A flexible time-varying coefficient rate model for panel count data.

Panel count regression is often required in recurrent event studies, where the interest is to model the event rate. Existing rate models are unable to handle time-varying covariate effects due to theoretical and computational difficulties. Mean models provide a viable alternative but are subject to the constraints of the monotonicity assumption, which tends to be violated when covariates fluctuate over time. In this paper, we present a new semiparametric rate model for panel count data along with related theoretical results. For model fitting, we present an efficient EM algorithm with three different methods for variance estimation. The algorithm allows us to sidestep the challenges of numerical integration and difficulties with the iterative convex minorant algorithm. We showed that the estimators are consistent and asymptotically normally distributed. Simulation studies confirmed an excellent finite sample performance. To illustrate, we analyzed data from a real clinical study of behavioral risk factors for sexually transmitted infections.

Regression analysis of general mixed recurrent event data.

In modern biomedical datasets, it is common for recurrent outcomes data to be collected in an incomplete manner. More specifically, information on recurrent events is routinely recorded as a mixture of recurrent event data, panel count data, and panel binary data; we refer to this structure as general mixed recurrent event data. Although the aforementioned data types are individually well-studied, there does not appear to exist an established approach for regression analysis of the three component combination. Often, ad-hoc measures such as imputation or discarding of data are used to homogenize records prior to the analysis, but such measures lead to obvious concerns regarding robustness, loss of efficiency, and other issues. This work proposes a maximum likelihood regression estimation procedure for the combination of general mixed recurrent event data and establishes the asymptotic properties of the proposed estimators. In addition, we generalize the approach to allow for the existence of terminal events, a common complicating feature in recurrent event analysis. Numerical studies and application to the Childhood Cancer Survivor Study suggest that the proposed procedures work well in practical situations.

Liver X receptor ß regulates the development of the dentate gyrus and autistic-like behavior in the mouse.

The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor ß (LXRß) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRß in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRß-null mice. In addition, LXRß deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRß in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRß-deficient mice.

Insight into the correlation between biochar amendment and shifts in bacterial community 4 years after a single incorporation in soybean- and maize-planted soils in northeastern China.

To date, there have been few reports examining the correlation between biochar treatments, crop species, and microbiome shifts. In this study, shifts in the soil bacterial community were investigated 4 years after a single incorporation of biochar in soils planted with soybeans and maize. Clear changes in the bacterial community composition and structure were detected in the soybean-planted soil amended with low-titer biochar (7.89 t/ha), whereas such changes in the maize-planted soil were not observed at the same biochar amendment rate, suggesting a more sensitive influence on the bacterial community in the soybean-planted soil than that in the maize-planted soil. Bacterial abundance in the maize-planted soil was reduced significantly with increasing biochar addition (15.78 and 47.34 t/ha), which was probably due to the inhibitory substances originating from biochar. Both the bacterial community and biomarkers in soil under biochar amendment varied with planted crops, bacterial communities responding differently to biochar amendment. All these results suggested that biochar might influence the bacterial community in maize- and soybean-growing soils under different mechanisms. Our findings should be valuable for an in-depth understanding of the potential mechanism of soil microbiome changes following biochar incorporation and for biochar application in agriculture.

Variable selection for recurrent event data with broken adaptive ridge regression.

Recurrent event data occur in many areas such as medical studies and social sciences and a great deal of literature has been established for their analysis. On the other hand, only limited research exists on the variable selection for recurrent event data, and the existing methods can be seen as direct generalizations of the available penalized procedures for linear models and may not perform as well as expected. This article discusses simultaneous parameter estimation and variable selection and presents a new method with a new penalty function, which will be referred to as the broken adaptive ridge regression approach. In addition to the establishment of the oracle property, we also show that the proposed method has the clustering or grouping effect when covariates are highly correlated. Furthermore, a numerical study is performed and indicates that the method works well for practical situations and can outperform existing methods. An application is provided.

Une riche littérature traite de l'analyse des événements récurrents, un type de données observé notamment dans les études médicales et dans les projets de recherche en sciences sociales. Par contre, peu de résultats de recherche portent sur la sélection de variables pour ces modèles. Les méthodes existantes peuvent être vues comme une généralisation directe de procédures pénalisées disponibles pour les modèles linéaires et peuvent offrir des performances inférieures aux attentes. Les auteurs proposent l'approche de régression ridge brisée adaptative où ils procèdent simultanément à l'estimation de paramètres et à la sélection de variables en exploitant une nouvelle fonction de pénalité. Ils prouvent la propriété d'oracle de leur méthode et montrent qu'elle possède une propriété de regroupement lorsque les covariables sont hautement corrélées. Ils présentent une étude numérique qui indique que leur méthode fonctionne bien dans des situations pratiques et peut même s'avérer plus performante que les approches existantes. Ils fournissent également un exemple d'application.

Curcumin Delays Retinal Degeneration by Regulating Microglia Activation in the Retina of rd1 Mice.

BACKGROUND/AIMS: Retinitis pigmentosa (RP) is characterized by degeneration of photoreceptors, and there are currently no effective treatments for this disease. However, curcumin has shown neuroprotectant efficacy in a RP rat and swine model, and thus, may have neuroprotective effects in this disease. METHODS: Immunofluorescence staining, electroretinogram recordings, and behavioral tests were used to analyze the effects of curcumin and the underlying mechanism in retinal degeneration 1 (rd1) mice. RESULTS: The number of apoptotic cells in the retina of rd1 mice at postnatal day 14 significantly decreased with curcumin treatment and visual function was improved. The activation of microglia and secretion of chemokines and matrix metalloproteinases in the retina were inhibited by curcumin. These effects were also observed in a co-culture of BV2 microglial cells and retina-derived 661W cells. CONCLUSIONS: Curcumin delayed retinal degeneration by suppressing microglia activation in the retina of rd1 mice. Thus, it may be an effective treatment for neurodegenerative disorders such as RP.

Stem-cell challenges in the treatment of Alzheimer's disease: a long way from bench to bedside.

Alzheimer's disease (AD) is the most prevalent type of dementia, and its neuropathology is characterized by deposition of insoluble ß-amyloid peptides, intracellular neurofibrillary tangles, and the loss of diverse neurons. Current pharmacological treatments for AD relieve symptoms without affecting the major pathological characteristics of the disease. Therefore, it is essential to develop new and effective therapies. Stem-cell types include tissue-specific stem cells, such as neural stem cells and mesenchymal stem cells, embryonic stem cells derived from blastocysts, and induced pluripotent stem cells (iPSCs) reprogrammed from somatic cells. Recent preclinical evidence suggests that stem cells can be used to treat or model AD. The mechanisms of stem cell based therapies for AD include stem cell mediated neuroprotection and trophic actions, antiamyloidogenesis, beneficial immune modulation, and the replacement of the lost neurons. iPSCs have been recently used to model AD, investigate sporadic and familial AD pathogenesis, and screen for anti-AD drugs. Although considerable progress has been achieved, a series of challenges must be overcome before stem cell based cell therapies are used clinically for AD patients. This review highlights the recent experimental and preclinical progress of stem-cell therapies for AD, and discusses the translational challenges of their clinical application.

Engineering hiPSC-CM and hiPSC-EC laden 3D nanofibrous splenic hydrogel for improving cardiac function through revascularization and remuscularization in infarcted heart.

Cell therapy has been a promising strategy for cardiac repair after myocardial infarction (MI), but a poor ischemic environment and low cell delivery efficiency remain significant challenges. The spleen serves as a hematopoietic stem cell niche and secretes cardioprotective factors after MI, but it is unclear whether it could be used for human pluripotent stem cell (hiPSC) cultivation and provide a proper microenvironment for cell grafts against the ischemic environment. Herein, we developed a splenic extracellular matrix derived thermoresponsive hydrogel (SpGel). Proteomics analysis indicated that SpGel is enriched with proteins known to modulate the Wnt signaling pathway, cell-substrate adhesion, cardiac muscle contraction and oxidation-reduction processes. In vitro studies demonstrated that hiPSCs could be efficiently induced into endothelial cells (iECs) and cardiomyocytes (iCMs) with enhanced function on SpGel. The cytoprotective effect of SpGel on iECs/iCMs against oxidative stress damage was also proven. Furthermore, in vivo studies revealed that iEC/iCM-laden SpGel improved cardiac function and inhibited cardiac fibrosis of infarcted hearts by improving cell survival, revascularization and remuscularization. In conclusion, we successfully established a novel platform for the efficient generation and delivery of autologous cell grafts, which could be a promising clinical therapeutic strategy for cardiac repair and regeneration after MI.

TLR4 monoclonal antibody blockade suppresses dextran-sulfate-sodium-induced colitis in mice.

BACKGROUND AND AIM: Ulcerative colitis (UC) refers to a kind of inflammatory bowel disease, of which the accurate pathogenesis is not yet well understood. Recently, the toll-like receptor 4 (TLR4) and the TLR4 signaling pathway have been proved as playing an important role in the pathogenesis of UC. The objective of this study was to evaluate the effect of TLR4 monoclonal antibody on dextran-sulfate-sodium-induced colitis in a mouse model. METHODS: We evaluated the effects of the TLR4 monoclonal antibody (TLR4mAb) on the development of dextran-sulfate-sodium-(DSS)-induced colitis. Tissue samples were evaluated by the disease activity index and histopathological score. Meanwhile, the mucosal mRNA expression of cytokines, tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta were analyzed by semiquantitative reverse transcription polymerase chain reaction. The mucosal protein P38-MAPK, c-jun and c-fos expressions of the TLR4-P38MAPK pathway were analyzed using Western blot. RESULTS: After the treatment with TLR4mAb against DSS-induced colitis, the bodyweight was significantly increased and both disease activity index and histopathological score were decreased significantly. Furthermore, the mucosal expression of messenger RNA of tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta were observed to be 8-15-fold more than the baseline, whereas the mucosal expressions of P38MAPK and c-jun were found to be decreased. CONCLUSION: Blocking TLR4 by TLR4mAb can prevent the development of DSS-induced colitis through the TLR4-P38MAPK-c-jun pathway.

Iron deficiency anaemia can be improved after eradication of Helicobacter pylori.

BACKGROUND: Recent guidelines on iron deficiency anaemia (IDA) have confirmed the aetiological role of Helicobacter pylori (H pylori), but the relationship still remains controversial. METHODS: Starting in May 2009, searches of the following databases were undertaken: Medline (1966 to April 2009), Embase (1980 to April 2009), the Cochrane library (1800 to June 2008), Cochrane Central Register of Controlled Trials, Premedline, Healthstar, CBMdisc and the Chinese National Knowledge Infrastructure Database (January 1970 to April 2009). Changes in haemoglobin (Hb) concentrations and serum ferritin (SF) concentrations were recorded for intervention and control groups. The meta-analysis used random effect models and subgroup analyses were performed to explain heterogeneity. RESULTS: Eight studies met the inclusion criteria. All studies were performed in Asia, an area with a high incidence of IDA and H pylori. The pooled analysis of eight studies showed that H pylori eradication therapy can improve IDA, since changes in Hb and SF concentrations in the intervention groups were higher than in controls. The weighted mean difference (WMD) of Hb was 12.88 g/l (95% CI 6.03 to 19.74 g/l, p<0.00001); the WMD of SF was 10.05 mug/l (95% CI 5.48 to 14.63 mug/l, p<0.00001). CONCLUSIONS: H pylori eradication therapy combined with iron administration is more effective than iron administration alone for the treatment of IDA. Eradication therapy has different effects on adults and children. Bismuth based triple therapy has a better response in terms of increased Hb and SF concentrations than proton pump inhibitor (PPI) based triple therapy.