Dexamethasone-loaded H2O2-activatable anti-inflammatory nanoparticles for on-demand therapy of inflammatory respiratory diseases.

Asthma is a common airway inflammatory disorder, characterized by increased infiltration of leukocytes and bronchoconstriction. Dexamethasone (DEX) has been widely used in the treatment of allergic asthma. However, long-term and frequent use of DEX has side effects. We therefore reasoned that if drug carriers have intrinsic anti-inflammatory and anti-asthmatic activity and synergize with drug payloads, a low dose of DEX could exert sufficient therapeutic effects. In this study, we developed DEX-loaded H2O2-activatable boronate maltodextrin (DEX-BM) nanoparticles. DEX-BM nanoparticles released DEX in a H2O2-triggered manner and remarkably suppressed the expression of pro-inflammatory cytokines in activated macrophages and lung epithelial cells. In the studies of a murine allergic asthma model, DEX-BM nanoparticles (5 mg/kg) effectively inhibited the inflammatory cell infiltration and airway inflammation than equivalent DEX and BM nanoparticles without noticeable side effects. We anticipate that DEX-BM nanoparticles hold great potential as therapeutic agents for various airway inflammatory diseases.

Pseudogout, an unconventional imitator of the lumbosacral spine with associated chronic epidural hematoma: illustrative cases.

BACKGROUND: Pseudogout, or calcium pyrophosphate dihydrate (CPPD) disease, is an inflammatory joint disease that most commonly involves the joints of the knees, ankles, and wrists. Pseudogout has also been known to involve the spine, especially the atlanto-occipital joint of the cervical spine, but there is limited documentation of its involvement in the lumbar spine. Though the atypical presentation of spinal pseudogout with findings consistent with discitis and epidural abscess has been documented, its presentation with associated chronic spinal epidural hematoma is a rare entity. OBSERVATIONS: The authors present two separate cases of pseudogout involvement of the lumbar spine, one case presenting with a clinical and radiographic picture consistent with discitis and epidural abscess and the other with radiographic and operative findings consistent with a chronic epidural hematoma. LESSONS: This case series demonstrates rare and atypical presentations of pseudogout within the lumbosacral spine.

Self-deliverable and self-immolative prodrug nanoassemblies as tumor targeted nanomedicine with triple cooperative anticancer actions.

Stimulus-responsive self-assembling prodrug-based nanomedicine has emerged as a novel paradigm in controlled drug delivery. All-trans retinoic acid (RA), one of vitamin A metabolites, induces apoptotic cancer cell death, but its clinical applications are limited by weak anticancer efficacy. To fully maximize the therapeutic potential of RA, we exploited the unique chemistry of arylboronic acid which undergoes hydrogen peroxide (H2O2)-triggered degradation to release quinone methide (QM) that alkylates glutathione (GSH) to disrupt redox homeostasis and is also converted into hydroxybenzyl alcohol (HBA) to suppress the expression of vascular endothelial growth factor (VEGF). Here, we report that boronated retinoic acid prodrug (RABA) can be formulated into self-deliverable nanoassemblies which release both RA and QM in a H2O2-triggered self-immolative manner to exert cooperative anticancer activities. RABA nanoassemblies exert anticancer effects by inducing reactive oxygen species (ROS)-mediated apoptosis, eliciting immunogenic cell death (ICD) and suppressing angiogenic VEGF expression. The excellent anticancer efficacy of RABA nanoassemblies can be explained by benefits of self-assembling prodrug-based drug self-delivery and cooperative anticancer actions. The design strategy of RABA would provide a new insight into the rational design of self-deliverable and self-immolative boronated prodrug nanoassemblies for targeted cancer therapy.

Vogt-Koyanagi-Harada disease occurring during pegylated interferon-α2b and ribavirin combination therapy for chronic hepatitis C.

Vogt-Koyanagi-Harada (VKH) disease is a multisystem syndrome characterized by ocular (uveitis and retinal detachment), neurological (headache, tinnitus, and meningitis), and integumentary (vitiligo, alopecia, and poliosis) involvement. Although the pathogenesis of VKH disease is not well understood, an autoimmune T-cell response to a melanocyte-associated antigen is considered to be a cause of VKH disease. The complex immunological response to interferon and ribavirin may induce or exacerbate the autoimmune condition; however, VKH disease is a very rare complication associated with interferon therapy in chronic hepatitis C. We report a case of VKH disease occurring during pegylated interferon-α2b and ribavirin combination therapy for chronic hepatitis C.

A New Methodology for Predicting Brittle Fracture of Plastically Deformable Materials: Application to a Cold Shell Nosing Process.

The traditional theory of ductile fracture has limitations for predicting crack generation during a cold shell nosing process. Various damage criteria are employed to explain fracture and failure in the nose part of a cold shell. In this study, differences in microstructure among fractured materials and analysis of their surfaces indicated the occurrence of brittle fractures. The degree of "plastic deformation-induced embrittlement" (PDIE) of plastically deformable materials affects the likelihood of brittle fractures; PDIE can also decrease the strength in tension due to the Bauschinger effect. Two indicators of brittle fracture are presented, i.e., the critical value of PDIE and the allowable tensile strength (which in turn depends on the degree of PDIE or embrittlement-effective strain). When the maximum principal stress is greater than the latter and the PDIE is greater than the former, our method determines the likelihood of brittle fracture. This approach was applied to an actual cold shell nosing process, and the predictions were in good quantitative agreement with the experimental results.

Targeting the mTOR pathway using novel ATP­competitive inhibitors, Torin1, Torin2 and XL388, in the treatment of glioblastoma.

Mechanistic target of rapamycin (mTOR), which functions via two multiprotein complexes termed mTORC1 and mTORC2, is positioned in the canonical phosphoinositide 3­kinase­related kinase (PI3K)/AKT (PI3K/AKT) pathways. These complexes exert their actions by regulating other important kinases, such as 40S ribosomal S6 kinases (S6K), eukaryotic translation initiation factor 4E (elF4E)­binding protein 1 (4E­BP1) and AKT, to control cell growth, proliferation, migration and survival in response to nutrients and growth factors. Glioblastoma (GB) is a devastating form of brain cancer, where the mTOR pathway is deregulated due to frequent upregulation of the Receptor Tyrosine Kinase/PI3K pathways and loss of the tumor suppressor phosphatase and tensin homologue (PTEN). Rapamycin and its analogs were less successful in clinical trials for patients with GB due to their incomplete inhibition of mTORC1 and the activation of mitogenic pathways via negative feedback loops. Here, the effects of selective ATP­competitive dual inhibitors of mTORC1 and mTORC2, Torin1, Torin2 and XL388, are reported. Torin2 exhibited concentration­dependent pharmacodynamic effects on inhibition of phosphorylation of the mTORC1 substrates S6KSer235/236 and 4E­BP1Thr37/46 as well as the mTORC2 substrate AKTSer473 resulting in suppression of tumor cell migration, proliferation and S­phase entry. Torin1 demonstrated similar effects, but only at higher doses. XL388 suppressed cell proliferation at a higher dose, but failed to inhibit cell migration. Treatment with Torin1 suppressed phosphorylation of proline rich AKT substrate of 40 kDa (PRAS40) at Threonine 246 (PRAS40Thr246) whereas Torin2 completely abolished it. XL388 treatment suppressed the phosphorylation of PRAS40Thr246 only at higher doses. Drug resistance analysis revealed that treatment of GB cells with XL388 rendered partial drug resistance, which was also seen to a lesser extent with rapamycin and Torin1 treatments. However, treatment with Torin2 completely eradicated the tumor cell population. These results strongly suggest that Torin2, compared to Torin1 or XL388, is more effective in suppressing mTORC1 and mTORC2, and therefore in the inhibition of the GB cell proliferation, dissemination and in overcoming resistance to therapy. These findings underscore the significance of Torin2 in the treatment of GB.

Effect of pretreatment conditions on particle size of bimetallic pt-au catalysts supported on ZnO/Al2O3 and its activity for toluene oxidation.

Bimetallic Pt-Au catalysts supported on ZnO/Al2O3 were prepared by incipient wetness impregnation (IW-IMP) method with different pretreatment conditions such as flow velocity, calcination temperature, and heating rate under H2 during the calcination procedure, and characterized by X-ray diffraction (XRD), CO chemisorption, and scanning transmission electron microscopy (STEM) equipped energy dispersive spectroscopy (EDS). Furthermore, catalytic activity for complete oxidation of toluene was measured using a flow reactor under atmospheric pressure. Finally, relationship between the particle sizes with pretreatment conditions and catalytic activity for toluene on the bimetallic Pt-Au catalysts was discussed. In these results, nanosized bimetallic Pt-Au particles on ZnO/Al2O3 could be prepared by IW-IMP method. Relationship between the Pt and Au particle size and activity for toluene oxidation was clearly observed.

Cox-2 and IL-10 polymorphisms and association with squamous cell carcinoma of the head and neck in a Korean sample.

Cyclooxygenase-2 (COX-2) is involved in inflammation and carcinogenesis. Interleukin-10 (IL-10) is also regarded as anti-inflammatory factors with the multi-functional ability to positively and negatively influence functional immunity and tumor development. Genetic polymorphisms of COX-2 and IL-10 might contribute to the development of squamous cell carcinoma of the head and neck (SCCHN). The purpose of this study was to evaluate the association of COX-2 and IL-10 single nucleotide polymorphisms (SNPs) with the risk of SCCHN in a Korean sample. We analyzed the COX-2 SNPs, -1329A>G, +1266C>T, and +6365T>C, and the IL-10 SNPs, -1082A>G, +920T>G, and +3917T>C, in 290 Korean SCCHN patients and 358 healthy controls. There was no significant association between the risk of SCCHN and the three COX-2 or three IL-10 SNPs. We analyzed three haplotypes (ht1, ht2, ht3) for COX-2 and found that COX-2 ht3+/+ was associated with a decreased risk of SCCHN in a Korean sample, compared with the COX-2 ht3 -/- genotype (P=0.03). Two haplotypes (ht1, ht2) of IL-10 were analyzed and there was no statistical significance in the distribution of haplotypes. Based on these results, the COX-2 haplotype ht3 can be used as a molecular biomarker to predict low risk groups of SCCHN in a Korean sample.

The biological effects of topical alginate treatment in an animal model of skin wound healing.

Wound healing is a dynamic and complex process of tissue repair that involves a number of cellular and molecular events. It proceeds from inflammatory response to reepithelialization and finally to formation of a permanent scar. Alginate is a polymer of guluronic and mannuronic acid that is used as a scaffolding material in biomedical applications. For the purpose of studying wound healing, full-thickness skin defects were produced on the dorsal area in rats. We measured the relative sizes of the wounds on days 3, 5, 7, 14, and 28. The wound sizes were decreased in the alginate-treated group compared with the control group and the vaseline-treated group. The expressions of transforming growth factor-beta1, fibronectin, and vascular endothelial growth factor were significantly decreased in the alginate-treated group compared with the control group, while the expression of collagen-I was increased in the alginate-treated group, as indicated by Western blotting and immunohistochemical staining. These data suggest that alginate has significant wound healing promoting activity. The results from the present study indicate that the effect of alginate on wound healing may involve biological mechanisms associated with the expression of transforming growth factor-beta1, fibronectin, vascular endothelial growth factor, and collagen-I.

Change of acoustic parameters before and after treatment in laryngopharyngeal reflux patients.

OBJECTIVES: To evaluate the usefulness of acoustic parameters as an indicator of laryngopharyngeal reflux (LPR) treatment efficacy. STUDY DESIGN: A prospective case series analysis. MATERIALS AND METHODS: From January to September 2005, we prospectively analyzed 40 patients who were diagnosed with laryngopharyngeal reflux by 24-hour ambulatory double-probe pH monitoring. Laryngopharyngeal reflux patients were treated medically and voice analysis was conducted three times: before treatment, 1 to 2 months after treatment, and 3 to 4 months after treatment. Jitter, shimmer, and harmonic-to-noise ratio (HNR) were analyzed as the acoustic parameters. Pre- and posttreatment reflux symptom index and reflux finding score were documented. RESULTS: Jitter, shimmer, and HNR had improved significantly at 1 to 2 months after treatment and were maintained at 3 to 4 months after treatment. Jitter was significantly correlated with reflux symptom index. CONCLUSION: Acoustic parameters can be used as indicators of treatment efficacy for laryngopharyngeal reflux disease.

Elevated intracellular cAMP exacerbates vulnerability to oxidative stress in optic nerve head astrocytes.

Glaucoma is characterized by a progressive loss of retinal ganglion cells and their axons, but the underlying biological basis for the accompanying neurodegeneration is not known. Accumulating evidence indicates that structural and functional abnormalities of astrocytes within the optic nerve head (ONH) have a role. However, whether the activation of cyclic adenosine 3',5'-monophosphate (cAMP) signaling pathway is associated with astrocyte dysfunction in the ONH remains unknown. We report here that the cAMP/protein kinase A (PKA) pathway is critical to ONH astrocyte dysfunction, leading to caspase-3 activation and cell death via the AKT/Bim/Bax signaling pathway. Furthermore, elevated intracellular cAMP exacerbates vulnerability to oxidative stress in ONH astrocytes, and this may contribute to axonal damage in glaucomatous neurodegeneration. Inhibition of intracellular cAMP/PKA signaling activation protects ONH astrocytes by increasing AKT phosphorylation against oxidative stress. These results strongly indicate that activation of cAMP/PKA pathway has an important role in astrocyte dysfunction, and suggest that modulating cAMP/PKA pathway has therapeutic potential for glaucomatous ONH degeneration.

Preparation of nanosized Pt-Au alloy catalyst and its activity in methanol oxidation.

The alloy catalyst has been widely used because it will be able to improve the activity and selectivity of the single metal catalyst in a given chemical reaction. In this study, the preparation and characteristics of nanosized Pt and Au particles on alumina and their catalytic activity were described. Nanosized Pt-Au catalysts were prepared by impregnation (IMP) method and deposition (DP) method using alumina or ZnO/Al2O3 as support. The size of Pt and Au particles were observed by transmission electron microscopy (TEM), energy dispersive spectroscope (EDS), and X-ray diffraction (XRD). Catalytic activity for oxidation of methanol was measured using a flow reactor. It could be seen that the Pt particle size and dispersion in the alloy catalysts was rarely influenced by preparation methods and Au particles coated by deposition method were well dispersed. TEM images showed that Au particles were well dispersed in the Pt/Au/ZnO/Al2O3 catalyst of which Au particles was supported by deposition method. The catalytic activity for methanol are given in the order of Pt-Au[IMP]/ZnO/Al2O3 > Pt[IMP]/Au[DP]/ZnO/Al2O3 > Au[DP]/Pt[IMP]/ZnO/Al2O3 > Pt-Au[DP]/ZnO/Al2O3. Therefore, Au particle size was doing not play an important role in increasing the oxidation activity, but the Au particles may promote the methanol oxidation.

Effect of nanosized gold particle addition to supported metal oxide catalyst in methanol oxidation.

Gold has rarely been utilized as a catalytic component because of its poor affinity to chemical species. It is however known that nanosized gold particles promote the dissociation of oxygen or hydrogen. In this study, alumina-supported metal oxide catalysts were prepared by impregnation method and applied to methanol oxidation. The dispersion form and size of the gold particles were observed by transmission electron microscopy (TEM). In the results, the maximum catalytic activity was obtained over the ZnO/Al2O3 catalyst, and the optimum loading was 4 wt%. Furthermore, nano-sized gold particles at various loadings were added to ZnO/Al2O3 catalyst by deposition method. The gold particles on Au/ZnO/Al2O3 catalyst were well dispersed and the catalyst activity was remarkably increased compared to ZnO/Al2O3 catalyst. The role of gold particles in the increased catalytic activity is discussed and a possible mechanism is presented.

Predictability of preoperative 18F-FDG PET for histopathological differentiation and early recurrence of primary malignant intrahepatic tumors.

OBJECTIVE: The limited studies with 18F-fluorodeoxyglucose (18F-FDG)-PET reported results and interpretations that differed between hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (IHCC). We investigated the correlation between preoperative PET results and postoperative prognosis, including early (time-to-recurrence<6 months) tumor recurrence, and histopathological tumor differentiation in patients who had undergone surgery for primary malignant intrahepatic tumors, including HCC and IHCC. MATERIALS AND METHODS: We retrospectively reviewed 357 patients who had undergone curative surgery for malignant hepatic tumors, including primary HCC or IHCC, other than Klatskin tumors at a tertiary academic hospital between January 2005 and June 2012. All patients had undergone an 18F-FDG PET/computed tomography scan preoperatively and the maximum standardized uptake value of the tumor (max SUV tumor) and the tumor-to-nontumor SUV ratio (TNR) were calculated from 18F-FDG uptake. Histopathological differentiation grading was confirmed postoperatively. RESULTS: Among the patients, 115 cases with primary malignant intrahepatic tumors fulfilled the inclusion criteria. On univariate analysis, preoperative max SUV tumor and TNR showed a correlation with the overall and early tumor recurrence of HCC, but only max SUV tumor was associated with overall and early recurrence of IHCC (P<0.05). When considering postoperative histopathological differentiation, a correlation between max SUV tumor and TNR with HCC and between max SUV tumor and IHCC was found (P<0.05). However, on multivariate analysis, only early recurrence was associated with TNR in HCC and with max SUV tumor in IHCC. CONCLUSION: A preoperative 18F-FDG PET scan can be considered a useful reference for postoperative tumor recurrence and histopathological differentiation in cases of primary malignant intrahepatic tumors. 18F-FDG PET scan results should be interpreted separately for malignant liver tumors.

Should colonoscopy be performed in patients with cryptogenic liver abscess?

BACKGROUND/AIM: The interruption of a mucosal barrier by colon cancer or a polyp can lead to the development of a liver abscess. This study aimed to evaluate the possible contribution of colon cancer to the development of liver abscess and the necessity of colonoscopy in patients presenting with cryptogenic liver abscess. METHODS: We reviewed the medical records of 268 patients diagnosed with liver abscess between January 2001 and April 2010. Among cases with no definite cause of liver abscess, differences between patients with and without colon cancer were evaluated in terms of clinical, laboratory, imaging, and microbiological findings. RESULTS: Pyogenic liver abscess with no apparent etiology was encountered 163 patients; colonoscopy was performed in 121 of these 163 patients. The tumor diagnosis was confirmed by total colonoscopy in 12/163 (7.4%) patients with adenocarcinoma and 8/163 (4.9%) patients with high-grade dysplasia. Nine patients were diagnosed with stage I, two patients with stage II, and one with stage III disease according to the tumor, nodes, and metastases (TNM) staging system for colorectal cancer. The prevalence of incidental colon cancer in patients with pyogenic liver abscess was significantly higher than that of normal individuals who underwent colonoscopy (0.8%, 90/11,272) at our health care center. CONCLUSIONS: Colon cancer may be one etiology of liver abscess. Colonoscopy should be considered in patients with pyogenic liver abscess with not an apparent primary source of infection.

CSF Otorrhea Resulting from Osteoradionecrosis of the Temporal Bone in a Patient with Recurrent Meningioma.

Osteoradionecrosis of the temporal bone is a very rare but potentially lethal complication of radiotherapy for head and neck or skull base tumors. Only two cases of osteoradionecrosis of the temporal bone complicating cerebrospinal fluid (CSF) otorrhea have been reported in the literature. This report describes a case of CSF otorrhea and osteoradionecrosis of the temporal bone in a patient with meningioma who was treated with tympanomastoid surgery and autologous fat obliteration in the mastoid.