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Background: Patients with psoriatic arthritis (PsA) have an increased cardiovascular (CV) risk. We should have strategies for primary cardiovascular prevention in PSA1). But there is no evidence of CV risk management and arterial stiffness about biologics in patients with PsA Objectives: To examine the effect of biologics plus conventional synthetic (cs) DMARDs on arterial stiffness in cs DMARDs resistant PsA patients in a cohort study design. Methods: 38 PSA and patients with moderate to severe active disease despite cs DMARDs treatment (disease activity score: DAPSA2) score>14) were received Biologics plus cs DMARDs. All patients have no previous history of CV. Arterial stiffness was assessed with cardio-ankle vascular index (CAVI, modified pulse wave velocity(PWV)) and augmentation index corrected for a heart rate of 75 beats per minute (AIx@75) at baseline and 24 weeks follow-up. Clinical data were collected at regular visits. CAVI is very similar to pulse wave velocity (PWV), and CAVI measures arterial wall stiffness independent of blood pressure and it is superior to brachial ankle PWV as an index of arterial stiffness2. Results: 35 PsA patients(18 patients adalimumab,13 patients infliximab, and 4 patients ustekinumab, respectively) completed this study, Treatment with biologics(10.88 ± 1.86 and 9.46± 1.14%; p = 0.006), attenuated the CAVI significantly from baseline to 24 weeks follow up. Treatment with biologics(36.4 ± 8.6, 32.1 ± 3.8%; p = 0.008) attenuated the aix@75 significantly from baseline to 24 weeks follow up. DAPSA score improved significantly from baseline to 24 weeks(17.45±6.33, 5.44±3.43: p=0.01). There are no significant differences among biologics about CAVI and aix@75. Surprisingly, improvement of CAVI and aIx@75 were not correlated disease activity at 24 weeks of biologics treatment (CAVI: p=0.91, aIx@75: p=0.88). Biologics improves arterial stiffness independently of its effects on disease activity, since even in high disease activity (4 cases; DAPSA score>28) is halted. Conclusion: These findings suggest that combination therapy, biologics with cs DMARDs not only reduced PsA disease activity but also limited vascular damage in patients with cs DMARDS resistant active PsA References [1] Soren Lund Kristensen, et al. Psoriasis, psoriatic arthritis and cardiovascular risk: are we closer to a clinical recommendation?Ann Rheum Dis. 2015; 74: 321-2. [2] Schoels MM, et al. Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using the DAPSA score. Ann Rheum Dis, 2016; 75: 811-8. Acknowledgement: Thank you for all paitents and colleagues. Disclosure of interests: None declared

Background: We previously reported that pulse exposure of cultured rat neurons to aluminum-maltol resulted in an abnormal distribution of both neurofilament-L (NF-L) and fast axonal transported proteins. It was also found that the presenilin 1 (PS1) missense mutation and aluminum affected early neuronal development of the mouse brain. It has been reported that the presenilin (PS) mutation alters neurite outgrowth, and the axonal transport of the amyloid precursor protein (APP)/PS complex is mediated by kinesin. The present study hypothesizes that aluminum might modulate axonal transport and neurite outgrowth in APP/PS mutant-bearing cells. Methods: We treated SH-SY5Y cells and HEK293 cells bearing FAD mutations with aluminum-maltol (Al-mal) (0, 250 µm, 500 µm, 1 mm, 2 mm) for 1 h, followed by propidium iodide (PI) and Calcein-AM staining, live and dead assay, double staining of NF-L/synaptophysin or APP/JNK interacting protein-1 (JIP-1) 3 days after treatment. Results: Apoptosis was induced Al-mal treatment in a dose-dependent manner in all cell lines. In SH-SY5Y cells bearing PS1 mutations, there were no differences in the rate of cell viability, except for morphological changes observed by Calcein-AM staining. The distribution of NF-L and synaptophysin was modified by PS1 mutations and aluminum, suggesting that the PS mutation induces neuronal dysfunction by disturbance of the axonal transport system. The APP mutation-bearing cell lines showed significant induction of apoptosis compared to that of wild-type cells. Oxidative stress might thus influence cell viability in APP mutation-bearing cells. Enhancement of JIP-1 staining may reflect a disturbance of the intracellular axonal transport system, as well as compensation due to apoptotic changes. Conclusion: The present results, when taken together, show that aluminum alters cell viability and the axonal transport system in FAD pathogenic mutation-bearing cells.

Background: Abnormal sprouting of neurites is one of the neuropathological features of Alzheimer's disease. The mechanism of neurite sprouting of cultured neurons remains unknown. Among small guanosine triphosphate binding proteins, participation of the Rho family has been speculated. Methods: The involvement of Rho-associated kinase in neurite sprouting and in amyloid beta (Αβ) production was investigated in primary cultured rat cortical neurons using morphometric analysis, immunohistochemistry and ELISA assay. Results: In a serum-free medium, Y-27632, a Rho-associated kinase specific inhibitor, was found on the neurite outgrowth; however, there was no effect of Y-27632 on Neurobasal/B27. A custom medium without insulin was prepared because insulin potentially influences neurite formation. In the insulin-free medium, 10 µmol/L Y-27632 appeared to promote neurite outgrowth, showing significant increases in neurite length and in the number of neurite terminals. Y-27632 generated abnormal neurites, which were positively stained by both MAP2 and neurofilament-L. Furthermore, the effect of Y-27632 on Αβ production in primary cultured rat cortical neurons was investigated. Inhibition of Rho-associated kinase increased the ratio of Αβ 42 /40+42. Conclusion: Our findings indicated that Rho-associated kinase might be involved not only in neurite sprouting, but also in Αβ production in primary cultured neurons. Considering these two effects, inhibition of Rho-associated kinase activity might be involved in the pathology of Alzheimer's disease.

In dark-reared animals, visual exposure is expected to induce drastic changes in both the physiology and anatomy of the cortical neurons, including the rearrangement of their cytoskeletal structures. Phosphorylation of neurofilament-L (NF-L) is probably associated with relatively short-term structural plasticity in vivo, because the assembly and disassembly of the filaments are regulated by phosphorylation of the head domain of NF-L. Thus, by using a series of site- and phosphorylation state-specific antibodies against NF-L, we examined how visual activation induces the phosphorylation of NF-L in the rat brain. We found no specific immunoreactivity for phosphorylated NF-L in the brain of naive rats, whereas one-hour ambient light exposure after dark rearing for ten weeks from birth induced marked phosphorylation of NF-L selectively. Also, the NF-L phosphorylation was found to be localized in the primary and secondary visual cortical areas. These findings suggest that the selective phosphorylation of NF-L plays an important role in the structural plasticity related to the visual experience.

Background: The pathology of Alzheimer's disease (AD) has not been fully elucidated. Presenilin 1 (PS1) mutation is one of the major genetic factors of AD, while aluminum is a candidate for the environmental risk factor. Methods: First, we investigated the influence of PS1 mutation on the neuronal development in ‘knock-in’ mice of PS1 1213T mutation. Next, the effect of prenatal exposure to aluminum on the neuronal development of the knock-in mice was examined. Results: In the newborns with the mutated PS1 allele, a tendency of delayed neurological development was seen and an abnormal distribution of neurofilaments was found, implying that the PS1 mutation might alter early neuronal development. Intraperitoneal administration of aluminum-maltol resulted in the increase of aluminum in brain tissues of newborns, and in abnormal distribution of neurofilaments. Furthermore, the PS1 mutation promoted a change in neurofilament distribution induced by exposure to aluminum. Conclusion: Thus, PS1 mutation and aluminum are suggested to affect early neuronal development, as reflected in some aspects of the pathology of AD.

Background Vimentin, which is one of the intermediate filaments, is the major cytoskeletal component in developing neurones or neuroblastoma cells. Rho-associated kinase (Rho-kinase), is rich in neurones and is found downstream of Rho. It is involved in the agonist-induced neurite retraction of neuronal cells, and phosphorylates vimentin at Ser-38 and Ser-71 resulting in in vitro disassembly of the filaments. Results We have investigated the distribution of vimentin phosphorylated by Rho-kinase in N2a neuroblastoma cells using site-specific phosphorylation-dependent antibodies. TM71 immunoreactivity, which specifically indicates Ser-71 phosphorylation on vimentin, was found in some neurites of dibutyryl cAMP-differentiated N2a cells. Transfection of the constitutively active form of Rho-kinase, CAT, significantly elevated TM71 immunoreactivity, and induced neurite retraction or cell rounding. Conversely, transfection of the dominant negative form of Rho-kinase, RB/PH(TT), or treatment of 10 μM Y-27632, a Rho-kinase specific inhibitor, abolished TM71 immuno-reactivity, and induced irregular neurite outgrowth. In contrast, 20 n M okadaic acid (OA) induced neurite retraction and specifically elevated TM71 immunoreactivity. In the OA-induced neurite retraction, tubulin disappeared in retracting neurites, where vimentin and actin remained co-localized. Furthermore, the OA-induced elevation of TM71 immunoreactivity and neurite retraction were completely blocked by pretreatment with 10 μM Y-27632, or by the ectopic expression of RB/PH(TT). Conclusions This study suggests that the localized phosphorylation of vimentin by Rho-kinase in neurites was closely related with the cellular morphology of N2a cells, and that the Rho-kinase activity towards vimentin was balanced with OA-sensitive phosphatases.

We recently reported that CaMKII-dependent phosphorylation of the neurofilament-L (NF-L) head domain was induced in the apical dendrites during long-term potentiation. Long-term depression (LTD) is another cellular model for neuronal plasticity. In the present study, we examined the phosphorylation of NF-L during hippocampal LTD using a series of phospho-specific antibodies against the NF-L head domain. During LTD, these antibodies visualized NF-L phosphorylation at Ser57 in the apical dendrites of the hippocampal pyramidal neurons. The assembly and disassembly of NF-L filaments are regulated by phosphorylation of its head domain. Thus, our results indicated that NF-L phosphorylation might be associated with alterations of the neuronal structure during LTD.

Fifty six year old male presented with a sudden, tender swelling of his right leg. A diagnosis of femoral vein thrombosis was made because of typical purple skin color and palpable thrombosed femoral vein with intact arterial flow and then anticoagulant and fibrinolytic therapy was initiated. Subsequently, he suffered from disorientation, spiking fever, thrombocytopenia, hemolytic anemia and renal failure, all of which were compatible with thrombotic thrombocytopenic purpura (TTP). As the swelling of the leg subsided, the entire skin of the leg became gangrenous in spite of the satistactory arterial circulation, which necessitated above knee amputation. Medical treatment consisted of corticosteroid, protease inhibitor and gamma globlin resulted in rapid improvement in all the clinical manifestations of TTP. Histological examination of the amputated of leg revealed the presence of multiple thrombotic occlusion of arterioles in calf muscles, which is compatible with changes in TTP. In this case, TTP was more likely triggered by the deep vein thrombosis, which has not been reported before as the underlying disease of TTP. Arteriole thrombosis was formed because of the stagnant venous drainage, which is also rare sequelae of TTP.

FAD mutations in presenilin-1 (PS1) cause attenuation of the induction of the endoplasmic reticulum (ER)-resident chaperone GRP78/BiP under ER stress, due to disturbed function of IRE1, the sensor for accumulation of unfolded protein in the ER lumen. PERK, an ER-resident transmembrane protein kinase, is also a sensor for the unfolded protein response (UPR), causing phosphorylation of eukaryotic initiation factor 2a (eIF2a) to inhibit translation initiation. Here, we report that the FAD mutant PS1 disturbs the UPR by attenuating both the activation of PERK and the phosphorylation of eIF2a. Consistent with the results of a disturbed UPR, inhibition of protein synthesis under ER stress was impaired in cells expressing PS1 mutants. These results suggest that mutant PS1 impedes general translational attenuation regulated by PERK and eIF2a, resulting in an increased load of newly synthesized proteins into the ER and subsequently increasing vulnerability to ER stress. 2002 Elsevier Science (USA). All rights reserved.

A potent anti-inflammatory compound, TAI-284, and its optical isomers were subjected to the pharmacological, toxicological and metabolic studies in rats, mice and guinea-pigs. In anti-inflammatory, analgesic and antipyretic activities examined in rats and mice, the d-isomer was the most potent, followed by the racemate, and the l-isomer was the lowest. Similar results were obtained regarding toxicity and ulcerogenicity. The d-isomer maintained the highest plasma level, followed in decreasing order by the racemate and the l-isomer, when they were administered orally to rats. In the same experiment, the plasma level of the l-isomer's metabolites was the highest, followed in decreasing order by that of the racemate's metabolites and that of the disomer's metabolites. In Vitro, the l-isomer was most rapidly transformed into the metabolites while the d-isomer was most slowly transformed. On the other hand, the d-isomer was as potent as the l-isomer in the anti-inflammatory activity in guineapigs. In this species TAI-284 is hardly biotransformed into the metabolites. It is postulated that the rate of biotransformation of these compounds has a great influence on their pharmacological activities.

The pharmacological activities of five metabolites of an anti-inflammatory compound, 6-chloro-5-cyclohexylindan-1-carboxylic acid (TAI-284) were investigated and compared with TAI-284 and phenylbutazone. The metabolite IIb (cis3'-hydroxy-cyclohexyl, β-form) was almost equivalent to TAI-284 regarding antiinflammatory activity as estimated by the carrageenin edema test, and was more active than TAI-284 in the analgesic activity estimated by the phenylquinone writhing test and determination of the ulcerogenic activity. The metabolites IIa (cis-4'hydroxy-cyclohexyl) and IV (cis-3'-hydroxy-cyclohexyl, α-form) had about half the anti-inflammatory activity and one third to one quarter the analgesic activity of TAI-284, however the degree of ulcerogenicity was considerably lower than that of TAI-284. 1 (4'-oxo-cyclohexyl) was less active, and III (trans-4'-hydroxy-cyclohexyl) showed the weakest activity comparable to that of phenylbutazone. Antipyretic activities of all five metabolites were much lower than those of TAI-284. As the pharmacological activities of metabolites varied greatly according to the position of the hydroxyl group on the cyclohexane ring of TAI-284, it is feasible that the distribution pattern and affinity of the metabolites for receptors could be modified.

The effect of 2-phenylaminoadenosine (CV-1808) against myocardial ischemia was studied in anesthetized dogs. During intravenous infusion of CV-1808 (0.25 and 0.5 microgram/kg/min for 10 min) the ST-segment elevation in the epicardial ECG induced by a 5-min occlusion of a coronary arterial branch was occasionally enhanced in association with cardiac acceleration. In a dose of 0.5 microgram/kg/min, the agent inhibited the ST elevation 30 and 60 min after administration. The same dose did not change myocardial blood flow in the ischemic area despite significant systemic hypotension. In hearts with continuous coronary occlusion, CV-1808 (0.3 and 1.0 microgram/kg, i.v. bolus) increased the retrograde blood flow from the ischemic area immediately after administration, suggesting a collateral vasodilating action. Nifedipine (0.5 and 2.5 microgram/kg/min, i.v. for 10 min) and nitroglycerin (0.5 and 5.0 microgram/kg/min, i.v. for 10 min) had no influence on the ischemic ST-segment elevation, while a significant inhibition was seen with propranolol (0.5 mg/kg, i.v.). A moderate hypotension was induced by CV-1808, nifedipine, and nitroglycerin, while a significant reduction in cardiac function was seen after dosing with propranolol.