Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus.

Objectives Avascular necrosis (AVN) is one of the most common causes of organ damage in patients with systemic lupus erythematosus (SLE) and often causes serious physical disability. The aims of this study were to investigate clinical risk factors associated with symptomatic AVN and to analyze their synergistic effects in a large SLE cohort in Korea. Methods Patients with SLE were enrolled and followed from 1998 to 2014 in the Hanyang BAE Lupus cohort, and damage was measured annually according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). AVN was confirmed by imaging study if patients had symptoms. To determine risk factors for AVN, clinical, laboratory and therapeutic variables were analyzed by logistic regression. Relative excess risk due to interaction (RERI), attributable proportion (AP), and synergy index (S) were calculated to measure interactions between significant variables. Results Among 1219 SLE patients, symptomatic AVN was the most common type of musculoskeletal damage (10.8%, n = 132). SLE patients with AVN showed an earlier onset age, demonstrated AVN more commonly in conjunction with certain other clinical manifestations such as renal and neuropsychiatric disorders, and received significantly higher total cumulative corticosteroid dose and immunosuppressive agents than did patients without AVN. However, in multivariable analysis, only two variables including use of a cumulative corticosteroid dose greater than 20 g (odds ratio (OR) 3.62, p = 0.015) and use of immunosuppressants including cyclophosphamide or mycophenolate mofetil (OR 4.51, p < 0.001) remained as significant risk factors for AVN. Patients with cumulative corticosteroid dose > 20 g and immunosuppressant use had a 15.44-fold increased risk for AVN, compared with patients without these risk factors ( p < 0.001). RERI, AP and S, which define the strength of interactions between two risk factors, were 9.01 (95% confidence interval (CI) 1.30-16.73), 0.58 (95% CI 0.36-0.81) and 2.66 (95% CI 1.42-4.99), respectively, supporting the presence of synergistic interactions in the development of symptomatic AVN in our Korean lupus cohort. Conclusions An individual risk assessment for AVN development should be made prior to and during treatment for SLE, especially in patients with high-dose corticosteroid and immunosuppressant use regardless of clinical manifestations and disease activity.

Vacuum sealing drainage as a pre-surgical adjunct in the treatment of complex (open) hand injuries: Report of 17 cases.

BACKGROUND: Few studies have been conducted to explore the use of the vacuum sealing drainage (VSD) technique in complex hand injuries. The aim of this study was to report outcomes in patients with complex hand injuries receiving VSD as a coadjuvant treatment prior to second-stage surgery. METHODS: This case series study retrospectively reviewed the patients who underwent VSD for treatment of hand injuries. Inclusion criteria for the study were: (1) traumatic soft tissue defects of the hand and wrist, accompanied by different degrees of injury and exposure of bone, tendon, or blood vessel; (2) the wound surface of hand and wrist was seriously contaminated and direct wound closure was not possible; and (3) the soft tissues of hand and wrist were seriously lacerated or avulsed, and showed necrosis or acute infection. After debridement, one-stage and/or two-stage repairs using healthy adjacent tissues were performed and the wound was covered by the VSD materials. The non-cytotoxic polyethylene alcohol hydration seaweed salt foam was applied during the VSD treatment for its good biocompatibility. The drainage tube was connected to the vacuum equipment and the negative pressures were set at -60kPa to -40kPa. The VSD device was left in place for 5 to 7 days before removal. Either free skin grafting or skin flap transplantation was used for wound closure and/or reconstructive surgery. The hand injury severity score was used to assess wound severity. The surgical results were scored using the total active motion classification. RESULTS: A total of 17 patients (13 and 4 patients had major and severe hand injuries), averaging 33.8 years were included. During the study period, 6 patients with severe hand injuries were not treated with VSD for the following reasons: (1) hemodynamic instability (n=1); (2) impaired coagulation function (n=1); (3) uncontrollable hemorrhage on the wound surface (n=2); and (4) exposure of the main blood vessels after surgical repair (n=2). VSD treatment was performed for an average of 7.4 days (range, 6-14 days) and the duration of wound healing averaged 23 days (range, 20-43 days). Wound infection was not reported prior to second-stage surgery. Only one of 17 patients had superficial necrosis at the flap edge, for a success rate of 94%. Average follow-up was 8.7 months (range, 4-13 months). Twelve (71%) patients reported excellent or good, four (23%) reported fair, and one (6%) reported poor results. CONCLUSION: The VSD can effectively promote safe and rapid repair of local soft tissues with good prognosis.

Re-activation of mitochondrial apoptosis inhibits T-cell lymphoma survival and treatment resistance.

T lymphocyte non-Hodgkin's lymphoma (T-NHL) represents an aggressive and largely therapy-resistant subtype of lymphoid malignancies. As deregulated apoptosis is a frequent hallmark of lymphomagenesis, we analyzed gene expression profiles and protein levels of primary human T-NHL samples for various apoptotic regulators. We identified the apoptotic regulator MCL-1 as the only pro-survival BCL-2 family member to be highly expressed throughout all human T-NHL subtypes. Functional validation of pro-survival protein members of the BCL-2 family in two independent T-NHL mouse models identified that the partial loss of Mcl-1 significantly delayed T-NHL development in vivo. Moreover, the inducible reduction of MCL-1 protein levels in lymphoma-burdened mice severely impaired the continued survival of T-NHL cells, increased their susceptibility to chemotherapeutics and delayed lymphoma progression. Lymphoma viability remained unaffected by the genetic deletion or pharmacological inhibition of all alternative BCL-2 family members. Consistent with a therapeutic window for MCL-1 treatment within the context of the whole organism, we observed an only minimal toxicity after systemic heterozygous loss of Mcl-1 in vivo. We conclude that re-activation of mitochondrial apoptosis by blockade of MCL-1 represents a promising therapeutic strategy to treat T-cell lymphoma.

Peptide fragment of thymosin ß4 increases hippocampal neurogenesis and facilitates spatial memory.

Although several studies have suggested the neuroprotective effect of thymosin ß4 (TB4), a major actin-sequestering protein, on the central nervous system, little is understood regarding the action of N-acetyl-serylaspartyl-lysyl-proline (Ac-SDKP), a peptide fragment of TB4 on brain function. Here, we examined neurogenesis-stimulative effect of Ac-SDKP. Intrahippocampal infusion of Ac-SDKP facilitated the generation of new neurons in the hippocampus. Ac-SDKP-treated mouse hippocampus showed an increase in ß-catenin stability with reduction of glycogen synthase kinase-3ß (GSK-3ß) activity. Moreover, inhibition of vascular endothelial growth factor (VEGF) signaling blocked Ac-SDKP-facilitated neural proliferation. Subchronic intrahippocampal infusion of Ac-SDKP also increased spatial memory. Taken together, these data demonstrate that Ac-SDKP functions as a regulator of neural proliferation and indicate that Ac-SDKP may be a therapeutic candidate for diseases characterized by neuronal loss.

Ischemic diabetic retinopathy as a possible prognostic factor for chronic kidney disease progression.

PURPOSE: To assess the value of diabetic retinopathy (DR) severity as a possible predictive prognostic factor for the progression of chronic kidney disease (CKD). PATIENTS AND METHODS: Retrospective cohort study. Patients (51) who were initially diagnosed with DR and CKD were enrolled and their medical records were evaluated. The following ophthalmic factors were assessed by fluorescein angiography at the initial visit: area of capillary nonperfusion, presence of neovascularization and vitreous hemorrhage, and DR grade. The effect of these factors on CKD progression over the 2-year period of the study, defined as doubling of serum creatinine or the development of end-stage renal disease requiring dialysis or renal transplant, was evaluated. RESULTS: The study included 51 patients with DR and CKD; of these, 11 patients (21.6%) were found to have proliferative DR (PDR) and seven patients (13.7%) had high-risk PDR at baseline. Patients with ischemic DR, who showed extensive capillary nonperfusion (≥ 10 optic disc areas) in the retina, had a greater risk for CKD progression (hazard ratio = 6.64; P = 0.002). CONCLUSION: We found that extensive capillary nonperfusion in the retina greatly increased the risk of progression of CKD in patients with DR. This suggests that the retina and the kidney may have shared risk factors for microvascular disease secondary to diabetes mellitus, and emphasizes the need for a team approach to diabetes care.

CHIP has a protective role against oxidative stress-induced cell death through specific regulation of endonuclease G.

Oxidative stress is implicated in carcinogenesis, aging, and neurodegenerative diseases. The E3 ligase C terminus of Hsc-70 interacting protein (CHIP) has a protective role against various stresses by targeting damaged proteins for proteasomal degradation, and thus maintains protein quality control. However, the detailed mechanism by which CHIP protects cells from oxidative stress has not been demonstrated. Here, we show that depletion of CHIP led to elevated Endonuclease G (EndoG) levels and enhanced cell death upon oxidative stress. In contrast, CHIP overexpression reduced EndoG levels, and resulted in reduced or no oxidative stress-induced cell death in cancer cells and primary rat cortical neurons. Under normal conditions Hsp70 mediated the interaction between EndoG and CHIP, downregulating EndoG levels in a Hsp70/proteasome-dependent manner. However, under oxidative stress Hsp70 no longer interacted with EndoG, and the stabilized EndoG translocated to the nucleus and degraded chromosomal DNA. Our data suggest that regulation of the level of EndoG by CHIP in normal conditions may determine the sensitivity to cell death upon oxidative stress. Indeed, injection of H2O2 into the rat brain markedly increased cell death in aged mice compared with young mice, which correlated with elevated levels of EndoG and concurrent downregulation of CHIP in aged mice. Taken together, our findings demonstrate a novel protective mechanism of CHIP against oxidative stress through regulation of EndoG, and provide an opportunity to modulate oxidative stress-induced cell death in cancer and aging.

Randomised phase II trial of docetaxel and sunitinib in patients with metastatic gastric cancer who were previously treated with fluoropyrimidine and platinum.

BACKGROUND: Docetaxel is widely used as a chemotherapeutic agent for gastric cancer treatment. A combined regimen with sunitinib demonstrated a synergistic antitumour effect in a preclinical model. The aim of this study was to evaluate the efficacy and safety of this combination in patients with unresectable or metastatic advanced gastric cancer following failure of treatment with a fluoropyrimidine and platinum combination. METHODS: This open-label, phase II, randomised trial enrolled patients with unresectable or metastatic gastric cancer. Patients were assigned to either a docetaxel monotherapy arm (D only arm: 60 mg m(-2), every 3 weeks) or a combination arm (DS arm: docetaxel+sunitinib 37.5 mg every day). The primary end point of the study was time to progression and the secondary end points were overall response rate, disease control rate, overall survival, and toxicity profile. A pharmacokinetic study was also performed. RESULTS: A total of 107 patients were entered into the study. The TTP was not significantly prolonged in the DS arm when compared with the D only arm (DS vs D only arm: 3.9 months (95% confidence interval (CI) 2.9-4.9) vs 2.6 months (95% CI 1.8-3.5) (P=0.206). The hazard ratio for TTP was 0.77 (95% CI 0.52-1.16). However, the objective response rate was significantly higher in the DS arm (41.1% vs 14.3%, P=0.002). Patients in the DS arm experienced stomatitis, diarrhoea, and hand-foot syndrome more frequently. CONCLUSION: The addition of sunitinib to docetaxel did not significantly prolong TTP, although it significantly increased response.

Elevated LDH and paranasal sinus involvement are risk factors for central nervous system involvement in patients with peripheral T-cell lymphoma.

BACKGROUND: The incidence and risk factors of central nervous system (CNS) involvement in peripheral T-cell lymphomas (PTCLs) are still unclear. PATIENTS AND METHODS: We analyzed 228 patients with PTCLs, excluding cases of extranodal natural killer/T-cell lymphoma and primary cutaneous T-cell lymphoma, by retrospectively collecting the clinical features and outcomes of the patients. RESULTS: Twenty events (8.77%, 20/228) of CNS involvement were observed during a median follow-up period of 13.9 months (range 0.03-159.43). Based on univariate analysis, elevated serum lactate dehydrogenase (LDH) level [P = 0.019, relative risk (RR) 5.904, 95% confidence interval (CI) 1.334-26.123] and involvement of the paranasal sinus (P = 0.032, RR 3.137, 95% CI 1.105-8.908) adversely affect CNS involvement. In multivariate analysis, both were independently poor prognostic factors for CNS relapse [elevated LDH level: P = 0.011, hazard ratio (HR) 6.716, 95% CI 1.548-29.131; involvement of the paranasal sinus: P = 0.008, HR 3.784, 95% CI 1.420-10.083]. The survival duration of patients with CNS involvement was significantly shorter than that of the patients without CNS involvement (P = 0.009), with median overall survival of 7.60 months (95% CI of 4.92-10.28) versus 27.43 months (95% CI of 0.00-57.38), respectively. CONCLUSIONS: Elevated LDH level and involvement of the paranasal sinus are two risk factors for CNS involvement in patients with PTCLs. Considering the poor prognoses after CNS relapse, prophylaxis should be considered with the presence of any risk factor.

Fitz-Hugh-Curtis Syndrome: single centre experiences.

This study was conducted to report 10 cases of Fitz-Hugh-Curtis Syndrome (FHCS) diagnosed with CT and 101 cases of FHCS-like lesion that suggested perihepatitis during laparoscopic surgery. We reviewed retrospectively the images of 3,674 laparoscopies for obstetrical and gynaecological diseases and analysed 10 cases of FHCS diagnosed by clinical patterns and CT. All the 10 cases showed liver capsular enhancement on CT. Among the 3,674 laparoscopies, we found 101 cases (2.7%) with FHCS like lesion. Among them, 23 cases were during laparoscopic procedure for endometriosis, 16 for gynaecological malignant tumours, 16 for benign adnexal diseases excluding endometriosis, 13 for uterine leiomyoma, 7 for pelvic inflammatory disease, 2 had peritoneal tuberculosis and 21 for other gynaecological diseases. Further consideration should be given for the causes of FHCS other than N. gonorrhoeae and C. trachomatis. Because FHCS may represent various clinical phases, other considerations and clinical classifications are necessary for treatment.

Axial length and intraoperative posterior vitreous detachment as predictive factors for surgical outcomes of diabetic vitrectomy.

AIMS: To evaluate the relationship of axial length (AXL), intraoperatively assessed posterior vitreous detachment (PVD) status, and surgical outcomes of diabetic vitrectomy. METHODS: Retrospective, consecutive case series. Clinical records were reviewed for 115 eyes (50 males, 65 females) with more than a 6-month follow-up who underwent diabetic vitrectomy from a single surgeon. Thirty-three eyes had vitreous haemorrhage, 37 had tractional retinal detachment (TRD) threatening the macula, 43 had TRD involving the macula, and two had neovascular glaucoma. AXL was measured preoperatively by ultrasonography, and PVD status was classified intraoperatively: broad vitreo-retinal adhesion as no PVD, PVD at the macular area with attachment at the disc as incomplete PVD, and complete PVD. RESULTS: Forty-four eyes had no PVD, 23 had incomplete PVD, and 48 had complete PVD. A majority of the no PVD group had macula off TRD (97.7%), whereas vitreous haemorrhage (68.7%) predominated in the complete PVD group. Longer AXLs were noted in the complete PVD group compared with the no PVD and incomplete PVD groups (ANOVA in three groups P=0.0001). Univariate analysis showed that AXL had an influence on anatomical success (P=0.02). Multiple logistic regression analysis yielded that PVD status is a significant predictor of the final best corrected visual acuity (BCVA)>20/100, and BCVA>20/40 (P=0.01, P=0.02). CONCLUSIONS: Intraoperatively assessed PVD status is a prognostic factor for functional outcomes of diabetic vitrectomy. Shorter AXL was associated with lesser PVD. In eyes with a lack of PVD, careful timing and decision of surgery are mandatory.

Silver-mirror-based multipass preamplifier for a broadband terawatt Ti:sapphire laser.

We have developed a silver-mirror-based multipass preamplifier for a broadband amplification in a terawatt Ti:sapphire laser. With the extremely broad bandwidth of the silver mirrors, a very broad amplified spectrum can be generated at an amplified energy of 4 mJ; the amplified spectral width is 65 nm at half maximum and 160 nm at -25 dB without any spectral shaping technique. Such a broad amplification can be explained well by the simulation that includes gain narrowing and gain saturation. Even after a further amplification to an energy of 600 mJ, the amplified spectrum is broad enough to support an approximately 20 fs transform-limited pulse duration.

Ultra-high oxidation resistance of suspended single-wall carbon nanotube bundles grown by an "all-laser" process.

Single-wall carbon nanotubes (SWCNTs) were laterally grown on SiO2/Si substrates by means of an "all-laser" growth process. Our "all-laser" process stands out by its exclusive use of the same pulsed UV laser, first, to deposit the CoNi nanocatalyst and, second, to grow SWCNTs through the laser ablation of a pure graphite target. The "all-laser" grown SWCNTs generally self-assemble into bundles (5-15 nm-diam.) sprouting from the CoNi nanocatalyst and laterally bridging the 2 microm gap separating adjacent catalysed electrodes (in either "suspended" or "on-substrate" geometries). A comparative study of the oxidation resistance of both suspended and on-substrate SWCNTs was achieved. The "all-laser" grown SWCNTs were subjected to annealing under flowing oxygen at temperatures ranging from 200 to 1100 degrees C. Systematic scanning electron microscopy observations combined with micro-Raman analyses revealed that more than 20% of suspended nanotubes were still stable at temperatures as high as 900 degrees C under flowing O2 while the on-substrate counterpart were completely burnt out at this temperature. Accordingly, the activation energy, as deduced from the Arrhenius plot, of the suspended SWCNTs is found to be as high as approximately 180 kJ mol(-1) (approximately 9 times higher than that of the on-substrate ones). The high quality (almost defect-free) of the nanotubes synthesized by the "all-laser" approach, their protected tips into the embedded CoNi catalyst nanolayer together with their suspended geometry are thought to be responsible for their unprecedented ultra-high oxidation resistance. This opens up new prospects for the use of these suspended nanotubes into nanodevices that have to operate under highly oxidizing environments.

Some technical aspects of magnetic stimulation coil design with the ferromagnetic effect.

The performance of the stimulation coil in a magnetic nerve stimulator can be improved by attaching a ferromagnetic structure to the coil. This reduces heat generation at the coil and increases magnetic field strength for a given unit of current. Some technical aspects of the design of a stimulation coil with a ferromagnetic structure have been studied. Finite element method analysis results are presented for the effect of size, depth and magnetic saturation of the ferromagnetic structure on the stimulation coil performance. The experimental results show that the stimulation coil performance is improved by up to 40% by the attaching of a ferromagnetic structure on the coil.

Formation and emission status of PCDDs/PCDFs in municipal solid waste incinerators in Korea.

This study was carried out to examine the formation and the emission status of polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDDs/PCDFs) in the flue gases of commercial-scale municipal solid waste (MSW) incinerators, and thus to provide the engineering data for the reduction of PCDDs/PCDFs emitted from MSW incinerators. The formation concentrations of the PCDDs/PCDFs generated at the outlet of waste heat boilers (WHB) were in the range of 1.18-29.61 ng-TEQ/N m3 (average 5.75 ng-TEQ/N m3), while the emission concentrations at the stacks were in the range of 0.026-4.548 ng-TEQ/N m3 (average 0.924 ng-TEQ/N m3). Two major 2,3,7,8-substituted congeners were 2,3,4,7,8-PeCDF and 2,3,4,6,7,8-HxCDF, and their concentrations were up to 50% and 64% of total TEQ values at the outlet of WHB and the stack, respectively. From the results of multi-regression analysis, the formation concentration of PCDDs/PCDFs could be predicted as follows with the correlation factor of r2 = 0.962: PCDDs/PCDFs (ng-TEQ/N m3) = 3.036 (Cl) + 0.094 (T1) - 0.472 (Combustibles) + 0.059 (CO) - 0.039 (THC) - 3.366 (H) + 22.157, where T1 (degrees C) is the temperature at the outlet of the WHB. Cl, Combustibles and H are given as percentages and the others are in parts per million.

Removal efficiencies of PCDDs/PCDFs by air pollution control devices in municipal solid waste incinerators.

Removal efficiencies of polychlorinated dibenzo-p-dioxins/polychlorinated dibenzofurans (PCDDs/PCDFs) by air pollution control devices (APCDs) in the commercial-scale municipal solid waste (MSW) incinerators with a capacity of above 200 ton/day were evaluated. The removal efficiencies of PCDDs/PCDFs were up to 95% when the activated carbon (AC) was injected in front of electrostatic precipitator (EP). Spray dryer absorber/bag filter (SDA/BF) had high removal efficiency (99%)) of PCDDs/PCDFs when a mixture of lime and AC was sprayed into the SDA. When the AC was not added in scrubbing solution, the whole congeners of PCDDs/PCDFs were enriched in the wet scrubber (WS) with negative removal efficiencies of -25% to -5731%. Discharge of PCDDs/PCDFs was decreased with increasing the proportions of AC added in scrubbing solution. Selective catalytic reduction (SCR) system had the removal efficiencies of up to 93% during the test operation.

Two glycosides from the stem bark of Tetracentron sinense.

Two glycosides, tetracentronsides A and B, were isolated from the stem bark of Tetracentron sinense Oliv., along with ten known compounds, beta-sitosterol, lupeol, betulinic acid, oleanolic acid, vanillic aldehyde, vanillic acid, maslinic acid, huazhongilexin, daucosterol and catechin. On the basis of spectral and chemical evidence, tetracentronside A and B were identified as 3,4,5-trimethoxyphenyl-O-6'-O-vanilloyl-beta-D-glucopyranoside and (8R, 8'R) 9-beta-D-glucopyranosyl dihydrocubebin, respectively.

Evidence for apical endocytosis in polarized hepatic cells: phosphoinositide 3-kinase inhibitors lead to the lysosomal accumulation of resident apical plasma membrane proteins.

The architectural complexity of the hepatocyte canalicular surface has prevented examination of apical membrane dynamics with methods used for other epithelial cells. By adopting a pharmacological approach, we have documented for the first time the internalization of membrane proteins from the hepatic apical surface. Treatment of hepatocytes or WIF-B cells with phosphoinositide 3-kinase inhibitors, wortmannin or LY294002, led to accumulation of the apical plasma membrane proteins, 5'-nucleotidase and aminopeptidase N in lysosomal vacuoles. By monitoring the trafficking of antibody-labeled molecules, we determined that the apical proteins in vacuoles came from the apical plasma membrane. Neither newly synthesized nor transcytosing apical proteins accumulated in vacuoles. In wortmannin-treated cells, transcytosing apical proteins traversed the subapical compartment (SAC), suggesting that this intermediate in the basolateral-to-apical transcytotic pathway remained functional. Ultrastructural analysis confirmed these results. However, apically internalized proteins did not travel through SAC en route to lysosomal vacuoles, indicating that SAC is not an intermediate in the apical endocytic pathway. Basolateral membrane protein distributions did not change in treated cells, uncovering another difference in endocytosis from the two domains. Similar effects were observed in polarized MDCK cells, suggesting conserved patterns of phosphoinositide 3-kinase regulation among epithelial cells. These results confirm a long-held but unproven assumption that lysosomes are the final destination of apical membrane proteins in hepatocytes. Significantly, they also confirm our hypothesis that SAC is not an apical endosome.

Planar gradient coil design by scaling the spatial frequencies of minimum-inductance current density.

Gradient coil inductance has been remarkably reduced by the minimum-inductance design technique, which minimizes the magnetic energy stored by the gradient coil. The planar gradient coil designed by this technique, however, often has poor magnetic field linearity. Scaling the spatial frequencies of the current density function derived by this method, the magnetic field linearity of the planar gradient coil can be greatly improved with a small sacrifice of gradient coil inductance. A figure of merit of the planar gradient coil has been found to be improved by scaling the spatial frequencies.

[Studies on the iridoid glucosides of the root of Lamiophlomis rotata (benth.) kudo, a medicinal plant in Xi zang (Tibet)].

Lamiophlomis rotata (Labiatae) is a Chinese folk medicinal plant in Xi-zang (Tibet), which has effects of promoting blood circulation to remove blood stasis, subduing swelling and alleviating pain. Four iridoid glucosides were isolated from the root of the species. On the basis of IR, UV, NMR, MS spectral data and chemical methods, their structures were identified as: 8-O-acetylshanzhiside methyl ester(I), 6-O-acetylshanzhiside methyl ester(II), penstemoside(III) and 7, 8-dehydropenstemoside(IV). The last one is a new compound.