Factors associated with dropout from an intradialytic exercise program among patients undergoing maintenance hemodialysis.

BACKGROUND: Continuation of an intradialytic exercise program is necessary to improve and maintain physical function in patients undergoing hemodialysis. Factors associated with dropout must be identified to ensure program continuation. This study aimed to investigate the dropout rates from an intradialytic exercise program at 6 and 12 months in patients undergoing hemodialysis and to identify dropout predictors. METHODS: This was a multicenter, retrospective observational study. Overall, 980 patients were enrolled in this study. Grip strength, 10-m walking speed, physical function, demographics and blood sampling data were measured at baseline, and dropouts were observed. Patients were classified as either continued or dropped out of the program at 6 and 12 months. The dropout rate was calculated for each time point. Multivariate logistic regression analysis was performed to identify the predictors of dropout. RESULTS: The dropout rate was 26.4% (n = 259) after 6 months, 24.1% (n = 172) between 6 and 12 months, and 44.3% (n = 424) overall at 1 year. Significant predictors of dropout after 6 months were slower 10-m walking speed, older age and high C-reactive protein level. Predictors of dropout after 12 months were slower 10-m walking speed and lower standardized dialysis volume. CONCLUSIONS: Walking capacity, age, inflammation and hemodialysis volume were determinants of dropout from the exercise program. Our findings provide new and important insights into the potential risk factors for dropout from long-term intradialytic exercise programs in patients undergoing hemodialysis.

Influence of Malnutrition on the Improvement of Physical Function by Intradialytic Resistance Exercise in Patients Undergoing Hemodialysis.

OBJECTIVE: Intradialytic exercise improves physical function. However, malnutrition may be an essential factor affecting the effectiveness of exercise to improve physical function. Few studies of the relationship between malnutrition and the effectiveness of intradialytic exercise to improve physical function exist. Therefore, this study investigated malnutrition at the beginning of intradialytic exercise and how it affects the subsequent improvement in physical function. METHODS: Patients who performed intradialytic exercise for 12 months were enrolled in this study. A Geriatric Nutritional Risk Index of 91.2 was defined as malnutrition. Patients were assigned to 2 groups using propensity score matching to adjust for confounding factors. Physical function outcomes were handgrip strength, isometric knee extension strength, short physical performance battery, and 10-m walking speed; these were compared at baseline, 3 months, 6 months, and 12 months. The 2 groups were further divided into another 2 groups as per whether the nutritional status had improved after 12 months; therefore, a total of 4 groups were analyzed. RESULTS: After matching, the data of 154 patients in each group were analyzed. During the intragroup comparison, isometric knee extension strength, short physical performance battery, and 10-m walking speed improved significantly in both groups after intradialytic exercise was started compared with before intradialytic exercise was started. However, there was no significant improvement in handgrip strength in the malnutrition group. There were no significant differences in any of the physical function measurements or changes from the baseline values among the 4 groups divided as per subsequent recovery of the nutritional status. CONCLUSION: Malnutrition may not impact the effectiveness of intradialytic exercise to improve lower-leg physical function. Its effect on the improvement of handgrip strength requires further investigation.

Classification of PD-L1 expression in various cancers and macrophages based on immunohistocytological analysis.

Programmed death (PD)-1/PD-ligand 1 (PD-L1) antibodies have shown an intense clinical effect in some patients with PD-L1+ tumors, and their applications have rapidly expanded to various cancer types with or without the application of new companion diagnostics (CDx) with a lower cutoff value and inclusion of macrophage evaluation. However, the pathological background explaining the difference in the cutoff value remains unknown. To address this, we evaluated tissue array samples from 231 patients with lung adenocarcinoma, 186 with lung squamous cell carcinoma, and 38 with renal cell carcinoma (RCC) who were not receiving PD-1/PD-L1 antibodies to investigate the relationship between PD-L1 expression on tumor cells and CD8+ T-cell infiltration in tumor tissues. PD-L1 expression in RCC was clearly lower than that in non-small-cell lung cancer (NSCLC) tissue, whereas CD8+ T-cell infiltration was low in all cancers. We next analyzed PD-L1 expression by interferon (α, ß, and γ) and LPS stimulation in both macrophages and 41 cancer cell lines derived from various organs and histological types. The PD-L1 expression patterns were classified into three types, which differed depending on each organ or tissue type. Interestingly, NSCLC cell lines showed highly diverse PD-L1 expression patterns compared with RCC cell lines. Conversely, PD-L1 expression was stronger and more prolonged in macrophages than in typical cell lines. Here, we revealed the diversity of the PD-L1 expression patterns in tumor cells and macrophages, demonstrating the pathological and cytological significance of the transition of cutoff values in PD-L1 CDx for PD-1/PD-L1 antibody administration.

Association between timing of speech and language therapy initiation and outcomes among post-extubation dysphagia patients: a multicenter retrospective cohort study.

BACKGROUND: Post-extubation dysphagia (PED) is recognized as a common complication in the intensive care unit (ICU). Speech and language therapy (SLT) can potentially help improve PED; however, the impact of the timing of SLT initiation on persistent PED has not been well investigated. This study aimed to examine the timing of SLT initiation and its effect on patient outcomes after extubation in the ICU. METHODS: We conducted this multicenter, retrospective, cohort study, collecting data from eight ICUs in Japan. Patients aged ≥ 20 years with orotracheal intubation and mechanical ventilation for longer than 48 h, and those who received SLT due to PED, defined as patients with modified water swallowing test scores of 3 or lower, were included. The primary outcome was dysphagia at hospital discharge, defined as functional oral intake scale score < 5 or death after extubation. Secondary outcomes included dysphagia or death at the seventh, 14th, or 28th day after extubation, aspiration pneumonia, and in-hospital mortality. Associations between the timing of SLT initiation and outcomes were determined using multivariable logistic regression. RESULTS: A total of 272 patients were included. Of them, 82 (30.1%) patients exhibited dysphagia or death at hospital discharge, and their time spans from extubation to SLT initiation were 1.0 days. The primary outcome revealed that every day of delay in SLT initiation post-extubation was associated with dysphagia or death at hospital discharge (adjusted odds ratio (AOR), 1.09; 95% CI, 1.02-1.18). Similarly, secondary outcomes showed associations between this per day delay in SLT initiation and dysphagia or death at the seventh day (AOR, 1.28; 95% CI, 1.05-1.55), 14th day (AOR, 1.34; 95% CI, 1.13-1.58), or 28th day (AOR, 1.21; 95% CI, 1.07-1.36) after extubation and occurrence of aspiration pneumonia (AOR, 1.09; 95% CI, 1.02-1.17), while per day delay in post-extubation SLT initiation did not affect in-hospital mortality (AOR, 1.04; 95% CI, 0.97-1.12). CONCLUSIONS: Delayed initiation of SLT in PED patients was associated with persistent dysphagia or death. Early initiation of SLT may prevent this complication post-extubation. A randomized controlled study is needed to validate these results.

Temporal virtual reality-guided, dual-task, trunk balance training in a sitting position improves persistent postural-perceptual dizziness: proof of concept.

BACKGROUND: Persistent postural-perceptual dizziness (PPPD) is a newly defined disorder characterized by functional dizziness. Due to its recent discovery, definitive treatment for PPPD has not been established; therefore, this study aimed to assess the effectiveness of virtual reality (VR)-guided, dual-task, trunk balance training for the management of PPPD using the mediVR KAGURA system. METHODS: We analyzed data of patients who presented with PPPD from January 1, 2021, to February 28, 2021. The VR group included patients who underwent mediVR KAGURA-guided training for 100 tasks (10 min). Patients with PPPD who received standard treatment and rehabilitation were assigned to the control group. Equilibrium tests were performed at baseline and immediately after mediVR KAGURA-guided training to examine its effectiveness in improving static and dynamic balance. Additionally, clinical questionnaires related to balance disorders were administered at baseline and 1 week after mediVR KAGURA-guided training to examine its effects on balance-related symptoms. The primary outcome was improvements in static and dynamic balance and Niigata PPPD Questionnaire (NPQ) scores. RESULTS: VR-guided training using mediVR KAGURA improved objective outcomes, including static and dynamic postural stability, after a single 10-min training session. Additionally, mediVR KAGURA-guided training improved scores on the Hospital Anxiety and Depression Scale and NPQ 1 week after the 10-min training session. CONCLUSION: VR-guided training using mediVR KAGURA represents a viable method for managing balancing ability, anxiety, and symptoms in patients with PPPD. Such training provides a safe and cost-effective solution for PPPD management. Further studies are required to evaluate the clinical efficacy of this strategy. TRIAL REGISTRATION: Institutional Ethics Committee of Kitano Hospital, approval number: 1911003. Registered 18 December 2019, https://kitano.bvits.com/rinri/publish_document.aspx?ID=426 .

Inhibition of heat shock protein 90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma.

We have previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a direct transcriptional target of TTF-1/NKX2-1, a lineage-survival oncogene in lung adenocarcinoma. ROR1 sustains prosurvival signaling from multiple receptor tyrosine kinases including epidermal growth factor receptor, MET, and insulin-like growth factor 1 receptor in part by maintaining the caveolae structure as a scaffold protein of cavin-1 and caveolin-1. In this study, a high throughput screening of the natural product library containing 2560 compounds was undertaken using a cell-based FluoPPI assay detecting ROR1-cavin-1 interaction. As a result, geldanamycin (GA), a known inhibitor of heat shock protein 90 (HSP90), was identified as a potential inhibitor of ROR1. Geldanamycin, as well as two GA derivatives tested in the clinic, 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), decreased ROR1 protein expression. We found that ROR1 physically interacted with HSP90α, but not with other HSP90 paralogs, HSP90ß or GRP94. Geldanamycin in turn destabilized and degraded ROR1 protein in a dose- and time-dependent manner through the ubiquitin/proteasome pathway, resulting in a significant suppression of cell proliferation in lung adenocarcinoma cell lines, for which the kinase domain of ROR1, but not its kinase activity or N-glycosylation, was required. Our findings indicate that HSP90 is required to sustain expression of ROR1 crucial for lung adenosarcoma survival, suggesting that inhibition of HSP90 could be a promising therapeutic strategy in ROR1-positive lung adenocarcinoma.

Conditional Ror1 knockout reveals crucial involvement in lung adenocarcinoma development and identifies novel HIF-1α regulator.

We previously reported that ROR1 is a crucial downstream gene for the TTF-1/NKX2-1 lineage-survival oncogene in lung adenocarcinoma, while others have found altered expression of ROR1 in multiple cancer types. Accumulated evidence therefore indicates ROR1 as an attractive molecular target, though it has yet to be determined whether targeting Ror1 can inhibit tumor development and growth in vivo. To this end, genetically engineered mice carrying homozygously floxed Ror1 alleles and an SP-C promoter-driven human mutant EGFR transgene were generated. Ror1 ablation resulted in marked retardation of tumor development and progression in association with reduced malignant characteristics and significantly better survival. Interestingly, gene set enrichment analysis identified a hypoxia-induced gene set (HALLMARK_HYPOXIA) as most significantly downregulated by Ror1 ablation in vivo, which led to findings showing that ROR1 knockdown diminished HIF-1α expression under normoxia and clearly hampered HIF-1α induction in response to hypoxia in human lung adenocarcinoma cell lines. The present results directly demonstrate the importance of Ror1 for in vivo development and progression of lung adenocarcinoma, and also identify Ror1 as a novel regulator of Hif-1α. Thus, a future study aimed at the development of a novel therapeutic targeting ROR1 for treatment of solid tumors such as seen in lung cancer, which are frequently accompanied with a hypoxic tumor microenvironment, is warranted.

The cleistogamy of the superwoman1-cleistogamy1 mutation is sensitive to low temperatures during the lodicule-forming stage.

We reported previously that the rice (Oryza sativa L.) cleistogamous mutation superwoman1-cleistogamy1 (spw1-cls1) was applicable to inhibit outcrossing between genetically modified varieties and their relatives, which causes pollen-mediated gene flow or disturbance of line purity. The cleistogamy of spw1-cls1 is caused by decreased protein-protein interactions between the mutant SPW1 and its partner proteins. Importantly, these interactions are restored under low-temperature conditions, but whether the cleistogamy of spw1-cls1 is affected by this phenomenon was unclear. In this study, we cultivated spw1-cls1 in various regions of Japan and confirmed that its flowers opened at low temperatures. Moreover, we compared the morphology of a series of lodicules generated at various temperatures. The results indicated that the cleistogamy of spw1-cls1 is thermosensitive and is gradually disturbed as the temperature decreases. This was correlated with the protein interaction pattern of the mutant SPW1 as reported previously. Then, we revealed the critical period for the low-temperature-induced instability of the phenotype of spw1-cls1 and examined the effect of daily temperature changes on cleistogamy. The results may facilitate simulation of the phenotype of spw1-cls1 at various temperatures and the prediction of regions where the cleistogamy of spw1-cls1 can be stably used to inhibit outcrossing.

The superwoman1-cleistogamy2 mutant is a novel resource for gene containment in rice.

Outcrossing between cultivated plants and their related wild species may result in the loss of favourable agricultural traits in the progeny or escape of transgenes in the environment. Outcrossing can be physically prevented by using cleistogamous (i.e. closed-flower) plants. In rice, flower opening is dependent on the mechanical action of fleshy organs called lodicules, which are generally regarded as the grass petal equivalents. Lodicule identity and development are specified by the action of protein complexes involving the SPW1 and OsMADS2 transcription factors. In the superwoman1-cleistogamy1 (spw1-cls1) mutant, SPW1 is impaired for heterodimerization with OsMADS2 and consequently spw1-cls1 shows thin, ineffective lodicules. However, low temperatures help stabilise the mutated SPW1/OsMADS2 heterodimer and lodicule development is restored when spw1-cls1 is grown in a cold environment, resulting in the loss of the cleistogamous phenotype. To identify a novel, temperature-stable cleistogamous allele of SPW1, targeted and random mutations were introduced into the SPW1 sequence and their effects over SPW1/OsMADS2 dimer formation were assessed in yeast two-hybrid experiments. In parallel, a novel cleistogamous allele of SPW1 called spw1-cls2 was isolated from a forward genetic screen. In spw1-cls2, a mutation leading to a change of an amino acid involved in DNA binding by the transcription factor was identified. Fertility of spw1-cls2 is somewhat decreased under low temperatures but unlike for spw1-cls1, the cleistogamous phenotype is maintained, making the line a safer and valuable genetic resource for gene containment.

Receptor tyrosine kinase-like orphan receptor 1, a target of NKX2-1/TTF-1 lineage-survival oncogene, inhibits apoptosis signal-regulating kinase 1-mediated pro-apoptotic signaling in lung adenocarcinoma.

We previously identified receptor tyrosine kinase-like orphan receptor 1 (ROR1) as a transcriptional target of the NKX2-1/TTF-1 lineage-survival oncogene in lung adenocarcinoma. ROR1 consequently sustains a favorable balance between pro-survival phosphatidylinositol 3-kinase-protein kinase B and pro-apoptotic apoptosis signal-regulating kinase 1 (ASK1)-p38MAPK signaling. In contrast to recent advances in understanding how ROR1 sustains pro-survival signaling, the mechanism of ROR1 repression of pro-apoptotic signaling remains rather elusive. In the present study, we investigated the underlying mechanism of ROR1-mediated inhibition of the ASK1-p38MAPK signaling pathway. Growth inhibition mediated by siROR1 was partially but significantly alleviated by ASK1 co-knockdown in lung adenocarcinoma cell lines. Also, ASK1 phosphorylation at Thr845, which reflects its activated state, was clearly inhibited by ROR1 overexpression in both steady state and oxidative stress-elicited conditions in MSTO-211H cells. In addition, we found that ROR1 was physically associated with ASK1 at the C-terminal serine threonine-rich domain of ROR1. Furthermore, ROR1 kinase activity was shown to be required to repress the ASK1-p38 axis and oxidative stress-induced cell death. The present findings thus support our notion that ROR1 sustains lung adenocarcinoma survival, at least in part, through direct physical interaction with ASK1 and consequential repression of the pro-apoptotic ASK1-p38 axis in a ROR1 kinase activity-dependent manner.

MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasis.

Cell migration driven by actomyosin filament assembly is a critical step in tumour invasion and metastasis. Herein, we report identification of myosin binding protein H (MYBPH) as a transcriptional target of TTF-1 (also known as NKX2-1 and TITF1), a master regulator of lung development that also plays a role as a lineage-survival oncogene in lung adenocarcinoma development. MYBPH inhibited assembly competence-conferring phosphorylation of the myosin regulatory light chain (RLC) as well as activating phosphorylation of LIM domain kinase (LIMK), unexpectedly through its direct physical interaction with Rho kinase 1 (ROCK1) rather than with RLC. Consequently, MYBPH inhibited ROCK1 and negatively regulated actomyosin organization, which in turn reduced single cell motility and increased collective cell migration, resulting in decreased cancer invasion and metastasis. Finally, we also show that MYBPH is epigenetically inactivated by promoter DNA methylation in a fraction of TTF-1-positive lung adenocarcinomas, which appears to be in accordance with its deleterious functions in lung adenocarcinoma invasion and metastasis, as well as with the paradoxical association of TTF-1 expression with favourable prognosis in lung adenocarcinoma patients.

Lung adenocarcinoma subtypes definable by lung development-related miRNA expression profiles in association with clinicopathologic features.

Accumulation of genetic and epigenetic changes alters regulation of a web of interconnected genes including microRNAs (miRNAs), which confer hallmark capabilities and characteristic cancer features. In this study, the miRNA and messenger RNA expression profiles of 126 non-small cell lung cancer specimens were analyzed, with special attention given to the diversity of lung adenocarcinomas. Of those, 76 adenocarcinomas were classified into two major subtypes, developing lung-like and adult lung-like, based on their distinctive miRNA expression profiles resembling those of either developing or adult lungs, respectively. A systems biology-based approach using a Bayesian network and non-parametric regression was employed to estimate the gene regulatory circuitry functioning in patient tumors in order to identify subnetworks enriched for genes with differential expression between the two major subtypes. miR-30d and miR-195, identified as hub genes in such subnetworks, had lower levels of expression in the developing lung-like subtype, whereas introduction of miR-30d or miR-195 into the lung cancer cell lines evoked shifts of messenger RNA expression profiles toward the adult lung-like subtype. Conversely, the influence of miR-30d and miR-195 was significantly different between the developing lung-like and adult lung-like subtypes in our analysis of the patient data set. In addition, RRM2, a child gene of the miR-30d-centered subnetwork, was found to be a direct target of miR-30d. Together, our findings reveal the existence of two miRNA expression profile-defined lung adenocarcinoma subtypes with distinctive clinicopathologic features and also suggest the usefulness of a systems biology-based approach to gain insight into the altered regulatory circuitry involved in cancer development.

(Dibenzoylmethanato)boron difluoride derivatives containing triphenylamine moieties: a new type of electron-donor/π-acceptor system for dye-sensitized solar cells.

(Dibenzoylmethanato)boron difluoride derivatives containing triphenylamine moieties were synthesized as a new type of electron-donor/π-acceptor system. These new compounds exhibited long-wavelength absorptions in the UV/Vis spectra, and reversible oxidation and reduction waves in cyclic voltammetry experiments. Their amphoteric redox properties are based on their resonance hybrid forms, in which a positive charge is delocalized on the triphenylamine moieties and a negative charge is localized on the boron atoms. Molecular orbital (MO) calculations indicate that their HOMO and LUMO energies vary with the number of phenylene rings connected to the difluoroboron-chelating ring. This is useful for optimizing the HOMO and LUMO levels to an iodine redox (I(-)/I3(-)) potential and a titanium dioxide conduction band, respectively. Dye-sensitized solar cells fabricated by using these compounds as dye sensitizers exhibited solar-to-electric power conversion efficiencies of 2.7-4.4 % under AM 1.5 solar light.

Age-associated effects of intradialytic exercise on physical function and nutritional status in patients receiving ambulatory hemodialysis: A multicenter cohort study.

INTRODUCTION: Intradialytic exercise is essential for improving physical function for older patients. This study aimed to examine the relationship between the effects of exercise therapy and aging. METHODS: This multicenter cohort study included 1176 patients aged 40-89 years, who participated in an intradialytic exercise program, comprising stretching and resistance training, three times per week for 12 months. Isometric knee extension strength (IKES), 10-m walking speed, Short Physical Performance Battery (SPPB), and Geriatric Nutritional Risk Index (GNRI) were measured at baseline and after 12 months. The patients were divided according to age as follows: 40-59, 60-69, 70-79, and 80-89 years. A linear mixed-effects model examined the improvement within-group and between-control differences, as the 40-59 age group was the control group. FINDINGS: The 40-59, 60-69, 70-79, and 80-89 age groups comprised 180, 317, 466, and 213 participants, respectively. Within-group differences, all the age groups significantly improved IKES and SPPB. The 10-m walking speed [0.02 (0.02) m/s] and GNRI [0.38 (0.33)] did not improved only in the 80-89 age group despite other age groups significantly improved. Between-control differences, IKES of the 70-79 age group [-0.24 (-0.42 to -0.06) %] was significantly lower improvement than control. GNRI of all the older groups were significantly smaller improvement than control (p < 0.05). DISCUSSION: The older group demonstrated difficulty in improving walking ability and nutritional status compared with the younger groups. Clinicians need to consider the difference in effectiveness due to age and prescribe intradialytic exercises accordingly.

An Experimental Study on the Addition of Bacteria to Residual Anticancer Drugs: Evaluation of the Effect on Bacterial Growth.

Using anticancer drugs as examples, we examined the possibility of reusing residual drugs. The use of residual drugs is not widespread owing to concerns regarding bacterial contamination. We combined anticancer drugs and bacteria to investigate their effects on bacterial growth. The anticancer drugs carboplatin, paclitaxel, etoposide, irinotecan, methotrexate, and 5-fluorouracil (5-FU) were mixed with Staphylococcus aureus, Enterococcus faecalis, Serratia marcescens, and Escherichia coli. After a certain period, the bacteria were counted. Irinotecan showed no antibacterial activity, whereas 5-FU exhibited high antibacterial activity against the tested bacteria. The 5-FU also showed a minimum inhibitory concentration value in the range of 8-80 µg/mL, depending on the bacterial species. 5-FU dose-dependently inhibited S. aureus growth at more than 0.8 µg/mL. Because protein synthesis systems are reportedly antibiotic targets, we used a cell-free protein synthesis system to confirm the mechanism of the antibacterial activity of the anticancer agent. 5-FU and methotrexate had direct inhibitory effects on protein synthesis. It has been suggested that even if residual drugs are contaminated with bacteria, there will be no microbial growth, or the microbes will be killed by the drug. With careful monitoring, 5-FU can potentially be used for antimicrobial purposes.

Outcomes of regenerative treatment for over 200 patients with tympanic membrane perforation.

OBJECTIVE: To evaluate outcomes of a regenerative treatment (RT) for over 200 patients with tympanic membrane perforation (TMP). The RT-TMP method involves a gelatin sponge, basic fibroblast growth factor (bFGF) and fibrin glue. METHODS: The study population included 216 patients and 234 ears (male: female =100:116; age 1-93 years). All enrolled patients were treated with RT-TMP in which TMP edges were disrupted mechanically and a gelatin sponge immersed in bFGF was inserted into the perforation. Fibrin glue was then dripped over the sponge. Patient outcomes including TMP closure rates, change in hearing level, and complications were obtained from retrospective medical chart reviews. The TMP was examined three or more weeks after surgery. The treatment was repeated up to 4 times until complete TMP closure was achieved. RESULTS: After mechanical disruption, the perforation size was Grade I, ≤1/3 of entire TM area in 22 ears (9.4 %), Grade II, 1/3-2/3 of entire TM in 77 ears (32.9 %) and Grade III, ≥2/3 of entire TM area in 135 ears (57.7 %). The overall TMP closure rates were 97.0 % (227/234). Complete TMP closure was achieved in 68.8 % (161/234), 22.6 % (53/234), 4.7 % (11/234) and 0.9 % (2/234) of ears after 1, 2, 3 and 4 treatments, respectively. In 7 of 234 ears (3.0 %), the TMPs were not closed completely after 4 treatments. There was no correlation between TMP size after mechanical disruption and number of treatments required to achieve complete closure (Fisher's exact test p = 0.70). The mean air-conduction hearing threshold at low frequency improved from 57.3 ± 16.7 dB before treatment to 37.3 ± 16.0 dB (p < 0.0001) after closure of TMPs. For middle and high frequencies, the improvement was 49.0 ± 19.3 dB to 36.9 ± 17.9 dB (p < 0.0001) and 57.7 ± 22.9 dB to 49.2 ± 23.3 dB (p < 0.0001), respectively. The mean air-bone gaps also improved significantly, and were within 10 dB at 250 Hz, 500 Hz and 1 kHz, and 11 dB at 2 kHz. One or more complications occurred in 32 patients (32/216; 14.8 %). The most common complication was formation of an epithelial pearl (16 ears; 6.8 %), followed by severe TM retraction (9 ears; 3.8 %) and otitis media with effusion (6 ears; 2.6 %). There were no serious complications that caused deterioration of the patient's general condition. CONCLUSION: Our results showed that RT-TMP had high success rates for TMP closure and good hearing improvement and produced no severe complications that could affect general health status. This novel therapy is simple, safe and minimally invasive, and could help improve the quality of life in patients with TMP.

Neuromelanin magnetic resonance imaging in Parkinson's disease and multiple system atrophy.

Pigmented neurons in the substantia nigra pars compacta (SNc) and locus coeruleus (LC) show decreased numbers differentially in Parkinson's disease (PD) and multiple system atrophy (MSA). Recent reports have described that fast spin-echo T1-weighted magnetic resonance imaging (MRI) by a 3-tesla machine can visualize neuromelanin-related contrast of the noradrenergic and dopaminergic neurons respectively in the LC and the SNc. Using neuromelanin MRI at 3 T, we investigated possible alterations of these catecholaminergic neurons in 32 PD and 9 MSA patients, and compared the results with those of 23 normal volunteers. The contrast ratio of the LC and SNc was decreased in MSA and PD patients, most prominently in the LC in MSA patients. The contrast ratio of the SNc was correlated with the Hoehn-Yahr stage of PD and the severity of neuroradiological abnormalities in MSA. These results indicate a potential diagnostic value of neuromelanin MRI to distinguish MSA patients from normal and PD patients.

Differences in the purpose of exercise between hemodialysis patients who continued or dropped out of exercise programs: a multicenter cohort study.

BACKGROUND: Selecting suitable exercise goals is crucial for fostering adherence to, and maintenance of, exercise therapy. We aimed to evaluate the variance in exercise objectives between individuals who continued and those who dropped out of a 6-month intradialytic exercise program by analyzing an open-ended questionnaire administered to patients undergoing hemodialysis. METHODS: The study consisted of outpatients (n = 541; mean age, 70 years) undergoing maintenance hemodialysis, who had been informed of an intradialytic exercise program and voluntarily agreed to participate. The primary outcome was the exercise purpose. The difference in exercise purpose was quantitatively analyzed between the exercise continuation and dropout groups. A co-occurrence network was created and concepts were constructed. The basic attributes were compared using chi-squared and independent t-tests. RESULTS: Over 6 months, 154 patients (28.5%) dropped out of the intradialytic exercise program. Concepts related to the goals of the program were: (1) physical function and condition, (2) addressing limitations, (3) maintaining daily life activities, and (4) physical condition recognition. Co-occurrence network analysis showed that the exercise continuation group established their objectives based on the health benefits of exercise, and proactively set goals rooted in comprehending their current issues and problems. The dropout group tended to perceive treatment passively as an extension of daily clinical practice, rather than actively formulating exercise objectives. CONCLUSION: The exercise objectives of those who continued the exercise program differed from those who dropped out. Patients in the exercise continuation group set more affirmative and specific exercise objectives, whereas those in the dropout group set more passive and abstract exercise objectives.

MYBPH inhibits NM IIA assembly via direct interaction with NMHC IIA and reduces cell motility.

Actomyosin filament assembly is a critical step in tumor cell migration. We previously found that myosin binding protein H (MYBPH) is directly transactivated by the TTF-1 lineage-survival oncogene in lung adenocarcinomas and inhibits phosphorylation of the myosin regulatory light chain (RLC) of non-muscle myosin IIA (NM IIA) via direct interaction with Rho kinase 1 (ROCK1). Here, we report that MYBPH also directly interacts with an additional molecule, non-muscle myosin heavy chain IIA (NMHC IIA), which was found to occur between MYBPH and the rod portion of NMHC IIA. MYBPH inhibited NMHC IIA assembly and reduced cell motility. Conversely, siMYBPH-induced increased motility was partially, yet significantly, suppressed by blebbistatin, a non-muscle myosin II inhibitor, while more profound effects were attained by combined treatment with siROCK1 and blebbistatin. Electron microscopy observations showed well-ordered paracrystals of NMHC IIA reflecting an assembled state, which were significantly less frequently observed in the presence of MYBPH. Furthermore, an in vitro sedimentation assay showed that a greater amount of NMHC IIA was in an unassembled state in the presence of MYBPH. Interestingly, treatment with a ROCK inhibitor that impairs transition of NM IIA from an assembly-incompetent to assembly-competent state reduced the interaction between MYBPH and NMHC IIA, suggesting that MYBPH has higher affinity to assembly-competent NM IIA. These results suggest that MYBPH inhibits RLC and NMHC IIA, independent components of NM IIA, and negatively regulates actomyosin organization at 2 distinct steps, resulting in firm inhibition of NM IIA assembly.