Behçet's Disease with Extremely High Levels of Urinary ß2-Microglobulin after Non-Steroidal Anti-Inflammatory Drug Treatment.

Behçet's disease is an inflammatory disease which manifests itself as various symptoms, such as uveitis, oral and genital aphthae, erythema nodosa, gastro-intestinal ulcerations and encephalopathy. Among the manifestations, renal dysfunction is reported in some percentage of the patients with this disorder. We experienced a middle-aged male with Behçet's disease who showed an extremely high level of urinary ß2-microglulin, which is one of the markers of renal dysfunction, despite normal serum creatinine levels. The patient was on non-steroidal anti-inflammatory drug (NSAID) therapy for 7 weeks, and this could have affected his renal dysfunction. The present report suggests that renal injury should not be underestimated in patients with Behçet's disease, especially in patients using NSAIDs.

[Undergraduate geriatric education in foreign countries].

In Japan, which has become a super-aged society, medical care for the elderly is more important than ever before. Geriatric education for medical students and young doctors is essential to ensure the best medical care possible for the elderly. In this paper, the Working Group for Education of the Japan Geriatrics Society collected and analyzed data and information on undergraduate education in the fields of geriatrics and gerontology at medical schools in various countries through the Internet, comparing the findings with those in Japan. Of the countries surveyed, 62% had undergraduate education in geriatrics and gerontology as mandatory subjects in medical school. Countries with advanced welfare programs, such as the United Kingdom, Germany, Austria, Denmark, Finland, Sweden, the Netherlands, Spain, Canada and New Zealand, performed substantial undergraduate education in geriatrics and gerontology. A lack of available staff and time for education was cited as a hurdle in many countries. The importance of education in geriatrics and gerontology is being emphasized in many countries, but few programs are satisfactory at present. The "struggle" to improve undergraduate education in geriatrics and gerontology therefore continues. We should endeavor to improve education in the fields of geriatrics and gerontology by working hand in hand with geriatricians and gerontologists around the world.

Reduced renal function is associated with prolonged hospitalization in frail older patients with non-severe pneumonia.

Objective: Pneumonia is a disease with high morbidity and mortality among older individuals in Japan. In practice, most older patients with pneumonia are not required ventilatory management and are not necessarily in critical respiratory condition. However, prolonged hospitalization itself is considered to be a serious problem even in these patients with non-critical pneumonia and have negative and critical consequences such as disuse syndrome in older patients. Therefore, it is essential to examine the factors involved in redundant hospital stays for older hospitalized patients with non-severe pneumonia, many of whom are discharged alive. Method: We examined hospitalized patients diagnosed with pneumonia who were 65 years and older in our facility between February 2017 and March 2020. A longer length of stay (LOS) was defined in cases in which exceeded the 80th percentile of the hospitalization period for all patients was exceeded, and all other cases with a shorter hospitalization were defined as a shorter LOS. In a multivariate logistic regression model, factors determining longer LOSs were analyzed using significant variables in univariate analysis and clinically relevant variables which could interfere with renal function, including fasting period, time to start rehabilitation, estimated glomerular filtration rate (eGFR), the Quick Sequential Organ Failure Assessment (qSOFA) score of 2 or higher, bed-ridden state. Results: We analyzed 104 eligible participants, and the median age was 86 (interquartile range, 82-91) years. Overall, 31 patients (30.7%) were bed-ridden, and 37 patients (35.6%) were nursing-home residents. Patients with a Clinical Frailty Scale score of 4 or higher, considered clinically frail, accounted for 93.2% of all patients. In multivariate analysis, for a decrease of 5 ml/min/1.73m2 in eGFR, the adjusted odds ratios for longer LOSs were 1.22 (95% confidence interval, 1.04-1.44) after adjusting for confounders. Conclusion: Reduced renal function at admission has a significant impact on prolonged hospital stay among older patients with non-severe pneumonia. Thoughtful consideration should be given to the frail older pneumonia patients with reduced renal function or with chronic kidney disease as a comorbidity at the time of hospitalization to prevent the progression of geriatric syndrome associated with prolonged hospitalization.

Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre.

NMO-IgG is a disease-specific autoantibody for neuromyelitis optica (NMO) and its target antigen is aquaporin-4 (AQP4) water channel. Recently, we established a sensitive anti-AQP4 antibody assay using human AQP4-transfected cells, which appeared more sensitive than the original NMO-IgG assay. So far, there has been no large-scale study on anti-AQP4 antibody titre in NMO and related disorders. We tested 148 sera of patients with NMO, high-risk syndrome of NMO, multiple sclerosis (MS), clinically isolated syndrome suggestive of MS and miscellaneous diseases. We analysed the relation of anti-AQP4 antibody titres and clinical and laboratory parameters. The sensitivity of anti-AQP4 antibody assay was 91% (95% CI 79-100) for NMO and 85% (65-100) for high-risk syndrome, and the specificity was 100% (91-100) for NMO and high-risk syndrome, that is, none with the other disorders was positive. Among 21 anti-AQP4 antibody-positive cases whose NMO-IgG were tested, 15 were NMO-IgG-positive and 6 were NMO-IgG-negative. Higher anti-AQP4 antibody titres were associated with complete blindness and extensive or large cerebral lesions on MRI. The lengths of spinal cord lesions on MRI were positively correlated with the titres of anti-AQP4 antibody at the nadir of exacerbations. A few patients who had short (approx. one to two vertebral segments) spinal cord lesions on MRI were also seropositive with low anti-AQP4 antibody titres, but did have other clinical and MRI features of NMO. Anti-AQP4 antibody titres became lower after high-dose methylprednisolone, and a follow-up showed anti-AQP4 antibody titres remained low in relapse-free periods under immunosuppression. Cerebrospinal fluid (CSF)-anti-AQP4 antibody was detected when the serum-antibody titres exceeded 512x, at the ratio of 1 (CSF) to 500 (serum). Using a sensitive assay, the results of the present study suggest that NMO and high-risk syndrome may be essentially anti-AQP4 antibody-associated disorders, and that the anti-AQP4 antibody titres have significant clinical and immunological implications in NMO.

Two subtypes of optic-spinal form of multiple sclerosis in Japan: clinical and laboratory features.

Seventy-seven cases of the optic-spinal form of multiple sclerosis (OSMS) were collected from 6 institutes in 3 cities of Japan, and the clinical and MRI features were analyzed. Two-thirds of the OSMS patients had longitudinally extensive spinal cord MRI lesions (LESL), and had clinical features similar to those of relapsing neuromyelitis optica which often causes severe disability. In contrast, OSMS patients without LESL tended to have milder disease and had some feature commonly seen in the conventional form of MS. The percentage of OSMS without LESL in total OSMS has recently been increasing. The present study suggests that LESL is crucially important for distinguishing the two subtypes of OSMS.

Introduction and overview of the special issue "Brain imaging and aging": The new era of neuroimaging in aging research.

It is well known that the brain is one of the organs particularly affected by aging in terms of function, relative to the gastrointestinal tract and liver, which exhibit less functional decline. There is also a wide range of age-related neurological disorders such as stroke, Alzheimer's disease, and Parkinson's disease. Therefore, it is very important to understand the relationship between functional age-related change and neurological dysfunction. Neuroimaging techniques including magnetic resonance imaging and positron emission tomography have been significantly improved over recent years. Many physicians and researchers have investigated various mechanisms of age-related cerebral change and associated neurological disorders using neuroimaging techniques. In this special issue of Ageing Research Reviews, we focus on cerebral- and neuro-imaging, which are a range of tools used to visualize structure, functions, and pathogenic molecules in the nervous system. In addition, we summarize several review articles about the history, present values, and future perspectives of neuroimaging modalities.

CSF-chemokines in HTLV-I-associated myelopathy: CXCL10 up-regulation and therapeutic effect of interferon-alpha.

We measured four chemokines in the cerebrospinal fluid (CSF) in human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) with ELISA. CXCL10/IP-10, a T cell type 1 (Th1)-associated chemokine, was significantly elevated in HAM/TSP compared with controls, and the values were even significantly higher in HAM/TSP than in multiple sclerosis (MS) in which CXCL10/IP-10 up-regulation was previously reported. Among Th2-associated chemokines, CCL17/TARC and CCL11/Eotaxin in HAM/TSP were not different from those in controls. As shown in MS, CCL2/MCP-1 was significantly lower in HAM/TSP than in control. Following interferon (IFN)-alpha therapy in HAM/TSP, CCL2/MCP-1 became significantly higher than that before therapy, which may reflect a Th2 induction, while CXCL10/IP-10 remained elevated.

Chemokine profile in the cerebrospinal fluid and serum of Vogt-Koyanagi-Harada disease.

We analyzed the concentrations of four chemokines in the cerebrospinal fluid (CSF) and sera in Vogt-Koyanagi-Harada disease (VKH), an autoimmune uveomeningitis syndrome against melanocyte-associated proteins, with ELISA. CSF-CXCL10/IP-10 and CSF-CCL17/TARC were significantly elevated in VKH than in controls. In the majority of VKH cases and controls, CSF-CXCL10 was higher than serum-CXCL10, and CSF-CCL17 was lower than serum-CCL17. CCL11/Eotaxin was not different between groups. CSF-CCL2/MCP-1 was significantly lower in VKH than in control. The changes in VKH were essentially similar to those in multiple sclerosis, a known Th1-dominant condition.

[Pathogenesis of optic-spinal MS].

We reviewed the clinical and immunological features of optic-spinal multiple sclerosis (OSMS), or relapsing neuromyelitis optica. OSMS has collected much attention as to whether it is a distinct entity from conventional MS (CMS). However, OSMS plus minor cerebral and brainstem/cerebellar involvement and the later conversion into CMS had been a diagnostic dilemma. To overcome such problems and delineate the features of OSMS, we analyzed 'Pure OSMS' with which patients had only relapsing optic neuritis and myelitis clinically and consistently normal brain MRI during 5 years or longer follow-ups. As a result, we found that this type of MS was characterized by a definite female preponderance and negative oligoclonal IgG bands (OB), although 'Pure OSMS' was heterogeneous with regards to the clinical severity and HLA class II alleles. Previously reported immunological data in OSMS include negative OB and no elevation of IL-10 or matrix metalloproteinase-9 in the cerebrospinal fluid (CSF) during relapses. In addition, we recently demonstrated that the CCR5+ Th1 cell subset in CSF during relapses, which significantly increased in CMS, remained low in OSMS. These unique clinical and immunological findings probably relate to fundamental differences in the pathogeneses of OSMS and CMS and deserve further characterization.

Establishment of a new sensitive assay for anti-human aquaporin-4 antibody in neuromyelitis optica.

Neuromyelitis optica (NMO) is a devastating neurologic disease characterized by severe optic neuritis and transverse myelitis. Recently, its disease-specific serum autoantibody, NMO-IgG, was discovered with indirect immunofluorescence. However, the substrates of the immunofluorescence assay were not human but mouse brain tissues, which could influence the sensitivity and specificity of the antibody. The target antigen of NMO-IgG was recently identified as aquaporin-4 (AQP4) water channel protein, which is mainly expressed in brain and spinal cord. In the present study, we have established human cell lines that stably express human AQP4 and used these cells to detect and titrate anti-AQP4 antibody present in the sera of patients with NMO by immunofluorescence assay. The results were compared with those of the original NMO-IgG assay. We tested the sera from 10 patients with NMO, 10 with MS and five with other neurological disorders. Among the patients with NMO, six were NMO-IgG-positive. However, using the new anti-AQP4 antibody assay, we showed that eight patients with NMO including the six NMO-IgG-positives were positive for anti-AQP4 antibody. The staining pattern of AQP4-expressing cells treated with each serum of these eight NMO patients corresponded to that with a commercially available anti-AQP4 antibody. The antibody titer (maximum serum dilution for positive staining) ranged from 64x to 16,384x. The serum dilution titers were reproducible in blinded studies. In contrast, the patients with MS or other neurological disorders showed negative for anti-AQP4 antibody. Thus, the newly developed anti-AQP4 antibody assay appears to have a higher sensitivity for NMO than the original NMO-IgG assay and is expected to be useful for the diagnosis of NMO.

Pure optic-spinal form of multiple sclerosis in Japan.

We evaluated the clinical and laboratory features of the optic-spinal form of multiple sclerosis (OSMS) with no brain lesions on repeated MRI--termed pure OSMS. By reviewing the medical records of 118 Japanese clinically definite multiple sclerosis patients seen between 1988-1999, we found 10 patients (8.5%), nine of whom were women, with only relapsing optic neuritis (ON) and myelitis (MY) clinically and consistently normal brain MRI during follow-ups of >or=5 years. Three patients suffered severe ON and MY, but the other seven had mild disease (six were graded 1 in the Disability Status Scale). Despite frequent relapses, mild pure OSMS was characterized by younger onset and mild spinal symptoms as in 'benign' classical multiple sclerosis (CMS). MRI often revealed multiple cervico-thoracic cord lesions of variable lengths. Oligoclonal IgG bands (OB) were negative in all cases. HLA-DPB1*0501, whose association with OSMS has been reported, was positive only in six patients (including three patients with severe pure OSMS). Four patients with DRB1*1501-DQB1*0602, to which CMS is closely linked, had mild disease. Though pure OSMS was heterogeneous with regard to clinical severity and human leukocyte antigen (HLA) class II alleles, this form of multiple sclerosis was characterized by a definite female preponderance and negative OB that distinguished it from CMS.