The effect of bisphosphonate and intermittent human parathyroid hormone 1-34 treatments on cortical bone allografts in rabbits.

AIM: This study compares the effect of bisphosphonate and intermittent PTH administration on haversian remodeling in cortical bone allografts in rabbits. MATERIALS AND METHODS: An intercalary heat-treated cortical bone allograft was applied to a segment skeletal defect in the left femur of Japanese white rabbits. The rabbits were randomly assigned to one of three groups: the vehicle control group (CNT); the bisphosphonate group (B group); and the intermittent PTH treatment group (P group). Periodic radiographic evaluation was performed and peripheral quantitative computerized tomography (pQCT) was used to evaluate the total bone area (Area), bone mineral density (BMD), and bone mineral content (BMC). The allografts also underwent histological examination. RESULTS: The P group was radiographically superior in the latter stage, compared with the other groups. pQCT analysis of the allografts showed that the B group had a significantly higher Area and BMC. These parameters in the latter stage were significantly lower in the P group than in the other groups. The allograft of the B group was histologically mostly necrotic bone, whereas allograft of the P group showed abundant newly formed bone. CONCLUSION: In rabbits, bisphosphonate prevents resorption, but suppresses remodeling and incorporation; by contrast, PTH increases resorption and accelerates allograft remodeling and incorporation. Based on our preliminary data, we suggest that further research on the manner of administration of bisphosphonate and PTH - which have contrasting effects - can be beneficial in maintaining bone strength and in regulating remodeling and allograft incorporation.

Characterization of human multicentric osteosarcoma using newly established cells derived from multicentric osteosarcoma.

PURPOSE: Human multicentric osteosarcoma (HMOS) is a rare, aggressive variant of osteosarcoma, and its etiology is not clear. We used newly established HMOS cells, which were derived from primary (HMOS-A) and secondary (HMOS-P) lesions, respectively, to perform a basic study analyzing the cellular biology and gene expression of HMOS. METHODS: We performed a cell growth assay, an invasion assay, DNA microarray analysis, quantitative real-time RT-PCR (Qrt-PCR), and a telomerase assay and compared the results between HMOS-A, HMOS-P, and human osteosarcoma (HOS) cell lines (MNNG-HOS and Saos-2). RESULTS: The cell biological analysis revealed that HMOS-A and HMOS-P had similar characteristics to Saos-2, and the invasion assay showed that they had similar characteristics to MNNG-HOS. The DNA microarray study showed that the gene expression profiles of HMOS-A and HMOS-P were similar to that of MNNG-HOS, but the overexpression of MMP-2, MMP-9, and MT1-MMP was observed in HMOS-A and HMOS-P, which was correlated with the invasiveness of the extracellular matrix, and collagen type-4 (COL-4) and VEGF were also detected. HMOS-A and HMOS-P showed low telomerase activity similar to Saos-2, which are known to be telomerase negative, but a similar telomere length and telomerase protein to MNNG-HOS. CONCLUSIONS: HMOS-A and HMOS-P demonstrated strong invasive ability, and their gene expression profiles correlated with the invasiveness of the extracellular matrix. Their telomerase activity was low, but they did not shown the typical features of alternative lengthening of telomeres (ALT). HMOS-A and HMOS-P are useful models for further study of various biological aspects and therapeutic manipulation of HMOS.

Effect of intermittent treatment with human Parathyroid Hormone 1-34 in SAMP6 senescence-accelerated mice.

We examined trabecular and cortical bone in the senescence-accelerated mouse prone 6 (SAMP6) murine model of senile osteoporosis after treatment with human PTH 1-34. Sixteen-week-old female SAMP6 mice were assigned to control and PTH groups. PTH (20 microg/kg) was administered sc 3 times a week for 12 weeks. The control mouse strain, senescence-accelerated mouse resistant 1 (SAMR1), was used for comparison. The femoral metaphysis and diaphysis were used to measure bone mineral density (BMD), analyze the trabecular and the cortical structure by micro-computed tomography, and for conducting the bone strength test. PTH significantly attenuated the loss of BMD, improved the trabecular bone microstructure, and increased the bone strength in the femoral metaphysis. We did not find any differences in the bone strength of the femoral diaphysis after PTH treatment, although the cortical bone volume and cortical thickness were improved. Although the cortical thickness increased, the cortical bone density decreased, likely because of the increase of cortical porosity in the distal metaphysis after administration of PTH.

Neuroradiologic and clinicopathologic features of oculoleptomeningeal type amyloidosis.

OBJECTIVE: To clarify the pathogenesis of leptomeningeal amyloidosis in familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C (FAP ATTR Y114C). METHODS: The authors analyzed eight FAP ATTR Y114C patients. Six patients showed CNS symptoms associated with leptomeningeal amyloidosis. To examine the function of the blood-CSF barrier and blood-brain barrier (BBB), the authors performed CSF and MRI studies. The authors also performed a histopathologic study of autopsy specimens to examine the distribution of amyloid deposition in the CNS. RESULTS: CSF study showed high total protein concentrations and increased albumin CSF/serum concentration quotients (Qalb; an indication of blood-CSF barrier function). MRI with gadolinium (Gd) revealed enhancement from brainstem to spinal cord. Serial brain MRI studies with FLAIR images after Gd administration showed Gd leakage into the subarachnoid space (two patients). These findings suggested the blood-CSF barrier and BBB dysfunctions. Constructive interference in steady state (CISS) three-dimensional Fourier transformation (CISS-3DFT) sequence analysis demonstrated amyloid-induced funiculus structures joining the spinal cord and dura mater (one patient). Histopathologic study revealed intense amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. These distributions of amyloid deposition are unique compared to other TTR related leptomeningeal amyloidosis. CONCLUSIONS: Patients with familial amyloidotic polyneuropathy amyloidogenic transthyretin Y114C had CNS disorders related to amyloid deposition in leptomeninges, vessel walls, and parenchyma in spinal cord and the brain. The pathogenesis of CNS disorders may reflect disruption of the blood-CSF barrier and blood-brain barrier by amyloid deposition.

Cerebral atrophy and its relation to cognitive impairment in Parkinson disease.

OBJECTIVE: Voxel-based morphometry was used to compare the amounts of gray matter in the brains of patients with Parkinson disease (PD) and normal control subjects (NCs) and to identify the specific regions responsible for cognitive dysfunction in PD. METHODS: Patients were classified into nondemented (ND) and demented (D) groups according to the criteria of the Diagnostic and Statistical Manual of Mental Disorders (4th ed.), and a group comparison was performed. In the ND patients, a correlation was also performed between local gray matter density and the score on Raven Colored Progressive Matrices (RCPM), a test of executive and visuospatial function. RESULTS: In patients with advanced ND-PD vs NCs, atrophic changes were observed in the limbic/paralimbic areas and the prefrontal cortex. In D vs ND patients, atrophic change was observed widely in the limbic/paralimbic system, including the anterior cingulate gyrus and hippocampus as well as the temporal lobe, dorsolateral prefrontal cortex, thalamus, and caudate nucleus. The RCPM score was positively correlated with the gray matter density in the dorsolateral prefrontal cortex and the parahippocampal gyrus. CONCLUSIONS: In patients with Parkinson disease (PD), atrophic changes occur mainly in the limbic/paralimbic and prefrontal areas. These atrophic changes may be related to the development of dementia in PD.

Occipital hypoperfusion in Parkinson's disease without dementia: correlation to impaired cortical visual processing.

OBJECTIVE: The purpose of this study was to analyse changes in regional cerebral blood flow (rCBF) in Parkinson's disease (PD) without dementia. METHODS: Twenty eight non-demented patients with PD and 17 age matched normal subjects underwent single photon emission computed tomography with N-isopropyl-p-[(123)I]iodoamphetamine to measure rCBF. The statistical parametric mapping 96 programme was used for statistical analysis. RESULTS: The PD patients showed significantly reduced rCBF in the bilateral occipital and posterior parietal cortices (p<0.01, corrected for multiple comparison p<0.05), when compared with the control subjects. There was a strong positive correlation between the score of Raven's coloured progressive matrices (RCPM) and the rCBF in the right visual association area (p<0.01, corrected for multiple comparison p<0.05) among the PD patients. CONCLUSIONS: This study showed occipital and posterior parietal hypoperfusion in PD patients without dementia. Furthermore, it was demonstrated that occipital hypoperfusion is likely to underlie impairment of visual cognition according to the RCPM test, which is not related to motor impairment.

Hyaluronan in synovial fluid of patients with loose total hip prosthesis. Comparison with hyaluronan in patients with hip osteoarthritis and idiopathic osteonecrosis of femoral head.

The concentration and molecular weight of hyaluronan (HA) in the synovial fluid of the hip joint were determined in 13 patients (aged 62.8 +/- 9.4 years) who had undergone prior total hip arthroplasty(THA), 23 patients (aged 65.0 +/- 8.2 years) with osteoarthritis of the hip joint (OA), and 13 patients (aged 40.2 +/- 2.7 years) with idiopathic osteonecrosis of the femoral head (ION). A sample of synovial fluid was obtained during revision THA because of loosening of the total hip prosthesis for the THA group, and during the first replacement surgery or osteotomy for the OA and ION groups. The concentration of HA in the synovial fluid was 0.64 +/- 0.42 mg/ml in the THA group, 1.07 +/- 0.28 mg/ml in the OA group, and 1.30 +/- 0.56 mg/ml in the ION group. The concentration of HA in the synovial fluid of the THA patients was significantly lower than that of the OA and ION patients (P = 0.0156 vs OA, P = 0.003 vs ION). The molecular weight of HA was 309 +/- 88.3 x 10(4) Da in the THA group, 377 +/- 201 x 10(4) Da in the OA group, and 240 +/- 148 x 10(4) Da in the ION group; these values do not differ significantly (P = 0.259 vs OA, P = 0.174 vs ION). Among the THA patients, there was no relation between the concentration of HA and the age of the patient, length of time since the first operation, or type of prosthesis fixation; there was also no relation between the molecular weight of HA and each of these factors. These results suggest that a pseudosynovial membrane is regenerated after THA, and that it produces HA of the same molecular weight as that in patients with OA and ION, although in smaller quantities.

Brainstem-type Lewy body disease presenting with progressive autonomic failure and lethargy.

The authors report an autopsy case characterized by progressive lethargy and autonomic failure with a distinctive pattern of occurrence of Lewy bodies. Autonomic dysfunction such as sleep apnea, orthostatic hypotension, dysuria, and hypohidrosis predominated with lethargy, whereas parkinsonism was not apparent. Numerous Lewy bodies were widely evident microscopically in brainstem nuclei and the intermediolateral cell columns of the spinal cord, as well as in the sympathetic ganglia, but were rare or absent in the cerebral cortex and other supratentorial structures. Marked neuronal loss was seen in the locus ceruleus, raphe nuclei, dorsal vagal nuclei, and intermediolateral cell columns, but neurons in the substantia nigra, other brain regions, and sympathetic ganglia appeared undiminished. This case represents a specific clinicopathologic form of Lewy body disease occurring predominantly in the brainstem, spinal cord, and sympathetic ganglia.

Content and sulfation pattern of keratan sulfate in hip osteoarthritis using high performance liquid chromatography.

OBJECTIVE: To determine the content and sulfation pattern of keratan sulfate (KS) in synovial fluid (SF) from patients with hip osteoarthritis (OA) and investigate its significance as a marker of cartilage matrix metabolism. METHODS: Hip SF samples were aspirated from 50 patients with OA. KS in the samples was digested to 2 disaccharide isomers, beta-galactosyl-(1-4)-6-0-sulfo-N-acetylglucosamine (L2) and beta-6-0-sulfo-galactosyl-(I-4)-6-0-sulfo-N-acetylglucosamine (LA) by keratanase II. Concentrations of these disaccharide isomers were determined by high performance liquid chromatography (HPLC), and their levels were investigated in relation to radiological stage of disease. RESULTS: Analysis of covariance (age as covariate) showed that the L2 levels in advanced stage OA were significantly lower than in early stage OA (p < 0.0001). L2 levels in terminal stage OA were also significantly lower than in early stage OA (p < 0.0001); however, no significant difference was observed between the L2 levels in advanced and terminal stage OA (p = 0.516). There were no significant differences in the levels of L4, L2 + L4, or the ratio of L4 to L2 at each disease stage. CONCLUSION: The levels of KS related disaccharide isomer vary with severity of disease in hip OA. Analysis of these KS related disaccharide isomers by HPLC provides information on both the content and sulfation pattern of KS in SF, reflecting the metabolism of cartilage aggrecan.

[A patient with choreoathetosis of the left upper extremity due to acute cerebral infarction].

A 71-year-old woman was admitted to our hospital because of involuntary movement of the left upper extremity. MR image of the brain 15 days after the onset revealed the low intensity in right posterior limb of internal capsule. The lesion was surrounded by thalamus, subthalamic nucleus, and globus pallidus with enhancement by Gd-DTPA. Surface EMG revealed irregular grouped discharge in short duration and grouped discharge in long duration in the left upper extremity. Those features are compatible with one of choreoathetosis. Choreoathetosis due to cerebral infarction in acute phase is rare. We discussed pathophysiology of this involuntary movement due to lacunar infarction of posterior limb of internal capsule in acute phase.

[Movement-related cortical potentials upon forward-stepping in patients with Parkinson disease].

We investigated movement-related cortical potentials(MRCPs) in 20 patients with Parkinson disease(PD group) and 6 normal age-matched controls when they were stepping forward volitionally from standing position. PD group was divided in three groups according to the clinical courses and motor function scores in Langston's criteria: Ia; within 6 years and higher than 20 points, Ib; within 6 years and within 20 points, II; over 6 years. In Ia group their negative slope(NS') was larger than those in the other three groups, while their Bereitschaftspotential showed no statistical difference. The results of our investigation shows that, in these cases, the function of cerebral cortex and/or cerebellum can be enhanced compensating the dysfunction of basal ganglia.

Slow negative cortical potential preceding the onset of postural adjustment.

We investigated whether a cortical potential exists, that is similar to the Bereitschaftspotential, preceding postural adjustment followed by voluntary ballistic rising on tiptoe in 10 healthy subjects. On the basis of the electromyogram (EMG) activities of the soleus muscle, the onsets of the premotion silent period (PMSP) and EMG discharge were determined. The negative potentials associated with a voluntary rise-on-tiptoe movement with respect to EMG onset were similar to the readiness potential associated with voluntary foot movement. The slopes of the slow negative potential associated with the PMSP onset were significantly more negative than those of the potential associated with rise-on-tiptoe movement, particularly over the frontal electrode positions. The results suggest that a cortical potential precedes postural adjustment that is followed by voluntary rising on tiptoe.

[Movement-related cortical potentials (MRCPs) and voluntary movement--clinical usefulness of MRCPs].

The gradient of negative slope (Ns') changed in parallel with the velocity of step movement in normal individuals. We can not evaluate the MRCPs without considering this factor among patients and/or subjects. We recorded the MRCPs of thirty nine patients with cerebellar ataxias and sixteen patients with Parkinson disease (PD). Goniometer was attached on the patient's wrist to measure the velocity of the wrist movement. In the patients with spinocerebellar degeneration with denate nucleus lesion (Machado-Joseph disease, DRPLA, MERRF, dyssynergia cerebellaris myoclonica, galactosialidosis), the gradients of Ns' were reduced, although the movements themselves were as fast as normal control. In the patients with spinocerebellar degeneration without this lesion, the MRCPs were able to record as normal control, and their gradients of Ns' became steeper according to the increase of the movement angular velocity. On the contrary, in the patients with Parkinson disease, the gradients of Ns' were steeper in the patients with slow movement than in those with fast movement. The MRCP helps us to investigate the pathophysiology of the movement disorders. It is desirable that physiological data on the MRCP are extensively accumulated.

Gastrointestinal dysfunction in Parkinson's disease detected by electrogastroenterography.

Electrogastroenterography (EGEG) is a method to record electrical activities of the stomach and the intestine using skin electrodes. We investigated whether this method could be used to detect gastrointestinal dysfunction in patients with idiopathic Parkinson's disease. EGEG recordings were done with ten patients with idiopathic Parkinson's disease and ten control subjects before and after a meal. The patients showed changes in EGEG that were markedly similar to those of acute stage of vagotomized patients reported previously. Patients' increase rate in amplitude of gastric activity after the meal (median: 1.19) was significantly (P < 0.05, Mann-Whitney test) smaller than that of the controls (median: 2.84), and normal temporal frequency decrease of gastric activity after the meal was not seen in the patient group. These results suggest vagal nerve dysfunction of patients with Parkinson's disease, though other possibilities could not be denied. EGEG may be useful to assess patients' gastrointestinal dysfunction though we need further study to elucidate the relation between pathophysiology of their symptoms and EGEG findings.

[Movement-related cortical potential upon stepping forward].

We investigated movement-related cortical potentials (MRCPs) in 10 healthy subjects when they were stepping the right leg forward volitionally from the standing position, and compared with MRCPs associated with the foot dorsiflexion solely in sitting position. We recorded electroencephalogram (EEG), electrooculogram, surface electromyogram (EMG) on lower limb, and statokinesigram. We examined each EMG onset and several points on the statokinesigram as trigger points. MRCPs triggered by the right tibialis anterior, the left gastrocnemius, and the left soleus muscle had slow negative potentials containing slow phase and steeper phase. The potentials of both phases had the largest gradient at Cz. MRCPs triggered by the EMG onset of these three muscles resembled those associated with the foot dorsiflexion in their wave form, time course, and distribution pattern, but spread widely over the anterior recording sites. On the other hand, MRCPs triggered by the first deviation on the statokinesigram--by that first deviation assumed to take the first and foremost movement in this paradigm, were found to be delayed after the trigger point. The tibialis anterior muscle contributes to elevating a foot, and the contralateral gastrocnemius and soleus muscle to sustaining the weight. We were able to record apparent MRCPs when we adopted these EMG bursts, which play an important role in stepping forward, as trigger points. These records will be useful to analyze the mechanism of gait disturbance.

[Movement-related cortical potential in patients with cerebellar dentate degeneration].

We reported movement-related cortical potentials (MRCPs) in 11 patients with lesion of the dentate nucleus (Machado-Joseph disease (MJD) 7 cases, dentato-rubro-pallido-luysian atrophy (DRPLA)1, myoclonus epilepsy associated with ragged-red fibers (MERRF)1, dyssynergia cerebellaris myoclonica (DCM) 2), and compared with those of 7 cases of multiple system atrophy (MSA) who were postulated to have mild dentate lesions (striato-nigral degeneration 2 cases, Shy-Drager syndrome 2, sporadic olivo-ponto-cerebellar atrophy 3), and 7 control subjects without any neurological findings. Further we classified the diseases into the following two groups based on the lesion of the dentate nucleus. One was MJD group that had normal or slightly abnormal electroencephalogram (EEG), and the other was DN group (DRPLA, MERRF, DCM) that had markedly abnormal EEG. One of the main findings from this study was smaller slope of the Ns' in the MJD and DN group and normal slope of BP. There was no significant difference in the slope of Ns' between MJD patients and DN patients. This result shows EEG abnormalities have no influence on MRCP recordings. These results suggest that Ns' component may reflect the function in the cerebellar dentate nucleus, and that MRCP is a useful diagnostic method in patients with cerebellar ataxia.