Deep vein thrombosis and its risk factors in neurodegenerative diseases: A markedly higher incidence in Parkinson's disease.

BACKGROUND: Information on the incidence and risk factors of deep vein thrombosis (DVT) in neurodegenerative diseases is limited. We aimed to determine the incidence of DVT among neurodegenerative disorders (amyotrophic lateral sclerosis [ALS], Parkinson's disease [PD], multiple system atrophy [MSA], and progressive supranuclear palsy [PSP]-corticobasal syndrome [CBS]) and the risk factors for the development of DVT. METHODS: Overall, 229 hospitalized patients with neurodegenerative diseases (65 patients with ALS, 61 with PD, 53 with MSA, and 50 with PSP-CBS) were included in this study. D-dimer value and ultrasonography of the leg vein were assessed to determine the presence or absence of leg DVT. We compared the DVT incidence among each disease group. To identify the risk factors for DVT, a multivariate analysis was performed. RESULTS: Of 229 patients, 34 had leg DVT; the incidence was significantly higher in patients with PD (38%) than in those with ALS (2%), MSA (5%), or PSP-CBS (4%). Patients with DVT were older, had a smaller waist circumference, had a longer disease duration, and had a high blood pressure (BP) variability. Multivariate analysis revealed that a PD diagnosis and female sex, with a high BP variability were predictive of leg DVT. CONCLUSIONS: Among the neurodegenerative diseases, the DVT incidence was markedly higher in PD than in ALS, MSA, and PSP-CBS. Several risk factors have been identified in patients with leg DVT. Recognition of these risk factors will improve patient care and guide the appropriate use of anticoagulants.

Smart Gateway for Healthcare Networks Based on Beam Steering Technology.

To ensure high-reliability communication in healthcare networks, this paper presents a smart gateway system that includes an angle-of-arrival (AOA) estimation and a beam steering function for a small circular antenna array. To form a beam toward healthcare sensors, the proposed antenna estimates the direction of the sensors utilizing the radio-frequency-based interferometric monopulse technique. The fabricated antenna was assessed based on the measurements of complex directivity and the over-the-air (OTA) testing in Rice propagation environments using a two-dimensional fading emulator. The measurement results reveal that the accuracy of the AOA estimation agrees well with that of the analytical data obtained through the Monte Carlo simulation. This antenna is embedded with a beam steering function employing phased array technology, which can form a beam spaced at 45° intervals. The ability of full-azimuth beam steering with regard to the proposed antenna was evaluated by beam propagation experiments using a human phantom in an indoor environment. The received signal of the proposed antenna with beam steering increases more than that of a conventional dipole antenna, confirming that the developed antenna has great potential of achieving high-reliability communication in a healthcare network.

Preserving the Ankle by the Masquelet Technique for the Large Bone Defect in the Distal Tibia in Children: A Case Report.

CASE: A 14-year-old adolescent girl sustained an open fracture of the foot after jumping off a building. Initial radiographs revealed large bone defect in the distal metaphysis of the comminuted tibia. The comminuted distal tibia was reconstructed by external fixation and internal fixation with bridge plating, followed by the Masquelet technique. After 12 months, the fracture healed without infection, and the patient could walk independently. CONCLUSION: In the case of a comminuted fracture of the contaminated distal tibia with a large bone defect, plate fixation and the Masquelet technique produced good outcomes.

Progressive medial temporal degeneration with TDP-43 pathology is associated with upper limb and bulbar onset types of amyotrophic lateral sclerosis.

OBJECTIVE: This study aimed to clarify the relationship between progressive medial temporal atrophy and onset subtype in patients with amyotrophic lateral sclerosis (ALS). METHODS: Medial temporal atrophy, ALS functional rating scale (ALSFRS), and cognitive function were assessed in 119 patients who were grouped into three ALS subtypes: bulbar, upper limb, and lower limb onset. Medial temporal atrophy, represented by a Z-score, was determined using an analysis software of magnetic resonance images known as the voxel-based specific regional analysis system for Alzheimer's disease (VSRAD). Among 119 patients, 60 underwent follow-up VSRAD, ALSFRS, and cognitive testing. The sequential data were compared among onset subtypes. Furthermore, TDP-43 pathology was assessed in 20 autopsied patients (including seven who underwent VSRAD before death) to examine the relationships among medial temporal atrophy, onset subtypes, and severity of the hippocampal TDP-43 pathology. RESULTS: Multiple regression analysis revealed that the Z-score at baseline was associated with the age of onset and duration of illness. A high Z-score at baseline and the bulbar/upper limb subtypes affected the progression rate of Z-score. Pathological examination revealed increased hippocampal TDP-43 pathology score associated with bulbar and upper limb subtypes. Moreover, the Z-score before death correlated with the hippocampal TDP-43 pathology score. CONCLUSION: Medial temporal atrophy in ALS is associated with bulbar and upper limb onset subtypes. This progression may be related to the extent of TDP-43 pathology.

Over-the-Air Testing of a Massive MIMO Antenna with a Full-Rank Channel Matrix.

This paper presents an over-the-air testing method in which a full-rank channel matrix is created for a massive multiple-input multiple-output (MIMO) antenna system utilizing a fading emulator with a small number of scatterers. In the proposed method, in order to mimic a fading emulator with a large number of scatterers, the scatterers are virtually positioned by rotating the massive MIMO antenna. The performance of a 64-element quasi-half-wavelength dipole circular array antenna was evaluated using a two-dimensional fading emulator. The experimental results reveal that a large number of available eigenvalues are obtained from the channel response matrix, confirming that the proposed method, which utilizes a full-rank channel matrix, can be used to assess a massive MIMO antenna system.

A Method of Implementing a 4 × 4 Correlation Matrix for Evaluating the Uplink Channel Properties of MIMO Over-the-Air Apparatus.

This paper presents a method of implementing a 4 × 4 correlation matrix for evaluating the uplink channel properties of multiple-input multiple-output (MIMO) antennas using an over-the-air measurement system. First, the implementation model used to determine the correlation coefficients between the signals received at the base station (BS) antennas via the uplink channel is described. Then, a methodology is introduced to achieve a 4 × 4 correlation matrix for a BS MIMO antenna based on Jakes' model by setting the initial phases of the secondary wave sources in the two-dimensional channel model. The performance of the uplink channel for a four-element MIMO terminal array antenna is evaluated using a two-dimensional bidirectional fading emulator. The results show that the measured correlation coefficients between the signals received via the uplink channel at the BS antennas using the proposed method are in good agreement with the BS correlation characteristics calculated using Monte Carlo simulation and the theoretical formula, thereby confirming the effectiveness of the proposed method.

Coexistence of neuronal intranuclear inclusion disease and amyotrophic lateral sclerosis: an autopsy case.

BACKGROUND: Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease. Pathologically, it is characterized by eosinophilic hyaline intranuclear inclusions in the cells of the visceral organs as well as central, peripheral, and autonomic nervous system cells. Recently, a GGC repeat expansion in the NOTCH2NLC gene has been identified as the etiopathological agent of NIID. Interestingly, this GGC repeat expansion was also reported in some patients with a clinical diagnosis of amyotrophic lateral sclerosis (ALS). However, there are no autopsy-confirmed cases of concurrent NIID and ALS. CASE PRESENTATION: A 60-year-old Taiwanese woman reported a four-month history of progressive weakness beginning in the right foot that spread to all four extremities. She was diagnosed with ALS because she met the revised El Escorial diagnostic criteria for definite ALS with upper and lower motor neuron involvement in the cervical, thoracic, and lumbosacral regions. She died of respiratory failure at 22 months from ALS onset, at the age of 62 years. Brain magnetic resonance imaging (MRI) revealed lesions in the medial part of the cerebellar hemisphere, right beside the vermis (paravermal lesions). The subclinical neuropathy, indicated by a nerve conduction study (NCS), prompted a potential diagnosis of NIID. Antemortem skin biopsy and autopsy confirmed the coexistence of pathology consistent with both ALS and NIID. We observed neither eccentric distribution of p62-positive intranuclear inclusions in the areas with abundant large motor neurons nor cytopathological coexistence of ALS and NIID pathology in motor neurons. This finding suggested that ALS and NIID developed independently in this patient. CONCLUSIONS: We describe a case of concurrent NIID and ALS discovered during an autopsy. Abnormal brain MRI findings, including paravermal lesions, could indicate the coexistence of NIID even in patients with ALS showing characteristic clinical phenotypes.

Full-Azimuth Beam Steering MIMO Antenna Arranged in a Daisy Chain Array Structure.

This paper presents a multiple-input, multiple-output (MIMO) antenna system with the ability to perform full-azimuth beam steering, and with the aim of realizing greater than 20 Gbps vehicular communications. The MIMO antenna described in this paper comprises 64 elements arranged in a daisy chain array structure, where 32 subarrays are formed by pairing elements in each subarray; the antenna yields 32 independent subchannels for MIMO transmission, and covers all communication targets regardless of their position relative to the array. Analytical results reveal that the proposed antenna system can provide a channel capacity of more than 200 bits/s/Hz at a signal-to-noise power ratio (SNR) of 30 dB over the whole azimuth, which is equivalent to 20 Gbps for a bandwidth of 100 MHz. This remarkably high channel capacity is shown to be due to two significant factors; the improved directivity created by the optimum in-phase excitation and the low correlation between the subarrays due to the orthogonal alignment of the array with respect to the incident waves. Over-the-air (OTA) experiments confirm the increase in channel capacity; the proposed antenna can maintain a constant transmission rate over all azimuth angles.

Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy.

BACKGROUND: An impairment of amyloid-ß (Aß) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. OBJECTIVE: This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). METHODS: Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. RESULTS: Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. CONCLUSION: In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA.

IL-6 and soluble IL-6 receptor stimulate the production of MMPs and their inhibitors via JAK-STAT and ERK-MAPK signalling in human chondrocytes.

Elevated concentrations of IL-6 (interleukin-6) and sIL-6r (soluble IL-6 receptor) in the synovial fluid and serum of patients with arthritis have been implicated in joint cartilage destruction. This study examined the effects of IL-6 and sIL-6r on the expression of MMPs (matrix metalloproteinases), TIMPs (tissue inhibitor of metalloproteinases), the plasminogen activation system including tPA (tissue-type PA), uPA (urokinase-type PA) and PAI-1 (PA inhibitor type 1) using chondrocytes derived from normal human femur cartilage. The cells were cultured with or without 50 ng/ml IL-6 and/or 30 ng/ml sIL-6r in the presence or absence of the JAK3 (Janus kinase 3) inhibitor WHI-P131 or the MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular signal protein kinase) kinase] inhibitor PD98059 for up to 28 days. The expression of MMPs, TIMPs, uPA, tPA and PAI-1 was investigated at the mRNA and protein levels. MMP protein expression and pSTAT3 (phosphorylation of signal transducer and activator of transcription 3) and pERK (phosphorylation of ERK) were also measured. Treatment with both IL-6 and sIL-6r markedly increased the expression of MMP-1, MMP-13, TIMP-1 and PAI-1, while significantly decreasing the expression of tPA and uPA and stimulating pSTAT3 and pERK. Adding WHI-P131 or PD98059 decreased IL-6 and sIL-6r enhancement of MMP-1, -3 and -13. The results suggest that IL-6 and sIL-6r stimulate the production of MMPs and their inhibitor via JAK-STAT and ERK-MAPK signalling in chondrocytes.

Interleukin-17F affects cartilage matrix turnover by increasing the expression of collagenases and stromelysin-1 and by decreasing the expression of their inhibitors and extracellular matrix components in chondrocytes.

Interleukin (IL)-17, a proinflammatory cytokine, is produced primarily by activated Th17 cells. IL-17 consists of six ligands that signal through five receptors (IL-17Rs); IL-17A and IL-17F share the highest homology in the family. Matrix metalloproteinases (MMPs) degrade the extracellular matrix during cartilage remodeling whereas tissue inhibitor of metalloproteinases (TIMPs) inhibit the action of MMPs. In the present study, we examined the effect of IL-17F on the degradation and synthesis of the extracellular matrix in cartilage using human articular chondrocytes. We examined the effect of IL-17F on the expression of IL-17Rs, MMPs, TIMPs, type II collagen, aggrecan, link protein, and cyclooxygenases (COXs), as well as on prostaglandin E2 (PGE2) production. We also examined the indirect effect of PGE2 on the above IL-17F-induced/reduced components using NS-398, a specific inhibitor of COX-2. Cells were cultured with or without IL-17F in the presence or absence of either an IL-17R antibody or NS-398 for up to 28 days. Expression of IL-17Rs, MMPs, TIMPs, type II collagen, aggrecan, link protein, and COXs at mRNA and protein levels was determined using real-time polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA), respectively. PGE2 production was determined by ELISA. The expression of all types of IL-17Rs was detected in chondrocytes. However, IL-17RE expression was extremely low, compared with other IL-17Rs. The expression of MMP-1, MMP-3, MMP-13, and COX-2 as well as PGE2 production were increased by addition of IL-17F, whereas the expression of IL-17RD, TIMP-2, TIMP-4, type II collagen, aggrecan, link protein, and COX-1 was decreased. The expression of IL-17RA, IL-17RB, IL-17RC, MMP-2, MMP-14, TIMP-1, and TIMP-3 was unaffected by addition of IL-17F. The IL-17R antibody blocked the stimulating/reducing effect of IL-17F on the expression of MMP-1, MMP-3, MMP-13, TIMP-2, TIMP-4, type II collagen, aggrecan, and link protein. NS-398 blocked the reducing effect of IL-17F on aggrecan expression, whereas it did not completely block the stimulating/reducing effects of IL-17F on the expression of MMP-1, MMP-3, MMP-13, TIMP-2, TIMP-4, type II collagen, and link protein. Our results suggest that IL-17F stimulates cartilage degradation by increasing the expression of collagenases (MMP-1 and -13) and stromelysin-1 (MMP-3) and by decreasing expression of their inhibitors (TIMP-2 and -4), type II collagen, aggrecan, and link protein in chondrocytes. Furthermore, our results suggest that the expression of aggrecan, link protein, and TIMP-4 decrease through the autocrine action of PGE2 in chondrocytes.

Interleukin-6 and soluble interleukin-6 receptor suppress osteoclastic differentiation by inducing PGE(2) production in chondrocytes.

This study examined how interleukin-6 (IL-6) and soluble IL-6 receptor (sIL-6r) influence osteoclastic differentiation through the function of chondrocytes. Chondrocytes were cultured with or without IL-6 and/or sIL-6r in the presence or absence of NS398, a specific inhibitor of cyclooxygenase (COX)-2, for up to 28 days. Chondrocytes were also cultured with or without IL-6 and sIL-6r for 28 days, and the conditioned medium from cells cultured without IL-6 and sIL-6r was used to induce differentiation of RAW264.7 cells into osteoclast precursors. Osteoclastic differentiation was assessed by tartrate-resistant acid phosphatase (TRAP) staining. Expression of osteoprotegerin (OPG), receptor activator of NF-κB ligand (RANKL), COX-2, and prostaglandin E(2) (PGE(2)) increased in cells exposed to IL-6 and sIL-6r, whereas expression of macrophage colony-stimulating factor (M-CSF) and bone resorption-related enzymes decreased. NS398 blocked the stimulatory/suppressive effects of IL-6 and sIL-6r on the expression of OPG, RANKL, and M-CSF. Fewer TRAP-positive multinucleated cells were detected after treatment with conditioned medium from IL-6- and sIL-6r-treated chondrocytes than after treatment with conditioned medium from untreated chondrocytes. These results suggest that IL-6 and sIL-6r interfere with osteoclast function through the involvement of chondrocytes. Specifically, they appear to suppress the differentiation of osteoclast precursors into osteoclasts by inducing chondrocytic PGE(2) production, which, in turn, increases OPG secretion and decreases M-CSF secretion by chondrocytes.

IL-1beta stimulates the expression of prostaglandin receptor EP4 in human chondrocytes by increasing production of prostaglandin E2.

Prostaglandin (PG) E(2), which exerts its actions via the PG receptors EP1-4, is produced from arachidonic acid by cyclooxygenase (COX)-1 and COX-2. The aim of this study was to investigate the mechanisms by which interleukin (IL)-1beta induces the expression of PG receptors in cultured human chondrocytes and to explore the role of PGE(2) in this process. The cells were cultured with 0, 10, or 100 U/mL IL-1beta with or without 1 muM celecoxib, a specific inhibitor of COX-2, for up to 28 days. Expression of the genes encoding COX-1, COX-2, and EP1-4 was quantified using real-time PCR, and expression of the corresponding proteins was examined using immunohistochemical staining. PGE(2) production was determined using ELISA. IL-1beta treatment caused a marked dose- and time-dependent increase in the levels of PGE(2), COX-2, and EP4 as compared with the untreated control. It did not affect the expression of COX-1, and it decreased the expression of EP1 and EP2. EP3 expression was not detected in either the absence or the presence of IL-1beta. When celecoxib was also present, IL-1beta failed to stimulate PGE(2) production and EP4 expression, but its stimulatory effect on COX-2 expression and its inhibitory effect on EP1 and EP2 expression were unchanged. IL-1beta increases the production of PGE(2), COX-2, and the PG receptor EP4 in cultured human chondrocytes. The increase in EP4 expression appears to be a result of the increased PGE(2) production.

IL-1beta suppresses the formation of osteoclasts by increasing OPG production via an autocrine mechanism involving celecoxib-related prostaglandins in chondrocytes.

Elevated interleukin (IL)-1 concentrations in synovial fluid have been implicated in joint bone and cartilage destruction. Previously, we showed that IL-1beta stimulated the expression of prostaglandin (PG) receptor EP4 via increased PGE(2) production. However, the effect of IL-1beta on osteoclast formation via chondrocytes is unclear. Therefore, we examined the effect of IL-1beta and/or celecoxib on the expression of macrophage colony-stimulating factor (M-CSF), receptor activator of NF-kappaB ligand (RANKL), and osteoprotegerin (OPG) in human chondrocytes, and the indirect effect of IL-1beta on osteoclast-like cell formation using RAW264.7 cells. OPG and RANKL expression increased with IL-1beta; whereas M-CSF expression decreased. Celecoxib blocked the stimulatory effect of IL-1beta. Conditioned medium from IL-1beta-treated chondrocytes decreased TRAP staining in RAW264.7 cells. These results suggest that IL-1beta suppresses the formation of osteoclast-like cells via increased OPG production and decreased M-CSF production in chondrocytes, and OPG production may increase through an autocrine mechanism involving celecoxib-related PGs.

A case of anti-aquaporin-4 and anti-glutamate receptor antibodies positive myelitis presented with modest clinical signs.

We present a case of anti-aquaporin-4 antibody-positive myelitis, which suggests the high-risk syndrome of neuromyelitis optica, whose modest clinical signs were in conspicuous contrast to the extensive spinal cord lesions demonstrated on magnetic resonance (MR) imaging. Follow-up MR imaging showed marked improvement of lesions. Interestingly, an anti-glutamate receptor antibody, which has been suggested to cause dysfunction of N-methy-D-aspartate receptor on neuron, was detected in the cerebrospinal fluid of the patient. We discuss the case and related literature.

Vascular oxidative stress in Alzheimer disease.

Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.

Oxidative damage to RNA in neurodegenerative diseases.

Since 1999, oxidative damage to RNA molecules has been described in several neurological diseases including Alzheimer's disease, Parkinson's disease, Down syndrome, dementia with Lewy bodies, prion disease, subacute sclerosing panencephalitis, and xeroderma pigmentosum. An early involvement of RNA oxidation of vulnerable neuronal population in the neurodegenerative diseases has been demonstrated, which is strongly supported by a recent observation of increased RNA oxidation in brains of subjects with mild cognitive impairment. Until recently, little is known about consequences and cellular handling of the RNA damage. However, increasing body of evidence suggests detrimental effects of the RNA damage in protein synthesis and the existence of several coping mechanisms including direct repair and avoiding the incorporation of the damaged ribonucleotides into translational machinery. Further investigations toward understanding of the consequences and cellular handling mechanisms of the oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies of the neurodegenerative diseases.

Compensatory responses induced by oxidative stress in Alzheimer disease.

Oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the pathologic hallmarks, neurofibrillary tangles and senile plaques. In the first stage of development of the disease, amyloid-beta deposition and hyperphosphorylated tau function as compensatory responses and downstream adaptations to ensure that neuronal cells do not succumb to oxidative damage. These findings suggest that Alzheimer disease is associated with a novel balance in oxidant homeostasis.