Treatment patterns and characteristics of patients with migraine: results from a retrospective database study in Japan.

BACKGROUND: Clinical characteristics and treatment practice of patients with migraine in Japan in real-world setting have not been fully investigated. We conducted a retrospective cohort study using claims database to understand the clinical practice of migraine in recent years and to characterize patients potentially not managed well by current treatment options. METHODS: Our study used data from the large claims database maintained by JMDC Inc. Patients with diagnosis of headache or migraine between January 1, 2018, and July 31, 2022, were defined as the headache cohort, and those with migraine diagnosis and prescription of migraine treatments among the headache cohort were included in the migraine cohort. In the headache cohort, characteristics of medical facilities and status of imaging tests to distinguish secondary headache were examined. Treatment patterns and characteristics of patients potentially not managed well by acute/preventive treatment were described in migraine cohort. RESULTS: In the headache cohort, 989,514 patients were included with 57.0% females and mean age of 40.3 years; 77.0% patients visited clinics (with ≤ 19 bed capacities) for their primary diagnosis, and 30.3% patients underwent imaging tests (computed tomography and/or magnetic resonance imaging). In the migraine cohort, 165,339 patients were included with 65.0% females and mean age of 38.8 years. In the migraine cohort, 95.6% received acute treatment while 20.8% received preventive treatment. Acetaminophen/non-steroidal anti-inflammatory drugs were most common (54.8%) as the initial prescription for migraine treatment followed by triptan (51.4%). First treatment prescription included preventive treatment in 15.6%, while the proportion increased to 82.2% in the fourth treatment prescription. Among patients with more than 12 months of follow-up, 3.7% had prescription patterns suggestive of risk of medication-overuse headache, and these patients were characterized by a higher percentage of females and a higher prevalence of comorbidities. CONCLUSIONS: This study revealed that approximately one-fifth of the patients with migraine visiting medical facilities use preventive drugs. The presence of potential patients at risk of medication-overuse headache and the role of clinics in migraine treatment were also described.

Role of complement components in vasculitic neuropathy associated with systemic lupus erythematosus and rheumatoid arthritis.

INTRODUCTION/AIMS: The mechanism of complement-mediated neurological injury in vasculitic neuropathy associated with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is unknown. The current study aimed to investigate the local activation of the complement system in vasculitic neuropathy associated with SLE and RA. METHODS: We analyzed sural nerve biopsy specimens collected from patients with SLE (n = 12) and RA (n = 12). The deposition of complement components comprising the classical and lectin pathways was assessed via immunohistochemistry. RESULTS: The disease duration was longer in the RA group than in the SLE group (median [interquartile range]: 11.5 [5.5-31.0] and 4 [2-10] y, respectively). Complement components were found in the epineurial blood vessel walls in patients with SLE and RA, but not in controls. Deposition of the classical pathway component C1q in the blood vessel wall was more commonly observed in the SLE group (71.3% [25.6-85.8]) than in the RA group (20.1% [10.5-35.6]). As for the lectin pathway component, the incidence of ficolin-3 deposition in the blood vessel wall was higher in the SLE group (42.3% [25.7-51.3]) than in the RA group (17.2% [10.3-26.8]). On the contrary, the mannose-binding lectin level was higher in the RA group (37.5% [21.7-51.4]) than in the SLE group (17.8% [11.4-31.0]). DISCUSSION: The classical and lectin pathways of the complement system may be involved in vasculitic neuropathy associated with SLE and RA.

Early ultrastructural lesions of anti-neutrophil cytoplasmic antibody- versus complement-associated vasculitis.

This study aims to describe electron microscopic findings of vasculitis associated with anti-neutrophil cytoplasmic antibody (ANCA) and complement. Sural nerve biopsy specimens were obtained from 10 patients with microscopic polyangiitis (MPA), a representative ANCA-associated vasculitis, and six patients with nonsystemic vasculitic neuropathy (NSVN), who were negative for ANCA but positive for complement deposition. In patients with MPA, attachment of neutrophils to epineurial vascular endothelial cells, migration of neutrophils to the extravascular space via the penetration of the endothelial layer, and release of neutrophil components to the extracellular space were observed. Such neutrophil-associated lesions were not observed in patients with NSVN. Nonetheless, morphological changes in epineurial vascular endothelial cells, such as increases in cytoplasmic organelles and cytoplasmic protrusions into the vascular lumen, were observed in patients with NSVN. Since these findings were observed where light microscopy-based findings suggestive of vasculitis (e.g., the disruption of vascular structures and fibrinoid necrosis) were absent, they were considered early lesions that preceded the formation of the so-called necrotizing vasculitis. In conclusion, this study enabled the visualization of distinctive early ultrastructural lesions associated with ANCA and complement. Further studies are needed to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of vasculitis.

In vivo visualization of eosinophil secretion in eosinophilic granulomatosis with polyangiitis: An ultrastructural study.

BACKGROUND: Although eosinophilic granulomatosis with polyangiitis (EGPA) has been considered as a single disease entity belonging to anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, several studies have suggested that in addition to the mechanisms associated with ANCA, those associated with eosinophils play a vital role in tissue damage. Nevertheless, the morphological bases underlying eosinophil-associated lesions have not been completely elucidated. METHODS: We investigated the electron microscopic findings of sural nerve biopsy specimens obtained from 18 patients with EGPA by focusing on the behavior of eosinophils, particularly the mode of secretion. RESULTS: Eosinophils tended to be located at sites close to endothelial cells within the lumina of epineurial small vessels. Attachment of eosinophils to endothelial cells was observed, particularly at the junction between neighboring endothelial cells, and some of these eosinophils appeared to escape from the vascular lumen to migrate into the extravascular interstitium. Furthermore, we observed eosinophil degranulation via piecemeal degranulation and cytolysis. Degranulating eosinophils were identified in both intravascular and extravascular compartments. Some of the small vessels appeared to be occluded by numerous eosinophils, and eosinophils attached by platelets were also observed, suggesting that coagulopathy occurs in EGPA. CONCLUSIONS: Both extravascular and intravascular eosinophils can induce tissue damage unrelated to classical necrotizing vasculitis associated with ANCA in patients with EGPA. Further research is necessary to elucidate the molecular basis of the induction of these fine structural changes, which will contribute to the development of targeted therapies based on specific mechanisms of eosinophil-related diseases.

Frictional Forces of Three Types of Lingual Appliance with Self-ligating Mechanisms.

AIM AND OBJECTIVE: The present study compared the frictional forces of three types of self-ligating lingual appliances. MATERIALS AND METHODS: The lingual appliances (2D, Forestadent; Alias, Ormco; and Clippy L, Tomy International) consisted of a self-ligating bracket (second premolar) and two self-ligating tubes (first and second molars) bonded to a stainless steel jig and attached to a "drawing-friction tester." Full-size and non-full-size stainless steel archwires were tested, and the static and kinetic friction acting on six lingual appliance/wire combinations was estimated (n = 5). Three-dimensional micro-computed tomography (micro-CT) analysis of each premolar bracket was performed. The frictional forces were compared between the bracket/wire combinations using the Kruskal-Wallis and Mann-Whitney U tests. RESULTS: The Alias and Clippy L bracket/wire combinations had greater contact between the wire surfaces and bracket slots compared to the 2D bracket/wire combination. For all lingual appliances, the static and kinetic frictional forces were significantly higher for the full-size than non-full-size archwire. The 2D bracket, which had a wider outer wing, had less frictional force than the other appliances. The Alias, which had a narrower outer wing, had a significantly lower frictional force than the Clippy L. CONCLUSIONS: Frictional force was significantly higher for heavier full-size bracket/archwire combinations than for non-full-size archwires. The 2D bracket had lower frictional force due to its archwire-holding mechanism. The outer wing width may influence the frictional resistance. CLINICAL SIGNIFICANCE: The frictional forces of self-ligating lingual appliances vary, and bracket design and archwire size may influence the frictional performance.

Esthetics of Orthodontic Appliances: Objective Evaluation by Spectrophotometry vs Subjective Evaluation Using the Visual Analog Scale Method.

AIM AND OBJECTIVE: In this study, we quantified the color of brackets and archwire appliances for an objective evaluation and investigated its relationship with subjective esthetic evaluation. MATERIALS AND METHODS: Five types of commercially available brackets (ceramic brackets C1, C2, and C3; plastic brackets P1 and P2) and three types of archwires (coated nickel-titanium archwires W1, W2, and W3) were used. The reflectance (%) and color (lightness: L*, hue: a*, b*) of each sample were quantified using a spectrophotometer (n = 5). Fifteen combinations of brackets and archwires were used. The esthetic evaluation was performed using the visual analog scale (VAS) method, and responses were obtained from 30 laypersons and 15 orthodontists. The mean VAS score was calculated, and the relationship between the reflectance and color of the bracket and archwire was discussed. RESULTS: The reflectance and L* of the brackets showed significantly higher values for C3 and C1 than for the others and lower values for P1 and P2. The reflectance and L* of the archwire showed significant differences among all samples. There was a high positive correlation between the reflectance and L*. There were statistically significant positive correlations between the layperson and orthodontist groups, between the VAS score and reflectivity, and between VAS score and L*. CONCLUSION: Our results showed that as the lightness and reflectance of the brackets and archwires increased, the subjective evaluation concerning their esthetic value was higher. CLINICAL SIGNIFICANCE: It is extremely difficult to evaluate esthetics despite the fact that patients' demands for esthetics have been increasing in recent years. If a method for evaluating esthetics is established, it should help in the development and selection of esthetic devices. The results of this study will facilitate the development of future study designs.

Ultrastructural mechanisms of macrophage-induced demyelination in Guillain-Barré syndrome.

OBJECTIVE: To describe the pathological features of Guillain-Barré syndrome focusing on macrophage-associated myelin lesions. METHODS: Longitudinal sections of sural nerve biopsy specimens from 11 patients with acute inflammatory demyelinating polyneuropathy (AIDP) exhibiting macrophage-associated demyelinating lesions were examined using electron microscopy. A total of 1205 nodes of Ranvier were examined to determine the relationship of the macrophage-associated demyelinating lesions with the nodal regions. Additionally, immunohistochemical and immunofluorescent studies were performed to elucidate the sites of complement deposition. RESULTS: Overall, 252 macrophage-associated myelin lesions were identified in longitudinal sections. Of these, 40 lesions exhibited complete demyelination with no association with the lamellar structures of myelin. In 183 lesions, macrophage cytoplasm was located at internodes without association with the nodes of Ranvier or paranodes. In particular, these internodal lesions were more frequent in one patient (152 lesions). In the remaining 29 lesions, the involvement of nodal regions was obvious. Lesions involving nodal regions were more frequently observed than those involving internodes in four patients. Invasion of the macrophage cytoplasmic processes into the space between the paranodal myelin terminal loops and the axolemma from the nodes of Ranvier was observed in three of these patients. Immunostaining suggested complement deposition corresponding to putative initial macrophage-associated demyelinating lesions. CONCLUSIONS: The initial macrophage-associated demyelinating lesions appeared to be located at internodes and at nodal regions. The sites at which the macrophages initiated phagocytosis of myelin might be associated with the location of complement deposition in certain patients with AIDP.

Clinicopathological characteristics of subtypes of chronic inflammatory demyelinating polyradiculoneuropathy.

OBJECTIVE: To evaluate the clinical and pathological correlations characterising each clinical subtype of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). METHODS: We assessed 106 consecutive patients who had CIDP fulfilling the European Federation of Neurological Societies and Peripheral Nerve Society criteria and had been referred for sural nerve biopsy. Patients with anti-neurofascin 155, anti-contactin 1 and anti-LM1 antibodies were excluded. RESULTS: 55 patients were classified as having typical CIDP. Regarding atypical CIDP, the multifocal acquired demyelinating sensory and motor (MADSAM) (n=15), distal acquired demyelinating symmetric (DADS) (n=16) and pure sensory (n=15) forms were major subtypes, while the pure motor (n=4) and focal (n=1) forms were rare. Nerve conduction studies revealed that distal motor latencies and F-wave latencies were markedly prolonged in the typical CIDP group but relatively preserved in the MADSAM group. Motor conduction velocity was conspicuously slowed in the DADS group, and distal motor latencies were markedly prolonged in the pure sensory group. Sural nerve biopsy specimens from patients with MADSAM, DADS and pure sensory type tended to show extreme variation in myelinated fibre density among fascicles due to focal myelinated fibre loss or onion-bulb formation, whereas patients with typical CIDP tended to show mild fascicular variation. Epineurial lymphocytic infiltration was conspicuous in cases with marked fascicular variation in myelinated fibre density. CONCLUSIONS: Preferential involvement of distal and proximal segments and uniform pathological features in typical CIDP indicate a role of humoral factors at sites where the blood-nerve barrier is deficient. By contrast, focal lesions in MADSAM, DADS and pure sensory forms may share neuropathic mechanisms primarily affecting the nerve trunk.

Intravenous immunoglobulin for maintenance treatment of multifocal motor neuropathy: A multi-center, open-label, 52-week phase 3 trial.

Intravenous immunoglobulin (IVIg) therapy is currently the only established treatment in patients with multifocal motor neuropathy (MMN), and many patients have an IVIg-dependent fluctuation. We aimed to investigate the efficacy and safety of every 3 week IVIg (1.0 g/kg) for 52 weeks. This study was an open-label phase 3 clinical trial, enrolling 13 MMN patients. After an induction IVIg therapy (0.4 g/kg/d for 5 consecutive days), maintenance dose (1.0 g/kg) was given every 3 weeks for 52 weeks. The major outcome measures were the Medical Research Council (MRC) sum score and hand-grip strength at week 52. This trial is registered with ClinicalTrials.gov, number NCT01827072. At week 52, 11 of the 13 patients completed the study, and all 11 had a sustained improvement. The mean (SD) MRC sum score was 85.6 (8.7) at the baseline, and 90.6 (12.8) at week 52. The mean grip strength was 39.2 (30.0) kPa at the baseline and 45.2 (32.8) kPa at week 52. Two patients dropped out because of adverse event (dysphagia) and decision of an investigator, respectively. Three patients developed coronary spasm, dysphagia, or inguinal herniation, reported as the serious adverse events, but considered not related with the study drug. The other adverse effects were mild and resolved by the end of the study period. Our results show that maintenance treatment with 1.0 g/kg IVIg every 3 week is safe and efficacious for MMN patients up to 52 weeks. Further studies are required to investigate optimal dose and duration of maintenance IVIg for MMN.

Paranodal dissection in chronic inflammatory demyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 antibodies.

OBJECTIVE: To investigate the morphological features of chronic inflammatory demyelinating polyneuropathy (CIDP) with autoantibodies directed against paranodal junctional molecules, particularly focusing on the fine structures of the paranodes. METHODS: We assessed sural nerve biopsy specimens obtained from 9 patients with CIDP with anti-neurofascin-155 antibodies and 1 patient with anti-contactin-1 antibodies. 13 patients with CIDP without these antibodies were also examined to compare pathological findings. RESULTS: Characteristic light and electron microscopy findings in transverse sections from patients with anti-neurofascin-155 and anti-contactin-1 antibodies indicated a slight reduction in myelinated fibre density, with scattered myelin ovoids, and the absence of macrophage-mediated demyelination or onion bulbs. Teased-fibre preparations revealed that segmental demyelination tended to be found in patients with relatively higher frequencies of axonal degeneration and was tandemly found at consecutive nodes of Ranvier in a single fibre. Assessment of longitudinal sections by electron microscopy revealed that detachment of terminal myelin loops from the axolemma was frequently found at the paranode in patients with anti-neurofascin-155 and anti-contactin-1 antibody-positive CIDP compared with patients with antibody-negative CIDP. Patients with anti-neurofascin-155 antibodies showed a positive correlation between the frequencies of axo-glial detachment at the paranode and axonal degeneration, as assessed by teased-fibre preparations (p<0.05). CONCLUSIONS: Paranodal dissection without classical macrophage-mediated demyelination is the characteristic feature of patients with CIDP with autoantibodies to paranodal axo-glial junctional molecules.

Transforming growth factor-ß signaling is upregulated in sporadic inclusion body myositis.

INTRODUCTION: In this study we aimed to determine whether transforming growth factor-ß (TGF-ß) signaling is dysregulated in sporadic inclusion body myositis (sIBM) muscle samples. METHODS: We examined TGF-ß signaling markers in muscle samples from 24 sIBM patients and compared them with those from 10 dermatomyositis (DM) patients using immunohistochemistry and Western blot analyses. RESULTS: Compared with the DM muscle fibers, the sIBM muscle fibers exhibited greater TGF-ß, TGF-ß receptor type I (TßRI), and TGF-ß receptor type II (TßRII) immunoreactivity in the cytoplasm, as well as greater phosphorylated Smad2 (pSmad2) immunoreactivity in the myonuclei. The signal intensities of TGF-ß, TßRI, and TßRII immunoreactivity correlated significantly with muscle fiber cross-sectional areas. Western blot analyses indicated higher expression levels of TGF-ß, TßRI, TßRII, and pSmad2 in the sIBM muscle samples than in the DM muscle samples. CONCLUSIONS: These data indicate that upregulation of TGF-ß signaling may be an important molecular event in sIBM. Muscle Nerve 55: 741-747, 2017.

Wear characteristics and inhibition of enamel demineralization by resin-based coating materials.

In this study, wear and inhibition of enamel demineralization by resin-based coating materials were investigated. Seven commercially available coating materials, with and without fillers, were used. A mechanical wear test was performed, and the specimens were then examined with a scanning electron microscope. Hardness and elastic modulus measurements for each material were obtained by nanoindentation testing. Thin layers of each material were applied on human enamel surfaces, which were subjected to alternating immersion in demineralizing and remineralizing solutions. The inhibition ability of enamel demineralization adjacent to the coating was estimated with depth-dependent mechanical properties using the nanoindentation test. The non-filled coating material showed significantly lower hardness, lower elastic modulus, and higher weight loss. There were no significant differences in weight loss among the six filled coating materials. After the alternating immersion protocol, the enamel specimens having application of coating materials with ion-releasing ability were harder than those in the other groups in some locations 1-11 µm from the enamel surface and within 300 µm from the edge of the coating materials. In conclusion, clinical use of the resin-based coating materials with ion-releasing ability may prevent demineralization of exposed enamel adjacent to the coating during treatment.

Inhibition of enamel demineralization and bond-strength properties of bioactive glass containing 4-META/MMA-TBB-based resin adhesive.

We investigated the enamel demineralization-prevention ability and shear bond strength (SBS) properties of 4-methacryloxyethyl trimellitic anhydride/methyl methacrylate-tri-n-butyl borane (4-META/MMA-TBB)-based resin containing various amounts (0-50%) of bioactive glass (BG). Disk-shaped specimens were immersed in distilled water and ions released were analysed by inductively coupled plasma atomic-emission spectroscopy. Samples were also immersed in lactic acid solution (pH 4.6) to estimate acid-neutralizing ability. Brackets were bonded to human premolars with BG-containing resins and the bonded teeth were alternately immersed in demineralizing (pH 4.55) and remineralizing (pH 6.8) solutions for 14 d. The enamel hardness was determined by nanoindentation testing at twenty equidistant distances from the external surface. The SBS for each sample was examined. The amounts of ions released [calcium (Ca), sodium (Na), silicon (Si), and boron (B)] and the acid-neutralizing ability increased with increasing BG content. After alternating immersion, the specimens bonded with the BG-containing resin with high BG content were harder than those in the other groups in some locations 1-18.5 µm from the enamel surface. Bioactive glass-containing (10-40%) resin had bond strength equivalent to the control specimen. Thus, the SBS obtained for BG-containing resin (6.5-9.2 MPa) was clinically acceptable, suggesting that this material has the ability to prevent enamel demineralization.

In vivo degradation of orthodontic miniscrew implants: surface analysis of as-received and retrieved specimens.

This study investigated in vivo degradation of Ti-6Al-4V alloy miniscrew implants. Miniscrew implants were placed in patients, and the surfaces were studied upon retrieval by scanning electron microscopy, microscale X-ray photoelectron spectroscopy, elastic recoil detection analysis and nanoindentation testing. Bone-like structures were formed on the retrieved specimens. The hardness and elastic modulus of the surfaces of the retrieved specimens were significantly lower than the as-received specimens, although no statistically significant differences were observed for the hardness and elastic modulus in the bulk region. Thick organic over-layer containing carbon, oxygen, and nitrogen, with the thickness greater than 50 nm, covered the retrieved specimens, and higher concentrations of hydrogen were detected in the retrieved specimens compared with the as-received specimens. Minimal degradation of the bulk mechanical properties of miniscrew implants was observed after clinical use, although precipitation of bone-like structures, formation of a carbonaceous contamination layer, and hydrogen absorption were observed on the surfaces of miniscrew implants.

Effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures.

BACKGROUND/OBJECTIVE: To investigate the effects of temperature changes and stress loading on the mechanical and shape memory properties of thermoplastic materials with different glass transition behaviours and crystal structures. MATERIALS/METHODS: Five thermoplastic materials, polyethylene terephthalate glycol (Duran®, Scheu Dental), polypropylene (Hardcast®, Scheu Dental), and polyurethane (SMP MM®, SMP Technologies) with three different glass transition temperatures (T g) were selected. The T g and crystal structure were assessed using differential scanning calorimetry and X-ray diffraction. The deterioration of mechanical properties by thermal cycling and the orthodontic forces during stepwise temperature changes were investigated using nanoindentation testing and custom-made force-measuring system. The mechanical properties were also evaluated by three-point bending tests; shape recovery with heating was then investigated. RESULTS: The mechanical properties for each material were decreased significantly by 2500 cycles and great decrease was observed for Hardcast (crystal plastic) with higher T g (155.5°C) and PU 1 (crystalline or semi-crystalline plastic) with lower T g (29.6°C). The Duran, PU 2, and PU 3 with intermediate T g (75.3°C for Duran, 56.5°C for PU 2, and 80.7°C for PU 3) showed relatively stable mechanical properties with thermal cycling. The polyurethane polymers showed perfect shape memory effect within the range of intraoral temperature changes. The orthodontic force produced by thermoplastic appliances decreased with the stepwise temperature change for all materials. CONCLUSIONS/IMPLICATIONS: Orthodontic forces delivered by thermoplastic appliances may influence by the T g of the materials, but not the crystal structure. Polyurethane is attractive thermoplastic materials due to their unique shape memory phenomenon, but stress relaxation with temperature changes is expected.

Schwann cell involvement in the peripheral neuropathy of spinocerebellar ataxia type 3.

AIMS: Spinocerebellar ataxia type 3 (SCA3) is an inherited spinocerebellar ataxia caused by the expansion of trinucleotide CAG repeats in the gene encoding ataxin-3. The clinical manifestations of SCA3 include peripheral neuropathy, which is an important cause of disability in a subset of patients. Although the loss of neurones in the dorsal root ganglion (DRG) has been postulated to be the cause of this neuropathy, the precise mechanism remains to be elucidated. METHODS: To clarify the clinicopathological characteristics of SCA3-associated peripheral neuropathy, we performed nerve conduction studies and histopathological analyses. Nerve conduction studies were carried out in 18 SCA3 patients. Immunohistochemical analyses of the anterior and posterior roots of the spinal cord and peripheral nerves were performed in five SCA3 patients. We also employed immunohistochemistry and immunoelectron microscopy analyses with an anti-polyglutamine antibody. RESULTS: The mean sensory nerve action potentials of the SCA3 patients were half of the normal values. The motor conduction velocities were decreased, and the distal latencies were also significantly prolonged in the nerves studied relative to the those in normal controls. Histopathological analyses detected axonal sprouting and myelin thinning in all cases. Ataxin-3 aggregates were found in the cytoplasm of Schwann cells in all of the SCA3 patients examined but not in control subjects. CONCLUSIONS: In addition to the previously reported neuronopathy, the results of the present study indicate that Schwann cells are involved in the formation of the pathogenic intracytoplasmic ataxin-3 protein aggregates in patients with SCA3-associated neuropathy.

Clinicopathological features of neuropathy associated with lymphoma.

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

Osteoblast differentiation of Gli1⁺ cells via Wnt and BMP signaling pathways during orthodontic tooth movement.

OBJECTIVES: Factors that induce bone formation during orthodontic tooth movement (OTM) remain unclear. Gli1 was recently identified as a stem cell marker in the periodontal ligament (PDL). Therefore, we evaluated the mechanism of differentiation of Cre/LoxP-mediated Gli1/Tomato+ cells into osteoblasts during OTM. METHODS: After the final administration of tamoxifen to 8-week-old Gli1-CreERT2/ROSA26-loxP-stop-loxP-tdTomato mice for 2 days, nickel-titanium closed coil springs were attached between the upper anterior alveolar bone and the first molar. Immunohistochemical localizations of ß-catenin, Smad4, and Runx2 were observed in the PDL on 2, 5, and 10 days after OTM initiation. RESULTS: In the untreated tooth, few Gli1/Tomato+ cells were detected in the PDL. Two days after OTM initiation, the number of Gli1/Tomato+ cells increased in the PDL on the tension side. On this side, 49.3 ± 7.0% of ß-catenin+ and 48.7 ± 5.7% of Smad4+ cells were found in the PDL, and Runx2 expression was detected in some Gli1/Tomato+ cells apart from the alveolar bone. The number of positive cells in the PDL reached a maximum on day 5. In contrast, on the compression side, ß-catenin and Smad4 exhibited less immunoreactivity. On day 10, Gli1/Tomato+ cells were aligned on the alveolar bone on the tension side, with some expressing Runx2. CONCLUSIONS: Gli1+ cells in the PDL differentiated into osteoblasts during OTM. Wnt and bone morphogenetic proteins signaling pathways may be involved in this differentiation.

Autoantibodies Against Dihydrolipoamide S-Acetyltransferase in Immune-Mediated Neuropathies.

BACKGROUND AND OBJECTIVES: This study aimed to identify disease-related autoantibodies in the serum of patients with immune-mediated neuropathies including chronic inflammatory demyelinating polyneuropathy (CIDP) and to investigate the clinical characteristics of patients with these antibodies. METHODS: Proteins extracted from mouse brain tissue were used to react with sera from patients with CIDP by western blotting (WB) to determine the presence of common bands. Positive bands were then identified by mass spectrometry and confirmed for reactivity with patient sera using enzyme-linked immunosorbent assay (ELISA) and WB. Reactivity was further confirmed by cell-based and tissue-based indirect immunofluorescence assays. The clinical characteristics of patients with candidate autoantibody-positive CIDP were analyzed, and their association with other neurologic diseases was also investigated. RESULTS: Screening of 78 CIDP patient sera by WB revealed a positive band around 60-70 kDa identified as dihydrolipoamide S-acetyltransferase (DLAT) by immunoprecipitation and mass spectrometry. Serum immunoglobulin G (IgG) and IgM antibodies' reactivity to recombinant DLAT was confirmed using ELISA and WB. A relatively high reactivity was observed in 29 of 160 (18%) patients with CIDP, followed by patients with sensory neuropathy (6/58, 10%) and patients with MS (2/47, 4%), but not in patients with Guillain-Barré syndrome (0/27), patients with hereditary neuropathy (0/40), and healthy controls (0/26). Both the cell-based and tissue-based assays confirmed reactivity in 26 of 33 patients with CIDP. Comparing the clinical characteristics of patients with CIDP with anti-DLAT antibodies (n = 29) with those of negative cases (n = 131), a higher percentage of patients had comorbid sensory ataxia (69% vs 37%), cranial nerve disorders (24% vs 9%), and malignancy (20% vs 5%). A high DLAT expression was observed in human autopsy dorsal root ganglia, confirming the reactivity of patient serum with mouse dorsal root ganglion cells. DISCUSSION: Reactivity to DLAT was confirmed in patient sera, mainly in patients with CIDP. DLAT is highly expressed in the dorsal root ganglion cells, and anti-DLAT antibody may serve as a biomarker for sensory-dominant neuropathies.