High-pressure phase diagrams of FeSe1-xTex: correlation between suppressed nematicity and enhanced superconductivity.

The interplay among magnetism, electronic nematicity, and superconductivity is the key issue in strongly correlated materials including iron-based, cuprate, and heavy-fermion superconductors. Magnetic fluctuations have been widely discussed as a pairing mechanism of unconventional superconductivity, but recent theory predicts that quantum fluctuations of nematic order may also promote high-temperature superconductivity. This has been studied in FeSe1-xSx superconductors exhibiting nonmagnetic nematic and pressure-induced antiferromagnetic orders, but its abrupt suppression of superconductivity at the nematic end point leaves the nematic-fluctuation driven superconductivity unconfirmed. Here we report on systematic studies of high-pressure phase diagrams up to 8 GPa in high-quality single crystals of FeSe1-xTex. When Te composition x(Te) becomes larger than 0.1, the high-pressure magnetic order disappears, whereas the pressure-induced superconducting dome near the nematic end point is continuously found up to x(Te) ≈ 0.5. In contrast to FeSe1-xSx, enhanced superconductivity in FeSe1-xTex does not correlate with magnetism but with the suppression of nematicity, highlighting the paramount role of nonmagnetic nematic fluctuations for high-temperature superconductivity in this system.

IGF-I gene transfer by electroporation promotes regeneration in a muscle injury model.

The goal of this study was to determine whether insulin-like growth factor-I (IGF-I) gene delivery by electroporation promotes repair after muscle injury. An injury-repair model was created using mice in which a hamstring muscle was cut and sutured. A total of 50 microg of IGF-I DNA or green fluorescent protein (GFP) DNA (both in pCAGGS) was injected into the lesion and introduced into muscle cells by electrostimulation using an electric pulse generator. The number of regenerating muscle fibers in the IGF-I DNA group was significantly more than that in the GFP DNA group at 2 weeks after injection. The diameter of regenerating muscle fibers from the IGF-I DNA group was larger than that of the GFP DNA group at 4 weeks after injection. There was no significant difference in the serum IGF-I concentration between the IGF-I DNA group and the GFP DNA group at 1, 2, and 4 weeks after injection. However, muscle IGF-I concentration in the IGF-I DNA injection group was significantly greater than that in the GFP DNA injection group at 2 weeks after injection. These results demonstrated that the effects of enhanced IGF-I production were local and limited to the injected area. The ratio (injected/uninjected; intact) of the amplitude of compound muscle action potentials (CMAP) in the IGF-I DNA injection group was greater than that in the GFP DNA injection group at 4 weeks after injection and of the control group. In conclusion, IGF-I gene transfer by electroporation proved to be a simple, safe, inexpensive, and effective method to promote the regeneration of injured muscles in our injury model.

Phase II evaluation of protracted infusion of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG) Trial (JCOG9407).

BACKGROUND: Surgery for advanced esophageal carcinoma has its limits as regards aggressiveness and therapeutic effect, therefore effective multimodality treatment is required to obtain better survival. The objective of this study was to evaluate whether daily continuous infusion of CDDP could achieve a higher clinical response rate with less toxicity than its drip infusion in the previous phase II study that we had conducted. METHODS: Patients with primary extensive or relapsed esophageal carcinoma after esophagectomy, which had distant organ metastasis and histologically proven SCC, were eligible for this study. A dose of 20 mg/m(2) of cisplatin and 800 mg/m(2) of 5-fluorouracil was given by continuous infusion for 24 h on days 1-5. This treatment was repeated every 4 weeks for up to four cycles. A total of 36 men and six women with a median age of 64 (range 39-75) years were registered and 36 patients were eligible. RESULTS: The overall response rate of the registered patients was 33.3% (12/36) and the median response duration was 175 days. Median survival time was 201.5 days and the 1-year survival rate was 27.8%. Change from bolus to continuous infusion of cisplatin affected neither the type nor the degree of toxicity. CONCLUSION: Daily continuous infusion of cisplatin was not associated with higher response or lower toxicity than those seen with the high-dose bolus or multibolus treatment regimens. We conclude that this regimen in this setting is not worthy of further phase III trials. JEOG is now evaluating other drug combination regimens.

Acute parietal and chief cell changes induced by a lethal dose of lipopolysaccharide in mouse stomach before thrombus formation.

The common lipopolysaccharide (LPS)-induced gastric lesions, such as erosions or ulcers, have been investigated in depth. Little is known, however, about the acute gastric lesions following a high dose of LPS. In a time-course study, ICR female mice were given a high subcutaneous dose of LPS (50 mg/kg). Mice were sacrificed at 4, 6, 12, and 24 hours after dosing and were assessed histopathologically for acute gastric lesions. The major gastric changes were seen in the fundic region and included vacuolar degeneration of parietal cells and apoptosis of chief cells. The vacuole in parietal cells was apparent as early as 4 hours postinjection (PI), and apoptosis of chief cells was apparent at 12 hours PI. Thrombus formation, in contrast, was not seen until 24 hours PI. No erosion, ulcer, or hemorrhage was seen in any gastric region in any of the treated animals at 24 hours PI. These results indicate that a subcutaneous high dose of LPS in mice causes vacuolar degeneration of parietal cells and apoptosis of chief cells before thrombus formation or subsequent ulcerative lesions.

Inhibitory effect of TNP-470 on experimental choroidal neovascularization in a rat model.

PURPOSE: To determine whether an angiogenic inhibitor, TNP- 470 (TNP), an analogue of fumagillin, inhibits choroidal neovascularization (CNV) induced by diode laser photocoagulation in a rat experimental model. METHODS: Fundus laser photocoagulation was performed on Brown Norway rats to induce CNV. In the treatment group, TNP was administered intraperitoneally at the time of laser photocoagulation and on day 7 (50 mg/kg at each time). The incidence of CNV formation was evaluated by fluorescein angiography. The retina was collected from the rats on days 1, 3, 7, and 14 after laser photocoagulation, and semiquantitative polymerase chain reaction (PCR) analyses for the expression of mRNA of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) were carried out. Localization of bFGF mRNA was studied by in situ reverse transcription-PCR (RT-PCR). The numbers of positively labeled cells for bFGF mRNA were compared between the TNP treatment and control groups. RESULTS: The incidence of CNV formation was 22.7% in the TNP-treated rats and that in the control rats was 61.4% (P < 0.001). The semiquantitative PCR analyses showed that bFGF mRNA was upregulated on days 3 and 7 in the control rats, but no significant changes were found in TNP-treated rats. There was no detectable difference in VEGF gene expression between the control and TNP-treated rats. bFGF mRNA was detected by in situ RT-PCR in the regenerated retinal pigment epithelial cells and cells of the outer and inner nuclear layers of the control rats. The number of positive cells for bFGF mRNA in the TNP treatment group was significantly smaller than that of the control group (P < 0.05) on days 3 and 14. CONCLUSIONS: TNP- 470 treatment reduced the incidence of laser-induced CNV formation in this experimental model. The expression of bFGF associated with CNV formation was also significantly reduced by the TNP treatment.

Diagnostic value of cervical somatosensory evoked potentials recorded from the intervertebral discs after median and ulnar nerve stimulation in cervical spondylotic myelopathy.

We have studied the cervical somatosensory evoked potentials (CSEPs) recorded referentially from serial intervertebral discs after stimulation of the median nerve or the ulnar nerve at the wrist in cervical spondylosis. In seven unilateral radiculopathies, the CSEPs evoked by stimulation on the asymptomatic side normally consisted of the P1-N1 and the P2-N2 components, which represented the potentials arising from the white matter and the gray matter, respectively. Of 21 myelopathies, the CSEPs revealed the white matter involvement with conduction block identified by abrupt P1-N1 amplitude reduction in 7, the gray matter involvement identified by P2-N2 amplitude reduction in 3, or a combination of both in 11. The CSEPs were useful not only for determining the level responsible for myelopathy but also for localizing the lesion in the transverse plane of the spinal cord.

Effects of fructose-induced hypertriglyceridemia on hepatorenal toxicity of acetaminophen in rats. II. Role of enhancement of fructose metabolism and overproduction of triglyceride in the liver and kidney on hepatorenal toxicity of acetaminophen.

Fructose-induced hypertriglyceridemic rats are resistant to hepatoxicity and susceptible to nephrotoxicity of acetaminophen (APAP) as compared with normal ones. The present studied were designed to evaluate how fructose-treatment affects the developmental mode of hepatorenal toxicity of APAP. First, following fructose-pretreatment for various durations (1 day, 1 week or 3 weeks), 1-day-fructose-pretreatment induced hypertriglyceridemia and enhancement of APAP-nephrectoxicity simultaneously. However, it took at least 3 weeks for fructose-pretreatment to reduce APAP-hepatotoxicity. Second, following fructose, sucrose or glucose-pretreatment for 3 weeks, fructose-pretreated rats showed marked hypertriglyceridemia and modification of APAP-hepatorenal toxicity. Sucrose-pretreated rats showed less effects than fructose-pretreated rats. Glucose-pretreated rats showed no changes in plasma triglyceride and APAP-hepatorenal toxicity. Third, rats with hypertriglyceridemia induced by olive oil or Triton WR-1339 which did not produce enhanced metabolism and triglyceride-overproduction in the liver and kidney showed no modification of APAP-hepatorenal toxicity. Pretreatment of glycerol which was metabolized in liver and kidney and induced an overproduction of triglyceride resulted in an enhancement of APAP-nephrotoxicity. These results indicate that an enhancement of fructose metabolism and an overproduction of triglyceride in liver and kidney are responsible for the modification of APAP-hepatorenal toxicity in fructose-induced hypertriglyceridemic rats.

Phase II study of chemoradiotherapy for advanced squamous cell carcinoma of the thoracic esophagus: nine Japanese institutions trial.

A phase II study of chemoradiotherapy for advanced squamous cell carcinoma of the thoracic esophagus was carried out cooperatively by nine Japanese institutions. Forty-five patients with thoracic advanced squamous cell carcinoma, who had T4 tumor or distant lymph node metastasis (M1(LYM)), were enrolled in the study for treatment with cisplatin (70 mg/m2) on days 1 and 36, and 5-fluorouracil infusion (700 mg/m2) on days 1-4 and 36-39 sandwiched around external beam irradiation (60 Gy over 6 weeks). Of the 45 evaluable patients, 37 (84.1%) completed the treatment. The overall response rate was 64.4%, and the complete response rate 8.9%. The median duration of response was 125.0 days for patients who achieved complete and partial response. The 50% median survival time was 215 days. There was one toxicity-related death due to radiation pneumonitis. The major form of toxicity exceeding grade 2 was myelosuppression and anorexia, but grade 4 toxicity was also observed (2 pulmonary, 1 severe hypoxemia, 1 severe cardiac failure and 1 mental disturbance). The results showed that this form of chemoradiotherapy had a satisfactory effect and might be useful for treatment of inoperable advanced esophageal cancer.

Substitution at codon 269 (glutamine --> proline) of the leptin receptor (OB-R) cDNA is the only mutation found in the Zucker fatty (fa/fa) rat.

We recently cloned one of spliced variant forms of rat leptin receptor (OB-R), which contains a short intracellular domain, and found obese-phenotype-linked nucleotide alteration in the extracellular domain of the cDNA from the Zucker (fa/fa) rat, which results in a glutamine269 to proline269 amino acid substitution. Reported herein are the cloning and sequencing of another spliced variant forms of rat OB-R cDNA with a long intracellular domain. Both forms of OB-R cDNA share the same extracellular domain. In the Zucker (fa/fa) rat, no changes in either the gene structure nor in the nucleotide sequence of the long intracellular domain were observed. However, the expression level of OB-R mRNA in the brain of Zucker (fa/fa) rat was higher than for lean littermates. These facts suggest that the substitution at codon 269 of the OB-R cDNA represents the crucial mutation which results in the obese phenotype of Zucker (fa/fa) rat.

Effects of transfection with the Cu, Zn-superoxide dismutase gene on xanthine/xanthine oxidase-induced cytotoxicity in fibroblasts from rat skin.

PURPOSE: The effects of transfection with the human Cu, Zn-superoxide dismutase (hSOD)4 gene on active oxygen-induced cytotoxicity in rat skin fibroblasts (FR) were studied for the purpose of developing the novel delivery system of hSOD using hSOD gene. METHODS: An expression plasmid for hSOD, pRc/RSV-SOD, was constructed and used to transfect FR cells. Xanthine (X)/xanthine oxidase (XO) system were used to generate active oxygen species. The effects of transfection with the hSOD gene on active oxygen-induced cytotoxicity were assessed by comparing the number of surviving cells and the level of lipid peroxidation in host and transformants after exposure to X/XO system. RESULTS: The cellular SOD activity in RSV-SOD cells transfected with pRc/RSV-SOD was significantly increased in comparison with host or RSV cells transfected with the pRc/RSV plasmid containing no hSOD gene as a control. Furthermore, Western blot analysis using an anti-hSOD antibody indicated the production of hSOD in RSV-SOD cells. On the other hand, although the numbers of surviving cells in both host and RSV-SOD cultures after exposure to X/XO system decreased in a time-dependent manner, the decrease in number of surviving RSV-SOD cells was less than that in host cells. In the presence of catalase, the decreases in number of surviving cells in both host and RSV-SOD cultures after exposure to the X/XO system were also less than those in the absence of catalase. However, the decreases in cell survival in RSV-SOD cultures were significantly less than those in host cells in the presence of catalase. Furthermore, the levels of lipid peroxidation in RSV-SOD cells exposed to the X/XO system in the presence or absence of catalase were lower than those in host cells. These results indicated that the increase in cellular SOD activity by transfection with the hSOD gene protects cells from oxidative stress. CONCLUSIONS: Human SOD gene therapy may be useful for treatment of diseases in which oxidative tissue damage is produced.

Safety and pharmacokinetics of iotrolan in hysterosalpingography. Retention and irritability compared with Lipiodol.

RATIONALE AND OBJECTIVES: The authors compared the safety and pharmacokinetics of Iotrolan (water-soluble) in hysterosalpingography (HSG) with those of Lipiodol (oil-soluble). METHODS: Iotrolan and Lipiodol were administered intraperitoneally at doses of 100 mg iodine/kg to female rabbits. Retention in the body was investigated by x-ray imaging, plasma kinetics, and urinary and fecal excretion. Irritability in the abdomen was investigated by histologic examination. RESULTS: Iotrolan was entirely excreted into the urine within 2 days after administration. Conversely, Lipiodol was excreted into the urine, had a half-life of 50 days, and was retained for more than 21 days in the abdomen. Iotrolan induced no inflammatory reaction in the abdomen, whereas Lipiodol induced a marked abdominal inflammatory reaction, including granuloma formation. Iotrolan had no effect on iodine concentration in the thyroid; Lipiodol increased iodine concentration significantly. CONCLUSIONS: Iotrolan, which is a water-soluble and nonionic dimeric contrast medium, has potential greater safety for use in HSG than Lipiodol.

Mechanism of phosphate adsorption to a three-dimensional structure of boehmite in the presence of bovine serum albumin.

A new microcrystalline boehmite (tentatively named PT-A) was synthesized as an efficient phosphate adsorbent to replace aluminum hydroxide gel. The characteristic structure of PT-A was examined by nitrogen adsorption/desorption, X-ray diffraction, deviation microscopy, and scanning electron microscopy to establish a pore structural model of PT-A. With this model structure, the details of the mechanism of interaction between PT-A and phosphate in the presence of bovine serum albumin (BSA) are discussed. PT-A is a spherical particle with a diameter of approximately 100 microns and a porous surface structure, and its inside is packed with boehmite microcrystals (crystallite size, 2 nm). PT-A has three types of pores in its structure: a micropore with a narrow size-distribution, a mesopore with a broad size-distribution, and a macropore (radii of pores are 0.7, 1-20, and approximately 300 nm, respectively). When phosphate was incubated with PT-A in human gastric and intestinal juices or in an aqueous solution containing BSA, the amounts of phosphate adsorbed by PT-A were not affected by the presence of proteins. The nitrogen adsorption/desorption isotherms and energy dispersive X-ray analyses demonstrated that phosphate could diffuse to the smaller tunnels freely even if the external surface of PT-A was covered with BSA. It was also demonstrated that the main site of adsorption for phosphate was in micropores of PT-A, whereas BSA was adsorbed only to the external surface and none entered inside smaller tunnels consisting of micro- and mesopores.

Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: a Japanese Esophageal Oncology Group Trial.

Thirty-nine patients with advanced measurable squamous cell carcinomas were treated with two or more courses of 70 mg cisplatin/m2 on day 1 and 700 mg infused 5-fluorouracil/m2 on days 1-5 every 21 days. The overall response rate was 35.9 (95% confidence limits, 24.8-55.1%). Responses were seen in primary sites in the esophagus of five patients, in the lung of seven, the liver of one and the mediastinal lymph nodes of one. The average response duration was 3.5 (range 1-12) mo for patients who achieved partial response. The average survival time after the first administration was 9.5 mo for patients who responded to the treatment whereas, for those who did not, it was 5.6 mo. The major form of toxicity was myelosuppression and there were six patients with grade 3 toxicity and one with grade 4. The present study was designed to evaluate the effectiveness of combined cisplatin and 5-fluorouracil for advanced squamous cell carcinoma, and the results showed that it had a reasonable effect and might possibly be used as a postoperative chemotherapy because of its mild side effects.

Effect of amino acid supplementation to low protein diet on brain and plasma levels of tryptophan and brain 5-hydroxyindoles in rats.

The contribution of amino acid transport across the blood-brain barrier toward the concentration of brain 5-hydroxyindoles [serotonin and 5-hydroxyindole acetic acid (5HIAA)] was investigated. Several amino acids were individually supplemented to a 5% whole egg protein diet. Close correlation between serum tryptophan, brain tryptophan and 5-hydroxyindoles were observed regardless of diet fed. When a large neutral amino acid (LNAA such as methionine, threonine, leucine or phenylalanine) was added to the control diet, brain 5-hydroxyindole concentration was lower than when the control diet was fed; however, when tryptophan was added, brain 5-hydroxyindole concentration was significantly higher. Lysine supplementation did not affect brain 5-hydroxyindole concentration. Leucine supplementation caused a lower tyrosine concentration in hypothalamus than the control diet, but phenylalanine supplementation caused higher hypothalamus level of tyrosine. There was no correlation between tyrosine and norepinephrine concentrations in hypothalamus (norepinephrine turnover might also be changed by the nutritional state). These observations indicate that the supplementation of an amino acid at two- or fourfold of the requirement to a low protein diet can generate major changes in the concentrations of neurotransmitters in rats.

Antibiotic prophylaxis against streptomycin-resistant and -susceptible Streptococcus faecalis endocarditis in rabbits.

This report describes the capacities of ampicillin, vancomycin, streptomycin, gentamicin, and combinations thereof to prevent endocarditis in rabbits challenged with either streptomycin-resistant (three strains) or streptomycin-susceptible (one strain) Streptococcus faecalis. Vancomycin (15 mg/kg) alone was effective in preventing infection with three of four strains, including two which were streptomycin resistant. Vancomycin (30 mg/kg) alone was effective against the other streptomycin-resistant strain. The vancomycin-gentamicin combination was the only therapeutic regimen to demonstrate complete prophylaxis for all strains regardless of streptomycin susceptibility. The ampicillin-gentamicin combination was variably effective despite in vitro synergism.

Therapy of experimental infective endocarditis due to antibiotic-tolerant Lactobacillus plantarum-bactericidal synergy of penicillin plus gentamicin. Correlation of in vitro susceptibility studies with in vivo efficacy.

Infective aortic valve endocarditis (IE) was induced in 40 rabbits with a penicillin (PNC)-tolerant, gentamicin (GM)-resistant strain of Lactobacillus plantarum; this isolate was synergistically killed in vitro by PNC + GM. The in vivo relevance of the in vitro observations was examined by determining the rates of eradication of endocardial L. plantarum by PNC versus PNC + GM. Mean vegetation L. plantarum titers were significantly lower (p less than 0.05) in PNC + GM treated rabbits versus both PNC-treated and control rabbits by 48 h of therapy. Also, PNC + GM more rapidly sterilized vegetations as compared to controls (p less than 0.025) and PNC-treated rabbits (p less than 0.05). Thus, in vivo antibiotic efficacy paralleled in vitro bactericidal studies, and may partially explain the relatively refractory nature of lactobacillary IE in humans treated with single beta-lactam antibiotics.