Vegetarian diets have been shown to improve glucose metabolism and reduce risk for diabetes in Westerners but whether Chinese vegetarian diets have the same benefits is unknown.
We evaluated the association between diet and diabetes/impaired fasting glucose (IFG) among 4384 Taiwanese Buddhist volunteers and identified diabetes/IFG cases from a comprehensive review of medical history and fasting plasma glucose.
Vegetarians had higher intakes of carbohydrates, fiber, calcium, magnesium, total and non-heme iron, folate, vitamin A, and lower intakes of saturated fat, cholesterol, and vitamin B12. Besides avoiding meat and fish, vegetarians had higher intakes of soy products, vegetables, whole grains, but similar intakes of dairy and fruits, compared with omnivores. The crude prevalence of diabetes in vegetarians versus omnivores is 0.6% versus 2.3% in pre-menopausal women, 2.8% versus 10% in menopausal women, and 4.3% versus 8.1% in men. Polytomous logistic regression adjusting for age, body mass index, family history of diabetes, education, leisure time physical activity, smoking and alcohol, showed that this vegetarian diet was negatively associated with diabetes and IFG in men (OR for diabetes: 0.49, 95% CI: 0.28–0.89; OR for IFG: 0.66, 95% CI: 0.46–0.95); in pre-menopausal women (OR for diabetes: 0.26, 95% CI: 0.06–1.21; OR for IFG: 0.60, 95% CI: 0.35–1.04); and in menopausal women (OR for diabetes: 0.25, 95% CI: 0.15–0.42; OR for IFG: 0.73, 95% CI: 0.56–0.95).
We found a strong protective association between Taiwanese vegetarian diet and diabetes/IFG, after controlling for various potential confounders and risk factors.
Pulmonary involvement is a common feature of MPA. Although alveolar hemorrhage is the most common pulmonary manifestation of MPA, a few recent studies have described instances of MPA patients with pulmonary fibrosis. Pulmonary fibrosis was seen to predate, be concomitant with, or occur after the diagnosis of MPA. The goal of this study was to describe the clinical features and prognosis of microscopic polyangiitis (MPA) patients whose initial respiratory presentation was pulmonary fibrosis.
We conducted a retrospective analysis of 19 MPA patients who presented with pulmonary fibrosis at Peking Union Medical College Hospital between 1990 and 2012.
Of 67 total MPA cases, 19 patients presented with pulmonary fibrosis. There were 8 males and 11 females, with a median age of 63.6 years. Common clinical manifestations included fever (89.5%), cough (84.2%), dyspnea (78.9%) and velcro rales (84.2%). Eleven patients experienced weight loss, several had kidney involvement, and most had an increased erythrocyte sedimentation rate and C-reactive protein. All were positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA), with 6 patients being positive at the time of their initial diagnosis of pulmonary fibrosis. Every patient had typical features of usual interstitial pneumonia on High-resolution CT. All were treated with corticosteroids and cyclophosphamide, which lead to an improvement in twelve cases. One of the remaining patients progressed slowly, whereas six died.
Patients with MPA, who also presented with pulmonary fibrosis in our cohort, were more likely to be older, female, and have extrapulmonic involvement. Most patients had a delayed positive ANCA. Corticosteroids plus cyclophosphamide was the remission-induction treatment scheme for all cases. The current prognosis for MPA patients with pulmonary fibrosis appears to be poor, suggesting that they may be candidates for new therapies.
Pulmonary fibrosis; Systemic vasculitis; ANCA
The distribution of allergens may vary with different geographic areas, suggesting the importance of local epidemiological data to support evidence-based prevention and management of allergic diseases. We investigated the distribution of common allergens in allergic patients in Guangzhou, southern China.
7,047 patients with allergic symptoms were examined for serum sIgE to 15 common allergens in this region, based on the protocol of reversed enzyme allergosorbent test.
4,869 (69.09%) of the subjects tested positive for sIgE to at least one of the 15 common allergens. There was no statistical difference in the overall rate of positive sIgE detection between males (3128/4523, 69.16%) and females (1741/2524, 68.98%). Der pteronyssinus and Der farinae were the most common aeroallergens, while eggs and cow’s milk the most common food allergens, responsible for higher positive rates of sIgE responses. A good correlation in positive sIgE response was found between Der pteronyssinus and Der farinae. By age-group analysis, we noted several peaks of sensitization to certain allergens: Der pteronyssinus, Der farinae, and Blomiatropicalis at age between 9 and 12; Blattellagermanica and mosquito at age between 15 and 18, cow’s milk before age 3; eggs and flour at age between 3 and 6; crabs and shrimps at age between 12 and 15. Along with older age, there was an ascending tendency in the overall positive rate of sIgE response to house dust mites among subjects who tested positive for sIgE to eggs or cow’s milk.
Der pteronyssinus, Der farinae, cow’s milk, and eggs are major allergens in Guangzhou. Sensitization to eggs and cow’s milk is more common at younger age, and then gives place to the increasing prevalence of sensitization to Der pteronyssinus and Der farinae at older age. Such a sequence of events may be a result of allergy march. Knowledge on the prevalence of allergen sensitization in different age groups would help early diagnosis and intervention of allergic diseases in this large geographical region.
Allergy; Distribution; Prevalence; Specific immunoglobulin E
The objective of this retrospective study was to analyze the clinical characteristics and prognosis of clear cell adenocarcinoma (CCA) in the post-diethylstilbestrol (DES) era and to evaluate the feasibility of fertility-preserving treatment. The records of 32 patients with CCAs who were treated at Peking Union Medical College Hospital from August 1986 to June 2012 were retrospectively reviewed. Three of the patients had undergone fertility-preserving treatment. The incidence of CCA among cervical adenocarcinomas was 15.2%. The median age was 38 years: 11 patients (34.4%) were diagnosed before 30 years of age and two (6.3%) after 70 years of age. Ten patients (31.2%) were nulliparous. No patient had been exposed to DES. Twenty-nine patients (90.6%) presented with obvious symptoms, and the cervix appeared abnormal in 26 patients (81.3%). Cervical Papanicolaou (Pap) tests were abnormal in all four patients in whom they were performed (three had high-grade squamous intraepithelial lesions and one had atypical squamous cells of undetermined significance). The distribution by stage was 56.3% stage I, 34.4% stage II, 6.3% stage III, and 3.1% stage IV. Treatments mainly included surgery for patients with stage I to IIA CCA and radiochemotherapy for patients with advanced CCA. The overall 5-year progression-free survival was 72.2%. Patients with stage I to IIA CCA had better 5-year progression-free survival than did patients with stage IIB to IV CCA (81.5% versus 40.0%, P=0.003). The three patients who had undergone fertility-preserving treatment had no recurrences. CCA may also affect adolescents and children without prior DES exposure, who are often misdiagnosed as having functional uterine bleeding. Radiotherapy appears to be effective for local control but to have no effect on distant recurrences. In our study, the prognosis of patients with early-stage CCA, including those who had undergone fertility-preserving treatment, was not inferior to that of patients with other types of cervical adenocarcinoma.
clear cell carcinoma; cervix; diagnosis; prognosis; fertility-preserving
A detailed pharmacoeconomic analysis was conducted to estimate the incremental cost-effectiveness of bortezomib, melphalan, and prednisone versus thalidomide, melphalan, and prednisone versus lenalidomide, melphalan, and prednisone with lenalidomide maintenance as therapy for previously untreated transplant-ineligible multiple myeloma patients. Bortezomib, melphalan, and prednisone was found to be the cost-effective option in the U.S. setting.
The outlook for transplant-ineligible multiple myeloma patients has improved enormously over recent years with the incorporation of new agents into standard regimens. Novel regimens combine melphalan and prednisone (MP) with bortezomib (VMP), with thalidomide (MPT), and with lenalidomide with (MPR-R) and without (MPR) lenalidomide maintenance. The efficacy, safety, and cost-effectiveness of these regimens have not yet been compared; therefore, we conducted a pharmacoeconomic analysis using data from randomized controlled trials versus MP.
Using a Markov model developed from a U.S. payer's perspective, we compared VMP with MPT and MPR-R over a lifetime horizon. MPT and MPR-R were chosen because, like VMP, they are superior to MP in response and outcomes. Data from the Velcade as Initial Standard Therapy in Multiple Myeloma (VISTA; VMP), Intergroupe Francophone du Myelome (IFM) 99–06 (MPT), and MM-015 (MPR-R) trials were used. The IFM 99–06 study was selected because of the superior activity in this study compared with other MPT studies. Using patient-level (VMP) and published (MPT, MPR-R) data, we estimated the health-state transition and adverse event probabilities for each regimen, related costs, and state-specific utility estimates. Costs (in 2010 U.S. dollars) and health outcomes were discounted at 3%.
Discounted lifetime direct medical costs were lowest with VMP at $119,102. MPT cost $142,452 whereas MPR-R cost $248,358. Incremental cost-effectiveness ratio calculations projected that VMP would confer cost savings and better health outcomes relative to MPT and MPR-R. We conclude that VMP is highly likely to be cost-effective compared with MP, MPT, and MPR-R.
Bortezomib; Lenalidomide; Thalidomide; Multiple myeloma; Cost-effectiveness
This claims-based, retrospective analysis examines total health care costs and patient burden associated with bortezomib, thalidomide, and lenalidomide treatment versus other therapies for multiple myeloma. Total health care costs and patient out-of-pocket costs were found to be higher for thalidomide and lenalidomide than for bortezomib and other therapies.
Treatment of multiple myeloma has dramatically improved with the introduction of bortezomib (BOR), thalidomide (THAL), and lenalidomide (LEN). Studies assessing health care costs, particularly economic burden on patients, are limited. We conducted a claims-based, retrospective analysis of total health care costs as well as patient burden (patient out-of-pocket costs and number of ambulatory/hospital visits) associated with BOR/THAL/LEN treatment versus other therapies (OTHER).
Treatment episodes starting between January 1, 2005 and September 30, 2010 were identified from the claims database of a large U.S. health plan. Health care costs and utilization were measured during 1 year after initiation and analyzed per treatment episode. Multivariate analyses were used to adjust for patient characteristics, comorbidities, and line of treatment.
A total of 4,836 treatment episodes were identified. Mean adjusted total costs were similar between BOR ($112,889) and OTHER ($111,820), but higher with THAL ($129,412) and LEN ($158,428). Mean adjusted patient out-of-pocket costs were also similar for BOR ($3,846) and OTHER ($3,900) but remained higher with THAL ($4,666) and LEN ($4,483). Mean adjusted rates of ambulatory visits were similar across therapies (BOR: 69.67; THAL: 66.31; LEN: 65.60; OTHER: 69.42).
Adjusted analyses of real-world claims data show that total health care costs, as well as patient out-of-pocket costs, are higher with THAL/LEN treatment episodes than with BOR/OTHER therapies. Additionally, similar rates of ambulatory visits suggest that any perceived advantage in patient convenience of the orally administered drugs THAL/LEN is not supported by these data.
Multiple myeloma; Antineoplastic agents; Cost analysis; Medicare; Cost of illness
Malnutrition is associated with increased risk of mortality in hemodialysis patients. And insufficient dietary intake is the common cause for malnutrition. So, in order to survey the dietary intake of hemodialysis patients and study the relationship between the dietary feature and nutritional status, a cross-sectional study was performed. 75 hemodialysis patients from South China participated in the dietary intake survey and nutrition assessment. A three-day diet diary record was used to estimate the major dietary macronutrients. Nutritional status was assessed by malnutrition-inflammation score (MIS) in addition to several related anthropometric measurements. Serum albumin, transferrin, and high-sensitivity C-reactive protein (CRP) were measured. Receiver operating characteristic (ROC) curve analysis was used to quantify the assessing value of independent parameters for nutritional status. The results showed that 48% patients were malnourished according to the MIS. The malnourished patients had a lower body mass index (BMI), fat mass (FM), albumin and a higher level of CRP, compared with normal nourished patients (P < 0.05). However, no significant differences of macronutrients (calories, protein, fat, carbohydrates, etc) were found between the two nutrition groups (P > 0.05). The multivariate regression analysis showed that the major macronutrients had no significant association with MIS (P > 0.05). In conclusion, malnutrition is very common in South China hemodialysis population and these data indicated that inflammation but not dietary macronutrients insufficiency might be the candidate cause for malnutrition in hemodialysis population.
To improve the operation current lowing of the Zr:SiO2 RRAM devices, a space electric field concentrated effect established by the porous SiO2 buffer layer was investigated and found in this study. The resistive switching properties of the low-resistance state (LRS) and high-resistance state (HRS) in resistive random access memory (RRAM) devices for the single-layer Zr:SiO2 and bilayer Zr:SiO2/porous SiO2 thin films were analyzed and discussed. In addition, the original space charge limited current (SCLC) conduction mechanism in LRS and HRS of the RRAM devices using bilayer Zr:SiO2/porous SiO2 thin films was found. Finally, a space electric field concentrated effect in the bilayer Zr:SiO2/porous SiO2 RRAM devices was also explained and verified by the COMSOL Multiphysics simulation model.
RRAM; Porous SiO2; Space charge limited current; Zr
Selenium (Se) is a necessary element for the biosynthesis of thyroid hormones. We investigated the relationship between selenium status, thyroid volume, and goiter in a cross-sectional study in an iodine-sufficient area.
We selected residents of Chengdu (over 18 years old and living in the city for more than 5 years) using a stratified cluster sampling technique. Fifteen hundred subjects were selected for the study, which involved a questionnaire survey, physical examination, thyroid ultrasound, serum thyroid function test, and determination of serum selenium level. Thyroid volume was calculated from the thickness, width, length, and a corrective factor for each lobe. Ultimately, 1,205 subjects completed the investigation and were included in our study. Additionally, 80 school-age children were selected to provide urine samples for urinary iodine analysis. We analyzed the data using appropriate nonparametric and parametric statistical tests.
The median urinary iodine value was 184 μg/L in school-age children, indicating iodine sufficiency. The median serum selenium level of the 1,205 subjects was 52.63 (interquartile range [IQR] : 40.40-67.00) μg/L. The median thyroid volume was 9.93 (IQR: 7.71-12.57) mL; both log-transformed serum selenium and log-transformed thyroid volume were Gaussian distributions (P = .638 and P = .046, respectively). The prevalences of goiter and thyroid nodules were 8.8% and 18.6%. The prevalences of positive thyroid autoantibodies, thyroperoxidase autoantibodies and thyroglobulin autoantibodies were 16.7%, 12.0%, and 11.1%, respectively. In the general linear regression model, there were positive associations between serum selenium and age, and body mass index. We found no association between serum selenium and thyroid-stimulating hormone. In simple linear regression analyses, we found no association between thyroid volume and serum selenium. There were no significant differences in serum selenium between persons with or without goiter. Serum selenium was not a risk factor for goiter.
In our study population, serum selenium was neither associated with thyroid volume nor with goiter in an iodine-sufficient area. More studies should be conducted by following non-goitrous persons over time and monitoring their selenium status.
Iodine; Selenium; Thyroid hormones; Thyroid volume; Thyroid goiter; Thyroid disease; Cross-sectional study
Human immunodeficiency virus type 1 (HIV-1) circulating recombinant form (CRF) 07_BC has caused serious HIV-1 epidemics among injecting drug users (IDUs) in East Asia. Little is known about the characteristics of the virus and its impact on disease progression among the infected individuals. In this study, we compared immunological progression between 423 IDUs infected with CRF07_BC and 194 men who have sex with men (MSM) with primary subtype B infection, and a representative full-length CRF07_BC molecular clone, pCRF07_BC, was constructed to characterize the virus. We found that IDUs infected with CRF07_BC had significantly slower immunological progression in the Cox proportional hazards model (hazard ratio: 0.30; 95% confidence interval: 0.13–0.69; P=0.004). The constructed recombinant CRF07_BC viruses had a reduced processing of the Gag/Gag-Pol polyproteins, a decreased incorporation of Vpr in the virus particle, tethering of virus particles on the plasma membrane and decreased virus growth kinetics. These phenotypes are related to the unique 7-amino acid deletion in the p6 of CRF07_BC, since complementation of the 7-amino acid in pCRF07_BC could improve the defective phenotypes. In summary, compared with MSM infected with HIV-1 subtype B, IDUs infected with CRF07_BC had slower immunological progression, which is likely correlated with interference of virus particle maturation by the 7-amino acid deletion in p6.
disease progression; growth kinetics; HIV subtype; injecting drug use; men who have sex with men; primary HIV infection
The present study was undertaken to evaluate the anti-depressive activity of turmerone after one-week administration by using a mouse forced swimming test (FST) and tail suspension test (TST).
Animals were divided into four groups (n = 10 /group): control (0.9% saline), the three doses of turmerone (1.25, 2.5, 5.0 mg/kg) for one-week treatment. To assess the effect of turmerone on locomotor activity, mice were evaluated in the open-field paradigm. Forced swimming test (FST) and Tail suspension test (TST) were used to take as a measure of antidepressant activity. The probable mechanisms of action of the anti-depressive effect of turmerone was also investigated by measuring the activity of monoamine oxidase-A and corticosterone levels in the blood and the levels of monoamines in the cortex, striatum, hippocampus and hypothalamus of the mice.
Turmerone (2.5, 5.0 mg/kg, p.o.) significantly reduced the immobility time of mice in both the FST and TST, but it did not significantly affect the ambulatory and total movements of mice. However, hyperactivity might explain the results. In addition, turmerone decreased the corticosterone level in the blood while it increased the levels of 5-HT in cortex, striatum, hippocampus, and hypothalamus, the level of NE in striatum and hippocampus, the levels of MHPG and DOPAC in hypothalamus, the level of 5-HIAA in striatum, and the level of DA in striatum, hippocampus, and hypothalamus. Turmerone (2.5, 5.0 mg/kg) decreased the activity of MAO-A in the frontal cortex and hippocampus of mouse brain.
After one-week administration, turmerone produced antidepressant-like effects. The mechanisms of action of anti-depressive effect of turmerone seemed to involve an increase of the monoamines level decreasing the MAO-A activity and the stress of mice.
Tumerone; Forced swimming test; Tail suspension test; Antidepressant; Monoamines
Sarcoidosis is a systemic granulomatous disease, which is thought to result from an aberrant immune response. CD4+ T lymphocytes play an important role in the development of granulomas. Previously, the immunopathogenesis of sarcoidosis was focused on Th1/Th2 disturbances. The aim of this study was to evaluate the balance between newer CD4+ T lymphocytes, i.e., Treg and Th17 cells. In our studies, a decrease in Treg cells and an increase in Th17 cells were observed in the peripheral blood and BALF of sarcoidosis patients. A significant increase in the Th17/Treg cell ratio was observed in sarcoidosis patients. After treatment with prednisone, the expression of Foxp3 mRNA was elevated in the peripheral blood, and expression of (ROR)γt mRNA showed a downward trend. These findings suggest that sarcoidosis is associated with an imbalance between Th17 and Treg cells in peripheral blood and BALF. Therefore, targeting the cytokines that affect the Th17/Treg ratio could provide a new promising therapy for pulmonary sarcoidosis.
granulomatous disease; sarcoidosis; regulatory T cells; Th17 cells; corticosteroids
Systemic chemotherapy is the basic palliative treatment for metastatic nasopharyngeal carcinoma (NPC); however, it is not known whether locoregional radiotherapy targeting the primary tumor and regional lymph nodes affects the survival of patients with metastatic NPC. Therefore, we aimed to retrospectively evaluate the benefits of locoregional radiotherapy. A total of 408 patients with metastatic NPC were included in this study. The mortality risks of the patients undergoing supportive treatment and those undergoing chemotherapy were compared with that of patients undergoing locoregional radiotherapy delivered alone or in combination with chemotherapy. Univariate and multivariate analyses were conducted. The contributions of independent factors were assessed after adjustment for covariates with significant prognostic associations (P < 0.05). Both locoregional radiotherapy and systemic chemotherapy were identified as significant independent prognostic factors of overall survival (OS). The mortality risk was similar in the group undergoing locoregional radiotherapy alone and the group undergoing systemic chemotherapy alone [multi-adjusted hazard ratio (HR) = 0.9, P = 0.529]; this risk was 60% lower than that of the group undergoing supportive treatment (HR = 0.4, P = 0.004) and 130% higher than that of the group undergoing both systemic chemotherapy and locoregional radiotherapy (HR = 2.3, P < 0.001). In conclusion, locoregional radiotherapy, particularly when combined with systemic chemotherapy, is associated with improved survival of patients with metastatic NPC.
Nasopharyngeal carcinoma; distant metastases; overall survival; radiotherapy; systemic chemotherapy
Angiostrongyliasis is an emerging communicable disease. Several different hosts are required to complete the life cycle of Angiostrongylus cantonensis. However, we lack a complete understanding of variability of proteins across different developmental stages and their contribution to parasite survival and progression. In this study, we extracted soluble proteins from various stages of the A. cantonensis life cycle [female adults, male adults, the fifth-stage female larvae (FL5), the fifth-stage male larvae (ML5) and third-stage larvae (L3)], separated those proteins using two-dimensional difference gel electrophoresis (2D-DIGE) at pH 4–7, and analyzed the gel images using DeCyder 7.0 software. This proteomic analysis produced a total of 183 different dominant protein spots. Thirty-seven protein spots were found to have high confidence scores (>95%) by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS). Comparative proteomic analyses revealed that 29 spots represented cytoskeleton-associated proteins and functional proteins. Eight spots were unnamed proteins. Twelve protein spots that were matched to the EST of different-stage larvae of A. cantonensis were identified. Two genes and the internal control 18s were chosen for quantitative real-time PCR (qPCR) and the qPCR results were consistent with those of the DIGE studies. These findings will provide a new basis for understanding the characteristics of growth and development of A. cantonensis and the host–parasite relationship. They may also assist searches for candidate proteins suitable for use in diagnostic assays and as drug targets for the control of eosinophilic meningitis caused by A. cantonensis.
High-content screening (HCS) has become a powerful tool for drug discovery. However, the discovery of drugs targeting neurons is still hampered by the inability to accurately identify and quantify the phenotypic changes of multiple neurons in a single image (named multi-neuron image) of a high-content screen. Therefore, it is desirable to develop an automated image analysis method for analyzing multi-neuron images.
We propose an automated analysis method with novel descriptors of neuromorphology features for analyzing HCS-based multi-neuron images, called HCS-neurons. To observe multiple phenotypic changes of neurons, we propose two kinds of descriptors which are neuron feature descriptor (NFD) of 13 neuromorphology features, e.g., neurite length, and generic feature descriptors (GFDs), e.g., Haralick texture. HCS-neurons can 1) automatically extract all quantitative phenotype features in both NFD and GFDs, 2) identify statistically significant phenotypic changes upon drug treatments using ANOVA and regression analysis, and 3) generate an accurate classifier to group neurons treated by different drug concentrations using support vector machine and an intelligent feature selection method. To evaluate HCS-neurons, we treated P19 neurons with nocodazole (a microtubule depolymerizing drug which has been shown to impair neurite development) at six concentrations ranging from 0 to 1000 ng/mL. The experimental results show that all the 13 features of NFD have statistically significant difference with respect to changes in various levels of nocodazole drug concentrations (NDC) and the phenotypic changes of neurites were consistent to the known effect of nocodazole in promoting neurite retraction. Three identified features, total neurite length, average neurite length, and average neurite area were able to achieve an independent test accuracy of 90.28% for the six-dosage classification problem. This NFD module and neuron image datasets are provided as a freely downloadable MatLab project at http://iclab.life.nctu.edu.tw/HCS-Neurons.
Few automatic methods focus on analyzing multi-neuron images collected from HCS used in drug discovery. We provided an automatic HCS-based method for generating accurate classifiers to classify neurons based on their phenotypic changes upon drug treatments. The proposed HCS-neurons method is helpful in identifying and classifying chemical or biological molecules that alter the morphology of a group of neurons in HCS.
We aimed to evaluate the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine–cystatin C equation in a cohort of elderly Chinese participants.
Materials and methods
Glomerular filtration rate (GFR) was measured in 431 elderly Chinese participants by the technetium-99m diethylene-triamine-penta-acetic acid (99mTc-DTPA) renal dynamic imaging method, and was calibrated equally to the dual plasma sample 99mTc-DTPA-GFR. Performance of the CKD-EPI creatinine–cystatin C equation was compared with the Cockcroft–Gault equation, the re-expressed 4-variable Modification of Diet in Renal Disease (MDRD) equation, and the CKD-EPI creatinine equation.
Although the bias of the CKD-EPI creatinine–cystatin C equation was greater than with the other equations (median difference, 5.7 mL/minute/1.73 m2 versus a range from 0.4–2.5 mL/minute/1.73 m2; P<0.001 for all), the precision was improved with the CKD-EPI creatinine–cystatin C equation (interquartile range for the difference, 19.5 mL/minute/1.73 m2 versus a range from 23.0–23.6 mL/minute/1.73 m2; P<0.001 for all comparisons), leading to slight improvement in accuracy (median absolute difference, 10.5 mL/minute/1.73 m2 versus 12.2 and 11.4 mL/minute/1.73 m2 for the Cockcroft–Gault equation and the re-expressed 4-variable MDRD equation, P=0.04 for both; 11.6 mL/minute/1.73 m2 for the CKD-EPI creatinine equation, P=0.11), as the optimal scores of performance (6.0 versus a range from 1.0–2.0 for the other equations). Higher GFR category and diabetes were independent factors that negatively correlated with the accuracy of the CKD-EPI creatinine–cystatin C equation (β=−0.184 and −0.113, P<0.001 and P=0.02, respectively).
Compared with the creatinine-based equations, the CKD-EPI creatinine–cystatin C equation is more suitable for the elderly Chinese population. However, the cost-effectiveness of the CKD-EPI creatinine–cystatin C equation for clinical use should be considered.
elderly; equation; glomerular filtration rate; serum creatinine; cystatin C
(S)-2-Hydroxypropylphosphonic acid epoxidase (HppE) is an unusual mononuclear iron enzyme that catalyzes the oxidative epoxidation of (S)-2-hydroxypropylphosphonic acid ((S)-HPP) in the biosynthesis of the antibiotic fosfomycin. HppE also recognizes (R)-2-hydroxypropylphosphonic acid ((R)-HPP) as a substrate and converts it to 2-oxo-propylphosphonic acid. To probe the mechanisms of these HppE-catalyzed oxidations, cyclopropyl- and methylenecyclopropyl-containing compounds were synthesized and studied as radical clock substrate analogues. Enzymatic assays indicated that the (S)- and (R)-isomers of the cyclopropyl-containing analogues were efficiently converted to epoxide and ketone products by HppE, respectively. In contrast, the ultrafast methylenecyclopropyl-containing probe inactivated HppE, consistent with a rapid radical-triggered ring-opening process that leads to enzyme inactivation. Taken together, these findings provide, for the first time, experimental evidence for the involvement of a C2-centered radical intermediate with a lifetime on the order of nanoseconds in the HppE-catalyzed oxidation of (R)-HPP.
epoxidase; fosfomycin biosynthesis; catalytic mechanism; cyclopropylcarbinyl radical probes
Heme oxygenase-1 (HO-1) has been implicated in cardiac dysfunction, oxidative stress, inflammation, apoptosis and autophagy associated with heart failure, and atherosclerosis, in addition to its recognized role in metabolic syndrome and diabetes. Numerous studies have presented contradictory findings about the role of HO-1 in diabetic cardiomyopathy (DCM). In this study, we explored the role of HO-1 in myocardial dysfunction, myofibril structure, oxidative stress, inflammation, apoptosis and autophagy using a streptozotocin (STZ)-induced diabetes model in mice systemically overexpressing HO-1 (Tg-HO-1) or mutant HO-1 (Tg-mutHO-1). The diabetic mouse model was induced by multiple peritoneal injections of STZ. Two months after injection, left ventricular (LV) function was measured by echocardiography. In addition, molecular biomarkers related to oxidative stress, inflammation, apoptosis and autophagy were evaluated using classical molecular biological/biochemical techniques. Mice with DCM exhibited severe LV dysfunction, myofibril structure disarray, aberrant cardiac oxidative stress, inflammation, apoptosis, autophagy and increased levels of HO-1. In addition, we determined that systemic overexpression of HO-1 ameliorated left ventricular dysfunction, myofibril structure disarray, oxidative stress, inflammation, apoptosis and autophagy in DCM mice. Furthermore, serine/threonine-specific protein kinase (Akt) and AMP-activated protein kinase (AMPK) phosphorylation is normally inhibited in DCM, but overexpression of the HO-1 gene restored the phosphorylation of these kinases to normal levels. In contrast, the functions of HO-1 in DCM were significantly reversed by overexpression of mutant HO-1. This study underlines the unique roles of HO-1, including the inhibition of oxidative stress, inflammation and apoptosis and the enhancement of autophagy, in the pathogenesis of DCM.
Existing methods for predicting protein crystallization obtain high accuracy using various types of complemented features and complex ensemble classifiers, such as support vector machine (SVM) and Random Forest classifiers. It is desirable to develop a simple and easily interpretable prediction method with informative sequence features to provide insights into protein crystallization. This study proposes an ensemble method, SCMCRYS, to predict protein crystallization, for which each classifier is built by using a scoring card method (SCM) with estimating propensity scores of p-collocated amino acid (AA) pairs (p = 0 for a dipeptide). The SCM classifier determines the crystallization of a sequence according to a weighted-sum score. The weights are the composition of the p-collocated AA pairs, and the propensity scores of these AA pairs are estimated using a statistic with optimization approach. SCMCRYS predicts the crystallization using a simple voting method from a number of SCM classifiers. The experimental results show that the single SCM classifier utilizing dipeptide composition with accuracy of 73.90% is comparable to the best previously-developed SVM-based classifier, SVM_POLY (74.6%), and our proposed SVM-based classifier utilizing the same dipeptide composition (77.55%). The SCMCRYS method with accuracy of 76.1% is comparable to the state-of-the-art ensemble methods PPCpred (76.8%) and RFCRYS (80.0%), which used the SVM and Random Forest classifiers, respectively. This study also investigates mutagenesis analysis based on SCM and the result reveals the hypothesis that the mutagenesis of surface residues Ala and Cys has large and small probabilities of enhancing protein crystallizability considering the estimated scores of crystallizability and solubility, melting point, molecular weight and conformational entropy of amino acids in a generalized condition. The propensity scores of amino acids and dipeptides for estimating the protein crystallizability can aid biologists in designing mutation of surface residues to enhance protein crystallizability. The source code of SCMCRYS is available at http://iclab.life.nctu.edu.tw/SCMCRYS/.
Coral harbor diverse and specific bacteria play significant roles in coral holobiont function. Bacteria associated with three of the common and phylogenetically divergent reef-building corals in the South China Sea, Porites lutea, Galaxea fascicularis and Acropora millepora, were investigated using 454 barcoded-pyrosequencing. Three colonies of each species were sampled, and 16S rRNA gene libraries were constructed individually. Analysis of pyrosequencing libraries showed that bacterial communities associated with the three coral species were more diverse than previous estimates based on corals from the Caribbean Sea, Indo-Pacific reefs and the Red Sea. Three candidate phyla, including BRC1, OD1 and SR1, were found for the first time in corals. Bacterial communities were separated into three groups: P. lutea and G. fascicular, A. millepora and seawater. P. lutea and G. fascicular displayed more similar bacterial communities, and bacterial communities associated with A. millepora differed from the other two coral species. The three coral species shared only 22 OTUs, which were distributed in Alphaproteobacteria, Deltaproteobacteria, Gammaproteobacteria, Chloroflexi, Actinobacteria, Acidobacteria and an unclassified bacterial group. The composition of bacterial communities within each colony of each coral species also showed variation. The relatively small common and large specific bacterial communities in these corals implies that bacterial associations may be structured by multiple factors at different scales and that corals may associate with microbes in terms of similar function, rather than identical species.
cyclin D3 (CCND3) is one of the three D-type cyclins that regulate the G1/S phase transition of the cell cycle. Expression of CCND3 is observed in nearly all proliferating cells; however, the presence of high levels of CCND3 has been linked to a poor prognosis for several types of cancer. Therefore, further mechanistic studies on the regulation of CCND3 expression are urgently needed to provide therapeutic implications. In this study, we report that a conserved RNA G-quadruplex-forming sequence (hereafter CRQ), located in the 5′ UTR of mammalian CCND3 mRNA, is able to fold into an extremely stable, intramolecular, parallel G-quadruplex in vitro. The CRQ G-quadruplex dramatically reduces the activity of a reporter gene in human cell lines, but it has little impact on its mRNA level, indicating a translational repression. Moreover, the CRQ sequence in its natural context inhibits translation of CCND3. Disruption of the G-quadruplex structure by G/U-mutation or deletion results in an elevated expression of CCND3 and an increased phosphorylation of Rb, a downstream target of CCND3, which promotes progression of cells through the G1 phase. Our results add to the growing understanding of the regulation of CCND3 expression and provide a potential therapeutic target for cancer treatment.
CCND3; RNA; cell cycle; quadruplex; translation
Profound alterations in immune responses associated with uremia and exacerbated by dialysis increase the risk of active tuberculosis (TB). Evidence of the long-term risk and outcome of active TB after acute kidney injury (AKI) is limited.
This population-based-cohort study used claim records retrieved from the Taiwan National Health Insurance database. We retrieved records of all hospitalized patients, more than 18 years, who underwent dialysis for acute kidney injury (AKI) during 1999–2008 and validated using the NSARF data. Time-dependent Cox proportional hazards model to adjust for the ongoing effect of end-stage renal disease (ESRD) was conducted to predict long-term de novo active TB after discharge from index hospitalization.
Out of 2,909 AKI dialysis patients surviving 90 days after index discharge, 686 did not require dialysis after hospital discharge. The control group included 11,636 hospital patients without AKI, dialysis, or history of TB. The relative risk of active TB in AKI dialysis patients, relative to the general population, after a mean follow-up period of 3.6 years was 7.71. Patients who did (hazard ratio [HR], 3.84; p<0.001) and did not (HR, 6.39; p<0.001) recover from AKI requiring dialysis had significantly higher incidence of TB than patients without AKI. The external validated data also showed nonrecovery subgroup (HR = 4.37; p = 0.049) had high risk of developing active TB compared with non-AKI. Additionally, active TB was associated with long-term all-cause mortality after AKI requiring dialysis (HR, 1.34; p = 0.032).
AKI requiring dialysis seems to independently increase the long-term risk of active TB, even among those who weaned from dialysis at discharge. These results raise concerns that the increasing global burden of AKI will in turn increase the incidence of active TB.
The placental hormone leptin has important functions in fetal and neonatal growth, and prevents depressed respiration in leptin-deficient mice. The effect of leptin on respiratory distress suffered by low birth weight and premature infants has been studied. However, it is unclear how leptin enhances lung maturity in the fetus and ameliorates neonatal respiratory distress. In the present study, we found that antenatal treatment with leptin for 2 d significantly enhanced the relative alveolus area and improved the maturity of fetal lungs in a rat model of fetal growth restriction (FGR). Mean birth weight and lung wet weight were higher in the leptin-treated group than in the PBS-treated group, indicating promotion of fetal growth. Leptin upregulated the intracellular expression and extracellular secretion of surfactant protein (SP) A in type-II alveolar epithelial cells (AECs) in vivo and in vitro. Dual positive effects of leptin were found on protein expression and transcriptional activity of thyroid transcription factor-1 (TTF-1), a nuclear transcription essential for branching morphogenesis of the lung and expression of SP-A in type-II AECs. Knockdown of TTF-1 by RNA interference indicated that TTF-1 may play a vital role in leptin-induced SP-A expression. These results suggest that leptin may have great therapeutic potential for the treatment of FGR, and leptin-mediated SP-A induction and lung maturity of the fetus are TTF-1 dependent.
Magnetic nanoparticles heated by an alternating magnetic field could be used to treat cancers, either alone or in combination with radiotherapy or chemotherapy. However, direct intratumoral injections suffer from tumor incongruence and invasiveness, typically leaving undertreated regions, which lead to cancer regrowth. Intravenous injection more faithfully loads tumors, but, so far, it has been difficult achieving the necessary concentration in tumors before systemic toxicity occurs. Here, we describe use of a magnetic nanoparticle that, with a well-tolerated intravenous dose, achieved a tumor concentration of 1.9 mg Fe/g tumor in a subcutaneous squamous cell carcinoma mouse model, with a tumor to non-tumor ratio > 16. With an applied field of 38 kA/m at 980 kHz, tumors could be heated to 60°C in 2 minutes, durably ablating them with millimeter (mm) precision, leaving surrounding tissue intact.
magnetic nanoparticles; hyperthermia; cancer; alternating magnetic field; intravenous delivery
Liver cirrhosis may lead to portal-systemic collateral formation and bleeding. The hemostatic effect is influenced by the response of collateral vessels to vasoconstrictors. Diabetes and glucose also influence vasoresponsiveness, but their net effect on collaterals remains unexplored. This study investigated the impact of diabetes or glucose application on portal-systemic collateral vasoresponsiveness to arginine vasopressin (AVP) in cirrhosis. Spraque-Dawley rats with bile duct ligation (BDL)-induced cirrhosis received vehicle (citrate buffer) or streptozotocin (diabetic, BDL/STZ). The in situ collateral perfusion was done after hemodynamic measurements: Both were perfused with Krebs solution, D-glucose, or D-glucose and NaF, with additional OPC-31260 for the BDL/STZ group. Splenorenal shunt vasopressin receptors and Gα proteins mRNA expressions were evaluated. The survival rate of cirrhotic rats was decreased by STZ injection. The collateral perfusion pressure changes to AVP were lower in STZ-injected groups, which were reversed by OPC-31260 (a V2R antagonist) and overcome by NaF (a G protein activator). The splenorenal shunt V2R mRNA expression was increased while Gα proteins mRNA expressions were decreased in BDL/STZ rats compared to BDL rats. The Gαq and Gα11 mRNA expressions also correlated with the maximal perfusion pressure changes to AVP. Diabetes diminished the portal-systemic collateral vascular response to AVP in rats with BDL-induced cirrhosis, probably via V2 receptor up-regulation and Gα proteins down-regulation.