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Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of β-amyloid-protein (Aβ) in the brain parenchyma. Sleep impairment is associated with AD and affects about 25–40% of patients in the mild-to-moderate stages of the disease. Sleep deprivation leads to increased Aβ production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aβ production. Here, we report temperature-dependent regulation of Aβ production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aβ production in amyloid precursor protein-overexpressing cells. We also found that high temperature (39 °C) significantly increased the expression levels of heat shock protein 90 (Hsp90) and the C-terminal fragment of presenilin 1 (PS1-CTF) and promoted γ-secretase complex formation. Interestingly, Hsp90 was associated with the components of the premature γ-secretase complex, anterior pharynx-defective-1 (APH-1), and nicastrin (NCT) but was not associated with PS1-CTF or presenilin enhancer-2. Hsp90 knockdown abolished the increased level of Aβ production and the increased formation of the γ-secretase complex at high temperature in culture. Furthermore, with in vivo experiments, we observed increases in the levels of Hsp90, PS1-CTF, NCT, and the γ-secretase complex in the cortex of mice housed at higher room temperature (30 °C) compared with those housed at standard room temperature (23 °C). Our results suggest that high temperature regulates Aβ production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Purpose To assess comorbidity burden and pain-management patterns among working-aged patients with knee osteoarthritis only (KOA/O) and patients with knee osteoarthritis plus osteoarthritis at another site (KOA/+) in Japan. Patients and methods Retrospective claims data analysis was conducted using the Japan Medical Data Center database. Working-aged adults (aged 40 to 71 years) with 5 years of follow-up and diagnosed with knee osteoarthritis (KOA) between January 1, 2011, and December 31, 2012, were evaluated. The first claim with a KOA diagnosis defined the index date. Patients were divided into two mutually exclusive cohorts: KOA/O and KOA/+. Longitudinal pain-management patterns during each year of follow-up were analyzed. Results A total of 2542 patients met study criteria: 1575 KOA/O and 967 KOA/+. Mean age and number of comorbidities were higher among the KOA/+ versus KOA/O cohort. Pharmaceutical treatment was received by 91.5% of patients in the KOA/+ compared with 85.1% of patients in the KOA/O cohort during the first year of follow-up. The most common pharmacological treatment received during the first year of follow-up was either topical or oral nonsteroidal anti-inflammatory drugs for both cohorts. During each year of follow-up, the KOA/+ cohort had greater proportion of patients with at least one health-care encounter (ie, hospital admissions, outpatient and pharmacy visits) and higher direct medical costs compared with the KOA/O cohort. Conclusion This study demonstrates that a greater proportion of the working population with KOA/+ received pain-related treatment compared with patients with KOA/O. Further studies are necessary to evaluate appropriate pain management for both KOA only and KOA with other sites.

The objective of the present analysis was to determine whether changes in Brief Pain Inventory (BPI) average pain scores by patient global impression of improvement (PGI‐I) category and the cut‐off for clinically important difference (CID) were different between Asian and Caucasian patients with chronic pain due to osteoarthritis. This analysis used data from 3 (Caucasian) and 2 (Asian) randomized, placebo‐controlled, 10‐ to 14‐week duloxetine studies for the treatment of patients ≥40 years of age with osteoarthritis pain. The receiver operating characteristic (ROC) analysis was used to characterize the association between changes in BPI average pain scores and PGI‐I levels at study endpoint. The CID was characterized by PGI‐I, and the cut‐off point for CID in BPI average pain scores was determined by the intersection of a 45‐degree tangent line with each ROC curve. Data from 668 Asian and 868 Caucasian patients were available for analysis. Baseline BPI average pain ratings including worst and least pain were comparable between Asians and Caucasians. Ratings for percentage change from baseline to endpoint for BPI average pain scores in Asian patients and Caucasian patients were similar across the 7 PGI‐I categories, regardless of age, gender, study, and treatment. The ROC analysis results of cut‐off points in BPI average pain scores demonstrated the raw change cut‐off was −3.0, and percentage change cut‐off was −40% for both Asian and Caucasian patients. Overall, the present analysis concludes changes in BPI average pain scores by PGI‐I category and the cut‐off for CID were similar for Asian and Caucasian patients with chronic pain due to osteoarthritis.

The purpose of the study involves measuring the threshold for electric currents (i.e., current perception threshold or CPT) under several stimulating current frequencies. Specifically, current perception threshold (CPT) was measured in 53 healthy volunteers between the ages of 21 and 67. The stimulation currents were applied on the right index finger with stimulus frequencies in the range of 50 Hz - 300 kHz. The method of limits and method of constant stimuli were combined to measure the CPT. In a manner consistent with the findings obtained by previous studies, the results indicated that CPT was higher in men than in women and in older individuals than in young subjects. Bioelectromagnetics. 9999:XX-XX, 2019. © 2019 Bioelectromagnetics Society.

The posterior parietal cortex (PPC) features close anatomical and functional relationships with the prefrontal cortex. However, the necessity of the PPC in executive functions has been questioned. The present study used the stop-signal task to examine response inhibition, an executive function that inhibits prepotent response tendency. The brain activity and resting-state functional connectivity were measured to analyze a parcellation-based network that was aimed at identifying a candidate PPC region essential for response inhibition in humans. The intraparietal sulcus (IPS) was activated during response inhibition and connected with the inferior frontal cortex and the presupplementary motor area, the two frontal regions known to be necessary for response inhibition. Next, transcranial magnetic stimulation (TMS) was used to test the essential role of the IPS region for response inhibition. TMS over the IPS region prolonged the stop-signal reaction time (SSRT), the standard behavioral index used to evaluate stopping performance, when stimulation was applied 30–0 ms before stopping. On the contrary, stimulation over the temporoparietal junction region, an area activated during response inhibition but lacking connectivity with the two frontal regions, did not show changes in SSRT. These results indicate that the IPS identified using the parcellation-based network plays an essential role in executive functions. SIGNIFICANCE STATEMENT Based on the previous neuropsychological studies reporting no impairment in executive functions after lesions in the posterior parietal cortex (PPC), the necessity of PPC in executive functions has been questioned. Here, contrary to the long-lasting view, by using recently developed analysis in functional MRI (“parcellation-based network analysis”), we identified the intraparietal sulcus (IPS) region in the PPC as essential for response inhibition: one executive function to stop actions that are inaccurate in a given context. The necessity of IPS for response inhibition was further tested by an interventional technique of transcranial magnetic stimulation. Stimulation to the IPS disrupted the performance of stopping. Our findings suggest that the IPS plays essential roles in executive functions.

Large basilar trunk aneurysm caused by bilateral occlusion of the proximal common carotid artery is rare. We treated one case with vertebral V3 portion-radial artery-distal common carotid artery (V3-RA-dCCA) bypass. Basilar trunk aneurysm and bilateral occlusion of the proximal CCA were found incidentally in a 70-year-old woman. During the next 5 years, the aneurysm gradually enlarged to 12 mm, and blood flow of the anterior circulation was supplied through the posterior communicating artery. V3-RA-dCCA bypass was performed to reduce the stress of blood flow and prevent aneurysm growth and rupture. After exposing the neck portion, forearm of RA, and V3 portion of the vertebral artery, we created a space just below the sternocleidomastoid muscle to bypass the RA. We flushed the RA with albumin to stiffen the artery and temporarily clamped the bilateral sides of the RA to prevent twisting. We anastomosed the V3 and RA with a 9–0 thread and temporarily clamped the V3. After flushing the RA with albumin to prevent twisting, we clamped the external and internal carotid arteries, opened the dCCA with a vascular punch to prevent arterial dissection, and anastomosed the RA to the dCCA. The patency of the bypass was confirmed with Doppler and indocyanine green video angiography. The postoperative course was uneventful, bypass patency was good, and the aneurysm did not expand further. V3-RA-dCCA bypass may be an effective and low-risk treatment for large basilar trunk aneurysms with bilateral occlusion of the proximal common carotid artery.

Objective Assess long-term comorbidity burden and pain management patterns among working-age patients with knee osteoarthritis (KOA) only without low back pain (LBP) (KOA-noLBP) and patients with KOA plus LBP (KOA+LBP) in Japan. Methods Retrospective claims data analyses were conducted on data from the Japan Medical Data Center (JMDC) database. Adult patients (≥40 years) with a diagnosis of knee osteoarthritis (KOA) (January 1, 2011–December 31, 2012) and 5 years of follow-up were evaluated. The first claim with a KOA diagnosis defined the index date. Longitudinal pain management patterns were assessed in both cohorts. Results Overall, 1,828 patients met study criteria (717 with KOA-noLBP; 1,111 with KOA+LBP). The mean age of patients with KOA-noLBP was 52.1 years, and that of patients with KOA+LBP was 53.1 years, with more females in the KOA+LBP cohort (49.4% vs. 55.0%). Regardless of cohort, >90% of patients received pharmacological intervention during the 5-year follow-up period. The most common regimen first received was either topical or oral nonsteroidal anti-inflammatory drugs. A higher mean number of pharmaceutical treatments were received by patients in the KOA+LBP cohort (3.6) than by patients in the KOA-noLBP cohort (2.7) during the follow-up period. Regardless of cohort, most of the direct medical cost was derived from medication. Conclusion This study demonstrates that a greater proportion of the JMDC population of working individuals with KOA were comorbid with LBP and received pain-related treatment in the long-term perspective relative to patients with KOA without LBP. Appropriate pain management for both KOA and LBP would be key for effective resource utilization in an aging society facing socioeconomic burdens

Hiroyuki Enomoto, 1 Shinji Fujikoshi, 2 Kei Ogawa, 1 Toshinaga Tsuji, 3 Sakae Tanaka 4 1Medicines Development Unit Japan, Eli Lilly Japan K.K., Tokyo 107-0052, Japan; 2Medicines Development Unit Japan, Eli Lilly Japan K.K., Kobe 651-0086, Japan; 3Medical Affairs Department, Shionogi & Co., Ltd., Shibata, Osaka 530-0012, Japan; 4Department of Orthopaedic Surgery, Faculty of Medicine, The University of Tokyo, Tokyo, JapanCorrespondence: Hiroyuki EnomotoMedicines Development Unit Japan, Eli Lilly Japan K.K., 4-15-1-13F, Akasaka, Minato-Ku, Tokyo 107-0052, JapanTel +81 3 5574 9143Fax +81 3 5574 9979Email enomoto_hiroyuki@lilly.comPurpose: This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT02248480) investigated relationships between changes in pain severity and changes in health-related quality of life (HRQoL) in duloxetine-treated patients with knee osteoarthritis (OA).Patients and Methods: Patients with knee OA and Brief Pain Inventory (BPI) average pain score ≥ 4 received duloxetine 60 mg/day or placebo for 14 weeks. Spearman rank correlation coefficients were calculated for change in pain severity, as assessed by the BPI, and change in HRQoL, as assessed by the items of the (i) 36-item Short-Form Health Survey (SF-36; a generic measure of HRQoL) and (ii) Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC; an OA-specific measure of HRQoL).Results: After 14 weeks of treatment, there was a significantly greater improvement (p< 0.001) for duloxetine (n=177) vs placebo (n=176) in BPI average pain severity score and significantly greater improvements (p< 0.01) for duloxetine vs placebo for 5 of the 8 SF-36 domains (including the Role-Physical, Bodily Pain, and Physical Functioning domains) and all 24 individual WOMAC items. The correlation between BPI change from baseline and SF-36 item change from baseline was statistically significant (p< 0.05) for 2 of the 8 SF-36 items (Bodily Pain, Physical Functioning) in duloxetine-treated patients. The correlation between BPI change from baseline and WOMAC item change from baseline was statistically significant for 22 of the 24 WOMAC items in duloxetine-treated patients.Conclusion: This post hoc analysis suggested that the pain reduction observed in duloxetine-treated patients with knee OA was associated with improvements in OA-specific aspects of HRQoL, ie, pain and physical functioning.Keywords: 36-item Short-form Health Survey, Brief Pain Inventory, placebo effect, Western Ontario and McMaster Universities Osteoarthritis Index

A previously conducted placebo-controlled, randomized, phase 3 study of 353 Japanese patients with knee osteoarthritis (OA) showed significant improvements for duloxetine vs placebo in pain and health-related quality of life (HRQoL) (ClinicalTrials.gov Identifier: NCT02248480). Reported here are post hoc subgroup analyses evaluating the efficacy of duloxetine according to the pattern of prior nonsteroidal anti-inflammatory drug (NSAID) use.Patients with knee OA pain received once-daily duloxetine or placebo for 14 weeks. Pain was evaluated using the Brief Pain Inventory (BPI) and HRQoL was evaluated using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Patients were divided into four subgroups based on their prior NSAID use: (i) no prior NSAID use; (ii) low-frequency NSAID use (14 days/month); (iii) high-frequency transdermal NSAID use (transdermal NSAIDs only; ≥14 days/month for the 3 months before study entry); and (iv) high-frequency other NSAID use (eg, oral NSAIDs only, both oral and transdermal NSAIDs; ≥14 days/month for the 3 months before study entry).In each of the four prior NSAID use subgroups, there were greater reductions in BPI average pain severity score for duloxetine vs placebo at all timepoints during the 14-week treatment period; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, the proportion of patients achieving a ≥50% reduction in BPI average pain severity score was higher for duloxetine vs placebo. In each subgroup, there were greater reductions in WOMAC total score for duloxetine vs placebo at all timepoints; the treatment*prior NSAID use interaction was not statistically significant. In each subgroup, there were greater reductions at Week 14 in WOMAC pain, stiffness, physical function, and total scores for duloxetine vs placebo.Duloxetine was consistently effective with respect to pain relief and HRQoL in Japanese patients with knee OA pain, regardless of the pattern of prior NSAID use.

Kaname Ueda,1 Nao Sasaki,2 Amir Goren,3 Shawna R Calhoun,4 Katsuhiro Shinjo,5 Hiroyuki Enomoto,5 Takeshi Muneta6 1Health Outcomes/Health Technology Assessment/Real World Evidence, Eli Lilly Japan, Kobe, Japan; 2Bio-Medicines, Medicines Development Unit, Eli Lilly Japan, Kobe, Japan; 3Health Outcomes, Kantar Health, New York, NY, USA; 4Health Outcomes, Kantar Health, Horsham, PA, USA; 5Bio-Medicines, Medicines Development Unit, Eli Lilly Japan, Tokyo, Japan; 6Department of Orthopaedic Surgery, National Disaster Medical Center, Tokyo, Japan Purpose: Patient satisfaction is an important outcome in successful osteoarthritis (OA) treatment. The aim of this study was to evaluate treatment satisfaction for medication (TSM) in people with knee OA (KOA), identify the factors predictive of treatment satisfaction, and describe the burden of illness.Patients and methods: This cross-sectional, patient-reported study used an Internet-based survey and analyzed responses of respondents with KOA (N=400) on characteristics including pain sites and levels (including pain ratings using the Numerical Rating Scale and Short-Form McGill Pain Questionnaire), treatment satisfaction (Global, Effectiveness, and Convenience scores) based on the Treatment Satisfaction Questionnaire for Medication (TSQM-9), and quality of life (QoL; based on the Arthritis Impact Measurement Scale 2-Short Form). Respondents with only KOA (n=237) were compared with those having KOA and additional painful sites (KOA+; n=163). Factors predicting TSM were identified using multivariable linear regression analyses.Results: Respondents with KOA were more likely to report intermittent pain for 3 months or more compared with those with KOA+ (58.6% vs 48.5%, respectively; P=0.044), while those with KOA+ were more likely to report consistent pain for 3 months or more (P=0.022). Respondents with KOA+ also had more difficulty due to their knee pain while sleeping (P=0.022) and resting (P=0.015). Reported TSM did not differ significantly across KOA vs KOA+ groups, with both groups reporting low satisfaction; all domains of QoL were worse for those with KOA+. Knee pain reduction by medication predicted higher satisfaction across domains, while lower pre-medication pain and post-medication pain matching expectations predicted higher TSQM-9 Global and Effectiveness scores.Conclusion: Medication treatment satisfaction rates were low among Japanese respondents with KOA. Given that lower pain, greater pain reduction post-medication, and meeting pain management expectations were predictive of higher satisfaction, treatment strategies that can better address pain may prove beneficial for overall patient satisfaction. Keywords: quality of life, AIMS2-SF, SF-MPQ, TSQM-9, knee osteoarthritis

Yuji Uchio,1 Hiroyuki Enomoto,2 Levent Alev,2 Yuki Kato,3 Hiroyuki Ishihara,3 Toshinaga Tsuji,4 Toshimitsu Ochiai,5 Shinichi Konno6 1Department of Orthopaedic Surgery, Shimane University School of Medicine, Shimane, Japan; 2Bio-Medicine, Medicines Development Unit, Eli Lilly Japan K.K., Kobe, Japan; 3Clinical Development Department, Shionogi & Co., Ltd., Osaka, Japan; 4Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 5Biostatistics Department, Shionogi & Co., Ltd., Osaka, Japan; 6Department of Orthopaedic Surgery, Fukushima Medical University School of Medicine, Fukushima, Japan Purpose: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. Patients and methods: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double-blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. Results: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (−2.57 vs. −1.80; adjusted mean difference: −0.77; 95% CI: −1.11 to −0.43; P

The Japan Fracture Observational Study (JFOS), a prospective observational study, investigated the real-world effectiveness of daily teriparatide to reduce clinical fracture risk in osteoporotic patients.In routine clinical practice, Japanese patients initiated on teriparatide 20 μg/day by subcutaneous injection were enrolled. The primary end-point was the rate of clinical fractures at 6-month intervals over 24 months. Bone mineral density (BMD), procollagen type 1 aminoterminal propeptide (P1NP), back pain, and health-related quality-of-life (HRQoL) information was collected.Of 1,996 patients at baseline, 90.1% were female, and mean age was 76.9 years. Teriparatide persistence at 12 and 24 months was 68.0% and 51.6%, respectively. Compared to the first 6-month treatment interval, the odds ratio of fractures decreased by 56.4% during 6-12 months, 51.6% during 12-18 months, and 58.8% during 18-24 months (all p .01). After 24 months, BMD increased by 17.2% (lumbar spine) and 7.9% (total hip). After 6 months, P1NP levels increased by 259.3%. A reduction in back pain (100 mm visual analog scale) of 16.1 mm at 3 months was maintained through 24 months. HRQoL (pain, daily living activities, general health) improved by ≥10% at each post-baseline time point. Of 279 (14.6%) patients with ≥1 adverse event (AE), 71 (3.7%) experienced ≥1 drug-related AE (investigator assessed), including nausea (0.7%), dizziness (0.4%), and decreased appetite (0.3%). Osteosarcoma was not reported; there were no new safety signals.JFOS demonstrated effectiveness of teriparatide 20 μg/day to reduce the risk of clinical fractures in Japanese patients in a real-world setting.

The reduction of plasticity with age has been shown by many previous papers in animal experiments. This issue can be studied in humans because several non-invasive brain stimulation techniques induce synaptic plasticity in the human brain. We investigated the influence of individuals' age on the responder rate of the long-term potentiation (LTP)-like effect induced by quadripulse magnetic stimulation (QPS). The participants were 107 healthy volunteers: 53 older participants (Mean ± SD 65.0 ± 1.5 years) and 54 younger participants (37.2 ± 8.7). The quadripulse stimulation with 5-ms inter-pulse interval (QPS5) was applied over the primary motor cortex (M1). We measured motor evoked potentials (MEPs) before QPS, and at five time points after QPS for up to 25 min. In each participant, average MEP amplitude (size) ratios were quantified. We first classified participants as responders and non-responders simply by comparing the size ratio with 1.0 for consistency with previous studies, then as "significant responders", "non-responders", and "opposite responders" for more detailed analysis by comparing the size ratio with the mean and standard deviation of the MEP size ratios of the sham condition. The degree of LTP-like effects induced by QPS5 was significantly smaller in the older group compared to the younger group. Also, the rates of responders and significant responders were lower in the older group (58 and 47%, respectively) compared to the younger group (80 and 76%, respectively). The age of the participants significantly affected the LTP-like effect induced by QPS5, which suggests that brain plasticity decreases with age.

Mobile phones are indispensable for daily life, and the adverse effects of the electromagnetic field (EMF) emitted by mobile phones have been a great concern. We studied the effects of long-term evolution (LTE) -like EMF for 30 min on an awake electroencephalogram (EEG). Thirty-eight healthy volunteers, aged 20-36 years old, participated in this study. The maximum local SAR (specific absorption rate) averaged over 10-g mass was 2.0 W/kg. The EEG was recorded before and after real or sham exposures. The effects of exposure conditions (real or sham) and the recording time (before, during, and after exposure) on each EEG power spectrum of θ, α, and β frequency ranges were analyzed. The θ and α band waves were enhanced after both exposure conditions. These results may be explained by the participants' drowsiness during the EEG recording in both exposures. We conclude that an LTE-like exposure for 30 min in this study showed no detectable harmful effects on awake EEGs in healthy humans.

After experiencing upper respiratory-tract symptoms, a 41-year-old woman developed encephalitis with consciousness disturbance and respiratory failure. She had external ophthalmoplegia and facial diplegia. Magnetic resonance imaging revealed a brainstem lesion with spared longitudinal pontine bundles. Abnormal findings of the brainstem auditory-evoked potentials and blink reflex supported brainstem damage. The patient was positive for anti-N-methyl-D-aspartate receptor (NMDAR) antibodies. Repeated immunological treatments improved her symptoms, but severe orthostatic hypotension emerged. A head-up tilt test revealed no arginine vasopressin response to hypotension. The atypical symptoms of this case highlighted that the brainstem is one of the pivotal regions in anti-NMDAR encephalitis.

The phase 3 teriparatide Fracture Prevention Trial showed significant reductions in vertebral (VF) and nonvertebral (NVF) fractures; however, patient exposure was insufficient for full analysis of low-incidence fractures, including hip. We assessed fracture results in pooled data from four prospective, observational teriparatide studies. Ambulatory women and men with osteoporosis received subcutaneous teriparatide 20 µg/day for up to 24 months per routine clinical practice. Fracture rates were compared between 6-month periods, using 0 to 6 months of treatment as the reference period. Analyses used a piecewise exponential model for first fracture. Hip, NVF, clinical VF (CVF), any clinical, and wrist fractures were assessed. For 8828 patients analyzed, mean age was 71 years; mean (SD) treatment duration was 17.4 (8.6) months. The rate of hip fracture decreased significantly for the > 12 to 18-month (- 47.7%) and > 18-month periods (-85.2%) versus the first 6 months of therapy, and for the > 18 versus the > 6 to 12-month period. NVF, CVF, and all clinical fractures were all significantly decreased in each post-reference period, with maximum decreases (> 18-month period) of 52.7%, 69.4%, and 61.2%, respectively, versus 0 to 6 months. No significant reduction was seen for rates of wrist fracture. Teriparatide treatment was associated with statistically significant decreases in hip fracture rate, particularly for > 18 months of treatment, and in NVF, CVF, and all clinical fracture rate in real-world patients. These results should be interpreted in the context of the non-controlled design of the source studies.

Atsushi Nishikawa,1 Fumito Yoshiki,2 Masanori Taketsuna,2 Kenta Kajimoto,2 Hiroyuki Enomoto2 1Global Patient Safety Japan, Quality and Patient Safety, Eli Lilly Japan K.K., 2Medicines Development Unit Japan, Eli Lilly Japan K.K., Kobe, Japan Abstract: Teriparatide (recombinant 1–34 N-terminal sequence of human parathyroid hormone) for the treatment of osteoporosis should be prescribed with caution in patients with severe stages of chronic kidney disease (CKD). However, in clinical settings, physicians and surgeons who treat such patients have few available options. We sought to further explore the safety and effectiveness of teriparatide for the treatment of osteoporosis in Japanese patients with severe stages of CKD. This was a post hoc analysis of a postmarketing surveillance study that included patients with osteoporosis at high risk of fracture and stage 4 or 5 CKD. Patients received subcutaneous teriparatide 20 µg daily for up to 24months. Safety profiles were assessed by physician-reported adverse drug reactions (ADRs). Effectiveness was assessed by measuring bone formation (via procollagen type 1 N-terminal propeptide [P1NP]), bone mineral density (BMD), and the incidence of clinical vertebral or nonvertebral fragility fractures. A total of 33 patients with severe stages of CKD (stage 4, n=30; stage 5, n=3) were included. All patients were female, and 81.8% had a history of previous fracture. No serious ADRs were recorded; a total of 4 ADRs were recorded for 4 of 33 patients. Increases in BMD and P1NP levels were observed both overall and in most individual patients. New fractures occurred in 1 patient with stage 5 CKD, but not in patients with stage 4 CKD. In this post hoc analysis conducted in Japan, teriparatide appeared to be effective for the treatment of osteoporosis in elderly female patients with severe stages of CKD, and no new safety concerns were observed. Keywords: bone mineral density, chronic kidney disease, fragility fracture, parathyroid hormone, teriparatide, safety&nbsp

Background Responses to plasticity-inducing brain stimulation protocols are highly variable. However, no data are available concerning the variability of responses to quadripulse stimulation (QPS). Objective We assessed the QPS parameters of motor cortical plasticity induction in a systematic manner, and later investigated the variability of QPS using optimal parameters. Methods First, two different interburst intervals (IBI) with the same total number of pulses were compared. Next we investigated three different IBIs with a different total number of pulses but with same duration of intervention. We also compared the after-effects of monophasic and biphasic QPS. Finally, variability of QPS was tested in 35 healthy subjects. Twenty motor evoked potentials (MEPs) were measured every 5–10 min for up to one hour after intervention. Results QPS at an IBI of 5 s produced MEPs changes that are dependent on the interstimulus interval of the four magnetic pulses, consistent with previous reports. Unexpectedly, QPS at an IBI of 2.5 s did not induce any plasticity, even with the same total number of pulses, that is, 1440. QPS at an IBI of 7.5 s produced a variable response but was likely to be comparable to conventional QPS. Biphasic QPS had shorter lasting after-effects compared with monophasic QPS. Finally, the after-effects of QPS were relatively consistent across subjects: more than 80% of subjects responded as expected in the excitatory QPS at an IBI of 5 s. Conclusions The IBI, total duration of the procedure and pulse waveform strongly affected the magnitude or duration of the plasticity induced by QPS. In this cohort, 80% of subjects responded to excitatory QPS as expected.

Exosomes are small extracellular vesicles secreted by variety of cell types such as neurons, astrocytes, and oligodendrocytes. It is suggested that exosomes play essential role in the maintenance of the neuronal functions and also in the clearance of amyloid-β (Aβ) from the brain. Aβ is well known to cause neuronal cell death, whereas little is known about its effect on astrocytes. In this study, we examined the effect of Aβ on release of exosomes from astrocytes in culture. We analyzed release of exosomes and apoE, both of which are known to remove/clear Aβ from the brain, in the culture medium of astrocytes. We found that exosome and apoE-HDL were successfully separated by density gradient ultracentrifugation demonstrated by distribution of their specific markers, flotillin and HSP90, and cholesterol, and morphological analysis using electron microscopy. Exosome release was significantly reduced by Aβ1-42 treatment in cultured astrocytes accompanied by an increased JNK phosphorylation. Whereas, apoE-HDL release remained unchanged. A JNK inhibitor restored the decreased levels of exosome release induced by Aβ treatment to levels similar to those of control, suggesting that Aβ1-42 inhibits exosome release via stimulation of JNK signal pathway. Because exosomes are shown to remove Aβ in the brain, our findings suggest that increased Aβ levels in the brain may impair the exosome-mediated Aβ clearance pathway.

Background: Distinguishing recipient cells from donor ligament cells is difficult in the early graft-healing phase after anterior cruciate ligament (ACL) reconstruction. The ability to track the distribution and differentiation of recipient cells using genetically engineered transgenic (Tg) animals would have significant clinical and research effects on graft healing after ACL reconstruction. Hypothesis: Kusabira-Orange Tg pigs may allow the tracking of recipient cells infiltrating the graft after ACL reconstruction. The repopulation of recipient cells within the graft would be apparent even in the early graft-healing phase when necrotic donor cells are still present. Study Design: Descriptive laboratory study. Methods: In 17 genetically engineered Tg pigs, which carried the red fluorescent protein Kusabira-Orange, ACL reconstruction was performed on the right knee using a digital flexor tendon harvested from wild-type pigs. Tissue samples harvested at different time points were subjected to histological, immunohistochemical, and electron microscopic analyses. Results: At 3 weeks postoperatively, recipient cells expressing red fluorescence embraced the graft and were infiltrating the central part of the graft. These cells with oval nuclei gradually infiltrated the gap of collagen fibers, losing their regular orientation. At 6 weeks, cellularity within the graft had doubled to match that of the native ACL, while acellular necrotic regions still existed centrally. Ubiquitous cellular distributions resembling the native ACL were observed at 24 weeks. Electron microscopic analysis showed that the mean collagen fibril diameter and density gradually decreased over 24 weeks. Conclusion: Genetically engineered pigs carrying the Kusabira-Orange gene were useful animal models for analyzing intrinsic and extrinsic cellular dynamics during the course of graft healing after ACL reconstruction. Cellular repopulation by recipient cells occurred in the very early stage, and the cellular distribution within the graft resembled that in the native ACL by 24 weeks, but the reconstructed graft had not restored the ultrastructure of the native ACL by that stage. Clinical Relevance: In allograft ACL reconstruction in a pig model, cellular repopulation was completed by 24 weeks after surgery, but the collagen matrix had not resumed the ultrastructure of the native ACL. Surgeons should be aware that risks may remain with returning to sports activities at 24 weeks after surgery.

Atsushi Nishikawa,1 Takehiro Ishida,2 Masanori Taketsuna,3 Fumito Yoshiki,4 Hiroyuki Enomoto4 1Global Patient Safety Japan, Quality and Patient Safety, 2Clinical Development Operations and Innovations, Medicine Development Unit Japan, 3Asia Pacific Statistical Sciences, Medicine Development Unit Japan, 4Medical Sciences, Medicines Development Unit Japan, Eli Lilly Japan K.K., Kobe, Japan Abstract: This postmarketing surveillance study assessed the safety and effectiveness of teriparatide in patients with osteoporosis at high risk of fracture in Japan. The patients received teriparatide 20 µg daily by subcutaneous injection, for a maximum of 24 months. Safety and effectiveness analyses were based on data from 1,847 patients who were predominantly female (92.6%) with a mean age of 75.4 years. A total of 157 adverse drug reactions (ADRs) were reported in 140 (7.58%) patients; the most common ADRs were hyperuricemia, nausea, and dizziness. Only six (0.32%) patients reported serious ADRs, the most common being nausea (two patients; 0.1%). Persistence with teriparatide treatment was 60.8% and 39.1% at 18 and 24 months, respectively. There were significant increases in biomarkers for bone formation (procollagen type I N-terminal propeptide and bone-specific alkaline phosphatase) and bone resorption (collagen type I cross-linked C telopeptide and tartrate-resistant acid phosphatase 5b) throughout the study. These were accompanied by significant increases in bone mineral density and low incidences of new vertebral and nonvertebral fractures. Patient-reported measurements for health-related quality of life revealed significant improvements from baseline in back pain and overall health-related quality of life (Short Form-8™ health survey). The results of this 24-month postmarketing surveillance study imply that teriparatide has a favorable safety profile and is effective in the treatment of patients with osteoporosis at high risk of fracture in Japan. Teriparatide may also be a useful treatment for osteoporosis in other societies with aging populations. Keywords: parathyroid hormone, bone biomarkers, bone mineral density, quality of life, safety

There are growing concerns about how electromagnetic waves (EMW) emitted from mobile phones affect human spermatozoa. Several experiments have suggested harmful effects of EMW on human sperm quality, motility, velocity, or the deoxyribonucleic acid (DNA) of spermatozoa. In this study, we analyzed the effects on human spermatozoa (sperm motility and kinetic variables) induced by 1 h of exposure to 1950 MHz Wideband Code Division Multiple Access (W-CDMA)-like EMW with specific absorption rates of either 2.0 or 6.0 W/kg, using a computer-assisted sperm analyzer system. We also measured the percentage of 8-hydroxy-2'-deoxyguanosine (8-OHdG) positive spermatozoa with flow cytometry to evaluate damage to DNA. No significant differences were observed between the EMW exposure and the sham exposure in sperm motility, kinetic variables, or 8-OHdG levels. We conclude that W-CDMA-like exposure for 1 h under temperature-controlled conditions has no detectable effect on normal human spermatozoa. Differences in exposure conditions, humidity, temperature control, baseline sperm characteristics, and age of donors may explain inconsistency of our results with several previous studies. Bioelectromagnetics. 37:373-381, 2016. © 2016 Wiley Periodicals, Inc.

Objective In patients with benign myoclonus epilepsy (ME), giant sensory-evoked potential (SEP) reflects the hyperexcitability of the sensory cortex. The aim of this study was to compare the effect of quadripulse transcranial magnetic stimulation (QPS) on the median nerve SEP between ME patients and healthy subjects. Methods Ten healthy volunteers and six ME patients with giant SEP participated in this study. QPSs at interpulse intervals (IPIs) of 5, 30, 50, 100, 500 and 1250 ms were applied over the left primary motor cortex (M1) for 30 min. The peak-to-peak amplitudes of N20 to P25 (N20–P25) and P25 to N33 (P25–N33) components were measured at the left somatosensory cortex. Results In healthy participants, the P25–N33 was bidirectionally modulated by QPS over M1, following the Bienenstock–Cooper–Munro (BCM) theory. The N20–P25 was not affected by any QPSs. In ME patients, the giant P25–N33 was potentiated after any QPSs. Furthermore, the N20–P25 was also potentiated after QPS at IPIs of 5, 30, 50 100 or 500 ms. Conclusions In ME patients, the cascade for long-term depression-like effects may be impaired. Significance The giant SEP was furthermore enhanced by QPS.

INTRODUCTION: Teriparatide significantly reduces fracture rates in clinical trials; however, those study populations were relatively restricted and included too few patients to analyze fracture outcomes within clinically important patient subgroups. We assessed fracture outcomes in subgroups of osteoporosis patients from 4 real-world teriparatide observational studies.METHODS: Patients received teriparatide 20 μg/day for up to 24 months. Fracture rates were compared between 0 to 6 months versus >6 months using a piecewise exponential model for first fracture. Analyses included incident clinical vertebral fractures (CVF) and nonvertebral fractures (NVF), and clinical fractures (CVF and NVF) by subgroups of gender, age RESULTS: The population included 8828 patients (8117 women, 92%) with mean (SD) age 71 (10.6) years and teriparatide treatment duration 17.4 (8.6) months. Overall, CVF, NVF, clinical fracture, and hip fracture rates decreased by 62%, 43%, 50%, and 56%, respectively (all p 6 months versus 0 to 6 months. Subgroup analyses all showed significantly decreased rates after >6 months except for NVF reduction in males (n = 710, fracture rate low during months 0 to 6) and in patients using glucocorticoids, and CVF in patients with prior hip fracture. The effects of teriparatide on CVF, NVF, and clinical fractures over time were statistically consistent in all subgroups except age for CVF (p = .074, patients CONCLUSIONS: Data from 4 real-world observational studies showed statistically significant reductions during teriparatide treatment in rates of CVF, NVF, and clinical fractures in clinically relevant patient subgroups. These results should be interpreted in the context of the non-controlled design of the source studies.

Hiroyuki Enomoto,1 Hitoshi Yasuda,2 Atsushi Nishiyori,3 Shinji Fujikoshi,4 Masashi Furukawa,5 Mitsuhiro Ishida,6 Masashi Takahashi,1 Toshinaga Tsuji,7 Aki Yoshikawa,8 Levent Alev9 1Bio-Medicine, Medicines Development Unit, Eli Lilly Japan K.K, Tokyo, Japan; 2Foundation of Shiga Health Research Center, Shiga, Japan; 3Project Management, Global Development Division, Shionogi & Co. Ltd., Osaka, Japan; 4Statistical Science, Medicines Development Unit, Eli Lilly Japan K.K., Kobe, Japan; 5Biostatistics, Biostatistics Department, Shionogi& Co. Ltd., Osaka, Japan; 6Clinical Research Development, Shionogi& Co. Ltd., Osaka, Japan; 7Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 8Scientific Communications, Medicines Development Unit, Eli Lilly Japan K.K, Kobe, Japan; 9Eli Lilly, Medical Department, Lilly Turkey, Istanbul, Turkey Purpose: Duloxetine and pregabalin are recommended as first-line treatments for diabetic peripheral neuropathic pain (DPNP). However, studies have not reported a direct comparison between duloxetine and pregabalin. We conducted a postmarketing, randomized, double-blind study to assess the noninferiority of duloxetine compared with pregabalin after 12 weeks of treatment in adult patients with DPNP in Japan (NCT02417935). Patients and methods: Patients (N = 303) with distal symmetrical DPNP were randomized to and were administered duloxetine (40–60 mg/day) or pregabalin (300–600 mg/day). The primary endpoint was the change from baseline in weekly mean of the 24-hour average pain score (numeric rating scale [NRS]). Noninferiority of duloxetine compared with pregabalin was assessed with the primary endpoint at week 12. Secondary measures, including night pain and worst pain, Brief Pain Inventory-Severity and Interference rating short form (BPI-SF), Clinical Global Impression of Improvement (CGI-I), Patient Global Impression of Improvement (PGI-I), and Neuropathic Pain Symptom Inventory (NPSI), health outcome measures (EuroQol 5-Dimension index and VAS), and safety were also assessed. Results: For the 24-hour NRS average pain score, the difference between the duloxetine and pregabalin groups was 0.072 (95% CI: – 0.295, 0.439), and the upper bound of the 95% CI (0.439) did not exceed the predefined noninferiority margin (0.51), at the end of the study period. For secondary outcome measures (night pain, worst pain, BPI-SF, CGI-I, PGI-I, NPSI) and health outcome measures, both the duloxetine and pregabalin treatment groups showed an improvement from baseline with no significant between-group difference. Duloxetine and pregabalin were well tolerated and the safety profiles were consistent with previously reported results. Conclusion: This study demonstrated the noninferior efficacy of duloxetine compared with pregabalin in the treatment of adult patients with DPNP. The safety analyses showed an acceptable tolerability based on safety profiles of duloxetine and pregabalin. Keywords: serotonin and norepinephrine reuptake inhibitor, diabetic peripheral neuropathic pain, duloxetine, Japan, noninferiority, pregabalin

Objective ADAMTS-4, also called aggrecanase 1, is considered to play a key role in aggrecan degradation in human osteoarthritic (OA) cartilage, but information about regulators of ADAMTS-4 aggrecanase activity remains limited. We undertook this study to search for molecules that modulate ADAMTS-4 activity. Methods Molecules copurified with ADAMTS-4 from ADAMTS-4–transfected chondrocytic cells were sequenced by nanoscale liquid chromatography tandem mass spectrometry. Binding activity was determined by immunoprecipitation and solid-phase binding assay. Effects on ADAMTS-4 activity were examined by aggrecan digestion assay. Expression of the binding molecule in OA cartilage and chondrocytes was examined by immunohistochemistry and reverse transcription–polymerase chain reaction. Results We identified CCN1 (Cyr61) as an ADAMTS-4–binding protein and showed specific binding to the ADAMTS-4 cysteine-rich domain. Aggrecanase activity of ADAMTS-4 was inhibited by interaction with CCN1. Expression of messenger RNA for CCN1 was significantly higher in human OA cartilage than in normal cartilage. CCN1 was immunolocalized to chondrocytes in OA cartilage, showing direct correlations of immunoreactivity with the Mankin score of cartilage lesions and chondrocyte cloning. CCN1 and ADAMTS-4 were commonly coexpressed in clustered chondrocytes. CCN1 expression in OA chondrocytes was down-regulated by interleukin-1α (IL-1α) and up-regulated by transforming growth factor β (TGFβ). ADAMTS-4 expression was induced by treatment with IL-1α or TGFβ, but aggrecanase activity was detected only under stimulation with IL-1α. TGFβ-treated chondrocytes exhibited aggrecanase activity when CCN1 expression was knocked down. Conclusion Our findings provide the first evidence that CCN1 suppresses ADAMTS-4 activity and that CCN1 overexpression is directly correlated with chondrocyte cloning in OA cartilage. Our results suggest that the TGFβ/CCN1 axis plays a role in chondrocyte cluster formation through inhibition of ADAMTS-4.

Levent Alev,1 Shinji Fujikoshi,2 Aki Yoshikawa,3 Hiroyuki Enomoto,1 Mitsuhiro Ishida,4 Toshinaga Tsuji,5 Kei Ogawa,1 Shinichi Konno6 1Bio-Medicine, 2Statistical Science, 3Scientific Communications, Medicines Development Unit, Eli Lilly Japan K.K., Kobe, 4Clinical Research Development, 5Medical Affairs Department, Shionogi & Co. Ltd, Osaka, 6Department of Orthopedic Surgery, Fukushima Medical University, Fukushima, Japan Introduction: Duloxetine has demonstrated efficacy in chronic low back pain (CLBP). We examined the predictors of response to duloxetine for CLBP.Patients and methods: This was a post hoc analysis of pooled data from 4 double-blind, randomized, placebo-controlled trials of duloxetine (60mg/day for 12–14weeks) in adult patients with CLBP. Primary outcome was proportion of patients with ≥30% reduction in Brief Pain Inventory (BPI) average pain (“pain reduction”) at 12–14weeks. The proportion of patients with ≥30% and ≥50% (secondary outcome) pain reduction in duloxetine and placebo groups was compared. Variables for responder analyses were early improvement (≥15% pain reduction at Week 2), sex, age, baseline BPI average pain score, duration of CLBP, and number of painful body sites according to the Michigan Body Map (≥2 vs 1 [isolated CLBP]; 1 trial); relative risk (RR) and 95% confidence interval (CI) were calculated.Results: Compared with placebo (n = 653), a greater proportion of duloxetine-treated patients (n = 642) achieved ≥30% (59.7% vs 47.8%; P < 0.001) and ≥50% pain reduction (48.6% vs 35.1%; P < 0.001). Among duloxetine-treated patients, early improvement was associated with greater likelihood of ≥30% (RR [95% CI], 2.91 [2.30–3.67]) or ≥50% (3.24 [2.44–4.31]) pain reduction. Women were slightly more likely than men to achieve ≥30% (RR [95% CI], 1.14 [1.00–1.30]) or ≥50% (1.17 [0.99–1.38]) pain reduction. Response rates were similar between age, CLBP duration, and baseline BPI average pain score subgroups. Patients with ≥2 painful sites were more likely to respond to duloxetine 60mg relative to placebo than patients with isolated CLBP (RR, duloxetine vs placebo [95% CI]: ≥30% reduction, ≥2 painful sites 1.40 [1.18–1.66], isolated CLBP 1.07 [0.78–1.48]; ≥50% reduction, ≥2 painful sites 1.51 [1.20–1.89], isolated CLBP 1.23 [0.81–1.88]).Conclusion: Early pain reduction was indicative of overall response. Patients with multiple painful sites had more benefit from duloxetine than patients with isolated CLBP. Keywords: Brief Pain Inventory, chronic pain, SNRI, low back pain, Michigan Body Map, multiple painful sites&nbsp

Hiroyuki Enomoto,1 Shinji Fujikoshi,2 Jumpei Funai,3 Nao Sasaki,4 Michael H Ossipov,5 Toshinaga Tsuji,6 Levent Alev,7 Takahiro Ushida8 1Medical Science, Eli Lilly Japan K.K., Tokyo, 2Statistical Science, 3Science Communications, 4Medical Science, Eli Lilly Japan K.K., Kobe, Japan; 5Clinical Division, inVentiv Health, LLC, Blue Bell, PA, USA; 6Medical Affairs Department, Shionogi & Co., Ltd., Osaka, Japan; 7Medical Department, Lilly Turkey, Istanbul, Turkey; 8Multidisciplinary Pain Center, Aichi Medical University, Nagakute, Aichi, Japan Background: Comorbid depression and depressive symptoms are common in patients with chronic low back pain (CLBP). Duloxetine is clinically effective in major depressive disorder and several chronic pain states, including CLBP. The objective of this post hoc meta-analysis was to assess direct and indirect analgesic efficacy of duloxetine for patients with CLBP in previous clinical trials. Methods: Post hoc path analyses were conducted of 3 randomized, double-blind, clinical studies of patients receiving duloxetine or placebo for CLBP. The primary outcome measure for pain was the Brief Pain Inventory, average pain score. A secondary outcome measure, the Beck Depression Inventory-II, was used for depressive symptoms. The changes in score from baseline to endpoint were determined for each index. Path analyses were employed to calculate the proportion of analgesia that may be attributed to a direct effect of duloxetine on pain.Results: A total of 851 patients (400 duloxetine and 451 placebo) were included in this analysis. Duloxetine significantly improved pain scores compared with placebo (p

The present study compared simultaneous and two-staged (stages 1 and 2 with 8-month interval on average) bilateral TKAs in terms of postoperative serological status and clinical consequences. The decrease in hemoglobin over 2 weeks postoperatively was similar between groups. C-reactive protein levels and creatine phosphokinase index peaking on day 2 were significantly higher in the simultaneous group than in either staged group (P0.05). Incidence of DVT on day 7 tended to be higher in the simultaneous group, but the difference was not significant. Considering the approximately 8-month interval and 2-month earlier functional recovery with stage 2 TKAs, 6 months were saved with the simultaneous bilateral TKA group. Collectively, simultaneous bilateral TKA is likely to offer a safe and effective procedure in appropriate clinical settings involving anti-bleeding and anti-venous thromboembolism prophylaxis.

Lateral retinacular release is still being performed in patients with recurrent patellar dislocation as an additional procedure with distal realignment or medial patellofemoral ligament (MPFL) reconstruction. However, consensus remains lacking regarding suitable indications for lateral retinacular release. A 20-year-old woman presented with patellar instability in both medial and lateral directions after undergoing lateral retinacular release with MPFL reconstruction. She displayed inherent systemic joint laxity meeting all seven Carter-Wilkinson criteria. Simultaneous MPFL revision and lateral retinaculum reconstruction successfully improved patellar instability in both directions. This case provides an example of iatrogenic medial patellar instability after failed lateral retinacular release.

Introduction Detection of both upper and lower motor neuron impairments is essential for making a diagnosis of amyotrophic lateral sclerosis (ALS). Although electrophysiological findings identifying lower motor neuron damage have been established, there are few useful objective biomarkers for upper motor neuron impairment. Here, we retrospectively investigated the utility of the central motor conduction time (CMCT) for the detection of upper motor neuron impairment in patients with ALS. Methods Fifty-five patients were diagnosed as ALS from 2007 to 2017 in our hospital. Forty-five ALS patients without any signal changes in the pyramidal tracts on magnetic resonance images and 10 healthy controls participated in this study. Electromyograms were recorded from the first dorsal interosseous and tibialis anterior muscles. Transcranial magnetic stimulation and magnetic motor root stimulation were performed to measure cortical and root latencies and obtained the CMCT. ALS patients were classified into two subgroups; positive and negative Babinski’s sign. The cortical and motor root latencies and CMCT were compared between two subgroups. Finally, we calculated the rates of ALS patients with abnormally prolonged CMCT (longer than mean +2 standard deviation of normal values). Results Cortical latency, motor root latency and CMCT were significantly longer in ALS group than the control group. There were no differences in the latencies and CMCT between the two subgroups of ALS patients. The CMCT was abnormally prolonged in 60% of ALS patients with positive Babinski’s sign and 50% of those with negative Babinski’s sign, respectively. Conclusion The CMCT is useful for detecting upper motor neuron impairment in patients with ALS without any clinical pyramidal signs. CMCT can pave the way for finding upper motor neuron impairment masked by lower motor neuron damage in ALS patients.

Background: This post hoc analysis of a Japanese phase 3 randomized study (ClinicalTrials.gov identifier: NCT01855919) investigated relationships between pain severity (assessed by the Brief Pain Inventory [BPI]) and disease-specific health-related quality of life (assessed by the 24-item Roland-Morris Disability Questionnaire [RDQ-24]) in duloxetine-treated patients with chronic low back pain (CLBP). Methods: Patients with CLBP duration >6 months and BPI average score ≥4 received duloxetine 60 mg/d (N = 230) or placebo (N = 226) for 14 weeks. Spearman rank correlation coefficients were calculated for (1) BPI change from baseline and RDQ item change from baseline and (2) BPI change from baseline and the RDQ item baseline score in duloxetine-treated patients. Results: Duloxetine treatment significantly improved the RDQ-24 total score compared with placebo; the greatest improvements were observed for RDQ02, RDQ17, and RDQ13. The strongest correlations between BPI change from baseline and RDQ item change from baseline were for RDQ13, RDQ23, and RDQ10. The correlation coefficients for the correlations between BPI change from baseline and the RDQ item baseline score were generally small. Discussion: This post hoc analysis suggested that improvement in pain severity was associated with improvement in the RDQ-24 total score and in some individual RDQ items in duloxetine-treated patients with CLBP. Furthermore, positive responses to duloxetine in terms of the RDQ13, RDQ23, and RDQ10 items may correlate with better pain responses. Clinical Trial Registry: The study described in this manuscript was registered at www.clinicaltrials.gov (NCT01855919).

We investigated the characteristics of patients who achieved Japanese-style deep flexion (seiza-sitting) after total knee replacement (TKR) and measured three-dimensional positioning and the contact positions of the femoral and tibial components. Seiza-sitting was achieved after surgery by 23 patients (29 knees) of a series of 463 TKRs in 341 patients. Pre-operatively most of these patients were capable of seiza-sitting, had a lower body mass index and a favourable attitude towards the Japanese lifestyle (27 of 29 knees). According to two-/three-dimensional image registration analysis in the seiza-sitting position, flexion, varus and internal rotation angles of the tibial component relative to the femoral component had means of 148° (sd 8.0), 1.9° (sd 3.2) and 13.4° (sd 5.9), respectively. Femoral surface contact positions tended to be close to the posterior edge of the tibial polyethylene insert, particularly in the lateral compartment, but only 8.3% (two of 24) of knees showed femoral subluxation over the posterior edge. The mean contact positions of the femoral cam on the tibial post were located 7.8 mm (sd 1.5) proximal to the lowest point of the polyethylene surface and 5.5 mm (sd 0.9) medial to the centre of the post, indicating that the post-cam contact position translated medially during seiza-sitting, but not proximally. Collectively, the seiza-sitting position seems safe against component dislocation, but the risks of posterior edge loading and breakage of the tibial polyethylene post remain.Cite this article: Bone Joint J 2013;95-B:782–7.

We hypothesized that the tibial plafond revealed a novel anatomical reference axis associated with the axial alignment through an image processing technique. The plafond axis (PLA) was defined as the line connecting the midpoints of the medial and lateral plafond margin. In terms of intraclass correlation coefficient, the reproducibility to identify the PLA was not less than that to identify a conventional trans-malleolar axis (TMA). When the proximal medial-lateral axis was applied, the tibial torsion with reference to the PLA and the TMA was 12.0° ± 8.4°, and 23.3° ± 8.6°, respectively. The PLA can be considered a reproducible reference and is expected to be applicable in preoperative planning as well as postoperative evaluation of the implant alignment in total knee arthroplasty.

Objective:To explore the efficacy and stimulation frequency dependence of repetitive transcranial magnetic stimulation (rTMS) over the supplementary motor area (SMA) in Parkinson disease (PD).Methods:In this randomized, double-blind, sham-controlled, multicenter study with a parallel design, a weekly intervention was performed 8 times. The effects were monitored up to 20 weeks. By central registration, participants were assigned to 1 of 3 arms of the study: low-frequency (1-Hz) rTMS, high-frequency (10-Hz) rTMS, and realistic sham stimulation. The primary end point was the score change of the Unified Parkinson's Disease Rating Scale (UPDRS) part III from the baseline. Several nonmotor symptom scales such as the Hamilton Rating Scale for Depression, apathy score, and nonmotor symptoms questionnaire were defined as secondary end points.Results:Of the 106 patients enrolled, 36 were allocated to 1-Hz rTMS, 34 to 10-Hz rTMS, and 36 to realistic sham stimulation. Results show 6.84-point improvement of the UPDRS part III in the 1-Hz group at the last visit of the 20th week. Sham stimulation and 10-Hz rTMS improved motor symptoms transiently, but their effects disappeared in the observation period. Changes in nonmotor symptoms were not clear in any group. No severe adverse event was reported.Conclusions:The 1-Hz rTMS over the SMA was effective for motor, but not nonmotor, symptoms in PD.Level of evidence:This study provides Class I evidence that 1-Hz rTMS over the SMA is effective for motor symptoms in PD.

Hyaluronan (HA) has an extraordinarily high turnover in physiological tissues, and HA degradation is accelerated in inflammatory and neoplastic diseases. CD44 (a cell surface receptor) and two hyaluronidases (HYAL1 and HYAL2) are thought to be responsible for HA binding and degradation; however, the role of these molecules in HA catabolism remains controversial. Here we show that KIAA1199, a deafness gene of unknown function, plays a central role in HA binding and depolymerization that is independent of CD44 and HYAL enzymes. The specific binding of KIAA1199 to HA was demonstrated in glycosaminoglycan-binding assays. We found that knockdown of KIAA1199 abolished HA degradation by human skin fibroblasts and that transfection of KIAA1199 cDNA into cells conferred the ability to catabolize HA in an endo-β- N -acetylglucosaminidase–dependent manner via the clathrin-coated pit pathway. Enhanced degradation of HA in synovial fibroblasts from patients with osteoarthritis or rheumatoid arthritis was correlated with increased levels of KIAA1199 expression and was abrogated by knockdown of KIAA1199. The level of KIAA1199 expression in uninflamed synovium was less than in osteoarthritic or rheumatoid synovium. These data suggest that KIAA1199 is a unique hyaladherin with a key role in HA catabolism in the dermis of the skin and arthritic synovium.

A retrospective study was conducted to examine the implementation status of newborn hearing screening (NHS) of 6,063 infants born in a single community hospital in Japan between 2005 and 2013. An automated auditory brainstem response device was used for NHS and an auditory brainstem response was mainly used for further diagnostic evaluation. Although the participation rate in the NHS was 88.8% in 2013, increasing year by year, it failed to reach 100% probably because NHS is a charged option under the current Japanese healthcare system. Among 40 (0.66%) infants who finally failed their NHS, 34 were referred for subsequent diagnostic evaluation and the remaining 6 were lost to follow-up. Thirty-one of these 34 were diagnosed as having hearing impairment and 3 (0.05%) were identified as having normal hearing, which is considered as a false positive. Both the final referral rate and the hearing impairment rate were significantly higher in the high-risk than in the low-risk group. Compared to the previous national report, the rate of bilateral hearing impairment (0.33%) was significantly higher in this study. Ten (38.5%) out of 26 in the high-risk group were most often diagnosed with otitis media with effusion (OME), while 4 (50%) out of 8 in the low-risk group were diagnosed as having sensorineural hearing loss. Seven (35%) out of 20 with bilateral hearing impairment attained a normal hearing level at a median age of 18 months. Although the primary aim of NHS is early detection of congenital permanent hearing loss, OME is observed commonly in NHS-failed infants. It is therefore important to examine the middle ear status carefully as part of the diagnostic evaluation. Thirty-four infants underwent further diagnostic evaluation at a median age of 46 days, and hearing aids were given in 10 of them at a median age of 5.6 months without delay. Because high-risk patients often tend to be lost to follow-up, otolaryngologists have to give a detailed explanation to caregivers and to build a solid support system for children with hearing impairment.

The effects of surgical approaches and patellar positions on joint gap measurement during total knee arthroplasty (TKA) remain unclear. We hypothesized that joint gap changes with different knee flexion angles would not be consistent within four different approaches and two different patellar positions.This study enrolled 80 knees undergoing posterior-stabilized TKA. For 60 varus knees, parapatellar, midvastus, and subvastus approaches were used in 20 knees each. For 20 valgus knees, a lateral subvastus approach was used. Component gap length and inclination were measured intra-operatively using a specific tensor device under 40 lb with the patella reduced or shifted laterally, at 0°, 45°, 90°, and 135° of knee flexion.Mean gap lengths at 45° and 90° of knee flexion were significantly larger with the parapatellar approach than with midvastus or lateral subvastus approaches (P0.05). Regarding gap inclination, varus angle increased linearly through the entire arc of flexion in all four approaches. When the patella was shifted laterally, gap lengths at 45°, 90°, and 135° were significantly reduced compared with those for the patella reduced in the subvastus approach, whereas gap length was constant in the parapatellar approach, regardless of patellar position.Joint gap kinematics was not consistent within four different approaches and two different patellar positions. Relatively large gaps at 45° and 90° were unique features for the parapatellar approach. Surgeons should be aware that the flexion gap is reduced when the patella is shifted laterally in vastus medialis-preserving approaches such as the subvastus approach.II.

Objective Vascular endothelial growth factor 165 (VEGF165) and its receptors, including neuropilin 1 (NRP-1), are overexpressed in human osteoarthritic (OA) articular cartilage, although their functional roles in the cartilage are not fully understood. An axon-guidance molecule, semaphorin 3A (Sema3A), which binds to NRP-1, acts as an antagonist of VEGF signaling in endothelial cells. The aim of this study was to examine the expression of Sema3A and the functions of the VEGF165/Sema3A/NRP-1 axis in OA cartilage. Methods The expression of Sema3A in OA and normal cartilage samples was examined by real-time polymerase chain reaction and immunohistochemical analyses. Functional analyses of VEGF165 and Sema3A were carried out using OA chondrocytes in culture. The migration activity of chondrocytes was examined in a monolayer wound assay. The effects of Sema3A on VEGF165-induced up-regulation of matrix metalloproteinases (MMPs) and intracellular signaling were also studied in cultured chondrocytes. Results Sema3A expression was significantly elevated in OA cartilage as compared to normal cartilage. Sema3A immunoreactivity directly correlated with the Mankin score and with chondrocyte cloning. VEGF165 promoted the migration of chondrocytes, and this activity was suppressed by VEGF receptor 2 tyrosine kinase inhibitors. Sema3A antagonized the chondrocyte migration promoted by VEGF165, and the activity was blocked by a selective inhibitor of, or small interfering RNA for, Sema3A. VEGF165-induced overexpression of MMPs and phosphorylation of ERK and focal adhesion kinase in chondrocytes were inhibited by Sema3A. Conclusion Our findings provide the first evidence that Sema3A is overexpressed, with a direct correlation with cloning, in OA cartilage and that it suppresses the VEGF165-promoted migration of chondrocytes. Our findings also suggest that Sema3A plays a role in chondrocyte cloning through inhibition of cell migration in OA cartilage.

It has been reported that the brain derived neurotrophic factor (BDNF) has some functional roles in inducing plasticity in the adult human brain and the Val66Met BDNF polymorphism affects the plasticity induction. In contrast, some long lasting effects were not fully induced in subjects with non-Val-Val polymorphism. In this communication, we retrospectively investigated whether this polymorphism affects the plastic changes induced by a newly developed stimulation method (quadripulse stimulation (QPS)) in 12 subjects. Both long-term potentiation (LTP) and long-term depression (LTD) like effects were induced by QPS for 30min in any types of BDNF Val66Met polymorphisms. This finding presents a striking contrast to the previous results, which showed reduced long-term effects elicited by some other induction methods in subjects with non-Val-Val polymorphism. Although we are not able to make a final conclusion about the effect of Val66Met BDNF polymorphism on QPS because of the small number of subjects studied, QPS may be less affected by the BDNF polymorphism than several other protocols for inducing LTP/LTD-like effects in humans. Several possibilities may explain this difference. One candidate possibility is that QPS may be long enough for inducing the late LTP/LTD like effect whereas the other stimulation methods may be long enough for early but not enough for late LTP/LTD like effect. It is conspicuous that the QPS for 30min does elicit stable bidirectional long-term effects even in subjects with non-Val-Val polymorphism of BDNF.

Purpose The purpose of this study was to investigate the clinical results of single-stage revision anterior cruciate ligament reconstruction (ACLR) after synthetic ligament failure. Methods The subjects comprised 20 patients who underwent revision ACLR after synthetic ligament failure. All revisions were performed with bone–patellar tendon–bone graft, and bone tunnel expansion after removal of synthetic materials was treated with bone plugs sized and trimmed as necessary to fill the bone tunnels. Clinical results were assessed at a mean of 2.8 years postoperatively, followed by comparison with the results of 20 primary ACLRs selected as case-matched controls. Assessment included the Lysholm score, International Knee Documentation Committee (IKDC) evaluation, instrumented laxity testing, and radiologic examination. Results Bone tunnel enlargement to 11 mm in diameter or greater was found in 10 of 20 revision ACLRs. However, favorable anteroposterior stability was obtained at final follow-up (1.4 ± 2.0 mm in revision ACLR group and 1.5 ± 1.5 mm in primary ACLR group). The overall Lysholm score improved significantly from preoperatively to final follow-up, but the revision ACLR group showed significantly worse results for the pain parameter than the primary ACLR group. The final IKDC results also showed significant postoperative improvement, but the number of cases with grade C was significantly higher in the revision ACLR group than in the primary ACLR group, which was attributed to radiologically confirmed osteoarthritis in the revision ACLR group. Conclusions Single-stage revision ACLR with bone–patellar tendon–bone graft after synthetic ligament failure yielded favorable results in terms of IKDC grade, Lysholm score, and anteroposterior stability, despite enlarged bone tunnels after removal of synthetic material. Inferior results for the radiologic and pain parameters of the IKDC and Lysholm scores were attributed to osteoarthritic changes inherent to the revision ACLR group. Level of Evidence Level III, therapeutic case-control study.

OBJECTIVEPrevious studies have suggested a correlation between interhemispheric sensorimotor networks and recovery from supplementary motor area (SMA) syndrome. In the present study, the authors examined the hypothesis that interhemispheric connectivity of the primary motor cortex in one hemisphere with the contralateral SMA may be important in the recovery from SMA syndrome. Further, they posited that motor cortical fiber connectivity with the SMA is related to the severity of SMA syndrome.METHODSPatients referred to the authors’ neurological surgery department were retrospectively analyzed for this study. All patients with tumors involving the unilateral SMA region, without involvement of the primary motor area, and diagnosed with SMA syndrome in the postoperative period were eligible for inclusion. Preoperative diffusion tensor imaging tractography (DTT) was used to examine the number of fiber tracts (NFidx) connecting the contralateral SMA to the ipsilateral primary motor area via the corpus callosum. Complete neurological examination had been performed in all patients in the pre- and postoperative periods. All patients were divided into two groups: those who recovered from SMA syndrome in ≤ 7 days (early recovery group) and those who recovered in ≥ 8 days (late recovery group). Differences between the two groups were assessed using the Student t-test and the chi-square test.RESULTSEleven patients (10 men, 1 woman) were included in the study. All patients showed transient postoperative motor deficits because of SMA syndrome. Tractography data revealed NFidx from the contralateral SMA to the ipsilateral primary motor area via the corpus callosum. The mean tumor volume (early 27.87 vs late 50.91 cm3, p = 0.028) and mean NFidx (early 8923.16 vs late 4726.4, p = 0.002) were significantly different between the two groups. Fisher exact test showed a significant difference in the days of recovery from SMA syndrome between patients with an NFidx > 8000 and those with an NFidx < 8000.CONCLUSIONSDiffusion tensor imaging tractography may be useful for predicting the speed of recovery from SMA syndrome. To the authors’ knowledge, this is the first DTT study to identify interhemispheric connectivity of the SMA in patients with brain tumors.

Mucoid degeneration of the anterior cruciate ligament (ACL) is an unusual entity that has been described only since 1999. With increasing use of magnetic resonance imaging (MRI) to evaluate the knee, a number of cases with this entity have been accumulated to date, and characteristic features of MRI have been accepted as important diagnostic information. Past experience can be summarized as showing that the patients are middleaged and they present with knee pain and limited motion but without clinical ligament instability. We report herein two cases of mucoid degeneration of the ACL in which the patients were in their twenties. These cases differed substantially from previously reported cases, not only in the much younger age but also in that the patients exhibited substantial subclinical ACL insuffi ciency manifesting only in an anesthetized condition. Despite their young age, both patients also presented with intercondylar osteophyte, which was removed at the time of operation to avoid impingement of the ACL. The causal relation between minor ACL insuffi ciency and such osteophyte formation warrants further consideration. Although partial debridement of degenerative ACL has been reported to alleviate knee pain and is the common therapeutic strategy for this entity, patients should be carefully followed particularly for knee instability postoperatively owing to the inherent loss of ACL integrity associated with mucoid degeneration. Case reports

Highly luminescent water-soluble InP/ZnS core−shell nanocrystals were prepared using a newly developed method that incorporates reactive phase transfer and photochemical processing. Poor-emitting InP nanocrystals (NCs, 2−4 nm) prepared solvothermally using toluene were transferred into alkaline aqueous solution containing thiol and zinc ions. When these NCs in aqueous solution were subsequently irradiated by ultraviolet (UV) light, they showed intense size-dependent photoluminescence (PL) from green to red due to the formation of a thick (more than 1 nm) ZnS shell on the NCs. The surface dissolution of the NCs, under conditions in which bulk InP does not dissolve due to its covalent bond nature, was observed at two steps: phase transfer and shell formation. This dissolution competed with the formation of the ZnS layer at the start of UV irradiation. Since the UV irradiation enables creation of a thick shell by optimizing the synthesizing conditions, high PL efficiency (30−68%) was obtained in water with s...

Mismatch negativity (MMN) is generated by a comparison between an incoming sound and the memory trace of preceding sounds stored in sensory memory without any attention to the sound. N100 (N1) is associated with the afferent response to sound onset and reflects early analysis of stimulus characteristics. MMN generators are present in the temporal and frontal lobe, and N1 generators are present in the temporal lobe. The parietal lobe is involved in MMN generation elicited by a change in duration. The anatomical network connecting these areas, lateralization, and the effect of the side of ear stimulation on MMN remain unknown. Thus, we studied the effects of low-frequency repetitive transcranial magnetic stimulation (rTMS) over the left parietal lobe on MMN and N1 in 10 healthy subjects. Low-frequency rTMS over the left parietal lobe decreased the amplitude of MMN following right ear sound stimulation, but the amplitude was unaffected with left ear sound stimulation. We observed no significant changes in the amplitude of N1 or the latency of MMN or N1. These results suggest that low-frequency rTMS over the left parietal lobe modulates the detection of early auditory changes in duration in healthy subjects. Stimulation that is contralateral to the side of the ear experiencing sound may affect the generation of duration MMN more than ipsilateral stimulation.