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1. Interleukin-12 (IL-12) may play a central role in the development and progression of rheumatoid arthritis by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effect of auranofin (AF), an anti-rheumatic gold compound, on IL-12 production in mouse macrophages and dendritic cells, and studied whether AF-mediated inhibition of IL-12 production could regulate a cytokine profile of antigen (Ag)-primed CD4(+) Th cells. 2. Treatment with AF significantly inhibited IL-12 production in lipopolysaccharide (LPS)-stimulated macrophages and also in CD40L-stimulated dendritic cells. AF-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. AF did not influence the cell surface expression of the class II MHC molecule and the costimulatory molecules CD80 and CD86. 3. Addition of recombinant IL-12 to cultures of AF-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in Ag-primed CD4(+) T cells. 4. The in vivo administration of AF resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with LPS or heat-killed Listeria monocytogenes (HKL), leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in Ag-primed CD4(+) T cells. 5. These findings may explain some known effects of AF including anti-rheumatic effects and the inhibition of encephalitogenicity, and point to a possible therapeutic use of AF in the Th1-mediated immune diseases such as autoimmune diseases.

2-Amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)- purine (SK1899) was tested as an oral prodrug for penciclovir. SK1899 was administered orally to rats and dogs at doses up to 2 and 0.68 mmol/kg, respectively. SK1899 was well absorbed, and the major metabolites detected in plasma and urine were penciclovir, the active antiviral compound, and 6-deoxypenciclovir (M4) in both species. In rats, SK1899 was rapidly and extensively metabolized to penciclovir, which reached the peak plasma concentration (C(max)) of 39.5 microM at 0.5 h after 0.2-mmol/kg dosing. The area under the plasma concentration-time curve (AUC) for penciclovir was 57.5 microM x h. After an oral dose of 0.034 mmol/kg to dogs, extensive conversion of SK1899 to penciclovir also occurred with slower rate of formation of penciclovir from M4 than in rats. The mean C(max) and AUC for penciclovir were 4.5 microM at 2.7 h and 28.2 microM x h, respectively. The 0- to 24-h urinary recovery of penciclovir represented 36.1 and 36.3% of dose to rats and dogs, respectively. Radioactivity was found in fetuses following an oral administration of [(14)C]SK1899 to pregnant rats, but no significant accumulation was observed. Although substantial milk transfer of [(14)C]SK1899 occurred in rats, the radioactivity in milk was rapidly cleared. The values of C(max), AUC, and urinary recovery of penciclovir after dosing with SK1899 to rats and dogs were similar or slightly higher than those from famciclovir. These data indicate that introduction of an isopropoxy carbonate group into one of the two hydroxyl groups of M4 did not significantly alter the oral bioavailability of penciclovir compared with famciclovir.

The effect of silibinin, an active component of Silybum marianum, on cellular differentiation was investigated in the human promyelocytic leukemia HL-60 cell culture system. Treatment of HL-60 cells with silibinin inhibited cellular proliferation and induced cellular differentiation in a dose-dependent manner. Cytofluorometric analysis and morphologic studies indicated that silibinin induced differentiation of HL-60 cells predominantly into monocytes. Importantly, strongly synergistic induction of differentiation into monocytes was observed when silibinin was combined with 5 nM 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)], a well-known differentiation inducer of HL-60 cells into the monocytic lineage. Silibinin enhanced protein kinase C (PKC) activity and increased protein levels of both PKCalpha and PKCbeta in 1,25-(OH)(2)D(3)-treated HL-60 cells. PKC and extracellular signal-regulated kinase (ERK) inhibitors significantly inhibited HL-60 cell differentiation induced by silibinin alone or in combination with 1,25-(OH)(2)D(3), indicating that PKC and ERK may be involved in silibinin-induced HL-60 cell differentiation.

A rare case of carotid cavernous fistula occurring during endovascular embolization of the left carotid cave aneurysm in a 48-year-old female is reported. It was thought to be caused by the tear of a small branch derived from the intracavernous internal carotid artery while the guidewire was passing the sharp posterior bend of the intracavernous internal carotid artery. The left carotid cave aneurysm was completely occluded with five Guglielmi detachable coils assisted by neck plasty technique. It was decided to follow-up the carotid cavernous fistula since it was asymptomatic. Follow-up angiogram performed two weeks later revealed spontaneous obliteration of the carotid cavernous fistula.

Summary: We report the imaging findings in two patients with proliferating trichilemmal tumors. In the first patient, the tumor arose on the lower lip, a very unusual location for this type of tumor, and showed malignant transformation with metastasis to a regional lymph node. It was seen as a poorly marginated soft-tissue mass with isointense signal on T1-weighted MR images and hyperintense signal on T2-weighted images. Large areas of high signal intensity caused by necrosis were also found within the tumor on T2-weighted images. After IV administration of contrast material, the mass showed significant enhancement, with considerable portions remaining unenhanced. In the second patient, the tumor originated from a preexisting trichilemmal cyst and occurred in the hair-bearing area of the posterior part of the neck. CT scans showed a well-encapsulated cystic mass that contained multiple speckled calcifications in a wall of variable thickness. There were several foci of smooth soft-tissue elevations from the inner wall of the mass, which corresponded histologically to proliferating portions of trichilemmal cyst.

While epitaxial CaF2 films grown on Si(111) at temperatures above 550 °C exhibited flat capacitance‐voltage (C‐V) curves, suggesting a pinned CaF2/Si(111) interface, we have observed unpinned C‐V curves from as‐deposited epitaxial CaF2 grown at 300 °C. Our results demonstrate that C‐V characteristics of CaF2/Si(111) are determined by the thermal history, rather than the crystalline quality, of the CaF2 film. Correlations among CaF2/Si interface state density, thermal stress, and atomic bonding at the interface are discussed.

Mouse fibroblasts (H-2(b)) were genetically engineered to express a co-stimulatory B7.1 and an IFN-gamma (Fb/IFN-gamma/B7.1). The Fb/IFN-gamma/B7.1 cells were then pulsed with an ovalbumin epitope (amino acids 257-264, SIINFEKL, H-2K(b)-restricted) as a model antigen (Fb/IFN-gamma/B7.1/OVA) and tested for the induction of OVA-specific cytotoxic T lymphocytes (CTLs) in C57BL/6 mice (H-2(b)). Genetically engineered fibroblasts lacking either IFN-gamma or B7.1 were constructed and used as controls. Immunization with the Fb/IFN-gamma/B7.1/OVA cells induced strong cytotoxic activity against OVA-expressing EL4 (EG7) tumor cells but not against other H-2(b) tumor cells, such as EL4, C1498, and B16F1. The magnitude of the cytotoxic response in mice with the Fb/IFN-gamma/B7.1/OVA cells was significantly higher than that in mice immunized with any other cell construct. CD8(+) T cells with OVA-specific cytotoxic activity were predominant in mice immunized with Fb/IFN-gamma/B7.1/OVA cells. Furthermore, treatment with Fb/IFN-gamma/B7.1/OVA cells significantly prolonged the survival period of EG7 tumor-bearing mice. Anti-tumor CTL immunity by the Fb/IFN-gamma/B7.1/OVA cells could be induced without the help of host antigen-presenting cells, CD4(+) T cells, or NK1.1(+) cells. Our results suggest that fibroblasts can be genetically modified into efficient antigen-presenting cells for the induction of antigen-specific CTL response in cancer immunotherapy.

To determine whether the paracrine secretion of interleukin (IL)-12 can efficiently convert immune responses characterized by high levels of synthesis of IL-4 and immunoglobulin E (IgE) into T helper 1 (Th1)-dominated responses, 3T3 fibroblasts were stably transfected to secrete IL-12 (480 units/10(6) cells/48 hr). Their effects on the T helper cell-mediated immune response were investigated in ovalbumin (OVA)-primed mice. Free mouse recombinant IL-12 was included as a control group. IL-12-secreting fibroblasts (3T3/IL-12) were more effective than free recombinant IL-12 at increasing OVA-specific interferon-gamma (IFN-gamma) production and decreasing OVA-specific IL-4 production in CD4+ T cells. In addition, injection with 3T3/IL-12 cells significantly increased anti-OVA immunoglobulin G2a (IgG2a) levels and decreased anti-OVA IgE levels in OVA-primed mice. This work suggests that IL-12-secreting fibroblasts can efficiently induce an antigen-specific Th1 response and may be beneficial in the treatment of diseases caused by undesirable T helper 2 (Th2)-dominated responses, including allergic diseases.

Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses characterized by high IFN-gamma and low IL-4 production. In this study we investigated whether retinoid-mediated inhibition of interleukin-12 production in mouse macrophages could regulate cytokine profile of antigen (Ag)-primed CD4(+) Th cells. Pretreatment with retinoids (9-cis-RA, all-trans-RA, TTNPB) significantly inhibited IL-12 production by mouse macrophages stimulated with lipopolysaccharide (LPS) or heated-killed Listeria monocytogenes (HKL). Retinoid-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4(+) T cells. Addition of recombinant IL-12 to cultures of retinoid-pretreated macrophages and CD4(+) T cells restored IFN-gamma production in CD4(+) T cells. The in vivo administration of 9-cis-RA resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in CD4(+) T cells. These findings may explain some known effects of retinoids including the inhibition of encephalitogenicity, and point to a possible therapeutic use of retinoids in the Th1-mediated immune diseases such as autoimmune diseases.

We have studied the use of tertiarybutylarsine (t‐BuAsH2) for organometallic vapor phase epitaxy (OMVPE) growth of AlGaAs/GaAs heterojunction bipolar transistors (HBTs). Good dc characteristics were achieved with t‐BuAsH2‐grown HBT structures, including common‐emitter current gains higher than 200 and 1000 for n‐p‐n and p‐n‐p structures, respectively. Near‐ideal current gain dependence on the collector current density was observed, indicating that the quality of AlGaAs was suitable for high‐performance HBTs. The microwave characteristics were also comparable to those of arsine‐grown HBTs. These results demonstrate that t‐BuAsH2 can successfully replace arsine for OMVPE growth of AlGaAs/GaAs HBT structures.

Immunogold densities for the 'classical' and 'novel' alpha chains of type IV collagen, laminin, and fibronectin are increased in the spikes in human membranous nephropathy (MN). To investigate the molecular mechanisms which underlie these changes in glomerular basement membrane (GBM) components, alpha1(IV) collagen, alpha4(IV) collagen, S-laminin, fibronectin, transforming growth factor (TGF)-beta1 and TGF-beta2 mRNA expression was examined in 12 renal biopsy specimens with MN and six renal biopsies with no detectable abnormality by RNA in situ hybridization. In controls, there were relatively low signals of alpha1(IV) collagen, alpha4(IV) collagen, S-laminin, and TGF-beta1 mRNAs, but there were no fibronectin or TGF-beta2 transcripts in glomerular cells. In MN, the number of alpha4(IV) collagen, alpha1(IV) collagen, S-laminin or TGF-beta1 mRNA-expressing cells per glomerular cross-section was significantly larger than in controls (p0.05), and fibronectin mRNA was occasionally expressed in glomerular visceral epithelial cells (GECs). No message for TGF-beta2 was seen in MN. The number of TGF-beta1 mRNA-expressing cells per glomerular cross-section significantly correlated with that of alpha1(IV) mRNA-expressing cells (p0.01). The MN patients with positivie signal for fibronectin mRNA exhibited more severe GBM thickening than those without (p0.05). These results indicate that the increased presence of GBM proteins in spikes of MN is associated with enhanced mRNA expression of these proteins. They also suggest that subepithelial deposits in MN stimulate GECs to produce TGF-beta1, which in turn could mediate the expression of GBM protein genes by GECs.

A novel gene, sps2, detected in mouse embryo at the early stages of development has been identified as an analog of the E. coli selenophosphate synthetase gene. Unlike the E. coli enzyme, the presence of selenocysteine in the mouse enzyme is indicated by a TGA codon in the open reading frame of the cDNA. Using an N-FLAG monoclonal antibody, it was shown that the full length N-FLAG-sps2 gene product was expressed in COS-7 cells. To investigate the biological activity of the sps2 gene product in vivo, the mutated sps2 gene, which contains cysteine in the place of the TGA encoded selenocysteine in the wild type, was expressed in the E. coli selD deficient mutant, MB08. Like the E. coli wild type selD gene, the mutant sps2 gene complemented the selD mutation. However, replacement of Cys with either Ala, Ser, or Thr resulted in a loss of ability to complement the selD mutation. The SPS2-CYS protein expressed in E. coli was purified and its catalytic activity was determined. The Km value for ATP was 0.75 mM and Vmax was 9.23 nmole/min/mg protein. These results confirm that the mouse embryonic sps2 gene encodes an eukaryotic selenophosphate synthetase, and that availability of selenophosphate as a selenium donor compound is widespread.

1 Interleukin-12 (IL-12) plays a central role in the immune system by driving the immune response towards T helper 1 (Th1) type responses which are characterized by high IFN-gamma and low IL-4 production. In this study we investigated the effects of curcumin, a natural product of plants obtained from Curcuma longa (turmeric), on IL-12 production by mouse splenic macrophages and the subsequent ability of these cells to regulate cytokine production by CD4+ T cells. 2 Pretreatment with curcumin significantly inhibited IL-12 production by macrophages stimulated with either lipopolysaccharide (LPS) or head-killed Listeria monocytogenes (HKL). 3 Curcumin-pretreated macrophages reduced their ability to induce IFN-gamma and increased the ability to induce IL-4 in Ag-primed CD4+ T cells. Addition of recombinant IL-12 to cultures of curcumin-pretreated macrophages and CD4+ T cells restored IFN-gamma production in CD4+ T cells. 4 The in vivo administration of curcumin resulted in the inhibition of IL-12 production by macrophages stimulated in vitro with either LPS or HKL, leading to the inhibition of Th1 cytokine profile (decreased IFN-gamma and increased IL-4 production) in CD4+ T cells. 5 These findings suggest that curcumin may inhibit Th1 cytokine profile in CD4+ T cells by suppressing IL-12 production in macrophages, and points to a possible therapeutic use of curcumin in the Th1-mediated immune diseases.

Interleukin-12 (IL-12) plays a pivotal role in the development of T-helper 1 (Th1) immune response, which may be involved in the pathogenesis of chronic inflammatory autoimmune disorders. In this study we investigated the effects of sulfasalazine, a drug for treating inflammatory bowel disease and rheumatoid arthritis, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). Sulfasalazine potently inhibited the production of IL-12 in a dose-dependent manner, in part through the down-regulation of nuclear factor kappaB (NFkappaB) activation in IL-12 p40 gene. Activation of macrophages by LPS resulted in markedly enhanced binding activities to the kappaB site, which significantly decreased upon addition of sulfasalazine as demonstrated by an electrophoretic gel shift assay. Importantly, macrophages pretreated with sulfasalazine either in vitro or in vivo reduced their ability to induce interferon-gamma (IFN-gamma) and increased the ability to induce IL-4 in antigen-primed CD4+ T cells. From these results, sulfasalazine may induce the Th2 cytokine profile in CD4+ T cells by suppressing IL-12 production in macrophages, and sulfasalazine-induced inhibition of IL-12 production in macrophages may explain some of the known biological effects of sulfasalazine.

In order to maintain in vivo anti-tumor efficacy of antigen (Ag)-specific T cells in adoptive immunotherapy for a prolonged period, we constructed a fusion protein (OVA/IL-2) containing ovalbumin (OVA) as a model tumor Ag, co-valently linked to murine interleukin-2 (IL-2). The OVA/IL-2 protein produced in a baculovirus expression system displayed potent IL-2 bio-activity. Immunization with the OVA/IL-2 protein after adoptive transfer of OVA-specific T cells maintained the OVA-specific cytotoxicity and cell number of adoptively transferred T cells long term in vivo, while a simple mixture of recombinant OVA (rOVA) and rIL-2 did not. The response was dependent on the injection doses and times of the OVA/IL-2 protein. Furthermore, weekly re-stimulation of adoptively transferred OVA-specific T cells with the OVA/IL-2 protein cured 70% of tumor-bearing mice. In contrast, re-stimulation with a mixture of rOVA and rIL-2 could not significantly prolong the survival period of tumor-bearing mice. These studies suggest that the co-valent linkage between IL-2 and antigen confines the effect of IL-2 to antigen-specific T cells, leading to efficient maintenance of the anti-tumor activity of adoptively transferred T cells.

The cDNAs for interferon-gamma (IFN-gamma) and allogeneic H-2Kd molecules were transfected into highly metastatic B16F10 melanoma cells (H-2b), and the synergistic effects of the antitumor immune responses by the doubly transfected cells (B16/Kd/IFN-gamma cells) were investigated in C57BL/6 mice (H-2b). The singly transfected B16F10 cells with either IFN-gamma or H-2Kd cDNA (B16/IFN-gamma or B16/Kd cells) were used as controls. The B16/Kd/IFN-gamma cells secreted biologically active IFN-gamma, and strongly expressed both syngeneic and allogeneic MHC class I antigens (H-2Kb and H-2Kd) on the same cell construct. Immunization with the doubly transfected B16/Kd/IFN-gamma cells induced higher anti B16F10 cellular cytotoxic responses than the single transfected B16/IFN-gamma or B16/Kd cells. Lyt-2.2 (CD8)+ T-cells were a major effector cell-type involved in the anti B16F10 responses and their cytotoxic activities were augmented in the immunized mice with the B16/Kd/IFN-gamma cells, as demonstrated by in vitro depletion experiments. The survival period of melanoma-bearing mice treated with the B16/Kd/IFN-gamma cells was significantly longer than that treated with the B16/IFN-gamma or B16/Kd cells. Furthermore, the treatment with the B16/Kd/IFN-gamma cells was capable of greatly inhibiting lung metastasis from small, established B16F10 footpad tumors. These results suggest that the augmented immunotherapeutic potentials can be achieved by the vaccination with IFN-gamma and allogeneic MHC class I genes transfected B16F10 melanoma cells.

With the introduction of a new cardiac prosthesis, it behooves surgeons and cardiologists to carefully monitor its performance. The ATS Medical prosthetic valve has been used at Guro Hospital in Korea since 1994.

The pharmacokinetic study on cis-(glycolato-O,O') [(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]-platinum(II) (SKI 2034R, NSC D642489) was performed in beagle dogs. A single dose of 2.0 mg/kg of SKI 2034R was given by i.v. bolus to three beagle dogs. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for SKI 2034R declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0--infinity) determined for ultrafiltrable platinum derived from SKI 2034R, as an active component, was 2.76 +/- 0.13 micrograms.h/ml (mean +/- S.D.), with an initial half-life of 0.15 +/- 0.09 hour, a terminal half-life of 0.96 +/- 0.12 hour, a total clearance of 12.07 +/- 0.67 ml/min/kg, and a steady-state volume of distribution of 0.82 +/- 0.06 1/kg.

The most common high resolution CT (HRCT) findings of bronchiolitis are centrilobular nodules and branching linear structures in the secondary pulmonary lobules or areas of air trapping. These findings can be helpful in suggesting the presence of bronchiolitis. However, they are nonspecific because there are overlapping features among various kinds of bronchiolitis. Bronchiolar or peribronchiolar inflammation appears as centrilobular nodule, while bronchiolectasis filled with secretions manifests with branching linear structure on HRCT. Air trapping is secondary to bronchiolitis. Proliferative bronchiolitis with the findings of patchy areas of consolidation or ground-glass opacity can be distinguished from other bronchiolitis. Mineral dust-induced bronchiolitis and peribronchiolar lesions in sarcoidosis present with perilymphatic (centrilobular plus perilobular) micronodules in the secondary pulmonary lobule. Bronchiolitis in hypersensitivity pneumonia appears with poorly defined centrilobular nodules, associated with ground-glass opacity and air trapping.

PURPOSE: To investigate the MR findings of childhood metachromatic leukodystrophy (MLD). METHODS: Nine MR imaging studies in seven children (five girls and two boys, 10 to 32 months old) with MLD were evaluated retrospectively for the extent and progression of white matter abnormalities and the presence of contrast enhancement. RESULTS: All seven cases showed symmetric, confluent high signal intensity on T2-weighted images in the periventricular white matter and centrum semiovale. A posterior predominance of white matter abnormalities was noted in all cases. Although initially spared from demyelination in all cases, in one case, the subcortical U fibers were later involved in demyelination of follow-up MR studies. Other sites of involvement were the genu (n = 5) and splenium (n = 6) of the corpus callosum, the posterior limbs of the internal capsule (n = 5), the descending pyramidal tracts (n = 4), the claustrum (n = 4), and the cerebral white matter (n = 2); diffuse brain atrophy was seen in two cases. No enhancement of the lesion was seen on any of the five postcontrast examinations. A "tigroid" pattern, previously described in cases of Pelizaeus-Merzbacher disease, was noted in the centrum semiovale in six cases. CONCLUSION: In late-infantile MLD, demyelination is more prominent in the occipital region. In addition to demyelination of the periventricular white matter, common manifestations include a "tigroid" pattern and involvement of the corpus callosum, the internal capsule, and the corticospinal tract.

The possible nature of metastable capture centers giving rise to persist photoconductivity (PPC) effect in As-doped p-ZnO was investigated using the photoluminescence result. Through the plot of log σph vs. 1/T and temperature-dependent PPC-decay process, the metastable trapping centers were extracted to be 15.1, 178.2, 180.6, and 291.9 meV. The shallow level of 15.1 meV was related to the binding energy of the neutral acceptor bound exciton. Also, the deep levels of 178.2 and 180.6 meV were caused by complex acceptor states of AsZn-2VZn located at 185 meV above the edge of the valence band. Furthermore, the trapping center of 291.9 meV was corresponded to the hole capture barrier of VZn located at 300 meV above the valence band. Therefore, these trapping centers were deeply related to the AX centers originating the native defects due to VZn or defect complexes of the As-implanted dopant in ZnO. Also, these defects, induced by the metastable AX centers, were concluded to be responsible for the PPC effect.

A pharmacokinetic study on cis-(glycolato-O,O)/ (4R,5R)-4,5-bis(aminomethyl)-1,3-dioxolane-2-spiro-1'- cyclohexane]platinum(II) (SKI 2032R) was performed in dogs. A single dose of 2.0 mg/kg of SKI 2032R was administered i.v. bolus to three beagle dogs. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for SKI 2032R declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0 --infinity) determined for ultrafiltrable platinum derived from SKI 2032R, as an active component, was 2.36 +/- 0.23 micrograms. h/ml (mean +/- S.D.), with an initial half-life of 0.23 +/- 0.20 hour, a terminal half-life of 1.32 +/- 0.49 hour, a total clearance of 14.17 +/- 1.50 ml/min/kg, and a steady-state volume of distribution of 1.21 +/- 0.24 l/kg.

The in vitro cytotoxicity of a new platinum complex, cis-malonato [(4R, 5R)-4,5-bis(aminomethyl)-1,3-dioxolane 2- spiro 1' cyclo-pentane]platinum(II) (SKI 2054R) and cisplatin (CDDP) was evaluated against two human stomach adenocarcinoma cell lines (MKN-45 and KATO III) and a human lung adenocarcinoma cell line (PC-14). The in vitro 50% inhibitory concentration (IC50) values of SKI 2054R and CDDP against MKN-45, KATO III, and PC-14 were 1.21 and 0.51, 2.11 and 0.83, and 2.90 and 0.77 micrograms/ml, respectively. The pharma-cokinetic and ex vivo pharmacodynamic studies on SKI 2054R and CDDP were performed in beagle dogs. Equitoxic doses of SKI 2054R and CDDP (7.0 and 3.0 mg/kg, respectively) were administered i.v. bolus to beagle dose in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the two drugs declined in a biexponential fashion. The mean area under the concentration-tine curve (AUC(0)--infinity) determined for ultrafiltrable platinum derived from SKI 2054R, as an active component was 6.61 +/- 2.34 micrograms . h/ml (mean +/- S.D.), with an initial half-life of 0.26 +/- 0.14 h, a terminal half-life of 1.57 +/- 0.71 hour, a total clearance of 17.65 +/- 4.99 ml/min/kg, and a steady-state volume of distribution of 1.46 +/- 0.11 l/kg. The ex vivo antitumor activity of SKI 2054R was assessed using the ultrafiltrable plasma against MKN-45, KATO III, and PC-14 by tetrazolium-dye (MTT) assay and was compared with that of CDDP using the antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value recorded for SKI 2054R was higher than that noted for CDDP; however, statistical difference was not observed between SKI 2054R and CDDP, suggesting that the antitumor activity of SKI 2054R is comparable to that of CDDP. These results suggest that SKI 2054R is a new platinum complex which is worth being evaluated further.

Genetic alterations are a common feature of the malignant phenotype. Among other properties, altered genes may be responsible for invasion and metastasis, as well as for resistance to chemotherapeutic agents. Under appropriate circumstances, the products of other altered genes expressed by malignant cells may act as tumor-associated T-cell epitopes, capable of provoking antitumor immune responses. As a novel means of augmenting the immunogenicity of the gene products, unfractionated, sheared genomic DNA from various tumor cell lines (B16F1 melanoma, B16F10 melanoma, MOPC-315 plasmacytoma, C1498 lymphoma, or J558 myeloma), or from non-neoplastic liver cells of tumor-free mice, was transfected into LM cells, a mouse fibroblast cell-line (H-2k) that had been modified previously by retroviral gene transfer to secrete interleukin-2 (IL-2). The IL-2-secreting transfected cell populations were then tested for their immunogenic properties toward B16F1 (H-2b) or C1498 (H-2b) cells in syngeneic C57BL/6 mice. The antitumor responses were specific for the type of tumor from which the DNA was obtained. The survival of C57BL/6 mice injected with a mixture of viable B16F1 cells and IL-2-secreting LM cells transfected with DNA from B16F1 cells was significantly prolonged. In a similar manner, the survival of C57BL/6 mice injected with a mixture of C1498 cells and IL-2-secreting LM cells transfected with DNA from C1498 cells was prolonged as well. The immunity was mediated predominantly by CD8+ and natural killer/lymphokine-activated killer (NK/LAK) cells. These data raise the possibility that a cell line altered previously for cytokine secretion may be readily modified to provide immunologic specificity for the neoplasms of individual cancer patients.

Focal segmental glomerulosclerosis (FSGS) is observed in severe or atypical preeclamptic patients biopsied postpartum. To further define the structural characteristics that might be related to atypical clinical manifestations in this disorder, we analyzed the postpartum renal biopsies of eight preeclamptic patients with FSGS by morphometry and studied the structural-functional relationships. For comparison, three postpartum biopsies with primary FSGS and eight nonpregnant subjects with primary FSGS were also studied. Mesangial volume fraction was increased in the preeclamptic FSGS group being 2 times that of the pregnant or nonpregnant primary FSGS group. Mean surface density of peripheral glomerular basement membrane (PGBM) per glomerulus was markedly decreased in the preeclampsia group being 1/3 that for the pregnant or nonpregnant primary FSGS group. Volume density of cortical interstitium in the preeclamptic FSGS was smaller than that of the primary FSGS group. In preeclamptic FSGS, mesangial volume fraction correlated inversely with PGBM surface area (r = -0.84; p0.01) and with creatinine clearance (Ccr) (r = -0.63; p0.05). PGBM surface area per glomerulus in preeclamptic FSGS correlated with Ccr (r = +0.63; p0.05). Mean volume density of cortical interstitium was not related to Ccr nor with the percentage of glomeruli with FSGS in preeclamptic FSGS. These results suggest that decreased glomerular filtration function in atypical preeclampsia is linked to decreased PGBM surface area, that results from mesangial expansion and particularly from mesangial interposition.

A large meningioma in the cerebellopontine angle manifested itself as a contralateral hemifacial spasm. On computed tomographic and magnetic resonance imaging scans, the brain stem was markedly displaced and distorted by the tumor. After total removal of the meningioma, the hemifacial spasm completely disappeared.

The pharmacokinetics and ex vivo pharmacodynamics studies on cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1, 3- dioxolane]platinum(II) (SKI 2053R, NSC D644591), cisplatin (CDDP), and carboplatin (CBDCA) were performed in beagle dogs. Equitoxic doses of SKI 2053R, CDDP, and CBDCA (7.5, 2.5, and 15.0 mg/kg, respectively) were given by i.v. bolus to three beagle dogs in a randomized crossover study. Plasma samples were analyzed for platinum by flameless atomic absorption spectrophotometry. Plasma concentrations of total and ultrafiltrable platinum for the three drugs declined in a biexponential fashion. The mean area under the concentration-time curve (AUC0--infinity) determined for ultrafiltrable platinum derived from SKI 2053R, as an active component, was 7.72 +/- 2.74 micrograms h ml-1 (mean +/- SD), with an initial half-life of 0.37 +/- 0.20 h, a terminal half-life of 2.19 +/- 0.93 h, a total clearance of 16.83 +/- 4.76 ml min-1 kg-1, and a steady-state volume of distribution of 1.57 +/- 0.30 l/kg. The ex vivo antitumor activity of SKI 2053R was assessed using the ultrafiltrable plasma against two human lung-adenocarcinoma cell lines (PC-9 and PC-14) and five stomach-adenocarcinoma cell lines (MKN-45, KATO III, SNU-1, SNU-5, and SNU-16) by tetrazolium-dye (MTT) assay and was compared with that of CDDP and CBDCA using an antitumor index (ATI) determined from the ex vivo pharmacodynamic results of inhibition rates (%) versus time curves. The mean ATI value was shown to be ranked in the following order: SKI 2053RCBDCACDDP. The mean ATI values recorded for SKI 2053R and CBDCA were significantly (P0.05) higher than that noted for CDDP; however, no statistically significant difference was observed between SKI 2053R and CBDCA, suggesting that the antitumor activity of SKI 2053R is superior to that of CDDP and is equivalent to that of CBDCA. These results suggest that SKI 2053R is a promising candidate for further development as a clinically useful anticancer drug.

The growth of a potentially antigenic tumor in an immunocompetent host is taken as an indication that the malignant cells 'escaped' the cytotoxic capacity of the immune system. An increase in our knowledge of the means by which antigens are processed and expressed allows a greater understanding of the mechanism that enables tumor cells to avoid host immunity. It provides a rationale for new, more innovative forms of treatment. Antigenic determinants are presented to cytotoxic T lymphocytes (CTLs) in the context of class I determinants, structures specified by genes within the major histocompatibility complex. Potentially antigenic tumors may express lower levels of class I determinants than surrounding non-neoplastic cells. As a consequence, the tumor-associated T cell epitopes formed by the malignant cells may go unrecognized by tumor-specific CTLs. The introduction of genes specifying class I determinants into low class I expressing tumor cells increased class I expression and restored the cells' immunogenic properties. Treatment of low class I expressing cells with interferon-gamma, or the introduction of the interferon-gamma gene into the cells resulted in an increase in the expression of class I determinants as well, and, as a consequence, recognition of the malignant cells by the immune system. Nevertheless, an immunotherapeutic strategy that stimulated a single anti-tumor effector mechanism might be unable to eliminate a heterogeneous tumor cell population. To investigate this point, mice with melanoma were treated with a mixture of interferon-gamma-secreting and IL-2-secreting cellular immunogens. The animals survived significantly longer than mice with melanoma treated with either the IL-2 or interferon-gamma-secreting immunogens alone. The complexity of the problem was illustrated by the fact that although survival was prolonged, tumor growth recurred in each instance.

An extracellular adenosine deaminase was isolated from the culture supernatant of Nocardioides sp. J-326TK and purified 193-fold to homogeneity. It had a specific activity of 4677 units/mg at 37 degrees C, was a monomeric protein as judged by SDS/PAGE, and was characterized with respect to M(r) (80,000 and 72,000 by gel filtration on Sephadex G-200 and SDS/PAGE respectively), pH optimum (6.0), temperature optimum (50 degrees C) and pI (7.6). The adsorption spectrum of the enzyme had a maximum at 280 nm and a minimum at 250 nm. The enzyme was stable at pH 6.5-7.5 and at temperatures below 30 degrees C. Adenosine and 2'-deoxyadenosine were deaminated and the respective Km values were 0.22 and 0.20 mM, but the enzyme was not active on adenine and 6-(gamma gamma'-dimethylallylamino)purine riboside. The enzyme reaction was promoted by Fe3+ and Sn2+, but potently inhibited by Hg2+, Ag2+, o-phenanthroline and pentachlorophenol, and noticeably inhibited by 8-bromoadenosine, theobromine and theophylline.

Twenty-five Tc/tw5 and 12 control mice were killed at different ages and radiographically and histologically examined. In addition, histochemical analysis was performed on muscles from four mutant and one control mouse. All Tc/tw5 mice were tailless and had a fluid-filled lumbar myelomeningocele. Radiographically, most animals had six instead of 10 lumbosacral vertebrae. Vertebral anomalies were common. The spinal cord was grossly abnormal: at the level of the plaque, it was replaced by patches of neural tissue intermingled with connective tissue and muscle. Affected skeletal muscles had small myofibers with centrally placed nuclei consistent with arrest of development at the myotubular stage secondary to denervation in early embryonic life. Abnormal nerves were smaller and had fewer axons. Tc/tw5 mice show features of neural tube and notochord dysplasia. These mutant mice may be useful as animal models of lumbosacral agenesis and myelomeningocele.

A retrovirus was used to introduce a provirus (pZipNeoSVIL-2) containing the gene for interleukin-2 (IL-2) along with a neor gene (confers resistance to G418) into LM cells, a mouse cell line expressing defined major histocompatibility complex class I antigens (H-2k). After initial selection in growth medium containing G418, IL-2 secretion was confirmed, and the cells were then cotransfected with genomic DNA from B16F1 or B16F10 melanoma cells, along with DNA from a plasmid (pHyg) that confers resistance to hygromycin. After a second round of selection in growth medium containing sufficient quantities of hygromycin to kill 100% of nontransfected cells but without further modification, the unfractionated populations of transfected cells were tested for their immunotherapeutic properties in C57BL/6 mice (H-2b) with established B16 melanomas (H-2b). Animals with melanomas treated with either of the transfected cell populations survived significantly (P0.01) longer than untreated mice or mice treated with irradiated (5000 rads) B16F1 melanoma cells. The animals also survived longer (P0.05) than mice with melanoma treated with IL-2-secreting LM cells transfected with genomic DNA from MOPC-315 cells, a nonimmunologically cross-reactive murine tumor. As determined by the capacity of monoclonal antibodies to T-cell subsets to inhibit the antimelanoma response in a 51Cr release assay, the antimelanoma immunity in mice immunized with cells transfected with genomic DNA from either B16F1 or B16F10 cells was mediated primarily by Lyt-2.2+ T-cells. These data raise the possibility that a generic, live cell tumor vaccine can be developed that can be modified to provide specificity for the neoplasms of individual patients.

The mechanical properties of Ni50Ti50 deposited on Si and 3C-SiC substrates were studied focussing on the interaction of the film and substrate. This interaction determines the transformation characteristics through interface accommodation and mechanical constraints exerted by the substrate stiffness. Substrate stiffness, controlled by the film/substrate thickness ratio, was found to have a substantial influence on the output energy of the film/substrate composite. A switch type composite based on this knowledge was fabricated and tested.

To investigate the Kondo effect in MgO-based magnetic tunnel junctions (MTJs) electron tunnelling spectroscopy was carried out in Co60Fe20B20/textured MgO(001)/Co70Fe30magnetic tunnel junctions at temperatures between 2 K and 300 K. The zero-bias anomaly (ZBA) or the logarithmic temperature-dependent peak was observed in dynamic resistance. This behaviour can explain consistently the reduced TMR ratio of MgO-based MTJs compared with the theoretical expectation at low temperature. The properties of ZBAs were also investigated for both single crystal MTJs and the MTJs with the boron-doped top ferromagnetic electrode in order to find out the origin of the Kondo effect.

✓ In order to examine the correlation between prognosis and the histological features of nuclear atypia, mitosis, endothelial proliferation, and necrosis in supratentorial adult astrocytomas, the authors reviewed 251 such cases treated at the Massachusetts General Hospital between 1972 and 1980. One point was given for the presence of each feature. The total number of features was translated into a grade as follows: none of the four features = Grade 1 (one patient), one feature = Grade 2 (36 patients), two features = Grade 3 (33 patients), and three or four features = Grade 4 (181 patients). The period of survival was significantly associated with grade, the presence or absence of each of the four histological features, patient's age, type of operation, radiation therapy, and extent of tumor (log rank, p < 0.05). The variables associated with grade were age (p < 0.001) and radiation therapy (p < 0.02). After adjustment for these variables using a Cox proportional-hazards model, the difference in overall survival time between patients in Grades 2 and 3 was not statistically significant. When comparable groups of patients were examined in terms of age or receipt of radiation therapy, the median survival times differed markedly. Patients 50 years of age or less had a median survival time of 68 months (Grade 2 tumors), 29 months (Grade 3 tumors), and 13 months (Grade 4 tumors). Patients over 50 years of age had a median survival time of 6 months (Grade 2 and 4 tumors) and 9 months (Grade 3 tumors). Those patients who had received radiation therapy had a median survival time of 68 months (Grade 2 tumors), 21 months (Grade 3 tumors), and 11 months (Grade 4 tumors). Those patients who did not receive radiation therapy had a median survival time of 1 month (Grade 2 tumors) and 2 months (Grade 3 and 4 tumors); over half of these patients died within 2 months of surgery. This grading system, originally proposed by Daumas-Duport, et al., is simple, objective, and reproducible, and correlates well with survival times. The authors recommend that astrocytomas be graded on a scale of 1 to 4, with Grade 1 reserved for the rare adult supratentorial astrocytoma with none of the four histological features.