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Objectives To report a case of borderline Brenner tumor Methods Case report and literature review Results A 70-year old woman had lower abdominal pain and was found to have a large tumor in the pelvic cavity which had both cystic and solid leisions by ultrasonography and MRI. We underwent a surgery of total hysterectomy, bilateral salpingo-oophorectomy, omentum resection, pelvic and para-aortic lymph node dissection according to a frozen section diagnosis of borderline or malignant tumor of the ovary. The final pathological diagnosis was borderline Brenner tumor, StgaeIC3, which shows an exuberant papillary transitional cellular component with mild nuclear atypia lined by mucinous columnar epithelium without invasion to the stroma. There is no recurrent and metastasis at postoperative 3 months. Conclusions Borderline Brenner tumor of the ovary is a rare tumor, which has only about 30 case reports of published English literatures. At present, we don’t have enough knowledge about the characteristics of the tumor to decide appropriate treatment. Additional collection of data of this tumor is necessary to establish diagnosis and treatment.

The outcomes of treatment for women with recurrent or advanced epithelial ovarian carcinoma previously treated with pacli- taxel plus platinum-based chemotherapy were analyzed.Retrospective analysis was performed in a total of 65 series of treatments provided for 35 patients with a history of paclitaxel plus platinum-based chemotherapy. The chemotherapy regimens used were classified into the following four types for analysis: conventional paclitaxel plus carboplatin therapy (TC arm), pegylated liposomal doxorubicin-containing regimens (PLD arm), CPT-11-containing regimens (CPT-11 arm), and others. Disease-control rates (DCRs) were compared and subjected to univariate analysis. Progression-free survival (PFS) was determined from the date of the first cycle of each chemotherapy with the Kaplan-Meier method, and comparisons were performed using the log-rank test.DCR was 80%, 71%, and 26% for the TC, PLD, and CPT-l arms, respectively. The median PFS was 286, 372, and 76 days for the TC, PLD, and CPT-11 arms, respectively. There was no discernible difference in PFS between the TC and the PLD arm. In contrast, PFS of the CPT- 11 arm was significantly shorter than that of the TC and PLD arms. In addition, three of seven (42.9%) treatments in the PLD arm maintained a progression-free period for longer than one year, while only one of 25 (4%) treatments in the TC arm maintained a progression-free period for more than one year.The PFS of PLD is similar to that of TC. PLD-containing regimens might have a potential benefit with a higher PFS over one year than the TC regimen.

Objectives and methods B7-H4 (DD-O110), a member of the B7 family, negatively regulates T cell-mediated immune response. Previous studies have shown that B7-H4 is highly expressed in endometrioid ovarian cancers with relatively low levels of expression in normal ovary which was confirmed by Western blot. The present study was designed to localize B7-H4 expression by immunohistochemistry (IHC) in normal endometrium, endometrial hyperplasia and uterine endometrioid adenocarcinoma. The pattern of B7-H4 localization was compared with the IHC detection of CD3 and CD8-positive T lymphocytes and CD14 positive macrophages to investigate the role of B7-H4 in the regulation of tumor immune surveillance. B7-H4 expression was evaluated in apoptotic tumor cells. Results The proportion and intensity of B7-H4 staining were increased in the progression from normal, hyperplastic and malignant endometrial glandular mucosa. B7-H4 showed a predominantly apical membranous staining (pattern 1) in normal and hyperplastic endometrial epithelium but showed intense circumferential membranous and cytoplasmic staining (pattern 2) in a majority of endometrioid carcinoma cases ( p =0.018). The proportion of B7-H4 positive tumor cells and staining intensity was also higher in high risk tumors than in low risk tumors ( p =0.001 and p =0.032, respectively). The proportion of B7-H4 positive tumor cells was inversely related to the number of CD3-positive and CD8-positive tumor-associated lymphocytes (TALs). There was a positive correlation between B7-H4 pattern 2 staining and both CD3-positive and CD8-positive tumor-infiltrating lymphocytes (TILs) ( p =0.039 and p =0.031, respectively). Conclusions B7-H4 is overexpressed in hyperplastic and malignant endometrial epithelium and is correlated with the number T cells associated with the tumor. These results suggest that B7-H4 overexpression may reflect a more aggressive biologic potential and may play a role in tumor immune surveillance mechanisms.

Zinc-chlorin 3 (see Fig. 2 in text) possessing a tertiary 3(1)-hydroxyl group and a 13-keto group was synthesized as a model for the antenna chlorophylls of green bacteria. Self-aggregation of 3 in nonpolar organic media was examined and compared to 1 and 2 possessing a primary and secondary 3(1)-hydroxyl group, respectively. Zinc-chlorin 3 self-aggregated in 1 vol% CH2Cl2-hexane to form oligomers and showed a red-shifted Qy maximum at 704 nm compared to the monomer (648 nm in CH2Cl2). This red-shift is larger than that of 2S (648--697 nm) and comparable to that of 2R (648--705 nm), but smaller than that of 1 (648--740 nm), indicating that while a single 3(1)-methyl group (prim-OH--sec-OH) suppressed close and/or higher aggregation, the additional 3(1)-methyl group (sec-OH--tert-OH) did not further suppress aggregation. The relative stability of the aggregates was in the order 12R-32S as determined by visible spectral analyses. Molecular modeling calculations on dodecamers of zinc-chlorins 1, 2R and 3 gave similar well-ordered energy-minimized structures, while 1 stacked more tightly than 2R and 3. In contrast, 2S gave a relatively disordered (twisted) structure. The calculated dodecameric structures could explain the visible spectral data of 1-3 in nonpolar organic media.

Insulation of superconducting magnet systems requires excellent electrical insulating properties, compressive strength and flexibility so that it can bear the compressive stress of the electromagnetic force and the shear stress caused by the deformation of each conductor in these magnets. GFRP is suitable for these insulation systems and most superconducting magnet systems use it. Although the interlaminar shear strength of GFRP is about a tenth of its compressive strength, this strength increases under a combination of stresses. GFRP strengths under shear/compressive loading are specified for optimum designs. Therefore, we can apply GFRP against shear/compressive loading for which static and fatigue strengths are the dominant factors in magnet life assessment. The coefficient of friction of the surface affects the static and fatigue behavior at low temperature. Two types of tests were carried out to simulate the combined stresses, and shear/compressive static and fatigue tests were performed at 77 K on GFRP. Employing different angle test fixtures, GFRP specimens were loaded with various levels of shear and compressive stress. We evaluated the strength of insulators that sustain compressive and frictional shear stresses to take into account the stress redistributions for cases both with and without the occurrence of surface slips. A new criterion for the shear/compressive static and fatigue failure is proposed in this study.

Using time-resolved fluorescence, we explored the energy transfer process(es) in supramolecular zinc chlorin aggregates co-aggregated with various kinds of energy traps. The energy transfer times f...

This paper describes numerical analysis of the transient temperature rise of the fuse elements in current-limiting fuses for protecting semiconductor devices such as semiconductor power diodes and thyristors from short-circuit faults. The transient temperature rise is obtained by using 3-D finite element method combining the analysis of current distribution in the fuse with the heat analysis of the fuse. The calculated results show good agreement with the experimental ones. It is shown that this 3-D analysis method is capable of evaluating a new design of current-limiting fuses instead of the conventional trial and error approach.

This paper introduces a computational method for predicting the temperature characteristics of steel quenching by induction heating. In this method, an eddy current analysis is coupled with a thermal analysis using the 3-D finite element method. The nonlinear characteristics of the electric conductivity of steel is taken into account. The validity of this method is confirmed through the comparison with measured results when applied to a steel blade quenching of an electric shaver.

The three-dimensional electron momentum distribution (3D-EMD) of β -PdH0.84 were determined by the Compton scattering technique with 115 keV X-ray synchrotron radiation. The obtained 3D-EMD shows the existence of the neck around the [1 1 1] direction in the Fermi surface, which agrees well with the result of the band structure calculation by the LDA-FLAPW method. This result indicates that the synchrotron-based Compton scattering technique can be used for the Fermiology of metal hydrides.

Studies on the relationship between n-value and heat treatment conditions of Nb/sub 3/Sn multifilamentary wires in addition to those on be are presented. The wire was manufactured in bronze process. It was heated in various conditions, then voltage-current (V-I) characteristics of each specimen were measured. In the range of the heat treatment temperature, n-value increases with temperature but J/sub c/ decreases. The properties were discussed based on the results of microscopic observation and were investigated with upper critical field (Bc/sub 2/). The results from these investigations suggest the dependence of n-value on Bc/sub 2/. >

To determine the N-linked oligosaccharide structure of beta-amyloid precursor protein (beta APP), soluble derivative of beta APP (APPs) was purified from the conditioned medium of beta APP cDNA-transfected C6 glioma cells. Two types of APPs with different molecular weight (larger APPs, L-APPs; smaller APPs, S-APPs) were obtained. The antibody against the N-terminal half of amyloid beta-protein showed no immunoreactivity with S-APPs, suggesting extensive truncation at the carboxyl terminus. From lectin blot analysis, the main structure of the N-linked oligosaccharide shared by L- and S-APPs was deduced to be of bi- or triantennary complex type with a fucosylated trimannosyl core and a bisecting GlcNAc residue. Additionally L-APPs was deduced to have Gal beta 1--4GlcNAc, Fuc alpha 1--2Gal beta and Sia alpha 2--6Gal beta structures on its outer chains. However, lectins which recognize Fuc alpha 1--2Gal beta and Sia alpha 2--6Gal beta structures showed no reactivity with S-APPs. The present results suggest that the processing of beta APP may be regulated via the heterogeneity in the fine structure of its sugar chains.

In this article, the influences of specimen size and deformation-mode on the fracture strength of single-crystal silicon (SCS) micro-beam structures are described. We have designed and developed a new materials test device that is able to apply pure torsion, torsion-bending-combined, and bending deformations to a micro-scale beam specimen. The differences in deformation-mode are determined by loading position and with or without plate support. The specimen made of SCS consists of a SCS plate supported by two SCS micro-beams, and a frame, and was fabricated by deep reactive ion etching (DRIE) with the same fabrication recipe. All the SCS specimens tested in those deformation-modes were fractured in a brittle manner at a laboratory temperature. The fractured strength was calculated assuming that all the specimens had an ideal flat surface, and the data were arranged using two-parameter Weibull distribution function. Both the specimen size and deformation-mode dependencies were apparently found. To estimate the “true” strength, finite element analyses (FEAs) using the models that included scalloping sidewalls were carried out. The revised strength data that were estimated by multiplying stress concentration factors into the original data suggested that no deformation-mode dependency on strength existed. Based on scanning electron microscopy (SEM) analyses, we have found that specimen size dependency was probably related to the number of nanoscale surface defects that were introduced during a DRIE process.

Wave forms of BEN (Broadband Electrostatic Noise) in the geomagnetic tail were first detected by the Wave Form Capture reciever on the GEOTAIL spacecraft. The results show that most of the BEN in the plasma sheet boundary layer (PSBL) are not continuous broadband noise but are composed of a series of solitary pulses having a special form which we term 'Electrostatic Solitary Waves (ESW)'. A nonlinear BGK potential model is proposed as the generation mechanism for the ESW based upon a simple particle simulation which considers the highly nonlinear evolution of the electron beam instability. The wave forms produced by this simulation are very similar to those observed by GEOTAIL and suggest that the nonlinear dynamics of the electron beam play an essential role in the generation of ESW.

We fabricated GaAs (Si doped, 40 A)/Al 0.25 Ga 0.75 As (undoped, 500 A) multiquantum well infrared photodetectors to realize a high efficiency. The detector is based on the intersubband transition from a bound state in the GaAs quantum well to extended continuum states above the AlGaAs barrier so that the excited electrons can flow easily. In order to improve the detectivity the incident surface is polished at 45° off the quantum well layers, to provide multireflection of the light in the devices. The photocurrent was observed at T = 77 K in the incident photon wavelength region of 6–10 μm with peak photocurrent at 8.3 μm. Since the operation mechanism is based on the photocurrent carried by the electrons in the extended continuum states excited from the bound state in GaAs wells, the band width is expected to be broader than the devices which utilize the transition between the bound states in the well. We calculated the absorption coefficient of photons by using the energy band structures obtained from Kronig-Penney model, and photocurrent with a simplified model. The results well explain the band width of the detectivity and also a weak structure (weak peaks) in the photocurrent.

A motor neuron disorder resembling that of amyotrophic lateral sclerosis was found in a patient who had received the intramuscular administration of a mixture of bovine brain gangliosides (Yuki, N., Sato, S., Miyatake, T., Sugiyama, K., Katagiri, T., and Sasaki, H. (1991) Lancet 337, 1109-1110). A very high titer of anti-GM2 IgM was detected in the patient's serum and the patient quickly recovered after plasmapheresis. The clinical course of the patient appeared to be different from amyotrophic lateral sclerosis and the anti-GM2 IgM was thought to be the culprit. The IgM reacted with GM2, GM1b-GalNAc, SPG(alpha 2-3)-GalNAc, and GD1a-GalNAc, but not with GA2 or GD2, meaning that the epitope recognized by the IgM was the GM2-like terminal structure, GalNAc beta 1-4(Neu-Ac alpha 2-3)Gal beta 1-. In this study, we found two novel GM2-epitope containing gangliosides, X1 and X2, in bovine brain gangliosides by TLC immunostaining using the patient's IgM. They were characterized as unique lacto-ganglio type gangliosides containing the following branching structures. [formula: see text] Their unusual structures may be immunogenic to humans to induce anti-GM2 antibody.

Through restriction enzyme digestion of 1,784 cosmid DNAs derived from human chromosome region Xq24→qter, we identified 353 NotI-linking cosmids (11 individual groups of overlapping NotI-linking cosmids at Xq24→q25, 6groupsatXq26→q27, and 19 groups at Xq28). Sixty-two of the 353 clones (DXS607-DXS668) contained multiple rare-cutter sites, including multiple Sacll sites within a 2-kb region, as well as one to six sites for BssHll, MluI, NotI, or NruI.

Phonon spectra of YBa2Cu4O8 have been measured in the range 110-1000 cm-1 and between 30 K and room temperature. All seven B1u-symmetry infrared-active phonons are observed at 119, 135, 200, 314, 332, 500 and 605 cm-1 at 290 K. The effect of decreasing temperature on phonons with frequencies >or approximately= 210 cm-1 has been studied and it is found that the 500, 314 and 605 cm-1 modes-and perhaps also the 332 cm-1 mode-exhibit changes in frequency, intensity and linewidth at the superconducting transition temperature (80 K). The observed phonon renormalization effects are compared to those previously observed in YBa2Cu3O7- delta . The authors' results suggest that polaron-phonon interactions may be important for the occurrence of superconductivity in these materials-e.g. via the Bose condensation of bipolarons.

A photoelectron spectroscopic study of superconducting ({ital Y}{sub 1{minus}{ital x}}Ca{sub {ital x}})Ba{sub 2}Cu{sub 4}O{sub {ital y}} ({ital x}=0.0, 0.05, and 0.10) was performed. The observation of the Fermi-edge-like structure of this material is reported here. In the photoelectron spectrum, a clear edge at the Fermi energy was observed even at room temperature (normal state) for all samples, indicating that the surfaces of these materials were stable and surface degradation due to oxygen loss seemed to be negligible in vacuum. This is consistent with the fact that (Y{sub 1{minus}{ital x}}Ca{sub {ital x}})Ba{sub 2}Cu{sub 4}O{sub {ital y}} has an excellent thermal stability in oxygen content up to high temperature in air.

We performed an electrophysiological study demonstrating inhibition of spontaneous muscle action potentials within a coculture of rat muscle and spinal cord by exposure to serum, as well as purified IgG, from patients with the acute motor axonal neuropathy (AMAN) variant of Guillain-Barré syndrome (GBS). However, exposure to serum from two patients with the acute inflammatory demyelinating polyneuropathy (AIDP) form of GBS had no effect. Using a whole-cell recording technique, we then investigated the effects of serum and purified IgG from patients with GBS on voltage-dependent calcium channel (VDCC) currents in nerve growth factor-differentiated PC12 cells. Serum from patients with GBS (AMAN) inhibited VDCC currents in PC12 cells, which was fully reversible by washing with the bath solution. Similarly, purified IgG from the serum of two patients with GBS (AMAN) also inhibited VDCC currents in PC12 cells. In contrast, sera from patients with AIDP and healthy volunteers did not affect VDCC currents in PC12 cells. These results suggest that muscle weakness in some patients with GBS might be induced by inhibition of Ca2+ channel currents within motor nerve terminals.

Proposes a neural network model for trajectory formation of a redundant manipulator, which has the ability to control the speed profile of its end effector to make it bell-shaped. The model consists of two networks, a trajectory planning network and a trajectory forming network. These networks are similar to Hopfield networks, but the difference of these networks is that the input capacitance in the trajectory forming network varies with time. At first, the manipulator moves from the initial posture to the target point using the trajectory planning network, and the input capacitance of the trajectory forming network is calculated for the information of the planned trajectory. The trajectory forming network controls the manipulator using the calculated input capacitance. The authors apply the proposed model to the trajectory formation of a planar manipulator with 3 joints. The authors get the result that the proposed model can make the speed profile of the end effector be bell-shaped.

Zinc analogues of bacteriochlorophylls c and d self-assembled in aqueous media with phospholipids. A methanol solution of zinc chlorin and alpha-lecithin was put in a cellulose tube and the inner methanol solvent was gradually replaced with water by dialysis to form the self-assembled oligomers. Visible absorption spectra of the aqueous solution showed that zinc chlorins formed J-aggregates within the hydrophobic core of alpha-lecithin assemblies and that the supramolecular structure of the aggregates depended upon the stereochemistry at the 3(1)-position and the alkyl substituents at the 8-, 12-, and 17(4)-positions of the zinc chlorin. When the aqueous aggregates were prepared with a mixture of 3(1)-epimers and/or 8-, 12-, or 17(4)-homologues of zinc 3(1)-hydroxy-13(1)-oxochlorins, the structurally distinct components coaggregated to make scrambled oligomers. However, during the dialysis, zinc 3(1)-hydroxy- and 7(1)-hydroxy-13(1)-oxochlorins slowly individually aggregated to give two structurally different oligomer units in the cellulose tube. In contrast, if the two zinc chlorin components rapidly self-assembled in an aqueous medium, these components coaggregated to form scrambled oligomers. The present study shows that both the molecular structure of the pigments and the speed of the oligomerization determine the molecular arrangement in chlorosome-type self-assembled oligomers.

We previously reported that ciliary neurotrophic factor (CNTF) increased the serum-free cell survival of immortalized motor neuron-like cells (NSC-34), and addition of the exogenous ganglioside GalNAc beta4(Neu5Ac alpha3)Gal beta4GlcCer (GM2) facilitated cell survival together with CNTF. Moreover beta 1,4 N-acetylgalactosaminyltransferase (GM2 synthase) activity increased in NSC-34 cells cultured with CNTF. We now have examined whether CNTF-induced cell survival is associated with the collaboration between GM2 and the CNTF receptor (CNTF-R). Despite the presence of CNTF (50 ng/ml), anti-CNTF-R antibody caused cell death and prevented the up-regulation of GM2 synthase expression. The addition of GM2 (1 to 20 microM) abrogated the anti-CNTF-R antibody effect which shortened cell survival and blocked GM2 synthase activation. Use of [125I]CNTF showed the specificity of CNTF binding in NSC-34 cells in situ. GM2 produced a 5-fold increase in the CNTF binding affinity per cell but did not change the binding site number. The study by metabolic labeling with [1-(14)C]N-acetyl-D-galactosamine ([14C]GalNAc) showed that biosynthesized GM2 was involved in the immunoprecipitation of CNTF-R. These findings indicate that up-regulated GM2 synthesis induces functional conversion of CNTF-R to the activated state, in which it has affinity for CNTF. We conclude that GM2 is a bio-regulating molecule of CNTF-R in motor neurons.

Hamster hearts transplanted into untreated rats undergo delayed xenograft rejection (DXR). This acute inflammatory response is associated with the deposition of anti-graft antibodies of the immunoglobulin (Ig)M isotype in the vasculature. We have previously shown that these antibodies are generated in a T cell-independent manner. In this study, we tested whether the generation of anti-graft IgM antibodies is involved in the pathogenesis of DXR. In addition, we tested whether the suppression of this antibody response would overcome DXR.Hamster hearts were transplanted into rats treated with an anti-mu monoclonal antibodies (mAb) to deplete circulating IgM or with an isotype-matched control mAb recognizing the dinitrophenyl epitope. T cell immunosuppression was achieved with cyclosporin A (CsA).Depletion of circulating IgM by anti-mu mAb inhibited DXR, whereas the control mAb had no effect on DXR. In anti-mu-treated rats, xenografts were rejected 5-7 days after transplantation through a T cell-dependent mechanism associated with the generation of antibodies of the IgG isotype. Combination of anti-mu with CsA suppressed the anti-graft IgM and IgG response and resulted in long-term xenograft survival (50 days). Xenograft long term survival occurred despite the return of anti-graft IgM antibodies to the circulation, a phenomenon referred to as accommodation.This study demonstrates that the pathogenesis of DXR can be initiated by anti-graft antibodies of the IgM isotype, which are generated in a T-cell independent manner. In addition, we show that under T cell immunosuppression, specific depletion of this IgM response by anti-mu mAb administration results in xenograft long-term survival and accommodation.

The present study examined the role of the rostral ventrolateral medulla (RVLM) in the modulation of acetylcholine (ACh) release by morphine. We examined the effect of morphine on the release of ACh in the RVLM of freely moving rats using the in vivo microdialysis method. The basal level of ACh was 303.0 +/- 28.2 fmol/20 microliter/15 min in the presence of neostigmine (10 microM). Morphine at a low dose of 5 mg/kg (i.p.) increased ACh release by the RVLM by 42.4%. A higher morphine dose (10 mg/kg i.p.) significantly increased the release of ACh by 75.4%, with a maximal effect (86.4%) at 75 min. This enhancement following i.p. administration of morphine was reversed by naloxone (1 mg/kg i.p.). Addition of morphine (10(-4) M) to the perfusion medium increased the ACh release by 85.8% of the predrug values. The increased ACh release induced by local application of morphine was reversed by pretreatment with naloxone (1 mg/kg i.p.). The antinociceptive effect of locally applied morphine into the RVLM was assessed using the hot-plate test and tail immersion test in unanesthetized rats. Local application of morphine (10(-4) M) via a microdialysis probe induced an increase in both tail withdrawal and hot-plate response. These findings suggest that morphine seems to exert a direct stimulatory effect on ACh release by the RVLM and that morphine-induced nociception is, in part, activated by the release of ACh in freely moving rats.

To explore the optimum dose of intravenous immunoglobulin (i.v.Ig) for treating patients with chronic inflammatory demyelinating polyrneuropathy and multifocal motor neuropathy, we compared the usefulness of i.v.Ig among 3 treatment doses. Fifty-nine patients were randomly divided into three treatment dosage groups: 20 patients for Group I using 50 mg/kg/day x 5 days, 19 patients Group II using 200 mg/kg/day x 5 days, and 20 patients Group III using 400 mg/kg/day x 5 days. We assessed clinically and electrophysiologically the effectiveness of the treatment at 5 weeks after the initial infusion. For patients in Group I and II who had not improved (or worsened) with the first treatment, we gave a one-step larger dose in the second treatment (i.e. 200 mg/kg/day x 5 days for those who had been given 50 mg/kg/day x 5 days, 400 mg/kg/day x 5 days for those who had been given 200 mg/kg/day x 5 days) after more than 9 weeks. We found that 15% of the patients in Group I, 21% in Group II and 60% in Group III improved dose-dependently with the first intravenous immunoglobulin treatment. Seven (47%) of 16 patients in Group I and 4 (40%) of 11 patients in Group II improved after the second treatment with larger doses. Adverse reactions including chill sensation, fever, skin eruption and increase in blood GOT and GPT levels were transient and mild. One patient in Group III developed left hemiparesis showing the small infarction in the right thalamus during the course of the treatment, but the symptom was mild. In conclusion, the high-dose intravenous immunoglobulin therapy (400 mg/kg/day x 5 days) is useful for treating patients with CIDP and MMN, although care must be taken of the risk of causing cerebral infarctions.

We have examined whether ciliary neurotrophic factor (CNTF) can alter serum-free cell survival of immortalized motor neuron-like cells, which were established by fusing mouse neuroblastoma N18TG2 with mouse motor neurons. One of the cell lines, NSC-34 exhibited cell survival in the presence of CNTF. NSC-34 preserves the most characteristics of motor neurons, such as the formation of neuromuscular junctions on co-cultured myotube. GM2 ganglioside is characteristic of motor neurons, and expressed highly in NSC-34. When NSC-34 was cultured with exogenous GM2 ganglioside and CNTF, GM2 facilitated the cell survival effect of CNTF. In the addition, beta 1,4 N-acetylgalactosaminyltransferase (GM2 synthase) activity was enhanced up to 3.9-fold by culture in the presence of CNTF. GM2 might be a functional modulator of CNTF in motor neurons. It might be presented to cell surface by its enzyme activation, and become a signal of early stage, when CNTF rescues motor neurons.

Accommodation designates the survival of vascularized grafts in the presence of circulating antigraft antibodies and complement. In the hamster-to-rat model, accommodation is associated with an ongoing T helper (Th)2 cytokine response and the expression of "protective genes" by the graft endothelial cells and smooth muscle cells. In this report, we tested whether accommodated xenografts would be protected from rejection upon retransplantation into second recipients treated with cyclosporine (CsA), a treatment that does not prolong survival of a fresh hamster heart.Long-term survival of hamster-to-rat cardiac xenografts was achieved using either CsA plus cobra venom factor (CVF) or CsA plus rapamycin. Xenografts that survived long term in their first recipients were retransplanted into second recipients treated with CsA.Long-term xenograft survival in CsA/CVF-treated recipients was associated with an ongoing Th2 response, expression of protective genes, and deposition of elicited xenoreactive antibodies and complement on the graft endothelium. In CsA/rapamycin-treated recipients, long-term xenograft survival occurred in the presence of basal levels of antigraft antibodies and was not associated with a Th2 cytokine response or the expression of protective genes. Xenografts from CsA/CVF-treated rats survived significantly longer upon retransplantation into second recipients treated with CsA (77.3%10 days) as compared with xenografts from CsA/rapamycin-treated rats (4-11 days) or naive hearts (3-4 days). Moreover, 30-35% of xenografts from CsA/CVF rats survived long term and accommodated in the second recipient.Accommodated xenografts can have significantly prolonged acceptance when retransplanted into second recipients treated with CsA alone; in contrast, naive hearts or hearts that survived long term in first recipients, but did not accommodate, did not survive long term in the second recipients. We suggest that prolonged survival of accommodated xenografts is due to the expression of the protective genes A20, bcl-2 bcl-xL, and heme oxygenase-1 in the xenograft endothelium and possibly smooth muscle cells.

The use of anti-B-cell and T-cell immunosuppressive agents leads to only a few weeks' survival of mouse-to-rat cardiac xenografts.BALB/c cardiac xenografts were transplanted to Lewis rats treated with cyclosporine (CsA) and/or cobra venom factor (CVF).CsA alone did not prolong xenograft survival (2.2+/-0.4 days), whereas CVF alone led to minimal prolongation of survival (5.6+/-0.8 days) as compared with nontreated recipients (2.4+/-0.5 days). The combination of CsA plus CVF, the latter given for either 2 days or 11 days, resulted in long-term survival of 14/16 hearts (100 days). Production of IgM elicited xenoreactive antibodies (EXA) peaked on day 4 after transplantation and decreased thereafter. Production of IgG EXA occurred only in the control group, whereas, in the CsA/CVF-treated group, IgG EXA were totally suppressed. Long-term surviving grafts showed (i) excellent preservation of morphology and minimal leukocyte infiltration, (ii) deposition of IgM, IgG and weak C3 deposition on the graft endothelium, (iii) low level infiltration by rat macrophages, (iv) replacement of mouse dendritic cells by class II+ rat macrophages, and (v) expression within endothelial and smooth muscle cells, macrophages, and myocytes of HO-1, a "protective gene" not seen in the rejected hearts.Our present findings suggest that long-term mouse-to-rat cardiac xenograft survival is induced by temporary suppression of C activation and sustained T-cell suppression leading to inhibition of IgG EXA production. Florid expression of a protective gene (HO-1) may contribute to survival.

Comparisons of "time of mating" (the time copulation begins) between lines selected for short and long developmental periods have been made in the melon fly, Bactrocera cucurbitae. These comparisons showed that longer development periods were associated with later initiation of mating. Crosses were also made between selected lines to ascertain the genetic basis of developmental period and time of mating. Comparisons of daily activity rhythms for four types of behavior (locomotion, preening, feeding, and wing vibration) between the selected lines showed the following; (1) locomotion and preening occurred in daytime for the short developmental period lines, versus mainly at night for the long developmental period lines; (2) feeding behavior occurred in daytime for both the short and the long developmental period lines; and (3) wing vibration, a component of courtship behavior of males, occurred at dusk for the short developmental period lines and at night for the long developmental period lines.

If complement (C) activation is prevented or the host is C depleted, discordant vascularized xenografts undergo delayed xenograft rejection (DXR), characterized by graft infiltration by macrophages (MO) and natural killer (NK) cells, endothelial cell activation, and widespread fibrin deposition. Given a lack of effect of T cell-directed therapies on development of DXR, we evaluated two novel agents, 15-deoxyspergualin (DSG) and leflunomide (LEF), with reported anti-B-cell and/or anti-MO actions.DSG and LEF were administered to C-depleted, splenectomized rat recipients of guinea pig cardiac xenografts, and their effects on graft survival and production of anti-guinea pig antibodies were determined. Serial intragraft events were studied by immunohistology using monoclonal antibodies to rat leukocytes, cytokines, and novel proteins, including rat MO lectin, which in other systems is important to MO binding, activation, and target cell killing.Median graft survival was 62 hr in cobra venom factor (CVF)-treated controls versus 108 hr (DSG), 129 hr (LEF), and 120 hr (DSG and LEF; all groups P0.01 vs. CVF alone). LEF and DSG each decreased (immunoglobulin M [IgM]) or abrogated (IgG) posttransplant production of anti-guinea pig antibodies. Immunohistologic studies showed that each agent also inhibited graft infiltration by NK and T cells, and expression of various cytokines, including the chemokine monocyte chemoattractant protein-1 (MCP-1), but did not affect the tempo or extent of MO infiltration. Consistent with this, the rapid induction of MO lectin postxenografting, and induction of MO lectin by rat MO exposed to guinea pig cells in vitro, were unaffected by therapy with DSG and/or LEF.LEF or DSG along with CVF can result in the longest prolongation of xenograft survival yet reported in this model, in conjunction with a dampening of host mononuclear cell responses, including suppression of B cell activation. However, the persistent influx of MO in this model, despite lack of C-, Fc receptor- or apparent chemokine-dependent mechanisms, suggests the presence of additional mechanisms for cell recruitment and activation. It was of importance that, in this regard, although MO depletion is technically difficult and can lead to undesired effects, the demonstration of rapid MO lectin induction postxenografting indicates opportunities for blockade of MO recruitment and functions during DXR by use of anti-MO lectin monoclonal antibodies or administration of competing sugars.

Rejection of guinea pig cardiac grafts in rats depleted of complement takes place in 3-4 days and involves progressive mononuclear cell infiltration and cytokine expression, fibrin and antibody deposition, and endothelial cell up-regulation of adhesion and procoagulant molecules, a process termed delayed xenograft rejection (DXR). The relative contribution of each effector mechanism and the role of T cells in this complex process are unknown, although small numbers of interleukin (IL) 2 receptor-positive T cells are present at the time of rejection. We investigated the importance of T cells in DXR by comparing discordant xenograft responses of nude rats, which lack T cell receptor (TCR)-alpha/beta+ cells, with those of normal Lewis rats. Nude or Lewis rats receiving guinea pig cardiac grafts were assigned to one of three groups: no therapy, daily administration of cobra venom factor (CVF), or splenectomy plus daily CVF. All untreated rats rejected their xenografts within 10-15 min, whereas grafts in complement-depleted recipients survived a further 3-4 days; splenectomy had no significant additional effect upon graft survival. Immunohistologic analysis in CVF-treated nude recipients with or without splenectomy showed: (1) considerable leukocyte infiltration of xenografts (mean +/- SD, 76+/-14 and 71+/-16 leukocytes/field, respectively, at 72 hr, compared with 68+/-17 in Lewis rats), consisting largely of macrophages (75% of total leukocytes) plus small numbers of natural killer cells (10-20%) with no detectable B or T cells (TCR-alpha/beta or TCR-gamma/delta); (2) at least 10-fold lower levels of intragraft IgM or IgG deposition than in corresponding Lewis recipients; and (3) considerable cytokine expression by intragraft macrophages (IL-12, tumor necrosis factor-alpha, monocyte chemoattractant protein-1, IL-1beta, IL-6, IL-7, IL-12) and natural killer cells (interferon-gamma), as well as up-regulation of tissue factor expression and dense fibrin deposition. Analysis of recipient sera of both control and nude rats by ELISA, for the binding of IgG or IgM to guinea pig platelets, showed a rapid rise after transplantation in the titers of IgM and IgG antibodies, which was abrogated by prior splenectomy; i.e., data from splenectomized xenograft recipients reflect the presence of only basal levels of IgM and IgG. Thus, our data in nude rats show rejection times and intragraft features of DXR comparable to those in immunocompetent Lewis recipients, despite a lack of detectable host T cells, and, in the case of splenectomized rats, only about one tenth of normal xenoreactive antibody levels. Our data document a new model in which to analyze the immunopathogenesis of DXR.

Extracts of the plant Sinomenium acutum have been used safely since ancient times in Chinese medicine for treatment of rheumatic diseases, and the purified alkaloid, sinomenine, was recently shown to have anti-inflammatory and antirheumatic effects. This study describes the effects of sinomenine in the high responder ACI--Lewis cardiac transplant model in which allograft rejection occurred at 5 days posttransplant. Treatment with sinomenine (15-30 mg/kg/day i.p.) or a subtherapeutic dose of cyclosporine (CsA, 1.5 mg/kg/day, i.m.) prolonged allograft survival only marginally (mean survival of 5.4 and 7.8 days, respectively). In contrast, the combination of sinomenine and CsA had a statistically significant synergistic effect, with a mean survival of 42.2 days (P0.001). Allografts harvested at day 5 from recipients treated with either sinomenine or CsA showed dense mononuclear cell infiltrates with widespread subepicardial infarcts, edema, and microvascular platelet and fibrin deposition. Immunohistologic analysis showed that intragraft leukocytes consisted of75% macrophages with approximately 10-20% T cells and5% B or NK cells. Mononuclear cell activation was shown by expression of IL-2R (CD25, 10-20%) and labeling for IL-2 (approximately 10%), and IFN-gamma (10-20%), as well as TNF-alpha (50%) and iNOS (50%), but only low levels of IL-4 or IL-10 (5%). Intragraft endothelial cells were activated, as shown by upregulation of MHC class II antigen and ICAM-1 (CD54) compared with only basal levels in normal donors hearts. Combined sinomenine/CsA therapy significantly enhanced graft morphology, resulting in only mild mononuclear cell infiltration, and an absence of infarcts, platelets, or fibrin deposition. Though residual intragraft mononuclear cells at day 5, as in control grafts, consisted primarily of macrophages plus small numbers of IL-2R+ T cells, these cells lacked expression of IL-2, had only low levels of IFN-gamma, but showed dense labeling for IL-4 and IL-10. In addition, TNF-alpha and iNOS were reduced to basal levels and no endothelial cell activation was observed, despite high titers of endothelium-bound IgM, IgG, and C3. Mitogen-induced in vitro proliferation of rat thymocytes was also more effectively decreased by the sinomenine/CsA combination than by either agent alone. These studies demonstrate the therapeutic value of sinomenine in transplantation, and indicate that this agent has novel and interesting antimacrophage, T cell, and endothelial effects that warrant further evaluation.

Platelet thrombi and vascular inflammation are prominent features of discordant xenograft rejection. The purinergic nucleotides ATP and ADP, which are secreted from platelets and released by injured endothelial cells (EC), are important mediators of these reactions. Quiescent EC express the ectoenzyme ATP-diphosphohydrolase (ATPDase; an apyrase), which exerts an important thromboregulatory function by hydrolyzing both ATP and ADP. We have shown that ATPDase activity is rapidly lost from the surface of the EC following ischemia-reperfusion injury and during xenograft rejection. The aim of this study was to supplement ATPDase activity within xenografts by infusion of soluble apyrases, and thereby validate the importance of local ATPDase activity in the modulation of xenograft rejection. Lewis rats underwent heterotopic cardiac xenografting from guinea pigs and apyrase was administered intravenously (200 U/kg) as a single dose to evaluate effects on hyperacute rejection (HAR). This initial dose was followed by a continuous apyrase infusion (8.0 U/kg/hr) directly into the graft aorta in combination with systemic cobra venom factor (CVF) administration to deplete complement when delayed xenograft rejection (DXR) was studied. Functional apyrase levels in vivo were assessed by the capacity of blood samples taken at the time of surgery and rejection to inhibit platelet aggregation in vitro. Apyrase administration significantly prolonged graft survival in HAR and DXR. Functional assays showed inhibition of platelet aggregation suggesting effective systemic antiaggregatory effects of the administered apyrases. Histologic studies showed that apyrase administration abrogated local platelet aggregation and activation in HAR and DXR. Our data demonstrate that local administration of apyrase prolonged discordant xenograft survival. These observations emphasize the potential importance of purinergic mediators in platelet activation during xenograft rejection.

Passive transfer of serum IgG or mononuclear cells from peripheral blood of a patient with paraneoplastic cerebellar degeneration (PCD) to rodents was carried out in order to examine the role of anti-Purkinje cell antibody (anti-Yo antibody) present in serum and cerebrospinal fluid of PCD patients. After a single injection of IgG into mouse brain, it was taken up by Purkinje cells and remained there for more than 36 h without Purkinje cell loss. Injection of PCD IgG together with complement or lipopolysaccharide-activated human macrophages or rat mononuclear cells into rat ventricles did not cause Purkinje cell loss. We also studied passive transfer of the PCD patient's lymphocytes to mice with severe combined immunodeficiency (SCID). We constructed a recombinant Yo fusion protein that has the leucine-zipper protein (Yo protein), the common epitope for anti-Yo antibody for immunizing mice, and that resulted in production of significant amounts of anti-Yo antibody. Spleen cells from these Yo protein immunized mice were injected intravenously or intracerebrally into naive mice that subsequently showed no neurological symptoms or loss of Purkinje cells. We conclude that the anti-Yo antibody, either in combination with or without complement or activated mononuclear cells, cannot be the sole cause of Purkinje cell loss.