Efficacy and safety of abatacept for systemic juvenile idiopathic arthritis: a systematic review.

OBJECTIVES: This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA). METHODS: Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan. RESULTS: Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases. CONCLUSIONS: Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms.

Necl-1/CADM3 regulates cone synapse formation in the mouse retina.

In vertebrates, retinal neural circuitry for visual perception is organized in specific layers. The outer plexiform layer is the first synaptic region in the visual pathway, where photoreceptor synaptic terminals connect with bipolar and horizontal cell processes. However, molecular mechanisms underlying cone synapse formation to mediate OFF pathways remain unknown. This study reveals that Necl-1/CADM3 is localized at S- and S/M-opsin-containing cones and dendrites of type 4 OFF cone bipolar cells (CBCs). In Necl-1-/- mouse retina, synapses between cones and type 4 OFF CBCs were dislocated, horizontal cell distribution became abnormal, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors were dislocated. Necl-1-/- mice exhibited aberrant short-wavelength-light-elicited signal transmission from cones to OFF CBCs, which was rescued by AMPA receptor potentiator. Additionally, Necl-1-/- mice showed impaired optokinetic responses. These findings suggest that Necl-1 regulates cone synapse formation to mediate OFF cone pathways elicited by short-wavelength light in mouse retina.

Epidemiology conduction of paediatric rheumatic diseases based on the registry database of the Pediatric Rheumatology Association of Japan.

OBJECTIVES: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. METHODS: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. RESULTS: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. CONCLUSION: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.

Effect of Green Tea and Tea Catechin on the Visual Motion Processing for Optokinetic Responses in Mice.

In general, catechins contained in green tea are believed to have positive effects on the human body and mental health. The intake of epigallocatechin gallate (EGCG), a major polyphenol in green tea, is known to be effective for retinal protection; however, whether green tea and/or EGCG affect visual function remains unknown. In the present study, we investigated the effect of green tea and EGCG on visual motion processing by measuring optokinetic responses (OKRs) in young adult and aging mice. Young and aging mice (C57BL6/J) were fed a control diet (control) or the test diet, which contained matcha green tea powder or green tea extract (dried sencha green tea infusion), for 1 month, and their OKRs were measured. They were then intraperitoneally administered saline (control) or EGCG, and OKRs were measured. We found that the OKRs of young and aging mice after green tea intake and after EGCG administration showed higher temporal sensitivity than those of control mice. The visual ability to detect moving objects was enhanced in young and aging mice upon intake of green tea or EGCG. From the above results, the visual motion processing for optokinetic responses by ingesting green tea was enhanced, which may be related to the effect of EGCG.

Deficiency of the neurodevelopmental disorder-associated gene Cyfip2 alters the retinal ganglion cell properties and visual acuity.

Intellectual disability (ID) is a neurodevelopmental disorder affecting approximately 0.5-3% of the population in the developed world. Individuals with ID exhibit deficits in intelligence, impaired adaptive behavior and often visual impairments. Cytoplasmic fragile X mental retardation 1 (FMR1)-interacting protein 2 (CYFIP2) is an interacting partner of the FMR protein, whose loss results in fragile X syndrome, the most common inherited cause of ID. Recently, CYFIP2 variants have been found in patients with early-onset epileptic encephalopathy, developmental delay and ID. Such individuals often exhibit visual impairments; however, the underlying mechanism is poorly understood. In the present study, we investigated the role of Cyfip2 in retinal and visual functions by generating and analyzing Cyfip2 conditional knockout (CKO) mice. While we found no major differences in the layer structures and cell compositions between the control and Cyfip2 CKO retinas, a subset of genes associated with the transporter and channel activities was differentially expressed in Cyfip2 CKO retinas than in the controls. Multi-electrode array recordings showed more sustained and stronger responses to positive flashes of the ON ganglion cells in the Cyfip2 CKO retina than in the controls, although electroretinogram analysis revealed that Cyfip2 deficiency unaffected the photoreceptor and ON bipolar cell functions. Furthermore, analysis of initial and late phase optokinetic responses demonstrated that Cyfip2 deficiency impaired the visual function at the organismal level. Together, our results shed light on the molecular mechanism underlying the visual impairments observed in individuals with CYFIP2 variants and, more generally, in patients with neurodevelopmental disorders, including ID.

Influence of Aging on the Retina and Visual Motion Processing for Optokinetic Responses in Mice.

The decline in visual function due to normal aging impacts various aspects of our daily lives. Previous reports suggest that the aging retina exhibits mislocalization of photoreceptor terminals and reduced amplitudes of scotopic and photopic electroretinogram (ERG) responses in mice. These abnormalities are thought to contribute to age-related visual impairment; however, the extent to which visual function is impaired by aging at the organismal level is unclear. In the present study, we focus on the age-related changes of the optokinetic responses (OKRs) in visual processing. Moreover, we investigated the initial and late phases of the OKRs in young adult (2-3 months old) and aging mice (21-24 months old). The initial phase was evaluated by measuring the open-loop eye velocity of OKRs using sinusoidal grating patterns of various spatial frequencies (SFs) and moving at various temporal frequencies (TFs) for 0.5 s. The aging mice exhibited initial OKRs with a spatiotemporal frequency tuning that was slightly different from those in young adult mice. The late-phase OKRs were investigated by measuring the slow-phase velocity of the optokinetic nystagmus evoked by sinusoidal gratings of various spatiotemporal frequencies moving for 30 s. We found that optimal SF and TF in the normal aging mice are both reduced compared with those in young adult mice. In addition, we measured the OKRs of 4.1G-null (4.1G -/-) mice, in which mislocalization of photoreceptor terminals is observed even at the young adult stage. We found that the late phase OKR was significantly impaired in 4.1G - / - mice, which exhibit significantly reduced SF and TF compared with control mice. These OKR abnormalities observed in 4.1G - / - mice resemble the abnormalities found in normal aging mice. This finding suggests that these mice can be useful mouse models for studying the aging of the retinal tissue and declining visual function. Taken together, the current study demonstrates that normal aging deteriorates to visual motion processing for both the initial and late phases of OKRs. Moreover, it implies that the abnormalities of the visual function in the normal aging mice are at least partly due to mislocalization of photoreceptor synapses.

Retinal ON and OFF pathways contribute to initial optokinetic responses with different temporal characteristics.

Visual information in the retina is processed via two pathways: ON and OFF pathways that originate from ON and OFF bipolar cells. The differences in the receptors that mediate signal transmission from photoreceptors imply that the response speed to light signals differs between ON and OFF pathways. We studied the initial optokinetic responses (OKRs) of mice using two-frame motion stimuli presented with interstimulus intervals (ISIs) to understand functional difference of these pathways. When two successive image frames were presented with an ISI, observers often perceived motion in the opposite direction of the actual shift. This directional reversal results from the biphasic nature of the temporal filters in visual systems whose characteristics can be estimated from the dependence on ISIs. We examined the dependence on ISIs in the OKRs of TRPM1-/- mice, whose ON bipolar cells are dysfunctional, as well as in those of wild-type control mice. Wild type and TRPM1-/- mice showed comparable OKRs in the veridical direction when no ISI was present. Both types of mice showed OKRs that decreased and eventually reversed as the ISI increased, but with a directional reversal at a shorter ISI in TRPM1-/- than wild-type mice. In addition, the temporal filters of TRPM1-/- mice estimated from dependence on ISIs were tuned for higher frequencies, suggesting that compared with wild-type mice, the visual system of TRPM1-/- mice responds to light signals with faster dynamics. We conclude that the ON and OFF pathways contribute to initial OKRs by providing visual signals processed with different temporal resolutions.

The findings of musculoskeletal ultrasonography on primary Sjögren's syndrome patients in childhood with articular manifestations and the impact of anti-cyclic citrullinated peptide antibody.

Objective: We researched the findings of musculoskeletal ultrasound sonography (MSUS) on primary Sjogren's syndrome in childhood (pSS-C) with articular manifestations. The correlation of rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) were investigated to evaluate the usefulness of MSUS on their articular prognosis. Method: The objective patients are pSS-C cases who visited our hospital complaining joint pain and/or joint swelling and for whom MSUS was performed. Result: Eight patients included 6 female and 2 male, 5 RF-positive patients and 3 ACPA- positive patients. The mean age of onset was 11.1 ± 3.0 years (352 physical joint findings and 284 MSUS findings. The number of joints found clinical articular manifestations was 58/352 joints, and arthritis detected by MSUS was 30/284 joints). In multivariate analysis, the odds ratio of clinical articular manifestations was significant high in RF-positivity (2.9, 95%CI 1.5-6.2). The odds ratio of arthritis detected by MSUS in ACPA-positivity was significant high (3.7, 95%CI 1.5-11.6), although odds ratio in RF-positivity had no statistical significance and a similar trend was seen in odds ratios of subclinical arthritis (4.9, 95%CI 1.6-18.0). Conclusion: It was indicated that MSUS is useful for pSS-C. ACPA-positive pSS-C patients have arthritis and subclinical arthritis more frequently than ACPA-negative patients.

Two-frame apparent motion presented with an inter-stimulus interval reverses optokinetic responses in mice.

Two successive image frames presented with a blank inter-stimulus interval (ISI) induce reversals of perceived motion in humans. This illusory effect is a manifestation of the temporal properties of image filters embedded in the visual processing pathway. In the present study, ISI experiments were performed to identify the temporal characteristics of vision underlying optokinetic responses (OKRs) in mice. These responses are thought to be mediated by subcortical visual processing. OKRs of C57BL/6 J mice, induced by a 1/4-wavelength shift of a square-wave grating presented with and without an ISI were recorded. When a 1/4-wavelength shift was presented without, or with shorter ISIs (≤106.7 ms), OKRs were induced in the direction of the shift, with progressively decreasing amplitude as the ISI increased. However, when ISIs were 213.3 ms or longer, OKR direction reversed. Similar dependence on ISIs was also obtained using a sinusoidal grating. We subsequently quantitatively estimated temporal filters based on the ISI effects. We found that filters with biphasic impulse response functions could reproduce the ISI and temporal frequency dependence of the mouse OKR. Comparison with human psychophysics and behaviors suggests that mouse vision has more sluggish response dynamics to light signals than that of humans.

Lrit1, a Retinal Transmembrane Protein, Regulates Selective Synapse Formation in Cone Photoreceptor Cells and Visual Acuity.

In the vertebrate retina, cone photoreceptors play crucial roles in photopic vision by transmitting light-evoked signals to ON- and/or OFF-bipolar cells. However, the mechanisms underlying selective synapse formation in the cone photoreceptor pathway remain poorly understood. Here, we found that Lrit1, a leucine-rich transmembrane protein, localizes to the photoreceptor synaptic terminal and regulates the synaptic connection between cone photoreceptors and cone ON-bipolar cells. Lrit1-deficient retinas exhibit an aberrant morphology of cone photoreceptor pedicles, as well as an impairment of signal transmission from cone photoreceptors to cone ON-bipolar cells. Furthermore, we demonstrated that Lrit1 interacts with Frmpd2, a photoreceptor scaffold protein, and with mGluR6, an ON-bipolar cell-specific glutamate receptor. Additionally, Lrit1-null mice showed visual acuity impairments in their optokinetic responses. These results suggest that the Frmpd2-Lrit1-mGluR6 axis regulates selective synapse formation in cone photoreceptors and is essential for normal visual function.

Versatile functional roles of horizontal cells in the retinal circuit.

In the retinal circuit, environmental light signals are converted into electrical signals that can be decoded properly by the brain. At the first synapse of the visual system, information flow from photoreceptors to bipolar cells is modulated by horizontal cells (HCs), however, their functional contribution to retinal output and individual visual function is not fully understood. In the current study, we investigated functional roles for HCs in retinal ganglion cell (RGC) response properties and optokinetic responses by establishing a HC-depleted mouse line. We observed that HC depletion impairs the antagonistic center-surround receptive field formation of RGCs, supporting a previously reported HC function revealed by pharmacological approaches. In addition, we found that HC loss reduces both the ON and OFF response diversities of RGCs, impairs adjustment of the sensitivity to ambient light at the retinal output level, and alters spatial frequency tuning at an individual level. Taken together, our current study suggests multiple functional aspects of HCs crucial for visual processing.

Prdm13 regulates subtype specification of retinal amacrine interneurons and modulates visual sensitivity.

Amacrine interneurons, which are highly diversified in morphological, neurochemical, and physiological features, play crucial roles in visual information processing in the retina. However, the specification mechanisms and functions in vision for each amacrine subtype are not well understood. We found that the Prdm13 transcriptional regulator is specifically expressed in developing and mature amacrine cells in the mouse retina. Most Prdm13-positive amacrine cells are Calbindin- and Calretinin-positive GABAergic or glycinergic neurons. Absence of Prdm13 significantly reduces GABAergic and glycinergic amacrines, resulting in a specific defect of the S2/S3 border neurite bundle in the inner plexiform layer. Forced expression of Prdm13 distinctively induces GABAergic and glycinergic amacrine cells but not cholinergic amacrine cells, whereas Ptf1a, an upstream transcriptional regulator of Prdm13, induces all of these subtypes. Moreover, Prdm13-deficient mice showed abnormally elevated spatial, temporal, and contrast sensitivities in vision. Together, these results show that Prdm13 regulates development of a subset of amacrine cells, which newly defines an amacrine subtype to negatively modulate visual sensitivities. Our current study provides new insights into mechanisms of the diversification of amacrine cells and their function in vision.

Role of the mouse retinal photoreceptor ribbon synapse in visual motion processing for optokinetic responses.

The ribbon synapse is a specialized synaptic structure in the retinal outer plexiform layer where visual signals are transmitted from photoreceptors to the bipolar and horizontal cells. This structure is considered important in high-efficiency signal transmission; however, its role in visual signal processing is unclear. In order to understand its role in visual processing, the present study utilized Pikachurin-null mutant mice that show improper formation of the photoreceptor ribbon synapse. We examined the initial and late phases of the optokinetic responses (OKRs). The initial phase was examined by measuring the open-loop eye velocity of the OKRs to sinusoidal grating patterns of various spatial frequencies moving at various temporal frequencies for 0.5 s. The mutant mice showed significant initial OKRs with a spatiotemporal frequency tuning (spatial frequency, 0.09 ± 0.01 cycles/°; temporal frequency, 1.87 ± 0.12 Hz) that was slightly different from the wild-type mice (spatial frequency, 0.11 ± 0.01 cycles/°; temporal frequency, 1.66 ± 0.12 Hz). The late phase of the OKRs was examined by measuring the slow phase eye velocity of the optokinetic nystagmus induced by the sinusoidal gratings of various spatiotemporal frequencies moving for 30 s. We found that the optimal spatial and temporal frequencies of the mutant mice (spatial frequency, 0.11 ± 0.02 cycles/°; temporal frequency, 0.81 ± 0.24 Hz) were both lower than those in the wild-type mice (spatial frequency, 0.15 ± 0.02 cycles/°; temporal frequency, 1.93 ± 0.62 Hz). These results suggest that the ribbon synapse modulates the spatiotemporal frequency tuning of visual processing along the ON pathway by which the late phase of OKRs is mediated.

Protein-4.1G-Mediated Membrane Trafficking Is Essential for Correct Rod Synaptic Location in the Retina and for Normal Visual Function.

In vertebrate retinal development, the axonal terminals of retinal neurons make synaptic contacts within narrow fixed regions, and these locations are maintained thereafter. However, the mechanisms and biological logic of the organization of these fixed synapse locations are poorly understood. We show here that a membrane scaffold protein, 4.1G, is highly expressed in retinal photoreceptors and is essential for the arrangement of their correct synapse location. The 4.1G-deficient retina exhibits mislocalization of photoreceptor terminals, although their synaptic connections are normally formed. The 4.1G protein binds to the AP3B2 protein, which is involved in neuronal membrane trafficking, and promotes neurite extension in an AP3B2-dependent manner. 4.1G mutant mice showed visual acuity impairments in an optokinetic response, suggesting that correct synapse location is required for normal visual function. Taken together, the data in this study provide insight into the mechanism and importance of proper synapse location in neural circuit formation.

Contributions of retinal direction-selective ganglion cells to optokinetic responses in mice.

In the mouse retina, there are two distinct groups of direction-selective ganglion cells, ON and ON-OFF, that detect movement of visual images. To understand the roles of these cells in controlling eye movements, we studied the optokinetic responses (OKRs) of mutant mice with dysfunctional ON-bipolar cells that have a functional obstruction of transmission to ON direction-selective ganglion cells. Experiments were carried out to examine the initial and late phases of OKRs. The initial phase was examined by measurement of eye velocity using stimuli of sinusoidal grating patterns of various spatiotemporal frequencies that moved for 0.5 s. The mutant mice showed significant initial OKRs, although the range of spatiotemporal frequencies that elicited these OKRs was limited and the response magnitude was weaker than that in wild-type mice. To examine the late phase of the OKRs, the same visual patterns were moved for 30 s to induce alternating slow and quick eye movements (optokinetic nystagmus) and the slow-phase eye velocity was measured. Wild-type mice showed significant late OKRs with a stimulus in an appropriate range of spatiotemporal frequencies (0.0625-0.25 cycles/°, 0.75-3.0 Hz, 3-48°/s), but mutant mice did not show late OKRs in response to the same visual stimuli. The results suggest that two groups of direction-selective ganglion cells play different roles in OKRs: ON direction-selective ganglion cells contribute to both initial and late OKRs, whereas ON-OFF direction-selective ganglion cells contribute to OKRs only transiently.

Protein kinase C-mediated regulation of matrix metalloproteinase and tissue inhibitor of metalloproteinase production in a human retinal müller cells.

PURPOSE: Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix (ECM) proteins in the retina. Breakdown of ECM proteins results in neovascularization and tractional retinal detachment, which eventually lead to the symptoms of proliferative diabetic retinopathy. Müller cells are reported to be one of the MMP-producing cells in the retina. However, the molecular mechanism of MMP production derived from Müller cells remains to be fully elucidated. MATERIALS AND METHODS: The human retinal Müller cell line (MIO-M1) was continuously-subcultured in high glucose (25 mM) condition. After the cells reached confluence, they were treated for 24 h with phorbol ester and/or a protein kinase C (PKC) inhibitor, GF109203X in high (25 mM) or low (5 mM) glucose condition. Gelatinase activities in conditioned medium were assessed using gelatin zymography. RT-PCR was performed to analyze the mRNA expression level of MMP-9. Western blot analysis used to detect the protein expression of tissue inhibitors of metalloproteinases (TIMPs). Electrophoresis mobility shift assay was conducted to examine transcription factors involved in MMP-9 transcription. RESULTS: We demonstrated the protein kinase C (PKC)-mediated regulation of proMMP-9 transcription and protein expression through the action of phorbol ester, an activator of PKC. Moreover, we demonstrated the expression of TIMPs, known as natural inhibitors of MMPs at the protein level in a human retinal Müller cell line for the first time, and report that production of these proteins was also regulated in a PKC-dependent manner. CONCLUSION: Our results suggest that imbalance between MMP and TIMP proteins may promote neovascularization by PKC activation in retinal Müller cells. In addition, the development of novel compounds with regulatory action on MMP and TIMP production through inhibiting PKC activity in retinal Müller cells may lead to new therapeutic approaches for the treatment and prevention of diabetic retinopathy.

Principal Fourier component of motion stimulus dominates the initial optokinetic response in mice.

Optokinetic responses (OKRs) are reflexive eye movements elicited by a moving visual pattern, and have been recognized in a variety of species. Several brainstem and cortical structures are known to be implicated in the generation of OKRs in primates, while the OKRs of afoveate mammals have been posited to be dominated by subcortical structures. To understand the subcortical mechanism underlying OKRs, the initial OKRs to horizontal quarter-wavelength steps applied to vertical grating patterns were studied in adult C57BL/6J mice under the monocular viewing conditions. The initial OKRs to sinusoidal gratings showed directional asymmetry with temporal-to-nasal predominance, a common characteristic of afoveate mammals that uses the subcortical structures to elicit OKRs. We then examined whether the OKRs of afoveate mammals are driven by the same visual features of the moving images as those in primates. The OKRs in mice were elicited by using the missing fundamental (mf) stimuli and its variants that had been used to understand the mechanism(s) underlying the cortical control of eye movements in primates. We obtained the results indicating that the OKRs of mice are driven by the principal Fourier component of moving visual image as in primates despite the differences in neural circuitries.

Impact of Clinical Response on Different Approved Doses in Japan and the United States.

The pharmaceutical industry has increasingly aimed to achieve efficient strategies for simultaneous international and worldwide development of medicines, and there has been a growing need to understand ethnic differences in drug evaluation. Japan is one of the unique countries in which substantial domestic clinical data are required for dose selection as well as for marketing authorization. However, it appears challenging to accumulate a large amount of data in a single country in the recent shift to international drug development. To gain a better understanding of the influence of ethnic factors, the dosages of the products approved in Japan during 2003-2010 were reviewed, and differences in clinical responses between Japan and the United States were evaluated using a modeling approach. Of new medicines (new molecular entities) approved in Japan, 39 products (28.1%) have been approved at a different dose level compared with the United States, of which 13 products have considerable difference, twice or greater. Of those 13 products, only 2 were suggested to have a different clinical response, although limited data availability should be taken into careful consideration. Further investigation is recommended to establish new approaches for appropriate dose selection and thereby increase the efficiency of international drug development.