Takeshi Sakiyama

Pathologic changes of glial cells in murine model of Niemann–Pick disease type C: Immunohistochemical, lectin-histochemical and ultrastructural observations

Abstract Background : In recent years, morbid states of glial cells have been reported in several neurodegenerative diseases. We studied neuropathologically the glial cells in a murine model of Niemann–Pick disease type C (NPC) to clarify involvement of glias, the most important supportive cells in the central nervous system, by the disease.

Importance of deletion of T at nucleotide 1559 in the tissue-nonspecific alkaline phosphatase gene in Japanese patients with hypophosphatasia.

Abstract. The tissue-nonspecific alkaline phosphatase (TNSALP) gene in four unrelated patients with hypophosphatasia was analyzed using polymerase chain reaction–single strand conformation polymorphism and the direct sequencing method. Of the participating patients, one had childhood-type and three had perinatal-type disease. All carried a deletion of T at cDNA number 1559, which causes a frameshift downstream from codon L503, as a heterozygote. In the childhood-type patient, an F310L mutation was detected in the opposite allele. Similarly, a perinatal-type patient carried a V365I mutation in the opposite allele. Mutations in the opposite alleles were not detected in the other two patients with perinatal-type disease. In addition, although both parents carried the deletion as a heterozygote in two families with childhood-type and perinatal-type disease, patients from those families were not homozygous for the deletion. Several single-nucleotide polymorphisms (SNPs) were also detected, which were shown to be useful for haplotype analysis. Allele frequency of the deletion among Japanese patients was 36% (10 of 28 alleles) but none occurred in Caucasian patients. These findings indicate that regardless of clinical type, deletion in the TNSALP gene occurs frequently among Japanese patients. Furthermore, haplotype analysis using SNPs suggested that the deletion might have derived from more than a single founder.

Heterogeneity of liver disorder in type B niemann-pick disease

Patients with type B Niemann-Pick disease (NPD) are known to be complicated with varying degrees of prognosis-determining liver dysfunction. To see heterogeneity of the dysfunction histologically, we performed liver biopsies on three NPD patients from three different families, who were diagnosed by enzyme assay of acid sphingomyelinase (ASM) and analysis of the ASM gene. In a severe case, of a female patient in her childhood, the liver showed definite fibrosis despite her age. In contrast, in a very mild case, of an adult male patient, the liver showed little fibrosis, though the ballooning of hepatocytes and infiltration of foamy histiocytes were observed in the tissue. Three homo-allelic mutations (S436R, A599T, and S231P) were identified in the patients. Thus, various hepatic phenotypes in type B NPD were shown to be caused by the heterogeneity of liver lesions originating from different ASM gene mutations.

A case of primary lateral sclerosis taking a prolonged clinical course with dementia and having an unusual dendritic ballooning

Motor neuron disease associated with dementia has provided unique opportunities for studying the pathomechanisms of both disorders. In most instances, the former is amyotrophic lateral sclerosis (ALS). In this paper, we report a case of primary lateral sclerosis (PLS) with dementia. An adult female developed slowly pro‐gressive spastic paraparesis and dementia over a period of 17 years and died at the age of 55. Autopsy disclosed neuronal loss of the motor cortex and prominent degeneration of the pyramidal tract. Cranial and spinal motor neurons were well preserved. Neither Bunina bodies nor ubiquitin‐positive inclusions were detected. The findings were compatible with PLS. Diffuse cerebral atrophy, and marked atrophy of the striatum and the thalamus was observed. Senile plaques and Alzheimers neurofibrillary tangles were absent, but an unusual clear ballooning of dendrites was observed in the molecular and Purkinje cell layers of the cerebellum, and the anterior horn of the spinal cord. Together with reports of two similar cases, it is suggested that this case should be categorized as a rare disease entity of PLS with dementia.

Potential Usefulness of the Kampo Medicine Yokukansan, Containing Uncaria Hook, for Paediatric Emotional and Behavioural Disorders: A Case Series

Background. Paediatric emotional and behavioural disorders (EBD) are relatively common diseases. Although nonpharmacologic and pharmacologic treatments are utilized in these cases, it is sometimes difficult to manage the symptoms of EBD. Historically, Uncaria hook has been used for treating nighttime crying and convulsions in children. Recent clinical studies have demonstrated that the Kampo medicine Yokukansan (YKS), which contains Uncaria hook, is efficacious for behaviour disorders in Alzheimers disease patients. Herein, we investigated the clinical efficacy and safety of YKS in a series of cases with paediatric EBD. Patients and Methods. We retrospectively reviewed all paediatric patients who sought Japanese Kampo therapy at our outpatient clinics between April 1, 2012, and April 30, 2013; we selected patients who were diagnosed with paediatric EBD and were treated with YKS. Results. After screening all candidates, 3 patients were eligible for this analysis. Their average age was 11.6 years (range 10–13 years). All 3 patients responded very well to YKS within 1 month. No drug-related adverse events were observed during the course of YKS treatment. Conclusion. Yokukansan may be efficacious for paediatric EBD. We believe these results warrant further evaluation of the clinical efficacy and safety of Yokukansan for paediatric EBD in a carefully designed, double-blind, randomized clinical study.

Long-term expressed human α-Galactosidase A in tissues of HαG transgenic mice

Background : Human alpha‐galactosidase A (hαG) is an essential lysosomal enzyme in catalyzing the hydrolysis of ceramide trihexoside in humans. Effects have been directed to develop effective gene and replacement therapies for the deficiency of hαG, Fabry disease. In recent years, hαG transgenic mice (TGM) have been established, and the expression of hαG in their general organs has been reported. However, detailed distribution of the cells expressing hαG have not yet been defined.

Collaboration of Japanese Kampo Medicine and Modern Biomedicine 2015

Worldwide, health care systems are increasingly highlighting the importance of traditional medicines. The World Health Organization (WHO) plans to introduce traditional medicine into the international classification of diseases (ICD) for the first time since it started in 1900. Kampo medicine is a traditional Asian medical system that is unique in many ways. Kampo was transferred from the ancient Han Chinese dynasty and uniquely developed in Japan, especially during the Edo period (1603–1867). The theoretical understanding and the use of the abdominal examination “Fukushin” to assess the patients constitutional state are particular to Kampo. After the Meiji restoration in 1867, Japans new government accepted only Western medicine from Europe and founded one medical licensure system. The result was suppression of acquired wisdom and insights with marginalization of practitioners until 1976. At that time, the Japanese Medical Association promoted its coverage by Japans National Health Insurance program by physicians who were trained in Western medicine. And now, all of Japans 80 medical schools teach Kampo medicine. As a result, roughly 90% of physicians use Kampo medicine in their daily practice. This is a very unique model of integration of traditional medicine and modern biomedicine. To better understand the promise of this integration, this special issue features Kampo medicine in the context of modern biomedicine. Many provocative articles are included in this special issue. To begin, K. Katayama et al. address the current situation of Kampo use in the National Health Care program. The authors analyzed 67,113,579 health care claim records and found that only 1.34% represented Kampo prescriptions. This suggests that a very small portion of conventional practice includes Kampo treatment even though many physicians use Kampo. H. Okamoto et al. present us with a case series of patients with refractory glossodynia. Among 39 patients, 69.2% of patients reported a beneficial effect. This is one of the examples in which Kampo treatment is effective even for the difficult cases in the Western biomedicine. K. Ogawa et al. show the usefulness of daiobotanpito for the treatment of acute diverticulitis. Y. Tanaka and T. Sakiyama report the case series of the usefulness of the Kampo treatment for pediatric emotional and behavioral disorders which were also refractory to the modern biomedicine. M. A. Bahar et al. reported that goshajinkigan prevents paclitaxel induced peripheral neuropathy without interfering with the anticancer action of paclitaxel in the basic research. Kampo medicines are often used for the purpose of the reduction of the side effects of chemotherapy for malignancies. K. Watanabe et al. report the potentially preventive effect of diabetic complications. Goshajinkigan is often used for the neuropathy from diabetes mellitus. Additionally, this Kampo medicine may be beneficial for the blood glucose control. K. Katayama et al. report a computer-based diagnostic way of Kampo patient patterns termed “Sho.” This represents a promising blend of modern technology for a new world of traditional medicine in the future. Y.-C. P. Arai et al. reported about Fukushin, Kampos unique diagnostic procedure. Certain Fukushin findings are related to the anxiety-depression levels. T. Namiki et al. report that cytosine-adenine (CA) repeat polymorphism of the estrogen receptor β gene can be the predictive biomarker of the effectiveness of Kampo medicine for the treatment of the climacteric syndrome. T. Yoshino et al. and H. Tokunaga et al. describe hie (cold sensation) and hiesho (cold disorder). Hie and hiesho are very important concepts in Kampo treatment. T. Yoshino et al. characterized hie and hiesho. H. Tokunaga et al. characterized the differences of male hie, female hie with menstruation, and female hie after menopause by data mining method. To conclude, S. Yakubo et al. summarize the history and pattern diagnosis of Kampo medicine. Together, these articles represent the promise and challenges present in the scientific understanding of Japans herbal medicine tradition. We hope these articles help the readers to understand and appreciate the potential power of Kampo medicine outside of Japan. We invite you to explore Kampo. Kenji Watanabe Gregory A. Plotnikoff Takeshi Sakiyama Heidrun Reissenweber-Hewel

Novel missense mutation in the purine nucleoside phosphorylase gene in a Japanese patient with purine nucleoside phosphorylase deficiency.

Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) deficiency are immunodeficiency disorders caused by inborn errors of purine metabolism. While in ADA deficiency, both humoral and cellular immunity are disturbed, cellular immunity is selectively disturbed in PNP deficiency. Deficiency of PNP is a heterogeneous disorder which can be considered a subset of severe combined immunodeficiency. Compared to ADA deficiency, PNP deficiency is very rare and approximately 35 cases have been reported.1 Purine nucleoside phosphorylase, a homotrimer, catalyzes the reversible phosphorylsis of the purine ribonucleosides and deoxyribonucleosides (inosine, deoxyinosine, guanosine and deoxyguanosine) to their respective purine bases and ribose-1-phosphates and deoxyribose-1-phosphates. Patients with PNP deficiency have recurrent infections, failure to thrive, neurological impairment, malignancies and autoimmune phenomena. Molecular analysis of PNP deficiency has been performed and many mutations have been identified. A novel homozygous missense mutation (Tyr166-Cys) in the first Japanese patient with PNP deficiency is reported in this study.

An autopsy case of hemilaterally dominant and systematic/extensive border zone infarction: Sequela of preceding atherosclerotic obstruction of one common carotid artery followed by repeated episodes of systemic hypotension

A 68‐year‐old man was admitted to St Marianna University Hospital on account of loss of consciousness with left hemiplegia. During the hospital recovery course with a rehabilitation procedure, the patients blood pressure was very unstable, fluctuating between high (210/110 mmHg) and low (110/70 mmHg) values accompanied by a fainting sensation. A second stroke of left hemiplegia took place 1 month later. Afterwards, his condition worsened to tetraplegia with dysarthria. Three months later, lung cancer with multiple metastasis including his left neck was found and he died from adynamic ileus 6 months after the onset of the present illness. Autopsy revealed nearly complete atheromatous obstruction and more than 50% stenosis, respectively, of his right common and internal/external carotid arteries. His intracranial arterial trunks and main branches were all patent with localized atherosclerosis of only moderate degree. The pathology of the brain existed predominantly in the right hemisphere in the border zone area between the anterior and middle cerebral arteries systematically with numerous disseminated foci of complete or incomplete necrosis, white matter and gray matter being involved independently. Involvement of centrum semiovale white matter is more extensive and intensive than that of gray matter. Of the gray matter, cerebral cortex as well as striatum, periventricular (the third ventricle) gray and cerebellar cortex was involved. The specific characteristic topography and distribution of the lesions together with their histopathology are described in detail with illustration. It is concluded that this case represents an outstanding example of hemodynamic cerebral circulatory insufficiency doubly caused by hemilateral carotid artery stenosis and repeated episodes of systemic hypotension.