[Simulation for Endovascular Treatment].

With the advent of high-resolution imaging and advancements in computational fluid dynamics(CFD)and computational structural mechanics(CSM)analyses, clinical simulation of endovascular intervention has gradually become feasible. Virtual stents have become indispensable for coil embolization. For braided stents, such as those with low-profile visualized intraluminal support and flow diverters, predicting postplacement elongation and contraction is challenging; however, software development has enabled more precise treatment planning. Additionally, simulations utilizing three-dimensional(3D)printer models can enable realistic simulations of procedures such as intracranial stents and Woven EndoBridge placement. This approach is beneficial for shunt disorders such as arteriovenous malformations and dural arteriovenous fistulas, offering 3D visualization of shunt access routes and intuitive treatment strategy planning, even for beginners. Furthermore, it can be applied to procedures such as open surgical clipping and nidus resection, aiding in the selection of suitable clips and considerations for ideal resection based on nidus curvature. Simulations using CFD, CSM, and 3D printers are crucial for training surgeons and handling new devices. Harnessing medicine-engineering synergy is essential, and regulatory approval(insurance coverage)and appropriate commercialization of simulations are paramount for the future.

Vertebral artery V3 portion-radial artery-distal common carotid artery (V3-RA-dCCA) bypass for large basilar trunk aneurysm with bilateral proximal common carotid artery occlusion-technical note.

BACKGROUND: 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. CASE DESCRIPTION: 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. CONCLUSION: 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.

High temperature promotes amyloid ß-protein production and γ-secretase complex formation via Hsp90.

Alzheimer's disease (AD) is characterized by neuronal loss and accumulation of ß-amyloid-protein (Aß) 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 Aß production; however, its mechanism remains largely unknown. We hypothesized that the increase in core body temperature induced by sleep deprivation may promote Aß production. Here, we report temperature-dependent regulation of Aß production. We found that an increase in temperature, from 37 °C to 39 °C, significantly increased Aß 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 Aß 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 Aß production by modulating γ-secretase complex formation through the binding of Hsp90 to NCT/APH-1.

Long-Term Pain Management and Health Care Resource Use Among an Employed Population in Japan with Knee Osteoarthritis Combined with Low Back Pain.

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.

An Essential Role of the Intraparietal Sulcus in Response Inhibition Predicted by Parcellation-Based Network.

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.

The Clinical Relevance of Pain Severity Changes: Is There Any Difference Between Asian and Caucasian Patients With Osteoarthritis Pain?

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.

Reduction of Hip and Other Fractures in Patients Receiving Teriparatide in Real-World Clinical Practice: Integrated Analysis of Four Prospective Observational Studies.

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.

An Open-Label, 52-Week, Phase III Trial of Duloxetine in Japanese Patients with Chronic Low Back Pain.

OBJECTIVE: To evaluate the safety and efficacy of duloxetine treatment for 52 weeks. DESIGN: Multicenter, open-label, phase III clinical study. SETTING: Forty-one medical institutions in Japan. SUBJECTS: Japanese patients with chronic low back pain (CLBP). METHODS: Duloxetine 60 mg once-daily was administered for 52 weeks. Safety was evaluated based on adverse events (AEs), vital signs, laboratory test values, electrocardiogram, Columbia-Suicide Severity Rating Scale, and occurrence of falls. The efficacy outcome measures were the Brief Pain Inventory (BPI; average pain, worst pain, least pain, and pain right now), BPI Interference, Patient's Global Impression of Improvement (PGI-I), Clinical Global Impressions of Severity (CGI-S), Roland-Morris Disability Questionnaire-24 (RDQ-24), 36-Item Short-Form Health Survey (SF-36), and European Quality of Life-5 Dimensions Questionnaire (EQ-5D). RESULTS: In total, 151 patients (83 who completed a 14-week placebo-controlled superiority trial and 68 newly registered patients) were enrolled. The incidence rates of AEs and adverse drug reactions (ADRs) were 86.1% and 50.3%, respectively. ADRs with an incidence of ≥5% were somnolence, constipation, nausea, and dry mouth. Treatment discontinuation for AEs occurred in 16 patients. A significant reduction in the BPI average pain score (mean ± SD) was observed at all assessment time points from week 2 (-1.02 ± 1.37) to week 50 (-2.26 ± 1.63), compared with baseline. BPI pain severity (worst pain, least pain, and pain right now), BPI Interference, PGI-I, CGI-S, RDQ-24, SF-36, and EQ-5D showed significant improvement. CONCLUSION: Japanese patients with CLBP had significant pain reduction over 52 weeks without new safety concerns.

Frequency-dependent current perception threshold in healthy Japanese adults.

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.

Prediction of recovery from supplementary motor area syndrome after brain tumor surgery: preoperative diffusion tensor tractography analysis and postoperative neurological clinical course.

OBJECTIVE Previous 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. METHODS Patients 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. RESULTS Eleven 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. CONCLUSIONS Diffusion 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.

Efficacy of duloxetine by prior NSAID use in the treatment of chronic osteoarthritis knee pain: A post hoc subgroup analysis of a randomized, placebo-controlled, phase 3 study in Japan.

BACKGROUND: 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. METHODS: 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). RESULTS: 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. CONCLUSIONS: 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.

The effect of age on the homotopic motor cortical long-term potentiation-like effect induced by quadripulse stimulation.

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.

Efficacy and safety of teriparatide in bisphosphonate-pretreated and treatment-naive patients with osteoporosis at high risk of fracture: Post hoc analysis of a prospective observational study.

BACKGROUND: Teriparatide is the first anabolic agent shown to reduce the risk of fractures in patients with osteoporosis. In Japan, teriparatide is prescribed to treat patients at high risk of fracture. Given that bisphosphonates are commonly used prior to teriparatide as treatment for osteoporosis, information on the effectiveness and safety of teriparatide with or without previous bisphosphonate treatment is helpful for physicians in clinical practice. This study aims to report the effectiveness and safety of teriparatide in treatment-naive and bisphosphonate-pretreated patients in Japan as real-world evidence. METHODS: A post hoc analysis of a postmarketing surveillance study was conducted in Japanese patients with osteoporosis at high risk of fracture who received 24-month treatment of daily teriparatide. Changes in bone turnover biomarkers and bone mineral density and incidence of new fractures were analyzed in treatment-naive as well as bisphosphonate-pretreated patients. RESULTS: The analysis included 1433 patients (treatment-naive, n = 659; bisphosphonate-pretreated, n = 774). Bone mineral density increased significantly from baseline at 24 months in both treatment-naive (lumbar spine, 13.45%; femoral neck, 5.16%; total hip, 4.46%) and bisphosphonate-pretreated (lumbar spine, 11.20%; femoral neck, 2.22%; total hip, 0.67%) patients. The incidence rates of new vertebral and nonvertebral fractures at 24 months were 1.69% and 3.37%, respectively, in treatment-naive patients and 3.60% and 5.56%, respectively, in bisphosphonate-pretreated patients. The incidence of adverse drug reactions was 6% in treatment-naive patients and 10% in bisphosphonate-pretreated patients. The most common adverse drug reaction in treatment-naive and bisphosphonate-pretreated patients was nausea (0.91%) and hyperuricaemia (1.81%), respectively. CONCLUSIONS: In this post hoc analysis, no new safety concerns and similar effectiveness of teriparatide were observed in Japanese patients with osteoporosis at high risk of fracture, regardless of their previous treatment status with bisphosphonates.

Effects of 1950 MHz W-CDMA-like signal on human spermatozoa.

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.

KIAA1199, a deafness gene of unknown function, is a new hyaluronan binding protein involved in hyaluronan depolymerization.

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-ß-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.

[Newborn Hearing Screening and Subsequent Diagnostic Evaluation: Analysis and Outcomes of 6,063 Infants Born in a Community Hospital].

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.

Effects of L-Dopa and pramipexole on plasticity induced by QPS in human motor cortex.

Abnormal plasticity has been reported in the brain of patients with Parkinson's disease (PD), especially in the striatum. Although both L-Dopa and dopamine agonist remain to be the mainstay of the treatment in PD, their differential effects on cortical plasticity are unclear. We applied quadripulse stimulation (QPS) over the primary motor cortex (M1) in ten normal subjects to induce bidirectional long-term motor cortical plasticity. A long-term potentiation (LTP)-like effect was induced in the primary motor cortex (M1) by high-frequency QPS5 (interpulse interval of 5 ms) over M1, whereas a long-term depression (LTD)-like effect was induced by low-frequency QPS50 (interpulse interval of 50 ms), and the effects lasted up to 90 min after the stimulation pulses have ceased. In a double-blind randomized placebo-controlled crossover design, L-Dopa carbidopa 100 mg, pramipexole 1.5 mg [150 mg LED (L-Dopa equivalent dose)], or placebo was administered to the subjects 30 min before applying QPS. L-Dopa enhanced both LTP- and LTD-like plasticity as compared to placebo. In contrast, neither an LTP-like effect nor an LTD-like effect was modulated by pramipexole. The lack of LTP enhancement by pramipexole is compatible with the finding that D1 activation strengthens LTP because pramipexole is almost purely a D2 agonist. The lack of LTD enhancement by pramipexole is also consistent with the finding that both D1 and D2 coactivation is required for LTD. This is the first report to show that dopamine enhances LTD as well as LTP in the human brain and that coactivation of D1 and D2 is a requisite for LTD enhancement in normal humans.

Comparison of postoperative morbidity between simultaneous bilateral and staged bilateral total knee arthroplasties: serological perspective and clinical consequences.

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 (P<0.05). 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.

Roles of the cerebellum and basal ganglia in temporal integration: Insights from a synchronized tapping task.

OBJECTIVE: The aim of this study was to clarify the roles of the cerebellum and basal ganglia for temporal integration. METHODS: We studied 39 patients with spinocerebellar degeneration (SCD), comprising spinocerebellar atrophy 6 (SCA6), SCA31, Machado-Joseph disease (MJD, also called SCA3), and multiple system atrophy (MSA). Thirteen normal subjects participated as controls. Participants were instructed to tap on a button in synchrony with isochronous tones. We analyzed the inter-tap interval (ITI), synchronizing tapping error (STE), negative asynchrony, and proportion of delayed tapping as indicators of tapping performance. RESULTS: The ITI coefficient of variation was increased only in MSA patients. The standard variation of STE was larger in SCD patients than in normal subjects, especially for MSA. Negative asynchrony, which is a tendency to tap the button before the tones, was prominent in SCA6 and MSA patients, with possible basal ganglia involvement. SCA31 patients exhibited normal to supranormal performance in terms of the variability of STE, which was surprising. CONCLUSIONS: Cerebellar patients generally showed greater STE variability, except for SCA31. The pace of tapping was affected in patients with possible basal ganglia pathology. SIGNIFICANCE: Our results suggest that interaction between the cerebellum and the basal ganglia is essential for temporal processing. The cerebellum and basal ganglia and their interaction regulate synchronized tapping, resulting in distinct tapping pattern abnormalities among different SCD subtypes.

Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation.

We have identified a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family, ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white-spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was identified using Adamts9(+/-);bt/bt mice, which have a fully penetrant cleft palate. Palate closure was delayed, although eventually completed, in both Adamts9(+/-);bt/+ and bt/bt mice, demonstrating cooperation of these genes. Adamts20 is expressed in palatal mesenchyme, whereas Adamts9 is expressed exclusively in palate microvascular endothelium. Palatal shelves isolated from Adamts9(+/-);bt/bt mice fused in culture, suggesting an intact epithelial TGFß3 signaling pathway. Cleft palate resulted from a temporally specific delay in palatal shelf elevation and growth towards the midline. Mesenchyme of Adamts9(+/-);bt/bt palatal shelves had reduced cell proliferation, a lower cell density and decreased processing of versican (VCAN), an extracellular matrix (ECM) proteoglycan and ADAMTS9/20 substrate, from E13.5 to E14.5. Vcan haploinsufficiency led to greater penetrance of cleft palate in bt mice, with a similar defect in palatal shelf extension as Adamts9(+/-);bt/bt mice. Cell density was normal in bt/bt;Vcan(hdf)(/+) mice, consistent with reduced total intact versican in ECM, but impaired proliferation persisted in palate mesenchyme, suggesting that ADAMTS-cleaved versican is required for cell proliferation. These findings support a model in which cooperative versican proteolysis by ADAMTS9 in vascular endothelium and by ADAMTS20 in palate mesenchyme drives palatal shelf sculpting and extension.