Silent KEL alleles identified from Japanese individuals with the Ko phenotype.

BACKGROUND AND OBJECTIVE: The rare Ko phenotype lacks all 36 antigens in the Kell blood system. The molecular basis of the Ko phenotype has been investigated, and more than 40 silent KEL alleles are reported by many investigators. The majority of silent alleles are the KEL*02 background. Here, we report molecular genetic analysis of the KEL gene in Japanese individuals with the Ko phenotype. MATERIALS AND METHODS: The Ko phenotype was screened from Japanese blood donors for several years using monoclonal anti-Ku or anti-K14 by an automated blood grouping system PK7300. Kell-related antigens were typed by standard tube tests. Genomic DNA was extracted from the blood samples, and KEL gene was analysed by polymerase chain reaction (PCR) and Sanger sequencing. RESULTS: We collected 35 Ko blood samples with K-k-, Kp(a-b-), Js(a-b-) and K14-. PCR and sequence analysis revealed that 11 individuals were homozygous for a mutant KEL allele with a c.299G>C (p.Cys100Ser) mutation (rs. 200268316). Three individuals were homozygous for the KEL*02N.24 allele that is c.715G>T (p.Glu239*), and one individual was homozygous for the KEL*02N.40 allele that is c.1474C>T (p.Arg492*). Five individuals were homozygous for novel KEL alleles with single-nucleotide mutations, four individuals had a c.2175delC (p.Pro725 fs*43), and one individual had a c.328delA (p.Arg110 fs*79). The remaining 15 individuals were compound heterozygous, and eight new alleles were identified from them. CONCLUSIONS: We identified three known and ten new silent KEL alleles from Japanese individuals with the Ko phenotype. The KEL allele with the c.299G>C (p.Cys100Ser) mutation was the most frequent.

Body weight and dysautonomia in early Parkinson's disease.

OBJECTIVES: Patients with Parkinson's disease (PD) begin to lose weight several years before diagnosis, which suggests weight variation is associated with some factor(s) that precede the onset of motor symptoms. This study aimed to investigate the association of autonomic nervous system with body weight in patients with PD. MATERIALS AND METHODS: The subjects were 90 patients with early de novo PD. We examined the associations of body mass index (BMI) with sympathetic nervous activity reflected in orthostatic intolerance or cardiac uptake of 123 I-metaiodobenzylguanidine and parasympathetic nervous activity reflected in constipation or heart rate variability (HRV). RESULTS: Twelve patients (13.3%) were overweight (BMI>25 kg/m2 ), 62 patients (68.9%) were normal-weight (18.5≦BMI<25 kg/m2 ), and 16 patients (17.8%) were underweight (BMI<18.5 kg/m2 ). Underweight patients had greater disease severity and decrease in blood pressure on head-up tilt-table testing, higher cardiac washout ratio of 123 I-metaiodobenzylguanidine, and lower HRV and complained of constipation more often than those with normal-weight or overweight patients. On multiple regression analyses, the correlation of these variables with BMI maintained statistical significance after adjustment for age, sex, symptom duration, and motor subtype. CONCLUSIONS: Dysautonomia and disease severity are closely related to body weight independently of age, sex, symptom duration, and motor subtype. Dysautonomia may play a partial role on weight variation in the early stage of PD.

Production of human monoclonal anti-Jk3, recognising an epitope including the Jk(a) /Jk(b) polymorphic site of the Kidd glycoprotein.

BACKGROUND AND OBJECTIVES: The Kidd blood group system consists of polymorphic antigens, Jk(a) (JK1) and Jk(b) (JK2), and a high-incidence antigen, Jk3. Anti-Jk3 is often observed in immunised Jk(a-b-) individuals. In this study, we aimed to establish a human hybridoma cell line secreting monoclonal anti-Jk3 (HIRO-294). MATERIALS AND METHODS: Peripheral blood lymphocytes of a Filipino woman with the Jk(a-b-) phenotype having anti-Jk3 were transformed with Epstein-Barr virus and then hybridised with the myeloma cell line JMS-3 using the polyethylene glycol (PEG) method. The reactivity and specificity of the anti-Jk3 were examined by serology and flow cytometry. RESULTS: Four hybridoma clones secreting anti-Jk3 were established and the antibody from one of these clones, HIRO-294, was examined. The reactivity of HIRO-294 was positive with 227 Jk(a+b-) red blood cells (RBCs), 298 Jk(a-b+) RBCs, and 1043 Jk(a+b+) RBCs, but was negative with 21 Jk(a-b-) RBCs. Eluates from Jk(a+b-) RBCs and Jk(a-b+) RBCs sensitised with the anti-Jk3 were cross-reacted with Jk(a-b+) RBCs and Jk(a+b-) RBCs, respectively. The reactivity of HIRO-294 was enhanced by the treatment of RBCs with ficin, trypsin, pronase and α-chymotrypsin, but was not changed by their treatment with neuraminidase, dithiothreitol and ethylenediaminetetraacetic acid (EDTA) glycine acid (GA). The RBCs sensitised by the anti-Jk3 were not agglutinated with the commercial reagents of anti-Jk(a) and anti-Jk(b) by saline test, whereas the nonsensitised RBCs or those sensitised by monoclonal anti-D [HIRO-3, immunoglobulin G (IgG) class] were agglutinated with those reagents. CONCLUSIONS: We established a human hybridoma cell line secreting monoclonal anti-Jk3 (HIRO-294). This antibody had unique specificity, recognising the Kidd glycoprotein including the Jk(a) /Jk(b) polymorphic site.

Characterization of the Asian myopathy patients with VCP mutations.

BACKGROUND AND PURPOSE: Mutations in the valosin-containing protein (VCP) gene are known to cause inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) and familial amyotrophic lateral sclerosis (ALS). Despite an increasing number of clinical reports, only one Asian family with IBMPFD has been described. METHODS: To characterize patients with VCP mutations, we screened a total of 152 unrelated Asian families who were suspected to have rimmed vacuolar myopathy. RESULTS: We identified VCP mutations in seven patients from six unrelated Asian families. Five different missense mutations were found, including a novel p.Ala439Pro substitution. All patients had adult-onset progressive muscle wasting with variable involvement of axial, proximal, and distal muscles. Two of seven patients were suggested to have mild brain involvement including cerebellar ataxia, and only one showed radiological findings indicating a change in bone. Findings from skeletal muscle indicated mixed neurogenic and myogenic changes, fibers with rimmed vacuoles, and the presence of cytoplasmic and nuclear inclusions. These inclusions were immunopositive for VCP, ubiquitin, transactivation response DNA-binding protein 43, and also histone deacetylase 6 (HDAC6), of which function is regulated by VCP. Evidence of early nuclear and mitochondrial damage was also characteristic. CONCLUSIONS: Valosin-containing protein mutations are not rare in Asian patients, and gene analysis should be considered for patients with adult-onset rimmed vacuolar myopathy with neurogenic changes. A wide variety of central and peripheral nervous system symptoms coupled with rare bone abnormalities may complicate diagnosis.

Cardiovascular dysautonomia in de novo Parkinson's disease without orthostatic hypotension.

BACKGROUND: Clinical symptoms of Parkinson's disease (PD) include not only motor distress, but also autonomic dysfunction. OBJECTIVE: To study the characteristics of subclinical autonomic nervous dysfunction in de novo PD without orthostatic hypotension (OH). METHODS: Autonomic nervous function including cardiac sympathetic gain was evaluated on the basis of cardiac radioiodinated metaiodobenzylguanidine (MIBG) uptake, the response to the Valsalva maneuver, and spectral analyses of the RR interval and blood pressure in 20 patients with de novo PD without OH. RESULTS: Decreased cardiac MIBG uptake was found even in patients with PD without OH. Hemodynamic studies using the Valsalva maneuver revealed that patients with PD without OH had preserved baroreceptor reflex sensitivity in phase II and phase IV. Blood pressures normally responded in early and late phase II, but not in phase IV. Blood pressure recovery time was slightly reduced in patients with PD without OH when compared with the value in controls. The low frequency component of the RR interval and systolic blood pressure and the ratio of RR-LF to RR-HF in de novo PD without OH were significantly reduced when compared with the control values, whereas the high frequency component of the RR interval did not differ significantly. CONCLUSION: These results show that latent cardiac and vasomotor sympathetic dysfunction but not parasympathetic dysfunction is already present in early stage de novo PD, even without orthostatic hypotension.

E variants found in Japanese and c antigenicity alteration without substitution in the second extracellular loop.

BACKGROUND: The molecular basis of E variants in the Japanese population is poorly understood. In this study, molecular analysis of E variants detected in Japanese by serologic methods was carried out. STUDY DESIGN AND METHODS: E variants from healthy Japanese blood donors were screened by serologic analysis using E MoAbs. Fifteen E variant samples were divided into three types--EFM, EKH, and EKK-on the basis of patterns of reactivity with five distinct E antibodies. The entire coding region of the Rh cDNAs from the E variant samples was analyzed by sequencing. RESULTS: Although the Rh cDNA sequences of the three types were different from each other, those of the EFM-type variants (RHEFM) had a partial DNA exchange in exon 5 between the RHCE and RHD genes, generating an RHcE variant (Gln233Glu, Met238Val). The cDNA of EKH-type variants (RHEKH) exhibited a point mutation (G461C) in exon 3 of the RHcE allele that resulted in an Arg154Thr substitution in the third external loop of the RhcE peptide. The EKK-type variant (RHEKK) carried a hybrid gene structure characterized by replacement of exons 1-3 (or 2-3) of the RHCE gene with those of the RHD gene. The RHD gene of a person possessing an E variant of the EKK type was also a hybrid gene, D-cE(2-3)-D or cE(1-3)-D (RHDKK). The E variants of types EKH and EKK showed weak c antigenicity. CONCLUSION: In serologic screening of 140,723 Japanese blood donors, 15 were found to possess E variants (0.011%). A new RHCE variant, RHEKH, was identified. On the basis of the variants found in this study, the c antigenicity seemed to be determined not only by Pro-103 but also by the structure of the third extracellular loop or the amino acids contained in it.

Cronkhite-Canada syndrome: report of two cases.

Two cases of Cronkhite-Canada syndrome are reported. In the first case, a 56-year-old woman had an adenoma of the colon, arising within the Cronkhite-Canada polyps, which was removed by endoscopic polypectomy. This suggests possible neoplastic transformation of polyps in this syndrome. She achieved remission with corticosteroids, but the polyposis recurred (only in the stomach) 7 months after the remission. In the recurrent polyposis, corticosteroid therapy resulted again in complete remission, which has lasted for 5 years. In the second case, a 69-year-old man developed typical manifestations of the syndrome while under emotional stress. He had a past history of chronic pityriasis lichenoides, and serum antinuclear antibody was positive. These findings suggested a possible role of autoimmune response in the pathogenesis of the syndrome. Corticosteroids were also effective in this patient.

Polymorphisms of RhD(Va) and a new RhD(Va)-like variant found in Japanese individuals.

BACKGROUND AND OBJECTIVES: Red cell type RhD(Va) lacks epD1 and 5 and is encoded by hybrid RHD-CE(5)-D alleles. We analyzed RhD(Va) and RhD(Va)-like samples in Japanese blood donors. MATERIALS AND METHODS: Ten RhD(Va) samples lacked epD1 and 5 and 3 RhD(Va)-like variants also lacked, epD2 and a part of 6/7. We identified the full-length nucleotide sequences of the complementary DNA (cDNA) synthesized from 4 samples: 3 of type D(Va) and the 4th a D(Va)-like variant. RESULTS: Although their sequences differed from each other, all the substitutions were exclusively in exon 5. Three D(Va) samples had hybrid RHD-CE(5)-D alleles, but the D(Va)-like variant had a unique nucleotide substitution with a single amino acid change, E233K. Exon 5 of the genomic DNA from all 13 samples was analyzed by sequencing. No other sequences were identified. CONCLUSION: All RhD(Va) and RhD(Va)-like variants had the substitution for E233. E233 seems to be a determinant of epD1 and 5. A new category of RhD variant, DYO, was identified.

Malignant insulinoma with extensive liver metastases presenting as disturbance of consciousness.

A 56-year-old man was referred to our hospital for evaluation of episodic disturbance of consciousness. Hypoglycemic symptoms were noted and Whipple's triad was satisfied. The 75 g OGTT and the glucagon test revealed a high baseline insulin level and hyperreactivity to glucagon. A pancreatic tumor and liver metastases were found by abdominal computed tomography (CT). Based on the finding of liver biopsy, the final diagnosis was malignant insulinoma with liver metastasis. He selected conservative treatment and no hypoglycemic crisis has occurred for one year since discharge. Early diagnosis and long-term follow-up is necessary since this tumor is slow growing.

Pial-glial barrier abnormalities in fetuses with Fukuyama congenital muscular dystrophy.

This report concerns light and electron microscopic studies on the central nervous system of a 20-week and an 18-week fetus with Fukuyama congenital muscular dystrophy (FCMD). The diagnosis of FCMD was established by prenatal molecular genetic analysis. Cerebral lesions containing neurites, subpial granular cells and glias, accompanied by cortical dysplasia were found in both cases. Small irregular defects, readily detectable by periodic acid-methenamine-silver staining or by immunohistochemical staining for S-100 protein, were observed in the cerebral surface. More severe dysplasia was evident at the areas with the larger defects. Surface defects were also observed in the cerebellum and brain stem, with brain tissue extruding into the leptomeninges. The pyramidal tract was aberrant in the pons and medulla oblongata. The spinal cord appeared normal by light microscopy. Electron microscopic examination revealed an abnormal configuration of the basement membrane and glial cytoplasmic membrane of the brain and spinal cord surfaces, including areas with no detectable defects by light microscopy. These findings suggest that abnormalities of the pial-glial barrier, especially the basement membrane and/or basement membrane-related structures, are involved in the genesis of cortical dysplasia.

Multifocal neurocytoma/gangliocytoma with extensive leptomeningeal dissemination in the brain and spinal cord.

This report describes an unusual neuronal tumor detected at the autopsy of a 17-year-old boy. The tumor showed multifocal parenchymal involvement with extensive leptomeningeal dissemination. The intraparenchymal lesions were small and located mainly in the subpial region of the cerebrum, cerebellum and spinal cord. Leptomeningeal dissemination was particularly pronounced at the base of the brain and around the spinal cord and presumably took place during the relatively long clinical course. The tumor was composed of small round cells and ganglion-cell-like cells. Only neuronal differentiation, as represented by immunostaining with antisynaptophysin antibody and the presence of dense-core vesicles in the cytoplasm, was evident in both types of cells. The small round cells appeared to exhibit the features of small, relatively mature neurons rather than those of neuroblasts. Moreover, our results suggested maturation from small round cells to ganglion-cell-like cells. The tumor appears to be related to gangliogliomas or dysembryoplastic neuroepithelial tumors, and we have chosen the term neurocytoma/gangliocytoma for the unusual lesion.

Serological analysis of monoclonal anti-E and -e with Japanese E/e variant red cells.

The agglutination patterns have been analyzed for the reaction between 24 monoclonal antibodies (MAB) with specificity for the Rh antigen E or e and red cells of E/e variant from Japanese blood donors. The MABs were tested for direct agglutination of papain treated cells at 20 degrees C. The reactions of a full titration series of each MAB with a E/e variant cell were compared to the reactions of that MAB with normal E + e + cells. Sixteen anti-E were divided into a minimum of 6 different agglutination patterns with 8 examples of E variant cells. Eight anti-e gave a minimum of 5 different agglutination patterns with 6 examples of e variant cells.

Gamma knife radiosurgery for cerebral arteriovenous malformations: an autopsy report focusing on irradiation-induced changes observed in nidus-unrelated arteries.

BACKGROUND: In radiosurgical treatment for an arteriovenous malformation (AVM), the effects of irradiation on the intranidal and perinidal angioarchitectures have seldom been analyzed histologically. An autopsy case is reported, studying an AVM treated by gamma knife radiosurgery. Postmortem studies following AVM-unrelated death were performed after a 2-year angiography had demonstrated complete nidus obliteration. Irradiation-induced changes were also observed in surrounding nidus-unrelated arteries and the choroid plexus, both of which were within the irradiation target. METHODS: Microscopic studies were performed using a coronal section of the brain including the center of the AVM, on which the percent isodose volume gradient, corrected with a magnification rate, was superimposed. RESULTS: This study disclosed that intimal hypertrophy can occur in a normal, AVM-unrelated pial artery due to irradiation of 10 Gy or more and that more remarkable intimal hypertrophy with fragmentation of the elastic laminae, or even complete occlusion, can occur in these arteries with 25 Gy. Similarly, irradiation-induced degeneration was present in the choroid plexus, which had been exposed to doses varying from 10 Gy to 25 Gy. CONCLUSIONS: A normal surrounding blood vessel may also be affected by high-dose, single-fraction irradiation though the abnormal vessels have been reported to be more susceptible.

Rebleeding of intracranial dissecting aneurysm in the vertebral artery following proximal clipping.

We describe a case of rebleeding from an intracranial vertebral dissecting aneurysm following proximal clipping. This case suggests that proximal clipping alone may not be an adequate surgical procedure to prevent rebleeding. Surgical treatment of intracranial dissecting aneurysms in the vertebral artery presenting as subarachnoid haemorrhage. (SAH) is discussed.

Quantitative investigations of placental terminal villi in maternal diabetes mellitus by scanning and transmission electron microscopy.

The structure of the terminal villi was observed in placentae from non-diabetic mothers and mothers with diabetes mellitus using scanning and transmission electron microscopy. The metabolic condition of maternal diabetes was tightly controlled. In the diabetic group, the diameter of the terminal villi was significantly smaller than in the control group. The ramification pattern of villi, classified into hypo-, moderate- and hyper-ramifications, was shown to be mostly moderate in the non-diabetics whereas most of the diabetic placentae had either hypo- or hyper-ramifications. Mothers with a longer duration of diabetes and complicated with retinopathy tended to have hypo-ramification; in these mothers, the weight of the neonates was significantly less than normal. Moreover, in the diabetic placentae, syncytial knots were found more frequently, the percentage of vasculo-syncytial membranes tended to be lower, and the trophoblastic basement membrane was significantly thicker than in the control. These abnormalities in the diabetic placentae were independent of the methods of delivery; they seem to be related with fetal growth retardation and poor neonatal outcome, which are commonly seen in diabetic pregnancy.

Long-term results of radiosurgery for arteriovenous malformation: neurodiagnostic imaging and histological studies of angiographically confirmed nidus obliteration.

Detailed follow-up results for 25 patients treated for cerebral arteriovenous malformation (AVM) with a gamma unit are presented. Complete nidus obliteration was angiographically confirmed in 16 (73%) of 22 cases receiving full-dose irradiation. There were no radiation- or AVM-related mortalities. However, we did experience one case of radiation-related morbidity and one of angiography-related mortality, the autopsy findings of which are discussed. Computed tomography scan and magnetic resonance imaging follow-up studies of radiosurgically treated AVMs indicated that increased enhancement of the nidus after contrast or gadolinium administration could persist even after obliteration of the AVM was angiographically confirmed.

A case of progressive supranuclear palsy with widespread senile plaques.

A case of progressive supranuclear palsy (PSP) with frontal lobe atrophy is reported, in which many senile plaques were widely distributed in the neocortex, the entorhinal cortex, the amygdala, and, to a lesser extent, the cerebellar cortex, but not in the hippocampus. Most of the plaques were of the diffuse and primitive types. They were well visualized by beta-protein immunostaining, modified Bielschowsky staining and methenamine silver staining, but were not seen by Bodian staining. The widespread distribution of senile plaques in the cerebral and cerebellar cortices was far beyond that seen in normal aging, and was reminiscent of concomitant Alzheimer's disease (AD). Unlike AD, however, this case had neither senile changes in the hippocampus nor neurofibrillary tangles in the amygdala and entorhinal cortex. It seems that many senile plaques may appear widely in the cerebral cortex and even, to a lesser extent, in the cerebellar cortex of some patients with PSP. Additional case studies using sensitive silver and amyloid antibody preparations are required to elucidate the presence of senile plaques in the cerebral cortex of PSP.

O papel do terapeuta ocupacional na hanseniase: atuacao no estado de Sao Paulo / The role of occupational therapist in leprosy: actuation in Sao Paulo state

O artigo trata da evolucao do papel do terapeuta ocupacional, no atendimento a pacientes hansenianos. No primeiro momento sao destacadas as atuacoes nos hospitais e ambulatorios especializados, com analise do tipo de intervencao realizada. No outro, sao analisadas as novas formas de atuacao nos Centros de Saude, com enfase na atencao primaria. O estudo foi completado com uma analise critica de um documento oficial que descreve as atribuicoes dos terapeutas ocupacionais nessa area.

Endoscopic appearance of the colon and small intestine of a patient with hemorrhagic enteric graft-vs.-host disease.

Endoscopic appearance of the gastrointestinal tract of a patient with severe hemorrhagic enteric graft-vs.-host disease (GVHD) is presented. A 29-year-old man with chronic myelogenous leukemia suffered from severe enteric GVHD after allogeneic bone marrow transplantation. Endoscopy showed hemorrhagic ulceration of the upper jejunum, terminal ileum, and colon at the onset of melena. Sections of biopsies were compatible with acute GVHD. Repeat endoscopy showed gradual healing of the lesions after steroid pulse and antilymphocyte globulin therapy, but the patient died of cytomegalovirus pneumonitis 14 months later. Autopsy revealed submucosal fibrosis of the small intestine and colon.