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In cases of radiological accidents, especially for victims exposed to high-dose total-body irradiation (TBI), the administration of appropriate approved hematopoietic drugs is the most rapid medical treatment for preventing severe acute radiation syndrome, which is associated with a high mortality rate. However, at present, there are few suitable pharmaceutical drugs available in Japan, aside from granulocyte colony-stimulating factor (G-CSF). Depending on the situation surrounding the accident, various drug treatment options and the development of effective drug therapies may be required. In the present study, we assessed various combinations of seven commercially available drugs-G-CSF, erythropoietin (EPO), romiplostim (RP), ancer (AN), cepharanthine (CE), leucon (LC) and leukoprol (LP)-in mice exposed to a lethal dose of 7 or 8 Gy of X-ray irradiation. Each drug was administered as a single or mixed intraperitoneal injection once or twice daily for three consecutive days. The single administration of the approved hematopoietic drugs CE, LC, or LP twice a day for 3 days significantly improved the 30-day survival rate of lethal TBI mice (p less than 0.05; 75%, 100%, or 100%, respectively) compared with the untreated TBI mice, accompanied by a gradual increase in the body weight. Furthermore, the combined administration of RP, EPO and G-CSF or single administration of RP alone gradually increased the body weight of mice exposed to lethal TBI, with 30-day survival rates of 75% or 100%, respectively (p less than 0.05). This study suggested that some new domestically approved hematopoietic drugs may have radiomitigative potential for mice exposed to lethal TBI, and the 12-h interval administration of LC or LP for 3 days to 7-Gy-TBI mice and 12-h interval administration of RP alone for 3 days to 8-Gy-TBI mice were the most suitable medications with respect to the 30-day survival rate. As long as the threat of nuclear disaster exists, diverse efforts in thefield of radiation emergency medicine, including the development of effective drug therapies, will be necessary.

Immune effector cell-associated neurotoxicity syndrome usually occurs within the first four weeks of chimeric antigen receptor (CAR)-T cell therapy. In addition, prolonged cytopenia is a long-term adverse effect following the use of CAR T-cell therapies. Here, we present a case of prolonged severe cytopenia followed by fatal CAR T-cell-mediated encephalitis. A 22-year-old male patient was referred to our hospital for a second relapse of B-cell precursor acute lymphoblastic leukemia (ALL), which was diagnosed 22 months after hematopoietic stem cell transplantation from an unrelated donor. CAR T-cells (tisagenlecleucel) were infused during the third cycle of complete remission after chemotherapy. The patient developed grade 2 cytokine release syndrome requiring a single dose of tocilizumab. Cytopenia was profound from day 30 onward, but no other serious complications were observed. On day 50, the patient developed sensory impairment, disturbing behavior, and confusion. Brain magnetic resonance imaging (MRI) scan and cerebrospinal fluid (CSF) analysis revealed no pathological findings. Severe neutropenia persisted despite G-CSF treatment, and the patient's neurological symptoms rapidly progressed from day 65. Brain MRI revealed hydrocephalus. The CSF showed elevated xanthochromia, mononuclear cell counts, and protein levels. A therapeutic attempt with prednisolone for encephalitis was ineffective, and the patient died on day 77 owing to neurological toxicity. Late-onset CAR T-cell-mediated encephalitis was suspected, although the CSF was not assessed for CAR T-cells. In addition, the patient developed prolonged and severe cytopenia. To the best of our knowledge, this is the first report of prolonged severe cytopenia followed by late-onset CAR T-cell-mediated encephalitis. These unexpected long-term adverse effects may occur and should also be considered., Competing Interests: The authors declare no conflict of interest. Disclosure forms provided by the authors are available on the website., (Copyright Ⓒ2024 Asia-Pacific Blood and Marrow Transplantation Group (APBMT).)

The prognosis of patients with osteosarcoma who experience recurrence or progression (R/P) is extremely poor, and more effective and less toxic therapies are needed. In the current study, the clinical data of osteosarcoma patients who experienced R/P were retrospectively analyzed to verify the reliability of O-6-methylguanine-DNA methyltransferase (MGMT) protein expression or MGMT promoter methylation for predicting the response to off-label temozolomide (TMZ)-containing chemotherapy. Of the 30 evaluable patients, 9 (30%) showed no/low MGMT protein expression, whereas all 16 evaluable patients had unmethylated MGMT promoter irrespective of MGMT protein expression levels. Twenty-three patients received TMZ-containing chemotherapy for measurable lesions (n = 14) or as adjuvant therapy following resection of recurrent lesions (n = 9). Among 14 patients with radiologically measurable lesions, the objective response rate was higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group with borderline significance (0%, p = 0.066). The 6-month progression-free survival (PFS) rate in patients with radiologically measurable lesions was significantly higher in the MGMT no/low-expression group (50.0%) than in the MGMT intermediate/high-expression group (0%, p = 0.036). In the multivariate analysis of the 23 patients receiving TMZ-containing chemotherapy, MGMT expression and disease status before TMZ-containing chemotherapy were significantly associated with PFS. No severe adverse effects were observed during TMZ-containing chemotherapy. MGMT protein expression, but not MGMT promoter methylation, could predict a favorable outcome in patients receiving TMZ-containing chemotherapy., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

[Purpose] In Japan, one measure against the novel coronavirus disease-2019 infection involves the public use of surgical masks. Research indicates that exercising while wearing a mask increases the physical burden, particularly affecting young people during high-intensity exercise. This study examined the effects of wearing masks while running in male university students. [Participants and Methods] The participants were 20 healthy male university students (21.6 ± 1.6 years). The participants underwent cardiopulmonary exercise tests with the masks on and off on different days until exhaustion. The following parameters were measured: exercise duration, Borg Scale rating (respiratory or lower extremities), surface temperature around the mouth, time to sweat onset, metabolic reaction, pulmonary ventilation, and cardiovascular reaction parameters. [Results] The results showed that VO 2 max remained consistent between the mask-on and mask-off conditions. However, minute ventilation, respiratory rate, and heart rate decreased in the mask-on condition, which correlated with a reduction in exercise duration. Furthermore, running with the mask significantly decreased the VE/VO 2 , VE/ VO 2 , Borg Scale rating of the lower extremities, and the time to sweat onset. [Conclusion] Running with a surgical mask affected respiratory function and decreased exercise duration in healthy male university students. However, it did not induce any changes in VO 2 max., Competing Interests: The authors declare no conflict of interest., (2024©by the Society of Physical Therapy Science. Published by IPEC Inc.)

Introduction: The current study investigated the relationship between the characteristics of a darts game, including the throwing motion toward a target, and mild cognitive impairment (MCI). To this end, we examined the associations between cognitive function and mental health, and the shift in center of gravity while throwing darts. In a preliminary investigation, a 1-month dart game intervention was conducted among older individuals living in the community. The participants were divided into the non-MCI and MCI groups, and the relationship between center of gravity movement during throwing and the presence of dementia was examined., Methods: The intervention lasted for 1 month and was tested on healthy older individuals (aged ≥ 65 years) recruited from the community. The Japanese version of the Montreal Cognitive Assessment and the Trail Making Test was used to assess cognitive function. Mental health was evaluated using the Kessler Psychological Distress Scale and the Subjective Well-being Inventory. The center of pressure was analyzed to determine the center of gravity shift during dart throwing., Results: The analysis of factors influencing the determination of the MCI score during the intervention revealed a tendency for the center of gravity shift to be associated as a protective factor in the non-MCI group, although this association did not reach statistical significance (odds ratio = 0.942, p  = 0.084). In the MCI group, a significant effect of age was observed in the MCI score (odds ratio = 1.539, p  = 0.007)., Conclusion: The current findings suggest that conducting center of gravity shift testing could potentially provide a helpful tool for predicting early decline in cognitive function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kawabata, Iida, Kunishige, Fukuda, Miyaguchi and Harada.)

Importance: Recent evidence indicates the efficacy of β-amyloid immunotherapy for the treatment of Alzheimer disease, highlighting the need to promote β-amyloid removal from the brain. Cilostazol, a selective type 3 phosphodiesterase inhibitor, promotes such clearance by facilitating intramural periarterial drainage., Objective: To determine the safety and efficacy of cilostazol in mild cognitive impairment., Design, Setting, and Participants: The COMCID trial (A Trial of Cilostazol for Prevention of Conversion from Mild Cognitive Impairment to Dementia) was an investigator-initiated, double-blind, phase 2 randomized clinical trial. Adult participants were registered between May 25, 2015, and March 31, 2018, and received placebo or cilostazol for up to 96 weeks. Participants were treated in the National Cerebral and Cardiovascular Center and 14 other regional core hospitals in Japan. Patients with mild cognitive impairment with Mini-Mental State Examination (MMSE) scores of 22 to 28 points (on a scale of 0 to 30, with lower scores indicating greater cognitive impairment) and Clinical Dementia Rating scores of 0.5 points (on a scale of 0, 0.5, 1, 2, and 3, with higher scores indicating more severe dementia) were enrolled. The data were analyzed from May 1, 2020, to December 1, 2020., Interventions: The participants were treated with placebo, 1 tablet twice daily, or cilostazol, 50 mg twice daily, for up to 96 weeks., Main Outcomes and Measures: The primary end point was the change in the total MMSE score from baseline to the final observation. Safety analyses included all adverse events., Results: The full analysis set included 159 patients (66 [41.5%] male; mean [SD] age, 75.6 [5.2] years) who received placebo or cilostazol at least once. There was no statistically significant difference between the placebo and cilostazol groups for the primary outcome. The least-squares mean (SE) changes in the MMSE scores among patients receiving placebo were -0.1 (0.3) at the 24-week visit, -0.8 (0.3) at 48 weeks, -1.2 (0.4) at 72 weeks, and -1.3 (0.4) at 96 weeks. Among those receiving cilostazol, the least-squares mean (SE) changes in MMSE scores were -0.6 (0.3) at 24 weeks, -1.0 (0.3) at 48 weeks, -1.1 (0.4) at 72 weeks, and -1.8 (0.4) at 96 weeks. Two patients (2.5%) in the placebo group and 3 patients (3.8%) in the cilostazol group withdrew owing to adverse effects. There was 1 case of subdural hematoma in the cilostazol group, which may have been related to the cilostazol treatment; the patient was successfully treated surgically., Conclusions and Relevance: In this randomized clinical trial, cilostazol was well tolerated, although it did not prevent cognitive decline. The efficacy of cilostazol should be tested in future trials., Trial Registration: ClinicalTrials.gov Identifier: NCT02491268.

Aims/introduction: It remains to be fully elucidated whether nutrition education by dietitians can lead to specific positive changes in the food choices of patients with diabetes., Materials and Methods: A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit and the control group that received nutritional education once a year. The total energy intake, energy-providing nutrients and 18 food groups were analyzed at baseline, and 1 and 2 years after the intervention in 87 patients. Furthermore, the relationship between the changes in hemoglobin A1c, body composition and changes in the total energy or energy-producing nutrient intake was analyzed in 48 patients who did not use or change hypoglycemic agents during the study period., Results: The total energy intake, carbohydrates, cereals, confections, nuts and seeds, and seasonings significantly decreased, and fish and shellfish intake significantly increased during the study period in the intensive intervention group, whereas these changes were not observed in the control group. The decrease in the total energy intake and carbohydrates after 2 years was significantly greater in the intensive intervention group than in the control group. The change in the total energy and carbohydrate intake showed a significant positive correlation with that in muscle mass. The multivariate analysis showed that the decrease in total energy intake was independently associated with that in muscle mass., Conclusion: Dietitian-supported intensive dietary intervention helps improve the diet of patients with type 2 diabetes., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Aims/introduction: This randomized controlled trial aimed to determine whether frequent nutritional education improves the clinical parameters associated with the onset and progression of diabetic kidney disease in type 2 diabetes mellitus patients., Materials and Methods: A total of 96 patients with type 2 diabetes and diabetic kidney disease were randomly assigned to the intensive intervention group that received nutritional education at every outpatient visit, and the usual intervention group that received nutritional education once a year. The anthropometric parameters, blood pressure, blood chemistry, albuminuria, protein and salt intake, and prescribed medications of 87 patients who completed the 2-year follow up were analyzed., Results: In the intensive intervention group, body mass index and salt intake significantly decreased over the study period. Hemoglobin A1c levels and body fat percentage were significantly lower in the intensive intervention group than in the usual intervention group. At the end of the 2-year intervention period, the intensive intervention group had significantly lower salt intake (8.1 vs 9.4 g/day) than the usual intervention group. A significant positive correlation was found between salt intake and albuminuria in the overall group and intensive intervention group (r = 0.26, P = 0.02, and r = 0.36, P = 0.02, respectively). The intensive intervention group had a significantly lower insulin use rate than the usual intervention group after the 2-year intervention period (18% vs 42%). No differences were found in estimated glomerular filtration rate and albuminuria., Conclusion: Intensive nutritional education is useful for alleviating the risk factors associated with the onset and progression of diabetic kidney disease., (© 2021 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Background: Current consensus recognizes the benefits of early intervention in palliative care consultation teams (PCCTs). As consultants, we should now attempt to improve the quality of our teams by utilizing a method mainly used in the business field. We aimed to investigate the effects of iterative evaluation of customer satisfaction surveys, filled by physicians and ward nurses in this study, for quality improvement of PCCTs., Methods: In October 2019, the participants filled the first questionnaire survey about palliative care and PCCTs at a 678-bed hospital, and improvement areas were uncovered. Refinements were planned and implemented, and then reevaluated using the second questionnaire survey in March 2020., Results: In addition to the characteristics of our clients evaluated from approximately 500 valid responses, the first survey showed that the response rate of the questionnaire, knowledge of palliative care and PCCTs, and publicity of the PCCT were recognized as issues needing attention. We planned to contrive ways to collect questionnaires, hold monthly workshops for palliative care, launch newsletters of palliative care, and go on client rounds. The second survey revealed improvements in the physicians' response rate (p = 0.02), the accuracy rate of application of PCCTs in Japan (p < 0.01), and ward nurses' confidence in opioid use (p = 0.04) and tendency toward easier accessibility to the PCCT (p = 0.07)., Conclusion: Continual quality improvements through iterative, customer satisfaction survey-driven evaluation are a widely established practice in the business field. By using this appropriately, we could enable PCCTs to improve their quality.

Introduction. Resistance against macrolide antibiotics in Mycoplasma pneumoniae is becoming non-negligible in terms of both appropriate therapy and diagnostic stewardship. Molecular methods have attractive features for the identification of Mycoplasma pneumoniae as well as its resistance-associated mutations of 23S ribosomal RNA (rRNA). Hypothesis/Gap Statement. The automated molecular diagnostic sytem can identify macrolide-resistant M. pneumoniae . Aim. To assess the performance of an automated molecular diagnostic system, GENECUBE Mycoplasma, in the detection of macrolide resistance-associated mutations. Methodology. To evaluate whether the system can distinguish mutant from wild-type 23S rRNA, synthetic oligonucleotides mimicking known mutations (high-level macrolide resistance, mutation in positions 2063 and 2064; low-level macrolide resistance, mutation in position 2067) were assayed. To evaluate clinical oropharyngeal samples, purified nucleic acids were obtained from M. pneumoniae -positive samples by using the GENECUBE system from nine hospitals. After confirmation by re-evaluation of M. pneumoniae positivity, Sanger-based sequencing of 23S rRNA and mutant typing using GENECUBE Mycoplasma were performed. Results. The system reproducibly identified all synthetic oligonucleotides associated with high-level macrolide resistance. Detection errors were only observed for A2067G (in 2 of the 10 measurements). The point mutation in 23S rRNA was detected in 67 (26.9 %) of 249 confirmed M. pneumoniae -positive clinical samples. The mutations at positions 2063, 2064 and 2617 were observed in 65 (97.0 %), 2 (3.0 %) and 0 (0.0 %) of the 67 samples, respectively. The mutations at positions 2063 and 2064 were A2063G and A2064G, respectively. The results from mutant typing using GENECUBE Mycoplasma were in full agreement with the results from sequence-based typing. Conclusion. GENECUBE Mycoplasma is a reliable test for the identification of clinically significant macrolide-resistant M. pneumoniae .

Recently, a new rapid assay for the detection of tcdB gene of Clostridioides difficile was developed using the GENECUBE. The assay can directly detect the tcdB gene from stool samples without a purification in approximately 35 minutes with a few minutes of preparation process. We performed a prospective comparative study of the performance of the assay at eight institutions in Japan. Fresh residual stool samples (Bristol stool scale ≥5) were used and comparisons were performed with the BD MAX Cdiff assay and toxigenic cultures. For the evaluation of 383 stool samples compared with the BD MAX Cdiff assay, the sensitivity, and specificity of the two assays was 99.0% (379/383), 98.1% (52/53), 99.1% (327/330), respectively. In the comparison with toxigenic culture, the total, sensitivity, and specificity were 96.6% (370/383), 85.0% (51/60), and 98.8% (319/323), respectively. The current investigation indicated the GENECUBE Clostridioides difficile assay has equivalent performance with the BD MAX Cdiff assay for the detection of tcdB gene of C. difficile., Competing Interests: This study was financially supported by TOYOBO Co., Ltd. The GENECUBE assay and the fee for the BD MAX assay were provided by TOYOBO Co., Ltd. Yosuke Kawashima, and Akio Sugiyama are employees of TOYOBO Co., Ltd. Shigeyuki Notake received a lecture fee from TOYOBO Co., Ltd. Hiromichi Suzuki received a lecture fee and advisory fee from TOYOBO Co., Ltd. This study was concurrently performed with the clinical evaluation of the rapid membrane enzyme immunoassay (C. DIFF QUIK CHEK, Abbott Japan Co., Ltd.), and St. Marianna University School of Medicine and Tsukuba Medical Center Hospital received fees for experiments and research expenses for the quality evaluation of the C. DIFF QUIK CHEK. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Context: There is little evidence of the effectiveness of aromatherapy massage in palliative care despite its popularity., Objectives: This study aimed to investigate the effects of a 30-minute single session of aromatherapy massage at night time on quality of sleep and fatigue in palliative care., Methods: A randomized controlled trial from January 2018 to March 2019. After being stratified by sex, participants were randomly assigned to an aromatherapy massage group and a control group. The effects of aromatherapy massage were evaluated on the massage day and the next day using the Richards-Campbell Sleep Questionnaire and the Brief Fatigue Inventory., Results: Of the 74 participants, data of 27 participants in the treatment group and 30 participants in the control group were analyzed. Analysis of covariance indicated that quality of sleep and fatigue did not improve owing to the aromatherapy massage, although usual fatigue in preceding 24 hours and enjoyment of life subscales of the Brief Fatigue Inventory showed signs of contribution (P = 0.07 and 0.09, respectively). Post hoc analyses indicated that higher age and performance status were factors with moderate correlation with better sleep (P = 0.03; r = 0.45 and P = 0.03; r = 0.40, respectively), and that older patients tended to experience greater improvement in fatigue (P = 0.02; r = -0.47)., Conclusion: A single aromatherapy massage session is no more effective than not having a massage in improving sleep quality in palliative care settings. However, older patients and those in poor health conditions may benefit from aromatherapy massage., (Copyright © 2020 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.)

Ionizing radiation induces severe oxidative stress, resulting in individual death by acute radiation syndrome. The nuclear factor-erythroid-2-related factor 2 (Nrf2) plays an important role in the antioxidant response pathway. Recently, romiplostim (RP), an idiopathic thrombocytopenic purpura therapeutic drug, was reported to completely rescue mice exposed to lethal total-body irradiation (TBI). However, the details underlying the mechanism for reducing radiation damage remain largely unknown. To elucidate the involvement of the master redox regulator Nrf2 in the radio-mitigative efficacy of RP on TBI-induced oxidative stress, expression of Nrf2 target genes in hematopoietic tissues such as bone marrow, spleen, and lung from mice treated with RP for three consecutive days after 7 Gy of X-ray TBI was analyzed. RP promoted the recovery of bone marrow cells from day 10 and the significant up-regulation of reduced nicotinamide adenine dinucleotide phosphate (NAD(P)H) dehydrogenase quinone 1 (Nqo1), glutamate-cysteine ligase catalytic subunit (Gclc) and glutamate-cysteine ligase modifier subunit (Gclm) was observed compared to the TBI mice. RP also promoted the recovery of splenic cells on day 18, and the significant up-regulation of Nqo1, Gclc and Gclm in spleen both on day 10 and 18 and Nqo1 and Gclm in lung on day 10 was observed compared to the TBI mice. The present study suggests that the radio-mitigative effects of RP indicates on the activation of Nrf2 target genes involved in redox regulation and the antioxidative function, especially Nqo1, Gclc and Gclm. It is indicating the importance of these genes in the maintenance of biological homeostasis in response to radiation-induced oxidative stress.

Objective: Driving ability in older people is affected by declining motor, cognitive and visual functions. We compared perceptual and cognitive skills and driving behaviour in a Japanese population., Methods: We used a driving simulator to measure the effects of spatial navigation skills and eye movements on driving ability. Participants were 34 older and 20 young adults who completed a simulated driving task involving a lane change and a right turn at an intersection. We used an eye tracker to measure gaze. We measured visual recognition (Benton Judgment of Line Orientation Test (BJLO)), spatial navigation (Card-Placing Test (CPT A & B)), visual perception (Raven's Colored Progressive Matrices (RCPM)) and driving ability (Stroke Drivers' Screening Assessment)., Results: Older participants scored significantly lower on the BJLO, CPT-A & B and RCPM, showed a significant correlation between gaze time and CPT-A & B scores (both p < .01) and had a longer gaze time. There were significant between-group differences in saccade switching (p < .01 right turn), distance per saccade (p < .05 for right turn and lane change) and saccade total distance (p < .05 right turn; p < .01 lane change). There was an association between age and rate of gaze at the right door mirror (p = 0.04)., Conclusion: The findings indicate that older drivers have poorer eye movement control and spatial navigation. This is likely to result in delayed responses and difficulties in predicting the on-coming driving environment. Driving simulation could help older drivers in their driving abilities.

Introduction: Patients with chronic kidney disease (CKD) depend on advice from healthcare professionals to avoid using unsuitable over-the-counter (OTC) drugs. Recently, qualified, registered nonpharmacist salespersons became licensed to sell OTC drugs in Japan. However, registered salespersons' knowledge and awareness of precautions regarding unsuitable OTC drugs for use in patients with CKD are unclear., Objectives: This study aimed to clarify the awareness, knowledge, and implementation of precautions by registered salespersons regarding OTC drugs used by patients with CKD. Additionally, we evaluated the change of registered salespersons' knowledge and awareness of this topic generated by a pharmacist intervention., Methods: A questionnaire survey and pharmacist intervention were applied to 175 registered salespersons. The intervention comprised a 50-minute lecture imparted by a pharmacist who was trained in nephrology. The knowledge, awareness, and implementation of precautions by participants with respect to nonsteroidal anti-inflammatory drugs (NSAIDs) and antacids were evaluated before and after the intervention., Results: Approximately half of the registered salespersons reported previous experience with selling OTC drugs that were inappropriate for patients with CKD (NSAIDs, 48.0%; antacids, 39.7%). Few participants recognized the need to check renal function when selling those drugs to such patients (NSAIDs, 25.7%; antacids, 47.5%). The registered salespersons' awareness and knowledge were significantly higher after the intervention than before it., Conclusion: The results indicate that before the intervention, the registered salespersons had low levels of awareness and knowledge regarding OTC drug use in patients with CKD despite having prior experience selling unsuitable OTC drugs. However, the pharmacist intervention improved the registered salespersons' awareness and knowledge. The educational program for registered salespersons might be necessary to prevent inappropriate OTC drug use by patients with CKD., Competing Interests: The authors have declared that no competing interests exist.

A 64-year-old woman with lymphoma-associated demyelinating neuropathy was treated by 6 cycles of R-CHOP with intravenous immunoglobulin in the first 2 cycles. We noted substantial improvement in the findings of a nerve conduction study (NCS) after the first cycle, followed by more protracted improvement during the second to sixth cycles. The improvement of the neurological symptoms paralleled the findings of the NCS. Our case provides important information for understanding the etiology and optimization of treatments for lymphoma-associated demyelinating neuropathy.

The extracellular signal-regulated kinase (ERK) is one of the principal hub proteins that transmit growth signals from upstream oncogene products including Ras and BRaf to downstream effector proteins. However, there are both reports supporting and refuting the increase in ERK activity in cancer tissues expressing the active Ras and BRaf proteins. We considered that the cell density might account for this discrepancy. To examine this possibility, we prepared Madin-Darby canine kidney (MDCK) cells that expressed an active HRas, NRas, KRas, or BRaf and an ERK biosensor based on the principle of Förster resonance energy transfer (FRET). As we anticipated, expression of the active Ras or BRaf increased ERK activity at low cell densities. However, the ERK activity was markedly suppressed at high cell densities irrespective of the expression of the active Ras or BRaf. Western blotting analysis with Phos-tag gel revealed the decrease of tyrosine and threonine-diphosphorylated active ERK and the increase of tyrosine-monophosphorylated inactive ERK at high cell density. In addition, we found that calyculin A, an inhibitor for PPP-subfamily protein serine/threonine phosphatases, decreased the tyrosine-monophosphorylated ERK. Our study suggests that PPP-subfamily phosphatases may be responsible for cell density-dependent ERK dephosphorylation in cancer cells expressing active Ras or BRaf protein., Competing Interests: The authors have declared that no competing interests exist.

Background: To effectively treat orthopaedic infections by methicillin-resistant strains, an early diagnosis is necessary. Bacterial cultures and real-time polymerase chain reaction (PCR) have been used to define methicillin-resistant staphylococci. However, even when patients display clinical signs of infections, bacterial culture and real-time PCR often cannot confirm infection. The aim of this study was to prospectively compare the utility of real-time PCR for the mecA gene detection following centrifugation of human samples with suspected orthopaedic infections., Results: In addition to the conventional real-time PCR method, we performed real-time PCR following centrifugation of the sample at 4,830×g for 10 min in a modified real-time PCR (M-PCR) method. We suspended cultured methicillin-resistant Staphylococcus aureus and generated standard dilution series for in vitro experiments. The in vitro detection sensitivity of the M-PCR method was approximately 5.06 times higher than that of the conventional real-time PCR method. We performed bacterial culture, pathological examination, real-time PCR, and M-PCR to examine the infectious fluids and tissues obtained from 36 surgical patients at our hospital. Of these, 20 patients who had undergone primary total hip arthroplasty were enrolled as negative controls. In addition, 15 patients were examined who were clinically confirmed to have an infection, including periprosthetic joint infection (eight patients), pyogenic spondylitis (two patients), infectious pseudoarthrosis (two patients), and after spine surgery (three patients). In one sample from a patient who developed infectious pseudoarthrosis and two samples from surgical site infections after spine surgery, the mecA gene was detected only by the M-PCR method. In one patient with infectious pseudoarthrosis, one patient with infection after arthroplasty, and two patients with purulent spondylitis, the detection sensitivity of the M-PCR method was increased compared with PCR (clinical sample average: 411.6 times)., Conclusions: These findings suggest that the M-PCR method is useful to detect methicillin-resistant strains infections. In addition, the centrifugation process only takes 10 min longer than conventional real-time PCR methods. We believe that the M-PCR method could be clinically useful to detect orthopaedic infections caused by methicillin-resistant strains.

The efficacy and safety of chemical prophylaxis to prevent the development of deep venous thrombosis (DVT) or pulmonary embolism (PE) following spine surgery are controversial because of the possibility of epidural hematoma formation. Postoperative venous thromboembolism (VTE) after spine surgery occurs at a frequency similar to that seen after joint operations, so it is important to identify the risk factors for VTE formation following spine surgery. We therefore retrospectively studied data from patients who had undergone spinal surgery and developed postoperative VTE to identify those risk factors. We conducted a retrospective clinical study with logistic regression analysis of a group of 80 patients who had undergone spine surgery at our institution from June 2012 to August 2013. All patients had been screened by ultrasonography for DVT in the lower extremities. Parameters of the patients with VTE were compared with those without VTE using the Mann-Whitney U-test and Fisher exact probability test. Logistic regression analysis was used to analyze the risk factors associated with VTE. A value of P < 0.05 was used to denote statistical significance. The prevalence of VTE was 25.0% (20/80 patients). One patient had sensed some incongruity in the chest area, but the vital signs of all patients were stable. VTEs had developed in the pulmonary artery in one patient, in the superficial femoral vein in one patient, in the popliteal vein in two patients, and in the soleal vein in 18 patients. The Mann-Whitney U-test and Fisher exact probability test showed that, except for preoperative walking disability, none of the parameters showed a significant difference between patients with and without VTE. Risk factors identified in the multivariate logistic regression analysis were preoperative walking disability and age. The prevalence of VTE after spine surgery was relatively high. The most important risk factor for developing postoperative VTE was preoperative walking disability. Gait training during the early postoperative period is required to prevent VTE.

Objective: The aim of our study was to investigate clinical and nutritional factors associated with renal involvement in patients with type 2 diabetes., Patients: We performed a cross-sectional study of 71 patients with type 2 diabetes who were being educated at our hospital from September 2006 to February 2008. The patients were divided into two groups; Group I consisted of 40 patients with both an estimated glomerular filtration rate (eGFR) of ≥ 60 mL/min/1.73 m(2) and normoalbuminuria, and Group II consisted of 31 patients with either microalbuminuria/overt proteinuria or an eGFR of <60 mL/min/1.73 m(2). We compared the age, body mass index (BMI), blood pressure, duration from onset of diabetes, use of hypoglycemic agents and insulin, biochemistry data, including HbA1c, pulse wave velocity corrected by blood pressure (PWVc) and the daily intake of several nutrients between the two groups. A multivariate logistic regression analysis was performed to identify factors independently associated with renal involvement., Results: Group II had significantly higher values for BMI, the duration of diabetes, triglycerides, uric acid and PWVc than Group I. Group II tended to have a high salt intake compared to Group I. The multivariate logistic analysis revealed that the daily salt intake, PWVc and uric acid were independent factors associated with renal involvement (odds ratio, 1.15, 1.84 and 2.00; 95% confidence interval, 1.02-1.31, 1.04-3.27 and 1.04-3.85, respectively)., Conclusion: Our data suggest that a high salt intake, in addition to arteriosclerosis, is associated with renal involvement in our cohort with type 2 diabetes.

Carmustine (BCNU) implants (Gliadel(®) Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

Carmustine (BCNU) implants (Gliadel ® Wafer, Eisai Inc., New Jersey, USA) for the treatment of malignant gliomas (MGs) were shown to enhance overall survival in comparison to placebo in controlled clinical trials in the United States and Europe. A prospective, multicenter phase I/II study involving Japanese patients with MGs was performed to evaluate the efficacy, safety, and pharmacokinetics of BCNU implants. The study enrolled 16 patients with newly diagnosed MGs and 8 patients with recurrent MGs. After the insertion of BCNU implants (8 sheets maximum, 61.6 mg BCNU) into the removal cavity, various chemotherapies (including temozolomide) and radiotherapies were applied. After placement, overall and progression-free survival rates and whole blood BCNU levels were evaluated. In patients with newly diagnosed MGs, the overall survival rates at 12 months and 24 months were 100.0% and 68.8%, and the progression-free survival rate at 12 months was 62.5%. In patients with recurrent MGs, the progression-free survival rate at 6 months was 37.5%. There were no grade 4 or higher adverse events noted due to BCNU implants, and grade 3 events were observed in 5 of 24 patients (20.8%). Whole blood BCNU levels reached a peak of 19.4 ng/mL approximately 3 hours after insertion, which was lower than 1/600 of the peak BCNU level recorded after intravenous injections. These levels decreased to less than the detection limit (2.00 ng/mL) after 24 hours. The results of this study involving Japanese patients are comparable to those of previous studies in the United States and Europe.

Partially fluorinated long-chain alcohols have been newly synthesized from a radical reaction, which is followed by a reductive reaction. The fluorinated alcohols have been investigated by differential scanning calorimetry (DSC) and compression isotherms in a Langmuir monolayer state. Their melting points increase with an increase in chain length due to elongation of methylene groups. However, the melting points for the alcohols containing shorter fluorinated moieties are lower than those for the typical hydrogenated fatty alcohols. Using the Langmuir monolayer technique, surface pressure (π)-molecular area (A) and surface potential (ΔV)-A isotherms of monolayers of the fluorinated alcohols have been measured in the temperature range from 281.2 to 303.2K. In addition, a compressibility modulus (Cs(-1)) is calculated from the π-A isotherms. Four kinds of the alcohol monolayers show a phase transition (π(eq)) from a disordered to an ordered state upon lateral compression. The π(eq) values increase linearly with increasing temperatures. A slope of π(eq) against temperature for the alcohols with shorter fluorocarbons is unexpectedly larger than that for the corresponding fatty alcohols. Generally, fluorinated amphiphiles have a greater thermal stability (or resistance), which is a characteristic of highly fluorinated or perfluorinated compounds. Herein, however, the alcohols containing perfluorobutylated and perfluorohexylated chains show the irregular thermal behavior in both the solid and monolayer states., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The Notch pathway regulates a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal development. In addition, the Notch pathway plays an important role in controlling tumorigenesis. However, the role of RBPJ, a transcription factor in the Notch pathway, in the development of tumors is largely unknown. In this study, we focused on the role of RBPJ in the pathogenesis of rhabdomyosarcoma (RMS). Our data showed that Notch pathway genes were upregulated and activated in human RMS cell lines and patient samples. Inhibition of the Notch pathway by a γ-secretase inhibitor (GSI) decreased the in vitro proliferation of RMS cells. Knockdown of RBPJ expression by RNAi inhibited the anchorage-independent growth of RMS cells and the growth of xenografts in vivo. Additionally, overexpression of RBPJ promoted the anchorage-independent growth of RMS cells. Further, we revealed that RBPJ regulated the cell cycle in RMS xenograft tumors and decreased proliferation. Our findings suggest that RBPJ regulates the RMS growth, and that the inhibition of RBPJ may be an effective therapeutic approach for patients with RMS.

In the fission yeast Schizosaccharomyces pombe, deletion of trt1(+) causes gradual telomere shortening, while deletion of pot1(+) causes rapid telomere loss. The double mutant between pot1 and RecQ helicase rqh1 is synthetically lethal. We found that the trt1 rqh1 double mutant was not synthetically lethal. The chromosome end fragments in both the trt1Δ rqh1Δ and the trt1Δ rqh1-hd (helicase dead) double mutants did not enter a pulsed-field electrophoresis gel. Both the trt1Δ rqh1Δ and the trt1Δ rqh1-hd double mutants were sensitive to the anti-microtubule drug thiabendazole. Moreover, the trt1Δ rqh1-hd double mutant displayed RPA foci on the chromosome bridge at high frequency in M phase cells. These phenotypes are very similar to that of the pot1Δ rqh1-hd double mutant, in which recombination intermediates accumulate at the chromosme ends in the M phase. These results suggest that the entangled chromosome ends, most likely recombination intermediates, are present in the M phase in the trt1Δ rqh1-hd double mutant.

Intracellular accumulation of altered proteins, including p62 and ubiquitinated proteins, is the basis of most neurodegenerative disorders. The relationship among the accumulation of altered proteins, autophagy, and spinal cord dysfunction by cervical spondylotic myelopathy has not been clarified. We examined the expression of p62 and autophagy markers in the chronically compressed spinal cord of tiptoe-walking Yoshimura mice. In addition, we examined the expression and roles of p62 and autophagy in hypoxic neuronal cells. Western blot analysis showed the accumulation of p62, ubiquitinated proteins, and microtubule-associated protein 1 light chain 3 (LC3), an autophagic marker, in the compressed spinal cord. Immunohistochemical examinations showed that p62 accumulated in neurons, axons, astrocytes, and oligodendrocytes. Electron microscopy showed the expression of autophagy markers, including autolysosomes and autophagic vesicles, in the compressed spinal cord. These findings suggest the presence of p62 and autophagy in the degenerated compressed spinal cord. Hypoxic stress increased the expression of p62, ubiquitinated proteins, and LC3-II in neuronal cells. In addition, LC3 turnover assay and GFP-LC3 cleavage assay showed that hypoxic stress increased autophagy flux in neuronal cells. These findings suggest that hypoxic stress induces accumulation of p62 and autophagy in neuronal cells. The forced expression of p62 decreased the number of neuronal cells under hypoxic stress. These findings suggest that p62 accumulation under hypoxic stress promotes neuronal cell death. Treatment with 3-methyladenine, an autophagy inhibitor decreased the number of neuronal cells, whereas lithium chloride, an autophagy inducer increased the number of cells under hypoxic stress. These findings suggest that autophagy promotes neuronal cell survival under hypoxic stress. Our findings suggest that pharmacological inducers of autophagy may be useful for treating cervical spondylotic myelopathy patients.