Search

In the multipulse linear predictive coding (LPC) speech synthesis, an autoregressive filter is excited by a multipulse excitation consisting of impulses of various amplitudes and locations. The authors statistically model the excitation signal as a zero mean Bernoulli-Gaussian process. The pulse locations are independently distributed with a probability distribution, and the pulse amplitudes are expressed as a Gaussian sequence with zero mean and finite variance. An algorithm is described for estimation of pulse amplitudes and locations based on the Bernoulli-Gaussian process when the number of pulses is given. Results from computer simulation are presented. >

Multiple endocrine neoplasia type 2 (MEN2) syndromes are inherited in an autosomal dominant fashion with high penetrance. There are three subtypes, namely, MEN2A (multiple endocrine neoplasia type 2A), MEN2B (multiple endocrine neoplasia type 2B), and familial medullary thyroid carcinoma. The variations in the RET gene play an important role in the MEN2 syndromes. In this work, we have developed a RET oligonucleotide microarray of 67 oligonucleotides to quickly detect RET mutations in MEN2 syndromes. The predominant RET mutations are missense mutations and are restricted to nine codons (codons 609, 611, 618, 620, 630, 634, 768, 804, and 918) in MEN2 syndromes. Missense mutations at codons 609, 611, 618, 620, and 634 have been identified in 98% of MEN2A families and in 85% of familial medullary thyroid carcinoma families. More than 95% of MEN2B patients also had a predominant mutation type at codon 918 (Met--Thr). RET oligonucleotide microarray can detect RET missense mutations at these nine codons. Theoretically, a total of 55 missense mutation types can occur at eight codons (codons 609, 611, 618, 620, 630, 634, 768, and 804). RET oligonucleotide microarray is designed to detect all of these 55 missense mutation types at these eight codons and one predominant type at codon 918. Fifty-six oligonucleotides were designed for the 56 mutation types at nine codons, and 11 oligonucleotides were designed for the wild types and positive controls. We found RET mutations in all eight of the Korean MEN2A families (a total of 75 members; 27 affected members, 19 gene carriers, and 29 unaffected members) using the developed RET oligonucleotide microarray and an automatic sequencing. Because we found only five mutation types from eight MEN2A families, the international collaborations are required to see whether the RET oligonucleotide microarray may be used as a genetic diagnostic tool. Taken together, the RET oligonucleotide microarray can function as a fast and reliable genetic diagnostic device, which simplifies the process of detecting RET mutations.

Reference(s) [1] Bril V, England J, Franklin GM, Backonja M, et al. American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011; 76(20): 1758–65. [2] O’Connor AB, Noyes K, Holloway RG. A cost-utility comparison of four first-line medications in painful diabetic neuropathy. Pharmacoeconomics. 2008; 26(12): 1045–64. [3] Bansal D, Bhansali A, HotaD, Chakrabarti A, et al. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009; 26(10): 1019–26.

Amytrophic lateral sclerosis is characterized by relentlessly progressive degeneration of spinal cord motor neurons. During the disease, the bcl-2 family genes have been reported to alter their expression levels. To understand the meaning of these changes, the expression pattern of Bax in rat spinal cord and its changing pattern during normal aging were investigated by immunohistochemical staining. Spatial expression of the protein showed a diffuse distribution pattern with immunoreactivity more prominent in the anterior hom. With advancement of age, the cell densities of Bax-positive cells tended to increase. The increasing expression of Bax might be positively associated with amyotrophic lateral sclerosis. This work demonstrates for the first time how Bax expression changes in rat spinal cord during normal aging.

Autoimmune diseases can be transmitted and eliminated by bone marrow transplantation (BMT). There have been several cases of autoimmune thyroid disease (AITD) occurring after BMT, but AITD remission has been rarely reported. We present four cases in which the remission or transfer of AITD occurred after an allogeneic BMT. Two patients with severe aplastic anemia (SAA) showed evidence of remission of Hashimoto's thyroiditis which they had before allogeneic BMT. One patient with SAA, which developed during treatment with propylthiouracil for Graves' disease, underwent allogeneic BMT and showed evidence of Graves' disease remission following BMT. In one patient, new AITD occurred after an allogeneic BMT from an HLA-matched sibling who already had AITD. These cases support the evidence that the immune system is newly reconstituted after BMT, and severe autoimmune disease can be an indication for BMT. To fully understand the real changes in autoimmune status after BMT, long-term prospective studies are necessary.

In a previous study, we reported increased NOS expression in the astrocytes in the spinal cord of SOD mutant transgenic mice that are used as ALS animal model. Recently, Messmer and Brune suggested that nitric oxide-induced apoptosis is intimately related with p53-dependent signaling pathway, and de la Monte et al. reported increased p53-immunoreactivity in the spinal cord of ALS patients. In the present study, we performed immunocytochemical studies to investigate the changes of p53-immunoreactivity in the brains of the mutant transgenic mice expressing a human Cu/Zn SOD mutation. Immunocytochemistry showed intensely stained p53-IR glial cells with the appearance of astrocytes in all levels of the spinal cord of the mutant transgenic mice, but no p53-IR glial cells were observed in the spinal cord of the control mice. P53-IR astrocytes were also detected in the brain stem of the mutant transgenic mice. In the medulla, they were observed in the medullary reticular formation, hypoglossal nucleus, vestibular nucleus, dorsal motor nucleus of the vagus and nucleus ambiguus. In the pons, their presences were noted in the pontine reticular formation, and trigeminal and facial nuclei. In the midbrain, astrocytes were detected in the mesencephalic reticular formation, red nucleus and periaqueductal gray matter. In the cerebellum, intensely stained p53-IR astrocytes were detected in the intracerebellar nuclei. In contrast to the mutant transgenic mice, no p53-IR astrocytes were detected in the brain stem and spinal cord of the control mice. Further multidisciplinary investigations involving p53-mediated cellular damage and pathogenesis of ALS are needed to clarify the importance of these results.

THE pattern of distribution in rat spinal cord and changing pattern during normal ageing of c-Fos expression were investigated by immunohistochemical staining in male Sprague-Dawley rats at the age of 1 week, 5 months and 2 years, c-Fos immunoreactivity was observed diffusely in gray matters in neonatal rats, preferentially located in deep dorsal horn and around central canal. Compared with those of neonatal rats, these cells decreased prominently in adult rats. In aged rats, immunoreactive cells were not seen in any segments. c-Fos immunoreactivity in spinal cord may be related to stress response, functional differentiation, and in part, neuronal death with target dependence. In conclusion, we demonstrated for the first time that c-Fos expression patterns change during normal ageing.

The distribution of the neuronal isoform of nitric oxide synthase (nNOS) in the spinal cord of transgenic mice expressing a mutated human copper/zinc superoxide dismutase gene was enhanced when investigated by immunocytochemistry. Immunocytochemistry showed intensely stained NOS-immunoreactive (IR) glial cells with the appearance of astrocytes in the spinal cord and brain stem of transgenic mice, but none were observed at these sites in control mice. Using antisera directed against GFAP, the specific marker for astrocyte, the glial cells were confirmed by immunocytochemistry to be astrocytes. This immunocytochemical evidence suggests that nitric oxide may mediate glutamate neurotoxicity, and this study provides the first in vivo evidence that nitric oxide may be implicated in the pathologic process of human familial amyotrophic lateral sclerosis.

The association of DUSP6 gene with schizophrenia and bipolar disorder: its possible role in the development of bipolar disorder

Copyright 2014 by The Korean Society of Clinical Neurophysiology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Address for correspondence; Kwang Woo Lee Department of Neurology, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: +82-2-2072-3215 Fax: +82-2-2072-7553 E-mail: kwoo@plaza.snu.ac.kr Case Report

BACKGROUND AND OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory demyelinating disorder of the central nervous system with a relapsing and remitting course. We aimed to identify factors associated with the time to next attack, including the effect of the natural disease course and the diverse treatment regimens, by applying a longitudinal statistical analysis to the individual attacks of each patient. METHODS: In total, 184 acute attacks among 58 patients with either NMO or NMO spectrum disorder with anti-aquaporin-4 antibody were assessed retrospectively. Patient demographics, clinical characteristics at each attack, and type of treatment during inter-attack periods were assessed. The dependent variable was defined as the time from each attack to the next attack (inter-attack interval). An exponential accelerated failure time model with shared gamma frailty was adapted for statistical analysis. RESULTS: A multivariable analysis revealed that the time from each attack to the next attack in NMO increased independently by 1.31 times (95% confidence interval (CI), 1.02-1.67; p = 0.035) with each additional cumulative attack experienced, by 5.34 times (95% CI, 1.57-18.13; p = 0.007) with combined azathioprine treatment and continued oral prednisolone, and by 4.26 times (95% CI, 1.09-16.61; p = 0.037) with rituximab treatment. CONCLUSION: The time to next attack in NMO can increase naturally in the later stages of the disease as the number of cumulative attacks increases. Nevertheless, both combined azathioprine treatment with continued oral prednisolone and rituximab treatment were also associated with a longer time to next attack, independently of the natural disease course of NMO.

BackgroundPatients with ALS may be exposed to variable degrees of chronic intermittent hypoxia. However, all previous experimental studies on the effects of hypoxia in ALS have only used a sustained hypoxia model and it is possible that chronic intermittent hypoxia exerts effects via a different molecular mechanism from that of sustained hypoxia. No study has yet shown that hypoxia (either chronic intermittent or sustained) can affect the loss of motor neurons or cognitive function in an in vivo model of ALS.ObjectiveTo evaluate the effects of chronic intermittent hypoxia on motor and cognitive function in ALS mice.MethodsSixteen ALS mice and 16 wild-type mice were divided into 2 groups and subjected to either chronic intermittent hypoxia or normoxia for 2 weeks. The effects of chronic intermittent hypoxia on ALS mice were evaluated using the rotarod, Y-maze, and wire-hanging tests. In addition, numbers of motor neurons in the ventral horn of the spinal cord were counted and western blot analyses were performed for markers of oxidative stress and inflammatory pathway activation.ResultsCompared to ALS mice kept in normoxic conditions, ALS mice that experienced chronic intermittent hypoxia had poorer motor learning on the rotarod test, poorer spatial memory on the Y-maze test, shorter wire hanging time, and fewer motor neurons in the ventral spinal cord. Compared to ALS-normoxic and wild-type mice, ALS mice that experienced chronic intermittent hypoxia had higher levels of oxidative stress and inflammation.ConclusionsChronic intermittent hypoxia can aggravate motor neuronal death, neuromuscular weakness, and probably cognitive dysfunction in ALS mice. The generation of oxidative stress with activation of inflammatory pathways may be associated with this mechanism. Our study will provide insight into the association of hypoxia with disease progression, and in turn, the rationale for an early non-invasive ventilation treatment in patients with ALS.

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that leads to progressive weakness of the respiratory and limb muscles. Consequently, most patients with ALS exhibit progressive hypoventilation, which worsens during sleep. The aim of this study was to evaluate the relationship between nocturnal hypoxia and cognitive dysfunction and to assess the pattern of nocturnal hypoxia in patients with ALS. Method: Twenty-five patients with definite or probable ALS underwent neuropsychologic testing, nocturnal pulse oximetry, and capnography. Patients were grouped according to the presence of nocturnal hypoxia (SpO(2)= 10% of the night) and their clinical characteristics and cognitive function were compared. Results: Compared to patients without nocturnal hypoxia, those with nocturnal hypoxia (n = 10, 40%) had poor memory retention (p = 0.039) and retrieval efficiency (p = 0.045). A cluster-of-desaturation pattern was identified in 7 patients (70%) in the Hypoxia Group. Conclusions: These results suggest that nocturnal hypoxia can be related to cognitive dysfunction in ALS. In addition, a considerable number of patients with ALS may be exposed to repeated episodes of deoxygenation-reoxygenation (a cluster-of-desaturation pattern) during sleep, which could be associated with the generation of reactive oxygen species. Further studies are required to define the exact causal relationships between these phenomena, the exact manifestations of nocturnal cluster-of-desaturation patterns, and the effect of clusters of desaturation on ALS progression.

Beta-amyloid precursor protein (betaAPP) has been shown to be involved in cell growth regulation. In spleen, the majority of cells showing betaAPP like immunoreactivity was found in the T cell-dependent zone. In Northern blot, the expression of betaAPP was increased to reach the peak at 72 h after the treatment of phytohemagglutinin (PHA). But, in cytofluorometry, almost all CD4(+) T helper/inducer cells and the majority of CD(8+) T suppressor/cytotoxic cells show betaAPP immunoreactivity which remained constant during the stimulation with PHA. These results suggest that betaAPP is a surface molecule of T lymphocyte and the turnover or release of APP might be increased with the treatment of T cell mitogen.

Background: The autophagy is the major route for lysosomal degradation of misfolded protein aggregates and oxidative cell components. We hypothesized that rapamycin (autophagy enhancer) would prolong the survival of motor neuron and suppress the disease progression in amyotrophic lateral sclerosis (ALS). Methods: A total of 24 transgenic mice harboring the human G93A mutated SOD1 gene were used. The clinical status involving rotarod test and survival, and biochemical study of ALS mice model were evaluated. Results: The onset of symptoms was significantly delayed in the rapamycin administration group compared with the control group. However, after the clinical symptom developed, the rapamycin exacerbated the disease progression and shortened the survival of ALS mice model, and apoptosis signals were up-regulated compared with control group. Conclusions: Even though further detailed studies on the relevancy between autophagy and ALS will be needed, our results revealed that the rapamycin administration was not effective for being novel promising therapeutic strategy in ALS transgenic mice and exacerbated the apoptosis.

Purpose Many treatment options to help relieve the symptoms of interstitial cystitis (IC) are available, but none are effective. Because no reports of transurethral ulcer resection with hydrodistention are available, we assessed the effects of such combined surgery for ulcerative IC. Materials and Methods Between June 2006 and June 2011, 87 female patients with IC who underwent transurethral resection with hydrodistention and were followed up for at least 12 months were included. Improvements in patients' voiding symptoms and pain were analyzed retrospectively by using a 3-day micturition chart and a 10-point visual analogue scale (VAS) before and after the operation. The global response assessment (GRA) was used to assess treatment satisfaction. Results The mean age of the 87 female patients was 59.1±10.1 years, and the mean follow-up period was 26.7±14.4 months. Mean maximum functional bladder capacity increased from 168.4±92.4 mL to 276.3±105.4 mL (1 month) and to 227.3±91.7 mL (12 months). The mean frequency of voiding decreased from 17.2±8.5 before to 10.6±5.3 after (1 month) surgery; however, it increased again to 13.3±4.8 at 12 months. The 10-point VAS score decreased from 9.1±0.8 to 1.2±0.3 (1 month); however, it increased again to 2.5±0.4 (3 months), 3.2±0.4 (6 months), and 5.3±0.5 (12 months) (p

Background The aim of this study was to investigate the influences of visceral adiposity on cardiovascular autonomic neuropathy (CAN) in patients with type 2 diabetes mellitus. Methods Two hundred eleven patients with type 2 diabetes participated in this study. Anthropometric and metabolic parameters were measured, and the visceral fat area was assessed using computed tomography. CAN was diagnosed using a cardiovascular reflex test. We analyzed the correlation between the visceral fat area and each parameter in this test. Results The mean age, body mass index (BMI), and duration of diabetes of the study population were 60±14 years (mean±standard deviation), 25.1±4.2 kg/m(2), and 12.3±8.9 years, respectively. The visceral fat area showed positive correlations with age, BMI, waist circumference, and subcutaneous fat area. There was no statistically significant difference in the cardiovascular reflex test outcome between genders. Univariate linear regression analysis showed that an increased visceral fat area diminished good heart rate response to a Valsalva maneuver (R(2)=4.9%, P=0.013 in an unadjusted model), but only in women. This statistical association was preserved after adjusting for age and BMI (R(2)=9.8%, P=0.0072). Conclusion The results of this study suggest that visceral adiposity contributes to an autonomic imbalance to some degree, as demonstrated by the impaired cardiovascular reflex test among women with type 2 diabetes.

There is controversy regarding definition of vitamin D inadequacy. We analyzed threshold 25-hydroxyvitamin D (25[OH]D) below which intact parathyroid hormone (iPTH) increases, and examined age- and sex-specific changes of 25(OH)D and iPTH, and association of 25(OH)D and iPTH with bone mineral density (BMD) in elderly Koreans. Anthropometric parameters, serum 25(OH)D and iPTH, lumbar spine and femur BMD by dual-energy radiography absorptiometry (DXA) were measured in 441 men and 598 postmenopausal women. iPTH increased below serum 25(OH) of 36.7 ng/mL in men, but failed to reach plateau in women. Femur neck BMD above and below threshold differed when threshold 25(OH)D concentrations were set at 15-27.5 ng/mL in men, and 12.5-20 ng/mL in postmenopausal women. Vitamin D-inadequate individuals older than 75 yr had higher iPTH than those aged ≤ 65 yr. In winter, age-associated iPTH increase in women was steeper than in summer. In conclusion, vitamin D inadequacy threshold cannot be estimated based on iPTH alone, and but other factors concerning bone health should also be considered. Older people seemingly need higher 25(OH)D levels to offset age-associated hyperparathyroidism. Elderly vitamin D-inadequate women in the winter are most vulnerable to age-associated hyperparathyroidism.

Background Multifocal motor neuropathy (MMN) is an immune-mediated disorder that is characterized by slowly progressive and asymmetrical weakness, but its pathophysiological mechanism is uncertain. The hypothesis that MMN is an immunological disease has been supported by the proven therapeutic effects of intravenous immunoglobulin and the detection of antiganglioside antibodies in MMN patients. The coexistence of MMN with other immune diseases has been rarely reported. Case Report A 37-year-old woman visited our hospital complaining of weakness in both hands. The clinical manifestations coincided well with MMN: predominantly distal upper-limb weakness, asymmetric involvement, a progressive course, absence of sensory symptoms, absence of pyramidal signs, and sparing of the cranial muscles. The electrophysiological findings also supported a diagnosis of MMN, with motor nerve conduction block in the median, ulnar, and radial nerves, without sensory nerve involvement. The patient was simultaneously diagnosed as having Hashimoto's thyroiditis, which is a well-known immune-mediated disease. Conclusions The concurrence of MMN and Hashimoto's thyroiditis in our patient is significant for understanding the immunological characteristics of the two diseases.

The acute peripheral neuropathy as one of hypereosinophilic syndrome is known to be a rare disorder. The authors experienced a dramatic case with acute peripheral neuropathy, hypereosinophilia in peripheral blood, and the positive anti-GM1 antibodies. The serum protein electrophoresis showed a diffusely increased gamma-globulin region and the polyclonal gammopathy was found by the immunoelectropheresis. There was no evidence of inflammatory myopathy in vastus lateralis muscle. The sural nerve biopsy was compatible with vascular neuropathy, as there were a few myelin digestion chambers, mild perineuronal fibrosis, and perivascular lymphoplasmocytic infiltration with focal organizing thrombosis. The clinical response to prednisone therapy was excellent.

Patients were diagnosed with IBP if there was no limb progression over six months. Patient demographics, clinical features and neurophysiological biomarkers, including cortical excitability using paired pulse, threshold tracking, transcranial magnetic stimulation, were recorded. IBP patients were compared to more typical bulbar-ALS patients. Results: From a cohort of 250 consecutive referrals, 32 patients with bulbar onset disease (11 males, 21 females, age 64.1±9.0 years) were identified. Twelve patients had IBP (3 male, 9 female, age 61.1±8.2 years) and twenty had bulbar-ALS (8 males, 12 females, age 65.9±9.3 years). IBP was characterized by female predominance and predominantly upper motor neuron bulbar features. In contrast, patients with bulbar-ALS had more prominent lower motor neuron bulbar features. The compound motor action potential amplitude was preserved in patients with IBP compared to patients with bulbar-ALS (7.1mV compared to 4.2mV, P< 0.05) as was the neurophysiological index (1.22 compared to 0.45, P< 0.05). Furthermore, cortical excitability was normal in patients with IBP and abnormal in patients with bulbar-ALS. Conclusions: Patients with IBP were predominantly female with prominent upper motor neuron bulbar features. Neurophysiologically, IBP patients had no evidence of peripheral lower motor neuron dysfunction and had normal cortical excitability. Neurophysiological biomarkers such as SICI may prove useful for patient diagnosis, selection and monitoring in clinical trials.