An inducible activation approach is used to interrogate the positive feedback circuit underlying self-amplification of PI3K signals in fibroblasts. The results show that local positive feedback between PI3K and HRas drives asymmetric membrane extension and cell migration.
Self-amplification of phosphoinositide 3-kinase (PI3K) signaling is believed to regulate asymmetric membrane extension and cell migration, but the molecular organization of the underlying feedback circuit is elusive. Here we use an inducible approach to synthetically activate PI3K and interrogate the feedback circuitry governing self-enhancement of 3′-phosphoinositide (3-PI) signals in NIH3T3 fibroblasts. Synthetic activation of PI3K initially leads to uniform production of 3-PIs at the plasma membrane, followed by the appearance of asymmetric and highly amplified 3-PI signals. A detailed spatiotemporal analysis shows that local self-amplifying 3-PI signals drive rapid membrane extension with remarkable directional persistence and initiate a robust migratory response. This positive feedback loop is critically dependent on the small GTPase HRas. Silencing of HRas abrogates local amplification of 3-PI signals upon synthetic PI3K activation and results in short-lived protrusion events that do not support cell migration. Finally, our data indicate that this feedback circuit is likely to operate during platelet-derived growth factor–induced random cell migration. We conclude that positive feedback between PI3K and HRas is essential for fibroblasts to spontaneously self-organize and generate a productive migratory response in the absence of spatial cues.
Acute hepatitis C virus infection is associated with high rates of spontaneous clearance and variable rates of treatment-induced clearance. The benefit of early treatment versus awaiting spontaneous clearance is unknown, as is the optimal timing of treatment.
We performed a MEDLINE and EMBASE search for the time period 1950 to October 2008. All English language abstracts using the search terms acute hepatitis C, hepatitis C and acute and hepatitis C and acute disease or acute infection were reviewed. Bibliographies were reviewed.
Twenty-two studies including 1075 patients met inclusion criteria. The sustained virologic response (SVR) rate for treated patients was 78%, significantly higher than 55.1% in untreated patients (OR =3.08, 95% CI 1.8-4.8 p value<0.0001). Mean time from diagnosis to spontaneous clearance was 9.7 weeks (SD 6.5). SVR rates varied inversely with time from acute HCV diagnosis. SVR rates for treatment within 12 weeks was 82.5% (95% CI 75.6-89.3), significantly better than the clearance rates in untreated patients (p<0.001). Response rates fell to 66.9% for treatment between 12 and 24 weeks, and decreased further to 62.5% for treatment beyond 24 weeks.
Rates of viral clearance in treated patients with acute hepatitis C virus infection were significantly higher than that in untreated patients. Treatment rates were highest when treatment was initiated within 12 weeks of diagnosis. Based on these findings, we would advocate a 12 week period of observation for spontaneous clearance before treatment initiation. If no clearance has occurred by 12 weeks, treatment should be initiated.
acute hepatitis C; meta-analysis; spontaneous clearance; sustained virologic response
With only a third of Latinos achieving sustained virologic response (SVR), there is a need for enhanced HCV treatment. Amantadine has been proposed to improve response rates in addition to standard therapy with peginterferon a and ribavirin. Our objective is to evaluate whether triple therapy with amantadine improves SVR rates in this special population.
Treatment-naíe Latino subjects with HCV genotype 1 infection were randomized to receive peginterferon [alpha]-2a plus weight-based ribavirin for 48 weeks (double therapy) or the same regimen plus amantadine 200 mg daily (triple therapy). The primary endpoint was SVR. Predictors of liver fibrosis using APRI and Forns indices were also evaluated.
We enrolled 124 patients with chronic hepatitis C genotype 1. Sixty-three received conventional therapy and 61 patients had triple therapy with amantadine. SVR at week 72 was achieved in 25 patients (39.7%) vs. 26 patients (42.6%) in the double and triple regimen, respectively (p = 0.561).After multivariate analysis, advanced fibrosis, obesity, and low pretreatment ALT levels were associated with non-response in both groups (p = 0.0234, p = 0.0012, p = 0.0249, respectively). APRI values delimited an area under the ROC curve (AUROC) of 0.724 and Forns index with AUROC of 0.733. There was no difference between both indices in predicting significant fibrosis (Knodell index: F3-F4).
Our study demonstrates that the addition of amantadine to standard treatment of chronic HCV does not improve SVR rates in Latino patients with genotype 1. Further research to improve response rates in this special population is needed.
Chronic hepatitis C; Amantadine; Latino; Peginterferon; Sustained virological response
Hepatitis B reactivation is a well-described complication in patients with inactive chronic hepatitis B receiving chemotherapy. Screening for HBV and preemptive therapy are recommended. However, the rates of HBV screening, prophylaxis and reactivation during rituximab-containing chemotherapy are unknown.
Patients and methods
We performed a retrospective study of patients with non-Hodgkin lymphoma (NHL) who received rituximab between August 1997 and September 2009. We evaluated patients for hepatitis B serologies, antiviral prophylaxis and hepatitis B reactivation during or up to 6 months after chemotherapy.
One thousand four hundred twenty nine patients underwent rituximab-containing chemotherapy for NHL. Hepatitis B serologies were documented in 524 (36.6%) patients. Of these, 20 (3.8 %) were HBsAg positive and 10 (50%) experienced HBV reactivation. Only half (5/10) had HBV serology documented prior to reactivation. Only 3/8 (37.5%) of patients with newly documented HBsAg positivity received antiviral prophylaxis. Virologic breakthrough occurred in 2 of the patients on chronic therapy, in one of three inactive carriers on prophylaxis and in 2 of 5 patients not receiving prophylaxis. Reactivation developed in another 5 patients not previously screened for hepatitis B. One patient developed ALF and died. Reactivation did not occur in 25 patients with isolated positive core antibody.
At tertiary care institutions hepatitis B serologies are infrequently assessed prior to rituximab-based chemotherapy and prophylaxis is uncommon. Greater adherence to recommendations for screening and prophylaxis is necessary. This suboptimal screening rate could be even lower in community hospitals and could result in significant harm to unscreened and unprophylaxed patients.
Chemotherapy; HBV Reactivation; Hepatitis B; HBV prophylaxis; Non-Hodgkin lymphoma; Rituximab
Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease (PD), inducing and accelerating dopaminergic (DA) neuron loss. Autophagy, a critical mechanism for clearing misfolded or aggregated proteins such as α-synuclein (α-SYN), may affect DA neuron survival in the midbrain. However, whether autophagy contributes to neuroinflammation-induced toxicity in DA neurons remains unknown.
Intraperitoneal injection of lipopolysaccharide (LPS, 5 mg/kg) into young (3-month-old) and aged (16-month-old) male C57BL/6J mice was observed to cause persistent neuroinflammation that was associated with a delayed and progressive loss of DA neurons and accumulation of α-SYN in the midbrain. The autophagic substrate-p62 (SQSTM1) persistently increased, whereas LC3-II and HDAC6 exhibited early increases followed by a decline. In vitro studies further demonstrated that TNF-α induced cell death in PC12 cells. Moreover, a sublethal dose of TNF-α (50 ng/ml) increased the expression of LC3-II, p62, and α-SYN, implying that TNF-α triggered autophagic impairment in cells.
Neuroinflammation may cause autophagic impairment, which could in turn result in DA neuron degeneration in midbrain.
MKC-1 is an orally available cell cycle inhibitor with downstream targets that include tubulin and the importin-β family. We conducted an open-label Phase II study with MKC-1 in patients with advanced pancreatic cancer.
Eligibility criteria included unresectable or metastatic pancreatic cancer, performance status of 1 or better, and failure of at least one prior regimen of chemotherapy. MKC-1 was administered orally, twice daily, initially at 100mg/m2 dosing for 14 consecutive days of a 28-day cycle. This schedule was modified during the trial to fixed and continuous dosing of 150mg per day.
20 of an original target of 33 patients were accrued, with a median age of 61 (range 44 to 81). No objective responses were observed, with one patient demonstrating stable disease. Overall survival was 101 days from the start of MKC-1 administration, and median time to progression was 42 days. The most common adverse events listed as related or possibly related to MKC-1 administration were hematologic toxicities and fatigue. One patient developed grade 5 (fatal) pancytopenia. Grade 3 and 4 events included cytopenias (lymphopenia, anemia), hyperbilirubinemia, pneumonia, mucositis, fatigue, infusion reaction, anorexia, and hypoalbuminemia.
MKC-1 administration was associated with substantial toxicity and did not demonstrate sufficient activity in patients with advanced pancreatic cancer to justify further exploration in this patient population.
Pancreatic cancer; Phase II; MKC-1; importin; tubulin
Whether acupuncture is efficacious for patients with functional dyspepsia is still controversial. So we designed a randomised controlled trial to settle the problem.
Methods and analysis
We designed a multicentre, two-arm, sham-controlled clinical trial. 200 participants with functional dyspepsia will be randomly assigned to the true acupuncture (TA) group and sham acupuncture (SA) group in a 1:1 ratio. Participants in the TA group will receive acupuncture at points selected according to syndrome differentiation. Participants in the sham acupuncture group will receive penetrations at sham points. Participants in both groups will receive 20 sessions of electroacupuncture in 4 weeks, five times continuously with a 2 day rest in a week. The primary outcome is the proportion of patients reporting the absence of dyspeptic symptoms at 16 weeks after inclusion. The secondary outcome includes a Short-Form Leeds Dyspepsia Questionnaire, the Chinese version of the 36-Item Short Form Survey, the Chinese version of the Nepean dyspepsia index, etc.
Ethics and dissemination
The study protocol has been approved by the institutional review boards and ethics committees of the first affiliated hospital of Chengdu University of TCM, the first affiliated hospital of Hunan University of TCM and Chongqing Medical University, respectively (from April to August 2012). The results of this trial will be disseminated in a peer-reviewed journal and presented at international congresses.
Complementary Medicine; Epidemiology; Gastroenterology
Vectors based on adeno-associated virus (AAV) are effective in gene delivery in vivo. Tissue-specific gene expression is often needed to minimize ectopic expression in unintended cells and undesirable consequences. Here we investigated if incorporation of target sequences of tissue-specific microRNA (miRNA) into AAV vectors could inhibit ectopic expression in tissues such as the liver and hematopoietic cells. First we inserted liver-specific miR-122 target sequences (miR-122T) into the 3′ untranslated region (UTR) of a number of AAV vectors. After intravenous delivery in mice, we found that 5 copies of the 20mer miR-122T reduced liver expression of luciferase by 50-fold and β-galactosidase (LacZ) by 70-fold. Five copies of miR-122T also reduced mRNA levels of a secretable protein (myostatin propeptide) from the AAV vector plasmid by 23–fold in the liver. However, gene expression in other tissues including the heart was not inhibited. Similarly, we inserted 4 copies of miR-142-3pT or miR-142-5pT, both hematopoietic lineage-specific, into the 3′ UTR of the AAV-luciferase vector. We wished to see if they could prolong transgene expression by inhibiting expression in antigen-presenting cells. However, in vivo luciferase gene expression in major tissues declined with time regardless of the miR-142 target sequences used. Quantitative analysis of the vector DNA in various tissues revealed that the decline of transgene expression in vivo was mainly due to promoter shut-off other than loss of AAV-transduced cells by immune destruction. Moreover, transgene expression was not detected in circulating mononuclear cells after delivering AAV9 vector with or without miR142T. These results demonstrate that live-specific miR-122 target sequence in AAV vectors was highly efficient in reducing liver expression, whereas hematopoietic miR-142 target sequences were ineffective in preventing decline of AAV vector gene expression in non-hematopoietic tissues resulted from promoter shut-off.
To profile hospitals by survival rates of colorectal cancer patients in multiple periods after initial treatment.
California Cancer Registry data from 50,544 patients receiving primary surgery with curative intent for stage I–III colorectal cancer in 1994–1998, supplemented with hospital discharge abstracts.
We estimated a single Bayesian hierarchical model to quantify associations of survival to 30 days, 30 days to 1 year, and 1–5 years by hospital, adjusted for patient age, sex, race, stage, tumor site, and comorbidities. We compared two profiling methods for 30-day survival and four longer-term profiling methods by the fractions of hospitals with demonstrably superior survival profiles and of hospital pairs whose relative standings could be established confidently.
Interperiod correlation coefficients of the random effects are (95 percent credible interval 0.27, 0.85), (0.20, 0.76), and (0.19, 0.82). The three-period model ranks 5.4 percent of pairwise comparisons by 30-day survival with at least 95 percent confidence, versus 3.3 percent of pairs using a single-period model, and 15–20 percent by weighted multiperiod methods.
The quality of care for colorectal cancer provided by a hospital system is somewhat consistent across the immediate postoperative and long-term follow-up periods. Combining mortality profiles across longer periods may improve the statistical reliability of outcome comparisons.
Cancer care; colorectal cancer; provider profiling; quality measurement; Bayesian inference
Background & Aims
There are no clinically available biomarkers for non-alcoholic steatohepatitis (NASH); differentiating between steatosis and NASH requires histologic evaluation. Non-invasive methods are needed to replace liver biopsy and its associated risks. Production of very-low density lipoprotein (VLDL) contributes to the development of NASH, and might be used to distinguish steatosis from NASH. However, it is not possible to measure levels of VLDL directly, in the clinic. Non-high density lipoprotein cholesterol (non-HDL-C) encompasses all apolipoprotein-B–containing lipoproteins, including VLDL, and can be calculated from standard lipid panels without additional cost.
We evaluated the ability of non-HDL-C to differentiate steatosis from NASH in a prospective study of 218 patients with suspected NASH (steatosis, n=100 and NASH, n=118).
Patients with NASH had a trend toward increased levels of non-HDL cholesterol, compared to those with steatosis (P=.08). However, among subjects not on lipid-lowering medications, those with NASH had significantly higher levels of non-HDL-C (144.6mg/dL), than those with steatosis (129.3mg/dL; P=.025). This difference remained significant when adjusted for levels of cholesterol and triglycerides, indicating that the difference results from increased levels of apolipoprotein B, including VLDL. These findings were validated in a cohort of 40 patients with steatosis or NASH who were not taking lipid-lowering agents. The NASH group had a significantly higher levels of non-HDL-C than the steatosis group (162.8mg/dL vs 145.9 mg/dL; P=.04).
NASH is associated with significantly higher levels of non-HDL-C than steatosis in patients who do not take lipid-lowering agents. This low-cost biomarker could be used in non-invasive differentiation between steatosis and NASH.
non-HDL cholesterol; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; diagnostic; blood test; clinical trial
The International Committee on Taxonomy of Viruses authorizes and organizes the taxonomic classification of viruses. Thus far, the detailed classifications for all viruses are neither complete nor free from dispute. For example, the current missing label rates in GenBank are 12.1% for family label and 30.0% for genus label. Using the proposed Natural Vector representation, all 2,044 single-segment referenced viral genomes in GenBank can be embedded in . Unlike other approaches, this allows us to determine phylogenetic relations for all viruses at any level (e.g., Baltimore class, family, subfamily, genus, and species) in real time. Additionally, the proposed graphical representation for virus phylogeny provides a visualization of the distribution of viruses in . Unlike the commonly used tree visualization methods which suffer from uniqueness and existence problems, our representation always exists and is unique. This approach is successfully used to predict and correct viral classification information, as well as to identify viral origins; e.g. a recent public health threat, the West Nile virus, is closer to the Japanese encephalitis antigenic complex based on our visualization. Based on cross-validation results, the accuracy rates of our predictions are as high as 98.2% for Baltimore class labels, 96.6% for family labels, 99.7% for subfamily labels and 97.2% for genus labels.
A meta-analysis was applied to evaluate the associations between tumor necrosis factor-α (TNF-α) −308G>A (rs1800629) polymorphism and type 2 diabetes mellitus (T2DM).
Hardy-Weinberg equilibrium (HWE) was employed to test genetic equilibrium among the genotypes of the selected literature. Power analysis was performed with the Power and Sample Size Calculation (PS) program. A fixed or random effect model was used on the basis of heterogeneity. Publication bias was quantified and examined with the Begg's funnel plot test and Egger's linear regression test. The meta-analysis was performed with Review Manager 5.1 and Stata 11.0.
There were 10 studies including 1425 T2DM patients and 1116 healthy control subjects involved in this meta-analysis. No significant publication bias was found in the studies. The pooled ORs (95% CIs) for TNF-α −308G>A of A vs. G allele and GA+AA vs. GG genotype were 1.63 (1.17–2.25) and 1.47 (1.17–1.85), respectively.
This meta-analysis result suggested that TNF-α −308G>A polymorphism was strongly associated with T2DM risk, and A allele at this locus might be a susceptibility allele for the development of T2DM in Han Chinese population.
Li-Fraumeni Syndrome (LFS) is a rare hereditary cancer syndrome associated with germline mutations in the TP53 gene. While sarcomas, brain tumors, leukemias, breast and adrenal cortical carcinomas are typically recognized as LFS- associated tumors, the occurrence of gastrointestinal neoplasms has not been fully evaluated. In this analysis, we investigated the frequency and characteristics of gastric cancer (GC) in LFS.
Pedigrees and medical records of 62 TP53 mutation-positive families were retrospectively reviewed from the Dana-Farber/National Cancer Institute LFS registry. We identified subjects with GC documented either by pathology report or death certificate, and performed pathology review of the available specimens.
Among 62 TP53 mutation-positive families, there were 429 cancer-affected individuals. GC was the diagnosis in the lineages of 21 (4.9%) subjects from 14 families (22.6%). The mean and median ages at GC diagnosis were 43 and 36 years, respectively (range 24-74 years), significantly younger compared to the median age at diagnosis in the general population based on SEER data (71 years). Five (8.1%) families reported 2 or more cases of GC and 6 (9.7%) families had cases of both colorectal and gastric cancers. No association was seen between phenotype and type/location of the TP53 mutations. Pathology review of the available tumors revealed both intestinal and diffuse histologies.
Early-onset GC appears to be a component of LFS, suggesting the need for early and regular endoscopic screening in individuals with germline TP53 mutations, particularly among those with a family history of GC.
Li Fraumeni syndrome; gastric cancer; hereditary gastric cancer syndromes; germline mutations; TP53
White matter abnormalities can cause network dysfunction that underlies major depressive disorder (MDD). Diffusion tensor imaging (DTI) is used to examine the neural connectivity and integrity of the white matter. Previous studies have implicated frontolimbic neural networks in the pathophysiology of MDD. Approximately 30% of MDD patients demonstrate treatment-resistant depression (TRD). However, the neurobiology of TRD remains unclear.
We used a voxel-based analysis method to analyze DTI data in young patients with TRD (n = 30; 19 males, 11 females) compared with right-handed, age- and sex-matched healthy volunteers (n = 25; 14 males, 11 females).
We found a significant decrease in fractional anisotropy (FA) (corrected, cluster size >50) in the left middle frontal gyrus (peak coordinates [−18 46–14]), left limbic lobe uncus (peak coordinates [−18 2–22]), and right cerebellum posterior lobe (peak coordinates [26–34 -40]). There was no increase in FA in any brain region in patients. We also found a significant negative correlation between mean regional FA values in the three areas and Beck Depression Inventory symptom scores.
We found significant differences in white matter FA in the frontal lobe, limbic lobe and cerebellum between TRD patients and controls. These data suggest that abnormalities of cortical-limbic-cerebellar white matter networks may contribute to TRD in young patients.
Treatment-resistant depression; Diffusion tensor imaging; Fractional anisotropy; Voxel-based analysis method
The goal of this study was to understand the knowledge about AIDS, identify the correlates and determine the prevalence of HIV infection, syphilis, HCV among migrant workers in Zhejiang, China.
A cross-sectional study using face-to-face anonymous questionnaire interviews was conducted and blood samples were collected for HIV, syphilis and Hepatitis C infection screening.
17,377 (92.8%) of 18,730 migrant workers approached were interviewed. Among 17,377 participants, the HIV/AIDS knowledge rate was 66.2%. A total of 12,694 (73%) of the participants reported having ever had sexual intercourse, with 30.1% of single participants reporting having had sexual intercourse. Among those respondents with sexual experiences, 7.5% admitted they had two or more sexual partners and 4.9% reported having had sex with casual (unpaid) partners in the previous 12 months, whilst 3.7% had paid for sex. More than half of those who had paid for sex (59.4%) had not used a condom every time in their sexual acts with the sex workers. Multiple logistic regression analysis indicated that high risk sexual behavior (defined as sex with a casual or commercial sex partner without using a condom consistently) was associated with being divorced or widowed (P<0.05 for single); male gender; shorter duration of stay in Zhejiang; working in factory, market or domestic service (P<0.05 for odd job); having a province of origin inside Zhejiang; and drug use. The prevalence of HIV and HCV infections were 0.02% (95% CI: 0.01%–0.06%) and 0.40% (95%CI: 0.31%–0.51%), respectively. The prevalence of syphilis among those who were sexually active was 0.55% (95% CI: 0.43%–0.70%). Risk factors for syphilis included shorter duration of stay in Zhejiang, ethnic minority status, being divorced or widowed and having had multiple sex partners.
Much greater efforts are needed to promote safer sex, and programs for the control of syphilis need to be tailored for migrant workers in China.
The amyloid precursor protein (APP) has been under intensive study in recent years, mainly due to its critical role in the pathogenesis of Alzheimer's disease (AD). β-Amyloid (Aβ) peptides generated from APP proteolytic cleavage can aggregate, leading to plaque formation in human AD brains. Point mutations of APP affecting Aβ production are found to be causal for hereditary early onset familial AD. It is very likely that elucidating the physiological properties of APP will greatly facilitate the understanding of its role in AD pathogenesis. A number of APP loss- and gain-of-function models have been established in model organisms including Caenorhabditis elegans, Drosophila, zebrafish and mouse. These in vivo models provide us valuable insights into APP physiological functions. In addition, several knock-in mouse models expressing mutant APP at a physiological level are available to allow us to study AD pathogenesis without APP overexpression. This article will review the current physiological and pathophysiological animal models of APP.
Alzheimer's disease; APP; Aβ; knock-in; animal models
The regulation of alternative mRNA splicing factors by extracellular cues and signal transduction cascades is poorly understood. Using an engineered extracellular signal-regulated kinase 2 (ERK2) that can utilize ATP analogs, we have identified the alternative mRNA splicing factor 45 (SPF45), which is overexpressed in cancer, as a novel coimmunoprecipitating ERK2 substrate. ERK2 phosphorylated SPF45 on Thr71 and Ser222 in vitro and in cells in response to H-RasV12, B-RAF-V600E, and activated MEK1. Jun N-terminal kinase 1 (JNK1) and p38α also phosphorylated SPF45 in vitro and associated with SPF45 in cells. SPF45 was differentially phosphorylated in cells by all three mitogen-activated protein (MAP) kinases in response to phorbol myristate acid (PMA), H2O2, UV, and anisomycin stimulation. ERK and p38 activation decreased SPF45-dependent exon 6 exclusion from fas mRNA in a minigene assay in cells. Stable overexpression of SPF45 in SKOV-3 cells dramatically inhibited cell proliferation in a phosphorylation-dependent manner through inhibition of ErbB2 expression. SPF45 overexpression also induced EDA inclusion into fibronectin transcripts and fibronectin expression in a phosphorylation-dependent and -independent manner, respectively, specifically affecting cellular adhesion to a fibronectin matrix. These data identify SPF45 as the first splicing factor regulated by multiple MAP kinase pathways and show effects of both SPF45 overexpression and phosphorylation.
There is uncertainty and debate regarding whether ischemic mitral regurgitation (MR) is a secondary epiphenomenon resulting from left ventricular (LV) dysfunction or confers an independent effect on exercise capacity and outcomes. We tested whether ischemic MR negatively impacts exercise capacity, cardiovascular morbidity and mortality in patients with coronary artery disease (CAD) and inferior wall motion abnormality patients, independent of LV dysfunction. Clinical follow-up over 5 years was obtained in 77 patients (age 64±10 years, LVEF 54±11%) with at least mild ischemic MR from CAD and evidence of inferior wall motion abnormality, who had exercise stress testing with perfusion imaging within 24 hours of echocardiography. Patients with active heart failure, ischemia, intrinsic valve disease, pulmonary and vascular disease were excluded. Exercise capacity (METs, peak double product) was tested for relation to MR (vena contracta (VC) and jet area), LV size and function, and pulmonary pressures. Cox proportional hazards analysis assessed whether MR predicted cardiovascular events, including hospitalization for heart failure, acute coronary syndrome, and myocardial infarction, and cardiovascular (CV) and total mortality. Univariate correlation identified MR with both VC (r=−0.674, p<0.0001) and MR jet area (r=−0.575, p<0.0001) as determinants of reduced functional capacity evaluated by METs, with VC the stronger predictor. MR VC > 2 mm (moderate ischemic MR) and age were independent predictors of CV events and death (HR 6.72 for MR, p=0.04). In conclusion, in patients with CAD and LV inferior wall motion abnormality, MR impacts negatively on exercise capacity and is associated with increased cardiovascular morbidity and mortality. This effect appears independent of degree of LV dysfunction.
exercise capacity; ischemic mitral regurgitation
Two long-standing research problems of interest to sociologists are sources of variations in social inequalities and differential contributions of the temporal dimensions of age, time period, and cohort to variations in social phenomena. Recently, scholars have introduced a model called Variance Function Regression for the study of the former problem, and a model called Hierarchical Age-Period-Cohort regression has been developed for the study of the latter. This article presents an integration of these two models as a means to study the evolution of social inequalities along distinct temporal dimensions. We apply the integrated model to survey data on subjective health status. We find substantial age, period, and cohort effects, as well as gender differences, not only for the conditional mean of self-rated health (i.e., between-group disparities), but also for the variance in this mean (i.e., within-group disparities)—and it is detection of age, period, and cohort variations in the latter disparities that application of the integrated model permits. Net of effects of age and individual-level covariates, in recent decades, cohort differences in conditional means of self-rated health have been less important than period differences that cut across all cohorts. By contrast, cohort differences of variances in these conditional means have dominated period differences. In particular, post-baby boom birth cohorts show significant and increasing levels of within-group disparities. These findings illustrate how the integrated model provides a powerful framework through which to identify and study the evolution of variations in social inequalities across age, period, and cohort temporal dimensions. Accordingly, this model should be broadly applicable to the study of social inequality in many different substantive contexts.
Hierarchical-Age-Period-Cohort-Variance-Function-Regression Model; Hierarchical Age-Period-Cohort Model; Variance Function Regression Model; health disparities
Patients with periodontitis seek periodontal-orthodontic treatment to address certain functional and aesthetic problems. However, little is known of the effect of periodontitis on orthodontic treatment. Thus, we compared the differences in peptide mass fingerprints of orthodontic patients with and without periodontitis by MALDI-TOF MS using a magnetic bead-based peptidome analysis of saliva samples. In this way, we aimed to identify and explore a panel of differentially-expressed specific peptides.
Saliva samples from 24 patients (eight orthodontic patients without periodontitis, eight with periodontitis and another eight with periodontitis but no orthodontic treatment) were analyzed, and peptide mass fingerprints were created by scanning MS signals using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) combined with magnetic beads. Nine mass peaks showed significant differences. Orthodontic patients in the group without periodontal disease showed higher mass peaks for seven peptides of the nine, whereas the mass peaks for the other two peptides were higher in the periodontal-orthodontic patients. Besides, these differentially-expressed peptides were sequenced.
The elucidated candidate biomarkers indicated interactions between periodontal condition and orthodontic treatment and their contributions to the changes of saliva protein profiles. Our results provide novel insight into the altered salivary protein profile during periodontal-orthodontic treatment, and may lead to the development of a therapeutic monitoring strategy for periodontics and orthodontics.
Periodontal-orthodontic treatment; Peptidome; Saliva; MALDI-TOF MS
The transcription factor NFκB is an important mediator of cell survival and inflammation in the immune system. In the central nervous system (CNS), NFκB signaling has been implicated in regulating neuronal survival following acute pathologic damage such as traumatic brain injury (TBI) and stroke. NFκB is normally bound by the principal inhibitory protein, IκBα, and sequestered in the cytoplasm. Activation of NFκB requires the degradation of IκBα, thereby freeing NFκB to translocate to the nucleus and activate the target genes. Mice deficient in IκBα display deregulated and sustained NFκB activation and early postnatal lethality, highlighting a critical role of IκBα in NFκB regulation.
We investigated the role of IκBα in regulating NFκB activity in the brain and the effects of the NFκB/IκBα pathway in mediating neuroinflammation under both physiological and brain injury conditions. We report that astrocytes, but not neurons, exhibit prominent NFκB activity, and that basal NFκB activity in astrocytes is elevated in the absence of IκBα. By generating mice with brain-specific deletion of IκBα, we show that IκBα deficiency does not compromise normal brain development. However, basal neuroinflammation detected by GFAP and Iba1 immunoreactivity is elevated. This leads to impaired inflammatory responses following TBI and worsened brain damage including higher blood brain barrier permeability, increased injury volumes and enlarged ventricle volumes.
We conclude that, in the CNS, astrocyte is the primary cell type subject to NFκB regulation. We further demonstrate that IκBα plays an important role in regulating NFκB activity in the brain and a robust NFκB/IκBα-mediated neuroinflammatory response immediately following TBI is beneficial.
NFκB; IκBα; Conditional knockout mice; TBI; Neuroinflammation; Cerebral blood flow; MRI
The phosphoinositide 3-kinase/Akt/mammalian target of rapamycin pathway plays a critical role in the pathogenesis of hepatocellular carcinoma (HCC). We performed a single-arm, phase 1/2 study of everolimus in patients with advanced HCC.
Patients with histologically confirmed measurable advanced HCC, 0–2 prior regimens, and adequate hematologic, hepatic, and renal functions received everolimus at 5 mg/day or 10 mg/day orally (6 weeks/cycle). The primary end points were determination of a safe dosage of everolimus (phase 1) and progression-free survival (PFS) at 24 weeks (phase 2).
Twenty-eight patients were enrolled and evaluable for efficacy and toxicity. No dose-limiting toxicities were observed at the 5 mg/day (n = 3) or 10 mg/day (n = 6) dosage level in phase 1. Twenty-five patients received everolimus at 10 mg/day. Grade 3–4 adverse events included lymphopenia (n = 3), aspartate transaminase (n = 3), hyponatremia (n = 2), and 1 patient each with anemia, alanine transaminase, hyperglycemia, proteinuria, rash, and hypoxia. One patient (4%) had partial response (95% confidence interval [CI], 0.9%–19.6%). The median PFS and overall survival were 3.8 months (95% CI, 2.1–4.6) and 8.4 months (95% CI, 3.9–21.1), respectively. The estimated PFS rate at 24 weeks was 28.6% (95% CI, 7.9%–49.3%).
Everolimus was well tolerated in patients with advanced HCC, and 10 mg/day was defined as the phase 2 dosage. Although the study did not proceed to the second stage of phase 2, preliminary antitumor activity was observed with everolimus in patients with advanced HCC, most of whom had prior systemic treatment.
hepatocellular carcinoma; everolimus; mTOR inhibitors; angiogenesis; clinical trial
No targeted immunotherapies reverse type 1 diabetes in humans. However, in a rodent model of type 1 diabetes, Bacillus Calmette-Guerin (BCG) reverses disease by restoring insulin secretion. Specifically, it stimulates innate immunity by inducing the host to produce tumor necrosis factor (TNF), which, in turn, kills disease-causing autoimmune cells and restores pancreatic beta-cell function through regeneration.
Translating these findings to humans, we administered BCG, a generic vaccine, in a proof-of-principle, double-blind, placebo-controlled trial of adults with long-term type 1 diabetes (mean: 15.3 years) at one clinical center in North America. Six subjects were randomly assigned to BCG or placebo and compared to self, healthy paired controls (n = 6) or reference subjects with (n = 57) or without (n = 16) type 1 diabetes, depending upon the outcome measure. We monitored weekly blood samples for 20 weeks for insulin-autoreactive T cells, regulatory T cells (Tregs), glutamic acid decarboxylase (GAD) and other autoantibodies, and C-peptide, a marker of insulin secretion. BCG-treated patients and one placebo-treated patient who, after enrollment, unexpectedly developed acute Epstein-Barr virus infection, a known TNF inducer, exclusively showed increases in dead insulin-autoreactive T cells and induction of Tregs. C-peptide levels (pmol/L) significantly rose transiently in two BCG-treated subjects (means: 3.49 pmol/L [95% CI 2.95–3.8], 2.57 [95% CI 1.65–3.49]) and the EBV-infected subject (3.16 [95% CI 2.54–3.69]) vs.1.65 [95% CI 1.55–3.2] in reference diabetic subjects. BCG-treated subjects each had more than 50% of their C-peptide values above the 95th percentile of the reference subjects. The EBV-infected subject had 18% of C-peptide values above this level.
We conclude that BCG treatment or EBV infection transiently modified the autoimmunity that underlies type 1 diabetes by stimulating the host innate immune response. This suggests that BCG or other stimulators of host innate immunity may have value in the treatment of long-term diabetes.
The A1C-Derived Average Glucose (ADAG) study demonstrated a linear relationship between HbA1c and mean plasma glucose (MPG). As glucose variability (GV) may contribute to glycation, we examined the association of several glucose variability indices and the MPG-HbA1c relationship.
RESEARCH DESIGN AND METHODS
Analyses included 268 patients with type 1 diabetes and 159 with type 2 diabetes. MPG during 3 months was calculated from 7-point self-monitored plasma glucose and continuous glucose monitoring. We calculated three different measures of GV and used a multiple-step regression model to determine the contribution of the respective GV measures to the MPG-HbA1c relationship.
GV, as reflected by SD and continuous overlapping net glycemic action, had a significant effect on the MPG-HbA1c relationship in type 1 diabetic patients so that high GV led to a higher HbA1c level for the same MPG. In type 1 diabetes, the impact of confounding and effect modification of a low versus high SD at an MPG level of 160 mg/dL on the HbA1c level is 7.02 vs. 7.43 and 6.96 vs. 7.41. All GV measures showed the same tendency.
In only type 1 diabetic patients, GV shows a significant interaction with MPG in the association with HbA1c. This effect is more pronounced at higher HbA1c levels. However, the impact of GV on the HbA1c level in type 1 diabetes is modest, particularly when HbA1c is close to the treatment target of 7%.
To understand the incidence of outpatient influenza cases in a subtropical area of China and the associated economic burden on patients' families.
A hospital-based prospective study was conducted in Zhuhai City during 2008–2009. All outpatient influenza-like illness (ILI) cases were identified in 28 sentinel hospitals. A representative sample of throat swabs from ILI cases were collected for virus isolation using Madin-Darby canine kidney cells. The incidence of outpatient influenza cases in Zhuhai was estimated on the basis of the number of influenza patients detected by the sentinel sites. A telephone survey on the direct costs associated with illness was conducted as a follow-up.
The incidence of influenza was estimated to be 4.1 per 1,000 population in 2008 and 19.2 per 1,000 population in 2009. Children aged <5 years were the most-affected population, suffering from influenza at the highest rates (34.3 per 1,000 population in 2008 and 95.3 per 1,000 population in 2009). A high incidence of 29.2–40.9 per 1000 population was also seen in young people aged 5–24 years in 2009. ILI activity and influenza virus isolations adopted a consistent seasonal pattern, with a summer peak in July 2008 and the longest epidemic period lasting from July–December 2009. The medical costs per episode of influenza among urban patients were higher than those for rural patients. A total of $1.1 million in direct economic losses were estimated to be associated with outpatient influenza during 2008–2009 in Zhuhai community.
Influenza attacks children aged <5 years in greater proportions than children in other age groups. Seasonal influenza 2008 and Pandemic influenza A (H1N1) 2009 had different epidemiological and etiological characteristics. Direct costs (mostly medical costs) impose an enormous burden on the patient family. Vaccination strategies for high-risk groups need to be further strengthened.