Intraoperative EABR Testing Predicts Strength of Cochlear Implant Stimulation Optimized After Long-Term Use in Pediatric Malformation Ears.

OBJECTIVE: This study focused on the intensities of cochlear implant (CI) stimulation in pediatric CI users with inner ear malformation or cochlear nerve deficiency (CND). In this population, CI programming is difficult because a large intensity of CI stimulation is required to achieve sufficient hearing, but the excess CI stimuli often induce facial nerve stimulation. We aimed to assess whether the results of intraoperative electrically evoked auditory brainstem responses (EABRs) testing predict maximum current levels of CI stimuli (cC levels) optimized by a behavioral-based method after long-term CI use. STUDY DESIGN: A retrospective case review. SETTING: A tertiary referral CI center. PATIENTS: A total of 116 ears with malformations (malformation group) and 63 control ears (control group) from patients younger than 18 years who received CI. The malformation group comprised 23 ears with a common cavity (CC), 26 with incomplete partition type 1 (IP-1), 26 with incomplete partition type 2 (IP-2), and 41 with CND. INTERVENTIONS: Diagnostic. MAIN OUTCOME MEASURES: Correlation between intraoperative EABR results and cC levels determined by the behavioral-based CI programming after long-term CI use. RESULTS: The CC, IP-1, and CND ears required significantly larger cC levels than the IP-2 ears and control groups. However, the cC levels increased to reach the plateau 1 year after surgery in all groups. Among the malformation group, 79 ears underwent intraoperative EABR testing. Greater than 80% of the CC, IP-1, and IP-2 ears and 54.8% of the CND ears exhibited evoked wave V (eV) and were included in the eV-positive category. Myogenic responses but no eV were observed in 18.2, 15.0, and 35.5% of the CC, IP-1, and CND ears, defined as the myogenic category. No eV or myogenic response was elicited in 9.7% of the CND ears. We focused on minimum current levels that elicited eV (eV levels) in the eV-positive category and maximum current levels that did not elicit any myogenic responses (myogenic levels) in the myogenic category. A significant relationship was detected between the eV levels and the cC levels. When analyzed in each malformation type, the eV levels significantly correlate with the cC levels in the CC and CND ears but not in the IP-1 and IP-2 ears, probably because of slight variation within the IP-1 group and the small number of the IP-2 group. The myogenic category did not show a significant relationship between the myogenic levels and cC levels, but the cC levels were similar to or smaller than the myogenic levels in most ears. CONCLUSIONS: This study confirmed that intraoperative EABR testing helps predict the optimal cC levels in malformation ears. EABR-based CI programming immediately after cochlear implantation, followed by behavioral-based CI programming, may allow us to achieve early postoperative optimization of CI maps even in young children with severe malformations.

1-(N,N-Dialkylcarbamoyl)-1,1-difluoromethanesulfonyl ester as a stable and effective precursor for a neopentyl labeling group with astatine-211.

Radiohalogens with a short half-life are useful radioisotopes for radiotheranostics. Astatine-211 is an α-emitting radiohalogen and is expected to be applicable to targeted α therapy. A neopentyl labeling group is an effective hydrophilic labeling unit for various radiohalogens, which includes 211At. In this study, a 1-(N,N-dialkylcarbamoyl)-1,1-difluoromethanesulfonyl (CDf) ester was developed as a stable precursor for labeling with 211At, 77Br and 125I through a neopentyl labeling group. The CDf ester remained stable in an acetonitrile solution at room temperature and enabled the successful syntheses of 211At-labeled compounds in a highly radiochemical conversion in the presence of K2CO3. 77Br- and 125I-labeled compounds can be prepared from the CDf ester without a base. The utility of the CDf ester was demonstrated in the synthesis of a benzylguanidine with a neopentyl 211At-labeling group. The developed method afforded a 32% radiochemical yield of 211At-labeled benzylguanidine. However, a partial deastatination was observed under acidic conditions during the removal of an N-Boc protecting group. Deprotecting these groups under milder acidic conditions may improve the radiochemical yield. In conclusion, the CDf ester facilitates the syntheses of 211At, 125I and 77Br-labeled compounds that use a neopentyl labeling group for radiotheranostic applications. Further optimization of protecting groups and reaction conditions should enhance the total radiochemical yield of the 211At-labeled compounds.

Copper-mediated radioiodination and radiobromination via aryl boronic precursor and its application to 125I/77Br-labeled prostate-specific membrane antigen imaging probes.

Prostate-specific membrane antigen (PSMA), expressed in prostate cancer cells, is being investigated extensively worldwide as a target for imaging and therapy of prostate cancer. Various radioiodinated PSMA imaging probes have been developed, and their structure has a peptidomimetic urea-based skeleton as a pharmacophore. For direct radioiodination of molecules containing these peptidomimetic structures, prior studies performed radioiododestannylation or electrophilic radioiodination of tyrosine residues. However, although these radiolabeling methods are frequently used, there are some issues with precursor toxicity and by-product production. Therefore, it is required to investigate a radiolabeling method that can be used for the radiosynthesis of radioiodinated PSMA imaging probes with urea-based peptidomimetic structures. We recently reported that copper-mediated radioiodination via a boronic precursor is an effective method for directly labeling a peptide. This radiohalogenation method was expected to be an effective method for radiosynthesis of PSMA imaging probes with a peptidomimetic structure. In this study, to confirm that this labeling method applies to the synthesis of the PSMA imaging probe, we synthesized PSMA imaging probes labeled with 125I and 77Br ([125I]mIB-PS and [77Br]mBrB-PS) using a copper-mediated radiohalogenation via common boronic precursors and investigated optimal boronic precursor and labeling conditions. As a result, the radiochemical yields of [125I]mIB-PS and [77Br]mBrB-PS were improved to > 93% at room temperature by optimizing the structure of the boronic precursor. We demonstrate that copper-mediated nucleophilic radiochemistry using a boronic precursor is a promising radiosynthetic method of PSMA imaging probes. Although we focused on the synthesis of PSMA imaging probes, the results in this study will also be useful for the synthesis of various radioiodine or radiobromine-labeled bioactive molecules.

Organic cation transporter 3 mediates the non-norepinephrine transporter driven uptake of meta-[211At]astato-benzylguanidine.

INTRODUCTION: Meta-[211At]astato-benzylguanidine ([211At]MABG) accumulates in pheochromocytoma via norepinephrine transporter (NET) and leads to a strong antitumor effect, but it also distributed in normal tissues non-specifically. Meta-[131I]iodo-benzylguanidine ([131I]MIBG), an iodine-labeled analog of [211At]MABG, is known to be transported by not only NET but also organic cation transporter (OCT). The involvement of OCT in [211At]MABG uptake is still largely unknown. We investigated the involvement of OCT in the non-NET-driven uptake of [211At]MABG both in vitro and in vivo. METHODS: [123I]MIBG and [211At]MABG uptake was investigated in PC-12 (rat pheochromocytoma cell line), NIH/3T3 (mouse fibroblasts cell line), ACHN (human renal cancer cell line), and BxPC-3 (human pancreatic cancer cell line). Herein, we used desipramine and dl-norepinephrine to inhibit NET, and we used steroids (hydrocortisone and prednisolone) to inhibit OCT3. The [211At]MABG uptake in OCT3-knockdown cells established with OCT3-selective siRNA was also investigated. We investigated the biodistribution of [211At]MABG in PC-12 tumor-bearing mice after a preloading of phosphate-buffered saline (PBS) or hydrocortisone solution. RESULTS: The uptake of both [123I]MIBG and [211At]MABG was significantly inhibited by desipramine in PC-12 cells but not the other cell lines. The expression of OCT3 was relatively higher than those of the other OCT subtypes in ACHN and BxPC-3 cells. The expression of OCTs was not observed in NIH/3T3 cells. The uptake of both [123I]MIBG and [211At]MABG in ACHN and BxPC-3 cells was significantly inhibited by the steroid treatments. The [211At]MABG uptake was also reduced in OCT3-knockdown cells (p < 0.001). The radioactivity of [211At]MABG was significantly reduced in normal tissues by the preloading of hydrocortisone. In contrast, there was an increasing trend of [211At]MABG uptake in the PC-12 tumors. The tumor-to-normal tissue ratio was significantly increased by the preloading of hydrocortisone compared to that of PBS. CONCLUSION: Our results suggest that OCT3 is involved in non-NET-driven [211At]MABG uptake. The preloading of hydrocortisone selectively reduced [211At]MABG accumulation in normal organs in vivo. OCT3 inhibition may therefore be beneficial for a reduction of the radiation risk in healthy organs in the treatment of malignant pheochromocytomas.

Nonclinical study and applicability of the absorbed dose conversion method with a single biodistribution measurement for targeted alpha-nuclide therapy.

BACKGROUND: We recently reported a new absorbed dose conversion method, RAP (RAtio of Pharmacokinetics), for 211At-meta-astatobenzylguanidine (211At-MABG) using a single biodistribution measurement, the percent injected dose/g. However, there were some mathematical ambiguities in determining the optimal timing of a single measurement of the percent injected dose/g. Thus, we aimed to mathematically reconstruct the RAP method and to examine the optimal timing of a single measurement. METHODS: We derived a new formalism of the RAP dose conversion method at time t. In addition, we acquired a formula to determine the optimal timing of a single measurement of the percent injected dose/g, assuming the one-compartment model for biological clearance. RESULTS: We investigated the new formalism's performance using a representative RAP coefficient with radioactive decay weighting. Dose conversions by representative RAP coefficients predicted the true [211At]MABG absorbed doses with an error of 10% or less. The inverses of the representative RAP coefficients plotted at 4 h post-injection, which was the optimal timing reported in the previous work, were very close to the new inverses of the RAP coefficients 4 h post-injection. Next, the behavior of the optimal timing was analyzed by radiolabeled compounds with physical half-lives of 7.2 h and 10 d on various biological clearance half-lives. Behavior maps of optimal timing showed a tendency to converge to a constant value as the biological clearance half-life of a target increased. The areas of optimal timing for both compounds within a 5% or 10% prediction error were distributed around the optimal timing when the biological clearance half-life of a target was equal to that of the reference. Finally, an example of RAP dose conversion was demonstrated for [211At]MABG. CONCLUSIONS: The RAP dose conversion method renovated by the new formalism was able to estimate the [211At]MABG absorbed dose using a similar pharmacokinetics, such as [131I]MIBG. The present formalism revealed optimizing imaging time points on absorbed dose conversion between two radiopharmaceuticals. Further analysis and clinical data will be needed to elucidate the validity of a behavior map of the optimal timing of a single measurement for targeted alpha-nuclide therapy.

Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading.

L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-211At-AAMP by increasing its accumulation in tumors.

Neopentyl Glycol as a Scaffold to Provide Radiohalogenated Theranostic Pairs of High In Vivo Stability.

The high in vivo stability of 2,2-dihydroxymethyl-3-[18F]fluoropropyl-2-nitroimidazole ([18F]DiFA) prompted us to evaluate neopentyl as a scaffold to prepare a radiotheranostic system with radioiodine and astatine. Three DiFA analogues with one, two, or without a hydroxyl group were synthesized. While all 125I-labeled compounds remained stable against nucleophilic substitution, only a 125I-labeled neopentyl glycol was stable against cytochrome P450 (CYP)-mediated metabolism and showed high stability against in vivo deiodination. 211At-labeled neopentyl glycol also remained stable against both nucleophilic substitution and CYP-mediated metabolism. 211At-labeled neopentyl glycol showed the biodistribution profiles similar to those of its radioiodinated counterpart in contrast to the 125I/211At-labeled benzoate pair. The urine analyses confirmed that 211At-labeled neopentyl glycol was excreted in the urine as a glucuronide conjugate with the absence of free [211At]At-. These findings indicate that neopentyl glycol would constitute a promising scaffold to prepare a radiotheranostic system with radioiodine and 211At.

Re-Evaluations of Zr-DFO Complex Coordination Chemistry for the Estimation of Radiochemical Yields and Chelator-to-Antibody Ratios of 89Zr Immune-PET Tracers.

(1) Background: Deferoxamine B (DFO) is the most widely used chelator for labeling of zirconium-89 (89Zr) to monoclonal antibody (mAb). Despite the remarkable developments of the clinical 89Zr-immuno-PET, chemical species and stability constants of the Zr-DFO complexes remain controversial. The aim of this study was to re-evaluate their stability constants by identifying species of Zr-DFO complexes and demonstrate that the stability constants can estimate radiochemical yield (RCY) and chelator-to-antibody ratio (CAR). (2) Methods: Zr-DFO species were determined by UV and ESI-MS spectroscopy. Stability constants and speciation of the Zr-DFO complex were redetermined by potentiometric titration. Complexation inhibition of Zr-DFO by residual impurities was investigated by competition titration. (3) Results: Unknown species, ZrHqDFO2, were successfully detected by nano-ESI-Q-MS analysis. We revealed that a dominant specie under radiolabeling condition (pH 7) was ZrHDFO, and its stability constant (logß111) was 49.1 ± 0.3. Competition titration revealed that residual oxalate inhibits Zr-DFO complex formation. RCYs in different oxalate concentration (0.1 and 0.04 mol/L) were estimated to be 86% and >99%, which was in good agreement with reported results (87%, 97%). (4) Conclusion: This study succeeded in obtaining accurate stability constants of Zr-DFO complexes and estimating RCY and CAR from accurate stability constants established in this study.

Absorbed dose simulation of meta-211At-astato-benzylguanidine using pharmacokinetics of 131I-MIBG and a novel dose conversion method, RAP.

OBJECTIVE: We aimed to estimate in vivo 211At-labeled meta-benzylguanidine (211At-MABG) absorbed doses by the two dose conversion methods, using 131I-MIBG biodistribution data from a previously reported neuroblastoma xenograft model. In addition, we examined the effects of different cell lines and time limitations using data from two other works. METHODS: We used the framework of the Monte Carlo method to create 3200 virtual experimental data sets of activity concentrations (kBq/g) to get the statistical information. Time activity concentration curves were produced using the fitting method of a genetic algorithm. The basic method was that absorbed doses of 211At-MABG were calculated based on the medical internal radiation dose formalism with the conversion of the physical half-life time of 131I to that of 211At. We have further improved the basic method; that is, a novel dose conversion method, RAP (Ratio of Pharmacokinetics), using percent injected dose/g. RESULTS: Virtual experiments showed that 211At-MABG and 131I-MIBG had similar properties of initial activity concentrations and biological components, but the basic method did not simulate the 211At-MABG dose. Simulated 211At-MABG doses from 131I-MIBG using the RAP method were in agreement with those from 211At-MABG, so that their boxes overlapped in the box plots. The RAP method showed applicability to the different cell lines, but it was difficult to predict long-term doses from short-term experimental data. CONCLUSIONS: The present RAP dose conversion method could estimate 211At-MABG absorbed doses from the pharmacokinetics of 131I-MIBG with some limitations. The RAP method would be applicable to a large number of subjects for targeted nuclide therapy.

Preclinical evaluation of new α-radionuclide therapy targeting LAT1: 2-[211At]astato-α-methyl-L-phenylalanine in tumor-bearing model.

INTRODUCTION: Targeted α-radionuclide therapy has attracted attention as a promising therapy for refractory cancers. However, the application is limited to certain types of cancer. Since L-type amino acid transporter 1 (LAT1) is highly expressed in various human cancers, we prepared an LAT1-selective α-radionuclide-labeled amino acid analog, 2-[211At]astato-α-methyl-L-phenylalanine (2-[211At]AAMP), and evaluated its potential as a therapeutic agent. METHODS: 2-[211At]AAMP was prepared from the stannyl precursor. Stability of 2-[211At]AAMP was evaluated both in vitro and in vivo. In vitro studies using an LAT1-expressing human ovarian cancer cell line, SKOV3, were performed to evaluate cellular uptake and cytotoxicity of 2-[211At]AAMP. Biodistribution and therapeutic studies in SKOV3-bearing mice were performed after intravenous injection of 2-[211At]AAMP. RESULTS: 2-[211At]AAMP was stable in murine plasma in vitro and excreted intact into urine. Cellular uptake of 2-[211At]AAMP was inhibited by treatment with an LAT1-selective inhibitor. After 24 h incubation, 2-[211At]AAMP suppressed clonogenic growth at 10 kBq/ml, and induced cell death and DNA double-strand breaks at 25 kBq/ml. When injected into mice, 2-[211At]AAMP exhibited peak accumulation in the tumor at 30 min postinjection, and radioactivity levels in the tumor were retained up to 60 min. The majority of the radioactivity was rapidly eliminated from the body into urine in an intact form immediately after injection. 2-[211At]AAMP significantly improved the survival of mice (P < 0.05) without serious side effects. CONCLUSION: 2-[211At]AAMP showed α-radiation-dependent cellular growth inhibition after it was taken up via LAT1. In addition, 2-[211At]AAMP had a beneficial effect on survival in vivo. These findings suggest that 2-[211At]AAMP would be useful for the treatment of LAT1-positive cancer. ADVANCES IN KNOWLEDGE AND IMPLICATIONS FOR PATIENT CARE: This is the first report of an LAT1-targeting radiopharmaceutical for α-radionuclide therapy; this agent would be applicable for the treatment of various types of cancer.

Anti-tumor effects and potential therapeutic response biomarkers in α-emitting meta-211At-astato-benzylguanidine therapy for malignant pheochromocytoma explored by RNA-sequencing.

Targeted α-particle therapy is a promising option for patients with malignant pheochromocytoma. Recent observations regarding meta-211At-astato-benzylguanidine (211At-MABG) in a pheochromocytoma mouse model showed a strong anti-tumor effect, though the molecular mechanism remains elusive. Here, we present the first comprehensive RNA-sequencing (RNA-seq) data for pheochromocytoma cells based on in vitro211At-MABG administration experiments. Key genes and pathways in the tumor α-particle radiation response are also examined to obtain potential response biomarkers. Methods: We evaluated genome-wide transcriptional alterations in the rat pheochromocytoma cell line PC12 at 3, 6, and 12 h after 211At-MABG treatment; a control experiment using 60Co γ-ray irradiation was carried out to highlight 211At-MABG-specific gene expression. For comparisons, 10% and 80% iso-survival doses (0.8 and 0.1 kBq/mL for 211At-MABG and 10 and 1 Gy for 60Co γ-rays) were used. Results: Enrichment analysis of differentially expressed genes (DEGs) and analysis of the gene expression profiles of cell cycle checkpoints revealed similar modes of cell death via the p53-p21 signaling pathway after 211At-MABG treatment and γ-ray irradiation. The top list of ranked DEGs demonstrated the expression of key genes on the decrease in the survival following 211At-MABG exposure, and four potential genes (Mien1, Otub1, Vdac1 and Vegfa genes) of 211At-MABG therapy. Western blot analysis indicated increased expression of TSPO in 211At-MABG-treated cells, suggesting its potential as a PET imaging probe. Conclusion: Comprehensive RNA-seq revealed contrasting cellular responses to γ-ray and α-particle therapy, leading to the identification of four potential candidate genes that may serve as molecular imaging and 211At-MABG therapy targets.

A convenient and reproducible method for the synthesis of astatinated 4-[211At]astato-l-phenylalanine via electrophilic desilylation.

The 211At-labeled compound, 4-[211At]astato-l-phenylalanine, is one of the most promising amino acid derivatives for use in targeted alpha therapy (TAT) for various cancers. Electrophilic demetallation of a stannyl precursor is the most widely used approach for labeling biomolecules with 211At. However, the low acid-resistance of the stannyl precursor necessitates the use of an N- and C-terminus-protected precursor, which results in a low overall radiochemical yield (RCY) due to the multiple synthetic steps involved. In this study, a deprotected organosilyl compound, 4-triethylsilyl-l-phenylalanine, was employed for the direct synthesis of astatinated phenylalanines. 211At was separately recovered from the irradiated 209Bi target using chloroform (CHCl3) and N-chlorosuccinimide-methanol (NCS-MeOH) solution. The RCYs of 4-[211At]astato-l-phenylalanine obtained from the triethylsilyl precursor with the use of 211At, isolated in CHCl3 and NCS-MeOH solution, were 75% and 64% respectively. In both cases, the retention time of the 4-[211At]astato-l-phenylalanine was found to be about 20 min, which showed reasonable correlation with the retention time of non-radioactive 4-halo-l-phenylalanines (4-chloro-, 4-bromo-, and 4-iodo-l-phenylalanine). The one-step reaction examined in this study involved mild reaction conditions (70 °C) and a short time (10 min) compared to the other currently reported procedures for astatination. Electrophilic desilylation was found to be very effective for the labeling of aromatic amino acids with 211At.

Are pension types associated with happiness in Japanese older people?: JAGES cross-sectional study.

BACKGROUND: Although many previous studies have examined the determinants of happiness in older adults, few have investigated the association between pension types and happiness. When compared to other conventional socioeconomic indicators, pension types may be more indicative of long-term socioeconomic status as they can reflect a person's job history over their life course. This study examined the association between pension types and happiness in Japanese older people. METHODS: Cross-sectional survey data from the Japan Gerontological Evaluation Study were used to analyze the association between pension types and happiness. The study population comprised 120152 participants from 2013. We calculated the prevalence ratios of happiness for the different pension types using Poisson regression models that controlled for age, sex, marital status, equivalent income, wealth, education level, working status, occupation, depression, and social support. RESULTS: After controlling for socioeconomic indicators, the prevalence ratios (95% confidence intervals) of happiness for no pension benefits, low pension benefits, and moderate pension benefits relative to high pension benefits were 0.77 (0.73-0.81), 0.95 (0.94-0.97), and 0.98 (0.97-0.99), respectively. However, the inclusion of depression as a covariate weakened the association between pension types and happiness. CONCLUSIONS: While pension types were associated with happiness after adjusting for other proxy measures of socioeconomic status, the association diminished following adjustment for depression. Pension types may provide rich information on socioeconomic status and depression throughout the course of life. In addition to conventional socioeconomic indicators, pension types should also be considered when assessing the determinants of happiness in older adults.

Hyperenhanced Rim Surrounding Liver Metastatic Tumors in the Postvascular Phase of Sonazoid-Enhanced Ultrasonography: A Histological Indication of the Presence of Kupffer Cells.

AIM: A hyperenhanced rim (termed 'HER') in the postvascular phase is detected in some cases of liver metastasis by Sonazoid-enhanced ultrasonography (US). Here, the association of the HER with histological features was investigated to clarify the cause of this characteristic imaging pattern. SUBJECTS AND METHODS: A total of 13 hepatic nodules obtained from 11 patients with metastatic liver cancer who underwent Sonazoid-enhanced US followed by surgical resection were analyzed. The distribution density of CD68-positive cells in the tumor rim and the nontumor area was calculated and compared between the HER-positive and HER-negative groups. The relation between the pathological features of the tumor rim and the rate of necrosis within the tumor was also investigated. RESULTS: In the HER-positive group (n = 8), the distribution density of CD68-positive cells was 2.9 ± 0.9, which was significantly higher than that (1.0 ± 0.3) in the HER-negative group (p < 0.05). Inflammatory cell infiltrates, including CD8-positive lymphocytes, were detected in all the HER-positive cases in the area surrounding the tumor, while fibrosis was observed in all the HER-negative cases. The necrotic area within the tumor was significantly larger in the HER-negative group. CONCLUSION: The HER-positive sign in liver metastases could reflect an increase in Kupffer cells in the tumor rim. The presence of the HER was associated with inflammatory cell infiltrates including CD8-positive lymphocytes surrounding the metastatic liver tumor.

Electrically evoked auditory brainstem response-based evaluation of the spatial distribution of auditory neuronal tissue in common cavity deformities.

OBJECTIVE: In a common cavity (CC) deformity, the cochlea and vestibule are confluent to form a single cavity without internal architecture, and distribution of auditory neuronal tissue is unclear. The purposes of this study are to reveal the spatial distribution of auditory neuronal tissue in CC deformity using electrically evoked auditory brainstem response (EABR) during cochlear implantation. STUDY DESIGN: Retrospective case review. SETTING: Cochlear implant (CI) center at a tertiary referral hospital. PATIENTS: Five patients with CC deformity who underwent cochlear implantation and intraoperative EABR testing. MAIN OUTCOME MEASURES: Spatial distribution of electrodes that elicited an evoked wave V (eV) in EABR testing was evaluated in each CC deformity. RESULTS: Electrically evoked auditory brainstem response testing demonstrated that electrodes attached on the inner wall of the anteroinferior cavity of the CC deformity successfully elicited a reproducible eV in all cases, and the latency of each eV was an approximately 4 ms, which is similar to those reported in patients without an inner ear malformation. Interestingly, in Case 1 with the lowest percentage of eV-positive electrodes (31.8%), CI-aided audiometric thresholds were changed, depending on the frequency allocation to eV-positive electrodes in the programming. Cochlear implant-mediated facial nerve stimulation was observed in 3 of 5 cases, and results of EABR testing were useful for optimizing the device program to decrease facial nerve stimulation without sacrificing CI-mediated auditory performance. CONCLUSION: The results of EABR testing suggested that auditory neuronal elements are distributed to the anteroinferior part of CC deformity, mainly around or near the inner wall of the cavity. In cases with CC deformity, EABR testing is useful to achieve the optimal electrode array placement and to adjust programming parameters of the implanted device, which might be essential to maximize CI outcomes and to decrease facial nerve stimulation.

Antimicrobially active cycloundecapeptides related to gramicidin S having a novel turn structure with cis D-Phe-Pro peptide bond.

Antimicrobially active cycloundecapeptides related to gramicidin S, cyclo(-Val1-Orn2-Leu3-X4-D-Phe5-Pro6-Val7-Orn8- Leu9-D-Phe10-Pro11-) (X= Leu (1), Ala (2), Orn (3), Lys (4) and Arg (5)), were synthesized. From the CD and NMR studies, 1-5 possess antiparallel -sheet conformation linked by a type II -turn around D-Phe10-Pro11 and a novel turn structure around X4-D-Phe5-Pro6 sequence with cis D-Phe-Pro peptide bond. The structural modifications at position 4 of 1-5 are beneficial to identification of novel antibiotic candidates without hemolytic activity.

Benefit of short-term iodide supplementation to antithyroid drug treatment of thyrotoxicosis due to Graves' disease.

OBJECTIVE: Combined treatment with anti-thyroid drugs (ATDs) and potassium iodide (KI) has been used only for severe thyrotoxicosis or as a pretreatment before urgent thyroidectomy in patients with Graves' disease. We compared methimazole (MMI) treatment with MMI + KI treatment in terms of rapid normalization of thyroid hormones during the early phase and examined the later induction of disease remission. DESIGN AND PATIENTS: A total of 134 untreated patients with Graves' disease were randomly assigned to one of four regimens: Group 1, MMI 30 mg; Group 2, MMI 30 mg + KI; Group 3, MMI 15 mg and Group 4, MMI 15 mg + KI. For easy handling, KI tablets were used instead of saturated solution of KI. KI was discontinued when patients showed normal free thyroxine (FT4) levels but MMI was continued with a tapering dosage until remission. Remission rate was examined during a 4- to 5-year observation. MEASUREMENTS: Serum FT4, FT3 and TSH were measured by chemiluminescent immunoassays. TSH receptor antibody (TRAb) was assayed with TRAb-ELISA. Goitre size was estimated by ultrasonography. RESULTS: After 2 weeks of treatment, normal FT4 was observed in 29% of patients in Group 1 and 59% (P < 0.05) of patients in Group 2. Furthermore, normal FT4 after 2 weeks of treatment was observed in 27% of patients in Group 3 and 54% (P < 0.05) of patients in Group 4. Similarly, FT3 normalized more rapidly in Groups 2 and 4 than in Groups 1 and 3. None of the patients showed an increase in thyroid hormones or aggravation of disease during combined treatment with MMI and KI. The remission rates in Groups 1, 2, 3 and 4 were 34%, 44%, 33% and 51%, respectively, and were higher in the groups receiving combined therapy but differences among four groups did not reach significance. CONCLUSIONS: Combined treatment with MMI and KI improved the short-term control of Graves' hyperthyroidism and was not associated with worsening hyperthyroidism or induction of thionamide resistance.

Syntheses of low-hemolytic antimicrobial gratisin peptides.

Antibiotic and hemolytic activities of gratisin (GR), cyclo(-Val(1)-Orn(2)-Leu(3)-d-Phe(4)-Pro(5)-d-Tyr(6)-)(2), and fifteen GR analogues, which have various d-amino acid residues in place of d-Tyr(6,6') residues, were examined. Among them, [d-Orn(6,6')]-GR, [d-Lys(6,6')]-GR and [d-Arg(6,6')]-GR showed the strong activity against both Gram-positive and Gram-negative bacteria. In addition, the antibiotics showed significantly reduced toxicity against human blood cells compared with gramicidin S, cyclo(-Val(1)-Orn(2)-Leu(3)-d-Phe(4)-Pro(5)-)(2).

Effect of levo-thyroxine replacement on non-high-density lipoprotein cholesterol in hypothyroid patients.

CONTEXT: Recently, non-high-density lipoprotein cholesterol (non-HDL-C), a measure of total cholesterol minus HDL-C, has emerged as a predictor of cardiovascular disease. OBJECTIVE: We evaluated the effect of L-T4 replacement on non-HDL-C levels in patients with primary hypothyroidism. METHODS: Thirteen patients with overt hypothyroidism and 26 patients with subclinical hypothyroidism participated in the study. The lipid profiles, including non-HDL-C, were measured in patients with hypothyroidism before and 3 months after L-T4 replacement was started. RESULTS: After L-T4 replacement, the serum concentrations of all lipoproteins, exclusive of lipoprotein (a) [Lp(a)], were significantly decreased in patients with overt hypothyroidism. In patients with subclinical hypothyroidism, the serum concentrations of total cholesterol, non-HDL-C, remnant-like particle cholesterol, and apolipoprotein B (Apo B) were significantly decreased, whereas no significant changes in the serum concentrations of low-density lipoprotein cholesterol, HDL-C, triglycerides, apolipoprotein A-I, and Lp(a) were observed. In all 39 patients, the reduction in the non-HDL-C levels correlated with the reduction in the low-density lipoprotein cholesterol, remnant-like particle cholesterol, and Apo B levels. However, the reduction in the non-HDL-C levels did not correlate with the reduction in the HDL-C, Lp(a), and apolipoprotein A-I levels. CONCLUSIONS: This study is the first to show that L-T4 replacement may reduce serum concentrations of non-HDL-C in patients with hypothyroidism. The study also suggests that such altered serum concentrations of non-HDL-C in hypothyroidism may be related to the disturbed metabolism of low-density lipoprotein, remnant lipoprotein, and Apo B.