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2.  Novel Compound Heterozygous Mutations in the Cathepsin K Gene in Japanese Female Siblings with Pyknodysostosis 
Molecular Syndromology  2012;2(6):254-258.
We report on female siblings with pyknodysostosis who showed common clinical and radiographic features including disproportionate short stature, dental abnormalities, increased bone density, open fontanelle, and acroosteolysis. Sequence analysis of the cathepsin K (CTSK) gene demonstrated compound heterozygous mutations (935 C>T, A277V and 489 G>C, R122P) in the affected siblings and a heterozygous mutation in their parents. The former missense mutation has previously been reported in 6 unrelated patients, and the latter seemed to be a novel mutation. Atomic model assessment of the CTSK gene revealed that the R122P mutant could disrupt hydrogen bonds binding with chondroitin 4-sulfate leading to a decrease in the collagen-degrading activity of cathepsin K.
doi:10.1159/000336581
PMCID: PMC3362291  PMID: 22822386
Cathepsin K; Chondroitin 4-sulfate; Compound heterozygous mutations; Pyknodysostosis
3.  CMT2C with vocal cord paresis associated with short stature and mutations in the TRPV4 gene 
Neurology  2010;75(22):1968-1975.
Background:
Recently, mutations in the transient receptor potential cation channel, subfamily V, member 4 gene (TRPV4) have been reported in Charcot-Marie-Tooth Type 2C (CMT2C) with vocal cord paresis. Other mutations in this same gene have been described in separate families with various skeletal dysplasias. Further clarification is needed of the different phenotypes associated with this gene.
Methods:
We performed clinical evaluation, electrophysiology, and genetic analysis of the TRPV4 gene in 2 families with CMT2C.
Results:
Two multigenerational families had a motor greater than sensory axonal neuropathy associated with variable vocal cord paresis. The vocal cord paresis varied from absent to severe, requiring permanent tracheotomy in 2 subjects. One family with mild neuropathy also manifested pronounced short stature, more than 2 SD below the average height for white Americans. There was one instance of dolichocephaly. A novel S542Y mutation in the TRPV4 gene was identified in this family. The other family had a more severe, progressive, motor neuropathy with sensory loss, but less remarkable short stature and an R315W mutation in TRPV4. Third cranial nerve involvement and sleep apnea occurred in one subject in each family.
Conclusion:
CMT2C with axonal neuropathy, vocal cord paresis, and short stature is a unique syndrome associated with mutations in the TRPV4 gene. Mutations in TRPV4 can cause abnormalities in bone, peripheral nerve, or both and may result in highly variable orthopedic and neurologic phenotypes.
GLOSSARY
= compound muscle action potential;
= Charcot-Marie-Tooth;
= Charcot-Marie-Tooth Type 2C;
= hereditary motor and sensory neuropathy;
= nerve conduction velocity;
= restriction fragment length polymorphism;
= spinal muscular atrophy;
= sensory nerve action potential;
= scapuloperoneal spinal muscular atrophy.
doi:10.1212/WNL.0b013e3181ffe4bb
PMCID: PMC3014233  PMID: 21115951
4.  A Novel X-linked 4-Repeat Tauopathy with Parkinsonism and Spasticity 
The parkinsonian syndromes comprise a highly heterogeneous group of disorders. Although 15 loci are linked to predominantly familial Parkinson’s disease (PD), additional PD loci are likely to exist. We recently identified a multi-generational family of Danish and German descent in which five males in three generations presented with a unique syndrome characterized by parkinsonian features and variably penetrant spasticity for which X-linked disease transmission was strongly suggested (XPDS). Autopsy in one individual failed to reveal synucleinopathy; however, there was a significant 4-repeat tauopathy in the striatum. Our objective was to identify the locus responsible for this unique parkinsonian disorder. Members of the XPDS family were genotyped for markers spanning the X chromosome. Two-point and multipoint linkage analyses were performed and the candidate region refined by analyzing additional markers. A multipoint LODmax score of 2.068 was obtained between markers DXS991 and DXS993. Haplotype examination revealed an approximately 20 cM region bounded by markers DXS8042 and DXS1216 that segregated with disease in all affected males and obligate carrier females and was not carried by unaffected at-risk males. To reduce the possibility of a false positive linkage result, multiple loci and genes associated with other parkinsonian or spasticity syndromes were excluded. In conclusion, we have identified a unique X-linked parkinsonian syndrome with variable spasticity and 4-repeat tau pathology, and defined a novel candidate gene locus spanning approximately 28 Mb from Xp11.2-Xq13.3.
doi:10.1002/mds.23085
PMCID: PMC3123999  PMID: 20629132
Genetic linkage; Parkinson’s disease/parkinsonism; X-linked parkinsonism; X-linked spastic paraparesis; tauopathy
5.  Safe endoscopic polypectomy of jejunal polyps with a detachable snare during double balloon enteroscopy 
Gut  2007;56(9):1324.
PMCID: PMC1954995  PMID: 17698874
jejunal polyps; endoscopic polypectomy; double balloon enteroscopy
6.  Hypermethylation-mediated reduction of WWOX expression in intraductal papillary mucinous neoplasms of the pancreas 
British Journal of Cancer  2009;100(9):1438-1443.
We have previously shown that WW domain-containing oxidoreductase (WWOX) has tumour-suppressing effects and that its expression is frequently reduced in pancreatic carcinoma. In this study, we examined WWOX expression in intraductal papillary mucinous neoplasm of the pancreas (IPMN) to assess the function of WWOX in pancreatic duct tumourigenesis using immunohistochemistry and methylation-specific polymerase chain reaction analysis. Among 41 IPMNs including intraductal papillary mucinous adenomas (IPMAs) and intraductal papillary mucinous carcinomas (IPMCs), loss or reduced WWOX immunoreactivity was detected in 3 (15%) of 20 IPMAs and 17 (81%) of 21 IPMCs. In addition, hypermethylation of the WWOX regulatory site was detected in 1 (33%) of 3 WWOX(−) IPMAs and 9 (53%) of 17 WWOX(−) IPMCs, suggesting that hypermethylation may possibly be important in the suppression of WWOX expression. Reduction of WWOX expression was significantly correlated with a higher Ki-67 labelling index but was not correlated with the ssDNA apoptotic body index. Interestingly, decreased WWOX expression was significantly correlated with loss of SMAD4 expression in these IPMNs. The results indicate that downregulation of WWOX expression by the WWOX regulatory region hypermethylation is critical for transformation of pancreatic duct.
doi:10.1038/sj.bjc.6604986
PMCID: PMC2694421  PMID: 19352382
WW domain-containing oxidoreductase; SMAD4; intraductal papillary mucinous neoplasm of the pancreas; hypermethylation
7.  Association of a polymorphism of the transforming growth factor-ß1 gene with cerebral amyloid angiopathy 
Background: A recent study showed that transforming growth factor-ß1 (TGF-ß1) induces amyloid-ß deposition in cerebral blood vessels and meninges of a transgenic mouse model of Alzheimer's disease (AD), and that TGF-ß1 mRNA levels are correlated with cerebral amyloid angiopathy (CAA) in human AD brains. A T/C polymorphism at codon 10 in exon 1 of the TGF-ß1 gene has been reported to be associated with the serum TGF-ß1 concentration. We investigated whether the TGF-ß1 polymorphism is associated with the risk of CAA.
Methods: The association between the severity of CAA and the T/C polymorphism at codon 10 in exon 1 of the TGF-ß1 was investigated in 167 elderly Japanese autopsy cases, including 73 patients with AD. The apolipoprotein E (APOE) genotype was also determined.
Results: The genotypes (TT/ TC/ CC) were associated with the severity of CAA significantly in all patients (p = 0.0026), in non-AD patients (p = 0.011), and APOE non-ε4 carriers (p = 0.0099), but not in AD patients or APOE ε4 carriers. The number of the T alleles positively correlated with the severity of CAA in all patients (p = 0.0011), non-AD patients (p = 0.0026), and APOE non-ε4 carriers (p = 0.0028), but not in AD patients or APOE ε4 carriers. The polymorphism was not significantly associated with AD.
Conclusions: Our results suggest that the polymorphism in TGF-ß1 is associated with the severity of CAA, especially in non-AD patients and APOE non-ε4 carriers.
doi:10.1136/jnnp.2003.034454
PMCID: PMC1739647  PMID: 15834029
8.  Association of neprilysin polymorphism with cerebral amyloid angiopathy 
Objectives: The risk of sporadic cerebral amyloid angiopathy (CAA) may be associated with genetic polymorphisms of molecules related to anabolism or catabolism of amyloid ß protein (Aß). The authors investigated whether a polymorphism of the gene (NEP) coding for neprilysin, an enzyme catabolising Aß, is associated with CAA.
Methods: The study analysed the GT repeat polymorphism in the enhancer/promoter region of NEP and severity of CAA in 164 necropsied elderly Japanese subjects.
Results: The subjects had NEP polymorphisms with 19 to 23 GT repeats and were classified into nine genotypes. CAA severity was significantly higher in the subjects with up to 40 repeats in total than those with more than 40 repeats (p=0.005). There was a significant correlation between the number of the shorter alleles (19 or 20 repeats) and CAA severity (p=0.024). In addition, there was no interaction between the NEP polymorphism and apolipoprotein E genotype.
Conclusions: These results suggest the association between the NEP polymorphism and the risk of CAA. Further study using more samples from populations with different ethnic backgrounds is necessary.
doi:10.1136/jnnp.74.6.749
PMCID: PMC1738486  PMID: 12754344
11.  Modulation of transforming growth factor β function in hepatocytes and hepatic stellate cells in rat liver injury 
Gut  2000;46(5):719-724.
BACKGROUND—Transforming growth factor β (TGF-β) regulates hepatocyte proliferation and biosynthesis of the extracellular matrix.
AIMS—This study investigated alternations in sensitivity to TGF-β1 and binding properties for ligand in hepatocytes and hepatic stellate cells (HSC) after CCl4 administration.
METHODS—Plasma TGF-β1 levels in rats after CCl4 administration were determined using ELISA. Effects of TGF-β1 were examined by DNA synthesis in hepatocytes and by measurement of fibronectin production in HSC after CCl4 administration. Binding of 125I TGF-β1 was tested in these cells.
RESULTS—Plasma TGF-β1 levels were increased as early as 24 hours and were maximal by 48 hours . The antiproliferative response to TGF-β1 decreased in hepatocytes at 48 hours and normalised at 72 hours. Fibronectin production of both normal and injured HSC was affected by TGF-β1 treatment. Cross linked ligand/receptor complexes were detected in normal hepatocytes and HSC. However, these levels decreased specifically in hepatocytes at 48 hours and normalised by 72 hours.
CONCLUSIONS—Downregulation of TGF-β receptor occurred in hepatocytes after chemical insult and TGF-β1 could not transduce its antiproliferative signal. Recovery of TGF-β receptor expression causes the signal to transduce to the nucleus at 72 hours. In HSC, whenever TGF-β1 is increased, TGF-β1 can transduce its signal for fibronectin production via its receptor because signalling receptors are expressed constantly.


Keywords: TGF-β receptor; liver regeneration; fibronectin; hepatocyte; hepatic stellate cell
doi:10.1136/gut.46.5.719
PMCID: PMC1727924  PMID: 10764719
14.  Subtraction ICG angiography in Harada's disease 
BACKGROUND/AIM—The significance of indocyanine green (ICG) angiography (ICGA) in Harada's disease still awaits clarification in many respects. This study investigates the details of choroidal lesions observed in Harada's disease by the subtraction method.
METHODS—Eight patients with Harada's disease were followed with ICGA. ICG angiograms were obtained with a Topcon high resolution digital fundus camera and processed with a Topcon IMAGEnet computer system. Image subtraction was conducted for analysing serial angiograms taken at about 2 second intervals during the dye transit phase and those taken in the early and middle phases of angiography.
RESULTS—Standard ICG images of acute stage disease showed delayed choroidal filling in the early phase. Mid phase angiograms showed areas with bright fluorescence of variable intensity, indicating intrachoroidal ICG leakage. With image subtraction of angiograms with an interval of seconds the choroidal vessels could be imaged sequentially, with the choroidal arteries visualised first, followed by the definition of the choriocapillaris and then the choroidal veins. The choroidal veins with delayed filling were visualised as positive images in serial subtraction angiograms. Subtraction with an interval of minutes showed uneven background fluorescence and bright fluorescence corresponding to the areas of intrachoroidal ICG leakage. After the disease subsided with steroid therapy, angiography revealed an improvement in delayed choroidal filling. Image subtraction by the second allowed a clear visualisation of improved choroidal venous filling, while subtraction by the minute showed homogeneous background fluorescence, eliminating brighter areas.
CONCLUSION—Subtraction ICGA demonstrated that delayed filling of the choroidal veins of varying severity occurs in association with hyperpermeability of the choroidal vessels in the course of Harada's disease.


PMCID: PMC1723125  PMID: 10381670
15.  Presenilin 1 intronic polymorphism is not associated with Alzheimer type neuropathological changes or sporadic Alzheimer's disease 
BACKGROUND—A genetic association between the presenilin 1 (PS-1) intronic polymorphism and sporadic Alzheimer's disease has been a matter of controversy. Recent findings have suggested that the PS-1 polymorphism is not associated with Alzheimer's disease or amyloid β-protein (Aβ) deposition in brains from patients with Alzheimer's disease.
OBJECTIVES—To elucidate the influence of the PS-1 polymorphism on Alzheimer type neuropathological changes and the development of Alzheimer's disease, the relation between the PS-1 polymorphism and quantitative severity of Alzheimer type neuropathological changes in the brains from patients with Alzheimer's disease and non-demented subjects was studied.
METHODS—The PS-1 and apolipoprotein E (ApoE) genotypes, were examined, together with the densities of the senile plaques, senile plaques with dystrophic neurites, and neurofibrillary tangles in the brains from 36 postmortem confirmed patients with sporadic Alzheimer's disease and 86 non-demented subjects. Association of the PS-1 polymorphism with sporadic Alzheimer's disease and ages at onset and duration of illness in Alzheimer's disease was also examined.
RESULTS—The PS-1 polymorphism was not associated with the senile plaques, senile plaques with dystrophic neurites, or neurofibrillary tangles in Alzheimer's disease or non-demented subjects. There was no association of the PS-1 intronic polymorphism with Alzheimer's disease, ages at onset, or durations of illness in Alzheimer's disease. The results remained non-significant even when the PS-1 genotype groups were divided into the subgroups withdifferent ApoE ε4 status.
CONCLUSIONS—The PS-1 intronic polymorphism does not itself have a direct causal role in the formation of Alzheimer type neuropathological changes or in the development of sporadic Alzheimer's disease.


PMCID: PMC2170047  PMID: 9576554
16.  Panencephalopathic type of Creutzfeldt-Jakob disease associated with cadaveric dura mater graft 
A 52 year old man with Creutzfeldt-Jakob disease who received a cadaveric dura mater graft 99 months before the onset is reported. The prion protein gene was homozygous for methionine at the polymorphic codon 129. Neuropathological examination disclosed a panencephalopathic type of Creutzfeldt-Jakob disease which was characterised by severe involvement of the cerebral white matter and cerebellum, as well as of the cerebral cortical and deep grey matter. Thus the panencephalopathic type of Creutzfeldt-Jakob disease may occur in association with cadaveric dura mater grafts.


PMCID: PMC2169772  PMID: 9343138
17.  Periodic phenomena in Proteus mirabilis swarm colony development. 
Journal of Bacteriology  1996;178(22):6525-6538.
Proteus mirabilis colonies exhibit striking geometric regularity. Basic microbiological methods and imaging techniques were used to measure periodic macroscopic events in swarm colony morphogenesis. We distinguished three initial phases (lag phase, first swarming phase, and first consolidation phase) followed by repeating cycles of subsequent swarming plus consolidation phases. Each Proteus swarm colony terrace corresponds to one swarming-plus-consolidation cycle. The duration of the lag phase was dependent upon inoculation density in a way that indicated the operation of both cooperative and inhibitory multicellular effects. On our standard medium, the second and subsequent swarm phases displayed structure in the form of internal waves visible with reflected and dark-field illumination. These internal waves resulted from organization of the migrating bacteria into successively thicker cohorts of swarmer cells. Bacterial growth and motility were independently modified by altering the composition of the growth medium. By varying the glucose concentration in the substrate, it was possible to alter biomass production without greatly affecting the kinetics of colony surface area expansion. By varying the agar concentration in the substrate, initial bacterial biomass production was unaffected but colony expansion dynamics were significantly altered. Higher agar concentrations led to slower, shorter swarm phases and longer consolidation phases. Thus, colony growth was restricted by higher agar concentrations but the overall timing of the swarming-plus-consolidation cycles remained constant. None of a variety of factors which had significant effects on colony expansion altered terracing frequencies at 32 degrees C, but the length of the swarming-plus-consolidation cycle was affected by temperature and medium enrichment. Some clinical isolates displayed significant differences in terracing frequencies at 32 degrees C. Our results defined a number of readily quantifiable parameters in swarm colony development. The data showed no connection between nutrient (glucose) depletion and the onset of different phases in swarm colony morphogenesis. Several observations point to the operation of density-dependent thresholds in controlling the transitions between distinct phases.
PMCID: PMC178539  PMID: 8932309
18.  Spastic tetraplegia as an initial manifestation of familial Alzheimer's disease. 
Two sisters with familial Alzheimer's disease developed spastic gait disturbance as an initial manifestation. Their gait disturbance progressed gradually, followed by dementia a few years later. Post-mortem examination of one of the patients disclosed degeneration of the thalamus and corticospinal tract in addition to numerous senile plaques and neurofibrillary tangles in the neocortex, both of which were confirmed by immunohistochemistry. This is the first report in which clinicopathological evaluation is sufficient to establish a new variant of Alzheimer's disease presenting initially as spastic tetraplegia.
Images
PMCID: PMC486076  PMID: 7561919
19.  Transfer of rheumatoid arthritis into severe combined immunodeficient mice. The pathogenetic implications of T cell populations oligoclonally expanding in the rheumatoid joints. 
Journal of Clinical Investigation  1995;96(4):1746-1758.
To investigate the pathogenicity of T cells infiltrating in the rheumatoid joints, mononuclear cells (MNC), predominantly T cells, isolated from either synovial fluid or synovial tissues of the patients with RA were transferred into severe combined immunodeficient (SCID) mice by intraarticular injections. According to our observations in this experimental system, patients with RA could be classified into at least two groups. In one group of patients, the infiltrating MNC induced synovial hyperplasia in the recipient SCID mice (the positive group). Whereas, in the other group no synovial hyperplasia was observed (the negative group). The induction of synovial hyperplasia observed in the positive group was prevented by an anti-human CD3 antibody (OKT3), indicating T cell mediation. Analysis of T cell receptor (TCR) V beta usage by reverse transcriptase polymerase chain reaction in the infiltrating MNC transferred into SCID mice revealed a marked skew towards the preferential use of certain V beta genes, which was not seen in the peripheral blood MNC, in only the positive group. The patterns of TCR/V beta skew were not uniform among the patients. The analysis of the PCR-amplified genes of such skewed TCR/ V beta by single strand conformational polymorphism showed distinct bands, indicating that the T cell populations expanding in rheumatoid joints of the positive group were oligoclonal. Furthermore, the enrichment of the T cell populations expressing such skewed TCR/V beta by in vitro stimulation of peripheral blood MNC of the patients with the relevant superantigen enabled the induction of synovial hyperplasia in the SCID mice. These results suggest that the pathogenic T cells could be activated locally in rheumatoid joints by certain antigens in some, but not in all patients with RA.
Images
PMCID: PMC185811  PMID: 7560066
20.  Ether polar lipids of methanogenic bacteria: structures, comparative aspects, and biosyntheses. 
Microbiological Reviews  1993;57(1):164-182.
Complete structures of nearly 40 ether polar lipids from seven species of methanogens have been elucidated during the past 10 years. Three kinds of variations of core lipids, macrocyclic archaeol and two hydroxyarchaeols, were identified, in addition to the usual archaeol and caldarchaeol (for the nomenclature of archaeal [archaebacterial] ether lipids, see the text). Polar head groups of methanogen phospholipids include ethanolamine, serine, inositol, N-acetylglucosamine, dimethyl- and trimethylaminopentanetetrol, and glucosaminylinositol. Glucose is the sole hexose moiety of glycolipids in most methanogens, and galactose and mannose have been found in a few species. Methanogen lipids are characterized by their diversity in phosphate-containing polar head groups and core lipids, which in turn can be used for chemotaxonomy of methanogens. This was shown by preliminary simplified analyses of lipid component residues. Core lipid analysis by high-pressure liquid chromatography provides a method of determining the methanogenic biomass in natural samples. There has been significant progress in the biosynthetic studies of methanogen lipids in recent years. In vivo incorporation experiments have led to delineation of the outline of the synthetic route of the diphytanylglycerol ether core. The mechanisms of biosynthesis of tetraether lipids and various polar lipids, and cell-free systems of either lipid synthesis, however, remain to be elucidated. The significance and the origin of archaeal ether lipids is discussed in terms of the lipid composition of bacteria living in a wide variety of environments, the oxygen requirement for biosynthesis of hydrocarbon chains, and the physicochemical properties and functions of lipids as membrane constituents.
PMCID: PMC372904  PMID: 8464404
21.  Self-similar colony morphogenesis by gram-negative rods as the experimental model of fractal growth by a cell population. 
The ability to form a fractal colony was shown to be common among several species of the family Enterobacteriaceae. Bacterial spreading growth in a two-dimensional field of nutrient concentration was indicated to be important for this experimental self-similar morphogenesis. As a basic analogy, the diffusion-limited aggregation model was suggested. Fractal dimensions of colonies were mostly in the range of values from 1.7 to 1.8, similar to those of the two-dimensional diffusion-limited aggregation model. Bacterial characteristics and culture conditions inducing changes in fractal patterns and growth rates were identified. The contribution of the bacterial multicellular nature to fractal morphogenesis is discussed.
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PMCID: PMC195579  PMID: 1599243
22.  Two necropsy cases of chronic encephalomyelitis: variants of Neuro-Behçet's syndrome? 
Two necropsy cases of chronic encephalomyelitis of unknown aetiology are presented. Skin hyperreactivity occurred in both cases although there were no mucocutaneo-ocular symptoms. There was confluent perivenous necrosis with marked glio-mesenchymal reactions and persistent inflammatory changes, predominantly in the diencephalon and brain stem. These cases are clinico-pathologically analogous to Neuro-Behcet's syndrome.
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PMCID: PMC1033120  PMID: 3216210

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