The tight junction protein occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice.

Blood-brain barrier (BBB) disruption contributes to brain injury and neurological impairment. Tight junctions (TJs) and cell-cell adhesion complexes develop between endothelial cells in the brain to establish and maintain the BBB. Occludin, the first transmembrane protein identified in TJs, has received intense research interest because numerous in vitro studies have suggested its importance in maintaining BBB integrity. However, its role in maintaining BBB integrity after ischemic stroke is less clear owing to the lack of in vivo evidence. This study aimed to investigate the dynamics and function of occludin across the acute and chronic phases after stroke using occludin-deficient mice. By photochemically induced thrombosis model, the expression of occludin was decreased in brain endothelial cells from ischemic lesions. The neurological function of occludin-deficient mice was continuously impaired compared to that of wild-type mice. BBB integrity evaluated by Evans blue and 0.5-kDa fluorescein in the acute phase and by 10-kDa fluorescein isothiocyanate-labeled dextran in the chronic phase was decreased to a greater extent after stroke in occludin-deficient mice. Furthermore, occludin-deficient mice showed decreased claudin-5 and neovascularization after stroke. Our study reveals that occludin plays an important role from the acute to the chronic phase after ischemic stroke in vivo.

Comparison of surgical outcomes of posterior surgeries between cervical spondylotic myelopathy and ossification of the posterior longitudinal ligament.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: To compare the surgical outcomes and complications of posterior decompression between individuals with cervical spondylotic myelopathy (CSM) and those with ossification of the posterior longitudinal ligament (OPLL). SETTING: Seventeen medical institutions in Japan. METHODS: This study included 814 individuals with CSM (n = 636) and OPLL (n = 178) who underwent posterior decompression. Propensity score matching of the baseline characteristics was performed to compare surgical outcomes and perioperative complications between the CSM and OPLL groups. RESULTS: Before propensity score matching, the OPLL group had higher percentage of male individuals, body mass index, and number of stenosis levels and longer duration of symptoms (P < 0.01, P < 0.01, P < 0.01, and P < 0.01, respectively). After matching, the baseline characteristics were comparable between the CSM (n = 98) and OPLL (n = 98) groups. The postoperative Japanese Orthopaedic Association (JOA) scores, preoperative-to-postoperative changes in the JOA scores, and JOA score recovery rates were not significantly different between the groups (P = 0.42, P = 0.47, and P = 0.09, respectively). The postoperative visual analog scale (VAS) score for neck pain and preoperative-to-postoperative changes in the VAS score for neck pain were not significantly different between the groups (P = 0.25 and P = 0.50, respectively). The incidence of perioperative complications was comparable between groups. CONCLUSION: Neurological improvement and complication rates after surgery were comparable between individuals with CSM and those with OPLL, suggesting similar effectiveness and safety of posterior decompression for both conditions.

Diabetes Does Not Adversely Affect Neurological Recovery and Reduction of Neck Pain After Posterior Decompression Surgery for Cervical Spondylotic Myelopathy: Results From a Retrospective Multicenter Study of 675 Patients.

STUDY DESIGN: Retrospective multicenter study. OBJECTIVE: The aim of this study was to identify the impact of diabetes on surgical outcomes of posterior decompression for cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: Although some previous studies have reported surgical outcomes of posterior decompression for CSM in diabetic patients, their results were inconsistent. METHODS: We included 675 patients with CSM who underwent posterior decompression. Patients were divided into diabetic (n = 140) and nondiabetic (n = 535) groups according to the diabetic criteria for glucose intolerance. Surgical outcomes as assessed by the Japanese Orthopedic Association (JOA) scores and visual analog scale (VAS) for neck pain were compared between groups. Subsequently, the functional outcomes of diabetic patients were compared between the mild (n = 131) and moderately severe (n = 9) groups. All patients were followed up for at least 1 year after surgery. RESULTS: Compared with the nondiabetic group, the diabetic group showed lower pre- and postoperative JOA scores (P = 0.025 and P = 0.001, respectively) and a lower JOA score recovery rate (RR) (P = 0.009). However, the preoperative-to-postoperative changes in JOA scores in the diabetic and nondiabetic groups were not significantly different (P = 0.988). Pre- and postoperative VAS for neck pain and postoperative reduction of neck pain were comparable between groups (P = 0.976, P = 0.913 and P = 0.688, respectively). Although statistical analysis was not performed due to the small underpowered sample size, functional outcomes assessed by the JOA score RR (43.3 ±â€Š37.1% vs. 45.3 ±â€Š33.9%) and preoperative-to-postoperative changes in JOA scores (3.0 ±â€Š2.2 vs. 2.7 ±â€Š2.5) were similar between the mild and moderately severe diabetes groups. CONCLUSION: CSM patients with diabetes experienced improvements in neurological function and neck pain as a result of posterior decompression to the same extent seen in patients without diabetes.Level of Evidence: 3.

Association of Susceptibility Genes for Adolescent Idiopathic Scoliosis and Intervertebral Disc Degeneration With Adult Spinal Deformity.

STUDY DESIGN: Genetic case-control study of single nucleotide polymorphisms (SNPs). OBJECTIVE: To examine the association of previously reported susceptibility genes for adolescent idiopathic scoliosis (AIS) and intervertebral disc (IVD) degeneration with adult spinal deformity (ASD). SUMMARY OF BACKGROUND DATA: ASD is a spinal deformity that develops and progresses with age. Its etiology is unclear. Several ASD susceptibility genes were recently reported using a candidate gene approach; however, the sample sizes were small and associations with ASD development were not determined. METHODS: ASD was defined as structural scoliosis with a Cobb angle more than 15° on standing radiographs, taken of patients at age 40 to 75 years in this study. Subjects in whom scoliosis was diagnosed before age 20 were excluded. We recruited 356 Japanese ASD subjects and 3341 healthy controls for case-control association studies of previously reported SNPs. We genotyped four known AIS-associated SNPs (rs11190870 in LBX1, rs6570507 in GPR126, rs10738445 in BNC2, and rs6137473 in PAX1) and three IVD degeneration-associated SNPs (rs1245582 in CHST3, rs2073711 in CILP, and rs1676486 in COL11A1) by the Invader assay. RESULTS: Among the AIS-associated SNPs, rs11190870 and rs6137473 showed strong and nominal associations with ASD (P = 1.44 × 10, 1.00 × 10, respectively). Of the IVD degeneration-associated SNPs, rs1245582 and rs2073711 showed no association with ASD, while rs1676486 showed a nominal association (P = 1.10 × 10). In a subgroup analysis, rs11190870 was significantly associated with a Cobb angle more than 20° in the minor thoracic curve (P = 1.44 × 10) and with a left convex lumbar curve (P = 6.70 × 10), and nominally associated with an apical vertebra higher than L1 (P = 1.80 × 10). CONCLUSION: rs11190870 in LBX1, a strong susceptibility SNP for AIS, may also be a susceptibility SNP for ASD. Thus, ASD and AIS may share a common genetic background. LEVEL OF EVIDENCE: 4.

Usefulness of end-diastolic ratio in carotid ultrasonography for the screening of dural arteriovenous fistula: a case series.

We report three cases in which carotid ultrasonography was useful for the diagnosis of dural arteriovenous fistula (dAVF). In all cases, dAVFs were fed by branches of the external carotid artery (ECA) and had retrograde leptomeningeal venous drainage. Carotid ultrasonography revealed high end-diastolic ratio (ED ratio) of the common carotid artery (CCA) (1.49-2.16) and low resistance index (RI) of the ECA (0.59-0.66). They were normalized after endovascular treatment (ED ratio of CCA 1.02-1.06, RI of ECA 0.75-0.87). In conclusion, high ED ratio of the CCA and low RI of the ECA might be a useful indicator for both screening and follow-up of dAVF.

P-Wave Terminal Force in Lead V1 Predicts Paroxysmal Atrial Fibrillation in Acute Ischemic Stroke.

BACKGROUND: Detection of paroxysmal atrial fibrillation (PAF) in cryptogenic stroke is critical to selecting an antithrombotic therapy for preventing recurrent stroke. However, the predictor of PAF in patients with acute ischemic stroke is not well elucidated. P-wave terminal force in lead V1 (PTFV1) is a standard electrocardiogram marker of left atrial abnormality. In this study, we aimed to investigate the utility of PTFV1 for the prediction of PAF in patients with acute ischemic stroke. METHODS: The study included 295 consecutive patients who had acute ischemic stroke and were admitted to the hospital between September 2014 and August 2016. Patients with a known history of PAF, persistent atrial fibrillation, or cardiac pacemaker were excluded from the study. The clinical characteristics of patients with or without PAF were compared, and multiple logistic regression analysis was performed to assess the independent contribution of each variable. RESULTS: Among 226 patients eligible for our analysis, 16 (7.1%) were diagnosed with PAF after admission. PTFV1 was significantly higher in patients with PAF than those without PAF (.051 versus .027 mm⋅s; P < .001). Multivariate analysis showed that PTFV1 per .01 mm⋅s increase was strongly associated with PAF (odds ratio, 1.61; 95% confidence interval, 1.24-2.09; P < .001). The optimal cutoff value of PTFV1 for the prediction of PAF was .04 mm⋅s. CONCLUSIONS: PTFV1 is a strong predictor of PAF detection in acute ischemic stroke.

External cavity diode laser with frequency drift following natural variation in air pressure.

A compact and mechanically very robust external cavity diode laser was made by removing any position adjusters such as precision screws and piezo actuators, taking advantage of a cat's eye retroreflector insensitive to misalignment. Under free-running operation during 150 h, the frequency drift followed natural variation in air pressure with a ratio of -66.6±0.1 MHz/hPa in a range between 1001.5 and 1013.6 hPa. The ratio was in good agreement with that estimated from variation in the effective cavity length derived from the relation between the pressure and the refractive index of air. These results indicate that an external cavity diode laser with predictable frequency drift was successfully created.

Atomic fountain clock with very high frequency stability employing a pulse-tube-cryocooled sapphire oscillator.

The frequency stability of an atomic fountain clock was significantly improved by employing an ultra-stable local oscillator and increasing the number of atoms detected after the Ramsey interrogation, resulting in a measured Allan deviation of 8.3 × 10(-14)τ(-1/2)). A cryogenic sapphire oscillator using an ultra-low-vibration pulse-tube cryocooler and cryostat, without the need for refilling with liquid helium, was applied as a local oscillator and a frequency reference. High atom number was achieved by the high power of the cooling laser beams and optical pumping to the Zeeman sublevel m(F) = 0 employed for a frequency measurement, although vapor-loaded optical molasses with the simple (001) configuration was used for the atomic fountain clock. The resulting stability is not limited by the Dick effect as it is when a BVA quartz oscillator is used as the local oscillator. The stability reached the quantum projection noise limit to within 11%. Using a combination of a cryocooled sapphire oscillator and techniques to enhance the atom number, the frequency stability of any atomic fountain clock, already established as primary frequency standard, may be improved without opening its vacuum chamber.

Generation of incoherent light from a laser diode subject to external optical injection from a superluminescent diode.

In this study, incoherent light with a spectral linewidth of 7 nm and 140 mW of power was generated from a laser diode (LD) into which incoherent light emitted from a superluminescent diode was injected with 2.7 mW of power. The spectral linewidth of the light from the LD was broadened to 12 nm when the diode's output power was reduced to 15 mW. In the process of transformation from single-mode laser light to incoherent light with a broad spectrum by increasing injection-light power, multimode laser oscillation and a noisy spectrum were found in the light from the LD. This optical system can be used not only for amplification of incoherent light but also as a coherence-convertible light source.

Changes in the cross-sectional area of deep posterior extensor muscles of the cervical spine after anterior decompression and fusion: 10-year follow-up study using MRI.

PURPOSE: To evaluate changes in the transverse area of deep posterior muscles of the cervical spine 10 years after anterior cervical decompression and fusion (ACDF), in comparison with healthy volunteers. METHODS: Thirty-one patients (22 males, 9 females, mean age at follow-up 59.3 years, mean follow-up 12.1 years) who had undergone preoperative MRI and non-instrumented ACDF within levels C3-4 to C5-6 were enrolled. 32 asymptomatic volunteers (17 males, 15 females; mean age, 54.7 years; mean follow-up, 11.7 years) who underwent MRI between 1993 and 1996 served as controls. Follow-up MRI was performed on both patients and control subjects, and the cross-sectional areas of deep posterior muscles were measured digitally at levels C3-4, 4-5, and 5-6. RESULTS: The mean total cross-sectional area in the ACDF and control groups was 4,693.6 ± 1,140.9 and 4,825.8 ± 1,048.2 mm(2) in the first MR study (P = 0.63), and 4,616.7 ± 1,086.0 and 5,036.7 ± 1,105.6 mm(2) at follow-up (P = 0.13). The total cross-sectional area in the ACDF group slightly decreased, while that in the control group increased (-77.1 ± 889.7 vs. 210.9 ± 622.0 mm(2), P = 0.14). The mean change in the cross-sectional area had no significant correlation with clinical symptoms, including neck pain or JOA score. CONCLUSIONS: ACDF patients did not show a marked decrease in the cross-sectional area of the deep posterior cervical muscles, but as compared with control subjects there was a slight decrease. A decrease in the cross-sectional area of these muscles after ACDF may not result in the axial symptoms as seen in patients treated by posterior surgery.

Beneficial compaction of spinal cord lesion by migrating astrocytes through glycogen synthase kinase-3 inhibition.

The migratory response of astrocytes is essential for restricting inflammation and preserving tissue function after spinal cord injury (SCI), but the mechanisms involved are poorly understood. Here, we observed stimulation of in vitro astrocyte migration by the new potent glycogen synthase kinase-3 (GSK-3) inhibitor Ro3303544 and investigated the effect of Ro3303544 administration for 5 days following SCI in mice. This treatment resulted in accelerated migration of reactive astrocytes to sequester inflammatory cells that spared myelinated fibres and significantly promoted functional recovery. Moreover, the decreased extent of chondroitin sulphate proteoglycans and collagen IV demonstrated that scarring was reduced in Ro3303544-treated mice. A variety of in vitro and in vivo experiments further suggested that GSK-3 inhibition stimulated astrocyte migration by decreasing adhesive activity via reduced surface expression of ß1-integrin. Our results reveal a novel benefit of GSK-3 inhibition for SCI and suggest that the stimulation of astrocyte migration is a feasible therapeutic strategy for traumatic injury in the central nervous system.

Reduced postoperative wound pain after lumbar spinous process-splitting laminectomy for lumbar canal stenosis: a randomized controlled study.

OBJECT: to reduce intraoperative damage to the posterior supporting structures of the lumbar spine during decompressive surgery for lumbar canal stenosis (LCS), lumbar spinous process-splitting laminectomy (LSPSL or split laminectomy) was developed. This prospective, randomized, controlled study was conducted to clarify whether the split laminectomy decreases acute postoperative wound pain compared with conventional laminectomy. METHODS: forty-one patients with LCS were enrolled in this study. The patients were randomly assigned to either the LSPSL group (22 patients) or the conventional laminectomy group (19 patients). Questionnaires regarding wound pain (intensity, depth, and duration) and activities of daily living (ADL) were administered at postoperative days (PODs) 3 and 7. Additionally, the authors evaluated the pre- and postoperative serum levels of C-reactive protein and creatine phosphokinase, the amount of pain analgesics used during a 3-day postoperative period, and the muscle atrophy rate measured on 1-month postsurgical MR images. RESULTS: data obtained in patients in the LSPSL group and in 16 patients in the conventional laminectomy group were analyzed. The mean visual analog scale for wound pain on POD 7 was significantly lower in the LSPSL group (16 ± 17 mm vs 34 ± 31 mm, respectively; p = 0.04). The mean depth-of-pain scores on POD 7 were significantly lower in the LSPSL group than in the conventional group (0.9 ± 0.6 vs 1.7 ± 0.8, respectively; p = 0.013). On POD 3, the mean serum creatine phosphokinase level was significantly lower in the LSPSL group (126 ± 93 U/L) than in the other group (207 ± 150 U/L) (p = 0.02); on POD 7, the mean serum C-reactive protein level was significantly lower in the LSPSL group (1.1 ± 0.6 mg/dl) than in the conventional laminectomy group (1.9 ± 1.5 mg/dl) (p = 0.04). The number of pain analgesics taken during the 3-day postoperative period was lower in the LSPSL group than in the conventional laminectomy group (1.7 ± 1.3 tablets vs 2.3 ± 2.4 tablets, respectively; p = 0.22). The mean muscle atrophy rate was also significantly lower in the LSPSL group (24% ± 15% vs 43% ± 22%; p = 0.004). CONCLUSIONS: lumbar spinous process-splitting laminectomy for the treatment of LCS reduced acute postoperative wound pain and prevented postoperative muscle atrophy compared with conventional laminectomy, possibly because of minimized damage to the paraspinal muscles.

Anti-IL-6-receptor antibody promotes repair of spinal cord injury by inducing microglia-dominant inflammation.

We previously reported the beneficial effect of administering an anti-mouse IL-6 receptor antibody (MR16-1) immediately after spinal cord injury (SCI). The purpose of our present study was to clarify the mechanism underlying how MR16-1 improves motor function after SCI. Quantitative analyses of inflammatory cells using flow cytometry, and immunohistochemistry with bone marrow-chimeric mice generated by transplanting genetically marked purified hematopoietic stem cells, revealed that MR16-1 dramatically switched the central player in the post-traumatic inflammation, from hematogenous macrophages to resident microglia. This change was accompanied by alterations in the expression of relevant cytokines within the injured spinal cord; the expression of recruiting chemokines including CCL2, CCL5, and CXCL10 was decreased, while that of Granulocyte/Macrophage-Colony Stimulating Factor (GM-CSF), a known mitogen for microglia, was increased. We also showed that the resident microglia expressed higher levels of phagocytic markers than the hematogenous macrophages. Consistent with these findings, we observed significantly decreased tissue damage and reduced levels of myelin debris and Nogo-A, the axonal growth inhibitor, by MR16-1 treatment. Moreover, we observed increased axonal regeneration and/or sprouting in the MR16-1-treated mice. Our findings indicate that the functional improvement elicited by MR16-1 involves microglial functions, and provide new insights into the role of IL-6 signaling in the pathology of SCI.

Anterior cervical decompression and fusion accelerates adjacent segment degeneration: comparison with asymptomatic volunteers in a ten-year magnetic resonance imaging follow-up study.

STUDY DESIGN: Prospective 10-year follow-up magnetic resonance imaging (MRI) study of patients who underwent anterior cervical decompression and fusion (ACDF) and healthy control subjects. OBJECTIVE: To clarify the incidence of adjacent segment degeneration during 10 years after ACDF. SUMMARY OF BACKGROUND DATA: There have been few studies which investigated incidence of progression of degenerative changes at adjacent segments in patients treated by ACDF comparing with healthy subjects. METHODS: Sixty-four patients who underwent ACDF (48 males, 16 females, mean age 47.3 years, mean follow-up 12.1 year) and 201 asymptomatic volunteers who underwent MRI in our previous study (113 males, 88 females, mean age; 41.1 year, mean follow-up; 11.7 years) were included in this study. The patients and control subjects underwent follow-up MRI in this study. Following MR findings were evaluated using a numerical grading system from C2-C3-C7-T1: (1) Decrease in signal intensity of disc (DSI), (2) Posterior disc protrusion (PDP), (3) Disc space narrowing, and (4) Foraminal stenosis. When an increase in at least one grade in any of the radiographic parameters was detected between the 2 time points, progression of disc degeneration was judged as present at the level of interest. RESULTS: Progression of DSI was significantly more frequent in ACDF group than in control group at C4-C5, while progression of PDP was significantly more frequent in ACDF group than in control group at all levels except for C5-C6. Progression of disc space narrowing and foraminal stenosis was significantly more frequent in ACDF group at C3-C4 and at C6-C7, respectively. CONCLUSION: Although both ACDF patients and control subjects demonstrated progression of disc degeneration during 10 years, ACDF patients had significantly higher incidence of progression of disc degeneration at adjacent segments than control subjects, while progression of disc degeneration at adjacent segments was not always related to development of clinical symptoms.

High-contrast dark resonances with linearly polarized light on the D1 line of alkali atoms with large nuclear spin.

High-contrast coherent population trapping signals were observed on the Cs D1 line by use of a bichromatic linear polarized light (lin‖lin field). A maximum absorption contrast of about 10% was obtained. This was nearly twice as high as that measured with the standard configuration of bichromatic circularly polarized light (σ-σ field). The results are compared with density matrix calculations of 4 and 5 level systems.

Broadly tunable ultraviolet light generation in a compact MgO-doped periodically-poled stoichiometric lithium tantalate optical parametric oscillator with a high-Q cavity.

A compact tunable UV laser source based on intracavity sum frequency generation in a MgO-doped periodically-poled stoichiometric lithium tantalate optical parametric oscillator is reported. UV output at an approximately 1 mW level of power over the range of 364 to 378 nm with a bandwidth of 0.5 nm was obtained with a crystal that has just one periodically-poled grating period. The full tuning range can be as much as approximately 68 nm, from 324 to 392 nm by varying the crystal temperature from room temperature to 250 degrees C. This will cover nearly the entire UVA range.

Regeneratively mode-locked fiber laser with a repetition rate stability of 4.9x10-15 using a hydrogen maser phase-locked loop.

We demonstrate an ultrastable regeneratively mode-locked fiber laser that employs a phase-locked loop (PLL) circuit with a hydrogen maser. The stability for an integration time of 1s was 6.2x10(-13), which is 16 times better than that of a conventional PLL laser. For an integration time of 1000s, the stability reached as high as 4.9x10(-15). The repetition-rate stability was limited by the synthesizer used for the PLL operation, and there was no additional fluctuation induced by the laser operation.

Mode-locked laser-type optical atomic clock with an optically pumped Cs gas cell.

We propose and demonstrate a mode-locked laser-type optical atomic clock with an optically pumped cesium (Cs) gas cell. By adopting the optically pumped Cs gas cell with a double resonance method as a frequency standard, we have successfully demonstrated an ultrastable rack-mount type Cs optical atomic clock with excellent short-term stability. The obtained frequency stabilities reached as high as 1.2 x 10(-12) for tau=1 s and 8.8 x 10(-14) for tau=100 s for a 9.1926 GHz microwave output signal.

A selective Sema3A inhibitor enhances regenerative responses and functional recovery of the injured spinal cord.

Axons in the adult mammalian central nervous system (CNS) exhibit little regeneration after injury. It has been suggested that several axonal growth inhibitors prevent CNS axonal regeneration. Recent research has demonstrated that semaphorin3A (Sema3A) is one of the major inhibitors of axonal regeneration. We identified a strong and selective inhibitor of Sema3A, SM-216289, from the fermentation broth of a fungal strain. To examine the effect of SM-216289 in vivo, we transected the spinal cord of adult rats and administered SM-216289 into the lesion site for 4 weeks. Rats treated with SM-216289 showed substantially enhanced regeneration and/or preservation of injured axons, robust Schwann cell-mediated myelination and axonal regeneration in the lesion site, appreciable decreases in apoptotic cell number and marked enhancement of angiogenesis, resulting in considerably better functional recovery. Thus, Sema3A is essential for the inhibition of axonal regeneration and other regenerative responses after spinal cord injury (SCI). These results support the possibility of using Sema3A inhibitors in the treatment of human SCI.