Association between oxidative stress and microRNA expression pattern of ALS patients in the high-incidence area of the Kii Peninsula.

Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disorder of the upper and lower motor neuron systems. The high incidence of ALS in the southern part of the Kii Peninsula of Japan (K-ALS) was reported in the 1960s, but it has gradually decreased to the worldwide average. Although causes of the high incidence of ALS in this area are unknown, our previous studies suggested that environmental factors, including essential mineral deficiency and increased metal-induced oxidative stress, play a role in its development. Recently, it has been reported that microRNAs (miRNA) contribute to the degeneration of nervous system such as ALS. The aim of this study is to explore specific miRNAs in K-ALS and evaluate relationships between oxidative stress. We comprehensively analyzed serum miRNAs and examined urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG), serum Cu/Zn superoxide dismutase (SOD) and serum Nɛ-hexanoyl lysin (HEL) as oxidative stress markers in the patients with K-ALS, sporadic ALS (S-ALS), residents in this area (K-residents) and controls from another area. The expression levels of miR-92a-3p and miR-486-5p in the patients with K-ALS were significantly higher than those in controls. The HEL levels were significantly higher in the patients with K-ALS than in those with S-ALS and controls. The expression levels of miR-92a-3p and miR-486-5p were not correlated with the levels of HEL. A set of high levels of miR-92a-3p, miR-486-5p and serum HEL may be a useful biomarker for K-ALS in the Kii Peninsula. The findings should be further studied by a large number of subjects.

Neutron activation analysis of scalp hair from ALS patients and residents in the Kii Peninsula, Japan.

The aim of this study was to evaluate the accumulation of transition metals in the scalp hair of amyotrophic lateral sclerosis (ALS) patients in the Koza/Kozagawa/Kushimoto (K) area (K-ALS) in the Kii Peninsula, Japan. Metal contents were measured in the unpermed, undyed hair samples of 88 K-residents, 20 controls, 7 K-ALS patients, and 10 sporadic ALS patients using neutron activation analysis at the Research Reactor Institute, Kyoto University. A human hair standard and elemental standards were used as comparative standards. The contents of Zn, Mn, and V were higher, while that of S was lower in K-ALS patients than in the controls. The content of Mn in K-ALS patients negatively correlated with clinical durations. The content of Al was significantly higher in K-residents than in the controls, with 15.9 % of K-residents having high Mn contents over the 75th percentile of the controls. The contents of Zn, Mn, and V were high in the scalp hair of K-ALS patients and correlated with the content of Al. The accumulation of these transition metals may chronically increase metal-induced oxidative stress, which may, in turn, trigger the neuronal degeneration associated with K-ALS.

[Changes in the incidence and clinical features of ALS in the Koza, Kozagawa, and Kushimoto area of the Kii Peninsula--from the 1960s to the 2000s (follow-up study)].

In the 1960's, ALS was highly prevalent in the southern part of the Kii Peninsula, especially in the Koza, Kozagawa, and Kushimoto area (K area). Thereafter, the incidence of ALS was considered to have gradually decreased, and the disease almost disappeared in the 1980's. However, new patients have been continuously identified in this area, and indicating the importance of studying the changes in the incidences of ALS. This study investigated the characteristic clinical features and incidence of ALS in K area during the following periods: period I: between 1967 and 1971, period II: between 1989 and 1999, and period III: between 2000 and 2008. Data on all patients with motor neuron disease were collected for each year within these periods from medical doctors and medical staff of the regional public health center and municipal office. Neurologists on our research team examined and assessed each of these patients on the basis of the El Escorial criteria. Probable and definite ALS patients diagnosed by neurologists using the El Escorial criteria in K area during the research periods were collected. The crude incidence rate of ALS in K area were similar in period I, i.e. 6.0/100,000, and in period III, i.e., 5.7/100,000. The age-, and sex-adjusted incidence (considering the 2000 census) in women in K area during period III, especially in Kozagawa district, was higher than that in periods I and II. The adjusted incidence rate in Kozagawa district was 8.8/100,000, and was higher than that in other areas of the world. The clinical features of patients in this area were quite similar to those of patients with classical ALS. Five patients from 3 families with a family history of ALS and 2 patients without a family history presented with the clinical features of ALS and PDC during these research periods. The mean age at onset for period III was higher than that in period I (p < 0.01). The frequency of ALS patients with upper-extremity onset in period III was lower than that in period I (p = 0.05), whereas the frequency of patients with bulbar-onset has recently increased. Conclusion The result of present study indicate that the recent incidence of ALS in K area is high, the age of onset has recently become higher and the number of bulbar-onset patients has increased. All the abovementioned findings could be attributed to an increase in the senility rate in the population. Between 2000 and 2008, the age-adjusted incidence in ALS for women in K area, especially in the Kozagawa district, was high, indicating an increase in that the incidence of ALS among women in this area after 2000. The factors responsible for the high incidence of ALS in this area remain to be clarified.

Psychological adjustment has a greater effect on health-related quality of life than on severity of disease in Parkinson's disease.

The objective of this study was to investigate the effect of psychological adjustment to Parkinson's disease (PD) on the health-related quality of life (HRQL) in patients with this condition. One hundred eighty-three patients (77 male, 106 female; mean age, 65.8 years) were evaluated using the Parkinson's Disease Questionnaire (PDQ-39) and the Japanese version of the Nottingham Adjustment Scale (NAS-J). Multiple regression analysis was performed using age and sex as the explanatory variables. Comparisons were made of changes in R2 when severity and psychological adjustment subscales were added. In addition, comparisons were made of HRQL scores between groups with different levels of psychological adjustment. R2 was higher when psychological adjustment was included in comparison with severity in the some subscales (emotional well-being, stigma, social support, cognition, communication, and bodily discomfort). HRQL was significantly lower in the low-adjustment group compared with other groups. Psychological adjustment had a greater effect than severity of disease on several subscales in the HRQL of patients with PD. This finding suggests that, in addition to any suppression of the progression of symptoms, psychological intervention may also be effective in enhancing the HRQL of patients with PD.

[MELAS-like episodes in an adult case with cytochrome c oxidase deficiency].

A 30-year-old man was hospitalized with dysarthria and weakness of his right arm and leg. Three months previously, he had noticed numbness and weakness of his right shoulder, which spread to involve his left leg but which improved after 8 months. On admission, neurological examination revealed limb kinetic apraxia and constructive apraxia of the right hand, motor aphasia, dysarthria, and spastic quadriplegia. Sensory examination revealed hyperalgesia and dysesthesia in the right arm and left leg. Deep tendon reflexes were hyperactive in all four extremities. And he had bilateral Babinski signs. Laboratory examination revealed pH 7.38, PCO2 46.1 Torr, PO2 93.4 Torr, BE 1.7, and blood lactate, 9.0 mg/dl (normal 5-20 mg/dl). Cerebrospinal fluid lactate level was 20.0 mg/dl. pyruvate 1.34 mg/dl. and protein 83 mg/dl. Blood lactate and pyruvate values were markedly elevated after aerobic exercise. T2WI brain MRI showed scattered high signal lesions in the left precentral and postcentral gyrus, right paracentral lobes, both superior frontal gyri, and right superior temporal gyrus. Right biceps brachi biopsy showed almost complete cytochrome c oxidase (COX) deficiency. There were no ragged-red fibers. There was marked decrease of COX activity: 2.7 nmol/min/mg-mitochondrial protein (normal range: 33.0 +/- 16.1, n = 7) in the biopsied muscle. Open brain biopsy (after permission from the patient and his family) revealed gliosis and perivascular infiltration of lymphocytes and macrophages without vascular proliferation. There was no mitochondrial DNA mutations, deletion or duplication, including tRNA-Leu 3243, 8993, 3271, 9176, 3291, and tRNA-Lys 8344, 8356, and 8363. From these findings, a diagnosis of COX deficiency presenting as MELAS-like episodes was done. His mother also showed abnormality on aerobic exercise test, but she had no episode of stroke or neurological dysfunction. Six months later, his aphasia and apraxia of the right hand had resolved, and at discharge he was able to ambulate with a cane. Ten months later, he returned to his work. There has been no recurrence of neurologic symptoms over the next 3 years and 10 months. This patient appears to represent a rare case of adult onset COX deficiency presenting as MELAS-like episodes.

[Effect of zonisamide on resting tremor resistant to antiparkinsonian medication].

The antiparkinsonian effect of zonisamide (ZNS), an antiepileptic agent, has been reported. Generally, resting tremor of patients with Parkinson's disease is not the main therapeutic target in this disease. However, depending on the social situation of the patient, the amelioration of the tremor may be necessary. In this study, we examined the effect of ZNS on tremor in nine patients who desired amelioration of their tremor. Except for tremor, they seemed to be under optimal therapeutic condition based on their daily activities. By the add-on administration of ZNS, the degree of tremor was reduced in seven out of nine patients (p < 0.0017). Although one patient felt sleepiness and two patients had a transient loss of appetite, all the patients tolerated the eight-week ZNS administration period. The final dose of ZNS was 100 mg/day in the majority of the patients. Although the mechanism of the antitremulous effect of ZNS is not yet clear, other than the enhancement of dopaminergic transmission, some specific action of the drug on tremor may exist. A more detailed random examination should be carried out.

[Validation of the Japanese version of the Parkinson's Disease Questionnaire].

UNLABELLED: The PDQ-39 (Parkinson's Disease Questionnaire-39) is a specific quality-of-life (QOL) scale for patients with Parkinson's disease (PD). It evaluates the dysfunction of daily living and quality of life. We developed the Japanese-translated version of PDQ-39 and examined the validity of the PDQ-39 in Japanese PD patients. SUBJECTS: A total of 156 patients with PD were studied (age 35-86 years, Hoehn-Yahr stage 1 to 4). None of the patients had dementia. METHODS: Semi-structured interviews were conducted by one trained interviewer. The PDQ-39, SF-36 (36-item short form of the Medical Outcome Study questionnaire), EQ5D (Euro Qol), and NAS-J (Nottingham Adjustment Scale Japanese version) were used for evaluation. The attending physician of each patient rated the patient's condition by using the UPDRS (Unified Parkinson's Disease Rating Scale). RESULTS: Exploratory factor analysis, Cronbach alpha, and construct validity were fair, and there were significant correlations between the results of the PDQ-39 and the corresponding parts of the UPDRS and SF-36, and the Hoehn-Yahr stage, respectively. CONCLUSION: The Japanese version of the PDQ-39 is valuable for evaluating the QOL of Japanese patients with PD. Results of comparison of PDQ-39 with other scales of the QOL such as NAS-J suggest the possibility that acceptance of the disease and feelings of self-achievement improve the QOL of patients with Parkinson's disease.

["Stunned myocardium" on echo cardiogram in myotonic dystrophy: a case report].

A 56-year-old woman with a 23 year-history of myotonic dystrophy was admitted to our hospital because of dysphagia and aspiration pneumonia. On admission, patient's ECG showed Ist degree of atrioventricular block and elongation of QRS (133 msec.). On the third hospital day, abnormal Q wave abruptly appeared in aVL associated with elevation of ST segment in V2 and V3, reverse T wave in I, II, III, aVF and V 2-6 leads on ECG. Echo cardiogram demonstrated asynergy at the apex and septal wall. Coronary angiography was normal. Left ventricular ejection fraction determined by left ventriculography decreased to 47.4%. Based on these findings, we thought "stunned myocardium" had developed. Biopsied myocardium from the apex, septum, and free wall showed non-specific findings including mild fibrosis and lymphocytic infiltration. Although overt myocardial disease is rare in myotonic dystrophy, myocardiac disease such as "stunned myocardium" not due to arrhythmia or coronary angiopathy may develop under severe infection, stress, and/or respiratory distress.

[Effect of quetiapine fumarate on drug-induced psychosis in patients with Parkinson's disease].

Among atypical antipsychotics, quetiapine is characterized by a lower incidence of aggravation of parkinsonism due to its lower affinity to D 2. In this study, the effect of quetiapine fumarate (quetiapine) on antiparkinsonian-drug-induced psychosis (e.g. hallucination and delusion) in patients with Parkinson's disease was examined. Ten patients with antiparkinsonian-drugs-induced psychosis were enrolled in this study. The average age of the patients was 69 years and the mean duration of illness was 7 years and 5 months. Psychosis and parkinsonism in these patients were assessed by the Japanese version of PANSS (Positive and Negative Symptom Scale) and UPDRS (Unified Parkinson's Disease Rating Scale) before and during administration of quetiapine, respectively. During the assessment of the effect of quetiapine, the antiparkinsonian drugs that the patients were taking were unchanged. In nine out of the 10 patients, psychotic symptoms disappeared following administration of a relative small dose of quetiapine. No remarkable aggravation of parkinsonism was observed. The present results indicate that quetiapine is an useful drug for treating antiparkinsonian-drug-induced psychosis in the patient with Parkinson's disease.