Melanocortin receptor accessory proteins (MRAPs) modulate signaling of melanocortin receptors in vitro. To investigate the physiological role of brain-expressed Melanocortin 2 Receptor Accessory Protein 2 (MRAP2), we characterized mice with whole body and brain-specific targeted deletion of Mrap2, both of which develop severe obesity at a young age. Mrap2 interacts directly with Melanocortin 4 Receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second messenger cyclic AMP, suggesting that alterations in Mc4r signaling may be one mechanism underlying the association between Mrap2 disruption and obesity. In a study of humans with severe, early-onset obesity, we found four rare, potentially pathogenic genetic variants in MRAP2, suggesting that the gene may also contribute to body weight regulation in humans.
Inorganic arsenic is a worldwide metalloid pollutant in environment. Although extensive studies on arsenic-induced toxicity have been conducted using in vivo and in vitro models, the exact molecular mechanism of arsenate toxicity remains elusive. Here, the RNA-SAGE (serial analysis of gene expression) sequencing technology was used to analyse hepatic response to arsenic exposure at the transcriptome level. Based on more than 12 million SAGE tags mapped to zebrafish genes, 1,444 differentially expressed genes (750 up-regulated and 694 down-regulated) were identified from a relatively abundant transcripts (>10 TPM [transcripts per million]) based on minimal two-fold change. By gene ontology analyses, these differentially expressed genes were significantly enriched in several major biological processes including oxidation reduction, translation, iron ion transport, cell redox, homeostasis, etc. Accordingly, the main pathways disturbed include metabolic pathways, proteasome, oxidative phosphorylation, cancer, etc. Ingenity Pathway Analysis further revealed a network with four important upstream factors or hub genes, including Jun, Kras, APoE and Nr2f2. The network indicated apparent molecular events involved in oxidative stress, carcinogenesis, and metabolism. In order to identify potential biomarker genes for arsenic exposure, 27 out of 29 up-regulated transcripts were validated by RT-qPCR analysis in pooled RNA samples. Among these, 14 transcripts were further confirmed for up-regulation by a lower dosage of arsenic in majority of individual zebrafish. Finally, at least four of these genes, frh3 (ferrintin H3), mgst1 (microsomal glutathione S-transferase-like), cmbl (carboxymethylenebutenolidase homolog) and slc40a1 (solute carrier family 40 [iron-regulated transporter], member 1) could be confirmed in individual medaka fish similarly treated by arsenic; thus, these four genes might be robust arsenic biomarkers across species. Thus, our work represents the first comprehensive investigation of molecular mechanism of asenic toxicity and genome-wide search for potential biomarkers for arsenic exposure.
The present study examined the downregulation of survivin expression by hypoxia-inducible factor-1α (HIF-1α) miRNA and its effect in the inhibition of A549 cell growth in vitro and in vivo. Survivin expression, apoptosis, proliferation and migration under normoxic and hypoxic conditions were assessed by standard methods. Cotransfection and chromatin immunoprecipitation were used to observe the effects of HIF-1α on survivin transcription. HIF-1α knockdown in A549 cells were injected into nude mice to examine survivin expression and suppression of tumorigenicity. Transfection of A549 cells with HIF-1α miRNA led to decreased expression of HIF-1α and survivin mRNA and protein. Survivin overexpression is mediated by HIF-1α by direct binding to a putative binding site in the survivin core promoter. HIF-1α-miRNA induced apoptosis and inhibited proliferation of A549 cells under hypoxic, but not normoxic, conditions, whereas transfection by survivin expression vectors partly rescued the apoptotic phenotype and revived cell proliferation under hypoxic conditions. However, cell migration was substantially suppressed by HIF-1α silencing under normoxic and hypoxic conditions. After A549 cells were xenografted in nude mice, survivin expression in mice treated with HIF-1α miRNA was downregulated, and tumor growth was significantly inhibited. Silenced HIF-1α gene expression induced apoptosis and suppressed growth of A549 cells by downregulating survivin expression in vitro and in vivo. Our results also provide a basis to target the HIF-1α pathway in lung cancer therapy.
Hypoxia-inducible factor-1α; miRNA; survivin; lung cancer
Although a great deal of progress has been made toward understanding the role of abscisic acid (ABA) in fruit ripening, many components in the ABA signalling pathway remain to be elucidated. Here, a strawberry gene homologous to the Arabidopsis gene ABI1, named FaABI1, was isolated and characterized. The 1641bp cDNA includes an intact open reading frame that encodes a deduced protein of 546 amino acids, in which putative conserved domains were determined by homology analysis. Transcriptional analysis showed that the levels of FaABI1 mRNA expression declined rapidly during strawberry fruit development as evidenced by real-time PCR, semi-quantitative reverse transcription–PCR, and northern blotting analyses, suggesting that the Ser/Thr protein phosphatase PP2C1 encoded by FaABI1 may be involved in fruit ripening as a negative regulator. The results of Tobacco rattle virus-induced gene silencing and PBI121 vector-mediated overexpression suggested that the down- and up-regulation of FaABI1 mRNA expression levels in degreening strawberry fruit could promote and inhibit ripening, respectively. Furthermore, alteration of FaABI1 expression could differentially regulate the transcripts of a set of both ABA-responsive and ripening-related genes, including ABI3, ABI4, ABI5, SnRK2, ABRE1, CHS, PG1, PL, CHI, F3H, DFR, ANS, and UFGT. Taken together, the data provide new evidence for an important role for ABA in regulating strawberry fruit ripening in the processes of which the type 2C protein phosphatase ABI1 serves as a negative regulator. Finally, a possible core mechanism underlying ABA perception and signalling transduction in strawberry fruit ripening is discussed.
Abscisic acid (ABA); overexpression; strawberry fruit ripening; Tobacco rattle virus; type 2C protein phosphatase ABI1; virus-induced gene silencing (VIGS).
Thinner retinal nerve fiber layer (RNFL) has been reported in Alzheimer’s disease (AD) patient. However, whether changes in RNFL thickness can predict the cognitive deterioration remains unknown. We therefore set out a prospective clinical investigation to determine the potential association between the attenuation of RNFL thickness and the deterioration of cognitive function over a period of 25 months. We assessed cognitive function using the Repeatable Battery for the Assessment of Neuropsychological Status and measured RNFL thickness employing optical coherence tomography in 78 participants (mean age 72.31 ± 3.98 years, 52% men). The participants were categorized as stable participants whose cognitive status remained no change (N = 60) and converted participants whose cognitive status deteriorated (N = 18). We found that there was an association between the attenuation of superior quadrant RNFL thickness and the deterioration of cognitive function in the stable participants. In the converted participants, however, there was an inverse association between the reduction of inferior quadrant RNFL thickness and decline of cognitive functions [scores of list recall (R = -0.670, P = 0.002), adjusted (R = -0.493, P = 0.031)]. These data showed that less reduction in the inferior quadrant of RNFL thickness might indicate a higher risk for the patients to develop cognitive deterioration. These findings have established a system to embark a larger scale study to further test whether changes in RNFL thickness can serve as a biomarker of AD, and would lead to mechanistic studies to determine the cellular mechanisms of cognitive deterioration.
biomarker; Alzheimer’s disease; mild cognitive impairment; dementia; retinal nerve fiber layer thickness; cognition
This study investigated the anti-tumour effects of the novel vascular disrupting agent plinabulin (NPI-2358) when given alone or combined with radiation.
Materials and Methods
Foot implanted C3H mammary carcinomas or leg implanted KHT sarcomas were used, with plinabulin (Nereus Pharmaceuticals, San Diego, USA) injected intraperitoneally. Dynamic contrast-enhanced magnetic resonance imaging measurements were made with gadolinium-DTPA on a 7-tesla magnet. Treatment response was assessed using either a regrowth delay (C3H mammary carcinoma) or clonogenic survival (KHT sarcoma) assay, or histological estimates of necrosis for both models.
Plinabulin (7.5 mg/kg) significantly reduced both IAUC and Ktrans within 1-hour after drug injection, reaching a nadir at 3-hours, but returning to normal within 24-hours. A dose-dependent decrease in IAUC and Ktrans, was seen at 3-hours. No significant anti-tumour effects were seen in the C3H mammary carcinoma until doses of 12.5 mg/kg and above were achieved, but started at 1.5 mg/kg in the KHT sarcoma. Irradiating tumours 1-hour after injecting plinabulin enhanced response in both models.
Plinabulin induced a time and dose dependent decrease in tumour perfusion. The KHT sarcoma was more sensitive than the C3H mammary carcinoma to the anti-tumour effects of plinabulin, while radiation response was enhanced in both models.
Plinabulin (NPI-2358); Vascular targeting; Radiation; C3H mammary carcinoma; KHT sarcoma; Magnetic Resonance Imaging
A novel Chinese chestnut (Castanea mollissima Bl.) mutant with extreme short catkins, here was named sck1 and has been characterized in the present study. This sck1 caused 6-fold shorter than wild-type catkins. Endogenous gibberellic acids markedly decreased in the mutant, and application of exogenous GA3 could partially restore the sck1 phenotype to the wild-type phenotype. Paclobutrazol (PP333), an antagonist of GAs biosynthesis, could significantly inhibit the wild-type catkins growth, and lead to a short catkins phenotype similar to the sck1. In addition, compared to the wild-type catkins, the mRNA expression level of ent-kaurenoic acid oxidase (KAO), a gibberellin biosynthsis key gene, was significantly down-regulated (P<0.01) in the sck1. Importantly, transient over-expression of a normal CmKAO gene in short catkins also could partially restore the wild-type phenotype. Real-time PCR and semi-quantitative analysis showed that the mRNA expression level of KAO was significantly up-regulated. In addition, transient RNA interference of CmKAO in wild-type catkins led the mRNA expression level of KAO decrease significantly and inhibited the wild-type catkins elongation strongly. Taken together, our results suggest that the lower gibberellic acids content that is due to decreased CmKAO expression level may contribute to the generation of the extreme short male catkins, sck1.
Whether healthy older people can benefit from cognitive training (CogTr) remains controversial. This study explored the benefits of CogTr in community dwelling, healthy, older adults and compared the effects of single-domain with multi-domain CogTr interventions.
A randomized, controlled, 3-month trial of CogTr with double-blind assessments at baseline and immediate, 6-month and 12-month follow-up after training completion was conducted. A total of 270 healthy Chinese older people, 65 to 75 years old, were recruited from the Ganquan-area community in Shanghai. Participants were randomly assigned to three groups: multi-domain CogTr, single-domain CogTr, and a wait-list control group. Twenty-four sessions of CogTr were administrated to the intervention groups over a three-month period. Six months later, three booster training sessions were offered to 60% of the initial training participants. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS, Form A), the Color Word Stroop test (CWST), the Visual Reasoning test and the Trail Making test (TMT) were used to assess cognitive function.
Multi-domain CogTr produced statistically significant training effects on RBANS, visual reasoning, and immediate and delayed memory, while single-domain CogTr showed training effects on RBANS, visual reasoning, word interference, and visuospatial/constructional score (all P < 0.05). At the 12-month posttest, the multi-domain CogTr showed training effects on RBANS, delayed memory and visual reasoning, while single-domain CogTr only showed effects on word interference. Booster training resulted in effects on RBANS, visual reasoning, time of trail making test, and visuospatial/constructional index score.
Cognitive training can improve memory, visual reasoning, visuospatial construction, attention and neuropsychological status in community-living older people and can help maintain their functioning over time. Multi-domain CogTr enhanced memory proficiency, while single-domain CogTr augmented visuospatial/constructional and attention abilities. Multi-domain CogTr had more advantages in training effect maintenance.
Clinical Trial Registration
Chinese Clinical Trial Registry. Registration number: ChiCTR-TRC-09000732.
Suppose a standard therapy (Standard) has been established to provide a clinically important reduction in risk of irreversible morbidity or mortality. In that setting, the safety and efficacy of an experimental intervention likely would be assessed in a clinical trial providing a comparison with Standard rather than a placebo arm. Such a trial often is designed to assess whether the efficacy of the experimental intervention is not unacceptably worse than that of Standard, and is called a non-inferiority trial. Formally, the non-inferiority trial usually is designed to rule out a non-inferiority margin, defined as the minimum threshold for what would constitute an unacceptable loss of efficacy.
Even though the literature has many important articles identifying various approaches to the design and conduct of non-inferiority trials, confusion remains especially regarding key considerations for selecting the non-inferiority margin. The purpose of this article is to provide improved clarity regarding these considerations.
We present scientific insights into many factors that should be addressed in the design and conduct of non-inferiority trials to enhance their integrity and reliability, and provide motivation for key considerations that guide the selection of non-inferiority margins. We also provide illustrations and insights from recent experiences.
Two considerations are essential, and should be addressed in separate steps, in the formulation of the non-inferiority margin. First, the margin should be formulated using adjustments to account for bias or lack of reliability in the estimate of the effect of Standard in the non-inferiority trial setting. Second, the non-inferiority margin should be formulated to achieve preservation of an appropriate percentage of the effect of Standard.
The considerations, in particular regarding the importance of preservation of effect, might not apply to settings where it would be ethical as well as clinically relevant to include both Standard and placebo arms in the trial for direct comparisons with the experimental intervention arm.
Non-inferiority trials with non-rigorous margins allow substantial risk for accepting inadequately effective experimental regimens, leading to the risk of erosion in quality of health care. The design and conduct of non-inferiority trials, including selection of non-inferiority margins, should account for many factors that can induce bias in the estimated effect of Standard in the non-inferiority trial and thus lead to bias in the estimated effect of the experimental treatment, for the need to ensure the experimental treatment preserves a clinically acceptable fraction of Standard's effect, and for the particular vulnerability of the integrity of a non-inferiority trial to the irregularities in trial conduct. Due to the inherent uncertainties in non-inferiority trials, alternative designs should be pursued whenever possible.
We constructed a corpus of digitized texts containing about 4% of all books ever printed. Analysis of this corpus enables us to investigate cultural trends quantitatively. We survey the vast terrain of ‘culturomics’, focusing on linguistic and cultural phenomena that were reflected in the English language between 1800 and 2000. We show how this approach can provide insights about fields as diverse as lexicography, the evolution of grammar, collective memory, the adoption of technology, the pursuit of fame, censorship, and historical epidemiology. ‘Culturomics’ extends the boundaries of rigorous quantitative inquiry to a wide array of new phenomena spanning the social sciences and the humanities.
Years of education are inversely related to the prevalence of major depressive disorder (MDD), but the relationship between the clinical features of MDD and educational status is poorly understood. We investigated this in 1970 Chinese women with recurrent MDD identified in a clinical setting.
Clinical and demographic features were obtained from 1970 Han Chinese women with DSM-IV major depression between 30 and 60 years of age across China. Analysis of linear, logistic and multiple logistic regression models were used to determine the association between educational level and clinical features of MDD.
Subjects with more years of education are more likely to have MDD, with an odds ratio of 1.14 for those with more than ten years. Low educational status is not associated with an increase in the number of episodes, nor with increased rates of co-morbidity with anxiety disorders. Education impacts differentially on the symptoms of depression: lower educational attainment is associated with more biological symptoms and increased suicidal ideation and plans to commit suicide.
Findings may not generalize to males or to other patient populations. Since the threshold for treatment seeking differs as a function of education there may an ascertainment bias in the sample.
The relationship between symptoms of MDD and educational status in Chinese women is unexpectedly complex. Our findings are inconsistent with the simple hypothesis from European and US reports that low levels of educational attainment increase the risk and severity of MDD.
Major depressive disorder; Education; Socio-economic status; Symptom
Diagnostic information for psychiatric research often depends on both clinical interviews and medical records. Although discrepancies between these two sources are well known, there have been few studies into the degree and origins of inconsistencies.
We compared data from structured interviews and medical records on 1,970 Han Chinese women with recurrent DSM-IV major depression (MD). Correlations were high for age at onset of MD (0.93) and number of episodes (0.70), intermediate for family history (+0.62) and duration of longest episode (+0.43) and variable but generally more modest for individual depressive symptoms (mean kappa = 0.32). Four factors were identified for twelve symptoms from medical records and the same four factors emerged from analysis of structured interviews. Factor congruencies were high but the correlation of factors between interviews and records were modest (i.e. +0.2 to +0.4).
Structured interviews and medical records are highly concordant for age of onset, and the number and length of episodes, but agree more modestly for individual symptoms and symptom factors. The modesty of these correlations probably arises from multiple factors including i) inconsistency in the definition of the worst episode, ii) inaccuracies in self-report and iii) difficulties in coding medical records where symptoms were recorded solely for clinical purposes.
The purpose of this study was to describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL). On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.
After completing this course, the reader will be able to:
Compare the survival benefits of rituximab in combination with fludarabine and cyclophosphamide to those of alemtuzumab, bendamustine, and ofatumumab in patients with CLL.Identify CLL patients for whom rituximab in combination with fludarabine and cyclophosphamide may be an appropriate first-line regimen.
This article is available for continuing medical education credit at CME.TheOncologist.com
To describe the clinical studies that led to the FDA approval of rituximab in combination with fludarabine and cyclophosphamide (FC) for the treatment of patients with chronic lymphocytic leukemia (CLL).
Materials and Methods.
The results of two multinational, randomized trials in CLL patients comparing rituximab combined with fludarabine and cyclophosphamide versus FC were reviewed. The primary endpoint of both studies was progression-free survival (PFS).
The addition of rituximab to FC decreased the risk of a PFS event by 44% in 817 previously untreated patients and by 24% in 552 previously treated patients. Median survival times could not be estimated. Exploratory analysis in patients older than 70 suggested that there was no benefit to patients when rituximab was added to FC. The safety profile observed in both trials was consistent with the known toxicity profile of rituximab, FC, or CLL.
On the basis of the demonstration of clinically meaningful prolongation of PFS, the FDA granted regular approval to rituximab in combination with FC for the treatment of patients with CLL. The magnitude of the treatment effect in patients 70 years and older is uncertain.
FDA; Rituximab; Chronic lymphocytic leukemia; Fludarabine; Cyclophosphamide
The light-harvesting chlorophyll a/b binding proteins (LHCB) are perhaps the most abundant membrane proteins in nature. It is reported here that the down-regulation or disruption of any member of the LHCB family, LHCB1, LHCB2, LHCB3, LHCB4, LHCB5, or LHCB6, reduces responsiveness of stomatal movement to ABA, and therefore results in a decrease in plant tolerance to drought stress in Arabidopsis thaliana. By contrast, over-expression of a LHCB member, LHCB6, enhances stomatal sensitivity to ABA. In addition, the reactive oxygen species (ROS) homeostasis and a set of ABA-responsive genes are altered in the lhcb mutants. These data demonstrate that LHCBs play a positive role in guard cell signalling in response to ABA and suggest that they may be involved in ABA signalling partly by modulating ROS homeostasis.
Abscisic acid signalling; Arabidopsis thaliana; light-harvesting chlorophyll a/b binding protein; reactive oxygen species; stomatal movement
The personality trait of neuroticism is a risk factor for major depressive disorder (MDD), but this relationship has not been demonstrated in clinical samples from Asia.
We examined a large-scale clinical study of Chinese Han women with recurrent major depression and community-acquired controls.
Elevated levels of neuroticism increased the risk for lifetime MDD (with an odds ratio of 1.37 per SD), contributed to the comorbidity of MDD with anxiety disorders, and predicted the onset and severity of MDD. Our findings largely replicate those obtained in clinical populations in Europe and US but differ in two ways: we did not find a relationship between melancholia and neuroticism; we found lower mean scores for neuroticism (3.6 in our community control sample).
Our findings do not apply to MDD in community-acquired samples and may be limited to Han Chinese women. It is not possible to determine whether the association between neuroticism and MDD reflects a causal relationship.
Neuroticism acts as a risk factor for MDD in Chinese women, as it does in the West and may particularly predispose to comorbidity with anxiety disorders. Cultural factors may have an important effect on its measurement.
Major depressive disorder; Anxiety disorders; Neuroticism
Ethylene signaling pathway leads to rapid gene activation by two hierarchies of transcription factors with EIN3/EIL proteins as primary ones and ERF proteins as secondary ones. The role of chromatin modifications during the rapid gene activation is not known. In this work we studied trimethylated histone H3 lysine 4 (H3K4me3) and lysine 27 (H3K27me3), two opposite histone methylation marks for gene activity, during the induction course of three ethylene-responsive genes (ERF1, AtERF14 and ChiB). We found that the three genes displayed different histone modification profiles before induction. After induction, H3K4me3 was increased in the 5′ region and the gene body of ERF1, while H3K27me3 was decreased in the promoter of AtERF14. But the modification changes were later than the gene activation. Analysis of other rapidly inducible ERF genes confirmed the observation. In addition, histone H2A.Z occupancy on the three genes and the association of the H3K27me3-binding protein LHP1 with AtERF14 and ChiB were not affected by the inductive signal. However, the mutation of genes encoding H2A.Z and LHP1 attenuated and enhanced respectively the induction of target genes and altered H3K4me3. These results indicate that the induction of ethylene-responsive genes does not require immediate modulation of H3K4me3 and H3K27me3 and dissociation of LHP1 and H2A.Z from the targets, and suggest that the chromatin structure of the genes before induction is committed for transcriptional activation and that H3K4me3 is not required for ethylene-responsive gene activation, but may serve as a mark for gene activity.
To investigate the association between neck circumference and central obesity, overweight, and metabolic syndrome in Chinese individuals with type 2 diabetes.
RESEARCH DESIGN AND METHODS
A total of 3,182 diabetic subjects (aged 20–80 years) were recruited from 15 community health centers in Beijing using a multistage random sampling approach.
Receiver operating characteristic analysis showed that the area under the curve for neck circumference and central obesity was 0.77 for men and 0.75 for women (P < 0.001). Furthermore, a neck circumference of ≥38 cm for men and ≥35 cm for women was the best cutoff point for determining overweight subjects. A neck circumference of ≥39 cm for men and ≥35 cm for women was the best cutoff point to determine subjects with metabolic syndrome.
In the present study, neck circumference is positively related with BMI, waist circumference, and metabolic syndrome in Chinese individuals with type 2 diabetes.
We recently reported that AFH14 participated in microtubule and actin filament interaction in cell division, and the AFH14 (FH1FH2) was important to the directly binding activity of microtubules and microfilaments. To preliminarily understand the function and localization of AFH14 in non-dividing cells, we overexpressed FH1FH2-RFP in onion epidermal cells, and found a fluorescence labeled filamentous network. The result of double labeling with different cytoskeleton reporter proteins indicated that FH1FH2-RFP co-localized with cortical microtubules. Treatment of cells expressing FH1FH2-RFP with cytoskeleton disrupting drugs confirms that FH1FH2-RFP binds to microtubules. Moreover, the binding of FH1FH2-RFP to microtubules were revealed to be dynamic by fluorescence recovery after photobleaching (FRAP) experiment. Time-lapse confocal microscopy showed that FH1FH2-RFP could display a dynamics similar to the microtubule dynamic instability. These data suggest that FH1FH2 domain may lead AFH14 function on cortical microtubules in non-dividing cells, and FH1FH2-RFP may be utilized as a microtubule reporter protein in living onion epidermal cells.
cortical microtubule; AFH14; non-dividing cell; microtubule dynamics; FRAP
Since 2003, the New Cooperative Medical Scheme (NCMS) has been implemented throughout rural China, usually covering delivery services in its benefit package. The objective of this study was to compare the difference of utilization of delivery services, expenditures, and local women's perceived affordability between women with and without reimbursement from NCMS.
A cross-sectional survey was carried out in two rural counties in Shaanxi province, China, during December 2008-March 2009. Women giving birth from April 2008 to March 2009 were interviewed by a structured questionnaire to collect information on utilization of delivery services. Multivariable analyses were used to compare the differences in outcomes between women with and without reimbursement from NCMS.
Of the total 1613 women interviewed, 747(46.3%) got reimbursement to cover their expenditure on delivery care (NCMS group) and 866(53.7%) paid delivery services entirely out of their own pocket (Non-NCMS group). Compared with the Non-NCMS group, the NCMS group had significantly more women who delivered at hospital. The rate of Caesarean section (CS), proportion of women seeking higher level services, and length of hospitalization were similar between the two groups. The total hospital costs for delivery services in the NCMS group was significantly smaller and after being reimbursed, the out-of-pocket payment in the NCMS group was less than a half of that in the Non-NCMS group. Fewer women in the NCMS group than in the Non-NCMS group considered their payment for delivery services expensive.
There was no evidence of overuse delivery services among the women reimbursed by NCMS. Total hospital costs and women's costs for delivery services were found lower in the NCMS group, subsequently alleviation on women's perceived financial affordability.
Collagen-induced arthritis (CIA) is an established mouse model of disease with hallmarks of clinical rheumatoid arthritis. Histone/protein deacetylase inhibitors (HDACi) are known to inhibit the pathogenesis of CIA and other models of autoimmune disease, although the mechanisms responsible are unclear. Regulatory T cell (Treg) function is defective in rheumatoid arthritis. FOXP3 proteins in Tregs are present in a dynamic protein complex containing histone acetyltransferase and HDAC enzymes, and FOXP3 itself is acetylated on lysine residues. We therefore investigated the effects of HDACi therapy on regulatory T cell function in the CIA model. Administration of an HDACi, valproic acid (VPA), significantly decreased disease incidence (p<0.005) and severity (p<0.03) in CIA. In addition, VPA treatment increased both the suppressive function of CD4+CD25+ Tregs (p<0.04) and the numbers of CD25+FOXP3+ Tregs in vivo. Hence, clinically approved HDACi such as VPA may limit autoimmune disease in vivo through effects on the production and function of FOXP3+ Treg cells.
T cell; suppression; autoimmunity; rheumatoid arthritis
To identify the gene responsible for the quantitative trait locus (QTL) Hdlq14, a high density lipoprotein cholesterol (HDL) QTL previously identified in a C57BL/6J x 129S1/SvImJ cross.
Methods and Results
Hdlq14 was first confirmed as an independent QTL by detecting it in an intercross between NZB/B1NJ and NZW/LacJ, two strains that had identical genotypes at nearby QTL genes on chromosome 1. Using the bioinformatics tools of combined cross data and haplotype analysis, we narrowed this QTL from a 45 Mb, 225 -gene region to 2 genes, Farp2 and Stk25. Sequencing and expression studies showed that Farp2 had an amino acid polymorphism in an important plekstrin domain and that Stk25 had a significant expression difference between the parental strains. These two genes are immediately adjacent to each other and share the same haplotype over 45 inbred strains. The haplotype was associated with a significant difference in HDL levels among these strains.
We confirmed Hdlq14 as a separate independent QTL for HDL and narrowed the region to two genes, Farp2 and Stk25 with considerable evidence for both. Additional studies are needed to choose between these two genes or to show that both are important in determining HDL levels.
HDL; QTL; Farp2; Stk25; mouse
Transcatheter closure of congenital heart defects with the use of septal occluders has been widely accepted as a preferred treatment; however, the high cost of these devices limits their clinical application in some countries. Few clinical data are available regarding lower-cost products. Accordingly, we evaluated the efficacy and safety of the Chinese-made Shanghai Shape Memory Alloy (SHSMA) occluder in patients with congenital heart defects. From December 2001 through December 2008, a total of 180 patients with congenital heart defects (ages, 3–68 yr; mean age, 17.35 ± 13.22 yr) underwent transcatheter closure with use of the SHSMA occluder: 73 had atrial septal defects; 64, ventricular septal defects; 40, patent ductus arteriosus; and 3, complex congenital defects. The mean diameters of the defects were 20 ± 7.6 mm (atrial septal), 4.9 ± 2.1 mm (ventricular septal), and 5.6 ± 2.2 mm (patent ductus arteriosus). The procedural success rates were 98.6% for atrial defects, 98.4% for ventricular defects, and 100% for patent ductus arteriosus and for complex defects. The overall incidences of sequelae were 5.5%, 9.4%, 2.5%, and 0, respectively. Six months postprocedurally, complete occlusion was associated with a significant decrease in the right ventricular Tei index in atrial septal defect patients (P <0.05) and with improvement of body mass index in 11 children. These results suggest that the SHSMA occluder is a safe, effective device for the transcatheter closure of congenital heart defects. For confirmation, a randomized controlled trial with more patients and a longer follow-up period is warranted.
Ductus arteriosus, patent/therapy; equipment design; heart catheterization/instrumentation; heart defects, congenital/therapy; heart septal defects, atrial/therapy; heart septal defects, ventricular/therapy; risk assessment; safety; septal occluder device; treatment outcome
Although the diagnosis of melancholia has had a long history, the validity of the current DSM-IV definition remains contentious. We report here the first detailed comparison of melancholic and nonmelancholic major depression (MD) in a Chinese population examining in particular whether these two forms of MD differ quantitatively or qualitatively.
DSM-IV criteria for melancholia were applied to 1,970 Han Chinese women with recurrent MD recruited from 53 provincial mental health centers and psychiatric departments of general medical hospitals in 41 cities. Statistical analyses, utilizing Student's t-tests and Pearson's χ2, were calculated using SPSS 13.0.
Melancholic patients with MD were distinguished from nonmelancholic by being older, having a later age at onset, more episodes of illness and meeting more A criteria. They also had higher levels of neuroticism and rates of lifetime generalized anxiety disorder, panic disorder, and social and agoraphobia. They had significantly lower rates of childhood sexual abuse but did not differ on other stressful life events or rates of MD in their families.
Consistent with most prior findings in European and US populations, we find that melancholia is a more clinically severe syndrome than nonmelancholic depression with higher rates of comorbidity. The evidence that it is a more “biological” or qualitatively distinct syndrome, however, is mixed.
major depression; melancholia; symptom; stressful life events