The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

Dose escalation study of carboplatin-pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer.

BACKGROUND: This study was designed to determine the recommended dose of carboplatin-pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed. RESULTS: The combination of carboplatin at an area under the concentration-time curve (AUC) of 5, and 500 mg/m(2) pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68-216 days) and the median overall survival time was 461 days (95% CI 168-754 days). CONCLUSIONS: This combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m(2)) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.

E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma.

Most cancer chemotherapeutic agents are administered at the maximum-tolerated dose (MTD) in short cycles with treatment breaks. However, MTD-based chemotherapies are often associated with significant toxicity and treatment breaks allow the opportunity for tumor regrowth and acquisition of chemoresistance. To minimize these drawbacks, a metronomic strategy, in which chemotherapeutics are administered at doses significantly below the MTD without treatment breaks, has been suggested by many investigators. The antitumor effect of metronomic chemotherapy may be partially due to inhibition of tumor angiogenesis, and it could be enhanced by a combination therapy, including antiangiogenic agents. In this study, we evaluated the synergistic effect of E10A, an adenovirus carrying the endostatin gene, the most potent inhibitors of tumor angiogenesis, in combination with weekly low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. The E10A induced mRNA and protein expressions of endostatin in H891 cells in vitro. E10A significantly enhanced the in vivo tumor growth inhibitory effect of cisplatin. Immunohistochemical analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay and anti-CD31 antibodies revealed that the combination of E10A and cisplatin induced high levels of cell apoptosis and inhibited tumor angiogenesis. Importantly, E10A increased the platinum concentrations in tumors to fivefold higher than that induced by cisplatin alone.

Hybrid quantum circuit with a superconducting qubit coupled to a spin ensemble.

We report the experimental realization of a hybrid quantum circuit combining a superconducting qubit and an ensemble of electronic spins. The qubit, of the transmon type, is coherently coupled to the spin ensemble consisting of nitrogen-vacancy centers in a diamond crystal via a frequency-tunable superconducting resonator acting as a quantum bus. Using this circuit, we prepare a superposition of the qubit states that we store into collective excitations of the spin ensemble and retrieve back into the qubit later on. These results constitute a proof of concept of spin-ensemble based quantum memory for superconducting qubits.

Effect of topotecan as second-line chemotherapy for small cell lung cancer patients with interstitial lung disease.

Small cell lung cancer with interstitial lung disease (ILD-SCLC) is difficult to treat because of the risk of fatal pneumonitis. Our study aims to evaluate the validity of topotecan (TOP) as chemotherapy for patients with relapsed ILD-SCLC. Overall survival was compared between TOP and other drugs as second-line treatments for ILD-SCLC patients. Forty-seven patients began chemotherapy and second-line treatment was administered in 48.5% of relapsed cases. The response rate of TOP for second-line therapy was 16.7%. Hematologic toxicities were grade 4 anemia, grade 3 neutropenia and grade 3 thrombocytopenia. Mild pulmonary toxicity was observed in 1 case. Patients receiving TOP as second-line treatment showed no significant difference in survival when compared to patients who underwent other regimens (median survival time 179 vs. 76 days; p =0.76). TOP is a well tolerated drug and is a viable candidate for second-line treatment of ILD-SCLC patients.

Microreview of Pityriasis versicolor and Malassezia species.

Recently 11 Malassezia species were isolated. Attention has focused on the relationship between Malassezia species and Malassezia-related disease. The causal fungus of Pityriasis versicolor is M. globosa. The conditions of mycelial form induction are not clear for M. globosa.

Identification of the carbon antisite-vacancy pair in 4H-SiC.

The metastability of vacancies was theoretically predicted for several compound semiconductors alongside their transformation into the antisite-vacancy pair counterpart; however, no experiment to date has unambiguously confirmed the existence of antisite-vacancy pairs. Using electron paramagnetic resonance and first principles calculations we identify the S15 center as the carbon antisite-vacancy pair in the negative charge state (C(Si)V-(C)) in 4H-SiC. We suggest that this defect is a strong carrier-compensating center in n-type or high-purity semi-insulating SiC.

Molecular analysis of malassezia microflora from patients with pityriasis versicolor.

BACKGROUND: Pityriasis versicolor (PV) is a superficial infection of the stratum corneum caused by Malassezia species. Eleven species have been identified within this genus, namely M. globosa, M. restricta, M. sympodialis, M. furfur, M. obtusa, M. slooffiae, M. pachydermatis, M. dermatis, M. japonica, M. yamatoensis, M. nana. M. furfur has long been identified as the causative fungus of PV. However, recent studies using the culture and isolation identified by morphological and physiological characteristics suggest that M. globosa is the causative agent of PV. OBJECTIVES: The aim of this study was to examine the distribution of PV microorganisms with a molecular-based non-culture method. PATIENTS: The subjects were 49 patients with PV (32 males, 17 females; 16-83 years old) who visited our outpatient clinic. METHODS: Samples were taken from lesions for direct microscopy with methylene blue and detected Malassezia species without M. pachydermatis and M. nana using a non-culture-based method consisting of nested PCR with specific primers. RESULTS: The most frequently isolated species were M. globosa and M. restricta (both 93.9%). Only M. globosa was detected from the lesion in which the mycelial form alone was observed microscopically, but M. restricta was not. CONCLUSIONS: Our results suggest that M. globosa is the causative agent of PV.

Divacancy in 4H-SiC.

Electron paramagnetic resonance and ab initio supercell calculations suggest that the P6/P7 centers, which were previously assigned to the photoexcited triplet states of the carbon vacancy-antisite pairs in the double positive charge state, are related to the triplet ground states of the neutral divacancy. The spin density is found to be located mainly on three nearest C neighbors of the silicon vacancy, whereas it is negligible on the nearest Si neighbors of the carbon vacancy.

[A case of lymphocutaneous sporotrichosis].

We report a case of lymphocutaneous sporotrichosis in a 69-year old man who had nodular-ulcerated lesions on the right hand and forearm. Small nodules remained on the right hand after 8 weeks of 0.5 g daily treatment with potassium iodide. Alternatively, terbinafine therapy (125 mg/day) resulted in healing with atrophic scars after 9 weeks without side effects. We reviewed 67 patients of cutaneous sporotrichosis in Japan from 1993 to 1999. Those cure rates (and mean durations of treatments in parentheses) are 90.9% (8.1 weeks) with potassium iodide, 86.6% (12.6 weeks) with itraconazole (100 mg/day) and 71.4% (12.8 weeks) with terbinafine (125 mg/day) treatments, respectively. These results lead us to consider a daily dose of 250 mg as more appropriate for terbinafine.

Characterization of an extracellular keratinase from Microsporum canis.

Extracellular keratinase (Ekase) 48-, 34- and 31.5-kDa polypeptides, which were isolated from Microsporum canis and examined by immunoblotting reacted with a monoclonal antibody against Ekase of M. canis. We analyzed the amino acid and determined the first 17 amino acid NH2-terminal sequences of the 48-, 34- and 31.5-kDa polypeptides. These polypeptides had a high aspartic acid, glycine and alanine content, respectively. The first 17 amino acid residues of the 34-kDa polypeptide were homologous to those of thermomycolin. This indicated that the 34-kDa polypeptide of Ekase is homologous to the thermomycolin produced by Malbranchea pulchella. Furthermore, Ekase was very heat-stable in the presence of 50 mM CaCl2 at 55 degrees C, since 50% of the initial activity remained. In contrast, no activity was detected after heating in the absence of CaCl2. These results indicate a close relationship between dermatophytes and M. pulchella.

[Dermatophytosis of the external auditory meatus].

Dermatophytosis of the external auditory meatus is believed to be a fairly rare disease. In the past three and a half years we have had seven cases of dermatophytosis in the external auditory meatus. All cases except one were associated with tinea of other lesions. Case 1: A 44-year-old man had tinea of the auricle, tinea pedis and tinea unguium. Case 2: A 14-year-old boy, the son of case 1 had no tinea elsewhere on his body, including the auricle. He scratched the auditory meatus with an earpick which his father had used. Case 3: A 62-year-old man had tinea of the auricle, tinea pedis and tinea unguium. Case 4: A 50-year-old man had tinea of the auricle, tinea pedis and tinea unguium. Case 5: A 36-year-old man had tinea of the auricle, tinea pedis, tinea unguium and tinea cruris. Case 6: A 30-year-old woman had tinea of the auricle. Case 7: A 68-year-old man had tinea of the auricle, tinea pedis, tinea unguium and tinea manuum. Endoscopic examination (except for cases 4 and 7) revealed dry cerumen from cartilaginous to bony region of the external auditory meatus. Direct examination using KOH method of the cerumen in all cases demonstrated numerous fungal elements. Fungal cultures identified Trichophyton rubrum except for cases 3 and 6. All cases were successfully treated with oral itraconazole or terbinafine. We suggest that tinea of the external auditory meatus is frequently associated with that of the auricle.

Dual infection of rabbits with human T cell lymphotropic virus types I and II.

Attempts were made to generate a rabbit model of dual infection with human T lymphotropic virus (HTLV) types I and II. Four groups (A, B, C, and D) of three rabbits each were used. Group A was inoculated with the RW-1 cell line coinfected with HTLV-I and HTLV-II and group B was transfused from a dually infected rabbit. Polymerase chain reaction (PCR) using primers specific for the pol region of each virus detected both HTLV-I and HTLV-II in all group A and two group B rabbits, but HTLV-II only in the remaining group B rabbit. Groups C and D already infected with HTLV-I and HTLV-II, respectively, were inoculated with an HTLV-II- or HTLV-I-producing cell line. One group C rabbit became PCR-positive for both viruses but the other five resisted superinfection with the respective viruses. During prolonged observation, three of the six dually infected rabbits converted to single (HTLV-I or HTLV-II) infection. The in vivo dual infection was confirmed by in vitro establishment of a lymphoid cell line coinfected with HTLV-I and HTLV-II. It was also possible to establish coinfected lymphoid cell lines from HTLV-I-infected rabbits by coculture with lethally irradiated HTLV-II-producing cells and vice versa. The mechanism of viral elimination in dually infected rabbits, as well as that of protective immunity against superinfection, remains to be elucidated.

Recovery of iodine-123 metaiodobenzylguanidine uptake associated with left ventricular functional recovery in a patient with dilated cardiomyopathy. Endomyocardial histological findings before and after the improvement of uptake.

A 58-year-old man with idiopathic dilated cardiomyopathy was treated with incremental administration of a beta-blocker (metoprolol) and an angiotensin converting enzyme inhibitor (enarapril). The left ventricular end-diastolic dimension and ejection fraction improved in 8 months from 83.3 mm and 17.3% to 46 mm and 69%, respectively. The washout ratio and heart-to-mediastinum ratio depicted on the delayed image for iodine-123 metaiodobenzylguanidine 123I-MIBG) uptake improved from 61.7% and 1.34 to 23.1% and 1.85, respectively, in association with improvement of left ventricular indices. Successive endomyocardial biopsy specimens disclosed reduction of the degrees of vacuolation, staining irregularity, and deformity of myocyte cytoplasm and nucleus compared to the findings before therapy. In this patient with dilated cardiomyopathy 123I-MIBG scintigraphy was useful for the evaluation of the effects of therapy. We conclude that it may be informative in the estimation of the histopathological abnormalities of the myocardium.

Biphenotypic leukemia with a new translocation, t(2;6)(q31;q23).

A t(2;6)(q31;q23) was found in a patient with acute biphenotypic leukemia. This cytogenetic change has not been reported previously in acute lymphocytic leukemia (ALL) or biphenotypic leukemia, although deletion of 6q has been frequently found in ALL.

Sequential changes in laminin and type IV collagen in the infarct zone--immunohistochemical study in rat myocardial infarction.

BACKGROUND: The healing process, which affects ventricular remodeling, is an important factor in the prognosis of myocardial infarction. We hypothesized that laminin and type IV collagen contribute to extracellular matrix assembly in healing after myocardial infarction. We examined sequential changes in these two components after experimental myocardial infarction in rats. MATERIALS AND METHODS: Hearts were excised from 1 day to 10 weeks after permanent left coronary ligation in rats. Immunohistochemical staining with a polyclonal antibody to laminin and type IV collagen was performed by the avidin-biotin-peroxidase method. RESULTS: Laminin: On day 3, laminin initially appeared in a wavy fashion in the granulation tissue of the infarct peripheral zone and was not restricted to the cell membrane; the staining distribution in the peripheral zone then gradually increased, reaching a maximum on days 7-11. The distribution progressed from the peripheral zone to the outer lesion of the central zone of the infarct for 1-2 days, and reached the center point after 2 weeks. The extent of the staining distribution gradually decreased after reaching this maximum, but the staining did not completely disappear. Type IV Collagen: Changes in type IV collagen were essentially the same as those in laminin. A wavy staining pattern of type IV collagen appeared in the infarct peripheral zone from day 3, reached its maximum extent on days 7-11, and decreased gradually thereafter. The distribution progressed from the peripheral zone to the outer lesion of the central zone for 1-2 days, reaching the center point after 2 weeks. CONCLUSIONS: Laminin and type IV collagen contribute to extracellular matrix formation in the infarct zone relatively early after myocardial infarction.

Establishment of novel lymphoid cell lines dually infected with human T cell lymphotropic viruses types I and II.

With the goal of establishing an in vitro system of dual infection with human T cell lymphotropic viruses (HTLV) types I and II, rabbit lymphocytes were cocultured with a mixture of lethally irradiated HTLV-I-producing Ra-1 and HTLV-II-producing RII cell lines. This gave rise to a lymphoid cell line, RW-1, that was dually infected with HTLV-I and -II as detected by immunofluorescence staining, electron microscopy, and polymerase chain reaction using primers specific for the pol and env regions of each virus and by Southern blot hybridization. Two clonal cell lines derived from RW-1 were also coinfected with the viruses, indicating that dual infection had occurred at the single cell level. The coinfection could be readily propagated to fresh lymphocytes by coculture with RW-1. In contrast, attempts to superinfect HTLV-I-infected lymphoid cell lines with HTLV-II and vice versa were consistently unsuccessful, suggesting receptor interference between HTLV-I and -II.

Autologous pericardial patch repair for postinfarction ventricular septal perforation.

Surgical therapy for ventricular septal perforation associated with acute myocardial infarction is thought to reduce ventricular chamber volume and distort the ventricle due to excision of the myocardium. A 69-year old man underwent elective surgery that used an autologous pericardial patch without excising the myocardium. Intraventricular repair using the autologous pericardial patch enabled preservation of ventricular geometry and chamber volume and did not result in a depression of cardiac function. Moreover, it has been reported that this surgical procedure protects against suture bleeding and decreases the amount of foreign material required, thus possibly reducing the risk of infectious complications.