Development of functionalized peptides for efficient inhibition of myostatin by selective photooxygenation.

For the inhibition of myostatin, which is an attractive strategy for the treatment of muscle atrophic disorders including muscular dystrophy, myostatin-binding peptides were synthesized with an on/off-switchable photooxygenation catalyst at different positions on the peptide chain. These functionalized peptides oxygenated and inactivated myostatin upon irradiation with near-infrared light. Among the peptides tested, a peptide (5) with the catalyst moiety at the 16 position induced myostatin-selective photooxygenation, and efficiently inhibited myostatin. These peptides exhibited low phototoxicity. Such functionalized peptides would provide a precedented strategy for myostatin-targeting therapy, in which myostatin is irreversibly and catalytically inactivated by photooxygenation.

New treatment strategy for cupulolithiasis associated with benign paroxysmal positional vertigo of the lateral canal: the head-tilt hopping exercise.

This study was performed to determine whether a novel treatment was effective against cupulolithiasis associated with benign paroxysmal positional vertigo (BPPV) of the lateral semicircular canal, which is characterized by apogeotropic direction-changing nystagmus. We herein describe our head-tilt hopping (HtH) exercise, which is designed to release otoconial debris strongly adhered to the cupula. The subjects were trained to hop while tilting their heads laterally. They completed 3 to 5 exercise sessions per day over a 4-week period. Each session ended with a 20-hop trial. The HtH exercises were performed by 27 patients with intractable lateral canal BPPV who exhibited positional vertigo and persistent nystagmus beating toward the uppermost ear for more than 4 weeks, despite performing therapeutic head shaking in the horizontal plane maneuver. All the patients were subjected to the supine roll test before and immediately after the first trial as well as after 1 and 4 weeks of the program to evaluate the effect of the treatment on their apogeotropic nystagmus. Nystagmus of 9 (33.3 %) patients disappeared immediately after the first training session. After 1 and 4 weeks of the training, the number of patients that had experienced either of these improvements had increased to 15 (55.6 %) and 19 (70.4 %) subjects, respectively. These results suggest that HtH exercises aimed at releasing otoconial debris from the cupula are feasible as a new therapy for cupulolithiasis associated with intractable lateral canal BPPV. However, further studies for comparison with control are required to confirm these preliminary results.

The effect of prostaglandin E1 on brainstem blood flow disturbance in an animal model of vertebrobasilar insufficiency.

Using an animal model of vertebrobasilar insufficiency (VBI), in which brainstem circulatory disturbance was induced in rats, we examined how prostaglandin E1 (PG-E1) affects brainstem blood flow (BBF) to clarify whether it is effective against VBI. Fifteen healthy male Wister rats that displayed positive responses to Preyer's reflex were used. Their BBF was continuously measured on the left side of the midline of the brainstem using laser Doppler flowmetry. A rat model of VBI, a pathological condition that presents with decreased BBF, was prepared by applying a vertebral artery clamp ipsilateral to the BBF measuring site and inducing hypotension of 60-70 mmHg by blood withdrawal. Saline as a control (n = 5), 5 ng/kg/min (n = 5) or 10 ng/kg/min (n = 5) PG-E1 at a dose was continuously administered to the rats using a motor-driven syringe pump. The effects of the drugs on the rats' BBF were evaluated. BBF, which was decreased by the unilateral vertebral artery clamping combined with blood withdrawal-induced hypotension, recovered in a dose-dependent manner after the administration of 5 or 10 ng/kg/min PG-E1, and complete recovery to the baseline level was achieved by 60 min treatment; however, no such effect was observed for intravenous saline. These results suggest that PG-E1 acts on local vessels and improves blood flow insufficiency in the brainstem in our animal model of VBI. PG-E1 might be useful as a cerebral vasodilator for VBI.

White emission of Yb²âº:fluoride glasses efficiently excited with near-UV light.

Various Yb²âº-containing fluoride glasses melting under a reductive atmosphere were prepared. The brightest white light emission was observed for an AlF3-based fluoride glass not containing Hf or Zr. The largest full width at half maximum of the white emission spectra was 202 nm. In addition, incorporation of chloride into the AlF3-based glass enabled efficient excitation with near-ultraviolet light corresponding to a GaN bandgap of 3.4 eV and the maximum internal quantum efficiency of Yb²âº: AlF3-based fluoride glass was 42%.

Inactivation of myostatin by photooxygenation using functionalized d-peptides.

Inhibition of myostatin is an attractive strategy for the treatment of muscular atrophic diseases such as muscular dystrophy. For the efficient inhibition of myostatin, functionalized peptides were developed by the conjugation of a 16-mer myostatin-binding d-peptide with a photooxygenation catalyst. These peptides induced myostatin-selective photooxygenation and inactivation under near-infrared irradiation, and were associated with little cytotoxicity or phototoxicity. The peptides are resistant to enzymatic digestion due to their d-peptide chains. These properties could contribute to the in vivo use of photooxygenation-based inactivation strategies targeting myostatin.

Development of Myostatin Inhibitory d-Peptides to Enhance the Potency, Increasing Skeletal Muscle Mass in Mice.

Myostatin is a key negative regulator of skeletal muscle growth, and myostatin inhibitors are attractive tools for the treatment of muscular atrophy. Previously, we reported a series of 14-29-mer peptide myostatin inhibitors, including a potent derivative, MIPE-1686, a 16-mer N-terminal-free l-peptide with three unnatural amino acids and a propensity to form ß-sheets. However, the in vivo biological stability of MIPE-1686 is a concern for its development as a drug. In the present study, to develop a more stable myostatin inhibitory d-peptide (MID), we synthesized various retro-inverso versions of a 16-mer peptide. Among these, an arginine-containing derivative, MID-35, shows a potent and equivalent in vitro myostatin inhibitory activity equivalent to that of MIPE-1686 and considerable stability against biodegradation. The in vivo potency of MID-35 to increase the tibialis anterior muscle mass in mice is significantly enhanced over that of MIPE-1686, and MID-35 can serve as a new entity for the prolonged inactivation of myostatin in skeletal muscle.

Efficient 521 nm all-fiber laser: splicing Pr(3+)-doped ZBLAN fiber to end-coated silica fiber.

We demonstrated a green all-fiber laser by splicing both ends of a Pr(3+)-doped ZBLAN fiber to silica fibers, whose ends were coated with a dielectric thin film. The output power and the slope efficiency were 322 mW and 53%, respectively, and the coupled pump power of the two blue GaN pump lasers in the silica fiber core was 652 mW. We estimated that the damage threshold of the spliced structure was at least 21 MW/cm². This splicing technique should be applicable for other wavelengths and glass fibers having low melting temperatures.

[Clinical analysis of metabolic syndrome in vertiginous diseases].

To explore the relationship between metabolic syndrome and vertigo, we measured waist circumference, plasma glucose, triglycerides and blood pressure in 333 subjects aged 20-79 years with vertigo. We found overall metabolic syndrome prevalence defined by Japanese diagnostic criteria to be 13.2%, similar to that in other national surveys by the Japanese Ministry of Health, Labour and Welfare. The 6-fold higher prevalence in men over women exceeded that of other reports, however. The highest frequency was in vertebrobasilar insufficiency (VBI) disorders, suggesting that conditions such as VBI in men with vertigo could involve metabolic syndrome as a risk factor for vertigo incidence.

Visible-NIR tunable Pr3+-doped fiber laser pumped by a GaN laser diode.

We demonstrated continuous wave laser operation with a tunable range of over 300 nm in the visible and near-infrared regions (479-497, 515-548, 597-737, 849-960 nm) using a single 9-cm Pr(3+)-doped ZBLAN fiber pumped by a GaN laser. The total tunable range was 6469 cm(-1), which is wider than that of conventional Ti:sapphire lasers.

[In vitro susceptibilities to levofloxacin and various antibacterial agents of 12,919 clinical isolates obtained from 72 centers in 2007].

We have reported in this journal in vitro susceptibilities of clinical isolates to antibiotics every year since 1992. In this paper, we report the results of an analysis of in vitro susceptibilities of 12,919 clinical isolates from 72 centers in Japan to selected antibiotics in 2007 compared with the results from previous years. The common respiratory pathogens, Streptococcus pyogenes, Streptococcus pneumoniae, Moraxella catarrhalis and Haemophilus influenzae maintained a high susceptibility to fluoroquinolones (FQs). The resistance of S. pyogenes to macrolides has been increasing every year and this was especially clear this year. Most strains of Enterobacteriaceae except for Escherichia coli showed a high susceptibility to FQs. Almost 30% of E. coli strains were resistant to FQs and the resistance increased further this year. FQs resistance of methicillin-resistant Staphylococcus aureus (MRSA) was approximately 95% with the exception of 45% for sitafloxacin (STFX). FQs resistance of methicillin-susceptible S. aureus (MSSA) was low at about 10%. FQs resistance of methicillin-resistant coagulase negative Staphylococci (MRCNS) was higher than that of methicillin-susceptible coagulase negative Staphylococci (MSCNS), but it was lower than that of MRSA. However, FQs resistance of MSCNS was higher than that of MSSA. FQs resistance of Enterococcus faecalis was 22.5% to 29.6%, while that of Enterococcusfaecium was more than 85% except for STFX (58.3%). In clinical isolates of Pseudomonas aeruginosa derived from urinary tract infections, FQs resistance was 21-27%, which was higher than that of P. aeruginosa from respiratory tract infections at 13-21%, which was the same trend as in past years. Multidrug resistant strains accounted for 5.6% in the urinary tract and 1.8% in the respiratory tract. Acinetobacter spp. showed high susceptibility to FQs. The carbapenem resistant strains, which present a problem at present, accounted for 2.7%. Neisseria gonorrhoeae showed high resistance of 86-88% to FQs. The results of the present survey indicated that although methicillin-resistant Staphylococci, Enterococci, E. coli, P. aeruginosa, and N. gonorrhoeae showed resistance tendencies, and other species maintained high susceptibility rates more than 90% against FQs, which have been used clinically for over 15 years.

Inactivation of myostatin by photo-oxygenation using catalyst-functionalized peptides.

Inhibition of myostatin is an attractive treatment for muscular dystrophy and other amyotrophic diseases. A myostatin-binding peptide was functionalized by equipped with an on/off switchable photo-oxygenation catalyst. This peptide induces a selective oxygenation of myostatin under near-infrared light, resulting in inactivation of myostatin. This peptide shows several orders of magnitude greater inhibitory effect than the original peptide.

Resveratrol­induced REG III expression enhances chemo­ and radiosensitivity in head and neck cancer in xenograft mice.

Identifying the key molecules that enhance chemo­ and radiosensitivity in head and neck squamous cell carcinoma (HNSCC) as well as reliable biomarkers for predicting recurrence and metastasis would be desirable to improve the prognosis of HNSCC. Previously, we have reported that Regenerating gene III (REG III) expression was associated with an improved survival rate for patients with HNSCC. In addition, resveratrol (3,4',5­trihydroxystilbene) significantly increased REG III expression in HNSCC cells, and significantly inhibited cell growth, enhanced chemo­ and radiosensitivity, and blocked the cancer invasion of HNSCC cells in vitro. In the present study, the effect of resveratrol on cancer progression in HNSCC was investigated in vivo using a xenograft nude mouse model. The results revealed that resveratrol increased the mRNA level of REG III in vivo, which was in agreement with our previous in vitro findings. Furthermore, REG III increased the antitumor effect of radiation or cisplatin in vivo, and resveratrol sensitized HNSCC to irradiation and cisplatin in vivo. These results indicated that resveratrol could increase the efficacy of cisplatin and irradiation through the REG III expression pathway, resulting in the inhibition of HNSCC progression in vivo.

Brain activation during the course of sentence comprehension.

The purpose of this study is to determine, by functional magnetic resonance imaging, how the activated regions of the brain change as a Japanese sentence is presented in a grammatically correct order. In this study, we presented constituents of a sentence to Japanese participants one by one at regular intervals. The results showed that the left lingual gyrus was significantly activated at the beginning of the sentence, then the left inferior frontal gyrus and left supplementary motor area, in the middle of the sentence, and the left inferior temporal gyrus, at the end of the sentence. We suggest that these brain areas are involved in sentence comprehension in this temporal order.

Effect of resveratrol on cancer progression through the REG â ¢ expression pathway in head and neck cancer cells.

Identification of reliable markers of chemo- and radiosensitivity and the key molecules that enhance the susceptibility of head and neck squamous cell carcinoma (HNSCC) to anticancer treatments is highly desirable. Previously, we have reported that regenerating gene (REG) â…¢ expression was such a marker associated with an improved survival rate for HNSCC patients. In the present study, we investigated the stimulators for induction of REG â…¢ expression using REG â…¢ promoter assay in HNSCC cells transfected with REG â…¢ promoter vector. We tested inflammatory cytokines, growth factors, polyphenols, PPARγ activator of thiazolidinediones, and histone deacetylase inhibitors, and found that 3,4',5-trihydroxy-trans-stilbene (resveratrol) significantly increased the REG â…¢ promoter activity and the mRNA levels of REG â…¢ in HNSCC cells. Moreover, we demonstrated the effect of resveratrol on cancer cell progression, such as cell proliferation, chemo­ and radiosensitivity and cancer invasion of HNSCC cells. Resveratrol significantly inhibited cell growth, enhanced chemo­ and radiosensitivity, and blocked cancer invasion of HNSCC cells. These data suggested that resveratrol could inhibit cancer progression through the REG â…¢ expression pathway in HNSCC cells.

Late laryngeal radionecrosis in severe arteriosclerosis.

Laryngeal necrosis is a serious complication that usually occurs within the first year following completion of radiotherapy, although it is reported that cases can develop after a long period of latency. Factors such as dosage and irradiation technique employed, tumour invasion into the laryngeal cartilage, infection, continued smoking, trauma and general vascular condition of the patient have been considered to increase the rate and degree of development of radionecrosis. We report an unusual case of laryngeal radionecrosis in a patient with hypertension, hyperlipidaemia, diabetes and a history of cigarette smoking, which developed 25 years after radiotherapy for laryngeal carcinoma. His systemic illnesses and continued smoking were speculated to have contributed to the progress of the radionecrosis, suggesting that cessation of smoking and control of arteriosclerotic diseases should be considered to decrease its incidence.

[Weekly docetaxel treatment for head and neck cancer].

A pilot study was conducted to evaluate the safety and efficacy of weekly docetaxel(DOC) treatment for head and neck cancer as compared with those of 3-weekly DOC treatment at 60 mg/m(2). Weekly DOC was administered at doses ranging from 25-30 mg/m(2)/wk (mean dosage, 40 mg/body/wk) for 3 weeks followed by a 1-week rest or for 6 weeks followed by a 2-week rest. Weekly DOC was administered to 18 patients (1 of whom received prior chemotherapy), and 3-weekly DOC was administered to 29 patients (10 of whom received prior chemotherapy). The overall response rate was 22.2% in the weekly DOC group and 47.8% in the 3-weekly DOC group. In advanced or recurrent cancer, the overall response rate plus long NC (stable disease for at least 6 months) rate was 40.0% in the weekly DOC group, and 42.9% in the 3-weekly DOC group. Only 1 (5.6%) case of grade 3 mucositis developed in the group receiving weekly DOC, while 12 cases of grade 3 or 4 neutropenia (41.4%) and 2 of grade 3 or 4 thrombopenia (6.9%) developed in the 3-weekly DOC group. Based on these results, weekly DOC treatment appears to be useful and feasible for outpatients with head and neck cancer, even in high-risk and elderly patients.

[Horizontal canal benign paroxysmal positional vertigo--its affected side and horizontal semicircular canal function].

We report horizontal canal BPPV (HC-BPPV) targeting its pathophysiology, the affected side, and the function of the horizontal semicircular canal, together with a review of the literature. Subjects were 13 patients with HC-BPPV visiting our vertigo outpatient clinic at Nara medical university hospital and a related hospital in the 2.5 years from January 2000 to June 2002. Subjects were classified into 7 with canalolithiasis and 6 patients of cupulolithiasis after a neurotological examination. CP was positive in 54% of all patients, 71% of those with canalolithiasis, and 33% of those with cupulolithiasis. To determine the affected side in HC-BPPV, we used the affected side by using the law of Ewald in canalolithaisis patients and the detection of a neutral diminishing nystagmus in cupulolithiasis patients. CP positive in caloric testing indicated insignificant dysfunction of the horizontal semicircular canal in canalolithiasis patients compared to that in cupulolithasis patients. The mechanism behind caloric nystagmus was thought to be a convection of endolymphatic fluid interrupted consequently by an otolith in the semicircular canal in canalolithiasis patients. In contrast, CP was positive in cupulolithiasis patients regarded as having no convection of endolymphatic fluid. The mechanism causing a difference in caloric test results between canalolithiasis and cupulolithiasis patients thus requires a larger patient population and further examination to be conclusive.

Cortical activation during reading aloud of long sentences: fMRI study.

The purpose of this study was to investigate human brain activity during the reading aloud of Japanese sentences using fMRI. Twenty-three right-handed normal Japanese subjects performed three reading tasks: covert reading of meaningful or meaningless sentences, and reading aloud of meaningful sentences. Areas in the bilateral frontal and temporal cortices were activated during the reading-aloud task compared with the covert reading task. In addition, activation of these brain areas showed significant positive correlation with the reading speed during the reading-aloud task. Our results indicate that bilateral frontal-temporal networks are involved in phonological processing during reading aloud.

[The usefulness of TS-1 for the treatment of head and neck cancer].

We investigated the usefulness of TS-1 for the treatment of head and neck carcinoma in 29 patients who received treatment on an outpatient basis at our institution. Among the 29 patients, 22 patients in whom the response was evaluable were included in the efficacy analysis. To assess the safety of TS-1, the severity of adverse events was examined in the 29 patients. Each course of treatment consisted of oral administration of TS-1 at a dose of 80 to 120 mg/day, depending on the body surface area (BSA), for 28 consecutive days, followed by a 14-day rest period. None of the patients showed complete response (CR), 7 showed partial response (PR), 10 showed no change (NC), and 5 showed progressive disease (PD). The response rate was thus 31.8%. Severe adverse events (grades 3 and 4) occurred in 2 patients. One developed grade 3 leukopenia and grade 4 thrombocytopenia. The other developed Stevens-Johnson syndrome that was assessed as grade 4. The findings indicate that TS-1 might be useful for the treatment of patients with head and neck carcinoma on an outpatient basis without affecting their quality of life (QOL), although careful monitoring is essential to watch for the development of severe adverse events.