Role of innate immune sensors, TLRs, and NALP3 in rheumatoid arthritis and osteoarthritis.

Innate immune sensors, Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain-like receptors (NLRs) participate in the induction of innate inflammatory and adaptive immune responses in rheumatoid arthritis (RA) and osteoarthritis (OA). Danger signals, e.g., heat-shock proteins (HSPs) and high mobility group box-1 protein (HMGB-1), internal ligands of TLRs, have been reported in the patients with RA and OA. In RA, TLR1-9 have been implicated in the pathogenesis. Although the precise role of each receptor is still unknown, immunohistochemical analyses of RA tissues after treatment of biologic disease modifying antirheumatic drugs showed phenotypic changes of immune cell types and residual expression of some TLRs. This suggests the potential for modulation of moderate/severe local joint inflammation, composed in particular of and possibly driven by the "auto-inflammatory" TLR+ cells, still responding to internal ligands derived from destroyed tissues. In OA, systematic profiling of TLR using a histological grading system recently showed that TLR+ cells are greater in number in the surface zone of grades 3 and 4 OA, but interestingly not grade 5. NACHT, LRR, and PYD domains-containing protein (NALP) 3 and related molecules have been also demonstrated both in RA and OA. In addition, a cross talk mechanism of TLR and NALP responsible for increasing joint inflammation has been suggested. Taken together, although OA is not basically an inflammatory disease, and is different from that of RA, pattern recognition receptors-signaling pathways, TLRs and NALP3 may play a role in the pathogenesis of both these conditions, probably as driving forces of progression. Precise and intensive analyses of both receptors, signal pathways, and cross talk mechanisms may provide a new therapeutic approach as molecular targets.

The use of arthrography in the diagnosis of temporomandibular joint synovial chondromatosis.

Synovial chondromatosis (SC) involving the temporomandibular joint (TMJ) is very rare and can occur in either or both cavities. Differentiation of the affected cavity in SC is therefore as important as making the diagnosis. This report presents a case of SC in which both cavities were thought to be affected, but arthrography using cone beam CT (CBCT) allowed us to see that involvement was limited to the superior joint cavity. In addition, we describe the usefulness of arthrographic CBCT for diagnosis and treatment planning in SC of the TMJ.

A genome-wide scan for tying-up syndrome in Japanese Thoroughbreds.

Tying-up syndrome, also known as recurrent exertional rhabdomyolysis in Thoroughbreds, is a common muscle disorder for racehorses. In this study, we performed a multipoint linkage analysis using LOKI based on the Bayesian Markov chain Monte Carlo method using 5 half-sib families (51 affected and 277 nonaffected horses in total), and a genome-wide association study (GWAS) using microsatellites (144 affected and 144 nonaffected horses) to map candidate regions for tying-up syndrome in Japanese Thoroughbreds. The linkage analysis identified one strong L-score (82.45) between the loci UCDEQ411 and COR058 (24.9-27.9 Mb) on ECA12. The GWAS identified two suggestive genomic regions on ECA12 (24.9-27.8 Mb) and ECA20 (29.3-33.5 Mb). Based on both results, the genomic region between UCDEQ411 and TKY499 (24.9-27.8 Mb) on ECA12 was the most significant and was considered as a candidate region for tying-up syndrome in Japanese Thoroughbreds.

Estimation of heritability for superficial digital flexor tendon injury by Gibbs sampling in the Thoroughbred racehorse.

The superficial digital flexor tendon (SDFT) injury causes considerable wastage of racing Thoroughbreds. In this study, the heritability of SDFT injury of the forelimbs was estimated in the Thoroughbred racehorses based on the Bayesian analysis with Gibbs sampling using threshold animal models. New horse patients of SDFT injury at the age of 2-5 years accommodated in the training centers in 2005 were used for the analyses. Based on clinical data of 8198 horses, heritability of SDFT was estimated to be the order of 0.17 (posterior mode) to 0.19 +/- 0.05 (posterior mean +/- posterior SD).

Estimation of heritability and genetic correlation for behavioural responses by Gibbs sampling in the Thoroughbred racehorse.

Genetic variation of the behaviour of racehorses is one of the major concerns for racehorse breeders. In this study, the heritabilities of behavioural responses to the inspections of conjunctiva, auscultation and blood sampling and the genetic correlations among them were estimated in the Thoroughbred racehorse. The estimation was done with Bayesian analysis with Gibbs sampling based on the univariate or bivariate threshold animal models. The behavioural responses were scored with four categories at the first entrance quarantine in Miho Training Center of Japan Racing Association from 1993 to 1995. The behavioural responses were treated as categorical or binary traits, with both showing similar results. The estimated heritabilities were in the range of 0.23-0.28, suggesting a genetic component in the variation on these traits. The estimated genetic correlations among the traits were very high (approximately 0.9), suggesting that these behavioural responses may be measures of the same trait. Because of the high genetic correlations, repeatability threshold model was applied assuming the responses to be a genetically identical trait measured with three different tests. The estimated heritabilities (approximately 0.23) were at the lower bound of the former estimates. The revealed high repeatabilities (0.97-0.98) suggest a strong contribution of the individual temperament on the behaviour of racehorses.

Estimation of heritability for Tying-up syndrome in the Thoroughbred racehorse by Gibbs sampling.

Tying-up is a condition that primarily affects the muscles of horses. In this study, the heritability of the Tying-up syndrome in the Thoroughbred racehorse was estimated by Bayesian analysis with Gibbs sampling based on the threshold model for binary traits. The data used were the clinical data in racehorses diagnosed by veterinarians of the Racehorse Clinics of Japan Racing Association from 2000 to 2003. The health status of the Tying-up was treated as a binary trait. In the genetic analysis, the effect of changing the amount of the pedigree or inbreeding information on the estimation of heritability was investigated, too. The heritability estimates with non-zero probability in the posterior densities were approximately 0.16-0.18 in minimum, suggesting that the heritability of the Tying-up is not zero at least. The posterior density distributions of the heritability estimates were generally more pointed and sharp with using inbreeding coefficients than without using it, suggesting that more stable estimations were obtained when inbreeding coefficients were used. Among the different amounts of pedigree and inbreeding information, the heritabilities obtained with three or four generations of pedigree using inbreeding coefficients seems to be preferable, i.e. heritability of 0.42 or 0.43 for Tying-up.

Serial measurement of polyethylene wear of well-fixed cementless metal-backed acetabular component in total hip arthroplasty: an over 10 year follow-up study.

Serial radiographic measurements of polyethylene wear were performed in 38 hips (33 patients) with primary cementless total hip arthroplasty (THA). The average follow-up period was 131.8 months. All prostheses were assessed as radiographically stable at the latest follow-up. A two-dimensional method was used to calculate the relative migration of the femoral head center to the cup center. The average total linear wear and wear rate were 1.22 mm and 0.11 mm/year, respectively. The degree of wear in the first 2 postoperative years accounted for nearly 40% of the total wear at the end of the study (average follow up: 131.8 +/- 10.0 months, +/-SD). The migration of the femoral head at an average period of 3. 4 months after operation accounted for 56% of the amount of wear in the first 2 years. Wear rate decreased gradually with time and stabilized after the fourth year. However, in 2 patients, a progressive increase in the wear rate was associated with severe osteolysis and failure of THA. Both creep and wear contributed to the femoral penetration into the polyethylene liner. The influence of creep cannot be ruled out, especially in the early period after operation. Polyethylene wear is a multifactorial process, and the study of individual wear patterns might be useful in identifying patients who are at risk of late failure of THA.

Use of an instrument sandwiched between the hoof and shoe to measure vertical ground reaction forces and three-dimensional acceleration at the walk, trot, and canter in horses.

OBJECTIVE: To develop an instrument that could be sandwiched between the hoof and shoe of horses and that would reliably measure vertical ground reaction forces and three-dimensional acceleration at the walk, trot, and canter. ANIMALS: 5 clinically sound Thoroughbreds. PROCEDURES: The recording instrument (weight, 350 g) consisted of 2 metal plates, 2 bolts, 4 load cells, and 3 accelerometers. It was mounted to the hoof with a glue-on shoe and devised to support as much load exerted by a limb as possible. The load cells and accelerometers were wired to a 16-channel transmitter, and transmitted signals were received and amplified with a telemetry receiver. RESULTS: The recording instrument could measure in real time the 4 components of the ground reaction force or their resultant force along with acceleration in 3 dimensions as horses walked, trotted, or cantered on a treadmill. Patterns of force-time curves recorded for consecutive strides were similar to each other and to those previously reported, using a force plate. CONCLUSIONS AND CLINICAL RELEVANCE: The recording instrument developed for use in the present study allowed us to record vertical ground reaction force and acceleration in 3 dimensions in horses at the walk, trot, and canter.

Bone grafting in cementless total hip replacement for congenital dysplasia of the hip.

We reviewed 27 cementless primary total hip replacements in patients with osteoarthrosis secondary to congenital dysplasia of the hip. Autogenous bone grafting was used as augmentation. On average the follow-up period was 9 years. Two hips were revised and three acetabular components were considered loose. In hips with loose cups the average graft coverage was significantly greater than in stable hips. The use of a cementless acetabular component is encouraging for reconstruction, although extensive grafting should be avoided. Our study suggests that cementless reconstruction in dysplastic hips yields a satisfactory outcome.

Refined structure of orthorhombic lysozyme crystallized at high temperature: correlation between morphology and intermolecular contacts.

The structure of orthorhombic hen egg-white lysozyme (HEWL) crystallized at 310 K has been refined at 1.7 A resolution. Large displacements of the side-chain atoms with respect to the tetragonal structure were observed in many places, in contrast to small displacements of the main-chain atoms. A chloride-ion binding site was observed at an interface of two molecules, but at a different position to the binding site in the tetragonal form. The analysis of intermolecular contacts in the crystal has shown the presence of three independent intermolecular contacts which are called macrobonds A, B and C. Arginine side chains are frequently involved in these macrobonds, suggesting that the high frequency of this residue in HEWL may be a possible reason for the multiple polymorphs of this protein. The crystal forms were determined using a light-reflecting device on a four-circle diffractometer. Correlations between crystal forms and the three-dimensional macrobond networks were interpreted in terms of their components in various crystallographic planes, making use of approximate strengths of hydrogen-bond and van der Waals interatomic forces.

Influence of rough track surfaces on components of vertical forces in cantering thoroughbred horses.

No kinetic data are available to indicate the influence of a rough track surface and the resultant loss of footing on the components of hoof vertical forces. The aim of the present study was to evaluate the influence of rough track surfaces on the components of hoof vertical forces. Seven clinically sound 2-year-old Thoroughbred horses had instrumented shoes attached to both of the fore hooves to obtain the magnitudes of consecutive forces exerted in the hoof. All horses were cantered at approximately 10 m/s on straight tracks of smooth and rough surfaces of woodchip and dirt. The instrumented shoe indicated in real time 4 component forces acting on the hoof via 4 transducers positioned on the lateral and medial sides of the toe (LT, MT) and the heel (LH, MH). The peak vertical component forces of the heel were about twice that of the toe. The variances of the 4 components of peak vertical forces significantly increased on the rough track surface of both the woodchip (Leading: LH, MH and MT; Trailing: MH and LT) and dirt (Leading: LH and LT; Trailing: MH and MT) tracks. The trajectories of the position of the resultant force acting on the hoof also tended to increase the variance on rough track surfaces. Therefore, running on a rough track changes the vertical hoof forces and the balance of the resultant hoof forces. These results suggest a mechanism by which the rough track surfaces may influence the soundness of the horse.

EMG activity of the muscles of the neck and forelimbs during different forms of locomotion.

We recorded the electromyographic (EMG) activity of 7 skeletal muscles in the forequarters and 1 in the hindquarters of 6 Thoroughbred horses during overground walking, swimming in a circular pool, and walking and trotting in a water treadmill. Bipolar fine wire electrodes were inserted into the muscles and the EMG signals were recorded using a telemetric system. The splenius exhibited tonic EMG activity during swimming. The brachiocephalicus showed its highest intensity during swimming followed by the walk and trot in the water treadmill and then walking overground. The triceps brachii caput longum had a similar activity pattern to the brachiocephalicus. The brachialis showed only weak EMG activity in all 3 types of locomotion. The extensor digitorum communis had higher intensity of EMG activity in the walk in the water treadmill than in other kinds of locomotion. The flexor digitorum profundus exhibited the most intense EMG activity during swimming. These results indicated that swimming evoked strong EMG activity in the antigravity muscles in spite of reduced gravitational force. Walking in the water treadmill may require more intensified EMG activity of the forelimb than the trot in the same treadmill.

Crystal structure of methionine aminopeptidase from hyperthermophile, Pyrococcus furiosus.

The structure of methionine aminopeptidase from hyperthermophile Pyrococcus furiosus (PfMAP) with an optimal growth temperature of 100 degreesC was determined by the multiple isomorphous replacement method and refined in three different crystal forms, one monoclinic and two hexagonal, at resolutions of 2.8, 2.9, and 3.5 A. The resolution of the monoclinic crystal form was extended to 1.75 A by water-mediated transformation to a low-humidity form, and the obtained diffraction data used for high-resolution structure refinement. This is the first description of a eukaryotic type methionine aminopeptidase structure. The PfMAP molecule is composed of two domains, a catalytic domain and an insertion domain, connected via two antiparallel beta-strands. The catalytic domain, which possesses an internal 2-fold symmetry and contains two cobalt ions in the active site, resembles the structure of a prokaryotic type MAP from Escherichia coli (EcMAP), while the structure of the insertion domain containing three helices has a novel fold and accounts for a major difference between the eukaryotic and prokaryotic types of methionine aminopeptidase. Analysis of the PfMAP structure in comparison with EcMAP and other mesophile proteins reveals several factors which may contribute to the hyperthermostability of PfMAP: (1) a significantly high number of hydrogen bonds and ion-pairs between side-chains of oppositely charged residues involved in the stabilization of helices; (2) an increased number of hydrogen bonds between the positively charged side-chain and neutral oxygen; (3) a larger number of buried water molecules involved in crosslinking the backbone atoms of sequentially separate segments; (4) stabilization of two antiparallel beta-strands connecting the two domains of the molecule by proline residues; (5) shortening of N and C-terminal tails and stabilization of the loop c3E by deletion of three residues.

High-resolution crystals of methionine aminopeptidase from Pyrococcus furiosus obtained by water-mediated transformation.

The monoclinic crystal form of methionine amino-peptidase from Pyrococcus furiosus (MAP-Pfu) has been crystallized from four different conditions. Native crystals belong to space group P2(1) with typical unit-cell dimensions a = 53.4, b = 85.1, c = 72.7 A, beta = 107.7 degrees and diffract to 2.9-4.5 A resolution. However, there is a problem of nonisomorphism among the crystals. Water-mediated transformation to low-humidity form occurs by reduction of the relative humidity of crystal environment to 79%. The unit-cell dimensions of transformed crystals are a = 51.9, b = 83.3, c = 70.3 A, beta = 105.9 degrees, and the calculated solvent content is 3.9% less than in original crystals. Transformation to low-humidity form is accompanied by 1.7 times reduction of overall temperature factors, extension of diffraction resolution up to 1.75 A, without change or reduction of crystal mosaicity, and improvement in stability to X-ray radiation. The water-mediated transformation also appears to relieve the problem of nonisomorphism among the original MAP-Pfu crystals.

Pituitary stalk meningioma: case report.

We report a 45-year-old woman with a meningioma which was in contact with only the pituitary stalk on MRI. As the pituitary stalk has no dura mater, we suggest this tumour may have originated from the arachnoid membrane of the pituitary stalk. Though some reports have shown that meningiomas can arise from sites lacking a dural component, this is the first report of a meningioma originating from the pituitary stalk.

Estimation of genetic correlations between racing times recorded at different racing distances by restricted maximum likelihood in Thoroughbred racehorses.

SUMMARY: Genetic correlations between racing times on track type (turf and dirt), and at racing distances on turf (1200 m, 1400 m, 1600 m, 1800 m, and/or 2000 m) and dirt (1000 m, 1200 m, 1400 m, 1600 m, 1700 m, and/or 1800 m) tracks, were estimated in Thoroughbred horses. (Co)variance components were estimated using multiple-trait derivative-free restricted maximum likelihood (MTDFREML). The data used were collected by the Japan Racing Association from 1992 to 1993. The generation 2 pedigree information was preferable for (co)variance estimates. The genetic correlations between racing times on turf and dirt tracks ranged from 0.69 to 0.31 (average 0.51). The genetic correlations between racing distances ranged from 0.68 to 1.00 (average 0.85) and from 0.53 to 1.00 (average 0.88) on turf and dirt tracks, respectively. These results suggest that the racing time per 100 m can be used for horse genetic evaluation within one track type. ZUSAMMENFASSUNG: Schätzung genetischer Korrelationen zwischen Rennzeiten von Vollblüternüber verschiednen Distanzen mittels restringierter Genetische Korrelationen zwischen Rennzeiten auf Rasen- und Erdbahnen, Renndistanzen auf Rasen- (1200, 1400, 1600, 1800 und 2000 m) und Erdbahnen (1000, 1200, 1400, 1600, 1700 und 2000 m) wurden für Vollblüter geschätzt. (Co)Varianzkomponenten wurden mittels Mehr-Merkmal Ableitungsfreier Restringierter Maximum Likelihood (MTDFREML) geschätzt. Die Unterlagen wurden von der Japanischen Renn Vereinigung 1992 und 1993 gesammelt. Generation 2 Abstammungsinformation war für die Co-Varianzschätzung günstig. Genetische Korrelationen zwischen Rennzeiten auf Rasen und auf Erdbahnen waren zwischen 0.69 und 0.31 (Durchschnitt 0.51), jene zwischen Distanzen zwischen 0.68 und 1.00 (Durchschnitt 0.85) und zwischen 0.53 und 1.00 (Durchschnitt 0.88) auf Rasen und Erdbahnen. Die Ergebnisse zeigen, daß Rennzeit per 100 m zur Bewertung der Pferde geeignet ist.

Crystallization and preliminary X-ray analysis of methionine aminopeptidase from the hyperthermophilic bacterium Pyrococcus furiosus.

Methionine aminopeptidase (MAP) from Pyrococcus furiosus (Pfu) has been crystallized in four different forms (A, B, C and D). Form A crystals belong to space group P2(1) with unit-cell dimensions a = 54.18, b = 85.72, c = 72.84 A, beta = 108.34 degrees. Forms B, C and D belong to space group P6(2(4)) with unit-cell dimensions a = 139.1, c = 63.7 A for form B, a = 198.6, c = 243.8 A for form C, and a = 111.0, c = 125.0 A for form D. Forms A and D diffract to 2.9 A, form B diffracts to 3.5 A, and form C crystals diffract to 4.5 A. Form A contains two molecules of MAP-Pfu per asymmetric unit. The binuclear metal center positions and a non-crystallographic twofold symmetry matrix has been determined for the form A crystals.

Assessment of autonomic nervous function by power spectral analysis of heart rate variability in the horse.

We studied power spectral analysis of heart rate (HR) variability in the horse, with the hypothesis that the quantitative information provided by the spectral analysis of HR variability reflects the interaction between sympathetic and parasympathetic regulatory activities. For this purpose, electrocardiogram, blood pressure (BP) and respiratory (Resp) waveform were simultaneously recorded from Thoroughbred horses (3-5 years old) and analyzed by power spectrum. There were two major spectral components at low-frequency (LF) and high-frequency (HF) bands for HR variability. The peak of Resp variability clearly occurred at the HF range. In contrast to Resp variability, the power spectra of BP variability occurred at lower frequencies. The maximum coherence between HR and Resp variabilities and HR and BP variabilities occurred at approximately 0.15 and approximately 0.03 Hz, respectively. These relationships were similar to the ensemble spectra. On the basis of these data, we have defined two frequency bands of interest: LF (0.01-0.07 Hz) and HF (0.07-0.6 Hz). Therefore, we believe that power spectral analysis of HR variability provides a very powerful technique for assessing autonomic nervous activity in the horse.

Benign convulsions with mild gastroenteritis: a report of 10 recent cases detailing clinical varieties.

To better define the characteristic clinical features of benign convulsions with mild gastroenteritis, recently recognized as a new entity in Japan, we reviewed all the 10 patients we have seen from 1992 to 1994. The clinical features have been previously reported in the literature to be afebrile generalized tonic-clonic seizures occurring between the first and the fifth sick day of mild gastroenteritis. In our series, four of 10 patients had convulsions before the onset of gastroenteritis. Overall, seizures were mostly brief and often repetitive occurring in cluster (19 seizures/10 episodes). Among these, a prolonged or partial seizure was frequently observed. In six of the 10 patients, the seizure type changed during an episode: from generalized to partial seizures (n = 2), from partial to generalized seizures (n = 2), or from partial to another type of partial seizures (n = 2). None in our series experienced a recurrence episode of afebrile convulsion during follow-up. These findings suggest that benign convulsions with mild gastroenteritis exhibit some variations in their clinical manifestation.