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- Susceptibility of Stenotrophomonas maltophilia clinical strains in China to antimicrobial combinations. [JOURNAL ARTICLE]
- J Chemother 2014 Mar 4.:1973947814Y0000000168.
We aimed to investigate the activity levels of several combinations of antimicrobials against Stenotrophomonas maltophilia. In this study, the antimicrobial susceptibility of S. maltophilia clinical isolates was determined, and the synergistic activity of three pairs of antimicrobial combinations was evaluated by the fractional inhibitory concentration index (FICI). The antimicrobial susceptibility in vitro against 83 S. maltophilia strains was greater for minocycline (80·7%) than for trimethoprim-sulfamethoxazole (51·8%), and levofloxacin (50·6%). The rate of resistance was highest for ticarcillin-clavulanate and ceftazidime (63·8%) and resistance to trimethoprim-sulfamethoxazole (TMP-SMX) was 48·2%. All three combinations were tested against susceptible isolates. Two of the combinations, TMP-SMX+ceftazidime and levofloxacin+ceftazidime were more effective than the combination of TMP-SMX+levofloxacin. We recommend acquiring more clinical data in order to explore combination therapy, which is a promising treatment of S. maltophilia infections.
- Functional abstraction as a method to discover knowledge in gene ontologies. [Journal Article]
- PLoS One 2014; 9(2):e90191.
Computational analyses of functions of gene sets obtained in microarray analyses or by topical database searches are increasingly important in biology. To understand their functions, the sets are usually mapped to Gene Ontology knowledge bases by means of over-representation analysis (ORA). Its result represents the specific knowledge of the functionality of the gene set. However, the specific ontology typically consists of many terms and relationships, hindering the understanding of the 'main story'. We developed a methodology to identify a comprehensibly small number of GO terms as "headlines" of the specific ontology allowing to understand all central aspects of the roles of the involved genes. The Functional Abstraction method finds a set of headlines that is specific enough to cover all details of a specific ontology and is abstract enough for human comprehension. This method exceeds the classical approaches at ORA abstraction and by focusing on information rather than decorrelation of GO terms, it directly targets human comprehension. Functional abstraction provides, with a maximum of certainty, information value, coverage and conciseness, a representation of the biological functions in a gene set plays a role. This is the necessary means to interpret complex Gene Ontology results thus strengthening the role of functional genomics in biomarker and drug discovery.
- The influence of zeolite (clinoptilolite) on the performance of a hybrid membrane bioreactor. [JOURNAL ARTICLE]
- Bioresour Technol 2014 Feb 8.:25-31.
This work aims to investigate the effect of clinoptilolite on the performance of membrane bioreactor (MBR). The control membrane bioreactor without clinoptilolite (CMBR) and the hybrid membrane bioreactor with clinoptilolite (HMBR), in two parallel simultaneous MBRs within long and short term filtration experiments, were studied. Sludge properties, transmembrane pressure (TMP) rise as an index for membrane fouling and nutrient removal from synthetic wastewater in the CMBR and HMBR were compared. In HMBR, sludge properties improvement such as 22.5% rise in MLSS, 7% more accumulation of large particles, reduction of soluble microbial products (SMP) to half of this value in CMBR, no increase in sludge volume index (SVI) and 66% TMP reduced. The results of short term filtration showed that the trend of TMP increase in terms of flux will be slower in HMBR. Improvement of biological wastewater treatment quality and ease of membrane operation are concluded from this study.
- Effect of fluoride gels supplemented with sodium trimetaphosphate on enamel erosion and abrasion: In vitro study. [Journal Article]
- Arch Oral Biol 2014 Mar; 59(3):336-40.
This in vitro study aims to evaluate the effect of low fluoride (F) gel associate sodium trimetaphosphate (TMP) on erosion with or without abrasion.Enamel blocks (4mm×4mm) selected through surface hardness (SH) is divided into five groups (n=12): gel without F and TMP (placebo), gel containing 4500ppm F (4500), gel containing 4500ppm F plus TMP5% (4500 TMP5%), gel containing 9000ppm F (9000), and gel containing 12,300ppm F (acid gel). Those groups were additionally subdivided into conditions of erosion (Ero) and of erosion plus abrasion (Ero/Abra). The blocks have undergone a single application of gel on the first day of the study. The erosion challenge was produced by Sprite Zero(®) for five minutes four times a day and abrasion was carried out by machine brushing for 15s. After the challenges, the surface hardness (%SH), wear and cross-sectional hardness (ΔKHN) were analyzed. The data were analyzed using a 2-way ANOVA test followed by a Student-Newman-Keuls (p<0.05).Lower values of %SH, wear and ΔKHN were observed for erosion challenge (p<0.001). The %SH was lower in groups treated with fluoride gels, differing in the placebo (p<0.05). With addition of TMP to the gel 4500, enamel wear was lower when compared with another groups (p<0.05).In vitro conditions, the 4500 5%TMP gel showed greatest effect against erosion and erosion/abrasion.
- Itraconazole vs. trimethoprim-sulfamethoxazole: A comparative cohort study of 200 patients with paracoccidioidomycosis. [JOURNAL ARTICLE]
- Med Mycol 2014 Jan 27.
Paracoccidioidomycosis (PCM) is a systemic mycosis endemic to Latin America. Brazil accounts for approximately 80% of cases, where it represents a major public health issue due to its disabling impact and the number of premature deaths it causes. We present a retrospective cohort study that was conducted in order to better understand factors that relate to cure of the infection in the treatment of 200 patients with PCM. We evaluated the influence of sociodemographic and clinical factors as well as therapeutic regimen (trimethoprim-sulfamethoxazole [TMP-SMX] and itraconazole) on the progress of PCM (cure and noncure). There was a higher incidence of cure (83%) among patients who regularly received treatment for their infections and completed the treatment protocol. Moreover, itraconazole (86.4%) was significantly superior to TMP-SMX (51.3%) in terms of cure rate and had a median treatment period that was significantly shorter (12 months) than that for TMP-SMX (23 months). A Cox proportional hazard regression model showed that use of itraconazole increased the hazard of cure, regardless of sex, age, education, clinical form, completion of treatment, and regularity. Although the results of this study show that itraconazole was the best treatment option for PCM patients, a double-blind, randomized, controlled trial is necessary to confirm this conclusion.
- Combination of caspofungin and low-dose trimethoprim/sulfamethoxazole for the treatment of severe Pneumocystis jirovecii pneumonia in renal transplant recipients. [Journal Article]
- Nephrology (Carlton) 2013 Nov; 18(11):736-42.
Pneumocystis jirovecii pneumonia (PJP) is a severe and life-threatening complication in immunocompromised patients. Trimethoprim/sulfamethoxazole (TMP-SMZ) is well known for its effectiveness as prophylaxis of PJP. However, the use of TMP-SMZ is associated with various adverse effects that may not be tolerated by critically ill patients. Caspofungin is recommended for invasive fungal infections, but the treatment of PJP after solid organ transplantation (SOT) is an off-label use of this drug. In this study, three cases of severe PJP in renal transplant recipients treated with a combination of caspofungin and low-dose TMP-SMZ were presented. Initial findings indicated that the combined treatment may be beneficial for the treatment of PJP and decrease the incidence of TMP-SMZ-related adverse effects.
- Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. [JOURNAL ARTICLE]
- J Clin Invest 2014 Feb 24.
Background. X-linked hypophosphatemia (XLH) is the most common heritable form of rickets and osteomalacia. XLH-associated mutations in phosphate-regulating endopeptidase (PHEX) result in elevated serum FGF23, decreased renal phosphate reabsorption, and low serum concentrations of phosphate (inorganic phosphorus, Pi) and 1,25-dihydroxyvitamin D [1,25(OH)2D]. KRN23 is a human anti-FGF23 antibody developed as a potential treatment for XLH. Here, we have assessed the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of KRN23 following a single i.v. or s.c. dose of KRN23 in adults with XLH. Methods. Thirty-eight XLH patients were randomized to receive a single dose of KRN23 (0.003-0.3 mg/kg i.v. or 0.1-1 mg/kg s.c.) or placebo. PK, PD, immunogenicity, safety, and tolerability were assessed for up to 50 days. Results. KRN23 significantly increased the maximum renal tubular threshold for phosphate reabsorption (TmP/GFR), serum Pi, and 1,25(OH)2D compared with that of placebo (P < 0.01). The maximum serum Pi concentration occurred later following s.c. dosing (8-15 days) compared with that seen with i.v. dosing (0.5-4 days). The effect duration was dose related and persisted longer in patients who received s.c. administration. Changes from baseline in TmP/GFR, serum Pi, and serum 1,25(OH)2D correlated with serum KRN23 concentrations. The mean t1/2 of KRN23 was 8-12 days after i.v. administration and 13-19 days after s.c. administration. Patients did not exhibit increased nephrocalcinosis or develop hypercalciuria, hypercalcemia, anti-KRN23 antibodies, or elevated serum parathyroid hormone (PTH) or creatinine. Conclusion. KRN23 increased TmP/GFR, serum Pi, and serum 1,25(OH)2D. The positive effect of KR23 on serum Pi and its favorable safety profile suggest utility for KRN23 in XLH patients. Trial registration. Clinicaltrials.gov NCT00830674. Funding. Kyowa Hakko Kirin Pharma, Inc.
- [Effect of Apollon siRNA combined with tetramethylpyrazine on proliferation and apoptosis of leukemia K562 cells]. [English Abstract, Journal Article]
- Zhongguo Dang Dai Er Ke Za Zhi 2014 Feb; 16(2):135-40.
To investigate the effect of small interfering RNA (siRNA) silencing Apollon gene combined with tetramethylpyrazine (TMP) on the proliferation and apoptosis of human chronic myeloid leukemia cell line K562.K562 cells were divided into blank control, negative control, and RNA interference (RNAi) group. For the RNAi group, the pGPHI-GFP-Neo-Apollon eukaryotic expression vector based on the best Apollon siRNA fragments screened out in previous experiments was constructed; the blank control group received no treatment, and the negative control group was transfected with negative plasmid vector. The mRNA and protein expression of Apollon was measured by RT-PCR and cell immunofluorescence, respectively. Additionally, TMP (320 μg/mL) was applied to set TMP, TMP+negative control, and TMP+RNAi groups. The cell viability and apoptosis rate were determined by MTT assay and flow cytometry, respectively.The constructed vector was stably expressed in K562 cells. The RNAi group had significantly lower mRNA and protein expression of Apollon than the blank control group and negative control (P<0.05). The RNAi group had significantly increased proliferation inhibition rate and apoptosis rate, as compared with the blank contorl group (P<0.05). The TMP+RNAi group had significantly increased proliferation inhibition rate and apoptosis rate, as compared with the RNAi, and TMP groups (P<0.05).Apollon siRNA can significantly inhibit the proliferation and promote the apoptosis of K562 cells, and the addition of TMP can further increase the proliferation inhibition rate and apoptosis rate, suggesting that siRNA technology combined with drugs has a significant potential value in the treatment of leukemia.
- Successful Outpatient Graded Administration of Trimethoprim-Sulfamethoxazole in Patients Without HIV and With a History of Sulfonamide Adverse Drug Reaction. [Journal Article]
- J Allergy Clin Immunol Pract 2014 Jan-Feb; 2(1):52-8.
The outcomes of trimethoprim-sulfamethoxazole (TMP-SMX) desensitization have been widely reported in the HIV literature but less so in the non-HIV literature.To evaluate the safety and efficacy of graded administration of TMP-SMX in patients without HIV and with a history of TMP-SMX adverse drug reaction (ADR).A retrospective chart review, 2004-2012, of all the patients without HIV seen in the Division of Allergic Diseases and with a history of TMP-SMX ADR who underwent outpatient graded administration of TMP-SMX was conducted. The medical record was reviewed for age, sex, details of the initial ADR to TMP-SMX, an indication for TMP-SMX administration, and outcome. Patients also were contacted by telephone, and medical records were reviewed to determine long-term outcomes.Seventy-two patients (46 women [64%]; mean [SD] age, 57.7 ± 13.89 years]) were included. The most common patient-reported reactions to TMP-SMX were rash 39 (54%), and hives 9 (13%). TMP-SMX administration was needed for the following indications: prophylaxis (62 [86%]) and treatment of infection (10 [14%]). Forty-three of the patients (60%) underwent a 1-day TMP-SMX administration protocol. Thirty-five of the 43 (81%) underwent a 6-step (90 minutes to 6 hours) protocol and 7 of the 43 (16%) underwent a novel 14-step TMP-SMX protocol. Twenty-nine (40%) underwent a >1-day TMP-SMX administration protocol. Our overall success rate was 90% (mean duration of 11 months). Ninety-eight percent of the patients successfully completed a 1-day graded administration protocol, and 76% successfully completed a >1-day protocol. TMP-SMX was stopped in 8 patients because of the ADR.We report the largest case series of successful outpatient graded administration of TMP-SMX with both 1-day and >1-day protocols, which have shown to be safe and well tolerated in patients without HIV and with a history of sulfonamide ADR.
- Antitumor cell-complex vaccines employing genetically modified tumor cells and fibroblasts. [Journal Article]
- Toxins (Basel) 2014; 6(2):636-49.
The present study evaluates the immune response mediated by vaccination with cell complexes composed of irradiated B16 tumor cells and mouse fibroblasts genetically modified to produce GM-CSF. The animals were vaccinated with free B16 cells or cell complexes. We employed two gene plasmid constructions: one high producer (pMok) and a low producer (p2F). Tumor transplant was performed by injection of B16 tumor cells. Plasma levels of total IgG and its subtypes were measured by ELISA. Tumor volumes were measured and survival curves were obtained. The study resulted in a cell complex vaccine able to stimulate the immune system to produce specific anti-tumor membrane proteins (TMP) IgG. In the groups vaccinated with cells transfected with the low producer plasmid, IgG production was higher when we used free B16 cell rather than cell complexes. Nonspecific autoimmune response caused by cell complex was not greater than that induced by the tumor cells alone. Groups vaccinated with B16 transfected with low producer plasmid reached a tumor growth delay of 92% (p ≤ 0.01). When vaccinated with cell complex, the best group was that transfected with high producer plasmid, reaching a tumor growth inhibition of 56% (p ≤ 0.05). Significant survival (40%) was only observed in the groups vaccinated with free transfected B16 cells.