The Relationship between Obesity-Related Factors and Graves' Orbitopathy: A Pilot Study.

Background and Objectives: The aim of this study was to investigate the relationships between obesity-related factors including body mass index (BMI), diabetes or prediabetes, hyperlipidemia, fasting plasma glucose, fasting plasma insulin, homeostasis model assessment-estimated insulin resistance (HOMA-IR), highly sensitive C-reactive protein (hs-CRP) and Graves' orbitopathy (GO). Materials and Methods: Eighty-four patients with Graves' disease (GD) (42 without GO and 42 with GO) were enrolled in this cross-sectional cohort study. Gender, age, GD treatment history, height, body weight, waist circumference, smoking status, co-morbidities, levels of free thyroxin, thyroid-stimulating hormone, thyroid-stimulating hormone receptor (TSHR) antibodies, fasting plasma glucose and insulin, and hs-CRP were recorded. The eye condition was evaluated using the consensus statement of the European Group of Graves' Orbitopathy (EUGOGO) and the NOSPECS classification. Results: In this study, multivariate regression analysis showed that BMI, fasting plasma insulin, and HOMA-IR were associated with the presence of GO after adjusting the age, gender, smoking, TSHR antibodies, and steroid usage (adjusted odd's ratio (aOR) 1.182, 95% confidence interval (95% CI), 1.003-1.393, p = 0.046; aOR 1.165, 95% CI, 1.001-1.355, p = 0.048; and aOR 1.985, 95% CI, 1.046-3.764, p = 0.036, respectively). In addition, BMI, fasting plasma glucose, fasting plasma insulin, HOMA-IR, and hs-CRP levels were positively correlated with the severity of GO. Conclusions: The findings of this study suggest that obesity-related factors, especially fasting plasma insulin and HOMA-IR, are related to GO. Our study highlighted the importance of obesity-related factors in GO. Obesity-related factors may cause the development of GO or occur simultaneously with GO.

Co-inhibition of Aurora A and Haspin kinases enhances survivin blockage and p53 induction for mitotic catastrophe and apoptosis in human colorectal cancer.

Colorectal cancer (CRC) is a leading cause and mortality worldwide. Aurora A and haspin kinases act pivotal roles in mitotic progression. However, the blockage of Aurora A and Haspin for CRC therapy is still unclear. Here we show that the Haspin and p-H3T3 protein levels were highly expressed in CRC tumor tissues of clinical patients. Overexpression of Haspin increased the protein levels of p-H3T3 and survivin in human CRC cells; conversely, the protein levels of p-H3T3 and survivin were decreased by the Haspin gene knockdown. Moreover, the gene knockdown of Aurora A induced abnormal chromosome segregation, mitotic catastrophe, and cell growth inhibition. Combined targeted by co-treatment of CHR6494, a Haspin inhibitor, and MLN8237, an Aurora A inhibitor, enhanced apoptosis and CRC tumor inhibition. MLN8237 and CHR6494 induced abnormal chromosome segregation and mitotic catastrophe. Meanwhile, MLN8237 and CHR6494 inhibited survivin protein levels but conversely induced p53 protein expression. Ectopic survivin expression by transfection with a survivin-expressed vector resisted the cell death in the MLN8237- and CHR6494-treated cells. In contrast, the existence of functional p53 increased the apoptotic levels by treatment with MLN8237 and CHR6494. Co-treatment of CHR6494 and MLN8237 enhanced the blockage of human CRC xenograft tumors in nude mice. Taken together, co-inhibition of Aurora A and Haspin enhances survivin inhibition, p53 pathway induction, mitotic catastrophe, apoptosis and tumor inhibition that may provide a potential strategy for CRC therapy.

A novel EGFR inhibitor suppresses survivin expression and tumor growth in human gefitinib-resistant EGFR-wild type and -T790M non-small cell lung cancer.

Tyrosine kinase inhibitors of epidermal growth factor receptor (EGFR-TKIs) are currently used therapy for non-small cell lung cancer (NSCLC) patients; however, drug resistance during cancer treatment is a critical problem. Survivin is an anti-apoptosis protein, which promotes cell proliferation and tumor growth that highly expressed in various human cancers. Here, we show a novel synthetic compound derived from gefitinib, do-decyl-4-(4-(3-(4-(3-chloro-4-fluorophenylamino)-7-methoxyquinazolin-6-yloxy)propyl) piper-azin-1-yl)-4-oxobutanoate, which is named as SP101 that inhibits survivin expression and tumor growth in both the EGFR-wild type and -T790M of NSCLC. SP101 blocked EGFR kinase activity and induced apoptosis in the A549 (EGFR-wild type) and H1975 (EGFR-T790M) lung cancer cells. SP101 reduced survivin proteins and increased active caspase 3 for inducing apoptosis. Ectopic expression of survivin by a survivin-expressed vector attenuated the SP101-induced cell death in lung cancer cells. Moreover, SP101 inhibited the gefitinib-resistant tumor growth in the xenograft human H1975 lung tumors of nude mice. SP101 substantially reduced survivin proteins but conversely elicited active caspase 3 proteins in tumor tissues. Besides, SP101 exerted anticancer abilities in the gefitinib resistant cancer cells separated from pleural effusion of a clinical lung cancer patient. Consistently, SP101 decreased the survivin proteins and the patient-derived xenografted lung tumor growth in nude mice. Anti-tumor ability of SP101 was also confirmed in the murine lung cancer model harboring EGFR T790M-L858R. Together, SP101 is a new EGFR inhibitor with inhibiting survivin that can be developed for treating EGFR wild-type and EGFR-mutational gefitinib-resistance in human lung cancers.

Autofluorescence Detection Method for Dental Plaque Bacteria Detection and Classification: Example of Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Streptococcus mutans.

The use of fluorescence spectroscopy for plaque detection is a fast and effective way to monitor oral health. At present, there is no uniform specification for the design of the excitation light source of related products for generating fluorescence. To carry out experiments on dental plaque, the fluorescence spectra of three different bacterial species (Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, and Streptococcus mutans) were measured by hyperspectral imaging microscopy (HIM). Three critical issues were found in the experiments. One issue was the unwanted spectrum generated from a mercury line source; two four-order low-pass filters were evaluated for eliminating the unwanted spectrum and meet the experimental requirements. The second issue was the red fluorescence generated from the microscope slide made of borosilicate glass; this could affect the observation of the red fluorescence from the bacteria; quartz microscope slides were found to reduce the fluorescence intensity by about 2 dB compared with the borosilicate slide. The third issue of photobleaching in the fluorescence of the Porphyromonas gingivalis was studied. This study proposes a method of classifying three bacteria based on the spectral intensity ratios (510/635 and 500/635 nm) under the 405 nm excitation light was proposed in this study. The sensitivity and specificity of the classification were approximately 99% and 99%, respectively.

A rapid drug release system with a NIR light-activated molecular switch for dual-modality photothermal/antibiotic treatments of subcutaneous abscesses.

Eradicating subcutaneous bacterial infections remains a significant challenge. This work reports an injectable system of hollow microspheres (HMs) that can rapidly produce localized heat activated by near-infrared (NIR) light and control the release of an antibiotic via a "molecular switch" in their polymer shells, as a combination strategy for treating subcutaneous abscesses. The HMs have a shell of poly(d,l-lactic-co-glycolic acid) (PLGA) and an aqueous core that is comprised of vancomycin (Van) and polypyrrole nanoparticles (PPy NPs), which are photothermal agents. Experimental results demonstrate that the micro-HMs ensure efficiently the spatial stabilization of their encapsulated Van and PPy NPs at the injection site in mice with subcutaneous abscesses. Without NIR irradiation, the HMs elute a negligible drug concentration, but release substantially more when exposed to NIR light, suggesting that this system is suitable as a photothermally-responsive drug delivery system. The combination of photothermally-induced hyperthermia and antibiotic therapy with HMs increases cytotoxicity for bacteria in abscesses, to an extent that is greater than the sum of the two treatments alone, demonstrating a synergistic effect. This treatment platform may find other clinical applications, especially for localized hyperthermia-based cancer therapy.

Injectable microbeads with a thermo-responsive shell and a pH-responsive core as a dual-switch-controlled release system.

Treating inflammation with a dual-switch-controlled release system: The release of a drug from the developed microbead system occurs only in response to both an increase in local temperature and an acidic environmental pH. This dual-switch-controlled release system has the advantages of distinguishing between inflamed and healthy tissues to improve treatment efficacy.

Inflammation-induced drug release by using a pH-responsive gas-generating hollow-microsphere system for the treatment of osteomyelitis.

In the conventional treatment of osteomyelitis, the penetration of antibiotics into the infected bone is commonly poor. To ensure that the local antibiotic concentration is adequate, this work develops an injectable calcium phosphate (CP) cement in which is embedded pH-responsive hollow microspheres (HMs) that can control the release of a drug according to the local pH. The HMs are fabricated using a microfluidic device, with a shell of poly(D,L-lactic-co-glycolic acid) (PLGA) and an aqueous core that contains vancomycin (Van) and NaHCO3. At neutral pH, the CP/HM cement elutes a negligible concentration of the drug. In an acidic environment, the NaHCO3 that is encapsulated in the HMs reacts with the acid rapidly to generate CO2 bubbles, disrupting the PLGA shells and thereby releasing Van locally in excess of a therapeutic threshold. The feasibility of using this CP/HM cement to treat osteomyelitis is studied using a rabbit model. Analytical results reveal that the CP/HM cement provides highly effective local antibacterial activity. Histological examination further verifies the efficacy of the treatment by the CP/HM cement. The above findings suggest that the CP/HM cement is a highly efficient system for the local delivery of antibiotics in the treatment of osteomyelitis.

Emergence and dissemination of blaOXA-23-carrying imipenem-resistant Acinetobacter sp in a regional hospital in Taiwan.

BACKGROUND: The distribution and characterization of OXA-type carbapenemases in Acinetobacter sp in Taiwan has less been reported. The aim of the study was to investigate the molecular epidemiology and OXA-type carbapenemase genes in a regional hospital in Taiwan. METHODS: Imipenem-resistant Acinetobacter sp were collected between 2005 and 2007 in a regional hospital. Genotyping was performed by pulsed-field gel electrophoresis. OXA-type carbapenemase genes were determined by multiplex polymerase chain reaction (PCR) and gene sequencing. RESULTS: A total of 136 isolates were collected. Fifty-six pulsotypes were identified. None of the pulsotypes established predominance throughout the 3-year period. Multiplex PCR of blaOXA genes showed that 99% (135/136) of the Acinetobacter sp possessed blaOXA51-like genes. The coexistences of blaOXA51-like/blaOXA-23-like and blaOXA51-like/blaOXA-24-like were detected in 19% (26/136) and 1% (2/136) of the isolates, respectively. Among blaOXA-23-like gene-carrying isolates, two isolates (Pulsotypes 18 and 20) were found in 2006 and the remainder (n=24), including Pulsotypes 27 (n=18), 29 (n=1), 52 (n=3), and 53 (n=2), were found in 2007. Sequencing performed on the 26 representative isolates confirmed the presence of the blaOXA-23 carbapenemase gene. Analysis of the genetic content of blaOXA-23 showed that these genes were presumably chromosomal and associated with the upstream-located insertion sequence ISAba1. CONCLUSIONS: The emergence and imminent widespread of blaOXA-23-carrying imipenem-resistant Acinetobacter sp appeared in Taiwan during the period from 2006 to 2007.

Role of integrons in antimicrobial susceptibility patterns of Acinetobacter baumannii.

The relationship between the presence and types of integrons and the antimicrobial susceptibility patterns of Acinetobacter baumannii was investigated. A total of 134 non-duplicated A. baumannii isolates, 54.5% (n=73) of which were subsequently found to carry class 1 integrons, were collected from a regional hospital in Taiwan between March and September 2007. Only two types of gene cassette array, aacA4-catB8-aadA1 and aacC1-orfP-orfP-orfQ-aadA1, were identified. Susceptibility data showed that those strains carrying integrons were significantly more resistant to all antibiotics tested except ampicillin/sulbactam and imipenem. An epidemiological study revealed that the same integron could be found in different unrelated strains. These findings suggest that the presence of integrons in A. baumannii is responsible for both the horizontal transfer of antibiotic-resistance genes related to aminoglycosides and chloramphenicol and also represents a marker of multidrug resistance and epidemic potential.

Distribution of blaOXA-carrying imipenem-resistant Acinetobacter spp. in 3 hospitals in Taiwan.

We investigated the molecular epidemiology and OXA-type carbapenemase genes of 83 imipenem-resistant Acinetobacter spp. collected from 2 university hospitals (hospitals A and B) and a regional hospital (hospital C) during 2007 in Taiwan. Genotyping by pulsed-field gel electrophoresis identified 51 pulsotypes. None of the pulsotypes established predominance throughout the 3 hospitals. Multiplex polymerase chain reaction of blaOXA genes showed that 100% (18/18), 91%(31/34), and 100% (31/31) of the Acinetobacter spp. collected from hospital A, B, and C, respectively, possessed blaOXA-51-like genes. None of the strains carrying blaOXA-23-like and blaOXA-24-like genes were found in hospital A. The coexistences of blaOXA-51-like/blaOXA-23-like and blaOXA-51-like/blaOXA-24-like genes detected in hospitals B and C were 26% (9/34) and 12% (4/34) and 58% (18/31) and 3% (1/31), respectively. Among blaOXA-23-like gene-carrying isolates collected from hospitals, clonal spread of strains carrying the blaOXA-23 gene was detected in the regional hospital but not the other 2 university hospitals. The results suggest that interhospital dissemination of imipenem-resistant Acinetobacter spp. was not found in these hospitals. The increasing percentage of OXA-23 in OXA-type carbapenemases in Acinetobacter spp. from the regional hospitals to medical centers deserves further attention in Taiwan.

Clinical features and molecular epidemiology of multidrug-resistant Acinetobacter calcoaceticus-A baumannii complex in a regional teaching hospital in Taiwan.

We conducted a case-controlled study in a regional teaching hospital in Taiwan to investigate the clinical features and molecular epidemiology of multidrug-resistant Acinetobacter calcoaceticus-A baumannii (MDR Acb) complex. Case patients had higher mortality than controls did. MDR Acb complex acquisition risk factors include longer hospital stays, higher ratio of nasogastric tube and Foley catheter use, and more carbapenem use. All available isolates were divided into 36 subtypes by pulsed-field gel electrophoresis. The proportion of the same subtypes with their appearance within 1 and 2 months was 62.5% and 87.5%, respectively. We concluded that many different MDR Acb complex clones could be found in a hospital and that the same clones often spread on a small scale within a short period of time if no outbreaks noted.

Characterization of antimicrobial resistance patterns and integrons in human fecal Escherichia coli in Taiwan.

Two hundred and twenty-five fecal strains of Escherichia coli isolated from 109 non-hospitalized adults in 2006 were investigated for susceptibility to antibiotics and for the presence of integrons. High resistance rates in fecal strains of E. coli were observed for streptomycin (52.0%), ampicillin (50.2%), piperacillin (50.2%), trimethoprim/sulfamethoxazole (47.6%) and chloramphenicol (33.8%). Integrons were found in 31.5% (71/225) of the strains using an integrase gene PCR assay. Among 71 integrase-positive strains, 65 strains belonged to class 1 integrons, while the remainder belonged to class 2. Gene cassette patterns of class 1 integrons were further characterized by PCR and direct sequencing. Among those class 1 integrase-containing isolates, the integron cassette region was amplified by PCR in 40.0% (26 of 65) of isolates. Five different antimicrobial resistance gene cassette arrays were found in those isolates. These gene cassettes included those encoding resistance to trimethoprim (dfrV, dfrA7, dfrA12, dfrA17) and streptomycin (aadA1, aadA2, aadA5). Among those gene cassette arrays, dfrA12-orfF-aadA2 was found in 53.8% (14/26) of the isolates. These findings indicate that multidrug resistance of fecal flora is common in Taiwan and that integrons play an important role in resistance to trimethoprim and streptomycin in humans.