Single-legged landing behavior of high school basketball players with chronic ankle instability.

OBJECTIVES: Anterior cruciate ligament injury is one of the most serious ligamentous injuries. The purpose is to compare the impact of the ankle joint on the knee during landing between athletes with chronic instability and a control group (coper group) and to verify the effects of the kinetic chain from other joints. DESIGN: Prospective study. SETTING: High school basketball. PARTICIPANTS: Participants were 62 female high school basketball players who had participated in team sports for >6 months. MAIN OUTCOME MEASURES: Player joint angles, movements, and moments. RESULTS: The knee valgus moment was significantly higher in the chronic ankle instability group than in the coper group (20%-60% [p < 0.01]; 80%-100% [p < 0.05]) during landing motion. The knee valgus moment was also significantly higher during the change from the maximum knee joint flexion position to the maximum extension (p < 0.05). In addition, the landing motions of the chronic instability group may have utilized suboptimal compensatory motor strategy on the sagittal plane, depending heavily on the knee joint's abduction moment. CONCLUSIONS: Our findings indicate that the chronic ankle instability group uses a different landing strategy pattern than the coper group by changing the joint moment and joint angle during landing, which may increase the risk of anterior cruciate ligament injury.

Detailed Clinical Features of PTPRQ-Associated Hearing Loss Identified in a Large Japanese Hearing Loss Cohort.

The PTPRQ gene has been identified as one of the genes responsible for non-syndromic sensorineural hearing loss (SNHL), and assigned as DFNA73 and DFNB84. To date, about 30 causative PTPRQ variants have been reported to cause SNHL. However, the detailed clinical features of PTPRQ-associated hearing loss (HL) remain unclear. In this study, 15,684 patients with SNHL were enrolled and genetic analysis was performed using massively parallel DNA sequencing (MPS) for 63 target deafness genes. We identified 17 possibly disease-causing PTPRQ variants in 13 Japanese patients, with 15 of the 17 variants regarded as novel. The majority of variants identified in this study were loss of function. Patients with PTPRQ-associated HL mostly showed congenital or childhood onset. Their hearing levels at high frequency deteriorated earlier than that at low frequency. The severity of HL progressed from moderate to severe or profound HL. Five patients with profound or severe HL received cochlear implantation, and the postoperative sound field threshold levels and discrimination scores were favorable. These findings will contribute to a greater understanding of the clinical features of PTPRQ-associated HL and may be relevant in clinical practice.

Apple polyphenols exhibits chondroprotective changes of synovium and prevents knee osteoarthritis.

Apple polyphenols (AP) have strong antioxidant and anti-inflammatory properties. We examined the effects of AP on the progression of osteoarthritis (OA) AP was administered to surgically-induced OA model rats for 4 or 8 weeks. This treatment suppressed inflammation and oxidative stress in the synovium, resulting in a decrease in the OA severity score, and the expression of tumor necrosis factor (TNF)-α and matrix metalloproteinase (MMP)-13 in the synovium. It was suggested that long-term administration of AP may be effective for the treatment of OA. In addition, superoxide dismutase (SOD) activity was enhanced in serum samples by AP. AP or its constituent procyanidin B2 (PC) were added to HIG-82 synoviocytes. The results showed that AP enhanced cell proliferation and hyaluronan production. This indicates that AP may improve synovial conditions in OA and suppress OA progression. These effects may be attributed to the antioxidant and anti-inflammatory properties of AP.

Detailed clinical features and genotype-phenotype correlation in an OTOF-related hearing loss cohort in Japan.

Mutations in the OTOF gene are a common cause of hereditary hearing loss and the main cause of auditory neuropathy spectrum disorder (ANSD). Although it is reported that most of the patients with OTOF mutations have stable, congenital or prelingual onset severe-to-profound hearing loss, some patients show atypical clinical phenotypes, and the genotype-phenotype correlation in patients with OTOF mutations is not yet fully understood. In this study, we aimed to reveal detailed clinical characteristics of OTOF-related hearing loss patients and the genotype-phenotype correlation. Detailed clinical information was available for 64 patients in our database who were diagnosed with OTOF-related hearing loss. As reported previously, most of the patients (90.6%) showed a "typical" phenotype; prelingual and severe-to-profound hearing loss. Forty-seven patients (73.4%) underwent cochlear implantation surgery and showed successful outcomes; approximately 85-90% of the patients showed a hearing level of 20-39 dB with cochlear implant and a Categories of Auditory Performance (CAP) scale level 6 or better. Although truncating mutations and p.Arg1939Gln were clearly related to severe phenotype, almost half of the patients with one or more non-truncating mutations showed mild-to-moderate hearing loss. Notably, patients with p.His513Arg, p.Ile1573Thr and p.Glu1910Lys showed "true" auditory neuropathy-like clinical characteristics. In this study, we have clarified genotype-phenotype correlation and efficacy of cochlear implantation for OTOF-related hearing loss patients in the biggest cohort studied to date. We believe that the clinical characteristics and genotype-phenotype correlation found in this study will support preoperative counseling and appropriate intervention for OTOF-related hearing loss patients.

Successful cochlear implantation in a patient with Epstein syndrome during long-term follow-up.

Epstein syndrome is a rare disease characterized by macrothrombocytopenia, nephritis and progressive sensorineural hearing loss (SNHL). This syndrome is presently recognized as an autosomal dominant disease caused by mutations of non-muscle myosin heavy chain 9 (MYH9). Little information is available about the progress of SNHL, the efficacy of cochlear implants (CI) or the perioperative management of thrombocytopenia in patients with Epstein syndrome. We herein report a case of a patient with Epstein syndrome with the MYH9:c.2105G>A:p.R702H variant who underwent cochlear implantation after 27 years of follow-up for her progressive SNHL. The deterioration rates of hearing were 3.48 dB/year on the right ear and 2.46 dB/year on the left ear. The patient derived benefits from CI and had a speech recognition test result (for sentences) of 93% at 6-months postoperatively. Thrombocytopenia was successfully managed without any bleeding complications by using eltrombopag, an oral thrombopoietic agent, making transfusion of platelets unnecessary. The accurate diagnosis of Epstein syndrome was made only after long-term follow-up as the thrombocytopenia was initially diagnosed as idiopathic thrombocytopenic purpura. This case report highlights the perioperative management of thrombocytopenia, the progress of SNHL and the potential pitfalls of diagnosis.

Liver Cirrhosis Complicated by Spontaneous Bacterial Peritonitis Caused by the Burkholderia cepacia Complex.

A 79-year-old man with underlying alcoholic liver cirrhosis presented with complaints of a fever, abdominal pain, and difficulty walking. A diagnostic work-up revealed liver atrophy and chylous ascites, and spontaneous bacterial peritonitis (SBP) was diagnosed based on the cell and neutrophil counts. The Burkholderia cepacia complex (Bcc) was detected on blood and ascitic fluid cultures. Although broad-spectrum antibiotic therapy was initiated, the infection was difficult to control, and the patient died of multiple organ failure. Bcc is often multidrug-resistant and difficult to treat. SBP caused by Bcc has been rarely reported and may have a serious course, thus necessitating caution.

Influence of initial dose intensity on efficacy of FOLFIRINOX in patients with advanced pancreatic cancer.

The combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) is the standard of care for advanced pancreatic cancer, but causes hematological and gastrointestinal toxicities, leading to treatment delay and dose reduction; optimal modification based on toxicities is needed. Therefore, we evaluated the effect of initial relative dose intensity (RDI) on FOLFIRINOX efficacy by conducting a Japanese nationwide survey. We evaluated overall survival (OS) and progression-free survival (PFS) of patients administered two or more cycles of FOLFIRINOX, and determined RDIs for each drug within the first two cycles. RDI's effect on efficacy was evaluated using a multivariate analysis with a Cox regression hazard model. Of 399 patients enrolled, 359 and 346 were evaluated for OS and PFS, respectively. Median RDI was 71.8%, 64.7%, 23.4%, and 76.9% for oxaliplatin, irinotecan, and bolus and continuous infusions of 5-FU, respectively. A high RDI for 5-FU bolus resulted in poor prognosis in terms of PFS (hazard ratio: 1.34; p = 0.022) and negatively correlated with objective response (coefficient: -0.70; p = 0.021), and a high RDI for CPT-11 positively correlated with objective response (coefficient: 1.02; p = 0.031). In conclusion, low and high RDIs for irinotecan and 5-FU bolus, respectively, resulted in poor FOLFIRINOX efficacy.

FOLFIRINOX for locally advanced pancreatic cancer: Results and prognostic factors of subset analysis from a nation-wide multicenter observational study in Japan.

BACKGROUND: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, leucovorin) treatment significantly improved overall survival in the recent phase III study and became a standard therapy for metastatic pancreatic cancer. However, treatment for locally advanced pancreatic cancer is still controversial. We conducted subset analyses from a nation-wide multicenter observational study in Japan to evaluate the tolerability and efficacy of FOLFIRINOX in patients with locally advanced pancreatic cancer and to investigate independent prognostic factors with pre-treatment variables. METHODS: The study included 66 patients with unresectable locally advanced pancreatic cancer from 27 institutions in Japan who received FOLFIRINOX as first-line treatment between December 20, 2013 and December 19, 2014 and surveyed until December 2015. RESULTS: The median age was 63 with the Eastern Cooperative Oncology Group performance status of 0 or 1. Major Grade 3 or 4 adverse events included neutropenia (64%), leukopenia (33%), febrile neutropenia (15%), and diarrhea (15%). Severe adverse event occurred in 14 patients (11%) without fatal event. The median overall survival and progression-free survival times were 18.5 and 7.6 months, respectively. The objective response rate 15.2% and the disease control rate was 81.9%. A high modified Glasgow prognostic score (mGPS, ≥1) (95%CI 1.96-12.5) and female (95%CI 0.20-0.97) were identified as independent poor prognostic factors. CONCLUSIONS: First-line FOLFIRINOX treatment for locally advanced pancreatic cancer seems to be effective with acceptable toxicities. A high mGPS may be associated with poor survival in patients with locally advanced pancreatic cancer who receive FOLFIRINOX. This study was registered at the UMIN Clinical Trials Registry (UMIN000014658).

Impact of UGT1A1 genetic polymorphism on toxicity in unresectable pancreatic cancer patients undergoing FOLFIRINOX.

Studies have indicated an association between UDP-glucuronosyltransferase-1A1 (UGT1A1) genetic polymorphisms and irinotecan-induced toxicity. We undertook this study to investigate the association between UGT1A1 genetic polymorphisms and toxicity in patients treated with the FOLFIRINOX (comprising oxaliplatin, irinotecan, fluorouracil, and leucovorin) chemotherapy regimen in the JASPAC 06 study. Patients screened for UGT1A1*6 and UGT1A1*28, and treated with either the original FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 180 mg/m2 , leucovorin 200 mg/m2 , bolus 5-fluorouracil [5-FU] 400 mg/m2 , and continuous 5-FU 2400 mg/m2 ) or a modified FOLFIRINOX (oxaliplatin 85 mg/m2 , irinotecan 150 mg/m2 , leucovorin 200 mg/m2 , and continuous 5-FU 2400 mg/m2 ) as first-line chemotherapy were included. Of 199 patients eligible for this analysis, 79 patients were treated with the original FOLFIRINOX regimen and 120 patients were treated with the modified FOLFIRINOX regimen. In the original FOLFIRINOX group, 54 were UGT1A1 WT, and 25 were UGT1A1 heterozygous type (-/*6, 12 patients; -/*28, 13 patients). In the modified FOLFIRINOX group, 64 were UGT1A1 WT and 56 were UGT1A1 heterozygous type (-/*6, 33 patients; -/*28, 23 patients). In the original FOLFIRINOX group, the incidence of diarrhea was significantly higher among patients with UGT1A1 heterozygous type than among those with UGT1A1 WT and the incidence of leukopenia and diarrhea was significantly higher among patients with UGT1A1 -/*6 than among those with UGT1A1 -/*28. Patients with UGT1A1 heterozygous type, especially those with UGT1A1 -/*6, tended to show a higher incidence rate of severe adverse events, but this was not statistically significant. However, for patients who received the modified FOLFIRINOX, there was no difference in the frequency of adverse events due to UGT1A1 status. In conclusion, patients with heterozygous UGT1A1 polymorphisms treated with the original FOLFIRINOX regimen experienced severe toxicity more frequently than patients with WT UGT1A1.

Nationwide Multicenter Observational Study of FOLFIRINOX Chemotherapy in 399 Patients With Unresectable or Recurrent Pancreatic Cancer in Japan.

OBJECTIVES: FOLFIRINOX (oxaliplatin, irinotecan, 5-fluorouracil, and leucovorin) is the standard therapy worldwide for unresectable pancreatic cancer; however, clinical data for Japanese patients are limited. Therefore, the observational study of FOLFIRINOX for patients with pancreatic cancer was conducted. METHODS: The study included 399 patients with unresectable or recurrent pancreatic cancer, from 27 institutions in Japan, treated with FOLFIRINOX and surveyed until December 2015. RESULTS: The median age was 63 years; in most patients, the Eastern Cooperative Oncology Group performance status was 1 or lower. The initial dose was reduced in 270 patients (68%). The main grade 3/4 toxicities were neutropenia (64%), anorexia (14%), and febrile neutropenia (13%). Fatal adverse events occurred in 5 patients, 4 of whom did not satisfy the main inclusion criteria of a previous Japanese phase II FOLFIRINOX study. The median overall survival and progression-free survival times were 10.8, and 4.5 months, respectively. The objective response rate was 21%, and the disease control rate was 61%. The median overall survival times were 11.1, 18.5, and 4.9 months in chemotherapy-naïve patients with metastatic, locally advanced, and recurrent disease, respectively. CONCLUSION: When carefully managed, FOLFIRINOX is acceptably safe and efficacious in Japanese patients with unresectable pancreatic cancer.

Cancer Cell Analyses at the Single Cell-Level Using Electroactive Microwell Array Device.

Circulating tumor cells (CTCs), shed from primary tumors and disseminated into peripheral blood, are playing a major role in metastasis. Even after isolation of CTCs from blood, the target cells are mixed with a population of other cell types. Here, we propose a new method for analyses of cell mixture at the single-cell level using a microfluidic device that contains arrayed electroactive microwells. Dielectrophoretic (DEP) force, induced by the electrodes patterned on the bottom surface of the microwells, allows efficient trapping and stable positioning of single cells for high-throughput biochemical analyses. We demonstrated that various on-chip analyses including immunostaining, viability/apoptosis assay and fluorescent in situ hybridization (FISH) at the single-cell level could be conducted just by applying specific reagents for each assay. Our simple method should greatly help discrimination and analysis of rare cancer cells among a population of blood cells.

Highly efficient single cell arraying by integrating acoustophoretic cell pre-concentration and dielectrophoretic cell trapping.

To array rare cells at the single-cell level, the volumetric throughput may become a bottleneck in the cell trapping and the subsequent single-cell analysis, since the target cells per definition commonly exist in a large sample volume after purification from the original sample. Here, we present a novel approach for high throughput single cell arraying by integrating two original microfluidic devices: an acoustofluidic chip and an electroactive microwell array. The velocity of the cells is geared down in the acoustofluidic chip while maintaining a high volume flow rate at the inlet of the microsystem, and the cells are subsequently trapped one by one into the microwell array using dielectrophoresis. The integrated system exhibited a 10 times improved sample throughput compared to trapping with the electroactive microwell array chip alone, while maintaining a highly efficient cell recovery above 90%. The results indicate that the serial integration of the acoustophoretic pre-concentration with the dielectrophoretic cell trapping drastically improves the performance of the electroactive microwell array for highly efficient single cell analysis. This simple and effective system for high throughput single cell arraying with further possible integration of additional functions, including cell sorting and downstream analysis after cell trapping, has potential for development to a highly integrated and automated platform for single-cell analysis of rare cells.

Synthesis of 5'-fluoro-2'-beta-methylneplanocin analogues.

Synthesis of 5'-fluoro-2'-beta-methylneplanocin analogues (5) was carried out. The cyclopentenone 16 was prepared from methyl mannopyranoside by using ring closing metathesis, stereoselective introduction of methyl group, and seleno cyclization as representative steps. Introduction of a fluorine atom was conducted by electrophilic fluorination. Antiviral activity of 5 will also be presented.