Background: Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. Methods: This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. Conclusion This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Background: Escherichia coli is the predominant causative pathogen for community-acquired urinary tract infections (UTIs), and the increase in fluoroquinolone-resistant E. coli is of great concern in Korea. The objectives of this study were to investigate the genotypic characteristics and molecular epidemiology of ciprofloxacin-resistant (CIP-R) E. coli isolated from community-acquired UTIs in Korea. Materials and Methods: E. coli samples isolated from the blood or urine were collected from patients with community-acquired acute pyelonephritis aged 15 years and more who were admitted to 12 Korean hospitals from 1st April 2010 to 29th February 2012. Phylogenetic typing, multilocus sequence typing, and molecular characterization of β-lactamase and plasmidmediated quinolone resistance determinants were performed for CIP-R E. coli isolates. Results: A total of 569 E. coli isolates were collected, and 122 (21.4%) isolates were CIP-R isolates. The most prevalent sequence type (ST) was ST131 (28.7%, 35/122), followed by ST393 (14.7%, 18/122), ST1193 (13.1%, 16/122), ST38 (9.0%, 11/122), and ST405 (8.2%, 10/122). The antimicrobial resistance rates of ST131 to cefepime (22.9%, 8/35), ST38 to gentamicin (100%, 11/11), and ST405 to cefotaxime (66.7%, 6/9) were significantly higher than the resistance rates of all other STs combined. Notably, 40% (4/10) of ST405 clones produced extendedspectrum β-lactamases and were co-resistant to trimethoprim/sulfamethoxazole. aac(6′)-1b-cr (20%, 7/35) and CTX-M-14 (40%, 4/10) were more frequently observed in ST131 and ST405 compared with other clones, respectively. Conclusions Among the CIP-R uropathogenic E. coli isolates in this study, ST131, ST38, and ST405 were specifically associated with antimicrobial resistance.

Despite significant advances in neuroscience research over the past several decades, the exact cause of AD has not yet fully understood. The metabolic hypothesis as well as the amyloid and tau hypotheses have been proposed to be associated with AD pathogenesis. In order to identify metabolome signatures from the postmortem brains of sporadic AD patients and control subjects, we performed ultra performance liquid chromatography coupled with linear ion trap-Orbitrap mass spectrometer (UPLC-LTQ–Orbitrap-MS). Not only our study identified new metabolome signatures but also verified previously known metabolome profiles in the brain. Statistical modeling of the analytical data and validation of the structural assignments discovered metabolic biomarkers associated with the AD pathogenesis. Interestingly, hypotaurin, myo-inositol and oxo-proline levels were markedly elevated in AD while lutamate and N-acetyl-aspartate were decreased in the postmortem brain tissue of AD patients. In addition, neurosteroid level such as cortisol was significantly increased in AD. Together, our data indicate that impaired amino acid metabolism is associated with AD pathogenesis and the altered amino acid signatures can be useful diagnostic biomarkers of AD. Thus, modulation of amino acid metabolism may be a possible therapeutic approach to treat AD.
Alzheimer Disease ; Amyloid ; Biomarkers ; Brain ; Chromatography, Liquid ; Humans ; Hydrocortisone ; Metabolism ; Metabolome ; Metabolomics ; Models, Statistical ; Neurosciences

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Although advances have been made in the treatment of MS, such as the use of IFN-β, glucocorticoids and stem cells, the therapeutic effects of these treatments are not sufficient. In the present study, we evaluated whether the combination of methylprednisolone (MP) and human bone marrow-derived mesenchymal stem cells (BM-MSCs) could enhance the therapeutic effectiveness in experimental autoimmune encephalomyelitis (EAE), a model for MS. EAE was induced by immunizing C57BL/6 mice with myelin oligodendrocyte glycoprotein 35-55 (MOG 35-55). The immunized mice received an intraperitoneal injection of MP (20 mg/kg), an intravenous injection of BM-MSCs (1 × 10⁶ cells) or both on day 14 after immunization. Combination treatment significantly ameliorated the clinical symptoms, along with attenuating inflammatory infiltration and demyelination, compared to either treatment alone. Secretion of pro-inflammatory cytokines (IFN-γ, TNF-α, IL-17) was significantly reduced, and anti-inflammatory cytokines (IL-4, IL-10) was significantly increased by the combination treatment as compared to either treatment alone. Flow cytometry analysis of MOG-reactivated T cells in spleen showed that combination treatment reduced the number of CD4⁺CD45⁺ and CD8⁺ T cells, and increased the number of CD4⁺CD25⁺Foxp3⁺ regulatory T cells. Furthermore, combination treatment enhanced apoptosis in MOG-reactivated CD4⁺ T cells, a key cellular subset in MS pathogenesis. Combination treatment with MP and BM-MSCs provides a novel treatment protocol for enhancing therapeutic effects in MS.
Animals ; Apoptosis ; Central Nervous System ; Clinical Protocols ; Cytokines ; Demyelinating Diseases ; Encephalomyelitis, Autoimmune, Experimental* ; Flow Cytometry ; Glucocorticoids ; Humans* ; Immunization ; Injections, Intraperitoneal ; Injections, Intravenous ; Mesenchymal Stromal Cells* ; Methylprednisolone* ; Mice ; Multiple Sclerosis ; Myelin-Oligodendrocyte Glycoprotein ; Spleen ; Stem Cells ; T-Lymphocytes ; T-Lymphocytes, Regulatory ; Therapeutic Uses

BACKGROUND: The objective of this study was to examine the usefulness of blood cultures and radiologic imaging studies for developing therapeutic strategies in community-acquired acute pyelonephritis (CA-APN) patients. MATERIALS AND METHODS: We prospectively collected the clinical data of CA-APN patients who visited 11 hospitals from March 2010 to February 2011. RESULTS: Positive urine and blood cultures were obtained in 69.3% (568/820) and 42.7% (277/648), respectively, of a total of 827 CA-APN patients. Blood culture identified the urinary pathogen in 60 of 645 (9.3%) patients for whom both urine and blood cultures were performed; the organisms isolated from urine were inconsistent with those from blood in 11 and only blood cultures were positive in 49 patients. Final clinical failure was more common in the bacteremic patients than the non-bacteremic ones (8.0% vs. 2.7%, P = 0.003), as was hospital mortality (3.6% vs. 0.3%, P = 0.003). Likewise, durations of hospitalization and fever were significantly longer. Bacteremia was independent risk factor for mortality (OR 9.290, 1.145-75.392, P = 0.037). With regard to radiologic studies, the detection rate of APN was 84.4% (445/527) by abdominal computed tomography and 40% (72/180) by abdominal ultrasonography. Eighty-one of 683 patients (11.9%) were found to have renal abscess, perinephric abscess, urolithiasis, hydronephorosis/hydroureter or emphysematous cystitis, which could potentially impact on clinical management. Patients with Pitt score ≥ 1, flank pain or azotemia were significantly more likely to have such structural abnormalities. CONCLUSION: Blood cultures are clinically useful for diagnosis of CA-APN, and bacteremia is predictive factor for hospital mortality. Early radiologic imaging studies should be considered for CA-APN patients with Pitt scores ≥1, flank pain or azotemia.
Abscess ; Azotemia ; Bacteremia ; Cystitis ; Diagnosis ; Diagnostic Imaging ; Fever ; Flank Pain ; Hospital Mortality ; Hospitalization ; Humans ; Mortality ; Prospective Studies ; Pyelonephritis* ; Risk Factors ; Ultrasonography ; Urolithiasis

OBJECTIVE: To comparatively investigate the expression of several integrins in specimens of human bone metastases and degenerative bone tissue. METHODS: Degenerative cancellous tissue was obtained from a sample of human degenerative spine. Thirteen human specimens were obtained from metastatic spine tumors, whose primary cancer was colon cancer (n=3), hepatocellular cancer (n=3), lung cancer (n=4), and breast cancer (n=3). The expression of vimentin and integrins alphav, beta1, and beta3 was assessed in metastatic and degenerative specimens by immunohistochemistry and real-time reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS: Immunohistochemical staining showed that vimentin and integrin alphav was broadly expressed in all tissues examined. By contrast, integrin beta1 was weakly expressed only in 38.4% (5/13) of tissues. Integrin beta3 was consistently negative in all cases examined. qRT-PCR analysis showed that vimentin gene expression was higher in all metastatic specimens, as compared to degenerative bone. The gene expression of integrin alphav in breast specimen was significantly higher than others (p=0.045). The gene expression of integrin beta1 was also higher in all metastatic specimens than in degenerative bone tissue. The gene expression of integrin beta3 was variable. CONCLUSION: Spinal metastatic tumors have mesenchymal characteristics such as increased expression of vimentin. The increased expression of integrin alphav and beta1 in spine metastatic tumors suggests that adhesive molecules such as integrin may have implications for the prevention of spine metastasis.
Adhesives ; Antigens, CD29 ; Bone and Bones ; Breast ; Breast Neoplasms ; Colonic Neoplasms ; Gene Expression ; Humans ; Immunohistochemistry ; Integrin alphaV ; Integrin beta3 ; Integrins* ; Liver Neoplasms ; Lung Neoplasms ; Neoplasm Metastasis ; Spine* ; Vimentin*

OBJECTIVE: Malignant gliomas are the most common primary tumors of the central nervous system and the prognosis of patients with gliomas is poor. The combination of interferon-bata (IFN-beta) and temozolomide (TMZ) has shown significant additive antitumor effects in human glioma xenograft models. Considering that the poor survival of patients with human malignant gliomas relates partly to the inability to deliver therapeutic agents to the tumor, the tropism of human bone marrow-derived mesenchymal stem cells (MSC) for malignant gliomas can be exploited to therapeutic advantages. We investigated the combination effects of TMZ and MSCs that secrete IFN-beta on gliomas. METHODS: We engineered human MSCs to secret mouse IFN-beta (MSC-IFN-beta) via adenoviral transduction and confirmed their secretory capacity using enzyme-linked immunosorbent assays. In vitro and in vivo experiments were performed to determine the effects of the combined TMZ and MSC-IFN-beta treatment. RESULTS: In vitro, the combination of MSC-IFN-beta and TMZ showed significantly enhanced antitumor effects in GL26 mouse glioma cells. In vivo, the combined MSC-IFN-beta and TMZ therapy significantly reduced the tumor size and improved the survival rates compared to each treatment alone. CONCLUSION: These results suggest that MSCs can be used as an effective delivery vehicle so that the combination of MSC-IFN-beta and TMZ could be considered as a new option for the treatment of malignant gliomas.
Animals ; Bone Marrow* ; Central Nervous System ; Enzyme-Linked Immunosorbent Assay ; Glioma* ; Heterografts ; Humans ; Interferon-beta* ; Mesenchymal Stromal Cells* ; Mice ; Prognosis ; Survival Rate ; Tropism

Minimally invasive surgery is being widely accepted in various fields of surgery. Although several appendectomy techniques have been reported but, there is no standardization. We report here the experiences of transumbilical endoscopic appendectomy in humans. Between July 2008 and September 2010, ten patients with appendicitis successfully underwent transumbilical endoscopic appendectomies. There were 7 cases of suppurative, 2 cases of gangrenous and 1 case of perforated in operative findings. The ages of the patients were 13-56 years (mean age, 32.7 +/- 15.4 years). Under general anesthesia, a 15-mm port was inserted through the umbilicus and then a two-channel endoscope was inserted in the peritoneal cavity. After appendix identification, counter-traction of the appendix with a direct abdominal wall puncture using a straight round needle prolene was performed to achieve good visualization of the operative field. Tissue dissection was performed using an endoscopic needle knife. Tissue grasping and resected appendix retrieval were done with endoscopic forceps. The average operation time was 79.5 +/- 23.6 minutes (range, 45 to 110 minutes). No procedures were converted to laparoscopic or open appendectomy. Hospital stay was 4-6 days. All patients completely recovered without complications. As it is highly maneuverable, we believe transumbilical endoscopic appendectomy can be a feasible method. And, as surgeons want to proceed from laparoscopic surgery to natural orifice transluminal endoscopic surgery, this procedure could be a triable method.
Abdominal Wall ; Anesthesia, General ; Appendectomy* ; Appendicitis ; Appendix ; Endoscopes ; Endoscopy ; Hand Strength ; Humans ; Laparoscopy ; Length of Stay ; Natural Orifice Endoscopic Surgery ; Needles ; Peritoneal Cavity ; Polypropylenes ; Punctures ; Surgical Instruments ; Surgical Procedures, Minimally Invasive ; Umbilicus

With increase of multi-drug resistant Escherichia coli in community-acquired urinary tract infections (CA-UTI), other treatment option with a therapeutic efficacy and a low antibiotic selective pressure is necessary. In this study, we evaluated in vitro susceptibility of E. coli isolates from CA-UTI to fosfomycin (FM), nitrofurantoin (NI), temocillin (TMO) as well as trimethoprim-sulfamethoxazole (SMX), ciprofloxacin (CIP) and cefepime (FEP). The minimal inhibitory concentrations were determined by E-test or agar dilution method according to the Clinical and Laboratory Standards Institute guidelines, using 346 E. coli collected in 12 Korean hospitals from March 2010 to February 2011. FM, NI and TMO showed an excellent susceptibility profile; FM 100% (346/346), TMO 96.8% (335/346), and NI 99.4% (344/346). Conversely, resistance rates of CIP and SMX were 22% (76/346) and 29.2% (101/349), respectively. FEP still retained an activity of 98.5%. In Korea, NI and TMO in addition to FM are a good therapeutic option for uncomplicated CA-UTI, especially for lower UTI.
Anti-Bacterial Agents/*administration & dosage ; Cell Survival/*drug effects ; Cephalosporins/administration & dosage ; Ciprofloxacin/administration & dosage ; Community-Acquired Infections/drug therapy/*microbiology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Resistance, Bacterial/drug effects ; Escherichia coli/*drug effects ; Escherichia coli Infections/drug therapy/*microbiology ; Fosfomycin/administration & dosage ; Humans ; Nitrofurantoin/administration & dosage ; Penicillins/administration & dosage ; Republic of Korea ; Sulfadoxine/administration & dosage ; Treatment Outcome ; Trimethoprim/administration & dosage ; Urinary Tract Infections/diagnosis/*microbiology

With increase of multi-drug resistant Escherichia coli in community-acquired urinary tract infections (CA-UTI), other treatment option with a therapeutic efficacy and a low antibiotic selective pressure is necessary. In this study, we evaluated in vitro susceptibility of E. coli isolates from CA-UTI to fosfomycin (FM), nitrofurantoin (NI), temocillin (TMO) as well as trimethoprim-sulfamethoxazole (SMX), ciprofloxacin (CIP) and cefepime (FEP). The minimal inhibitory concentrations were determined by E-test or agar dilution method according to the Clinical and Laboratory Standards Institute guidelines, using 346 E. coli collected in 12 Korean hospitals from March 2010 to February 2011. FM, NI and TMO showed an excellent susceptibility profile; FM 100% (346/346), TMO 96.8% (335/346), and NI 99.4% (344/346). Conversely, resistance rates of CIP and SMX were 22% (76/346) and 29.2% (101/349), respectively. FEP still retained an activity of 98.5%. In Korea, NI and TMO in addition to FM are a good therapeutic option for uncomplicated CA-UTI, especially for lower UTI.
Anti-Bacterial Agents/*administration & dosage ; Cell Survival/*drug effects ; Cephalosporins/administration & dosage ; Ciprofloxacin/administration & dosage ; Community-Acquired Infections/drug therapy/*microbiology ; Dose-Response Relationship, Drug ; Drug Combinations ; Drug Resistance, Bacterial/drug effects ; Escherichia coli/*drug effects ; Escherichia coli Infections/drug therapy/*microbiology ; Fosfomycin/administration & dosage ; Humans ; Nitrofurantoin/administration & dosage ; Penicillins/administration & dosage ; Republic of Korea ; Sulfadoxine/administration & dosage ; Treatment Outcome ; Trimethoprim/administration & dosage ; Urinary Tract Infections/diagnosis/*microbiology