Reinvestigation of the virulence of Rhodococcus equi isolates from patients with and without AIDS.

Rhodococcus equi emerged as a zoonotic pathogen of human immunodeficiency virus-infected patients over the last three decades. Two virulence plasmid types of R. equi, pVAPA and pVAPB associated with equine and porcine isolates, have been recognized, and more recently, pVAPN, a novel host-associated virulence plasmid in R. equi, was found in bovine and caprine isolates. We reinvestigated 39 previously reported isolates of R. equi from patients with and without acquired immunodeficiency syndrome (AIDS) by detecting vapA, vapB and vapN using PCR and plasmid profiling. After excluding one isolate that could not be cultured from frozen storage, eight isolates carried a virulence plasmid encoding vapA (pVAPA), 10 carried a virulence plasmid encoding vapB (pVAPB), seven carried a virulence plasmid encoding vapN (pVAPN) and 13 were negative for those genes. Of the 29 isolates from patients with AIDS, 7, 10 and 5 harboured pVAPA, pVAPB and pVAPN respectively. Among nine isolates from patients without AIDS, one and two harboured pVAPA and pVAPN respectively. This study demonstrated that pVAPN-positive R. equi existed in human isolates before 1994 and reaffirmed that equine-associated pVAPA-positive, porcine-associated pVAPB-positive and bovine- or caprine-associated pVAPN-positive R. equi are widely spread globally. Because domestic animals might be major sources of human infection, further research is needed to reveal the prevalence of pVAPN-positive R. equi infection in cattle and goats.

Positive association of free triiodothyronine with pancreatic ß-cell function in people with prediabetes.

AIM: To analyse the effects of thyroid hormones on ß-cell function and glucose metabolism in people with prediabetes who are euthyroid. METHODS: A total of 111 people who were euthyroid underwent 75-g oral glucose tolerance tests, of whom 52 were assigned to the normal glucose tolerance and 59 to the prediabetes groups. Homeostatic model assessment of ß-cell function, insulinogenic index and areas under the curve for insulin and glucose were evaluated as indices of pancreatic ß-cell function. RESULTS: In both groups, BMI, fasting insulin, homeostasis model assessment ratio and HDL cholesterol correlated significantly with all indices of pancreatic ß-cell function. Free triiodothyronine correlated positively with all insulin secretion indices in the prediabetes group. Multiple linear regression analysis showed that free triiodothyronine was an independent variable that had a positive correlation with all indices of ß-cell function in the prediabetes group. By contrast, no such correlation was found in the normal glucose tolerance group. CONCLUSIONS: Free triiodothyronine is associated with both basal and glucose-stimulated insulin secretion in people with prediabetes who are euthyroid; therefore, the regulation of insulin secretion by thyroid hormones is a potentially novel therapeutic target for the treatment of diabetes.

Flexibility and torsional behaviour of rotary nickel-titanium PathFile, RaCe ISO 10, Scout RaCe and stainless steel K-File hand instruments.

AIM: To assess and compare the flexibility and torsional resistance of PathFile, RaCe ISO 10 and Scout RaCe instruments in relation to stainless steel K-File hand instruments. METHODOLOGY: Rotary PathFile (sizes 13, 16 and 19; .02 taper), Race ISO 10 (size 10; 0.02, 0.04 and 0.06 tapers), Scout RaCe (sizes 10, 15 and 20; 0.02 taper) and hand K-File (sizes 10, 15 and 20; 0.02 taper) instruments were evaluated. Alloy chemical composition, phases present and transformation temperatures were determined for the NiTi instruments. For all instruments, diameters at each millimetre from the tip as well as cross-sectional areas at 3 mm from the tip were measured based on ANSI/ADA Specification No. 101 using image analysis software. Resistance to bending and torsional resistance were determined according to specification ISO 3630-1. Vickers microhardness measurements were also taken in all instruments to assess their strength. Data were analysed using analysis of variance (α = 0.05). RESULTS: The alloys used in the manufacture of the three types of NiTi instruments had approximately the same chemical composition, but the PathFile instruments had a higher Af transformation temperature and contained a small amount of B19' martensite. All instruments had diameter values within the standard tolerance. The bending and torsional resistance values were significantly increased relative to the instrument diameter and cross-sectional area. CONCLUSIONS: PathFile instruments were the most flexible and the least torque resistant, whilst the stainless steel instruments were the least flexible although they were more torque resistant than the NiTi instruments.

Pulpal Temperature Variances During Step-by-step Adhesive Restorative Procedure Using Three Different High-irradiance Light-curing Units.

The rise in temperature in pulp tissues is related not only to heat transfer by high-irradiance light-curing units (LCUs), but also to restorative procedures. This research aimed to compare the rise in pulp temperature (PT) induced by three LCUs at each restorative step while considering the influence of resin composite shade and thickness. To accomplish this, the investigators used a proposed experimental model replicating pulp fluid circulation with a controlled, simulated intraoral temperature in bovine incisors. The recorded external and internal PT ranged from 36.7°C to 37.1°C and 32.7°C to 33.0°C, respectively. A significant decrease of internal temperature was recorded during class V preparation, followed by a progressive and representative rise of temperature in the subsequent restorative steps. The temperature was significantly higher during light curing of the adhesive system using Valo compared to light curing using Elipar and Radii Cal. However, none of the analyzed devices produced a temperature that exceeded the pulp tolerance limit (a temperature increase over 5.5°C). The paired test showed no significant difference in pulp temperature associated with the thickness of the increment of resin composite. However, shade was found to have more influence on the amount of energy absorbed by pulp tissue-A1 samples showed significantly higher temperature variation compared to samples using the A4 shade of resin composite. To conclude, the microcirculation and the performance of procedures under constant air-water flux dissipate the heat absorbed by the pulp. Additionally, the data suggest that all three LCUs analyzed can be safely used in clinical procedures, and that the resin composite shade may influence the amount of irradiance delivered to the tooth surface and represents a significant factor in pulp temperature variance.

Physical and mechanical properties of twisted or ground nickel-titanium instruments.

AIM: To compare the flexibility, torsional resistance and structural and dimensional characteristics of instruments produced by twisting with those of a geometrically similar nickel-titanium (NiTi) system produced by a grinding process. METHODOLOGY: The mean diameters along the flute and the pitch length of size 25, .04 taper, size 25, .06 taper, and size 25, .08 taper Twisted File (TF) (SybronEndo, Orange, CA, USA), and size 25, .04 taper, and size 25, .06 taper RaCe instruments (FKG, La Chaux-de-Fonds, Switzerland) (n = 10 each) were measured according to ANSI/ADA specification No. 101. Two pairs of instruments were found to have similar diameters at 3 mm from the tip: TF size 25, .06 taper and RaCe size 25, .04 taper, and TF size 25, .08 taper and RaCe size 25, .06 taper. The cross-sectional areas at 3 mm from the tip were determined. These instruments were then submitted to energy-dispersive X-ray spectroscopy, X-ray diffraction, differential scanning calorimetry (DSC), and Vickers microhardness measurements. Bending moment at 45° and maximum torque at fracture were measured (n = 10) according to specification ISO 3630-1. Data were analysed using analysis of variance (α = 0.05). RESULTS: The two types of instruments had approximately the same chemical composition, phase constitution, and austenite finishing temperatures. TF instruments had significantly (P ≤ 0.001) lower Vickers microhardness values and were more flexible than RaCe instruments (P = 0.016), but had similar (TF size 25, .08 taper and RaCe size 25, .06 taper, P = 0.916) or significantly higher (TF size 25, .06 taper and RaCe size 25, .04 taper, P ≤ 0.001) torsional resistance. CONCLUSIONS: Comparison of TF and RaCe instruments of similar measured dimensions revealed that the different manufacturing methods employed for producing these instruments gave rise to different mechanical behaviours.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1)/suppressor of cytokine signaling 1 (SOCS1) inhibits insulin signal transduction pathway through modulating insulin receptor substrate 1 (IRS-1) phosphorylation.

Signal transducer and activator of transcription (STAT)-induced STAT inhibitor 1 (SSI-1) is known to function as a negative feedback regulator of cytokine signaling, but it is unclear whether it is involved in other biological events. Here, we show that SSI-1 participates and plays an important role in the insulin signal transduction pathway. SSI-1-deficient mice showed a significantly low level of blood sugar. While the forced expression of SSI-1 reduced the phosphorylation level of insulin receptor substrate 1 (IRS-1), SSI-1 deficiency resulted in sustained phosphorylation of IRS-1 in response to insulin.Furthermore, SSI-1 achieves this inhibition both by binding directly to IRS-1 and by suppressing Janus kinases. These findings suggest that SSI-1 acts as a negative feedback factor also in the insulin signal transduction pathway through the suppression of IRS-1 phosphorylation.

CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides.

Natural killer T (NKT) lymphocytes express an invariant T cell antigen receptor (TCR) encoded by the Valpha14 and Jalpha281 gene segments. A glycosylceramide-containing alpha-anomeric sugar with a longer fatty acyl chain (C26) and sphingosine base (C18) was identified as a ligand for this TCR. Glycosylceramide-mediated proliferative responses of Valpha14 NKT cells were abrogated by treatment with chloroquine-concanamycin A or by monoclonal antibodies against CD1d/Vbeta8, CD40/CD40L, or B7/CTLA-4/CD28, but not by interference with the function of a transporter-associated protein. Thus, this lymphocyte shares distinct recognition systems with either T or NK cells.

Torsional behaviour of rotary NiTi ProTaper Universal instruments after multiple clinical use.

AIM: To assess the influence of multiple clinical uses on the torsional behaviour of ProTaper Universal rotary NiTi instruments. METHODOLOGY: Root canal treatments were performed on patients using the ProTaper Universal rotary system to prepare canals. Ten sets of instruments were used by an experienced endodontist, each set being used in five molar teeth. After clinical use, S1, S2, F1 and F2 instruments were analysed for damage by optical and scanning electron microscopy. The used sets, along with a control group of 10 sets of new instruments, were then torsion tested based on the ISO 3630-1 specification. Data obtained were subjected to a one-way analysis of variance (anova) with alpha = 0.05. RESULTS: The use of the ProTaper Universal rotary instruments by an experienced endodontist allowed for the cleaning and shaping of the root canal system of five molar teeth without fracture. The maximum torque for instruments S2, F1 and F2, and the angular deflection at fracture for instruments S2 and F1 were significantly lower following clinical use. The largest decrease in maximum torque was 18.6% (P = 0.014) for S2 instruments. The same maximum percent decrease was found for angular deflection at fracture for F1 instruments (P = 0.009). CONCLUSIONS: Torsional resistance and angular deflection of used instruments, as compared to that of new instruments, were reduced following clinical use.

Optimization of antimicrobial therapy in vancomycin-resistant enterococcal bacteraemia using a rapid detection Gram-positive blood culture assay.

Rapid molecular blood culture Gram-positive (BC-GP) assay can promptly identify vancomycin-resistant enterococcal (VRE) bloodstream infections (BSIs). We sought to evaluate patients with VRE BSI following the pre (N = 44) and post (N = 20) implementation of Verigene BC-GP assay. The average time to detection of VRE was 25.9 ± 4.1h (95% confidence interval (CI): 17.6-34.1; P < 0.001) earlier with Verigene BC-GP assay. Compared to patients in the pre-Verigene BC-GP period, the mean adjusted difference in time to administration of anti-VRE therapy was 18.2 ± 7.8h (95% CI: 2.5-33.8; P = 0.024) earlier among patients in the post-Verigene BC-GP period.

The effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament reconstruction: An animal study.

OBJECTIVES: To compare the effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament (ACL) reconstruction animal model. METHODS: Anterior cruciate ligament reconstruction using the plantaris tendon as graft material was performed on both knees of 24 rabbits (48 knees) to mimic ACL reconstruction by two different suspensory fixation devices for graft fixation. For the adjustable fixation device model (Socket group; group S), a 5 mm deep socket was created in the lateral femoral condyle (LFC) of the right knee. For the fixed-loop model (Tunnel group; group T), a femoral tunnel penetrating the LFC was created in the left knee. Animals were sacrificed at four and eight weeks after surgery for histological evaluation and biomechanical testing. RESULTS: Histologically, both groups showed a mixture of direct and indirect healing patterns at four weeks, whereas only indirect healing patterns were observed in both groups at eight weeks. No significant histological differences were seen between the two groups at four and eight weeks in the roof zone (four weeks, S: mean 4.8 sd 1.7, T: mean 4.5 sd 0.5, p = 0.14; eight weeks, S: mean 5.8 sd 0.8, T: mean 4.8 sd 1.8, p = 0.88, Mann-Whitney U test) or side zone (four weeks, S: mean 5.0 sd 1.2, T: mean 4.8 sd 0.4, p = 0.43; eight weeks, S: mean 5.3 sd 0.8,T: mean 5.5 sd 0.8, p = 0.61, Mann-Whitney U test) . Similarly, no significant difference was seen in the maximum failure load between group S and group T at four (15.6 sd 9.0N and 13.1 sd 5.6N) or eight weeks (12.6 sd 3.6N and 17.1 sd 6.4N, respectively). CONCLUSION: Regardless of bone tunnel configuration, tendon-bone healing after ACL reconstruction primarily occurred through indirect healing. No significant histological or mechanical differences were observed between adjustable and fixed-loop femoral cortical suspension methods.Cite this article: Y. Sato, R. Akagi, Y. Akatsu, Y. Matsuura, S. Takahashi, S. Yamaguchi, T. Enomoto, R. Nakagawa, H. Hoshi, T. Sasaki, S. Kimura, Y. Ogawa, A. Sadamasu, S. Ohtori, T. Sasho. The effect of femoral bone tunnel configuration on tendon-bone healing in an anterior cruciate ligament reconstruction: An animal study. Bone Joint Res 2018;7:327-335. DOI: 10.1302/2046-3758.75.BJR-2017-0238.R2.

The recognition and incidence of peroneal tendon dislocation associated with a fracture of the talus.

AIMS: The purposes of this study were to clarify first, the incidence of peroneal tendon dislocation in patients with a fracture of the talus and second the factors associated with peroneal tendon dislocation. PATIENTS AND METHODS: We retrospectively examined 30 patients (30 ankles) with a mean age of 37.5 years, who had undergone internal fixation for a fracture of the talus. Independent examiners assessed for peroneal tendon dislocation using the pre-operative CT images. The medical records were also reviewed for the presence of peroneal tendon dislocation. The associations between the presence of dislocation with the patient characteristics or radiological findings, including age, mechanism of injury, severity of fracture, and fleck sign, were assessed using Fisher's exact tests. RESULTS: The pre-operative CT images showed peroneal tendon dislocation in eight out of 30 patients. Dislocation was found later in one patient whose pre-operative CT image had not shown dislocation. The overall incidence of peroneal tendon dislocation was 30% (9/30). The presence of dislocation was associated with the presence of a fleck sign (p = 0.03). CONCLUSIONS: Surprisingly, approximately one-third of the patients who underwent internal fixation for a fracture of the talus had peroneal tendon dislocation. This was associated with a fleck sign. Cite this article: Bone Joint J 2017;99-B:489-93.

The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair.

OBJECTIVES: The aim of this study was to investigate the effect of granulocyte-colony stimulating factor (G-CSF) on mesenchymal stem cell (MSC) proliferation in vitro and to determine whether pre-microfracture systemic administration of G-CSF (a bone marrow stimulant) could improve the quality of repaired tissue of a full-thickness cartilage defect in a rabbit model. METHODS: MSCs from rabbits were cultured in a control medium and medium with G-CSF (low-dose: 4 µg, high-dose: 40 µg). At one, three, and five days after culturing, cells were counted. Differential potential of cultured cells were examined by stimulating them with a osteogenic, adipogenic and chondrogenic medium.A total of 30 rabbits were divided into three groups. The low-dose group (n = 10) received 10 µg/kg of G-CSF daily, the high-dose group (n = 10) received 50 µg/kg daily by subcutaneous injection for three days prior to creating cartilage defects. The control group (n = 10) was administered saline for three days. At 48 hours after the first injection, a 5.2 mm diameter cylindrical osteochondral defect was created in the femoral trochlea. At four and 12 weeks post-operatively, repaired tissue was evaluated macroscopically and microscopically. RESULTS: The cell count in the low-dose G-CSF medium was significantly higher than that in the control medium. The differentiation potential of MSCs was preserved after culturing them with G-CSF.Macroscopically, defects were filled and surfaces were smoother in the G-CSF groups than in the control group at four weeks. At 12 weeks, the quality of repaired cartilage improved further, and defects were almost completely filled in all groups. Microscopically, at four weeks, defects were partially filled with hyaline-like cartilage in the G-CSF groups. At 12 weeks, defects were repaired with hyaline-like cartilage in all groups. CONCLUSIONS: G-CSF promoted proliferation of MSCs in vitro. The systemic administration of G-CSF promoted the repair of damaged cartilage possibly through increasing the number of MSCs in a rabbit model.Cite this article: T. Sasaki, R. Akagi, Y. Akatsu, T. Fukawa, H. Hoshi, Y. Yamamoto, T. Enomoto, Y. Sato, R. Nakagawa, K. Takahashi, S. Yamaguchi, T. Sasho. The effect of systemic administration of G-CSF on a full-thickness cartilage defect in a rabbit model MSC proliferation as presumed mechanism: G-CSF for cartilage repair. Bone Joint Res 2017;6:123-131. DOI: 10.1302/2046-3758.63.BJR-2016-0083.

Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088, topoisomerase I inhibitors with an indolocarbazole structure.

The antitumor drugs NB-506 and J-107088 are potent topoisomerase I inhibitors with an indolocarbazole structure. To clarify the factors involved in resistance to these drugs, we established two NB-506-resistant mouse fibroblast cell lines (LY/NR1 and LY/NR2), a human colon carcinoma cell line (HCT116/NR1), and a lung cancer cell line (PC13/NR1). These cell lines were highly resistant to NB-506 and J-107088, and LY/NR2 cells showed markedly reduced accumulation and strong efflux of NB-506, suggesting activation of a drug efflux pump in the resistant cells. To identify the molecules responsible for efflux of NB-506, we compared the gene expressions of the mouse resistant LY/NR1 cells, LY/NR2 cells, and their parental cells by oligonucleotide microarray. Of 34,020 genes analyzed, we found that an ATP-binding cassette transporter BCRP/MXR/ABCP (BCRP) gene showed the highest increase in the expression, 31-fold higher in the LY/NR2-resistant cells than in their parental cells. The selective overexpression of this gene was also detected in the two human resistant cell lines, suggesting the involvement of breast cancer resistant protein (BCRP) in the resistance and efflux of these drugs. Finally, a PC-13 cell line transfected with BCRP expression vector displayed 22- and 17-fold resistance to NB-506 and J-107088 and enhanced efflux activity of J-107088. However, the transfectants were not resistant to mitoxantrone or topotecan, the drugs previously thought to be the substrates of BCRP. Thus, our study presents a novel mechanism of drug resistance mediated by BCRP.

Treatment of hepatic metastasis of the colon26 adenocarcinoma with an alpha-galactosylceramide, KRN7000.

Colorectal liver metastasis is clinically a major problem. We examined the antitumor activity of KRN7000, an alpha-galactosylceramide, on mice with liver metastases of adenocarcinoma Colon26 cells. KRN7000 treatment, beginning 1 day after tumor inoculation (day 1), significantly inhibited tumor growth in the liver, and its potency was equal to that of interleukin 12. KRN7000 treatment from day 3 caused regression of established Colon26 nodules. KRN7000 administration resulted in a high percentage of cured mice that acquired tumor-specific immunity. In addition, it appeared that highly activated, liver-associated natural killer cells made the major contribution to the killing of Colon26 cells in the liver. These results suggest that KRN7000 may be useful for the treatment of colorectal liver metastasis.

Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors.

The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs) for allogeneic transplantation still need to be clarified, particularly in children. We compared the kinetics, efficacy, and safety of PBSC mobilization by granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years) and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures. Serum trough levels of G-CSF determined by ELISA were significantly lower in the 16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05). Although the WBC counts on days 4 and 5 were significantly higher in adults than in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+ cells/unit of blood were identical. The number of blood CD34+ cells collected per unit of blood processed was identical in both donor populations. We propose that PBSCs could be effectively mobilized and collected in small children so that they could be donors for adult patients.

Effects of age and stress on regional noradrenaline metabolism in the rat brain.

Levels of noradrenaline (NA) and its major metabolite, 3-methoxy-4-hydroxyphenylethyleneglycol sulfate (MHPG-SO4), were determined in eight brain regions of non-stressed rats at 2, 10 and 15 months of age, and of rats at 2 and 15 months of age stressed by immobilization for 3 hours. The NA levels in older rats were significantly lower in the hypothalamus, pons + med.obl. and midbrain, and higher in the amygdala, thalamus, hippocampus and cerebral cortex as compared to those of 2 month old rats. The MHPG-SO4 levels in the older rats were significantly lower in the hypothalamus, amygdala, pons + med.obl. and midbrain, and higher only in the cerebral cortex than those in 2 month old rats. Immobilization stress caused significant increases in NA turnover in all brain regions of both 2 and 15 month old rats. Age-related difference in the degree of stress-induced change in NA metabolism was found only in the hypothalamus; the increase of MHPG-SO4 by stress was greater in 2 month old rats than in 15 month old rats, although both age groups of rats showed the same degree of NA reduction by stress. These data suggest that brain NA metabolism changes in an age-related fashion, and that apparent regional differences exist in the pattern of these changes. Specifically, it appears that there is an age-related difference in the response of noradrenergic neurons to stress in the hypothalamus.

Gastric GATA-6 DNA-binding protein: proteolysis induced by cAMP.

The rat gastric GATA DNA-binding protein, GATA-6 (GATA-GT1), was stably expressed in CHO-K1 cells. The GATA-6 protein was localized in the nucleus but not in the cytoplasm. Interestingly, when cells were treated with dibutyryl cAMP, the GATA-6 protein was specifically degraded. Such a phenomenon was not observed in the presence of 5'-AMP or dibutyryl cGMP. The cellular level of the GATA-6 protein was restored upon removal of dibutyryl cAMP. Degradation was also induced by cholera toxin, which increased the cellular cAMP concentration, and was inhibited by a protein kinase A inhibitor. However, activators of protein kinase C did not have any effect. The degradation was inhibited by proteasome inhibitors (PSI (benzyloxycarbonyl-Ile-Glu(O-t-Bu)-Ala-leucinal) and MG115 (benzyloxycarbonyl-Leu-Leu-norvalinal)) but not by those of lysosomes and serine proteases. These results suggest that a kinase-mediated protein phosphorylation is the cellular signal for degradation of the GATA-6 protein. This finding constitutes a novel aspect of regulation by GATA DNA-binding proteins, which are essential for developmental processes and tissue-specific transcription.

Novel combretastatin analogues effective against murine solid tumors: design and structure-activity relationships.

A series of combretastatin A-4 (CA-4) analogues were synthesized, and their cytotoxic effects against murine Colon 26 adenocarcinoma and inhibitory activity on tubulin polymerization were evaluated. Since CA-4 has limited aqueous solubility, the target compounds were designed to improve solubility by introduction of a nitrogen-containing group. Among the compounds synthesized, those with an amino moiety in place of the phenolic OH of CA-4 showed potent antitubulin activity and cytotoxicity against murine Colon 26 adenocarcinoma in vitro. Some of the compounds which were potent in vitro were evaluated in the murine tumor model Colon 26 in vivo. Among these, 13bHCl, 21aHCl, and 21bHCl showed significant antitumor activity in the animal model, while CA-4 was ineffective. 13bHCl and 21aHCl were further evaluated in two murine tumor models (Colon 38 and 3LL) and human xenografts HCT-15. These compounds showed potent antitumor activity comparable or superior to that of CDDP. The structure-activity relationships of this series of compounds are also discussed.

Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety.

A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and 3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.