Clinical application of antithrombogenic hydrogel with long poly(ethylene oxide) chains

Thirty clinical tests on PVC drain tubes coated with hydrophilic copolymer with long poly(ethylene oxide) chains (PEO-COAT) were carried out. Controls were non-coated PVC drain tubes. Thrombogenesis was observed in 24 out of 30 non-coated PVC drain tubes (80%) and in only 4 out of 30 PEO-COAT drain tubes (13%). PEO-COAT drain tubes significantly suppressed absorption of plasma proteins and adhesion of platelets. The excellent antithrombogenic property of this hydrophilic polymer, already suggested by in vitro and in vivo experiments, was demonstrated here clinically.     

Involvement of cysteine residues in the biological activity of the active fragments of guinea pig neutrophil cationic peptides.

Guinea pig neutrophil cationic peptides (GNCPs) are single-chain polypeptides with 31 amino acid residues containing six cysteine residues, which exhibit both antibacterial and histamine-releasing activities in vitro. In this study, the role of the sulfhydryl groups in defining the antibacterial and histamine-releasing activities of the active fragments of GNCP-1 (Arg-1 to Tyr-14 [Arg-1-Tyr-14] and Arg-15-Tyr-27 peptides) was examined by using peptides containing alkylated or nonalkylated sulfhydryl groups. Alkylation slightly increased the histamine-releasing activity of the Arg-15-Tyr-27 (RRLGTCIFQNRVY) peptide but abrogated the antibacterial activity. Alkylation of the Arg-1-Tyr-14 (RRCICTTRTCRFPY) peptide similarly reduced the antibacterial activity of this fragment but had minimal effect on the histamine-releasing activity. These findings suggest that cysteine residues with free sulfhydryl groups play an important role in the expression of the antibacterial activity of the active fragments of GNCP-1.     

Restricted expression of transgenic HLA-DRA gene in thymic epithelial cells and its role in acquisition of T cell tolerance to self-superantigens and processed DRα-derived peptide

We have established a set of transgenic mouse lines in which the HLA-DRA gene was expressed in different cell types. In one line (DRα-24), DRαEβ^b molecules were expressed on thymic medullary and cortical epithelial cells and all lineages of bone marrow-derived antigen-presenting cells (APC) except for thymic macrophages. By contrast, expression of the molecules in another line (DRα-30) was found on thymic medullary and cortical epithelial cells but not on bone marrow-derived APC in the thymus and periphery. To evaluate the role of thymic epithelial cells in acquisition of T cell tolerance, comparative analysis of DRα-24 and DRα-30 was performed. In DRα-30, T cells expressing TcR Vβ5 and Vβ11 were eliminated to comparable levels to those in DRα-24, suggesting that expression of the DRαEβ^b molecules on thymic epithelial cells are sufficient for clonal deletion of the self-superantigen-reactive T cells. In addition, CD4⁺ T cells from DRa-30 as well as those from DRα-24 were tolerant to DRα-derived peptide/I-A^b complex expressed on spleen cells from DRα-24 even in the presence of exogenous interleukin-2. These observations suggest that expression of the DRα chain in thymic epithelial cells could induce T cell tolerance directed toward naturally processed DRα-derived peptide bound to I-A^b molecules, probably via clonal deletion of the self-reactive T cells.     

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

We have previously described the use of sirolimus (SRL) as primary immunosuppression following heart transplantation (HT). The advantages of this approach include attenuation of cardiac allograft vasculopathy (CAV), improvement in glomerular filtration rate (GFR), and reduced malignancy. However, in some patients SRL may cause significant proteinuria. We sought to investigate the prognostic value of proteinuria after conversion to SRL. CAV progression and adverse clinical events were studied. CAV progression was assessed by measuring the Δ change in plaque volume (PV) and plaque index (PI) per year using coronary intravascular ultrasound. Proteinuria was defined as Δ urine protein ≥300 mg/24 h at 1 year after conversion to SRL. Overall, 137 patients were analyzed (26% with proteinuria). Patients with proteinuria had significantly lower GFR (P = .005) but similar GFR during follow-up. Delta PV (P < .001) and Δ PI (P = .001) were significantly higher among patients with proteinuria after adjustment for baseline characteristics. Multivariate Cox regression analysis showed higher all-cause mortality (hazard ratio 3.8; P = .01) with proteinuria but similar risk of CAV-related events (P = .61). Our results indicate that proteinuria is a marker of baseline renal dysfunction, and that HT recipients who develop proteinuria after conversion to SRL have less attenuation of CAV progression and higher mortality risk.     

Exploratory assessment of treatment‐dependent random‐effects distribution using gradient functions

In analyzing repeated measurements from randomized controlled trials with mixed‐effects models, it is important to carefully examine the conventional normality assumption regarding the random‐effects distribution and its dependence on treatment allocation in order to avoid biased estimation and correctly interpret the estimated random‐effects distribution. In this article, we propose the use of a gradient function method in modeling with the different random‐effects distributions depending on the treatment allocation. This method can be effective for considering in advance whether a proper fit requires a model that allows dependence of the random‐effects distribution on covariates, or for finding the subpopulations in the random effects.     

Immunoelectron microscopy of AMPA receptor subunits reveals three types of putative glutamatergic synapse in the rat vestibular end organs

To characterize the synapses between hair cells and afferent nerve endings in the rat vestibular end organs, the ultrastructural localization of AMPA receptor subunits (GluR1-4) was examined by postembedding immunogold cytochemistry. Immunoreactivities for GluR2/3 and GluR4 were associated with the synapses between type I hair cells and the surrounding chaliceal nerve endings and with the bouton type nerve endings contacting type II hair cells. There was no detectable immunoreactivity for GluR1. A third type of immunoreactive synapse was found between the outer face of chalices and type II hair cells. While the linear densities of gold particles (particles per micrometer postsynaptic specialization) of bouton type endings and chaliceal nerve endings were the same, the former type of ending showed larger postsynaptic specializations and, hence, a higher number of receptor molecules. These data indicate that there are three types of putative glutamatergic synapse in the vestibular end organ.     

Prednisolone plus low-dose aspirin improves the implantation rate in women with autoimmune conditions who are undergoing in vitro fertilization

Objective: To evaluate the effect of prednisolone plus low-dose aspirin (PSL/LDA) in women with autoimmune conditions who were enrolled in an IVF-ET program.

Design: A retrospective clinical study.

Setting: In vitro fertilization unit, Niigata University Hospital, Niigata, Japan.

Patient(s): Three hundred seven women who underwent IVF-ET between January 1996 and December 1997.

Intervention(s): Prednisolone (10 mg/d) and aspirin (81 mg/d) were administered to the women with autoantibodies who chose to participate.

Main Outcome Measure(s): Pregnancy and implantation rates with IVF-ET.

Result(s): Women undergoing IVF who had positive antinuclear antibodies, with or without antiphospholipid antibodies, had significantly lower pregnancy and implantation rates than did women without autoantibodies (14.8% versus 21.7% and 6.8% versus 10.4%, respectively). The administration of PSL/LDA to women with antinuclear antibodies significantly improved the outcome of IVF-ET (40.6% pregnancy rate and 20.3% implantation rate).

Conclusion(s): A high proportion of women who are undergoing IVF-ET have autoantibodies, which are associated with poor IVF outcomes. The administration of PSL/LDA to these women may improve their implantation rate.