Morphine pharmacokinetics following intra-articular administration of a novel sustained release opioid (CDS-PM-101) for the relief of post-operative orthopaedic pain.
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Animals↗
Biomedical subjects
J Chen
Publications and source records attributed to J Chen.
Porcine small intestine submucosa (SIS) is not an acellular collagenous matrix and contains porcine DNA: possible implications in human implantation.
Porcine small intestinal submucosa (SIS) has been recommended as a cell-free, biocompatible biomaterial for the repair of rotator cuff tendon tear. However, we have observed noninfectious edema and severe pain in patients who have undergone SIS implantation for tendon repair. The aim of this study was to conduct an independent assessment of the safety and efficacy of Restore SIS membrane. The Restore orthobiologic implant was examined by histology and the nested PCR technique using porcine immunoreceptor DAP12 gene to examine if SIS membrane contained porcine cells or DNA, respectively. The material was also implanted into mice and rabbits for the evaluation of biological reaction and inflammatory response. Restore SIS was found to contain multiple layers of porcine cells. Chloroacetate esterase staining showed that some of these cells were mast cells. Nested PCR of the DAP12 gene demonstrated that Restore SIS contained porcine DNA material. Subcutaneous implantation of Restore SIS membrane in mice, and in rabbits for rotator cuff tendon repair, showed that the membrane caused an inflammatory reaction characterized by massive lymphocyte infiltration. In conclusion, Restore SIS is not an acellular collagenous matrix, and contains porcine DNA. Our results contradict the current view that Restore SIS is a cell-free biomaterial, and that no inflammatory response is elicited by its implantation. We suggest that further studies should be conducted to evaluate the clinical safety and efficacy of SIS implant biomaterials.
Adaptor Proteins, Signal Transducing↗
Measuring injury and repair of myelin and neurons in multiple sclerosis.
Neuroprotection in MS needs to be considered in the context of several pathological processes: limitation of acute inflammatory injury to myelin and axons, remyelination, survival of demyelinated axons, and limitation of more diffuse, nonlesional pathology that affects myelin and axons. Advanced MRI techniques are capable of reporting on all of these different pathological features of MS and will be an important aspect of the assessment of neuroprotection strategies in MS, when these become available.
Animals↗
The role of D1 dopamine receptors and phospho-ERK in mediating cytotoxicity. Commentary.
Striatal neurodegeneration observed in several neurological diseases, occurs through unknown mechanisms. Recent evidence suggests that its pathogenesis may be linked, in part, to high synaptic levels of dopamine (DA), which can then cause neurotoxicity of striatal neurons through mitogen-activated protein kinases (MAPKs). Here we comment on the role of extracellular signal-regulated kinase (ERK) activation in the cytotoxicity mediated upon activation of the D1 DA receptor, and describe a possible mechanism for phospho-ERK (p-ERK) in inducing cytotoxicity.
Animals↗
Motexafin gadolinium induces mitochondrially-mediated caspase-dependent apoptosis.
Motexafin gadolinium (MGd, Xcytrin) is a tumor-localizing redox mediator that catalyzes the oxidation of intracellular reducing molecules including NADPH, ascorbate, protein and non-protein thiols, generating reactive oxygen species (ROS). MGd localizes to tumors and cooperates with radiation and chemotherapy to kill tumor cells in tissue culture and animal models. In this report, we demonstrate that MGd triggers the mitochondrial apoptotic pathway in the HF-1 lymphoma cell line as determined by loss of mitochondrial membrane potential, release of cytochrome c from mitochondria, activation of caspase-9 prior to caspase-8, cleavage of PARP and annexin V binding. There was minimal effect on MGd-induced apoptosis by the caspase inhibitor z-VAD-fmk, even though caspase-3 activity (as measured by DEVD-cleavage) was completely inhibited. However, MGd-induced apoptosis was reduced to baseline levels by the more potent caspase inhibitor Q-VD-OPh, demonstrating that MGd-induced apoptosis is indeed caspase-dependent. Apoptosis induced by dexamethasone, doxorubicin and etoposide (mediated through the mitochondrial pathway) was also more sensitive to inhibition by Q-VD-OPh than z-VAD-fmk. Our results demonstrating differential sensitivity of drug-induced apoptosis to caspase inhibitors suggest that the term "caspase-independent apoptosis" cannot be solely defined as apoptosis that is not inhibited by z-VAD-fmk as has been utilized in some published studies.
Amino Acid Chloromethyl Ketones↗
Improved psychomotor performance in aged mice fed diet high in antioxidants is associated with reduced ex vivo brain interleukin-6 production.
Psychomotor performance is decreased in the aged. This study investigated the relationship between brain oxidative stress, interleukin-6 (IL-6) production by brain tissue ex vivo and psychomotor deficits during aging, and the effects of feeding an antioxidant-rich diet on ex vivo brain IL-6 production and motor function in aged mice. Male BALBc mice reared in SPF conditions and ranging in age from 3 to 24 months were studied. There was a precipitous decline in motor function after 12 months of age and an increase in brain lipid peroxidation and IL-6 production by coronal brain slices ex vivo. In another study, 12-month-old mice were fed diets formulated to provide a disparate range of antioxidants. At 18 months of age psychomotor coordination, motor learning, and ex vivo brain IL-6 production were evaluated. Mice fed an antioxidant-rich diet had improved psychomotor coordination compared to mice fed diet adequate or low in antioxidants. When mice were tested on successive days, only those fed adequate and high antioxidants exhibited motor learning. Analysis of IL-6 production by coronal brain slices indicated that as dietary antioxidants increased, IL-6 production decreased. Collectively, these data indicate that antioxidants improve psychomotor performance in aged mice, and suggest antioxidants may be useful for reducing brain IL-6 production, which has been shown to increase in aged mice.
Aging↗
Tissue- and bone cell-specific expression of bone sialoprotein is directed by a 9.0 kb promoter in transgenic mice.
Bone sialoprotein (BSP) is a phosphorylated glycoprotein that is expressed almost exclusively in mineralizing connective tissues. In bone, expression of BSP correlates with the differentiation of osteoblasts and the onset of mineralization. To determine how the tissue- and differentiation-specific transcription of BSP is regulated, various lengths of promoter sequence were ligated to a luciferase reporter and stably transfected into a rat stromal bone marrow cell line, RBMC-D8 and undifferentiated C3H10T1/2 cells. Luciferase transcription of reporter constructs including 5.4 kb (mBSP5.4Luc) and 9.0 kb (mBSP9.0Luc) of the BSP promoter was strongly up-regulated in parallel with endogenous BSP mRNA in differentiating SBMCs, but not in C3H10T1/2 cells. In contrast, 0.1 kb and 1.4 kb BSP promoter constructs did not show selective expression. To determine tissue-specific expression in vivo, transgenic mice expressing reporter constructs for the 9.0 kb promoter and a 4.8 kb promoter lacking two upstream Cbfa1/Runx2 elements (mBSP9.0Luc and mBSP4.8Luc, respectively) were generated. Analysis of various tissues collected from 1-, 4-, 7-, 14-, and 42-day-old mice revealed extremely high levels of luciferase activity in calvaria, mandible, and tibia of the mBSP9.0Luc mice. In contrast, soft tissues showed negligible luciferase expression. Mice harboring the 4.8 kb transgene also showed selective luciferase expression but displayed a significantly lower activity in mineralized tissues. Northern hybridization of endogenous BSP mRNA and immunostaining of BSP in mBSP9.0Luc mice showed a temporo-spatial expression pattern consistent with the luciferase activity. These results indicate that regulatory elements within the 9.0 kb region of the promoter are required for strong, tissue- and differentiation-specific expression of BSP.
Animals↗
Variation of CD4+ and CD8+ T lymphocytes as predictor of outcome in renal allograft recipients who developed acute respiratory distress syndrome caused by cytomegalovirus pneumonia.
INTRODUCTION: We investigated the variation of CD4+ and CD8+ T lymphocytes in renal allograft recipients who developed acute respiratory distress syndrome (ARDS) caused by cytomegalovirus (CMV) infection and their relationship to patients outcome. METHODS: Twenty one cadaveric renal allograft recipients who developed ARDS caused by CMV infection were enrolled in this study. CD4+ and CD8+ T lymphocytes were examined in peripheral blood on five occasions: the admission day (day 0) to ICU as ARDS, day 5, day 10, day 15 in ICU, and discharge day. A value taken in the second month after transplantation was assumed to be the preinfection value. RESULTS: Among 13 surviving patients, the numbers of CD4+ and CD8+ T cells and their ratio increased as the patients recovered. The numbers of CD4+ T cells increased significantly on day 10, day 15, and at discharge day compared with day 0 (P < .05). The number of CD8+ T cells on discharge day and the ratios after day 10 were also significantly higher than those on day 0 (P < .05). In eight nonsurviving patients, the numbers of CD4+ and CD8+ T cells and their ratio was similar to day 0. The number of CD4+ and CD8+ cells after day 5 and their ratio after day 10 were significantly lower than those of survival group (P < .05). CONCLUSION: The variations of CD4+ and CD8+ T lymphocytes and their ratio are useful indicators of the severity of disease and the outcome of patients with CMV infections accompanying ARDS after renal transplantation. Nevertheless, it may be helpful to evaluate the efficiency of ongoing treatment methods in these patients.
CD4 Lymphocyte Count↗
Late developing C4d-positive humoral renal allograft rejection associated with withdrawal of mycophenolate mofetil.
In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body's humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.
Acute Disease↗
ATR and GADD45alpha mediate HIV-1 Vpr-induced apoptosis.
The human immunodeficiency virus type-1 (HIV-1) accessory gene vpr encodes a conserved 96-amino-acid protein that is necessary and sufficient for the HIV-1-induced block of cellular proliferation. Expression of vpr in CD4+ lymphocytes results in G2 arrest, followed by apoptosis. In a previous study, we identified the ataxia telangiectasia-mutated (ATM) and Rad3-related protein (ATR) as a cellular factor that mediates Vpr-induced cell cycle arrest. In the present study, we report that the breast cancer-associated protein-1 (BRCA1), a known target of ATR, is activated in the presence of Vpr. In addition, the gene encoding the growth arrest and DNA damage-45 protein alpha (GADD45alpha), a known transcriptional target of BRCA1, is upregulated by Vpr in an ATR-dependent manner. We demonstrate that RNAi-mediated silencing of either ATR or GADD45alpha leads to nearly complete suppression of the proapoptotic effect of Vpr. Our results support a model in which Vpr-induced apoptosis is mediated via ATR phosphorylation of BRCA1, and consequent upregulation of GADD45alpha.
Apoptosis↗
Primary adenovirus-specific cytotoxic T lymphocyte response occurs after viral clearance and liver enzyme elevation.
The virus-specific cytotoxic T lymphocyte (CTL) response is a major obstacle to effective delivery of adenovirus gene therapy. However, its relative role in viral clearance, transgene elimination and hepatotoxicity remains unclear. In this paper, we present an analysis of viral clearance and liver toxicity in relation to the induction of the virus-specific CD8 T-cell response revealed by an MHC class I tetramer. A surprisingly high number of tetramer+ CD8 T cells were found in the liver and lung and reached peak values at days 8 and 10, respectively, post-infection. Nearly 100% of these tetramer+ CD8 T cells expressed high levels of granzyme B and IFNgamma. Remarkably, liver viral load and liver enzyme elevation peaked early, at days 2 and 4, respectively, post-infection, before the specific CTL response was detectable. After generation of CTLs, there was only minimal liver damage or further decrease in virus titer. These results indicated that the primary peak response of tetramer+ CTLs does not correlate with the elimination of adenovirus or liver cytotoxic response.
Adenoviridae↗
Tightly-regulated suicide gene expression kills PSA-expressing prostate tumor cells.
We have previously shown that a dual system for controlling gene expression that relies both on transcriptional regulation and DNA recombination mediated by the site-directed recombinase, Flp, effectively controls the expression of a gene encoding diphtheria toxin (DT-A). In this study, we investigated the use of a chimeric modified enhancer/promoter sequence of the human prostate-specific antigen (PSA) gene to regulate DT-A expression in human prostate cancer cells in culture, in xenografts derived from these cells, and in autochthonous tumors in TRAMP mice. Following adenoviral delivery of DNA encoding PSA promoter-driven Flp recombinase and DT-A, we demonstrate that this transcriptional/DNA recombination control strategy effectively activates DT-A expression in a manner that correlates with the amount of PSA and androgen in cells. Significantly, the size of xenografts was reduced by 50%, and tumor cells in TRAMP mice died following intratumoral injection of DT-A viruses. Direct injection of virally-delivered DT-A into normal mouse prostates resulted in a dramatic reduction in the size of the gland. Our results suggest that the PSA promoter-driven Flp recombinase regulatory system will allow for targeted death of PSA-expressing cells. When combined with newly developed strategies for targeted gene delivery, this approach holds promise as an effective systemically-administered therapy for metastatic prostate cancer.
Adenoviridae↗
'Survival gene' Bcl-xl potentiates DNA-raised antitumor immunity.
T-cell priming is strongly affected by the longevity of antigen-bearing dendritic cells (DCs), which are typically short-lived in lymphoid tissues. 'Survival gene' Bcl-xl is critical for the lifespan of DCs in vivo. Here, we showed that in vivo coadministration of Bcl-xl under control of the DC-specific promoter (CD11c-Bcl-xl) and TRP2hsp70 DNA prolonged T-cell stimulation by DCs and augmented TRP2-specific-IFN-gamma-producing CD8+ T-cell responses. Consistent with these findings, enhanced protection and significant therapeutic immunity to B16 melanoma was generated by this coimmunization strategy, which also augmented therapeutic immunity to GL-26 tumor. In this B16 melanoma model, results from animal experiments with depletion of immune cells indicate that CD8+ T cells and NK cells are important in the antitumor immunity induced by this coimmunization strategy. These observations suggest that 'survival gene' Bcl-xl potentiates the magnitude of antigen-specific-CD8+ T-cell responses and the efficacy of antitumor immunity induced by DNA vaccine, and is relevant for the design of in vivo targeted DC-based vaccine strategies to improve immunity against cancer.
Animals↗
Clinical and cytogenetic features of 508 Chinese patients with myelodysplastic syndrome and comparison with those in Western countries.
Myelodysplastic syndrome (MDS) is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and leukemia progression. Racial differences may exist on clinical pictures and the molecular events leading to MDS, which are heterogeneous. To better define the clinical and cytogenetic features in Chinese patients, a retrospective multicentric study was performed in 508 MDS cases. Compared with Western countries, Chinese patients showed younger age (median: 49 vs 65-73 years), lower percentages of RARS (2.8 vs 6.6-15.3%), and CMML (5.2 vs 11.7-30.6%). Cytogenetically, among 367 cases with evaluable data, abnormal karyotypes were found in 136 cases, including 56 numerical and 80 structural changes. Incidences of single chromosome 5 and 7 abnormalities were lower than those in Western countries (2.2 vs 17.8-42.5%). However, complex cytogenetic aberrations and chromosome translocations were frequently observed and related to poor prognosis. Both multiple chromosome deletions and translocations were detected in advanced subtypes (RAEB and RAEB-T). Analysis of 200 cases revealed a higher incidence of hepatitis-B-virus infection than that in non-MDS population (21.00 vs 9.75%). This study further confirmed: (1) different genetic/environmental backgrounds between Asian and Western MDS populations; (2) a strong predictive value of cytogenetic abnormalities on disease outcome and involvement of genomic instability in leukemia clone development.
Adolescent↗
Effect of daidzein on egg-laying performance in Shaoxing duck breeders during different stages of the egg production cycle.
The effect of a phyto-oestrogen, daidzein, on the laying performance of Shaoxing female ducks was examined in three experiments performed at different stages of the egg production cycle. Egg-laying rate, egg weight, egg composition, feed conversion ratio, hatchability characteristics of eggs and body weight, ovary and oviduct weight, as well as changes in serum concentrations of T3, T4 and E2 were recorded as response criteria. In the first experiment, 68 young ducks, 100 d of age, were given a basal diet (maize-soybean meal) with or without 3 mg of daidzein/kg diet for 42 d. Daidzein did not affect the onset of lay but apparently decreased egg-laying rate and mean egg weight as well as the feed conversion ratio. In the second experiment, 240 breeding ducks, 402 d of age, were allotted at random to three groups and given the basal diet containing daidzein at 0 (control), 3 (Da1) and 5mg/kg (Da2) for 35d. Egg-laying rate, mean egg weight and feed conversion ratio increased in both Da1 and Da2 groups. However, an adverse effect of daidzein on fertility and hatchability was observed. In the third experiment, 320 breeding ducks, 415 d of age, were fed on the basal diet with or without 5mg of daidzein/kg diet for 63 d. Egg-laying rate increased by 7.7%, average egg weight tended to increase, whereas yolk/albumen ratio decreased. Daidzein-treated ducks had higher body weight and oviduct weight compared with their controls. Elevated plasma T4 and E2 concentrations accompanied these phenotypic changes, but serum T3 was not affected. It is suggested that daidzein exerts divergent effects on the egg-laying performance of Shaoxing ducks under different physiological conditions and this action is dose-dependent. The changes in circulating E2 imply possible participation of endogenous oestrogen in the mechanism of daidzein action.
Animals↗
The influence of dietary sodium chloride, arginine:lysine ratio, and methionine source on apparent ileal digestibility of arginine and lysine in acutely heat-stressed broilers.
The present study was carried out to determine the ileal digestibility of Arg and Lys in acutely heat-stressed broilers using diets varying in Arg:Lys ratio, NaCl concentration, and Met Source. Male broilers were maintained at 22 degrees C from 21 to 33 d of age and then at 32 degrees C from 33 to 38 d of age. From 28 to 38 d of age, birds were fed a diet with an Arg:Lys ratio of 1.05 and 3 g of supplemental NaCl/kg of diet with or without L-arg free base to increase the Arg:Lys to 1.35, and with or without 3 g/kg of additional NaCl. Methionine was supplied as equimolar amounts of DL-Met or 2-hydroxy-4-(methylthio)-butanoic acid in a 2 x 2 x 2 design. At 38 d of age, digesta were collected from the terminal ileum, and amino acid analyses were conducted on feed and digesta samples and compared with acid-insoluble ash (dietary celite) to calculate the apparent ileal digestibilities of Lys and Arg. Increasing the NaCl concentration and the presence of HMB significantly decreased the digestibility of both Arg and Lys, whereas increasing the Arg:Lys ratio increased the digestibility of only Arg but did increase BW gain (P = 0.08). An interaction between dietary NaCl and Arg:Lys ratio as well as the 3-way interaction suggested that dietary NaCl could affect the apparent ileal digestibility of Arg and Lys at certain Arg:Lys ratios and the response may be influenced by the Met source.
Amino Acids↗
Identification of a new HLA-A*0201-restricted CD8+ T cell epitope from hepatocellular carcinoma-associated antigen HCA587.
For the development of peptide-based cancer immunotherapies, we aimed to identify specific HLA-A*0201-restricted CTL epitopes in hepatocellular carcinoma (HCC) associated antigen HCA587, which has been identified as a member of the cancer/testis (CT) antigens highly expressed in HCC. We first combined the use of an HLA-A*0201/peptide binding algorithm and T2 binding assays with the induction of specific CD8(+) T cell lines from normal donors by in vitro priming with high-affinity peptides, then IFN-gamma release and cytotoxicity assays were employed to identify the specific HLA-A*0201 CD8(+) T cell epitope using peptide-loaded T2 cells or the HCA587 protein(+) HCC cell line HepG2. In the six candidate synthesized peptides, two peptides showed higher binding ability in T2 binding assays. No. 2 peptide, encompassing amino acid residues FLAKLNNTV (HCA587(317-325)), was able to activate a HCA587-specific CD8(+) T-cell response in human lymphocyte cultures from two normal donors and two HCC patients, and these HCA587-specific CD8(+) T cells recognized peptide-pulsed T2 cells as well as the HCA587 protein(+) HCC cell line HepG2 in IFN-gamma release and cytotoxicity assays. The results indicate that no. 2 peptide is a new HLA-A*0201-restricted CTL epitope capable of inducing HCA587-specific CTLs. Our data suggest that identification of this new HCA587/HLA-A*0201 peptide FLAKLNNTV may facilitate the design of peptide-based immunotherapies for the treatment of HCA587-bearing HCC patients.
Antigens, Neoplasm↗
Role of curli fimbriae in mediating the cells of enterohaemorrhagic Escherichia coli to attach to abiotic surfaces.
AIMS: The objectives of this study were to evaluate the role of curli in assisting the cells of enterohaemorrhagic Escherichia coli (EHEC) in attaching to abiotic surfaces and to determine the influence of cell-surface contact time on the efficiency of the attachment. METHODS AND RESULTS: Three pairs of EHEC cultures, each with a curli-expressing and a noncurli-expressing variant (O111:H- 7-57C+ and O157:H7 5-9C-, O157:H7 5-11C+ and 5-11C-, as well as O103:H2 7-52C+ and 7-52C-), were allowed to interact with polystyrene, glass, stainless steel and rubber surfaces at 28 degrees C for 24 h (short-term attachment) or 7 days (long-term attachment). The quantities of the cells that attached to the surfaces were measured daily in the long-term attachment study, and in 4 h intervals in the short-term attachment study. Quantification of the cells that attached to the surfaces was accomplished with a crystal violet binding assay. The results of the long-term attachment study indicated that 7-57C+ attached to the polystyrene and glass surfaces more efficiently (P < 0.05) than did 5-9C-. The curli-expressing variant of 5-11 possessed a better ability to adhere to the polystyrene and glass surfaces than did its noncurli-expressing counterpart (P < 0.05). The differences in attachment between 7-52C+ and 7-52C- on polystyrene and stainless steel surfaces were statistically significant (P < 0.05). However, the attachment of the pair on the glass surfaces was statistically insignificant (P > 0.05). In addition, the two members of all three EHEC pairs attached equally well to rubber surfaces (P > 0.05). In the short-term attachment study, only the pair of 7-52 attached differently on glass and stainless steel surfaces (P < 0.05). CONCLUSIONS: These results suggest that curli could be an important cell surface component to mediate the attachment of some EHEC cells to certain abiotic surfaces. Cell-surface contact time could have a significant influence on EHEC attachment to abiotic surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: The study signifies a possible role of curli in assisting the cells of EHEC in attaching to food-contact surfaces. It underlines the importance of cleaning and sanitizing food-contact surfaces regularly and thoroughly, and of identifying chemical agents that can effectively remove the attached EHEC cells from these surfaces.
Bacterial Adhesion↗