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Concurrent chemoradiotherapy (CCRT) is one of the most promising treatments for advanced head and neck cancer (HNC). On the other hand, CCRT may induce severe edema in laryngo-pharyngeal structures in association with radiation. This is a report of a 66-year-old man with severe obstructive sleep apnea (OSA) associated with edema in laryngo-hypopharynx after CCRT for advanced laryngeal and hypopharyngeal cancer. Tracheostomy was avoided and OSA was controlled by continuous positive airway pressure (CPAP). Subjective symptoms of sleepiness were improved. Though laryngeal edema appeared during the course of CCRT in this case, OSA was not evaluated until snoring had been pointed out and he complained of sleepiness. CCRT for laryngeal and hypopharyngeal cancer have a risk of occurrence of OSA due to irreversible mucous edema in the upper airway. Patients for whom CCRT is planned should be informed about the occurrence of OSA before the treatment because symptoms associated with OSA can negatively impact not only the daytime quality of life but also increase the risk of cardiovascular events. The OSA treatment for post CCRT would be expected to have a positive impact on not only cardiovascular and metabolic systems but also on the cancer treatment survival rate.

Mutations in RAS or BRAF are associated with poor prognosis and resistance to epidermal growth factor receptor (EGFR)-targeted therapy in colorectal cancer (CRC). Despite their common ability to activate downstream genes such as MEK and ERK, the therapeutic benefit of MEK inhibitors for patients with RAS/BRAF mutant CRC is limited, highlighting the need for biomarkers to predict the efficacy of MEK inhibition. Previously, we reported that a change in phosphorylation of ribosomal protein S6 (pS6) after MEK inhibition was significantly associated with sensitivity to MEK inhibition in gastric cancer cells. Here, we investigated the value of the response in pS6 for predicting the efficacy of trametinib, a MEK inhibitor, in patients with RAS/BRAF mutant CRC using patient-derived CRC organoids. We found that a subset of CRC cell lines and organoids were sensitive to trametinib. The change in phosphorylated ERK, a downstream molecule of the RAS/RAF/MEK pathway, was not significantly associated with trametinib sensitivity. On the other hand, only those with sensitivity showed a reduction of pS6 levels in response to trametinib. The change in pS6 after trametinib treatment was detectable by Western blotting, immunohistochemistry or immunocytochemistry. We also demonstrated an impact of MEK inhibition on pS6 in vivo using a xenograft model. Our data suggest that, in combination with patient-derived organoids, immunostaining-based detection of pS6 could be useful for prediction of trametinib sensitivity.

Background Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous deletion or intragenic mutation of the SMN1 gene. It is well-known that high copy number of its homologous gene, SMN2, modifies the phenotype of SMN1-deleted patients. However, in the patients with intragenic SMN1 mutation, the relationship between phenotype and SMN2 copy number remains unclear. Methods We have analyzed a total of 515 Japanese patients with SMA-like symptoms (delayed developmental milestones, respiratory failures, muscle weakness etc.) from 1996 to 2019. SMN1 and SMN2 copy numbers were determined by quantitative polymerase chain reaction (PCR) method and/or multiplex ligation-dependent probe amplification (MLPA) method. Intragenic SMN1 mutations were identified through DNA and RNA analysis of the fresh blood samples. Results A total of 241 patients were diagnosed as having SMA. The majority of SMA patients showed complete loss of SMN1 (n = 228, 95%), but some patients retained SMN1 and carried an intragenic mutation in the retaining SMN1 (n = 13, 5%). Ten different mutations were identified in these 13 patients, consisting of missense, nonsense, frameshift and splicing defect-causing mutations. The ten mutations were c.275G > C (p.Trp92Ser), c.819_820insT (p.Thr274Tyrfs*32), c.830A > G (p.Tyr277Cys), c.5C > T (p.Ala2Val), c.826 T > C (p.Tyr276His), c.79C > T (p.Gln27*), c.188C > A (p.Ser63*), c.422 T > C (p.Leu141Pro), c.835-2A > G (exon 7 skipping) and c.835-3C > A (exon 7 skipping). It should be noted here that some patients with milder phenotype carried only a single SMN2 copy (n = 3), while other patients with severe phenotype carried 3 SMN2 copies (n = 4). Conclusion Intragenic mutations in SMN1 may contribute more significantly to clinical severity than SMN2 copy numbers.

Background Restless legs syndrome (RLS) is a neurological disorder characterized by leg restlessness and dysesthesia. Although the relationship between RLS and heart failure (HF) has been reported, the prevalence and clinical significance of RLS in patients with HF remain to be elucidated. Methods and Results We enrolled consecutive patients with HF who were admitted to our institutions. RLS was diagnosed using the International Restless Legs Syndrome Study Group criteria. Subjective sleepiness, sleep quality, and quality of life (QoL) were assessed using the Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and 8-item Short Form (SF-8), respectively. Among the 133 patients, 18 (13.6%) had RLS and were younger than those without RLS (62.4±13.4 vs 70.0±12.2, P = .017). The RLS group had significantly disrupted sleep quality and QoL, with greater PSQI score (8.0±3.2 vs 5.9±3.3, P = .015) and lower SF-8 physical component summary (PCS) score (35.6±6.5 vs 40.7±9.5, P = .031), despite similar ESS and SF-8 mental component summary scores. In the multivariable regression analysis, RLS was associated with greater PSQI (β=0.211; P = .014) and lower PCS score (β=−0.177; P = .045). Conclusion In the patients with HF, RLS was prevalent, and sleep quality and QoL may be disrupted by RLS.

Other than genetically engineered mice, few reliable platforms are available for the study of hematopoietic stem cell (HSC) quiescence. Here we present a platform to analyze HSC cell cycle quiescence by combining culture conditions that maintain quiescence with a CRISPR-Cas9 genome editing system optimized for HSCs. We demonstrate that preculture of HSCs enhances editing efficiency by facilitating nuclear transport of ribonucleoprotein complexes. For post-editing culture, mouse and human HSCs edited based on non-homologous end joining and cultured under low-cytokine, low-oxygen, and high-albumin conditions retain their phenotypes and quiescence better than those cultured under the proliferative conditions. Using this approach, HSCs regain quiescence even after editing by homology-directed repair. Our results show that low-cytokine culture conditions for gene-edited HSCs are a useful approach for investigating HSC quiescence

Constipation in children can be classified as transient or chronic and as functional or organic. Although most pediatric constipation is functional, organic constipation may be masked by a chronic course. We encountered a case of chronic constipation refractory to treatment with rectal fixation and subsequently diagnosed it as organic constipation.A 14-year-old boy experienced chronic constipation since 8 years of age, and used to attempt defecation for more than 1 h at a time. The symptoms did not improve with conservative treatment such as medications. Rectal contrast revealed that the rectum was flexed ventrally and separated from the sacrum, with dilatation of the intestine on the oral side. He was diagnosed with organic constipation due to insufficient fixation of the rectum to the sacrum, and underwent laparoscopic rectal fixation. Postoperative rectal contrast revealed that the rectum had traveled along the curved surface of the sacrum. Defecation remarkably improved after the surgery.In this case, chronic organic constipation occurred due to insufficient fixation of the rectum to the sacrum, and could be resolved by rectal fixation. We should recognize insufficient fixation of the rectum to the sacrum as one of the causes of chronic constipation, and treat childhood chronic constipation accordingly.

This study examines households’ immediate responses to the potential for tsunami generated by 2011 earthquakes in New Zealand and Japan. Surveys conducted in Christchurch, New Zealand and Hitachi, Japan investigated pre-impact tsunami hazard communication, immediate post-impact expectations that these earthquakes would cause tsunamis, the information sources that respondents used after the shaking stopped, and household evacuation in anticipation of a tsunami. The results reveal some similar patterns as well as some significant differences in the ways that households in the two cities reacted to the tsunami threat. The results show that both cities had very low levels of pre-impact tsunami hazard communication and, possibly as a result, about half of the respondents significantly underestimated tsunami arrival times. Moreover, face-to-face conversation and telephone were the most important sources of disaster information in both communities after the shaking stopped. However, Hitachi households had a higher level of tsunami risk perception, expected sooner tsunami arrival times, and were more likely to evacuate than Christchurch households. Regression analyses indicate that risk perception was the only significant predictor of evacuation and Hitachi location, which was probably a proxy for shaking duration, was the only significant predictor of risk perception. However, these regression equations accounted for little variance, so further research is needed to better understand the tsunami evacuation process.

Monospermic fertilization in the frog, Xenopus laevis, is ensured by a fast-rising, positive fertilization potential to prevent polyspermy on the fertilized egg, followed by a slow block with the formation of a fertilization envelope over the egg surface. In this paper, we found that not only the enzymatic activity of sperm matrix metalloproteinase-2 (MMP-2) was necessary for a sperm to bind and/or pass through the extracellular coat of vitelline envelope, but also the hemopexin (HPX) domain of MMP-2 on the sperm surface was involved in binding and membrane fusion between the sperm and eggs. A peptide with a partial amino acid sequence of the HPX domain caused egg activation accompanied by an increase in [Ca(2+)]i in a voltage-dependent manner, similar to that in fertilization. The membrane microdomain (MD) of unfertilized eggs bound the HPX peptide, and this was inhibited by ganglioside GM1 distributed in the MD. The treatment of sperm with GM1 or anti-MMP-2 HPX antibody allows the sperm to fertilize an egg clamped at 0 mV, which untreated sperm cannot achieve. We propose a model accounting for the mechanism of voltage-dependent fertilization based on an interaction between the positively charged HPX domain in the sperm membrane and negatively-charged GM1 in the egg plasma membrane.

Introduction/Background When an evaluation focuses on movement, there is little chance of error by oversight, even by an inexperienced therapist. This study aimed to clarify relationship between the medial longitudinal arch (MLA), foot dorsiflexion range of motion (DF), and the dynamic gait parameters. Material and method This study evaluated 20 participants (16 males, 4 females; mean age 21.2 ± 0.4 years). MLA was measured using the navicular drop test (ND) developed by Brody. DF was measured with the knee in extension. Dynamic data were collected with a 9-camera, motion capture system with 3 force plates. The participants performed barefoot gait five times. The gait parameters were navicular height, DF, dynamic navicular drop, ankle moment peak value in stance phase (AMP), and maximum dorsiflexion range of motion, with the ankle moment value and DF measured at 12%, 31%, and 50% of the gait cycle, respectively. These gait parameters were compared using coefficients of correlation for ND and DF. For statistical analysis, we used Pearson's correlation coefficient using the IBM SPSS statistical software (version 21), and P Results ND did not show a relationship with any gait parameters. However, DF showed a negative correlation with ankle moment at 50% (P = 0.003, r = −0.623) and AMP (P = 0.008, r = −0.574) Conclusion These findings show that DF is more important than ND in gait assessment. In the terminal stance, when DF is limited, the ankle moment shows a higher value. When DF is larger, this is reversed. Eccentric contraction using stretch-reflection was observed in the terminal stance phase. In our opinion, a reflective factor strongly influences gait movement. Thus, evaluation of DF before gait assessment is essential.

The development of automated detection systems for animal behaviors is increasing in value in terms of saving time, objective analysis and reducing the need for well-trained experimenters. SCLABA(®) (Noveltec Inc., Kobe, Japan) is a commercially available analysis system originally developed for analyzing scratching behaviors in rodents, based on distances between points in videotaped images. Here, we used this software to automate analysis of abdominal licking behavior associated with visceral pain in mice.Yellow and green spots were applied to the snout and the lower abdominal region of mice respectively to provide reference points for automated analysis of video recordings. Abdominal licking behavior after intracolonic administration of 0.3% capsaicin solution as a measure of visceral pain was determined based on changes in the inter-spot distance.A distance threshold between the colored spots was chosen based on manual measurements showing that 99% of minimal distances were below this threshold. Using this threshold, the number of licks determined by the automated analysis significantly and positively correlated with that determined by manual observation (R(2)=0.95 and p0.001). The neurokinin-1 receptor antagonist GR205171A dose-dependently inhibited capsaicin-induced licking detected by automated analysis.We demonstrated that visceral pain-related licking behaviors after intracolonic capsaicin treatment can be automatically detected by applying commercially available image analysis software. This automated experimental system is very efficient and useful to evaluate antinociceptive effect of a test compound on visceral pain.

Background Cancer is a major cause of death in patients undergoing haemodialysis. However, information about the actual clinical practice of chemotherapy for patients with cancer undergoing haemodialysis is lacking. We conducted a nationwide survey using questionnaires on the clinical practice of chemotherapy for such patients. Patients and methods The nationwide survey included patients undergoing haemodialysis who were subsequently diagnosed with cancer in 20 hospitals in Japan from January 2010 to December 2012. We reviewed their clinical data, including cancer at the following primary sites: kidney, colorectum, stomach, lung, liver, bladder, pancreas and breast. The questionnaires consisted of the following subjects: (1) patient characteristics; (2) regimen, dosage and timing of chemotherapy; and (3) clinical outcome. Results Overall, 675 patients were registered and assessed for main primary cancer site involvement. Of 507 patients with primary site involvement, 74 patients (15%) received chemotherapy (44 as palliative chemotherapy and 30 as perioperative chemotherapy). The most commonly used cytotoxic drugs were fluoropyrimidine (15 patients), platinum (8 patients) and taxane (8 patients), and the dosage and timing of these drugs differed between institutions; however, the dosage of molecular targeted drugs (24 patients) and hormone therapy drugs (15 patients) was consistent. The median survival time of patients receiving palliative chemotherapy was 13.0 months (0.1–60.3 months). Three patients (6.8%) died from treatment-related causes and nine patients (20%) died of causes other than cancer. Of the 30 patients who received perioperative chemotherapy, 6 (20%) died of causes other than cancer within 3 years after the initiation of chemotherapy. Conclusion Among the haemodialysis patients with cancer who received chemotherapy, the rates of mortality from causes other than cancer might be high for both palliative and perioperative chemotherapy. Indications for the use of chemotherapy in patients undergoing haemodialysis should be considered carefully.