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.

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.

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.

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.

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.

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.

Non-tuberculous mycobacterial infection of the parotid gland in an immunocompetent elderly patient.

We experienced an extremely rare case in which combined antibacterial therapy for a non-tuberculous mycobacteria (NTM) infection of the parotid gland achieved a favourable outcome in an elderly immunocompetent patient. Although a 79-year-old man, who presented with swelling and fistula formation in the left parotid gland region, initially received combined antituberculous therapy due to a positive result of acid-fast staining, the lesion did not respond to these agents. Thereafter, since the culture examination did not detect Mycobacterium tuberculosis or NTM, we excluded tuberculosis and considered the possibility of an NTM infection caused by a rare mycobacterial species. Therefore, we switched to the clarithromycin-based antibacterial treatment for eight consecutive months without a surgical intervention, resulting in the complete disappearance of the lesion and no evidence of recurrence detected for 4 years. This conservative chemotherapy might be a feasible alternative to a surgical intervention for treatment against NTM infections of the parotid gland.

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%.

Efficacy of FDG-PET for defining gross tumor volume of head and neck cancer.

We analyzed the data for 53 patients with histologically proven primary squamous cell carcinoma of the head and neck treated with radiotherapy between February 2006 and August 2009. All patients underwent contrast-enhanced (CE)-CT and (18)F-fluorodeoxyglucose (FDG)-PET before radiation therapy planning (RTP) to define the gross tumor volume (GTV). The PET-based GTV (PET-GTV) for RTP was defined using both CE-CT images and FDG-PET images. The CE-CT tumor volume corresponding to a FDG-PET image was regarded as the PET-GTV. The CE-CT-based GTV (CT-GTV) for RTP was defined using CE-CT images alone. Additionally, CT-GTV delineation and PET-GTV delineation were performed by four radiation oncologists independently in 19 cases. All four oncologists did both methods. Of these, PET-GTV delineation was successfully performed in all 19 cases, but CT-GTV delineation was not performed in 4 cases. In the other 15 cases, the mean CT-GTV was larger than the PET-GTV in 10 cases, and the standard deviation of the CT-GTV was larger than that of the PET-GTV in 10 cases. Sensitivity of PET-GTV for identifying the primary tumor was 96%, but that of CT-GTV was 81% (P < 0.01). In patients with oropharyngeal cancer and tongue cancer, the sensitivity of CT-GTV was 63% and 71%, respectively. When both the primary lesions and the lymph nodes were evaluated for RTP, PET-GTV differed from CT-GTV in 19 cases (36%). These results suggested that FDG-PET is effective for defining GTV in RTP for squamous cell carcinoma of the head and neck, and PET-GTV evaluated by both CE-CT and FDG-PET images is preferable to CT-GTV by CE-CT alone.

Diabetic mice show an aggravated course of herpes-simplex virus-induced facial nerve paralysis.

HYPOTHESIS: Bell's palsy is highly associated with diabetes mellitus. BACKGROUND: The cause of Bell's palsy in diabetes mellitus is not completely understood. Diabetic mononeuropathy or reactivation of herpes simplex virus type 1 (HSV-1) may be responsible for the facial paralysis seen in diabetic patients. We previously reported transient and ipsilateral facial paralysis in mice inoculated with HSV-1. In this study, we examined the neuropathogenesis of HSV-1 in diabetic mice to clarify the relationship between Bell's palsy and diabetes mellitus. METHODS: We compared the incidence and course of facial paralysis after HSV-1 inoculation in diabetic and nondiabetic mice groups. Diabetic mice were prepared by intraperitoneal streptozotocin injection. Facial nerve damage was assessed by electrophysiologic and histopathologic examinations. RESULTS: Compared with the nondiabetic group, the incidence of facial nerve paralysis was significantly increased in the diabetic mice. Electrophysiologic examinations and histopathologic changes also revealed that the facial nerve damage was more severe in the diabetic group. CONCLUSION: The aggravated course of HSV-1 infection in diabetes suggests that HSV-1 may be the main causative factor for the increased incidence of facial paralysis in diabetic patients.

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.

Laryngeal carcinoma in a non-smoker female patient with thyroid carcinoma: report of a case.

Laryngeal carcinoma is usually encountered in smoker men, and thyroid carcinoma is sometimes discovered incidentally during treatment for these patients. However, this coexistence of malignancies could occur in non-smoker female. We report an unusual case of multiple primary malignancies in the larynx and the thyroid gland. The laryngeal carcinoma was suspected to be related to the malignant transformation of the papillomas. The case suggests the importance of meticulous examination in the head and neck region for treatment of cervical metastatic lymph nodes with negative cytology in non-smoker female.

Cortical activation in the processing of passive sentences in L1 and L2: an fMRI study.

The question of whether the bilingual brain processes a first and second language (L1 and L2, respectively) differently is a central issue in many psycholinguistic and neurolinguistic studies. This study used functional magnetic resonance imaging (fMRI) to investigate whether late bilinguals process structurally complex sentences in L1 and L2 in different cortical networks. For this purpose, we directly compared brain activity during the processing of active and passive sentences in both L1 and L2. We asked 36 healthy subjects to judge whether or not a presented sentence was semantically plausible. Both L1 and L2 activated the left hemispheric language-related regions such as the left inferior frontal, superior/middle temporal, and parietal cortices. However, we found different activation patterns between L1 and L2 in the processing of passive sentences. Passive sentences elicited greater activation than their active counterparts in the left pars triangularis, the premotor area, and the superior parietal lobule in Japanese, but not in English. Furthermore, there was a significant interaction between sentence type (active versus passive) and language (Japanese versus English) in the left pars orbitalis. The results of this study indicate that late bilinguals use similar cortical regions to comprehend both L1 and L2. However, when late bilinguals are presented with structurally complex sentences, the involvement of these regions differs between L1 and L2. These results suggest that, in addition to age of L2 acquisition and L2 proficiency, differences in grammatical construction affect cortical representation during the comprehension of L1 and L2.

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.