p-wave superconductivity in iron-based superconductors.

The possibility of p-wave pairing in superconductors has been proposed more than five decades ago, but has not yet been convincingly demonstrated. One difficulty is that some p-wave states are thermodynamically indistinguishable from s-wave, while others are very similar to d-wave states. Here we studied the self-field critical current of NdFeAs(O,F) thin films in order to extract absolute values of the London penetration depth, the superconducting energy gap, and the relative jump in specific heat at the superconducting transition temperature, and find that all the deduced physical parameters strongly indicate that NdFeAs(O,F) is a bulk p-wave superconductor. Further investigation revealed that single atomic layer FeSe also shows p-wave pairing. In an attempt to generalize these findings, we re-examined the whole inventory of superfluid density measurements in iron-based superconductors and show quite generally that single-band weak-coupling p-wave superconductivity is exhibited in iron-based superconductors.

In situ heating TEM observations on carbide formation and α-Fe recrystallization in twinned martensite.

The microstructural evolution of twinned martensite in water-quenched Fe-1.6 C (wt.%) alloys upon in situ heating was investigated using transmission electron microscopy (TEM). In the as-quenched samples, a high density of a body-centred cubic (bcc) {112} 〈111〉 -type twinning structure exists in the martensite structure. Upon in situ heating to approximately 200-250 °C, carbides (mainly θ-Fe3C cementite) accompanying a detwinning process were observed only in the originally twinned region. The carbides were absent in the originally untwinned (twin-free) region. The experimental results have suggested that the formation of the carbides depends on the twinning-boundary ω-Fe metastable phase, which can be stabilised by interstitial carbon atoms. When the specimens were heated, the twinning-boundary ω-Fe(C) transformed into carbide (mainly θ-Fe3C cementite) particles on the original {112} twinning planes. Further heating resulted in substantial recrystallisation of α-Fe fine particles, which formed immediately after martensite transformation. The results presented here should be helpful in understanding the microstructural evolution of various carbon steels.

Lath formation mechanisms and twinning as lath martensite substructures in an ultra low-carbon iron alloy.

Lath martensite is the dominant microstructural feature in quenched low-carbon Fe-C alloys. Its formation mechanism is not clear, despite extensive research. The microstructure of an Fe-0.05 C (wt.%) alloy water-quenched at various austenitizing temperatures has been investigated using transmission electron microscopy and a novel lath formation mechanism has been proposed. Body-centered cubic {112}〈111〉-type twin can be retained inside laths in the samples quenched at temperatures from 1050 °C to 1200 °C. The formation mechanism of laths with a twin substructure has been explained based on the twin structure as an initial product of martensitic transformation. A detailed detwinning mechanism in the auto-tempering process has also been discussed, because auto-tempering is inevitable during the quenching of low-carbon Fe-C alloys. The driving force for the detwinning is the instability of ω-Fe(C) particles, which are located only at the twinning boundary region. The twin boundary can move through the ω ↔ bcc transition in which the ω phase region represents the twin boundary.

Sorafenib plus hepatic arterial infusion chemotherapy with cisplatin versus sorafenib for advanced hepatocellular carcinoma: randomized phase II trial.

BACKGROUND: Sorafenib (Sor) is acknowledged as a standard therapy for advanced hepatocellular carcinoma (HCC). This trial was conducted to evaluate the effect of addition of hepatic arterial infusion chemotherapy with cisplatin (SorCDDP) to Sor for the treatment of advanced HCC. PATIENTS AND METHODS: We conducted a multicenter open-labeled randomized phase II trial in chemo-naïve patients with advanced HCC with Child-Pugh scores of 5-7. Eligible patients were randomly assigned 2:1 to receive SorCDDP (sorafenib: 400 mg bid; cisplatin: 65 mg/m2, day 1, every 4-6 weeks) or Sor (400 mg bid). The primary end point was overall survival. RESULTS: A total of 108 patients were randomized (Sor, n = 42; SorCDDP, n = 66). The median survival in the Sor and SorCDDP arms were 8.7 and 10.6 months, respectively [stratified hazard ratio (95% confidence interval), 0.60 (0.38-0.96), P = 0.031]. The median time to progression and the response rate were, respectively, 2.8 months and 7.3% in the Sor arm and 3.1 months and 21.7% in the SorCDDP arm. The adverse events were more frequent in the SorCDDP arm than in the Sor arm, but well-tolerated. CONCLUSION: SorCDDP yielded favorable overall survival when compared with Sor in patients with advanced HCC. CLINICAL TRIAL REGISTRATION: UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), identification number: UMIN000005703.

Telaprevir impairs renal function and increases blood ribavirin concentration during telaprevir/pegylated interferon/ribavirin therapy for chronic hepatitis C.

We aimed to examine the relationship between renal dysfunction and anaemia that may develop during combination therapy involving pegylated interferon, ribavirin and telaprevir (PEG-IFN/RBV/TVR) for the treatment of chronic hepatitis C. Sixty-eight patients with genotype 1b high viral loads were treated with PEG-IFN/RBV/TVR. Peg-IFN and RBV doses were administered according to body weight. TVR was prescribed at 2250 mg/day for 44 patients and at 1500 mg/day for 24 patients who had low haemoglobin level (<12 g/dL). When anaemia had developed, the RBV dose was decreased. The serum TVR concentration at day 8 was measured, and the serum RBV concentration was measured serially. The estimated glomerular filtration rate (eGFR) was estimated to assess renal function. At week 1, serum TVR concentration was not correlated with a decrease in eGFR; however, the TVR dose, on a weight basis (mg/kg), and eGFR were correlated (r = 0.2691; P = 0.0265). Moreover, there was a negative correlation between eGFR and RBV serum concentration (r = −0.3694; P = 0.0025), and the serum RBV concentration and decrease in the haemoglobin were significantly correlated from week 1 to week 8. In triple therapy, the TVR dose per weight is correlated with a decline in renal function. Thus, the serum concentration of RBV increases, with a concomitant decrease in haemoglobin. It is important to adjust the doses of TVR and RBV to avoid excessive serum RBV levels and the development of severe anaemia, to achieve a good clinical effect.

Renoprotective effects of telmisartan on renal injury in obese Zucker rats.

The purpose of the present study was to investigate the renoprotective effect of telmisartan, an angiotensin II receptor antagonist, on the early stages of diabetic nephropathy in obese Zucker rats, which is a type 2-related diabetes mellitus model. Telmisartan 1, 3 or 10 mg/kg/day was orally administered to 7-week-old rats that demonstrated glucose tolerance without albuminuria or proteinuria, for 24 consecutive weeks (Experiment A). In another experiment (Experiment B), oral administration of telmisartan 10 mg/kg/day was initiated at the age of 16 weeks after the rats demonstrated marked proteinuria, and continued for 24 weeks. Telmisartan inhibited the increase in proteinuria and albuminuria in a dose-dependent manner, and the inhibition for all telmisartan groups was statistically significant by the completion of administration (Experiment A). Telmisartan also displayed similar inhibitory effects on proteinuria and albuminuria in Experiment B. Histologically, telmisartan [3 and 10 mg/kg/day] was associated with a significant decrease in the progression of glomerulosclerosis, and significantly improved interstitial cell infiltration, interstitial fibrosis and dilation and atrophy of renal tubules. Furthermore, telmisartan treatment was associated with a tendency towards normalized plasma lipids (total cholesterol and triglyceride). Our results suggest that telmisartan has a definite renoprotective effect against renal injury in type II diabetic nephropathy.

Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer.

Although mutation of APC or CTNNB1 (beta-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a beta-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis.

Intradural microsurgery and extradural gamma knife surgery for hypoglossal schwannoma: case report and review of the literature.

There have been only 26 cases of hypoglossal schwannomas reported to originate intradurally and extend extradurally into the hypoglossal canal. This 31-year-old mother of two children presented with a 5-day history of progressive headache, nausea, vomiting and vertigo. Her neurological exam was significant for nystagmus and left tongue deviation with marked atrophy. An initial head CT revealed extensive left hypoglossal canal erosion with 4th ventricle compression. T1-weighted MR images with contrast revealed a 4x3 cm left cerebellopontine angle non-homogeneously enhancing mass with an intracranial cystic component and prominent extension into the eroded hypoglossal canal. A left lateral suboccipital craniotomy was performed for subtotal microsurgical resection of the intradural posterior fossa mass. A schwannoma was diagnosed after resection and gamma knife surgery (GKS) was performed three months later for the extradural residual tumor without further deficits. This is a rare report of a hypoglossal schwannoma in a young patient who was treated with a multimodality approach in order to minimize risks. A review of the literature and discussion of the respective benefits of microsurgery versus GKS and long-term follow-up issues are presented.

Plasma level of a 5-fluorouracil metabolite, fluoro-beta-alanine correlates with dihydropyrimidine dehydrogenase activity of peripheral blood mononuclear cells in 5-fluorouracil treated patients.

5-fluorouracil (5-FU) is mostly metabolized after administration, and the metabolizing enzyme, dihydropyrimidine dehydrogenase (DPD), seems to be the rate-limiting factor. However, there are few reports on the final metabolite, fluoro-beta-alanine (FBAL). We report here the results of determination of the FBAL level in 5-FU treated patients and the correlation between the FBAL level and the DPD activity in peripheral blood mononuclear cells (PBMCs). Blood samples were collected from 20 patients, who had received continuous intravenous infusion (CIV) of 5-FU (320 mg/m2/24 hr) after resection of colorectal cancer, and the FBAL level was determined by high performance liquid chromatography (HPLC), after derivatizing into o-phthalaldehyde (OPA) and detecting fluorescence. DPD activity was measured in cytosol prepared from PBMCs using HPLC radioassay. The average FBAL plasma level during CIV of 5-FU was 911.0 ng/ml (521.0 to approximately 1834.6 ng/ml) and that of DPD activity in PBMCs was 282.6 pmol/min/mg-protein (145.0 to approximately 568.0 pmol/min/mg-protein). There was a significant correlation between the FBAL level and the DPD activity (r=0.805, p<0.0001). FBAL level in plasma may be useful in predicting the DPD activity in PBMCs, however, further studies are required considering the small number of cases in this study.

Identification of the region in Escherichia coli DnaA protein required for specific recognition of the DnaA box.

DnaA protein binds specifically to a 9-base- pair motif called the DnaA box. Domain IV comprises 94 amino acid residues and is required for DNA binding. Using nuclear magnetic resonance analysis, we investigated the interaction between DnaA domain IV and both a DnaA box and a non-specific oligonucleotide that has a reduced affinity for DnaA. The 1H-15N HSQC spectrum of DnaA domain IV showed prominent chemical shift perturbations on six residues (Arg399, Ala404, Leu422, Asp433, Thr435 and Thr436) in the presence of the DnaA box. Through homology modeling, we located all of these residues on one side surface of the DnaA domain IV molecule. Moreover, we compared the chemical shift perturbation of the 1H-15N HSQC spectrum in the presence of the DnaA box with that in the presence of a non-specific oligonucleotide, and the results suggested that Leu422 imparts specificity in binding with the DnaA box.

Start-up of full-scale anaerobic digesters treating municipal solid waste.

Raising organic loading rate, and the behavior of dissolved CODcr (D-CODcr), VFA and specific methanogen activity, were investigated through a laboratory experiment for the start-up of a sludge recycling center. Moreover, application for MPN-PCR methods using a gene as a direct technique to measure the quantity of methanogen was attempted. It was recognized that specific methanogen activity depends on the quantity of methanogen, and that gas production does not reflect the condition of methane fermentation. The methane fermentation condition was checked through the specific methanogen activity and analysis of D-CODcr. The target organic loading rate was reached in the short period of about 30 days, and rapid start-up was successfully attained for a full-scale anaerobic digester.

Relationship between head orientation and torsional eye movements in goldfish during linear acceleration.

We analyzed torsional eye movements of normal goldfish during sinusoidal linear acceleration, altering the orientation of the fish on the linear accelerator in the yaw plane over a range of 90 degrees and in the pitch plane up to 30 degrees. We video-recorded changes of torsional eye movements associated with a body rotation in the yaw and pitch plane and analyzed them frame by frame. In normal fish, we observed clear torsional eye movements for stimuli of 0.1 G linear accelerations along the body axis in the horizontal position. Torsion occurred in the opposite direction of resultant force produced by linear acceleration and gravity. Though the amplitude of these compensatory responses increased with increasing magnitude of acceleration up to 0.5 G, the torsion angle did not fully compensate the angle calculated from gravity and linear acceleration. Furthermore, the torsion angle decreased as the longitudinal body axis deviated from the direction of linear acceleration. For the body axis perpendicular to the direction of acceleration, torsional eye movement was still observed. When we tilted the fish in the pitch plane, compensatory eye torsion occurred. The response amplitude to acceleration decreased for both head-up and head-down up to 30 degrees. These results suggested the existence of specific connections between the otolith organ and ocular muscles.

Distal cement mantle thickness with a triangular distal centralizer inserted into the stem tip in cemented total hip arthroplasty.

Fifty-seven hips undergoing a primary cemented total hip arthroplasty with use of a triangular distal centralizer inserted into the stem tip were investigated, with a special focus on distal cement mantle thickness. The subjects were 43 women and 3 men. When evaluated on conventional anteroposterior and lateral radiographs, the relative incidence of thin cement mantles in zones 3 or 5 owing to the distal centralizer was 15.8% (9 hips). Unsatisfactory findings were that the distal centralizer and distal part of the stem shifted to the cortex in 7 hips and bent or failed at the inserted site in 2 hips. There is risk of generating a thin cement mantle with use of the triangular centralizer and its insertion into the stem tip.

Tolerance of point substitution of methionine for isoleucine in hen egg white lysozyme.

X-ray structure determination of proteins by using the multiple-wavelength anomalous dispersion method targeting selenomethionine is now widely employed. Isoleucine was examined for the second choice of the substitution of methionine next to leucine. We performed a systematic mutational study of the substitutions of methionine for isoleucine. All mutated lysozymes were less stable than the wild-type by about 1 kcal/mol and it is suggested that this instability was caused by the change in residual hydrophobicity from isoleucine to methionine. The X-ray structures of all mutant lysozymes were very similar to that of the wild-type. In addition, both the accessible surface areas and the conformation of the side chain of methionine in all mutant lysozymes were similar to those of the side chain at the respective isoleucine in the wild-type. Therefore, it is suggested that the mutation from isoleucine to methionine in a protein can be considered as a "safe" substitution.

A congenital dermal sinus presenting the muscle fasciculation and hypertrophy.

OBJECTIVE: To report unique and unknown clinical features of muscle fasciculation and muscle hypertrophy in a case of congenital dermal sinus. PATIENTS: A 16-year-old girl presented with continuous fasciculation, often cramp, and hypertrophy of the left calf muscle. The radiography showed spina bifida of L4, L5 and S1. MRI revealed dermal sinus tract from the skin dimple of the back to the dura mater, and connected to the intradural inclusion tumor. At surgery the inclusion tumor contained many short hairs, and the cauda equina were severely adherent. Microdissection of the tumor and the adhesion was performed. At 2 years after surgery fasciculation decreased but continued; however, painful cramps of the calf muscle do not occur. CONCLUSIONS: Short hairs of dermoid and the adherence might be irritative to the cauda equina. The hyperactivity of the stimulated motor neuron may cause the muscle fasciculation leading to hypertrophy of the calf muscle.

Increase in doxorubicin cytotoxicity by inhibition of P-glycoprotein activity with lomerizine.

Acquired resistance to chemotherapy is a major problem during cancer treatment. One mechanism for drug resistance is overexpression of the MDR (multidrug resistance)1 gene encoding the transmembrane efflux pump, P-glycoprotein (P-gp). Calcium channel blockers such as verapamil, nifedipine and nicardipine have been shown to reverse cellular drug resistance by inhibiting P-gp drug efflux. This study evaluated whether a new calcium channel blocker, lomerizine, influenced doxorubicin (Dox) cytotoxicity and P-gp activity in a P-gp-expressing cell line compared to a non-expressing subline. Verapamil, and even more markedly, lomerizine, increased cellular uptake of calcein transported by P-gp in a P-gp-expressing erythroleukemia cell line, K562-Dox. Ten microM of lomerizine reduced the IC50 of doxorubicin in the K562-Dox from 60000 ng/ml to 800 ng/ml, whereas the IC50 of doxorubicin in the K562 subline was only marginally affected by these drugs. Lomerizine showed greater reduction in P-gp efflux than verapamil at an equimolar concentration. These results suggest that lomerizine has the clinical potential to reverse tumor MDR involving the efflux protein P-gp.

Stabilization of hen egg white lysozyme by a cavity-filling mutation.

Stabilization of a protein using cavity-filling strategy has hardly been successful because of unfavorable van der Waals contacts. We succeeded in stabilizing lysozymes by cavity-filling mutations. The mutations were checked by a simple energy minimization in advance. It was shown clearly that the sum of free energy change caused by the hydrophobicity and the cavity size was correlated very well with protein stability. We also considered the aromatic-aromatic interaction. It is reconfirmed that the cavity-filling mutation in a hydrophobic core is a very useful method to stabilize a protein when the mutation candidate is selected carefully.

Detection of hypermethylation of the p16(INK4A) gene promoter in chronic hepatitis and cirrhosis associated with hepatitis B or C virus.

BACKGROUND/AIM: Inactivation of the p16(INK4A) (p16) tumour suppressor gene by promoter region hypermethylation has been demonstrated not only in many types of tumours, including hepatocellular carcinoma (HCC), but also in early preneoplastic lesions in the lung, colon, oesophagus, and pancreas. The aim of this study was to examine the methylation status of the p16 promoter in pre- and/or non-neoplastic liver diseases. PATIENTS/SUBJECTS/METHODS: The methylation status of p16 was evaluated in 22 HCC, 17 cirrhosis, 17 chronic hepatitis, nine primary biliary cirrhosis (PBC), eight autoimmune hepatitis, seven drug induced liver disease, six fatty liver, and three normal liver tissues using methylation specific polymerase chain reaction (MSP). p16 protein expression was also examined by immunohistochemical staining. RESULTS: Methylation of the p16 promoter was detected in HCC (72.7%, 16/22) and also in cirrhosis (29.4%, 5/17) and chronic hepatitis (23.5%, 4/17), all of which were positive for hepatitis B or C virus infections. Methylation was not detected in any of the other samples. All methylation positive HCC, cirrhosis, and chronic hepatitis samples showed loss of p16 expression, and a significant correlation was found between methylation and loss of expression. Analysis of serial samples from individual patients with methylation positive HCC revealed that loss of p16 expression with promoter methylation occurred in 18 of 20 patients at the stage of chronic hepatitis without clinically detectable carcinoma. CONCLUSIONS: Our results suggest that methylation of the p16 promoter and the resulting loss of p16 protein expression are early events in a subset of hepatocarcinogenesis and that their detection is useful in the follow up of patients with a high risk of developing HCC, such as those with hepatitis B or C viral infections.

Studies on the effects of microgravity on the ultrastructure and function of cultured mammalian cells.

Four cultures of monkey kidney cell line, JTC-12, were flown on the Spacelab-J (SL-J) mission during 8 days. The results of the present study showed that the space flight gave no essential effect on morphology, cell cycle, glucose consumption and urokinase production of the mammalian culture cell. However, the cell proliferation slightly decreased under microgravity. Moreover, the lack of gravity induced the trypsin-treated dissociated cells to keep floating in the culture medium. Therefore, the attachment of the cells onto the substratum was delayed, and that caused difficulties in subculturing the cells. The present research also offered some important information on techniques for establishment of cell cultures in space laboratories.