NUDT15 R139C causes thiopurine-induced early severe hair loss and leukopenia in Japanese patients with IBD.

The efficacy of thiopurines, including azathioprine (AZA) and 6-mercaptopurine (6MP), has been demonstrated for the treatment of inflammatory bowel disease (IBD). The most common and serious adverse event of treatment with thiopurines altered by doctors is leukopenia. Hair loss is also a serious event that could be a critical reason for patients to decline thiopurine treatment. Thiopurine-induced severe hair loss causes cosmetic problems, and it takes a long time to recover. In a recent study, NUDT15 R139C was strongly associated with thiopurine-induced leukopenia in Korean and Caucasian populations. In this study, we performed an association study to investigate and replicate the association of R139C with adverse events of thiopurines in Japanese patients. A total of 142 Japanese patients with IBD, with histories of thiopurine treatment, were examined. NUDT15 R139C was genotyped using a custom TaqMan genotyping assay. Adverse events including leukopenia were reviewed from medical records. The 6MP dose was adjusted to AZA equivalents by multiplying with 2 as a thiopurine dose. Five patients developed severe hair loss and all of them were risk homozygous (T/T) for R139C. No early severe hair loss was observed in patients with the C/T or C/C genotype (P=3.82 × 10(-16), odds ratio=212). The association of R139C with early (<8 weeks) leukopenia (white blood cells<3000 mm(-3)), which was previously reported in Korean patients, was replicated in our Japanese IBD cohort (P=1.92 × 10(-16), odds ratio=28.4). However, we could not confirm the association with late leukopenia in the Japanese subjects. Patients with the C/T genotype discontinued treatment or required thiopurine dose reduction significantly earlier than patients with the C/C genotype (P=1.45 × 10(-4)); however, on manipulating the doses, there was no significant difference in the thiopurine continuation rates between the groups. In the maintenance period, the frequencies of 6MP usage were higher, and the doses of thiopurines were significantly lower in patients with the C/T genotype than in those with the C/C genotype (0.574±0.316 mg kg(-1) per day vs 1.03±0.425 mg kg(-1) per day, P=6.21 × 10(-4)). NUDT R139C was significantly associated with early severe hair loss in Japanese patients with IBD. We also verified the previously reported association of R139C with early leukopenia in a different East Asian population. It is recommended that treatment with thiopurines should be avoided for patients with the T/T genotype. Low-dose 6MP (0.2-0.3 mg kg(-1) per day) could be used rather than AZA for the patients with C/T genotype to continue thiopurine treatments. However, late leukopenia and other several adverse events could not be completely predicted by R139C genotypes.

HLA-B is the best candidate of susceptibility genes in HLA for Japanese ulcerative colitis.

Recently, a genome-wide association study for ulcerative colitis (UC) in the UK population was reported, and several susceptibility loci including the human leukocyte antigen (HLA) region were identified. The strongest association in the HLA region was found at a 400 kb haplotype block containing HLA-DRB1. In Japanese population, previous study suggested the association between UC and HLA-B*52; however, HLA typing was determined using serotyping with the small sample size. The purpose of this study was to perform an association study in HLA-B by genotyping. A total of 320 patients with UC and 322 healthy controls were recruited in this case-control study. All subjects were Japanese. Genotyping of HLA-B was performed by polymerase chain reaction using a sequence-specific primer. When the allele frequencies were compared, significant associations were found with B*52 [odds ratio (OR) = 3.65, P = 1.6 x 10(-17), P(c) = 3.7 x 10(-16)] and B*4002 (OR = 0.52, P = 0.00030, P(c) = 0.0068). The allele frequency of B*52 was significantly higher in patients diagnosed before 40 years of age than in those diagnosed after 40 years (OR = 1.79, P = 0.010, P(c) = 0.020). A combination association map of Japanese UC using our current and previous studies showed two equal peaks of association on HLA-DRB1 and HLA-B, indicating the possible existence of two casual variants in the HLA region inside and outside the 400 kb block found in UK. We conclude that HLA-B contributes to the susceptibility to Japanese UC, especially cases with younger age of onset. The strength of association for HLA-B was equal to that for HLA-DRB1 in Japanese UC, in contrast to the UK population.

Effect of osmolarity on glycosaminoglycan production and cell metabolism of articular chondrocyte under three-dimensional culture system.

OBJECTIVES: This study examined how physiological levels of extracellular osmolarity influence proteoglycan accumulation in articular chondrocytes in a three-dimensional culture system. METHODS: Cells were obtained from metacarpal phalangeal joints of 18-24 month bovine. They were cultured for 6 days in alginate beads at 4 million cells/ml in DMEM containing 6% FBS under 21% O2. Medium osmolarity was altered by NaCl addition over the range 270-570 mOsm and monitored using a freezing point osmometer. Profiles across intact beads were determined by manual counting using fluorescent probes and transmission electron microscope. Lactate production was measured enzymatically and glycosaminoglycan (GAG) accumulation was measured using a modified dimethylmethylene blue assay. Rate of sulfate GAG synthesis was measured using a standard 35S-sulfate radioactive method. RESULTS: The cell viability was similar for the high and low osmolarity cultures. However, confocal microscopy showed that the cells were the largest under 270 mOsm and became smaller with increasing osmotic pressure. GAG production was largest in the 370mOsm, and the capacity for GAG production and cell metabolism (lactate production) was low under hypo-osmolarity and hyper-osmolarity, and cell deaths were often observed on electron microscopy. CONCLUSIONS: In our model the prevailing osmolarity was a powerful regulator of GAG accumulation by cultured chondrocytes. These results thus indicate GAG synthesis rates are regulated by GAG concentration, with implications both for the aetiology of osteoarthritis and for tissue engineering.

Findings in a patient with herpes simplex viral meningitis associated with acute retinal necrosis syndrome.

We report the case of a 41-year-old man with clinical findings of viral meningitis associated with acute retinal necrosis syndrome in his right eye. MR images showed right optic nerve enlargement and high-intensity signal abnormalities in the region of the left lateral geniculate body and the left occipital lobe.

[Corticobasal degeneration: symptomatological, brain-imaging and electrophysiological studies].

Eight cases of clinically diagnosed corticobasal degeneration (CBD) were studied with reference to their symptomatology, brain-imagings and electrophysiological findings. The diagnosis was based on the combination of limb-kinetic apraxia (cortical sign), akinetic-rigid sign (extrapyramidal) and their unilateral predominance. Magnetic resonance imaging (MRI) and 123I-IMP or 99mTc-HMPAO SPECT findings were used to reinforce the diagnosis. The age at onset of 8 cases (4 males, 4 females) was 61 to 80 years (mean 66). Other common symptoms on admission consisted of dysequilibrium (8 cases), dysarthria (8), grasp reflex (6), supranuclear gaze palsy (6), tremor (6), limb dystonia (6) and alien limbs (5). MRI revealed parietal (3 cases) or frontoparietal (3) atrophy. SPECT showed decrease in cerebral blood flow in frontoparietal (3 cases) or frontoparietotemporal lobes (5). SPECT surpassed MRI to detect unilateral predominance of the lesions. With magnetic stimulation of the head and neck central motor conduction time (CMCT) was normal, while motor inhibitory periods (IPs) were significantly shorter in CBD patients compared with those in normal controls and the patients with Parkinson's disease. In 3 patients with reflex myoclonus, giant SEPs were not evoked, though with positive C-reflex, suggesting an elevated excitability of cerebral cortex unrelated to the production of giant SEPs.

[Clinical analysis of paralytic shellfish poisoning following ingestion of oysters].

We describe five patients of paralytic shellfish poisoning (PSP) following ingestion of oysters in January 1991, in Nagato, Yamaguchi. The five patients (four men and one woman, age range:37-80 years) developed symptoms three-nine hours after consuming oysters. Symptoms included paresthesia of the mouth and tongue (three), paresthesia of the extremities (five), and quadriparesis (five). The median duration of neurological symptoms was 16 hours. All five patients completely recovered. Although PSP is rare as compared with globe fish poisoning in Japan, the fatality rate of PSP is 8%-9%, with deaths occurring in one-12 hours secondary to respiratory failure. PSP is an important disorder for differential diagnosis of acute paralytic illnesses, such as globe fish poisoning, botulism, acute polyradiculoneuropathy, fisher syndrome, myasthenia gravis, and periodic paralysis.

[A case of multiple cerebral infarctions associated with hemichorea induced by amantadine hydrochloride].

We report an 80-year-old woman with hemichorea probably due to amantadine hydrochloride. She visited our hospital because of gait disturbance and decreased mental activity. She was diagnosed as multiple cerebral infarctions and treated with 100 mg/day of amantadine hydrochloride. After two weeks she showed choreic movement of the face and right arm and leg. Haloperidol was administered and her choreic movement disappeared. Brain MRI showed multiple cerebral infarctions in the white matter. There was no lesion in the left basal ganglia. SPECT showed hyperperfusion in the left basal ganglia when choreic movement appeared. After choreic movement disappeared, SPECT showed no asymmetrical blood flow. These findings suggest hemichorea was related to hyperfunction of dopaminergic neurons in the left basal ganglia.

[Isolated inferior rectus muscle paresis from midbrain infarction].

A 74-year-old woman, with hypertension and dilated cardiomyopathy, presented with sudden onset of diplopia without vertigo and other neurological symptom. Examination revealed left inferior rectus muscle paresis. Other neurological findings were normal. She had no cerebellar ataxia and sensori-motor dysfunction. Magnetic resonance imaging showed increased signal intensity on T2-weighted and proton density-weighted images in the right ventral midbrain, compatible with infarction involving the fascicular oculomotor fibers. Complete resolution of the diplopia and normal ocular motility were noted 3 months after the onset of the diplopia. Focal ischemic midbrain lesions should be considered in cases of isolated partial oculomotor nerve paresis.

[Two siblings with sarcoidosis diagnosed by younger sister's central nervous symptoms].

We report two siblings with sarcoidosis; the younger sister had symptoms of central nervous system, and both sisters had subcutaneous mass lesions in the gluteal region. Case 1. A 30-year-old woman presented with two episodes of right leg paresis. On admission, neurological examination revealed right leg weakness, spasticity of both legs, increased deep tendon reflexes in all extremities, urinary disturbance and hearing loss of the right ear, but she had no meningeal signs. Serological studies were normal including angiotensin converting enzyme. Cerebrospinal fluid revealed elevated protein to 340 mg/dl, mild pleocytosis, decreased glucose. CSF culture was negative, and cytology showed no malignant cells. Enhanced MR imaging showed diffuse leptomeningeal enhancement in both the brain around basal meninges and the whole spinal cord. Case 2. A 34-year-old woman (the elder sister of Case 1) presented with visual disturbance. She had been diagnosed to have bilateral iritis at Hiroshima Red Cross Hospital before visiting our hospital. Neurological examination and serological studies were normal. In both cases, left gluteal subcutaneous mass was detected and its biopsy revealed characteristic sarcoid nodules and confirmed the diagnosis of sarcoidosis. A tendency of familial occurrence and positive associations of the specific HLA antigens in sarcoidosis have been reported. Though the diagnosis of neurosarcoidosis has been difficult without extraneurological signs, sarcoidosis should be considered as a differential diagnosis in all the patients with myelopathy, and enhanced MRI and measure of CSF angiotensin converting enzyme seem to be useful for diagnosis and evaluation of drug effect during the course of steroid therapy.

[Progressive ataxic hemiparesis with asymmetric cortical and cerebral peduncular atrophy--report of two cases].

We report two patients, 73- and 70-year-old men, characterized by progressive hemiparesis and homolateral limb ataxia as the main clinical symptoms; magnetic resonance (MR) imaging of the brain revealed asymmetric cerebral cortical and peduncular atrophy; 99mTc-ECD single photon emission computed tomography (SPECT) of brain showed decreased RI uptake in the cerebral hemisphere correlated with clinical deficits. Brain SPECT of case 1 showed decreased RI uptake in the cortex of the right hemisphere and the left cerebellar hemisphere ("crossed cerebellar diaschisis; CCD"). These findings indicate that ataxia of our patients may depend on the lesions of the corticopontocerebellar tracts, although it is possible that ataxia may be related to lack of spatial orientation associated with parietal lobe lesion. The mechanism of the occurrence of asymmetric cerebral peduncular atrophy would be explained by wallerian degeneration of the pyramidal tract and other cortically originated fibers associated with the cortical degeneration. From these clinical and radiologic features, it seems likely that our two patients are categorized in the "asymmetric cortical degeneration syndromes", and we propose the term "progressive ataxic hemiparesis" for our patients.

[A case of secondary carnitine deficiency due to anorexia nervosa and severe liver damage].

We reported an 18-year-old woman with anorexia nervosa and liver damage who showed carnitine deficiency. Her unbalanced diet had little carnitine, and severely damaged liver could not synthesize carnitine. Since total parenteral nutrition (TPN) and tube-feed formulas contain little or no carnitine, the patient had progressive weakness and muscle atrophy. Muscle biopsy revealed variability of fiber diameter, type 1 fiber atrophy and copious amount of lipid granules. Carnitine deficiency must be diagnosed in the early stage by muscle biopsy or muscle carnitine levels, and treated with oral intake of L-carnitine.

[Guillain-Barré syndrome associated with anti-GalNAc-GD1a antibody subsequent to Campylobacter jejuni enteritis].

We report a 15-year-old man with Guillain-Barré syndrome (GBS) following Campylobacter jejuni enteritis. Neurologic examination revealed distal muscle weakness and mild disturbance of superficial sense on right plantar area. Serial electrophysiologic studies indicated that the predominant process was axonal degeneration of motor nerves. Thin-layer chromatography with immunostaining revealed that serum IgG strongly reacted with GalNAc-GD1a and weakly with GM2, but did not react with GM1. This is the first report of GBS subsequent to C. jejuni enteritis associated with anti-GalNAc-GD1a antibody.

[A case of rapidly progressive T cell type malignant lymphoma which started with multiple cranial neuropathy].

A 35-year-old man had suffered from recurrent right trigeminal nerve palsy and flaccid paraparesis for about five months. Cerebrospinal fluid (CSF) showed a marked increase of protein (400 mg/dl) and mononuclear cells (146/mm3), but there were no malignant cells. Antibiotic therapy remitted his inguinal and mediastinal lymph nodes swelling, and trigeminal nerve palsy had recovered spontaneously. Then he developed left trigeminal and facial nerve palsy, mononeuropathy multiplex, and cauda equina syndrome. Nerve conduction studies revealed delayed velocity and reduction of amplitude. Enhanced magnetic resonance imaging showed increased signal intensity in bilateral trigeminal nerves, left internal auditory meatus, and meninges of the basal cistern. Also, there were two mass lesions in cauda equina. They were operated by orthopedist, and were not malignant. After that, CSF cells of malignant lymphoma were elevated and revealed T cell type (large cell). Then the patient exacerbated in bulbar palsy and died. When there is lymph node swelling with multiple neurological deficits, despite remission of lesions and signs, biopsies should be positively pursued early in the patient's clinical course.

[A case of painful involuntary contraction of the left latissimus dorsi muscle, successfully treated with left thoracodorsal nerve resection].

A 66-year-old Japanese man underwent the resection of the upper lobe of the left lung for primary lung cancer. One year later, his back muscles neighboring the operation scar gradually began to twitch upwards intermittently. The involuntary muscle twitch was accompanied with severe local pain, and intensity of the pain and contraction slowly increased. The abnormal muscle contractions were confined to the left latissimus dorsi muscle on needle EMG. The pain and movement ceased by blocking of either thoracodorsal nerve or brachial plexus, and disappeared finally by resection of the nerve. The impulses causing involuntary, painful contractions were thought to originate in the damaged thoracodorsal nerve, transmitted to CNS and re-transmitted to the thoracodorsal nerve.

[Clinical analysis of benign transient shuddering-like involuntary movement in elderly people].

We described 9 patients who developed acute onset benign transient shuddering-like involuntary movement in elderly people. There was no consciousness disturbance or sensorimotor dysfunction. There were finger tremor, dysarthria, or gait disturbance in some patients. Asterixis was observed in the upper extremities in 2 patients. Duration of an involuntary movement was less than 1 second, and the series of the involuntary movements continued for several days. This state appeared acutely and disappeared within 0.5 -4 days in the natural course without any sequelae. Oral administration of clonazepam was very effective to suppress this tremulousness. Seven of 9 patients developed recurrence. Although the cause of this syndrome remains unknown, we believe that this condition is clinically important for differential diagnosis of acute onset involuntary movements in elderly people.

[18p-syndrome with bilateral pyramidal tract signs, dystonia of the lower extremities and concentric visual field defect].

A case, diagnosed as 18p-syndrome by typical clinical appearance and by chromosomal analysis, presented with multiple nervous system defects consisting of bilateral pyramidal tract signs, weakness and focal dystonia of the lower extremities, and concentric visual field defect. Chromosomal analysis revealed karyotype 46, X, dic (Y;18) (p11;p11), inv(9) (p11q13), and the points of chromosomal breakages were thought to be in the short arm of chromosome 18 and in the short arm of Y chromosome. 18p-syndrome is caused by a chromosomal deletion, and presents with a wide variety of clinical appearances. Many cases have been reported since the original descriptions by de Grouchy in 1963, though with few mentions of neurological deficits other than mental retardation. Furthermore, there have been no reports of pyramidal tract signs, weakness and focal dystonia of the lower extremities, or visual field defect, without recognizable anatomical abnormalities. Our case of 18p-syndrome is quite rare because of multiple nervous system abnormalities mentioned above, not accompanied by malformations of the central nervous system.

[A case of cough headache with Chiari malformation (type I)].

A 38-year-old woman complained for about 5 years of attacks of headache elicited by coughing, sneezing, and laughing. These attacks became more frequent and more severe. Physical examination showed a short and broad neck. Neurological examination revealed no abnormality. Magnetic resonance imaging demonstrated the Chiari malformation (type I) and the cerebral venous angioma in left frontal white matter. A posterior decompression by suboccipital craniectomy with C1 laminectomy was performed. The headache completely disappeared. Before and after the operation, we measured the intracranial subdural pressure by a small pressure transducer. The raised cranial pressure by the Valsalva's maneuver prolonged for more than one minute. Postoperatively, the raised cranial pressure by the Valsalva's maneuver decreased rapidly. We consider that the cough headache of this patient was associated with a valve-like blockage by the Chiari malformation (type I) at the foramen magunum, resulting in cranio-spinal pressure dissociation by interference with downward pulsation. We believe that there was no correlation between the cough headache and the cerebral venous angioma.

[A case presenting with Raeder's syndrome-like symptoms due to vertebral artery aneurysm].

A 50-year-old man complained of headache around his left orbit, left frontal pain and paresthesia associated with left incomplete Horner syndrome. MRI demonstrated a mass at the level of medulla oblongata. Left vertebral angiogram revealed an aneurysm of left vertebral artery. Following the removal of the aneurysm, these Raeder's syndrome-like symptoms improved. Therefore, they were probably caused by a compression of the spinal tract of the trigeminal nerve and the central sympathetic tract by the aneurysm. This is the first report of Reader's syndrome-like symptoms caused by vertebral artery aneurysm, thus indicating that MRI and cerebral angiogram are necessary for differential diagnosis of this syndrome.

[A case of isolated adrenocorticotropic hormone deficiency with adrenocorticosteroid-responsive brain edema and repeated confusions].

A 60-year-old man developed confusional state with severely abnormal electroencephalogram and brain edema on computed tomography (CT) of brain. Adrenocorticosteroid therapy was dramatically effective for the confusional state and brain edema. The reduction of adrenocorticosteroid induced confusional states, and they disappeared with the increase of adrenocorticosteroid. When brain edema on CT disappeared, T 2-weighted magnetic resonance imagings revealed diffuse high signal in the white matter. A diagnosis of isolated adrenocorticotropic hormone deficiency was made by endocrinological examinations and clinical features. We suggest that brain edema in this patient is due to deficiency of glucocorticoid. High intensity area in the white matter may show the degeneration of the white matter following brain edema.

[Clinical and MRI correlation in multiple system atrophy].

By using magnetic resonance imaging (MRI), we studied 11 patients with multiple system atrophy (MSA): 5 olivo-pontocerebellar atrophy (OPCA), 2 Shy-Drager syndrome (SDS), and 4 striatonigral degeneration (SND). The diagnoses of OPCA, SDS and SND were clinically made. The MR images were performed on 1.5 tesla MRI unit (Siemens Asahi Medical, Magnetom H15), using a T2-weighted spin echo (SE) sequence (TR: 2000-3000ms, TE: 80-90ms), a T1-weighted SE sequence (TR: 550, TE: 15), and a proton density-weighted (PD) SE sequence (TR: 2000-3000, TE: 12-22). In the patients with OPCA, MRI revealed cerebellar and brainstem atrophy and degeneration of pontine transverse fibers more marked than in the patients with SDS and SND. T2-weighted images showed low intensity in posterolateral putamina in one OPCA patient and all of SDS and SND patients. PD images demonstrated the abnormal slit-like high signals in posterolateral putamina in three SND. The degree of cerebellar ataxia was not well correlated with cerebellar and brainstem atrophy and degeneration of pontine transverse fibers. There was a positive correlation between the atrophy of cerebellum and brainstem and the duration of cerebellar ataxia. In most of the patients with parkinsonism, MRI demonstrated abnormal low signals in putamina on T2-weighted images. There were positive correlations between the abnormal low signals putamina and the duration and severity of parkinsonism. Though abnormal low signals in lateral putamina may be seen in normal aging and other disorders on T2-weighted images, it is useful to evaluate parkinsonism in MSA.(ABSTRACT TRUNCATED AT 250 WORDS)