Clinical and laboratory features of patients with osteomalacia initially presenting with neurological manifestations.

Patients with osteomalacia often visit the neurology department with conditions mimicking other myopathies. We analyzed clinical features of osteomalacia patients who visited the neurology department. These patients frequently presented with hypocalcemia, hypovitaminosis D, and pain with less severe weakness. Osteomalacia should be considered when patients present with pain and weakness. INTRODUCTION: Osteomalacia is a disease of bone metabolism; however, some patients with osteomalacia initially visit the neurology department. As these patients often complain of weakness and gait disturbance, osteomalacia can be confused with other myopathies. We analyzed the clinical features of patients with osteomalacia who visited the neurology department. METHODS: We retrospectively reviewed the medical records. Osteomalacia was diagnosed based on symptoms, laboratory features, and imaging results. We compared the characteristics of patients with osteomalacia who visited the neurology department with (1) those who did not visit the neurology department and (2) patients with idiopathic inflammatory myopathy. RESULTS: Eighteen patients with osteomalacia visited the neurology department (NR group). The common etiologies in the NR group included tumors or antiepileptic medication, whereas antiviral medication was the most common in patients who did not visit the neurology department (non-NR group). The NR group showed lower serum calcium (p = 0.004) and 25-hydroxyvitamin D (p = 0.006) levels than the non-NR group. When compared with patients with inflammatory myopathy, both groups showed proximal dominant weakness. However, pain was more common in osteomalacia than in myopathy (p = 0.008), and patients with osteomalacia showed brisk deep tendon reflex more often (p = 0.017). Serum calcium (p = 0.003) and phosphate (p < 0.001) levels were lower in osteomalacia than in myopathy. CONCLUSIONS: It was not uncommon for patients with osteomalacia to visit the neurology department. The clinical presentation of these patients can be more complex owing the superimposed neurological disease and accompanying hypocalcemia. Osteomalacia should be considered when patients present with pain and weakness.

Discovery of pathogenic variants in a large Korean cohort of inherited muscular disorders.

Inherited muscular disorders (IMDs) are clinically and genetically heterogeneous genetic disorders. We investigated the mutational spectrum and genotype-phenotype correlations in Korean patients with IMD. We developed a targeted panel of 69 known IMD genes and recruited a total of 209 Korean patients with IMD. Targeted capture sequencing identified 994 different variants. Among them, 98 variants were classified as pathogenic/likely pathogenic variants; 38 were novel variations. A total of 39 patients had the pathogenic/likely pathogenic variants. Among them, 75 (36%) patients were genetically confirmed, and 18 (9%) patients had one heterozygous variant of recessive myopathy. However, two genetically confirmed patients had an additional heterozygous variant of another recessive myopathy. Four patients with one heterozygous variant of a recessive myopathy showed different phenotypes, compared with the known phenotype of the identified gene. The major causative genes of Korean patients with IMDs were DMD (19 patients), COL6A1 (9), DYSF (9), GNE (7), LMNA (7), CAPN3 (6), and RYR1 (5). This study showed the mutational and clinical spectra in Korean patients with IMD and confirmed the usefulness of strategies utilizing targeted sequencing.

Impact of smoking on neurodegeneration and cerebrovascular disease markers in cognitively normal men.

BACKGROUND AND PURPOSE: Smoking is a major risk factor for cognitive decline and dementia. However, the exact pathobiology of smoking remains unknown. The effects of smoking on cortical thickness as a biomarker of neurodegeneration or white matter hyperintensities and lacunes as biomarkers of cerebrovascular burden were concurrently evaluated. METHODS: Our study included 977 cognitively normal men who visited a health promotion centre and underwent medical check-ups, including 3.0 T magnetic resonance imaging. Participants were categorized into never smoker, past smoker or current smoker groups and pack-years and the years of smoking cessation were used as continuous variables. RESULTS: The current smoker group exhibited cortical thinning in frontal and temporo-parietal regions compared with the never smoker group. These effects were particularly prominent in smokers with a high cumulative exposure to smoking in the current smoker group. However, there was no association between smoking and the severity of white matter hyperintensity or number of lacunes. CONCLUSION: Our findings indicate that smoking might impact on neurodegeneration rather than cerebrovascular burdens in cognitively normal men, suggesting that smoking might be an important modifiable risk factor for the development of Alzheimer's disease.

Characterization and phylogenetic analysis of the swine leukocyte antigen 3 gene from Korean native pigs.

We investigated the phylogenetic relationships between pig breeds, compared the genetic similarity between humans and pigs, and provided basic genetic information on Korean native pigs (KNPs), using genetic variants of the swine leukocyte antigen 3 (SLA-3) gene. Primers were based on sequences from GenBank (accession Nos. AF464010 and AF464009). Polymerase chain reaction analysis amplified approximately 1727 bp of segments, which contained 1086 bp of coding regions and 641 bp of the 3'- and 5'-untranslated regions. Bacterial artificial chromosome clones of miniature pigs were used for sequencing the SLA-3 genomic region, which was 3114 bp in total length, including the coding (1086 bp) and non-coding (2028 bp) regions. Sequence analysis detected 53 single nucleotide polymorphisms (SNPs), based on a minor allele frequency greater than 0.01, which is low compared with other pig breeds, and the results suggest that there is low genetic variability in KNPs. Comparative analysis revealed that humans possess approximately three times more genetic variation than do pigs. Approximately 71% of SNPs in exons 2 and 3 were detected in KNPs, and exon 5 in humans is a highly polymorphic region. Newly identified sequences of SLA-3 using KNPs were submitted to GenBank (accession No. DQ992512-18). Cluster analysis revealed that KNPs were grouped according to three major alleles: SLA-3*0502 (DQ992518), SLA-3*0302 (DQ992513 and DQ992516), and SLA-3*0303 (DQ992512, DQ992514, DQ992515, and DQ992517). Alignments revealed that humans have a relatively close genetic relationship with pigs and chimpanzees. The information provided by this study may be useful in KNP management.

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.

Population-specific spectrum of the F11 mutations in Koreans: evidence for a founder effect.

The aim of this study was to investigate a mutation spectrum of F11 among Korean patients with factor XI (FXI) deficiency and to determine the haplotypes of mutations frequently found in Koreans. Thirteen unrelated patients from non-consanguineous families with FXI deficiency were included in the study. In the mutation analysis, the most frequently found mutations were Q263X (four cases; 31%) and Q226X (three cases; 23%). The frequency of Q263X-bearing haplotype was significantly different between normal and patient groups (p = 0.001), which is consistent with a founder effect of Q263X mutation. Testing for the presence of these two mutations should be the first genetic screening in Korean patients with FXI deficiency.

Self-assembled growth of nanocomposites consisting of TiO(2) nanopillars and Pb(Zr(0.52)Ti(0.48))O(3) thin films.

We report for the first time the self-assembled growth of nanocomposites of 'TiO(2) nanopillars on Pb(Zr(0.52)Ti(0.48))O(3) (PZT) thin films' using a modified sol-gel processing. Both TiO(2) nanopillars and PZT thin films are simultaneously formed during the post-annealing process. The growth behaviours of TiO(2) nanopillars are controlled by adjusting the Ti excess amounts of PZT solutions and the post-annealing conditions. The self-assembled growth can be explained on the basis of the combined effects of five factors which can have influence during the annealing process: a Ti ion diffusion to the film surface, a phase separation of PZT and TiO(2), a void formation on the film surface, a Ti oxidation at the film surface under oxygen atmosphere, and a nanopillar growth on the film surface.

An aggressive form of familial amyloid polyneuropathy caused by a Glu54Gly mutation in the transthyretin gene.

We report a patient with familial amyloid polyneuropathy. Gene analysis revealed a heterozygous Glu54Gly substitution (A-to-G change) in the transthyretin gene. This is the first case of a Glu54Gly substitution that was devoid of a Gly6Ser substitution. Compared with the previously reported case with compound heterozygotes of Glu54Gly and Gly6Ser, the age of onset in our case is much younger and another characteristic findings were the amyloid vasculopathy and the multiple organ involvement. A Glu54Gly mutation is amyloidogenic by itself and a Gly6Ser mutation may offer some protection from the Glu54Gly mutant.

Monitoring biofilm detachment under dynamic changes in shear stress using laser-based particle size analysis and mass fractionation.

Biofilm detachment under a dynamic change in shear stress was monitored using Focused Beam Reflectance Measurements (FBRM, LASENTEC) and mass fractionation. An annular reactor was used to grow biofilm with glucose as substrate. Changing the rotational speed on the inner cylinder of the annular reactor from 150 RPM to 420 RPM induced a step increase in shear stress. It was observed that the rate of detachment increased rapidly after increasing shear stress and then returned to the previous level. Erosion was the dominant process of detachment under steady state operation, whereas sloughing was dominant following the sudden increase in shear stress. After reaching steady state detachment under high shear conditions, the rotational speed was decreased for a 12-hour period. During this brief period of lower shear, the biofilm adjusted to this new condition. When the shear stress was increased again, another sharp increase in effluent solids concentration was observed. A decrease in density indicates that the biofilm became more vulnerable to shear stress after being subjected to this short period of low shear.

Evaluation of design parameters of osseointegrated dental implants using finite element analysis.

Finite element analyses were performed for various shapes of dental implant to study effects on stress distribution generated in the surrounding jaw bone and to determine an optimal thread shape for even stress distribution. It was found that the square thread shape filleted with a small radius was more effective on stress distribution than other dental implants used in the analyses. Additional analyses were performed on the implant with the thread shape obtained from previous analyses for varying other design parameters, such as the width of thread end and height of thread for various load directions, to determine the optimal dimensions of the implant. Stress distribution was more effective in the case when the width of thread end and the height of thread were 0.5p and 0.46p, respectively, where p is the screw pitch. Then, using the optimal implant thread dimensions determined previously, stress analyses were performed with various screw pitches and implant lengths, to investigate effects on stress distribution and to find the way to reduce the maximum effective stress generated in the jaw bone. Results show that the maximum effective stress decreased not only as screw pitch decreased gradually but also as implant length increased.

Prolonged jaundice following percutaneous coronary intervention and ticlopidine therapy.

Ticlopidine, an adenosine diphosphate receptor blocker, is widely used to prevent subacute stent thrombosis after percutaneous coronary intervention. Along with neutropenia and thrombotic thrombocytopenic purpura, cholestatic hepatitis is one of the most serious potential side-effects of ticlopidine therapy. Four patients with prolonged jaundice after ticlopidine therapy, including one fatal case, are presented. Alternative antithrombotic therapy for subsequent percutaneous coronary intervention is also described. Clopidogrel therapy was found to be safe and effective in two patients with a history of ticlopidine-related cholestatic hepatitis.

Effect of inhibitor of tumor necrosis factor-alpha on experimental otitis media with effusion.

Tumor necrosis factor (TNF)-alpha is important in the pathogenesis of otitis media with effusion (OME). The purpose of this study was to determine the effect of TNF-alpha antagonist on the outcome of lipopolysaccharide (LPS)-induced OME in rats. Otitis media was induced by injecting Pseudomonas aeruginosa LPS transtympanically. Another (combination) group was pretreated with TNF-alpha antagonist, soluble TNF receptor type I (sTNF RI), before transtympanic injection of LPS. Saline and phosphate-buffered saline solutions were used as controls. Twelve hours after the transtympanic injection, otoscopic examination and aspiration of middle ear effusion (MEE) were done. The temporal bones in each group were examined histopathologically, and the vascular permeability of the middle ear mucosa was measured by the Evans blue vital dye technique. In the LPS and combination groups, MEE developed in 90% and 0% of ears, respectively. The combination group showed less inflammation, less mucosal thickening, and significantly decreased vascular permeability as compared to the LPS group. Transtympanic administration of sTNF RI appears to suppress the development of LPS-induced OME. This study suggests that TNF-alpha antagonist, along with antibiotics, may have an adjunctive role in the future treatment of MEE.

Acquired pendular nystagmus with voluntary inhibition.

This report documents a case of voluntary inhibition of acquired pendular nystagmus after head trauma. A 30-year-old male developed oscillopsia and decreased visual acuity, as well as findings of acquired pendular nystagmus with voluntary inhibition after head trauma. The EOG finding was horizontal 18-20 Hz bilateral symmetrical pendular nystagmus in all directions of gaze at near and distant fixation. Nystagmus did not change with 14 Prism Diopter base-out prisms on both eyes, but it was possible to abolish it intentionally. Baclofen and Clonazepam had no effect in improving the patient's symptoms and EOG finding.

Effect of tumor necrosis factor-alpha on experimental otitis media with effusion.

OBJECTIVES/HYPOTHESIS: Up to the present, many reports have demonstrated that local immune response is associated with maintenance and persistence of effusion in the middle ear cavity. Resulting retention of inflammatory cells and mediators in the middle ear results in ongoing effusion. The purpose of this study was to clarify the role of tumor necrosis factor in experimental otitis media with effusion, which was induced by transtympanic injection of tumor necrosis factor in the rats. STUDY DESIGN: Four groups were designed in two experiments. The purpose of experiment 1 was to confirm that transtympanic injection of TNF-alpha produces the middle ear effusion. In experiment 2, TNFsolRI was used to evaluate the possibility as an inhibitor in otitis media with effusion. METHODS: The histopathological changes were observed under light microscope, and the changes in microvascular permeability were examined using Evans blue vital dye technique. RESULTS: Middle ear effusion was developed in 70% of specimens, and histopathological changes, such as subepithelial edema and marked infiltration of neutrophils, were present in 100% at 24 hours after administration of tumor necrosis factor-alpha through transtympanic approach. Extravasation of Evans blue dye was found in all specimens injected by tumor necrosis factor-alpha, which was qualified using a fluorescence microscope and quantified using a spectrophotometer. These histopathological findings and changes in microvascular permeability were significantly reduced by tumor necrosis factor soluble receptor type I. CONCLUSIONS: Neutrophil infiltration, subepithelial edema, increased microvascular permeability, and resultant effusion were indirectly proved to be induced by tumor necrosis factor-alpha. We hope that this study may contribute to understanding the role of tumor necrosis factor-alpha in otitis media with effusion and clarifying the future role of tumor necrosis factor soluble receptor type I in preventing otitis media with effusion.

Induction of alpha1-acid glycoprotein mRNA by cytokines and differentiation in human colon carcinoma cell.

The mRNA for the alpha1-acid glycoprotein (AAG) was expressed not only in hepatoma cells, but also in non-hepatic cancer cells. The expression of the AAG mRNA in HT-29 human colon carcinoma cells is induced by cytokines, IL-6, IL-1, and TNF-alpha, in a manner characteristic of the acute phase response, and the expression of AAG mRNA was up-regulated in differentiated HT-29 cells.

The central conduction time in posterior tibial and pudendal nerve somatosensory evoked potentials.

The somatosensory evoked potentials (SEPs), following stimulation of both the posterior tibial nerve (PTSEP) and pudendal nerve (PNSEP), comprise of the lumbar negative, subcortical and cortical potential. These can be used to assess the long somatosensory pathway, including peripheral, intraspinal and intracranial conduction along the entire length. This study aimed to compare the central conduction time between the PTSEP and the PNSEP, and to investigate the relationship between the intraspinal and intracranial conduction time in the SEP pathway. The SEPs following stimulation of the posterior tibial nerve at the ankle and the pudendal nerve at the shaft of the penis were analyzed in 20 normal male subjects. The central conduction of the PNSEP was found to be slower than that of the PTSEP (p <0.05). This difference is due to a delay in conduction rather than that of intracranial conduction.

Altered remodeling of nucleolar machineries in cultured hepatocytes treated with thioacetamide.

Thioacetamide (TA) is converted into a hyperacetylating agent which causes hepatic necrosis, regeneration, cirrhosis and cancerous transformation. One of the most characteristic toxicities of TA in rat is observed with a 50 mg/kg per day which induces nucleolar enlargement different from that in regenerating liver. From TA-treated liver, the nucleoli were isolated and characterized for an altered nucleolar signal transduction system. Immunochemistry revealed that the poisoned nucleoli had increased levels of both nucleolus specific proteins (nucleophosmin and nucleolin) and various signal molecules (CK2, Erk1/2, p38, protein kinases A and C, and cyclin A). Using flow cytometry, the nucleoli were found to be in G2-arrested nuclei. Manifestation of the nucleolar enlargement could be readily observed using an ex vivo hepatocyte culture. There were two types of nucleolar enlargement. One was observed in normal hepatocytes with light density of enlarged nucleoli. The other was in TA-treated hepatocytes with dense and compact density of enlarged nucleoli, which contained a 3 to 5-fold higher nudeophosmin content than the control. In vitro induction of nucleolar enlargement with TA was possible. As soon as the hepatocytes anchored on a collagen coat, exogeneous TA (higher than 1 microg/mL) could induce dense and compact nucleoli. However, when an exogeneous drug was added after monolayer formation (1 day), no drug-induced nucleolar enlargement was observed.

Incidence and characterization of Listeria spp. from foods available in Korea.

A total of 410 domestic Korean food samples were analyzed for the presence of Listeria spp. by the conventional U.S. Department of Agriculture protocol, and presumptive strains were identified by morphological, cultural and biochemical tests according to Bergey's manual and confirmed by API-Listeria kit. Among the total 410 food samples, 46 samples (11.2%) were found to be contaminated with Listeria species. Among the 46 strains of Listeria spp. isolates, 8 strains (17.42%) for Listeria monocytogenes, 3 strains (6.5%) for Listeria seeligeri, 33 strains (71.7%) for Listeria innocua, and 2 strains (4.4%) for Listeria welshimeri were identified, respectively. Also, only beef, chicken, pork, frozen foods, and sausage were contaminated with L. monocytogenes, and the other products were free of L. monocytogenes. Of 46 Listeria spp. isolates, L. innocua (71.7%) was the most predominantly isolated in a variety of foods compared to other Listeria spp. An in vitro virulence assay for Listeria spp. using myeloma and hybridoma cells from murine and human sources was performed. The result showed that only L. monocytogenes killed approximately 95 to 100% hybridoma cells after 6 h and the other Listeria species, such as L. innocua, L. seeligeri, and L. welshimeri strains had about 0 to 10% lethal effect on hybridoma cells. Also, an antibiotic susceptibility test showed that Listeria spp. isolates were very susceptible to the antibiotics tested, except for nalidixic acid. Also, serotyping results showed 75% of L. monocytogenes isolates from beef, chicken, and frozen pizza belonged to serotype 1 and 25% from sausage were type 4.

Haploinsufficiency of protamine-1 or -2 causes infertility in mice.

Protamines are the major DNA-binding proteins in the nucleus of sperm in most vertebrates and package the DNA in a volume less than 5% of a somatic cell nucleus. Many mammals have one protamine, but a few species, including humans and mice, have two. Here we use gene targeting to determine if the second protamine provides redundancy to an essential process, or if both protamines are necessary. We disrupted the coding sequence of one allele of either Prm1 or Prm2 in embryonic stem (ES) cells derived from 129-strain mice, and injected them into blastocysts from C57BL/6-strain mice. Male chimeras produced 129-genotype sperm with disrupted Prm1 or Prm2 alleles, but failed to sire offspring carrying the 129 genome. We also found that a decrease in the amount of either protamine disrupts nuclear formation, processing of protamine-2 and normal sperm function. Our studies show that both protamines are essential and that haploinsufficiency caused by a mutation in one allele of Prm1 or Prm2 prevents genetic transmission of both mutant and wild-type alleles.

A case report of inflammatory pseudotumor involving the clivus: CT and MR findings.

The authors describe a rare case of inflammatory pseudotumor involving the clivus, where a soft tissue mass lesion, with extension into the prevertebral retropharyngeal space and the cavernous sinuses, was detected by CT and MRI. The mass resembled a malignant tumor or aggressive infectious lesion, and the final diagnosis of inflammatory pseudotumor was a diagnosis of exclusion, decided after histopathological examination.