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.

Precisely and Efficiently Enzyme Response Microspheres with Immune Removal Escape Loaded with MCC950 Ameliorate Cardiac Dysfunction in Acute Myocardial Infarction.

Although the percutaneous coronary intervention (PCI)treatment can improve the survival rate of acute myocardial infarction (AMI) patients, the early granulocytes response within 6 hours can induce second injuries during the reperfusion process. The new drug delivery system MMP9 hydrolytic microspheres (NMM) with negatively charged surface was designed out and MCC950 (MCC) was loaded into NMM (NMM-M), MCC is the inhibitor of nucleotide binding oligomerization domain (NOD)-like receptor, pyrin containing domain 3 (NLRP3)-inflammasome which is the key promoter of granulocytes-induced injury. NMM-M could effectively escape the phagocytosis of immune phagocytes in the blood, and target the ischemic region based on the electrostatic attraction and the attraction of enzyme to substrate, and sudden release the loaded MCC within 2 hours. The released MCC can inhibit the NLRP3-inflammasome activity, and then further inhibit the secretion of inflammatory factors in granulocytes which are the main factors of early inflammatory damage, and improving cardiac function, realizing the goal of pre-treatment. Therefore, NMM may be a new delivery system, which can provide the accurately, sufficient and rapidly drug deliver, and MCC may be a novel candidate drug in AMI treatment, which may be hopeful in the future.

Toxicity and mechanism of mesoporous silica nanoparticles in eyes.

The study on the safety of nanomaterials in eyes is still in its early stages. In this study, we put our focus on the effect of one important nanoparticle feature - large surface area - to assess eye safety. To this end, mesoporous silica nanoparticles (MSiNPs) were for the first time employed as a model to evaluate their toxicity in eyes. The porosity of the MSiNPs endows them with a large surface area and the ability to attach to surrounding chemical or biological molecules, further enhancing their surface reactivity and toxic effects. Therefore, to better mimic MSiNP exposure in real environments, we also introduced other hazardous substances such as silver ions (Ag+) to the system and then investigated their synergistic nanotoxicity. Our results showed that the exposure to MSiNPs-Ag+ and even Ag+ at a safe dose, resulted in more significant toxicity than the MSiNPs alone, as evidenced from cell viability, apoptosis, reactive oxygen species (ROS) production, and DNA damage experiments. RNA-Sequencing analysis revealed that the mRNA surveillance signalling pathway plays a unique role in regulating MSiNPs-Ag+-induced cytotoxicity. Besides this, severe corneal damage and dry eye were observed in rat models upon exposure to MSiNPs-Ag+ compared to MSiNPs. Most importantly, we also proposed a protein corona-based therapy to treat MSiNP-induced corneal disease, where the corneal damage could be rescued by fetal bovine serum (FBS) treatment.

Rescue of Retinal Degeneration in rd1 Mice by Intravitreally Injected Metformin.

Retinitis pigmentosa (RP) is a progressive hereditary retinal degenerative disease in which photoreceptor cells undergo degeneration and apoptosis, eventually resulting in irreversible loss of visual function. Currently, no effective treatment exists for this disease. Neuroprotection and inflammation suppression have been reported to delay the development of RP. Metformin is a well-tested drug used to treat type 2 diabetes, and it has been reported to exert beneficial effects in neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease. In the present study, we used immunofluorescence staining, electroretinogram (ERG) recordings and RNA-Seq to explore the effects of metformin on photoreceptor degeneration and its mechanism in rd1 mice. We found that metformin significantly reduced apoptosis in photoreceptors and delayed the degeneration of photoreceptors and rod bipolar cells in rd1 mice, thus markedly improving the visual function of rd1 mice at P14, P18, and P22 when tested with a light/dark transition test and ERG. Microglial activation in the outer nuclear layer (ONL) of the retina of rd1 mice was significantly suppressed by metformin. RNA-Seq showed that metformin markedly downregulated inflammatory genes and upregulated the expression of crystallin proteins, which have been demonstrated to be important neuroprotective molecules in the retina, revealing the therapeutic potential of metformin for RP treatment. αA-crystallin proteins were further confirmed to be involved in the neuroprotective effects of metformin in a Ca2+ ionophore-damaged 661W photoreceptor-like cell line. These data suggest that metformin exerts a protective effect in rd1 mice via both immunoregulatory and new neuroprotective mechanisms.

Olfactory Ensheathing Cells Grafted Into the Retina of RCS Rats Suppress Inflammation by Down-Regulating the JAK/STAT Pathway.

The inflammatory microenvironment in the retina plays a vital role in the pathogenesis and progression of retinitis pigmentosa (RP). Microglial inflammatory cytokines production leads to gliosis and apoptosis of retinal neurons, and ultimately, visual loss. Cell-based therapies using grafted olfactory ensheathing cells (OECs) have demonstrated modulation of degenerative microenvironments in the central nervous system (CNS), in a number of animal models. However, mechanisms by which grafted OECs can reduce degeneration in the retina are not well understood. In the present study, we set up an in vitro OEC/BV2 microglia co-culture system, and an in vivo royal college of surgeons (RCS) rat model, used cell transplantation, immunohistochemistry, RT-PCR, western blot to explore the mechanisms by which OECs affect expression of pro- or anti-inflammatory cytokines and polarization of M(IL-6) and M(Arg1) type microglial activation in the retina. We found that compared with the LPS (Lipopolysaccharide) and olfactory nerve fibroblast (ONF), the OEC and BV2 co-culture group modulate microglial cytokines releasing toward the anti-inflammation, and away from the pro-inflammation, which was followed by higher IL-4 and IL-10 and lower TNF-a and IL-6 in their expression levels. In vivo, the transplantation group significantly reduced activated resident microglia/infiltrated macrophage, and expression of pro-inflammatory cytokines in RCS rats retina, increased anti-inflammatory cytokines in transplantation area. Additionally, we found that OECs expressed SOCS3 and down-regulated the JAK2/STAT3 (Janus Kinase 2/Signal Transducer and Activator of Transcription 3) pathway. Thirdly, OEC transplantation reduced Caspase-3 expression, protected inner retinal neurons and photoreceptors and therefore, delayed the visual function degeneration. In conclusion, our data suggest that OECs delay retinal degeneration in RP, at least in part through immunomodulation of microglia via the JAK/STAT pathway.

Epothilone B Benefits Nigral Dopaminergic Neurons by Attenuating Microglia Activation in the 6-Hydroxydopamine Lesion Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is characterized by loss of dopamine (DA) neurons in the substantia nigra pars compacta (SNc) and a subsequent reduction in striatal DA levels. Recent studies have shown that systemic administration of subtoxic doses of epothilone B (EpoB), a microtubule stabilizing agent, enhances axonal regeneration. However, the underlying alterations in cellular mechanisms remain undetermined. In the present study, we investigated the neuroprotective effects of EpoB on DA neurons in mouse model of PD induced by 6-hydroxyDA (6-OHDA) and in vitro. The results indicated that EpoB improved behavioral deficits, protected the nigrostriatal dopaminergic projections and restored DA level in the striatum of mice exposed to 6-OHDA. Meanwhile, EpoB attenuated microglia activation in the SNc of PD mice. Furthermore, EpoB treatment ameliorated 6-OHDA induced cytotoxicity to MN9D dopaminergic cells in a co-culture transwell system of BV2/MN9D cells, and redistributed the cytoskeleton of microglial BV2 and caused the morphological transition, inhibited the polarization to the M1 phenotype by suppressing expression of pro-inflammatory factors including interleukin (IL)-1ß, IL-6 and tumor necrosis factor (TNF)-α. Overall, our study suggested that EpoB treatment protects nigral DA neurons and projections through limiting the cytotoxicity of activated microglia in 6-OHDA lesioned mice.

Citalopram restores short-term memory deficit and non-cognitive behaviors in APP/PS1 mice while halting the advance of Alzheimer's disease-like pathology.

Alzheimer's disease (AD) is the most common cause of dementia. In addition to cognitive impairments, deficits in non-cognitive behaviors are also common neurological sequelae in AD. Here, we show that complex behavioral deficits in 7-month-old APPswe/PSEN1dE9 (APP/PS1) mice include impairments in object recognition, deficient social interaction, increased depression and buried marbles. Citalopram, one of the selective serotonin reuptake inhibitors (SSRIs), ameliorated the amyloid deposition in AD patients and transgenic animal models. After treatment for 4 weeks, citalopram rescued the deficits in short-term memory, sociability and depression in these mice. Further immunohistochemical analysis showed chronic citalopram treatment significantly attenuated ß-amyloid deposition and microglial activation in the brains of APP/PS1 mice as demonstrated previously. Parvalbumin (PV) interneurons, which are the primary cellular subtype of GABAergic neurons and considered indispensable for short-term memory and social interaction, also contributed to the progress of depression. Additionally, we found the citalopram could significantly increase the PV-positive neurons in the cortex of APP/PS1 mice without alteration in the hippocampus, which might contribute to the improvement of behavioral performance. Our findings suggest that citalopram might be a potential candidate for the early treatment of AD.

Toxicity of silicon dioxide nanoparticles with varying sizes on the cornea and protein corona as a strategy for therapy.

The human cornea is exposed directly to particulate matter (PM) in polluted air. This exposure can cause eye discomfort and corneal injury. Ultrafine PM (diameter <100 nm) is thought to be particularly harmful to health, but there is limited research investigating its toxicity to the eye. In this study, we evaluated toxicity differences among 30-, 40-, 100- and 150-nm silicon dioxide nanoparticles (SiO2 NPs) on the cornea. A 24-hour in vitro exposure of primary human corneal epithelial cells (hCECs) to ultrafine (30 and 40 nm) SiO2 NPs produced toxicity, as evidenced by cell membrane damage, reduced cell viability, increased cell death and mitochondrial dysfunction. In vivo exposure to the same nanoparticles produced observable corneal injury. These effects were more severe with ultrafine than with fine (100 and 150 nm) SiO2 NPs. Common antioxidant compounds, e.g., glutathione, did not protect the cornea from SiO2 NP-induced damage. However, foetal bovine serum (FBS) did significantly reduce toxicity, likely by forming a protective protein corona around the nanoparticles. This finding suggests that FBS (or its derivatives) may be a useful clinical therapy for corneal toxicity caused by ultrafine particulates.

Direct reprogramming of fibroblasts into neural stem cells by single non-neural progenitor transcription factor Ptf1a.

Induced neural stem cells (iNSCs) reprogrammed from somatic cells have great potentials in cell replacement therapies and in vitro modeling of neural diseases. Direct conversion of fibroblasts into iNSCs has been shown to depend on a couple of key neural progenitor transcription factors (TFs), raising the question of whether such direct reprogramming can be achieved by non-neural progenitor TFs. Here we report that the non-neural progenitor TF Ptf1a alone is sufficient to directly reprogram mouse and human fibroblasts into self-renewable iNSCs capable of differentiating into functional neurons, astrocytes and oligodendrocytes, and improving cognitive dysfunction of Alzheimer's disease mouse models when transplanted. The reprogramming activity of Ptf1a depends on its Notch-independent interaction with Rbpj which leads to subsequent activation of expression of TF genes and Notch signaling required for NSC specification, self-renewal, and homeostasis. Together, our data identify a non-canonical and safer approach to establish iNSCs for research and therapeutic purposes.

Bioconcentration kinetics of PCBs in various parts of the lifecycle of the tadpoles Xenopus laevis.

Polychlorinated biphenyls (PCBs) in Xenopus laevis have been reported only for a few congeners. Additionally, there is very little information on the ability of Xenopus laevis to bioconcentrate PCBs. To address these issues, the tadpole Xenopus laevis was exposed to Aroclor1254 mixtures in water at room temperature for 110 d followed by an additional 110 d of nonspiked PCBs in the water for the control group. During the whole process, bioconcentration factors (BCFs) of PCBs ranged from 1180 to 15670. For most PCB congeners, the highest and lowest bioconcentrations of the kinetic curves were found to be remarkably simultaneous, respectively. All 141 PCB congeners under the same experimental conditions had no linear correlation on the lgBCF versus lgK(ow) relationship. The relationship between lgBCFs and lgK(ow) followed a parabolic pattern indicative of selective bioconcentration, suggesting that the kinetic curves of the PCB congeners observed in the lifecycle of the tadpoles may be concentrated due to the amphibian special species and internal metabolism. In contrast, lgBCFs for PCBs were inversely related to lgK(ow), suggesting that a metabolism of the higher K(ow)' PCB congeners occurred. These results support the author's conclusion that the tadpole Xenopus laevis plays major roles in the bioconcentration of PCB congeners, and demonstrated that the exposure kinetic curves of PCB congeners are complex. Besides the amphibian metamorphous development, the lifecycle of the tadpole Xenopus laevis also may be of importance in determining the bioconcentration of PCB congeners.