cRel:p50) pathway, NFAT, CREB and C/EBPdelta. This culminates in the upregulation of a number of nuclear genes including Cathepsin L, RyR1, Glut4 and Akt1. We observed that stress regulated transcription activation of nuclear genes involves a cooperative interplay between NFkappaB (cRel:p50), C/EBPdelta, CREB, and NFAT. Our results show that the functional synergy of these factors requires the stress-activated heterogeneous nuclear ribonucleoprotein, hnRNPA2 as a transcriptional coactivator. We report here that mitochondrial stress leads to induced expression and activation of serine threonine kinase Akt1. Interestingly, we observe that Akt1 phosphorylates hnRNPA2 under mitochondrial stress conditions, which is a crucial step for the recruitment of this coactivator to the stress target promoters and culmination in mitochondrial stress-mediated transcription activation of target genes. We propose that mitochondrial stress plays an important role in tumor progression and emergence of invasive phenotypes.

Human liver mitochondrial cytochrome P450 2D6--individual variations and implications in drug metabolism.

Constitutively expressed human cytochrome P450 2D6 (CYP2D6; EC 1.14.14.1) is responsible for the metabolism of approximately 25% of drugs in common clinical use. It is widely accepted that CYP2D6 is localized in the endoplasmic reticulum of cells; however, we have identified this enzyme in the mitochondria of human liver samples and found that extensive inter-individual variability exists with respect to the level of the mitochondrial enzyme. Metabolic assays using 7-methoxy-4-aminomethylcoumarin as a substrate show that the human liver mitochondrial enzyme is capable of oxidizing this substrate and that the catalytic activity is supported by mitochondrial electron transfer proteins. In the present study, we show that CYP2D6 contains an N-terminal chimeric signal that mediates its bimodal targeting to the endoplasmic reticulum and mitochondria. In vitro mitochondrial import studies using both N-terminal deletions and point mutations suggest that the mitochondrial targeting signal is localized between residues 23-33 and that the positively-charged residues at positions 24, 25, 26, 28 and 32 are required for mitochondrial targeting. The importance of the positively-charged residues was confirmed by transient transfection of a CYP2D6 mitochondrial targeting signal mutant in COS-7 cells. Both the mitochondria and the microsomes from a CYP2D6 stable expression cell line contain the enzyme and both fractions exhibit bufuralol 1'-hydroxylation activity, which is completely inhibited by CYP2D6 inhibitory antibody. Overall, these results suggest that the targeting of CYP2D6 to mitochondria could be an important physiological process that has significance in xenobiotic metabolism.

Oncogene-mediated inhibition of glycogen synthase kinase 3 beta impairs degradation of prolactin receptor.

Prolactin receptors (PRLr) expressed in a majority of breast cancer are activated by prolactin and growth hormone. The PRLr is commonly stabilized in human breast cancer due to decreased phosphorylation of residue Ser(349), which, when phosphorylated, recruits the beta Trcp E3 ubiquitin ligase and facilitates PRLr degradation. Here, we show that constitutive oncogenic signaling downstream of ErbB2 and Ras stabilizes PRLr via inhibitory phosphorylation of glycogen synthase kinase-3beta (GSK3 beta) on Ser(9). Importantly, inactivation of GSK3 beta correlates with elevated levels of PRLr protein in clinical human breast cancer specimens. Additional studies using pharmacologic, biochemical, and genetic approaches reveal that GSK3 beta is a bona fide PRLr kinase that phosphorylates PRLr on Ser(349) and is required for the recognition of PRLr by beta Trcp, as well as for PRLr ubiquitination and degradation.