CANE, a Component of the NLRP3 Inflammasome, Promotes Inflammasome Activation.

The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3, also called cryopyrin) inflammasome is an intracellular innate immune complex, which consists of the pattern-recognition receptor NLRP3, the adaptor apoptosis-assciated speck-like protein containing a caspase recruitment domain, and procaspase-1. Aberrant activation of the NLRP3 inflammasome causes an autoinflammatory disease called cryopyrin-associated periodic syndrome (CAPS). CAPS is caused by gain-of-function mutations in the NLRP3-encoding gene CIAS1; however, the mechanism of CAPS pathogenesis has not been fully understood. Thus, unknown regulators of the NLRP3 inflammasome, which are associated with CAPS development, are being investigated. To identify novel components of the NLRP3 inflammasome, we performed a high-throughput screen using a human protein array, with NLRP3 as the bait. We identified a NLRP3-binding protein, which we called the cryopyrin-associated nano enhancer (CANE). We demonstrated that CANE increased IL-1ß secretion after NLRP3 inflammasome reconstitution in human embryonic kidney 293T cells and formed a "speck" in the cytosol, a hallmark of NLRP3 inflammasome activity. Reduced expression of endogenous CANE decreased IL-1ß secretion upon stimulation with the NLRP3 agonist nigericin. To investigate the role of CANE in vivo, we developed CANE-transgenic mice. The PBMCs and bone marrow-derived macrophages of CANE-transgenic mice exhibited increased IL-1ß secretion. Moreover, increased autoinflammatory neutrophil infiltration was observed in the s.c. tissue of CANE-transgenic versus wild-type mice; these phenotypes were consistent with those of CAPS model mice. These findings suggest that CANE, a component of the NLRP3 inflammasome, is a potential modulator of the inflammasome and a contributor to CAPS pathogenesis.

Experimental conditions in which dyads outperform individuals in a task of force produced by two people.

When participants control periodic isometric force cycling between two target forces, they more accurately control force in a joint action than in an individual action. In some other studies, however, individuals tend to outperform dyads in joint action. The present study thus examined experimental conditions in which dyads outperformed individuals in a task of force produced by two people. This study consisted of two tasks with two target conditions and three force production conditions. The individual task was performed by one participant, and the joint task was performed by two participants. In absolute and relative target conditions, the participants made continuous, discrete, and periodic isometric pressing movements with the index finger. Although no difference was seen in force error between tasks in the continuous condition, the joint task had a smaller error than the individual task in the two other conditions. The joint task had a smaller variable force than the individual task in the periodic conditions, but no difference was seen in force variability between tasks in the two other conditions. Participants mainly controlled force in both tasks in the continuous condition. In the periodic or discrete condition at a prescribed interval, however, participants had to control both force and timing in the individual task, and muscle force must be mainly controlled to compensate for force errors by synchronizing interpersonal force outputs in the joint task. Thus, dyads can reduce the dimensionality of the control problem because they can synchronize their action which provides timing information.

Hypoxic Culture Maintains Cell Growth of the Primary Human Valve Interstitial Cells with Stemness.

The characterization of aortic valve interstitial cells (VICs) cultured under optimal conditions is essential for understanding the molecular mechanisms underlying aortic valve stenosis. Here, we propose 2% hypoxia as an optimum VIC culture condition. Leaflets harvested from patients with aortic valve regurgitation were digested using collagenase and VICs were cultured under the 2% hypoxic condition. A significant increase in VIC growth was observed in 2% hypoxia (hypo-VICs), compared to normoxia (normo-VICs). RNA-sequencing revealed that downregulation of oxidative stress-marker genes (such as superoxide dismutase) and upregulation of cell cycle accelerators (such as cyclins) occurred in hypo-VICs. Accumulation of reactive oxygen species was observed in normo-VICs, indicating that low oxygen tension can avoid oxidative stress with cell-cycle arrest. Further mRNA quantifications revealed significant upregulation of several mesenchymal and hematopoietic progenitor markers, including CD34, in hypo-VICs. The stemness of hypo-VICs was confirmed using osteoblast differentiation assays, indicating that hypoxic culture is beneficial for maintaining growth and stemness, as well as for avoiding senescence via oxidative stress. The availability of hypoxic culture was also demonstrated in the molecular screening using proteomics. Therefore, hypoxic culture can be helpful for the identification of therapeutic targets and the evaluation of VIC molecular functions in vitro.

The possession of exon 2 or exon 3 variants in the MEFV gene promotes inflammasome activation in Japanese patients with familial Mediterranean fever with a heterozygous exon 10 mutation.

OBJECTIVES: The modification and pathogenesis of MEFV exon 2 or 3 variants in familial Mediterranean fever (FMF) remains unclear. We compared the clinical and laboratory characteristics between the coexistence and noncoexistence of MEFV exon 2 or 3 variants in patients with FMF that had a heterozygous MEFV exon 10 mutation. METHODS: We excluded patients with FMF that had two MEFV exon 10 mutations in one or more alleles and/or MEFV mutations in exons other than in exons 2, 3, or 10. Finally, we reviewed 131 Japanese patients with FMF that had a heterozygous MEFV exon 10 mutation, and they were divided into the groups with and without MEFV exon 2 or 3 variants of 97 and 34, respectively. RESULTS: All patients with MEFV exon 2 variants had either E148Q and/or L110P variants, none of patients had exon 3 variants. In the univariate analysis, the group with variants had significantly earlier onset, a higher percentage of thoracic pain with febrile attacks, a higher frequency of attack, and a higher IL-18 level at remission compared to the group without variants (all, p<0.05). Importantly, multivariate analyses showed that the coexistence of MEFV exon 2 variants was independently and significantly associated with earlier onset of FMF and thoracic pain (both, p<0.05). CONCLUSIONS: Our results suggested that coexistence of MEFV exon 2 variants have additional effects on manifestations of FMF with MEFV exon 10 mutations. Our findings highlighted the modifications and pathogenesis of such MEFV variants in FMF.

Next-generation sequencing of the whole MEFV gene in Japanese patients with familial Mediterranean fever: a case-control association study.

OBJECTIVES: We aimed to identify the whole nucleotide sequence of the Mediterranean fever (MEFV) gene in familial Mediterranean fever (FMF) and reveal novel single nucleotide variants (SNVs) associated with the susceptibility of FMF. METHODS: SeqCap capturing technique followed by Illumina next-generation sequencing have been used to assess two hundred SNVs in the whole region of MEFV in 266 Japanese patients with FMF and 288 ethnically matched controls. We performed an association analysis using these SNVs to identify genetic variants that predispose to FMF. RESULTS: We identified the two most significant SNVs [rs28940578; M694I in exon 10, odds ratio (OR) = 153, p=2.47×10-21 and rs3743930; E148Q in exon 2, OR = 1.65, p<0.0005]. Stratified analysis identified rs28940578 as a risk allele in typical FMF. Haplotype AG, defined by rs401298 and rs28940578, was the most significant and prevalent among patients with typical FMF compared with controls (22.4% vs. 0%, respectively; OR = 137, p=1.44×10-31). Haplotype GTC, defined by rs11466018, rs224231, and rs401877, was the most significant among patients with typical FMF without the rs28940578 mutation compared with controls (15.9% vs. 6%, respectively; OR = 12.4, p=0.004). CONCLUSIONS: rs28940578 is associated with the highest risk in typical FMF cases. This is consistent with results from previous studies in Japan. We found a novel MEFV gene haplotype that confers susceptibility of FMF among typical FMF without the rs28940578 mutation. There were no relevant SNVs identified in MEFV among the atypical FMF group.

Force asymmetry deteriorates complementary force production during joint action.

The present study aimed to determine the effects of force asymmetry on interpersonal force production. This study consisted of an individual task executed by one participant at a time in a pair, and three joint tasks executed by two participants simultaneously under conditions of 1:1, 1:0.75, and 1:0.5. Two individuals produced discrete forces at the same time so that the sum of forces they produced was the target force in the joint task. Under the 1:1 condition, the target force was the sum of the maximum voluntary contraction (MVC) produced by the index finger of each participant × 0.1 (10% MVC). Under the 1:0.75 condition, the investigators manipulated the force produced by only one of the pair, for example, B, but not A. The feedback was also scaled as a result. The target force was the MVC of participant A + the MVC of participant B × 0.75 × 0.1. Similarly, the target force under the 1:0.5 condition was the MVC of participant A + the MVC of participant B × 0.5 × 0.1. The present study found that forces produced by pairs were negatively correlated and the correlation value was higher under the 1:1 condition than the 1:0.75 and 1:0.5 conditions. The absolute error was smaller under the 1:1 condition than the 1:0.5 condition. Complementary force production was attenuated and the error increased as differences between forces produced by two participants increased. Thus, asymmetry of forces produced by pairs deteriorated complementary force production and interpersonal performance.

MicroRNA-204-3p inhibits lipopolysaccharide-induced cytokines in familial Mediterranean fever via the phosphoinositide 3-kinase γ pathway.

Objective: We sought to identify the microRNA (miRNA) profile and potential biomarkers in FMF and to clarify their gene targets to elucidate the pathogenesis of FMF. Methods: We performed an miRNA microarray using serum from FMF patients in attack and in remission. We then examined the expression of miRNAs in macrophages derived from THP-1 cells stimulated with toll-like receptor (TLR) ligands. Macrophages derived from THP-1 cells transfected with pre-miRNA were stimulated with lipopolysaccharides (LPSs) for the quantification of inflammatory cytokine production. To identify the target genes, we overexpressed their miRNA and performed a complementary DNA microarray. Transfection with reporter construct and the precursor miRNA was performed to confirm the suppression of target mRNA. Results: We found that miR-204-3p was greatly decreased in the serum from FMF patients in attack. The expression of miR-204-3p was suppressed by LPS stimulation in the macrophages derived from THP-1 cells and the inhibition of miR-204-3p significantly induced the production of TLR4-related cytokines. The bioinformatic analysis showed that miR-204-3p is predicted to target genes implicated in the TLR pathway through the regulation of PI3Kγ signalling. The reporter assay revealed that miR-204-3p directly suppressed the luciferase activity of 3'-UTR of PIK3CG reporter construct. The inhibition of PI3Kγ resulted in decreased amounts of IL-6 and IL-12p40 in monocytes from FMF patients. Conclusion: These data suggest that serum miR-204-3p has potential as a useful biomarker in FMF patients and that miR-204-3p serves as a suppressor of inflammatory cytokine production in FMF by targeting the PI3Kγ pathway.

Bidirectional transfer between joint and individual actions in a task of discrete force production.

The present study examined bidirectional learning transfer between joint and individual actions involving discrete isometric force production with the right index finger. To examine the effects of practice of joint action on performance of the individual action, participants performed a pre-test (individual condition), practice blocks (joint condition), and a post-test (individual condition) (IJI task). To examine the effects of practice of the individual action on performance during the joint action, the participants performed a pre-test (joint condition), practice blocks (individual condition), and a post-test (joint condition) (JIJ task). Whereas one participant made pressing movements with a target peak force of 10% maximum voluntary contraction (MVC) in the individual condition, two participants produced the target force of the sum of 10% MVC produced by each of them in the joint condition. In both the IJI and JIJ tasks, absolute errors and standard deviations of peak force were smaller post-test than pre-test, indicating bidirectional transfer between individual and joint conditions for force accuracy and variability. Although the negative correlation between forces produced by two participants (complementary force production) became stronger with practice blocks in the IJI task, there was no difference between the pre- and post-tests for the negative correlation in the JIJ task. In the JIJ task, the decrease in force accuracy and variability during the individual action did not facilitate complementary force production during the joint action. This indicates that practice performed by two people is essential for complementary force production in joint action.

Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis.

Nucleotide-binding oligomerization domain-containing protein (Nod) 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP), a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2). Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS)/early-onset sarcoidosis (EOS). For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA). Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.

Motor control hierarchy in joint action that involves bimanual force production.

The concept of hierarchical motor control has been viewed as a means of progressively decreasing the number of variables manipulated by each higher control level. We tested the hypothesis that turning an individual bimanual force-production task into a joint (two-participant) force-production task would lead to positive correlation between forces produced by the two hands of the individual participant (symmetric strategy) to enable negative correlation between forces produced by two participants (complementary strategy). The present study consisted of individual and joint tasks that involved both unimanual and bimanual conditions. In the joint task, 10 pairs of participants produced periodic isometric forces, such that the sum of forces that they produced matched a target force cycling between 5% and 10% of maximum voluntary contraction at 1 Hz. In the individual task, individuals attempted to match the same target force. In the joint bimanual condition, the two hands of each participant adopted a symmetric strategy of force, whereas the two participants adopted a complementary strategy of force, highlighting that the bimanual action behaved as a low level of a hierarchy, whereas the joint action behaved as an upper level. The complementary force production was greater interpersonally than intrapersonally. However, whereas the coherence was highest at 1 Hz in all conditions, the frequency synchrony was stronger intrapersonally than interpersonally. Moreover, whereas the bimanual action exhibited a smaller error and variability of force than the unimanual action, the joint action exhibited a less-variable interval and force than the individual action.

Vibrio parahaemolyticus effector proteins suppress inflammasome activation by interfering with host autophagy signaling.

Bacterial pathogens utilize pore-forming toxins or sophisticated secretion systems to establish infection in hosts. Recognition of these toxins or secretion system by nucleotide-binding oligomerization domain leucine-rich repeat proteins (NLRs) triggers the assembly of inflammasomes, the multiprotein complexes necessary for caspase-1 activation and the maturation of inflammatory cytokines such as IL-1ß or IL-18. Here we demonstrate that both the NLRP3 and NLRC4 inflammasomes are activated by thermostable direct hemolysins (TDHs) and type III secretion system 1 (T3SS1) in response to V. parahaemolyticus infection. Furthermore, we identify T3SS1 secreted effector proteins, VopQ and VopS, which induce autophagy and the inactivation of Cdc42, respectively, to prevent mainly NLRC4 inflammasome activation. VopQ and VopS interfere with the assembly of specks in infected macrophages. These data suggest that bacterial effectors interfere with inflammasome activation and contribute to bacterial evasion from the host inflammatory responses.

Dysregulated mature IL-1ß production in familial Mediterranean fever.

OBJECTIVE: The aim of this study was to analyse the role of circulating cleaved IL-1ß in patients with FMF. METHODS: We enrolled 20 patients with FMF (5 males and 15 females), 22 patients with RA (4 males and 18 females) and 22 healthy controls (6 males and 16 females). Serum levels of serum amyloid A (SAA) were measured by ELISA. We also determined whether IL-1ß was present as the cleaved form (p17) in the sera of FMF patients by immunoblotting using anti-cleaved IL-1ß antibody. RESULTS: Although SAA concentrations were elevated in the sera, there was no significant difference in these concentrations between FMF patients and RA patients. Immunoblot analysis demonstrated that the cleaved form of IL-1ß (p17) was present in sera from FMF patients during febrile attack periods, but not in healthy controls. Bands representing the cleaved form of IL-1ß were not detected in serum from FMF patients at non-febrile attack periods or remission periods under colchicine treatment. The amounts of cleaved IL-1ß (p17) were significantly higher in patients with FMF compared with those in patients with RA in the inflammatory phase. CONCLUSION: The cleaved form of IL-1ß is a valuable biomarker for monitoring disease activity and response to colchicine treatment in patients with FMF. It might be useful to discriminate FMF from other non-IL-1ß-mediated inflammatory disorders.

A leader-follower relationship in joint action on a discrete force production task.

The present study examined the development of a leader-follower relationship in joint action performed by participants with different skill levels. Two participants were instructed to produce discrete isometric forces such that the sum of the forces was the target force. The task did not prescribe the onset time or share of force each participant contributed to the target force. Although novices with low force variability did not produce an earlier force than those with high force variability in the novice-novice group, experienced participants produced an earlier force than novices in the novice-experienced group. While participants with low force variability always produced a stronger force than those with high force variability in both the groups, there was no significant difference in force distributions between participants with low and high force variabilities. Although a novice-experienced pair produced force more complementarily than a novice-novice pair in the first practice block, the difference between pairs vanished after the first practice block, suggesting that leader-follower relations were not always beneficial to task performance. In addition, practice of the joint action did not transfer to individual action.

Effects of speech on both complementary and synchronous strategies in joint action.

If two people row a boat, they often call to each other to synchronize their strokes. It is anticipated that such a call promotes periodic joint action. The present study thus examined the effects of speech on both complementary and synchronous strategies in joint action using the same task as we used previously (Masumoto and Inui in J Neurophysiol 109:1307-1314, 2013a). Ten pairs of participants produced periodic isometric forces such that the sum of the forces they produced was the target force cycling between 5 and 10 % of maximum voluntary contraction with an interval of 1,000 ms with the right hand. There were three speech conditions crossed with the presence or absence of visual information. Whereas two participants synchronized an utterance/ba/with the peak and valley forces in the 'Both' condition, one synchronized it with both forces in the 'One-side' condition, and nobody uttered it in the 'None' condition. When the total force was visible, the One-side and Both conditions exhibited lower correlations than the None condition, although the correlation between forces produced by two participants was negative in all conditions. When the total force was invisible, although the coherence between force and time series produced by two participants was low under the None condition, it was high at 1 and 3 Hz under the One-side and Both conditions. Thus, although periodically uttering a syllable worsened complementary force production when the target was visible, it promoted synchronization of their performance to each other's timing when the target was invisible.

Defect of suppression of inflammasome-independent interleukin-8 secretion from SW982 synovial sarcoma cells by familial Mediterranean fever-derived pyrin mutations.

Familial Mediterranean fever (FMF) is a recessive inherited autoinflammatory syndrome. Patients with FMF have symptoms such as recurrent fever and abdominal pain, sometimes accompanied by arthralgia. Biopsy specimens have revealed substantial neutrophil infiltration into synovia. FMF patients have a mutation in the Mediterranean fever gene, encoding pyrin, which is known to regulate the inflammasome, a platform for processing interleukin (IL)-1ß. FMF patients heterozygous for E148Q mutation, heterozygous for M694I mutation, or combined heterozygous for E148Q and M694I mutations, which were found to be major mutations in an FMF study group in Japan, suffer from arthritis, the severity of which is likely to be lower than in FMF patients with M694V mutations. Expression plasmids of wild-type (WT) pyrin and mutated pyrin, such as E148Q, M694I, M694V, and E148Q+M694I, were constructed, and SW982 synovial sarcoma cells were transfected with these expression plasmids. IL-8 and IL-6 were spontaneously secreted from the culture supernatant of SW982 cells without any stimulation, whereas IL-1ß and TNF-α could not be detected even when stimulated with lipopolysaccharide. Notably, two inflammasome components, ASC and caspase-1, could not be detected in SW982 cells by Western blotting. IL-8 but not IL-6 secretion from SW982 cells was largely suppressed by WT pyrin, but less suppressed by mutated pyrin, which appeared to become weaker in the order of E148Q, M694I, E148Q+M694I, and M694V mutations. As for IL-8 and IL-6, similar results were obtained using stable THP-1 cells expressing the WT pyrin or mutated pyrins, such as M694V or E148Q, when stimulated by LPS. In addition, IL-8 secretion from mononuclear cells of FMF patients was significantly higher than that of healthy volunteers when incubated on a culture plate. Thus, our results suggest that IL-8 secretion from SW982 synovial sarcoma cells suppressed by pyrin independently of inflammasome is affected by pyrin mutations, which may reflect the activity in FMF arthritis.

Microvasculature of carotid atheromatous plaques: hemorrhagic plaques have dense microvessels with fenestrations to the arterial lumen.

BACKGROUND: Microvessels in atheromatous plaques are well known to play a role in plaque vulnerability associated with intraplaque hemorrhage, but their architecture remains unclear. The morphometry of the microvasculature and hemorrhage of human carotid atheromatous plaques (CAPs) were evaluated, and 3-dimensional (3D) reconstruction of the microvessels was performed. METHODS: CAPs were obtained by endarterectomy in 42 patients. The specimens were analyzed using light microscopy. Plaque hemorrhage was defined as an area-containing red blood cells (>1 mm2). To determine the histopathologic features of plaque hemorrhage, the plaque area was divided into 4 regions: cap, shoulder, lipid/necrotic core, and media. Then, the density of microvessels and macrophages in each region was quantified. Two representative lesions with either hemorrhagic or nonhemorrhagic plaque were cut into 90 serial sections. The sections were double stained with anti-CD34 and anti-α smooth muscle actin antibodies, scanned using a digital microscope, and reconstructed using TRI-SRF2 software. RESULTS: The hemorrhagic plaques showed a higher density of microvessels than nonhemorrhagic plaques in the shoulder, cap, and lipid/necrotic core (P=.03, .009, and .001, respectively), and there was positive correlations between its density and macrophages in each regions (P<.001, .001, and .019, respectively). 3D imaging also revealed dense microvessels with a network structure in the cap and shoulder regions of hemorrhagic plaques, and some of the vessels were fenestrated to the arterial lumen. CONCLUSIONS: The microvasculature of plaques with intraplaque hemorrhage was dense, some of which fenestrated to the arterial lumen. The pathologic 3D imaging revealed precise architecture of microvasculature of plaques.

Two heads are better than one: both complementary and synchronous strategies facilitate joint action.

If two people lift and carry an object, they not only produce complementary forces on the object but also walk in synchrony. Previous studies have not examined how two types of coordination strategy are adopted simultaneously. The present study thus tested the hypothesis that complementary and synchronous strategies simultaneously facilitate the action coordination performed by two people. Ten pairs of participants produced periodic isometric forces such that the sum of forces they produced was the target force cycling between 5% and 10% of maximum voluntary contraction with an interval of 1,000 ms (joint action), while individuals alone produced the same target forces with the right hand (individual action). The correlation between forces produced by two participants was highly negative when the total force was visible, indicating that the two participants produced complementary forces. When the image of the total or partner force was presented, the coherence between force-time series produced by two participants was highest at 1 Hz. The relative phase angles were also distributed at the 0-20° phase region. These innovative findings indicate that two participants simultaneously adopted both complementary and temporal synchronous strategies exclusively when the total force was visible. With the vision of total force, surprisingly, while the joint action exhibited a less variable force than the individual action, the joint action exhibited a smaller absolute error of forces than the individual action. These new findings indicated that the joint action controlled force more accurately than the individual action.

Effects of visual information on perceived posture of an experimental phantom foot.

Our previous studies showed that a fully extended finger, wrist, and elbow became a flexed phantom hand and arm with ischemic anesthesia, and vice versa (Inui et al. in J Physiol 589:5775-5784, 2011, Exp Brain Res 221:369-375, 2012a, Exp Brain Res 218:487-494, 2012b). It was anticipated that if the ankle and knee were fixed in full extension or flexion before and during ischemic anesthesia, the perceived positions would move in the opposite direction. The present study examined what happened when participants looked at their fixed foot and leg at the end of the anesthesia. Using the left ankle and knee, ten healthy participants demonstrated the perceived postures of the right joints during an ischemic block of the right thigh (40 min) and after they looked at the right joints at the end of the block. When the right ankle and knee were fully extended before and during the block, the final joints were perceived as flexed by all participants, and vice versa. Although there was no significant difference between joints for the magnitude of the perceived changes in flexion, the magnitude in the knee was larger than that in the ankle in extension. At the end of the experiment, when participants were allowed to see their foot, its perceived position reverted to that indicated by them earlier, during the first 25 min of cuff inflation. This new finding suggests that the position of limbs is coded by visual input more dominantly than by proprioceptive input in the brain.

Effects of movement duration on error compensation in periodic bimanual isometric force production.

Recent studies using bimanual force production have examined how factors influence redundancy in the nervous system. The present study examined effects of different movement durations on bimanual force control strategies. Ten healthy male participants produced periodic isometric forces such that the sum of two finger forces was a target cycling between 5 and 10 % of maximum voluntary contraction during five movement durations (500, 750, 1,000, 1,250, and 1,500 ms). Correlations between the two finger forces changed from positive to negative with an increase in duration. The polynomial regression analysis indicates that while the correlations between two finger forces were most negative at the target duration of 1,250 ms, they became more positive as the durations deviated from 1,250 ms. Similarly, while force variability was smallest at the target duration of 1,250 ms, it increased as the durations deviated from 1,250 ms. These findings suggested that while the duration of 1,250 ms might be a natural frequency of both fingers, bimanual force strategies changed from force error compensation to force coupling as the durations deviated from 1,250 ms. In addition, while the variance in the sum of two finger forces (the task-relevant variance) decreased with movement duration, the difference between both the finger forces (the task-irrelevant variance) did not change with the duration. Thus, a decrease in the task-relevant variance with movement duration resulted in the negative correlation between the two finger forces and the small force variability.

IgG4-related disease-like fibrosis as an indicator of IgG4-related lymphadenopathy.

The significance of IgG4-related diseases including IgG4-related lymphadenopathy has recently been recognized worldwide. Inflammatory pseudotumors in lymph nodes, as well as in other organs, are also recognized as IgG4-related diseases. Only a few case reports have described IgG4-related lymphadenopathy with fibrosis (IgG4-fibrosing lymphadenopathy), and IgG4-fibrosing lymphadenopathy has not been compared clinicopathologically with non-IgG4-related lymphadenopathy with fibrosis. We have evaluated the pathologic features in 13 patients with IgG4-fibrosing lymphadenopathy, including IgG4 and IgG expression in lymph nodes, and compared these features with those of patients with non-IgG4-related lymphadenopathy with fibrosis with reactive inguinal lymphadenopathy and focal fibrosis and lymph nodes at least 10 mm in diameter. IgG4-fibrosing lymphadenopathy was characterized by lymphoplasmacytic and eosinophilic infiltration, many IgG4-positive plasma cells in fibrotic areas, and high serum IgG4 concentrations. The IgG4-positive/IgG-positive plasma cell ratio was significantly higher in the IgG4-fibrosing lymphadenopathy than in the non-IgG4-fibrosing lymphadenopathy group. The presence of even minor fibrosis with characteristics of IgG4-related disease such as IgG4-fibrosing lymphadenopathy may facilitate the diagnosis of IgG4-related lymphadenopathy.