Primary open-angle glaucoma (POAG) is one of the leading causes of blindness worldwide. The association between the APOE ε2/ε3/ε4 polymorphism and the risk of POAG has been widely reported, but the results of previous studies remain controversial. To comprehensively evaluate the APOE ɛ2/ɛ3/ε4 polymorphism on the genetic risk for POAG, we performed a systematic review and meta-analysis of previously published studies. The PubMed and Web of Science databases were systematically searched to identify relevant studies. Data were extracted from these studies and odds ratios with corresponding 95% confidence intervals were computed to estimate the strength of the association. Stratified analyses according to ethnicity and sensitivity analyses were also conducted for further confirmation. A total of nine studies were eligible for the meta-analysis, and these studies included data on 1928 POAG cases and 1793 unrelated match controls. The combined results showed that there were no associations between the APOE ε2/ε3/ε4 polymorphism and POAG risk in any of the 10 comparison models. The analysis that was stratified by ethnicity subgroups also failed to reveal a significant association. The sensitivity analysis confirmed the stability and reliability of the findings. There was no risk of publication bias. Our meta-analysis provides strong evidence that the APOE ε2/ε3/ε4 polymorphism is not associated with POAG susceptibility in any populations.
Epithelial-mesenchymal transition (EMT) is important for tumor metastasis. Detection of EMT protein expression and observation of morphological changes are commonly used to identify EMT. Diffusion-weighted magnetic resonance imaging (DW-MRI) and measuring apparent diffusion coefficient (ADC) values are noninvasive techniques for characterizing tumor microenvironments. We investigated the difference in ADC values between epithelial- and mesenchymal-like subcutaneous mouse xenografted tumors using DW-MRI. Epithelial-like MM189 PB-Klf4 and BL322 PB-Klf4 cells were generated from tumor suppressive Kruppel-like factor 4 (Klf4)-expressing mesenchymal-like MM189 and BL322 cells. The ADC values of xenografted tumors from epithelial-like MM189 PB-Klf4 and BL322 PB-Klf4 were significantly lower than those from their mesenchymal-like counterparts (p < 0.05 and p < 0.01, respectively). Our results suggested that DW-MRI is a potential tool for observing mesenchymal- or epithelial-like characteristics of subcutaneous xenografted tumors.
diffusion-weighted magnetic resonance imaging; epithelial; mesenchymal; apparent diffusion coefficient; mouse xenografts
Circulating tumor cells (CTCs) are shed into the bloodstream from primary and metastatic tumor deposits. Their isolation and analysis hold great promise for the early detection of invasive cancer and the management of advanced disease, but technological hurdles have limited their broad clinical utility. We describe an inertial focusing–enhanced microfluidic CTC capture platform, termed “CTC-iChip,” that is capable of sorting rare CTCs from whole blood at 107 cells/s. Most importantly, the iChip is capable of isolating CTCs using strategies that are either dependent or independent of tumor membrane epitopes, and thus applicable to virtually all cancers. We specifically demonstrate the use of the iChip in an expanded set of both epithelial and nonepithelial cancers including lung, prostate, pancreas, breast, and melanoma. The sorting of CTCs as unfixed cells in solution allows for the application of high-quality clinically standardized morphological and immunohistochemical analyses, as well as RNA-based single-cell molecular characterization. The combination of an unbiased, broadly applicable, high-throughput, and automatable rare cell sorting technology with generally accepted molecular assays and cytology standards will enable the integration of CTC-based diagnostics into the clinical management of cancer.
Mitsugumin 53 (MG53), a muscle-specific TRIM family protein, is an essential component of the cell membrane repair machinery. Here we examined the translational value of targeting MG53 function in tissue repair and regenerative medicine. Although native MG53 protein is restricted to skeletal and cardiac muscle tissues, beneficial effects that protect against cellular injuries are present in non-muscle cells with overexpression of MG53. In addition to the intracellular action of MG53, injury to the cell membrane exposes a signal that can be detected by MG53, allowing recombinant MG53 protein to repair membrane damage when provided in the extracellular space. Recombinant human MG53 (rhMG53) protein purified from Escherichia coli fermentation provided dose-dependent protection against chemical, mechanical, or UV-induced damage to both muscle and non-muscle cells. Injection of rhMG53 through multiple routes decreased muscle pathology in the mdx dystrophic mouse model. Our data support the concept of targeted cell membrane repair in regenerative medicine, and present MG53 protein as an attractive biological reagent for restoration of membrane repair defects in human diseases.
Hepatocellular carcinoma (HCC) is a highly vascular tumor through the process of angiogenesis. To evaluate more non-invasive techniques for assessment of blood flow (BF) in HCC, this study examined the relationships between BF of HCC measured by computer tomography (CT) perfusion imaging and four circulating angiogenic factors in HCC patients. Interleukin 6 (IL-6), interleukin 8 (IL-8), vascular endothelial growth factor (VEGF), and platelet derived growth factor (PDGF) in plasma were measured using Bio-Plex multiplex immunoassay in 21 HCC patients and eight healthy controls. Circulating IL-6, IL-8 and VEGF showed higher concentrations in HCC patients than in controls (p < 0.05), and predicted HCC occurrence better than chance (p < 0.01). Twenty-one patients with HCC received 21-phase liver imaging using a 64-slice CT. Total BF, arterial BF, portal BF, arterial fraction (arterial BF/total BF) of the HCC and surrounding liver parenchyma, and HCC-parenchyma ratio were measured using a dual-vessel model. After analyzing the correlations between BF in HCC and four circulating angiogenic factors, we found that the HCC-parenchyma ratio of arterial BF showed a significantly positive correlation with the level of circulating IL-8 (p < 0.05). This circulating biomarker, IL-8, provides a non-invasive tool for assessment of BF in HCC.
hepatocellular carcinoma; blood flow; circulating angiogenic factors; CT perfusion; interleukin 8
Statins reduce cardiovascular risks but increase the risk of new-onset diabetes (NOD). The aim of this study is to determine what effect, if any, statins have on the risk of NOD events in a population-based case-control study. An evaluation of the relationship between age and statin-exposure on NOD risks was further examined in a female Asian population.
In a nationwide case-controlled study, the authors assessed 1065 female NOD patients and 10650 controls with matching ages, genders and physician visit dates. The impact of statin-exposure on NOD was examined through multiple logistic regression models. Subgroup analysis for exploring the risk of NOD and statin-exposure in different age groups was performed.
Statin-exposure was statistically significantly associated with increased new-onset diabetes risks using multivariate analysis. Interaction effect between age and statin-exposure on NOD risk was noted. For atorvastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted odds ratio [OR], 8.0; 95% confidence interval [CI], 2.57–24.90). For rosuvastatin, the risk of cDDDs>60 was highest among the 40–54 year-olds (adjusted OR, 14.8; 95% CI, 2.27–96.15). For simvastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted OR, 15.8; 95% CI, 5.77–43.26). For pravastatin, the risk of cDDDs>60 was highest among the 55–64 year-olds (adjusted OR, 14.0; 95% CI, 1.56–125.18).
This population-based study found that statin use is associated with an increased risk of NOD in women. The risk of statin-related NOD was more evident for women aged 40–64 years compared to women aged 65 or more, and was cumulative-dose dependent. The use of statins should always be determined by weighing the clinical benefits and potential risks for NOD, and the patients should be continuously monitored for adverse effects.
Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Tumor dissemination to the extra-hepatic region of the portal vein, lymph nodes, lungs or bones contributes to the high mortality seen in HCC; yet, the molecular mechanisms responsible for HCC metastasis remain unclear. Prior studies have suggested a potential link between accumulated cytoplasm-localized p16 and tumor progression. Here we report that p16 enhances metastasis-associated phenotypes in HCC cells – ectopic p16 expression increased cell migration in vitro, and lung colonization after intravenous injection, whereas knockdown of endogenous p16 reduced cell migration. Interestingly, analysis of p16 mutants indicated that the Cdk4 interaction domain is required for stimulation of HCC cell migration; however, knockdown of Cdk4 and Cdk6 showed that these proteins are dispensable for this phenomenon. Intriguingly, we found that in p16-positive HCC samples, p16 protein is predominantly localized in the cytoplasm. In addition, we identified a potential role for nuclear-cytoplasmic shuttling in p16-stimulated migration, consistent with the predominantly cytoplasmic localization of p16 in IHC-positive HCC samples. Finally, we determined that p16-stimulated cell migration requires the Cdc42 GTPase. Our results demonstrate for the first time a pro-migratory role for p16, and suggest a potential mechanism for the observed association between cytoplasmic p16 and tumor progression in diverse tumor types.
Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.
Methodology and Principal Findings
An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.
Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.
Purpose. To compare the diagnostic performance of digital breast tomosynthesis (DBT) and digital mammography (DM) for breast cancers. Materials and Methods. Fifty-seven female patients with pathologically proved breast cancer were enrolled. Three readers gave a subjective assessment superiority of the index lesions (mass, focal asymmetry, architectural distortion, or calcifications) and a forced BIRADS score, based on DM reading alone and with additional DBT information. The relevance between BIRADS category and index lesions of breast cancer was compared by chi-square test. Result. A total of 59 breast cancers were reviewed, including 17 (28.8%) mass lesions, 12 (20.3%) focal asymmetry/density, 6 (10.2%) architecture distortion, 23 (39.0%) calcifications, and 1 (1.7%) intracystic tumor. Combo DBT was perceived to be more informative in 58.8% mass lesions, 83.3% density, 94.4% architecture distortion, and only 11.6% calcifications. As to the forced BIRADS score, 84.4% BIRADS 0 on DM was upgraded to BIRADS 4 or 5 on DBT, whereas only 27.3% BIRADS 4A on DM was upgraded on DBT, as BIRADS 4A lesions were mostly calcifications. A significant P value (<0.001) between the BIRADS category and index lesions was noted. Conclusion. Adjunctive DBT gives exquisite information for mass lesion, focal asymmetry, and/or architecture distortion to improve the diagnostic performance in mammography.
Female breast tissue has a rich vascular supply and carries a high risk of excessive bleeding during large-core needle biopsy. It is crucial to shorten bleeding time and reduce hematoma size after the procedure. Currently, more efficient hemostatic dressings are becoming available.
Material and Methods
The bleeding time and hematoma size after breast biopsy with use of either Instant Clot Pad (ICP) dressings or cotton gauze were compared.
ICP could attract a vast number of red blood cells and formed blood clots in about 30 s (in vitro blood clotting test). In clinical breast biopsy examinations, the average bleeding time with ICP was significantly reduced to about 2.9 min as compared to 6.4 min with cotton gauze (p < 0.005). The average hematoma size was also reduced with the use of ICP (0.89 cm3) as compared to cotton gauze (1.28 cm3). In patients with benign breast disease, ICP significantly reduced hematoma size.
ICP used after breast biopsy could shorten the bleeding time in all patients, and significantly reduce the hematoma size in patients with benign compared to those with malignant breast disease.
Breast biopsy; Hemostasis; Bleeding time; Hematoma
Metformin and statins have shown promise for cancer prevention. This study assessed whether the effect of metformin on prostate cancer (PCa) incidence varied by statin use among type 2 diabetic patients.
RESEARCH DESIGN AND METHODS
The study cohort consisted of 5,042 type 2 diabetic male patients seen in the Veteran Administration Health Care System who were without prior cancer and were prescribed with metformin or sulfonylurea as the exclusive hypoglycemic medication between fiscal years 1999 and 2005. Cox proportional hazards analyses were conducted to assess the differential hazard ratio (HR) of PCa due to metformin by statin use versus sulfonylurea use, where propensity scores of metformin and statin use were adjusted to account for imbalances in baseline covariates across medication groups.
Mean follow-up was ∼5 years, and 7.5% had a PCa diagnosis. Statin use modified the effect of metformin on PCa incidence (P < 0.0001). Metformin was associated with a significantly reduced PCa incidence among patients on statins (HR 0.69 [95% CI 0.50–0.92]; 17 cases/533 metformin users vs. 135 cases/2,404 sulfonylureas users) and an increased PCa incidence among patients not on statins (HR 2.15 [1.83–2.52]; 22 cases/175 metformin users vs. 186 cases/1,930 sulfonylureas users). The HR of PCa incidence for those taking metformin and statins versus those taking neither medication was 0.32 (0.25–0.42).
Among men with type 2 diabetes, PCa incidence among metformin users varied by their statin use. The potential beneficial influence on PCa by combination use of metformin and statin may be due to synergistic effects.
Mycobacterium tuberculosis; Microfluidics; Genotyping; Micromolding; Laser-induced fluorescence
Glioblastoma multiforme (GBM) is the most aggressive type of glioma and carries the poorest chances of survival. There is therefore an urgent need to understand the mechanisms of glioma tumorigenesis and develop or improve therapeutics. The aim of this study was to assess the possible prognostic value of cyclin-dependent kinase 6 (CDK6) and the effects of microRNA-495 (miR-495) manipulation on CDK6 expression and cell survival in glioma cells.
Analyses of clinical specimens from GBM patients were used. Expression of CDK6 was analyzed by real-time polymerase chain reaction (RT-PCR), Western blotting, and immunohistochemistry. Expression of CDK6 was also analyzed after over-expression of miR-495 in T98 cells; both cell proliferation and RB phosphorylation were examined. Cell proliferation, cell cycle distribution, and RB phosphorylation were also examined after knockdown of CDK6 in U87-MG and T98 cells.
Analyses of clinical specimens from GBM patients identified that CDK6 is significantly expressed in gliomas. CDK6 antigen expression was higher in tumor cores and margins than in adjacent normal brain tissues, and higher levels of CDK6 expression in the tumor margin correlated with decreased survival. Over-expression of miR-495 in T98 cells downregulated the expression of CDK6 and inhibited retinoblastoma phosphorylation, and knockdown of CDK6 in U87-MG and T98 cells by siRNAs resulted in cell cycle arrest at the G1/S transition and inhibition of cell proliferation.
This study revealed miR-495 is down-regulated in glioma tissues. Furthermore, miR-495 regulated CDK6 expression and involved in glioma cell growth inhibition, which indicated the possible role of miR-495 in tumor progression.
CDK6; Glioblastoma multiforme; MicroRNA-495; Tumor progression
The purpose of this study is to assess the preclinical therapeutic efficacy of magnetic resonance imaging (MRI)-monitored focused ultrasound (FUS)-induced blood-brain barrier (BBB) disruption to enhance Temozolomide (TMZ) delivery for improving Glioblastoma Multiforme (GBM) treatment. MRI-monitored FUS with microbubbles was used to transcranially disrupt the BBB in brains of Fisher rats implanted with 9L glioma cells. FUS-BBB opening was spectrophotometrically determined by leakage of dyes into the brain, and TMZ was quantitated in cerebrospinal fluid (CSF) and plasma by LC-MS\MS. The effects of treatment on tumor progression (by MRI), animal survival and brain tissue histology were investigated. Results demonstrated that FUS-BBB opening increased the local accumulation of dyes in brain parenchyma by 3.8-/2.1-fold in normal/tumor tissues. Compared to TMZ alone, combined FUS treatment increased the TMZ CSF/plasma ratio from 22.7% to 38.6%, reduced the 7-day tumor progression ratio from 24.03 to 5.06, and extended the median survival from 20 to 23 days. In conclusion, this study provided preclinical evidence that FUS BBB-opening increased the local concentration of TMZ to improve the control of tumor progression and animal survival, suggesting its clinical potential for improving current brain tumor treatment.
Brazilein, a natural, biologically active compound from Caesalpinia sappan L., has been shown to exhibit anti-inflammatory and antioxidant properties and to inhibit the growth of several cancer cells. This study verifies the antioxidant and antitumor characteristics of brazilein in skin cancer cells and is the first time to elucidate the inhibition mechanism of adipocyte differentiation, cestocidal activities against Hymenolepis nana, and reduction of spontaneous movement in Anisakis simplex. Brazilein exhibits an antioxidant capacity as well as the ability to scavenge DPPH• and ABTS•+ free radicals and to inhibit lipid peroxidation. Brazilein inhibited intracellular lipid accumulation during adipocyte differentiation in 3T3-L1 cells and suppressed the induction of peroxisome proliferator-activated receptor γ (PPARγ), the master regulator of adipogenesis, suggesting that brazilein presents the antiobesity effects. The toxic effects of brazilein were evaluated in terms of cell viability, induction of apoptosis, and the activity of caspase-3 in BCC cells. The inhibition of the growth of skin cancer cells (A431, BCC, and SCC25) by brazilein is greater than that of human skin malignant melanoma (A375) cells, mouse leukemic monocyte macrophage (RAW 264.7 cells), and noncancerous cells (HaCaT and BNLCL2 cells). The anthelmintic activities of brazilein against Hymenolepis nana are better than those of Anisakis simplex.
Tandem mass spectrometry (MS/MS) analysis is a powerful tool for newborn screening, and many rare inborn errors of metabolism are currently screened using MS/MS. However, the sensitivity of MS/MS screening for several inborn errors, including citrin deficiency (screened by citrulline level) and carnitine uptake defect (CUD, screened by free carnitine level), is not satisfactory. This study was conducted to determine whether a second-tier molecular test could improve the sensitivity of citrin deficiency and CUD detection without increasing the false-positive rate.
Three mutations in the SLC25A13 gene (for citrin deficiency) and one mutation in the SLC22A5 gene (for CUD) were analyzed in newborns who demonstrated an inconclusive primary screening result (with levels between the screening and diagnostic cutoffs).
The results revealed that 314 of 46 699 newborns received a second-tier test for citrin deficiency, and two patients were identified; 206 of 30 237 newborns received a second-tier testing for CUD, and one patient was identified. No patients were identified using the diagnostic cutoffs. Although the incidences for citrin deficiency (1:23 350) and CUD (1:30 000) detected by screening are still lower than the incidences calculated from the mutation carrier rates, the second-tier molecular test increases the sensitivity of newborn screening for citrin deficiency and CUD without increasing the false-positive rate.
Utilizing a molecular second-tier test for citrin deficiency and carnitine transporter deficiency is feasible.
Newborn screening; Founder mutation; Second-tier molecular test; Citrin deficiency; Carnitine uptake defect
Hypnotics have been reported to be associated with dementia. However, the relationship between insomnia, hypnotics and dementia is still controversial. We sought to examine the risk of dementia in patients with long-term insomnia and the contribution of hypnotics.
Data was collected from Taiwan’s Longitudinal Health Insurance Database. The study cohort comprised all patients aged 50 years or older with a first diagnosis of insomnia from 2002 to 2007. The comparison cohort consisted of randomly selected patients matched by age and gender. Each patient was individually tracked for 3 years from their insomnia index date to identify whether the patient had a first diagnosis of dementia. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).
We identified 5693 subjects with long-term insomnia and 28,465 individuals without. After adjusting for hypertension, diabetes mellitus, hyperlipidemia, and stroke, those with long-term insomnia had significantly higher risks of dementia (HR, 2.34; 95% CI, 1.92–2.85). Patients with long-term insomnia and aged 50 to 65 years had a higher increased risk of dementia (HR, 5.22; 95% CI, 2.62–10.41) than those older than 65 years (HR, 2.33; 95% CI, 1.90–2.88). The use of hypnotics with a longer half-life and at a higher prescribed dose predicted a greater increased risk of dementia.
Patients with long-term use of hypnotics have more than a 2-fold increased risk of dementia, especially those aged 50 to 65 years. In addition, the dosage and half-lives of the hypnotics used should be considered, because greater exposure to these medications leads to a higher risk of developing dementia.
Expression of the hominoid-specific TBC1D3 oncoprotein enhances growth factor receptor signaling and subsequently promotes cellular proliferation and survival. Here we report that TBC1D3 is degraded in response to growth factor signaling, suggesting that TBC1D3 expression is regulated by a growth factor-driven negative feedback loop. To gain a better understanding of how TBC1D3 is regulated, we studied the effects of growth factor receptor signaling on TBC1D3 post-translational processing and turnover. Using a yeast two-hybrid screen, we identified CUL7, the scaffolding subunit of the CUL7 E3 ligase complex, as a TBC1D3-interacting protein. We show that CUL7 E3 ligase ubiquitinates TBC1D3 in response to serum stimulation. Moreover, TBC1D3 recruits F-box 8 (Fbw8), the substrate recognition domain of CUL7 E3 ligase, in pull-down experiments and in an in vitro assay. Importantly, alkaline phosphatase treatment of TBC1D3 suppresses its ability to recruit Fbw8, indicating that TBC1D3 phosphorylation is critical for its ubiquitination and degradation. We conclude that serum- and growth factor-stimulated TBC1D3 ubiquitination and degradation are regulated by its interaction with CUL7-Fbw8.
ABCG2, also known as BCRP, is a half ATP-binding cassette (ABC) transporter that localizes to plasma membranes. Recently, a number of studies have investigated the relationship between the C421A polymorphism in ABCG2 and cancer risk in multiple populations and various types of cancers; however, this relationship remains unclear. Therefore, we performed a meta-analysis to further explore this association.
The meta-analysis incorporated 10 studies involving a total of 3593 cases and 5875 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the date extracted from the studies to evaluate the strength of association. We also analyzed the heterogeneity and sensitivity of each report and the publication bias of the studies.
Overall, our results showed that there appeared to be a significant association between the ABCG2 C421A polymorphism and decreased cancer susceptibility (heterozygote-AC versus CC: OR = 0.759, 95%CI = 0.620-0.930; dominant effects model-AA/AC versus CC: OR = 0.771, 95%CI = 0.634-0.938; additive effects model-A allele versus C allele: OR = 0.809, 95%CI = 0.687-0.952). Similarly, decreased cancer risk was also found after stratification of the SNP data by cancer type, ethnicity and source of controls in heterozygote model, dominant effects model and additive effects model.
We found that the ABCG2 C421A polymorphism is a protective factor for developing cancer. The same relationship was found when the studies were stratified by cancer type, ethnicity and source of controls.
To examine the change in use of “High Risk Medications for the Elderly,” as defined by the National Committee on Quality Assurance's Healthcare Effectiveness Data and Information Set (HEDIS) quality measure (HEDIS HRME), by older outpatient veterans over a three year time period. We also sought to identify risk factors for HEDIS HRME exposure overall, and among the most commonly used drug classes.
Longitudinal retrospective database analysis.
Outpatient clinics within the Department of Veterans Affairs (VA).
Veterans aged 65 by October 1, 2003 and who received VA care at least once each year until September 30, 2006.
Rates of use of HEDIS HRME overall and by specific drug classes each year FY04-06.
In our cohort of 1,567,467, high risk medication exposure was reduced from 13.1% to 12.3% between FY04-06 (p<0.01). High risk antihistamines (e.g., diphenhydramine), opioid analgesics (e.g., propoxyphene), skeletal muscle relaxants (e.g., cyclobenzaprine), psychotropics (e.g., long half-life benzodiazepines), endocrine (e.g., estrogen), and cardiac medications (e.g., short-acting nifedipine) had modest but statistically significant (p<0.01) reductions (range -3.8% to -16.0%); nitrofurantoin demonstrated a statistically significant increase (+36.5%; p<0.01). Overall HEDIS HRME exposure was more likely for men, Hispanics, those receiving more medications, psychiatric comorbidity, and those without prior geriatric care. Exposure was lower for individuals exempt from copayment. Similar associations were seen between ethnicity, polypharmacy, psychiatric comorbidity, access to care factors and use of individual HEDIS HRME classes.
HEDIS HRME drug exposure decreased slightly in an integrated health care system. Risk factors for exposure were not consistent across drug groups.Future studies should examine whether interventions to further reduce HEDIS HRME use results in an improvement in health outcomes.
Inappropriate prescribing; quality of care; aged; pharmacoepidemiology
Localized Ge nano-dot formation by laser treatment was investigated and discussed in terms of strain distribution. The advantage of this technique is patterning localization of nano-dots without selective epitaxial growth, reducing costs and improving throughput. Self-assembled Ge nano-dots produced by excimer laser annealing statistically distributed dot density and size dependent on laser energy. Improvement in the crystallization quality of the dots was also studied, and a strain analysis was undertaken.
Re-crystallization; Self-assembled; Excimer laser
1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), a commercial chemotherapeutic drug for treating malignant brain tumors, has poor thermal stability and a short half-life. Immobilization of BCNU on a nanocarrier might increase the thermal stability of BCNU and extend its half-life.
Nanosized graphene oxide (GO) could be modified by polyacrylic acid (PAA) to improve the aqueous solubility and increase the cell penetration efficacy of the nanocarrier. PAA–GO intended as a drug carrier for BCNU was prepared and characterized in this study. The size and thickness of PAA–GO was investigated by transmission electron microscopy and atomic force microscopy, and the presence of PAA functional groups was confirmed by electron spectroscopy for chemical analysis and thermogravimetric analysis. BCNU was conjugated to PAA–GO by covalent binding for specific killing of cancer cells, which could also enhance the thermal stability of the drug.
Single layer PAA–GO (about 1.9 nm) with a lateral width as small as 36 nm was successfully prepared. The optimum drug immobilization condition was by reacting 0.5 mg PAA–GO with 0.4 mg BCNU, and the drug-loading capacity and residual drug activity were 198 μg BCNU/mg PAA–GO and 70%, respectively. This nanocarrier significantly prolonged the half-life of bound BCNU from 19 to 43 hours compared with free drug and showed efficient intracellular uptake by GL261 cancer cells. The in vitro anticancer efficacy of PAA–GO–BCNU was demonstrated by a 30% increase in DNA interstrand cross-linking and a 77% decrease in the IC50 value toward GL261 compared with the same dosage of free drug.
Nanosized PAA–GO serves as an efficient BCNU nanocarrier by covalent binding. This nanocarrier will be a promising new vehicle for an advanced drug delivery system in cancer therapy.
graphene oxide; BCNU; glioma cells; drug delivery; thermal stability
Haemophilus parasuis (H. parasuis) is the etiological agent of Glässer's disease in pigs. Currently, the molecular basis of this infection is largely unknown. The innate immune response is the first line of defense against the infectious disease. Systematical analysis on host innate immune response to the infection is important for understanding the pathogenesis of the infectious microorganisms.
A total of 428 differentially expressed (DE) genes were identified in the porcine alveolar macrophages (PAMs) 6 days after H. parasuis infection. These genes were principally related to inflammatory response, immune response, microtubule polymerization, regulation of transcript and signal transduction. Through the pathway analysis, the significant pathways mainly concerned with cell adhesion molecules, cytokine-cytokine receptor interaction, complement and coagulation cascades, toll-like receptor signaling pathway, MAPK signaling pathway, suggesting that the host took different strategies to activate immune and inflammatory response upon H. parasuis infection. The global interactions network and two subnetworks of the proteins encoded by DE genes were analyzed by using STRING. Further immunostimulation analysis indicated that mRNA levels of S100 calcium-binding protein A4 (S100A4) and S100 calcium-binding protein A6 (S100A6) in porcine PK-15 cells increased within 48 h and were sustained after administration of lipopolysaccharide (LPS) and Poly (I:C) respectively. The s100a4 and s100a6 genes were found to be up-regulated significantly in lungs, spleen and lymph nodes in H. parasuis infected pigs. We firstly cloned and sequenced the porcine coronin1a gene. Phylogenetic analysis showed that poCORONIN 1A belonged to the group containing the Bos taurus sequence. Structural analysis indicated that the poCORONIN 1A contained putative domains of Trp-Asp (WD) repeats signature, Trp-Asp (WD) repeats profile and Trp-Asp (WD) repeats circular profile at the N-terminus.
Our present study is the first one focusing on the response of porcine alveolar macrophages to H. parasuis. Our data demonstrate a series of genes are activated upon H. parasuis infection. The observed gene expression profile could help screening the potential host agents for reducing the prevalence of H. parasuis and further understanding the molecular pathogenesis associated with H. parasuis infection in pigs.
Diabetes is a major cause of functional decline among older adults, but the role of glycemic control remains unclear. This article assesses whether better glycemic control is associated with better maintenance of lower-extremity function over time in older adults with diabetes.
RESEARCH DESIGN AND METHODS
Participants (n = 119) in the San Antonio Longitudinal Study of Aging, ages 71–85, who met American Diabetes Association diabetes criteria were followed over a 36-month period. Seven measures of A1C (HbA1c) were obtained at 6-month intervals; three measures of lower-extremity function were obtained at 18-month intervals using the Short Physical Performance Battery (SPPB). A two-step analytic approach was used, first, to identify distinct glycemic control classes using latent growth mixture modeling and, second, to examine trajectories of lower-extremity function based on these classes using path analysis.
Two glycemic control classes were identified: a poorer control class with higher means (all >7%) and higher within-subject variability in HbA1c and a better control class with lower means (all <7%) and lower within-subject variability. The short-term and long-term maintenance of lower-extremity function, assessed by the association between the first and second SPPB measures and the first and third SPPB measures, were both greater in the better control class than in the poorer control class.
Among older adults with diabetes, better glycemic control may improve both short-term and long-term maintenance of lower-extremity function.
Malignant glioma is a common and severe primary brain tumor with a high recurrence rate and an extremely high mortality rate within 2 years of diagnosis, even when surgical, radiological, and chemotherapeutic interventions are applied. Intravenously administered drugs have limited use because of their adverse systemic effects and poor blood–brain barrier penetration. Here, we combine 2 methods to increase drug delivery to brain tumors. Focused ultrasound transiently permeabilizes the blood–brain barrier, increasing passive diffusion. Subsequent application of an external magnetic field then actively enhances localization of a chemotherapeutic agent immobilized on a novel magnetic nanoparticle. Combining these techniques significantly improved the delivery of 1,3-bis(2-chloroethyl)-1-nitrosourea to rodent gliomas. Furthermore, the physicochemical properties of the nanoparticles allowed their delivery to be monitored by magnetic resonance imaging (MRI). The resulting suppression of tumor progression without damaging the normal regions of the brain was verified by MRI and histological examination. This noninvasive, reversible technique promises to provide a more effective and tolerable means of tumor treatment, with lower therapeutic doses and concurrent clinical monitoring.
BCNU; glioma; magnetic nanoparticle; MRI; ultrasound