Kenichi Hirano

Minocycline selectively inhibits M1 polarization of microglia

Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1G93A mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1G93A mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

Primary spinal cord tumors: review of 678 surgically treated patients in Japan. A multicenter study

PurposeTo clarify the relative frequency of various histopathological primary spinal cord tumors and their features in Japanese people and to compare this data with other reports.MethodsPrimary spinal cord tumor surgical cases from 2000 to 2009, which were registered in our affiliated hospital database were collected. We examined age at surgery, sex, anatomical location, vertebral level of the tumor, and pathological diagnosis in each case.ResultsOf the 678 patients in our study, 377 patients (55.6xa0%) were males and 301 patients (44.4xa0%) were females (male/female ratio 1.25). The mean age at surgery was 52.4xa0years. Of these tumors, 123 cases (18.1xa0%) were intramedullary, 371 cases (54.7xa0%) were intradural extramedullary, 28 cases (4.1xa0%) were epidural, and 155 cases (22.9xa0%) were dumbbell tumors. The pathological diagnoses included 388 schwannomas (57.2xa0%), 79 meningiomas (11.6xa0%), 54 ependymomas (8.0xa0%), 27 hemangiomas (4.0xa0%), 23 hemangioblastomas (3.4xa0%), 23 neurofibromas (3.4xa0%), and 9 astrocytomas (1.3xa0%). The male/female ratios for schwannomas, meningiomas, ependymomas, hemangiomas, hemangioblastomas, neurofibromas, malignant lymphomas, and lipomas are 1.4, 0.34, 1.3, 1.5, 2.3, 1.3, 2.7 and 2.3, respectively.ConclusionThis is the first published research in English on the epidemiology of primary spinal cord tumors in Japanese people. Similar to other reports from Asian countries, our data indicates a higher male/female ratio overall for spinal cord tumors, a higher proportion of nerve sheath cell tumors, and a lower proportion of meningiomas and neuroepithelial tumors compared to reports from non-Asian countries. Data in the current study represent the characteristics of primary spinal cord tumors in Asian countries.

Physical performance tests are useful for evaluating and monitoring the severity of locomotive syndrome

BackgroundThe concept of the locomotive syndrome (LS), first proposed in Japan in 2007, has become widely accepted, and the 25-question Geriatric Locomotive Function Scale (GLFS-25), a quantitative, evidence-based diagnostic tool for LS, has been developed. However, the association between the GLFS-25 score and the outcome of physical capacity tests has never been investigated. Furthermore, which physical tests are good indices for evaluating and monitoring the severity of locomotive syndrome have not been identified. In addition, the impact of knee and low back pain on locomotive syndrome is unclear. The purpose of this study is to confirm the validity of GLFS-25 by demonstrating its significant correlation with the outcome of physical function tests and to determine which tests are good indicators for monitoring the severity of LS. The secondary aim of the project is to investigate how much influence knee and low back pain may have on the LS of the middle-aged and elderly.MethodsA total of 358 subjects were drawn from a general health checkup in a rural area of Japan. We measured back muscle strength, grip strength, one-leg standing time with eyes open, 10-m gait time, timed up-and-go test, maximum stride, functional reach, height, weight, % body fat and bone mineral density, and we obtained a visual analog scale of low back pain and knee pain. The degree of the locomotive syndrome was evaluated using the GLFS-25. Associations of all the variables with the GLFS-25 score were analyzed using both univariate and multivariate analyses.ResultsThe GLFS-25 score was significantly higher in females than in males in both the total and in the age older than 60xa0years groups. The GLFS-25 score showed a significant positive correlation with age (rxa0=xa00.360), knee pain (rxa0=xa00.576), low back pain (rxa0=xa00.526), timed up-and-go test (rxa0=xa00.688) and 10-m gait time (rxa0=xa00.634), and it showed a significant negative correlation with one-leg standing time with eyes open (rxa0=xa0−0.458), maximum stride (rxa0=xa0−0.408), functional reach test (rxa0=xa0−0.380), back muscle strength (rxa0=xa0−0.364) and grip strength (rxa0=xa0−0.280). Multiple regression analysis indicated that knee pain (βxa0=xa00.282), low back pain (βxa0=xa00.304), one-leg standing time (βxa0=xa0−0.116), timed up-and-go test (βxa0=xa0−0.319) and back muscle strength (βxa0=xa0−0.090) were significantly associated with the GLFS-25 score. Grip strength (βxa0=xa0−0.99) was a good substitute for back muscle strength in the multiple regression analysis.ConclusionsWe confirmed the validity of GLFS-25 by demonstrating a significant correlation and association of its score with the outcome of a series of functional performance tests. One-leg standing time with eyes open, timed up-and-go test and grip strength proved to be easy, reliable and safe performance tests to evaluate and monitor an individual’s severity of LS as a complement to the GLFS-25. We also proved that knee and low back pain significantly impact the degree of LS.

Influence of spinal sagittal alignment, body balance, muscle strength, and physical ability on falling of middle-aged and elderly males

ObjectiveRisk factors for falling in elderly people remain uncertain, and the effects of spinal factors and physical ability on body balance and falling have not been examined. The objective of this study was to investigate how factors such as spinal sagittal alignment, spinal range of motion, body balance, muscle strength, and gait speed influence falling in the prospective cohort study.MethodsThe subjects were 100 males who underwent a basic health checkup. Balance, SpinalMouse® data, grip strength, back muscle strength, 10-m gait time, lumbar lateral standing radiographs, body mass index, and fall history over the previous year were examined. Platform measurements of balance included the distance of movement of the center of pressure (COP) per second (LNG/TIME), the envelopment area traced by movement of the COP (E AREA), and the LNG/E AREA ratio. The thoracic/lumbar angle ratio (T/L ratio) and sagittal vertical axis (SVA) were used as an index of sagittal balance.ResultsLNG/TIME and E AREA showed significant positive correlations with age, T/L ratio, SVA, and 10-m gait time; and significant negative correlations with lumbar lordosis angle, sacral inclination angle, grip strength and back muscle strength. Multiple regression analysis showed significant differences for LNG/TIME and E AREA with T/L ratio, SVA, lumbar lordosis angle and sacral inclination angle (R2xa0=xa00.399). Twelve subjects (12xa0%) had experienced a fall over the past year. Age, T/L ratio, SVA, lumbar lordosis angle, sacral inclination angle, grip strength, back muscle strength, 10-m gait time, height of the intervertebral disc, osteophyte formation in radiographs and LNG/E AREA differed significantly between fallers and non-fallers. The group with SVAxa0>xa040xa0mm (nxa0=xa018) had a significant higher number of subjects with a single fall (6 single fallers/18: pxa0=xa00.0075) and with multiple falls (4 multiple fallers/18: pxa0=xa00.0095).ConclusionGood spinal sagittal alignment, muscle strength and 10-m gait speed improve body balance and reduce the risk of fall. Muscle strength and physical ability are also important for spinal sagittal alignment. Body balance training, improvement of physical abilities including muscle training, and maintenance of spinal sagittal alignment can lead to prevention of fall.

The influence of locomotive syndrome on health-related quality of life in a community-living population

ObjectivesThe Japanese Orthopaedic Association (JOA) has proposed the term “locomotive syndrome” (LS) to designate a condition in individuals with musculoskeletal disease in high-risk groups who are highly likely to require nursing care. The present study investigated the influence of LS on the quality of life (QOL) of a community-living population.MethodsA total of 386 subjects ≥xa050xa0years of age were enrolled in the study. Those whose scores on the 25-question Geriatric Locomotive Function Scale were ≥16 were defined as having LS. Participants answered the JOA Back Pain Evaluation Questionnaire (JOABPEQ) and visual analogue scales (VAS) for low back pain, leg pain, leg numbness, and left and right knee pain; the Roland Morris Disability Questionnaire (RDQ); and the Short Form 36 (SF-36). We compared the scores on the three QOL measures between subjects diagnosed with and without LS.ResultsThere were 62 people defined as having LS. Subjects with LS scored significantly lower on the JOABPEQ and SF-36 than those without LS. They also had significantly higher scores on the five VASs and the RDQ compared with those without LS.ConclusionsWe found that LS strongly impacted QOL and the scores from the VASs. LS appears to be a useful concept for screening subjects who are experiencing a lowered QOL due to musculoskeletal diseases, especially degenerative lumbar diseases and knee osteoarthritis.

CD44 expression in astrocytes and microglia is associated with ALS progression in a mouse model.

Amyotrophic lateral sclerosis (ALS) is a motor neuron-specific neurodegenerative disease. An increasing body of evidence suggests that, in addition to cell autonomous regulation, i.e., pathological changes in motor neurons, non-cell autonomous mechanisms involving glial cells play critical roles in the pathogenesis of ALS. CD44 functions as a receptor for osteopontin and hyaluronan, and has been implicated in inflammation associated with neuronal injuries. However, this membrane glycoprotein has been poorly studied in ALS. Here we investigated its expression during ALS progression using SOD1(G93A) mice. CD44 expression increased around the onset of disease and then increased continuously. Astrocytes and microglia expressed CD44 in vivo. Consistent with these findings, primary cultured microglia began to express CD44 upon activation with LPS and interferon-γ. CD44 expression in primary cultured astrocytes was also enhanced by activation with interferon-γ+TNF-α or bFGF alone. As CD44 was detected in cell lysate, but not in culture media of astrocytes and microglia, it was likely that these glial cells expressed a membrane-bound form of CD44. Our study demonstrates that CD44 expression in astrocytes and microglia is closely associated with the pathogenesis of ALS, and suggests that inflammatory responses involving CD44 may play a role in this disease.

Influence of lumbar kyphosis and back muscle strength on the symptoms of gastroesophageal reflux disease in middle-aged and elderly people

ObjectiveThe objectives of this study was to clarify the relationship between kyphosis and Gastroesophageal reflux disease (GERD) by evaluation of spinal alignment, obesity, osteoporosis, back muscle strength, intake of oral drugs, and smoking and alcohol history in screening of a community population to determine the factors related to GERD symptoms.Summary of background dataGERD increases with age and is estimated to occur in about 30% of people. Risk factors for GERD include aging, male gender, obesity, oral medicines, smoking, and alcohol intake. It has also been suggested that kyphosis may influence the frequency of GERD, but the relationship between kyphosis and GERD is unclear.Subjects and methodsWe examined 245 subjects (100 males and 145 females; average age 66.7xa0years old) in a health checkup that included evaluation of sagittal balance and spinal mobility with SpinalMouse®, GERD symptoms using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire, body mass index, osteoporosis, back muscle strength, number of oral drugs taken per day, intake of nonsteroidal anti-inflammatory drugs (NSAIDs), intake of bisphosphonates, and smoking and alcohol intake.ResultsMultivariate logistic regression analysis including all the variables showed that lumbar lordosis angle, sagittal balance, number of oral drugs taken per day, and back muscle strength had significant effects on the presence of GERD (OR, 1.10, 1.11, 1.09 and 1.03; 95%CI, 1.03–1.17, 1.02–1.20, 1.01–1.18 and 1.01–1.04; pxa0=xa00.003, 0.015, 0.031 and 0.038, respectively). The other factors showed no association with GERD.ConclusionThis study is the first to show that lumbar kyphosis, poor sagittal balance; increased number of oral drugs taken per day, and decreased back muscle strength are important risk factors for the development of GERD symptoms. Thus, orthopedic surgeons and physicians should pay attention to GERD in elderly patients with spinal deformity.

Ablation of keratan sulfate accelerates early phase pathogenesis of ALS.

Biopolymers consist of three major classes, i.e., polynucleotides (DNA, RNA), polypeptides (proteins) and polysaccharides (sugar chains). It is widely accepted that polynucleotides and polypeptides play fundamental roles in the pathogenesis of neurodegenerative diseases. But, sugar chains have been poorly studied in this process, and their biological/clinical significance remains largely unexplored. Amyotrophic lateral sclerosis (ALS) is a motoneuron-degenerative disease, the pathogenesis of which requires both cell autonomous and non-cell autonomous processes. Here, we investigated the role of keratan sulfate (KS), a sulfated long sugar chain of proteoglycan, in ALS pathogenesis. We employed ALS model SOD1G93A mice and GlcNAc6ST-1−/− mice, which are KS-deficient in the central nervous system. Unexpectedly, SOD1G93AGlcNAc6ST-1−/− mice exhibited a significantly shorter lifespan than SOD1G93A mice and an accelerated appearance of clinical symptoms (body weight loss and decreased rotarod performance). KS expression was induced exclusively in a subpopulation of microglia in SOD1G93A mice, and became detectable around motoneurons in the ventral horn during the early disease phase before body weight loss. During this phase, the expression of M2 microglia markers was transiently enhanced in SOD1G93A mice, while this enhancement was attenuated in SOD1G93AGlcNAc6ST-1−/− mice. Consistent with this, M2 microglia were markedly less during the early disease phase in SOD1G93AGlcNAc6ST-1−/− mice. Moreover, KS expression in microglia was also detected in some human ALS cases. This study suggests that KS plays an indispensable, suppressive role in the early phase pathogenesis of ALS and may represent a new target for therapeutic intervention.

Impact of spinal imbalance and back muscle strength on locomotive syndrome in community-living elderly people

BackgroundThe Japanese Orthopaedic Association has proposed the term locomotive syndrome (“locomo”) to designate a condition of individuals in high-risk groups with musculoskeletal disease who are highly likely to require nursing care. The specific characteristics of “locomo” must still be determined. The spinal column is a major and important component affected by “locomo,” but no literature has examined the relationship between spinal factors and “locomo.” The current study investigates the influence of spinal factors on “locomo” in the elderly.MethodsA total of 135 subjects >70xa0years old were enrolled in the study (Yakumo study). Those answering yes to least one of the seven categories in the self-assessment checklist for “locomo” were defined as having “locomo.” We evaluated lateral lumbar radiographs, sagittal parameters, sagittal balance using the spinal inclination angle (SIA) as an index, spinal mobility as determined with SpinalMouse®, back muscle strength (BMS), and body mass index (BMI).ResultsAge, BMS, and SIA showed significant correlations with “locomo” and five of the seven self-assessment categories. Multivariate logistic regression analysis indicated that a decrease in BMS (OR 0.971, pxa0<xa00.001) and an increase in SIA (OR 1.144, pxa0<xa00.05) were significantly associated with “locomo.” BMS had significant negative correlations with age (rxa0=xa0−0.363), SIA (rxa0=xa0−0.294), and lumbar kyphosis (rxa0=xa0−0.254), and positive correlations with sacral slope angle (rxa0=xa00.194). SIA had significant negative correlations with BMS (rxa0=xa0−0.294), lumbar spinal range of motion (ROM) (rxa0=xa0−0.186) and total spinal ROM (rxa0=xa0−0.180), and positive correlations with age (rxa0=xa00.403) and lumbar kyphosis (rxa0=xa00.593).ConclusionsA decrease in BMS and an increase in SIA may be the most important risk factors for “locomo.” Lumbar kyphosis is an important factor related to BMS and SIA. Back muscle strengthening and lumbar spinal ROM exercises could be useful for improving the status of an individual suffering from “locomo.”

Predictors of aggravation of cervical spine instability in rheumatoid arthritis patients: the large joint index

BackgroundImproved rheumatic drugs have provided significant benefits, but activities of daily living are not improved if spinal symptoms are overlooked. Furthermore, the appropriate timing for examining the cervical spine during follow-up is unclear.MethodsTo evaluate the relations of cervical spine instabilities and an index for cervical spine lesion in rheumatoid arthritis (RA) based on extremity radiographs, we examined preoperative radiographs of 100 RA patients who underwent total knee arthroplasty. Radiographic results for eight large joints (bilateral shoulders, elbows, hips, and knees) were graded as follows: Larsen grade ≥2 for each joint was scored as 1 point, which we refer to as the “large joint index” (LJI), based on 0–8 points. The associations of radiographic cervical lesions with LJI, Ranawat class, the disease duration, RA drugs, or blood analysis data were evaluated.ResultsAtlantoaxial subluxation (AAS) (≥5 mm) was found in 45 patients, vertical subluxation (VS) (≤13 mm) in 42, a posterior atlantodental interval (PADI) (<14 mm) in 21, and subaxial subluxation (SAS) (≥3 mm) in 23. Most patients with a PADI < 14 mm (19/21, 90%) were complicated with both AAS and VS. LJI had a significant association with AAS (P < 0.0001), VS (P < 0.01), and PADI (P < 0.01). The PADI was significantly lower (P < 0.0001) and the LJI was significantly higher (P < 0.01) in patients of Ranawat class II compared to patients of Ranawat class I. The disease duration, age at surgery, and age at onset were also significantly associated with cervical instabilities.ConclusionsPADI should be recognized as a predictor of paralysis with anteroposterior instability and vertical and middle-low cervical spine instability. The LJI proposed in this study has the possibility of being a predictor of cervical lesions. Patients with RA onset at a young age and a long disease duration also have a risk of progression of cervical spine instability.