Overview of MS: proposal of new MS definition/classification and review of the results of recent clinical trials

Recurrent Devic' s neuromyelitis optica (NMO) and Asian optic-spinal multiple sclerosis (MS) used to be defined as a syndrome with selective clinical optic-spinal presentation. Recent discoveries have prompted us to propose a new definition for MS as chronic autoimmune central nervous system myelin/glial disorder syndrome consisting of two subtypes: myelin/oligodendroglial disorder (classic demyelinating MS) and astroglial disorder (NMO). Subtype differentiation in clinical practice are not clear in many Japanese MS patients. Significant progress in the treatment of demyelinating type MS has been made recently and we are now going into the era of 2nd generation disease modifying therapies. Natalizumab, Fingolimod, Alemtuzumab, and Rituximab probably will change the MS disease course tremendously and make the patient' s quality of life much better than during the era of interferon treatment.     

Clinical subtypes of multiple sclerosis and the immuno-pathogeneses

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). MS is classified into clinical subtypes, such as relapsing-remitting MS, primary and secondary progressive MS, benign MS and malignant MS. In Japan, the classification based on the lesion distribution is also commonly used. There are two subtypes in this classification, conventional MS, in which demyelinating plaques are disseminated within CNS, and optic spinal MS, or relapsing neuromyelitis optica, characterized by the selective involvement of the optic nerves and spinal cord. Clinical manifestations and MRI findings of the clinical subtypes and their immuno-pathology are reviewed with emphasis on the unique features of Japanese MS.     

Magnetic resonance imaging for the diagnosis of multiple sclerosis

Magnetic resonance imaging(MRI) is very useful as a method form confirming the lesion distribution of multiple sclerosis(MS). Although MS should be diagnosed primarily on clinical grounds, MRI aids the diagnosis by providing paraclinical evidence for the dissemination in both time and space. Recently, a new guideline for MS diagnosis was proposed by International Panel. This guideline set out to integrate MRI into the overall diagnostic scheme because of its unique sensitivity to pathological changes. In Japanese, however, the so-called optic-spinal form of MS, which is characterized by the selective involvement of the optic nerves and the spinal cord, is relatively common. Moreover, most of Japanese MS patients without oligoclonal bands show atypical brain lesions which do not fulfill the MRI criteria for brain abnormality.     

Neutralizing Antibodies Are Associated with a Reduction of Interferon-β Efficacy during the Treatment of Japanese Multiple Sclerosis Patients

Multiple sclerosis (MS) is a chronic immune-mediated inflammatory demyelinating disease of the central nervous system. Interferon-β (IFN-β) has been used as the first line therapy for MS treatment in Japan, but patients treated with IFN-β may develop antibodies, known as neutralizing antibodies (NAbs), which abrogate its therapeutic effects. Intramuscular IFN-β 1a and subcutaneous IFN-β 1b are currently available in Japan, but large-scale studies evaluating the prevalence and clinical implications of NAbs against these IFN-β preparations in MS patients have only been performed in Caucasian populations. NAbs positivity has been reported to be associated with HLA-DRB1 alleles, suggesting that the positivity might differ among populations with distinct genetic backgrounds. Clinical information and sera were collected from 229 consecutive MS patients treated with IFN-β in 4 centers in Japan. Sera were tested for NAbs using a luciferase reporter gene assay. In total, 5.2% of IFN-β-1a-treated patients (4/77) and 30.3% of IFN-β-1b-treated patients (46/152) were positive for Nabs. The frequency of NAbs was highest in patients treated for 13 to 24 months. Clinical relapse and contrast-enhancing lesions in the magnetic resonance imaging increased together with NAbs titers in this group. In conclusion, the prevalence of NAbs in Japanese MS patients is similar to that in Caucasian populations and is associated with an increase in disease activity. Therefore, routine NAbs testing is recommended also in Asian populations to ensure the early identification of patients who would benefit from a change in therapy.     

Frequency of Chronic Headaches in Japanese Patients With Multiple Sclerosis: With Special Reference to Opticospinal and Common Forms of Multiple Sclerosis

Background.— Headache is common in Western patients with multiple sclerosis (MS), but its frequency has not been reported in Asian patients. In Asians, the opticospinal form of MS, showing similar characteristics to relapsing neuromyelitis optica in Westerners, is regarded as a different subtype from conventional MS. Objectives.— The aim of this study was to clarify the frequency of primary and chronic secondary headaches in Japanese patients with MS and the factors associated with the emergence of such headaches. Methods.— We investigated 127 consecutive patients with clinically definite MS. Frequencies of primary and chronic secondary headaches were compared according to clinical subtype, administration of interferon beta, and anti‐aquaporin‐4 antibody status. Results.— The frequency of patients with primary and chronic secondary headaches at the time of interview was 64/127 (50.4%); the frequency of migraine was 26/127 (20.4%) and that of tension‐type headache was 38/127 (29.9%). The frequencies of patients with primary and chronic secondary headaches and migraine without aura after the onset of MS were higher in patients undergoing interferon beta therapy than in those not on the therapy (42.4% vs 23.4%, P < .05 and 15.1% vs 4.3%, P = .05, respectively). There were no significant differences in the frequency of primary and chronic secondary headaches based on clinical subtype of MS. However, among patients not receiving interferon beta, the occurrence of migraine with aura after the onset of MS was significantly higher in patients with anti‐aquaporin‐4 antibody than in patients without the antibody (13.3% vs 0.0%, P < .05). Conclusions.— In Japanese patients with MS, the frequency of primary and chronic secondary headaches, especially migraine, was higher than in the general Japanese population. Administration of interferon beta was related to a higher frequency of primary and chronic secondary headaches, especially migraine without aura, irrespective of clinical subtype of MS.     

急性横贯性脊髓炎的临床及MRI特征分析

目的探讨急性横贯性脊髓炎(ATM)首次发作的临床及MRI影像特征。材料与方法回顾性分析我院2006年7月至2012年7月间56例急性横贯性脊髓炎患者首次发作的临床、MRI影像学特征(至少2年的随访结果以协助最终诊断)。结果 (1)56例ATM患者首次发作后必须至少1次随访并随访时间超过2年,临床确诊为:多发性硬化(MS)19例(19/56,33.9%),视神经脊髓炎(NMO)10例(10/56,17.9%),系统性自身免疫性疾病3例(3/56,5.4%),类感染病因4例(4/56,7.1%),特发性横贯性脊髓炎20例(20/56,35.7%)。(2)所有患者均有脊髓病变平面以下不同程度的运动、深浅感觉及自主神经功能障碍。(3)MRI特征:颈髓18例,胸髓17例,颈胸髓受累13例,胸腰髓受累8例;33例病变脊髓轻度肿胀,23例脊髓形态未见异常;病灶平均长度为4.7个脊髓节段,病灶占据脊髓2/3以上横断面积29例,27例占据面积小于脊髓横断面的2/3;15例脊髓病变区无强化,41例病变区呈条状、斑片状等强化。结论结合临床和MRI影像特征,有利于ATM的诊断和鉴别诊断。     

Growth deceleration in Japanese schoolchildren with special reference to those in the city of Sendai

From the national and regional statistics on the body dimensions of schoolchildren at the 6th year grade in primary schools (i.e., 11-year-olds) and at the 3rd year grade in junior high schools (i.e., 14-year-olds), the secular gains in height and weight by the children of the same age were calculated for the three periods of 1960-4, 1972-76 and 1976-81. Compared with the first period (i.e., 1960-4) when the growth acceleration was maximal, the secular gain was apparently reduced in the second and third study periods (i.e. 1970's) to the level of 1/2 to 1/3 of that in the first period, and was next to nil in some districts. Such deceleration was coupled with changes in seasonal growth patterns and diminution of urban-rural gaps both in the body size and the secular gain. For example, the body dimensions of the children in the City of Sendai did not differ in 1981 between the core part of the city and the surroundings, while the difference had been observed till late 1970's. The 1979 measurements of height and weight of Japanese children are compared with counterpart values observed in other countries.     

Anti-aquaporin 4-antibody detection system

To clarify the epidemiological and clinicopathological features of Japanese patients previously diagnosed as optic-spinal multiple sclerosis (OSMS)/neuromyelitis optica (NMO), we developed anti-AQP4 antibody assay and NMO-IgG immunohistochemistry and tested the presence of the antibody in a large population of patients. Almost 70% of OSMS/NMO with long spinal cord lesions were positive for this antibody. Antibody-positive patients were more likely to be female and blind, and had more relapses yearly and 68% of patients showed cerebral lesions on brain MRI and low frequency of oligoclonal bands in cerebrospinal fluid. The antibody titers related closely to the disease activity. The lesions involved were closely related to the areas of abundant AQP4 water channel expression. These evidence suggested the pathomechanical relations of the antibody to this disease.     

241例心跳骤停与心肺脑复苏的回顾性分析

目的 探讨心跳骤停患者的临床特点及救治经验，以提高心肺脑复苏成功率。方法 回顾性分析我科1990年10月至2002年10月十二年间院内及院外急救的241例心跳骤停患者的临床资料，初步分析治疗与预后的关系。结果 241例心跳骤停患者中，初步复苏成功10例，最终复苏成功(心肺脑均复苏)仅4例，复苏率分别为4．62％、1．82％。1990至1998年间复苏成功率较低，初步复苏成功率1．38％，最终复苏成功率0。1999至2002年间复苏成功率明显提高，初步复苏成功率8．24％，最终复苏成功率4．12％。自1998年我科开展院外急救以来，尚无一例院外心跳骤停者复苏成功。结论 心跳骤停患者抢救成功与否与抢救人员专业水平、抢救开始时间、抢救措施正确与否、对室颤患者能否早期除颤及患者原发病是否可逆等因素密切相关。     

Temporal trends in prevalence of diabetes mellitus in a population-based cohort of incident myocardial infarction and impact of diabetes on survival

OBJECTIVE: To determine the temporal trends in prevalence of confirmed diabetes mellitus (DM), time from the date DM criteria were met to myocardial infarction (MI), and impact of DM on survival. SUBJECTS AND METHODS: A retrospective cohort design was used to identify residents of Olmsted County, Minnesota, with incident MI from 1979 to 1998. The MI cases were characterized according to prevalent DM. Cases with and without DM were followed up for vital status until January 1, 2003. RESULTS: Of 2171 MI cases, 364 (17%) met criteria for prevalent DM. In the age- and sex-adjusted logistic regression models, the odds of prevalent DM Increased 3% with each Increasing year between 1979 and 1998 (95% confidence Interval [CI], 1%-5%; P=.007). Survival for MI cases with DM was unchanged between 1979-1983 and 1994-1998 (P=.74). For all MI cases, age-, sex-, and DM-adjusted risk of death decreased 3% from 1979 to 1998 (95% CI, 1%-5%) per year for 28-day survival (P=.02) and 2% (95% CI, 1%-3%) per year for 5-year survival (P=.02). There was a significant adverse effect of DM on 5-year survival after MI (age-, sex-, and calendar year-adjusted hazard ratio, 1.70; 95% CI, 1.38-2.09; P<.001). The adverse effect of DM persisted after adjusting for other cardiovascular disease risk factors, MI severity, and reperfusion therapy (hazard ratio, 1.66; 95% CI, 1.34-2.05; P<.001) and was unchanged over time (interaction between DM and calendar year, P=-.63). CONCLUSION: These data indicate that the prevalence of DM among patients with MI is increasing and that its adverse impact on survival after MI remains unchanged.     

Electrophysiolgical diagnosis for multiple sclerosis

Evoked potentials(EPs) in daily practice contain brainstem auditory evoked potentials (BAEPs), short-latency somatosensory evoked potentials(SSEPs), pattern-reversal visual evoked potentials(PVEPs) and motor evoked potentials(MEPs) with transcranial magnetic stimulation(TMS). In this review, we summarize the EP findings in Caucasian and Japanese MS. EPs can confirm the presence of lesions in patients with suspected involvement, and document the presence of clinically unsuspected lesions. In addition, the combined use of these EPs in each patients, so-called multimodality EPs, enables us to evaluate multiple aspects of sensory and motor systems. In 73 Japanese MS, the abnormality rates were 10.3% in median nerve SSEP, 37.1% in posterior tibial nerve SSEP, 35.6% in upper limb MEP, 56.1% in lower limb MEP, 39.3% in PVEP and 34.3% in BAEP. The frequency of clinically unsuspected lesions was about 30% in each EP. These findings are in good agreement with the recent fact that conventional MS have been increased in Japan. Other electrophysiological methods such as multimodality VEPs, pain-related SEPs, paired TMS and event related potentials(P300) may be useful for the diagnosis or evaluation of MS.     

Loss of aquaporin-4 in active perivascular lesions in neuromyelitis optica: a case report

Neuromyelitis optica (NMO) is clinically characterized by severe optic neuritis and transverse myelitis. In Japan, NMO has been named optic-spinal multiple sclerosis (OSMS) and it has been thought to be a subtype of multiple sclerosis (MS). However, several clinical and laboratory findings suggest NMO or OSMS is distinct from MS. Recently, the disease-specific antibody (NMO-IgG) was found in the serum from NMO patients, and its target antigen was identified as aquaporin-4 (AQP4) water channel protein which is mainly expressed in astroglial foot processes. However, the pathogenetic role of AQP4 in NMO remains unknown. We herein report a typical case of NMO in which immunohistochemical analysis showed a lack of AQP4 in the spinal cord lesions. The loss of AQP4 was evident in the central gray matter, especially in the perivascular lesions where immunoglobulins and complements were deposited, and glial fibrillary acidic protein (GFAP) staining was weak in those lesions. However, GFAP was strongly stained at the reactive astrogliosis surrounding the lesions. Myelin basic protein (MBP)-stained myelinated fibers were relatively preserved in the lesions where AQP4 was lost. In contrast to these NMO lesions, AQP4 was expressed predominantly in the gray matter in control spinal cords, and AQP4 was preserved in demyelinating MS lesions. Our findings suggest that astrocytic impairment associated with humoral immunity against AQP4 may be primarily involved in the lesion formation of NMO, and that the pathomechanisms of NMO are different from those of MS in which demyelination is the primary pathology.     

Epidemiology of Barrett's esophagus--comparison of Japan and the West

We compared the epidemiology of Barrett's esophagus in Japan and the West. Japan GERD Society Study Committee conducted the epidemiological survey in 2,595 patients who underwent endoscopy the first time, confirming that Barrett's mucosa was observed in 536 patients (20.8%) out of 2,577. But Barrett's esophagus (>3 cm of columnar lined epithelium) was detected only 5 (0.2%). The prevalence of typical Barrett's esophagus was markedly low in Japanese compared with Westerners. In Western, the incidence of Barrett's esophagus has increased markedly since the 1970s. It is estimated that Barrett's esophagus is found in approximately 6-12% of patients undergoing endoscopy for symptoms of GERD and in 1% or less of unselected patient populations undergoing endoscopy.     

四川大学华西医院47年肾切除手术回顾

目的 了解行肾切除手术疾病谱、疾病的临床表现及诊治方法的演变,探讨避免肾脏切除保留肾单位的术式,以期提高对肾脏疾病的诊治水平.方法 回顾性分析泌尿外科1955年1月-2001年12月收治入院22 603例患者的临床资料,对其中行肾切除手术的1 952例进行分析.根据肾切除手术病因,将疾病分为3类:肾肿瘤、肾结核、其他疾...     

Resistance to cefotaxime and seven other beta-lactams in members of the family Enterobacteriaceae: a 3-year survey in France.

During the second quarter each of 1988, 1989, and 1990, a French collaborative study group, including 12 university hospital laboratories, surveyed the resistance to beta-lactams of clinical isolates from hospitalized patients: consecutively, 10,641, 10,692, and 9,382 isolates were tested. The distribution of bacterial species over time was similar in each laboratory. The susceptibilities of microorganisms to amoxicillin, ticarcillin, cephalothin, cefoxitin, cefotaxime (CTX), ceftazidime (CAZ), aztreonam (ATM), and imipenem (IPM) were measured by the disk diffusion method in accordance with the recommendations of the Antibiogram Committee of the French Society for Microbiology. Five reference strains were included for quality control. Extended-spectrum beta-lactamases were detected by the synergistic effect of the combination of clavulanic acid-amoxicillin with CTX, CAZ, and ATM in the double-diffusion test. A synergistic effect with CTX, CAZ, and ATM was detected for 1.5% of all strains, mainly those of Klebsiella pneumoniae (13.3%). For this species, the synergy test enabled the detection of roughly 50% of the resistant strains misclassified as susceptible on the basis of interpretative standards. Extended-spectrum beta-lactamases disseminated in 1990 in most enterobacterial species but at a low frequency. Important variations in the percentages of resistant strains were observed in terms of bacterial species, hospitals, and wards. However, when the total number of strains was considered, the percentages of resistance to newer beta-lactams remained low.     

Epidemiology and treatment of diabetic ketoacidosis in a community population

We evaluated the epidemiology of diabetic ketoacidosis in the period 1960-1979. In Frederiksborg County, Denmark, the incidence of ketoacidosis at the county hospital increased from 60 per 100,000 in the period 1943-1963 to 120 per 100,000 in the period 1960-1979. In the investigation period we found an increasing incidence confined to urban areas. Precipitating factors were not somatic in 53% of the cases. Patients in the lowest social class (V) were in a higher risk group, experiencing ketoacidosis more often and having a higher frequency of severe acidosis. Forty-nine percent of the patients have had a diabetes duration of more than 5 yr. The lethality rate decreased from the period 1943-1963 and was 4.7% in the investigation period 1960-1979.     

Age- and gender-specific distributions of hepatitis B virus (HBV) genotypes in Japanese HBV-positive blood donors

BACKGROUND: There are an increasing number of reports on the hepatitis B virus (HBV) genotype distribution in acute or chronic HBV-infected patients in Japan; however, reports on the HBV genotype of blood donors are few. To compare the HBV genotypes of hepatitis B surface antigen (HBsAg)-positive blood donors with infected patients, all the HBsAg-positive donors' genotypes were determined.
STUDY DESIGN AND METHODS: Data on Japanese blood donors from October 2006 to September 2007 were obtained from the Japanese Red Cross database. The number of available samples was 1979, and the HBV genotypes were determined in 1887 samples. The six major genotypes of HBV (A-F) were determined by enzyme-linked immunosorbent assay. The presence of the immunoglobulin M (IgM) antibody against the HBV core antigen was determined by enzyme immunoassay among all HBsAg-positive donors.
RESULTS: A significant difference in the HBV genotype distribution between donors and patients was in the C/B genotype ratio. The ratios were low in blood donors (2.0-3.9) and high in patients (5.3-18.2). The genotype B ratio increases from 13.8% in teenage donors to 42.4% in those in their 50s; however; the genotype C ratio decreases from 83.1% in teenage donors to 55.1% in those in their 50s. In both IgM antibody against hepatitis B core antigen and nucleic acid test–positive donors, genotypes A and B were restricted to male donors.
CONCLUSIONS: The age-specific distribution of HBV genotypes in Japanese blood donors was observed in the B/C genotype ratio. The gender-specific distribution of HBV genotype A, which originated from the US or Western countries, was observed in male Japanese donors.     

Impaired fasting glucose and the risk of hypertension in Japanese men between the 1980s and the 1990s. The Osaka Health Survey.

OBJECTIVE: To determine whether impaired fasting glucose (IFG) increased the risk for hypertension in two large Japanese cohorts during the different time periods. RESEARCH DESIGN AND METHODS: We prospectively investigated two Japanese cohorts: a 1980s population, comprising 4,130 normotensive and nondiabetic men aged 35-60 years entered between 1981 and 1983, and a 1990s population, comprising 4,319 normotensive and nondiabetic men aged 35-60 years entered between 1991 and 1992. Data on lifestyle factors were obtained from questionnaires. IFG was defined as a fasting plasma glucose level > or = 110 and < 126 mg/dl. RESULTS: During the 4-year observation period, 708 cases of hypertension were confirmed in the 1980s and 848 cases were confirmed in the 1990s. In both the 1980s and 1990s populations, IFG was associated with the risk of hypertension. The frequency of IFG in men in the 1990s group was twice as high as that in the 1980s group. The multivariate-adjusted odds ratio (OR) of hypertension was 1.54 (95% CI, 1.01-2.34) for men with IFG in the 1980s population and 1.73 (1.31-2.29) in the 1990s population, compared with those without IFG in the two populations. In the 1990s population, among lean men with a BMI < or = 23 kg/m2, men with IFG had a multivariate-adjusted OR of hypertension of 2.31 (1.46-3.65) compared with those without IFG. CONCLUSIONS: This study demonstrated direct correlation between IFG and hypertension and greater incidence of this hypertension in the 1990s group than in the 1980s group.     

荧光原位杂交技术在慢性淋巴细胞白血病检测中的应用评估

本研究探讨与评估应用间期荧光原位杂交技术(FISH)检测慢性淋巴细胞白血病(CLL)遗传学异常的价值。应用间期FISH技术检测32例初诊CLL患者的del(13q14.3)、del(11q22.3)、del(17p13.1)、del(13q14)和12号染色体三体,同时对免疫表型不典型的10例初诊患者检测IGH/CCND1融合基因。结果表明,在32例病例组中FISH检测出26例(81.3%)基因异常,包括D13S25缺失14例,RB1缺失11例,12号染色体三体9例,P53缺失6例,ATM缺失4例;涉及1种基因异常的12例,其中12号染色体三体7例,D13S25缺失3例,P53缺失1例,ATM缺失1例;涉及2种基因异常的11例,其中D13S25/RB1缺失的7例,另4例均包含P53缺失;涉及3种以上基因异常的病例3例;10例免疫表型表达CD5+CD23-的初诊患者中2例IGH/CCND1(+)。结论:应用间期FISH技术检测CLL基因组的异常,可大大提高异常染色体的检出率,各基因异常有其不同的特点;IGH/CCND1融合基因的检测在CLL诊断中有重要意义。