Association between seropositivity and discontinuation of tumor necrosis factor inhibitors due to ineffectiveness in rheumatoid arthritis.

INTRODUCTION/OBJECTIVES: Discontinuation of biologic therapy in rheumatoid arthritis is attributable to various reasons, with the most important cause being insufficient response. In this study, we investigated the association between rheumatoid factor (RF) and anti-citrullinated protein autoantibody (ACPA) status and the discontinuation of tumor necrosis factor inhibitors (TNFi) therapy due to insufficient response in bio-naïve rheumatoid arthritis (RA) patients. METHOD: This study included patients enrolled in the Tsurumai Biologic Communication Registry in Japan. The crude comparison of TNFi discontinuation due to ineffectiveness between seropositive and seronegative patients was analyzed using the cumulative incidence function of competing events and Gray test. We assessed the associations between baseline patient characteristics and discontinuation of TNFi therapy due to insufficient response using Fine-Gray proportional hazard regression. Fine-Gray proportional hazard analysis considered competing events of interest, including insufficient response, adverse event, palliation, and personal reasons. RESULTS: Of 1237 patients evaluated, 79.3% were positive for RF and 85.4% for ACPA; 72.6% were double positive and 11.1% were double negative. TNFi therapy had been discontinued because of insufficient response at 200 weeks in 19.8% RF-positive, 16.7% RF-negative, 23.0% ACPA-positive, and 13.8% ACPA-negative patients. There was a significantly higher discontinuation rate due to insufficient response in ACPA-positive patients than in ACPA-negative patients using Gray test, with a similar trend as that for RF status. RF positivity was significantly predictive of the discontinuation of TNFi therapy due to ineffectiveness using Fine-Gray proportional hazard regression analysis after adjusting for baseline characteristics, including age, sex, stage, class, disease activity at baseline, methotrexate use, and prednisolone use [hazard ratio 1.73 (95% confidence interval 1.07-2.80)]. CONCLUSIONS: Using Fine-Gray proportional hazard regression, we demonstrated that RF positivity was related to a higher discontinuation rate of TNFi therapy due to ineffectiveness in bio-naïve RA patients. Key Points • RF positivity is related to a higher discontinuation rate of TNFi therapy due to ineffectiveness. • ACPA is not predictive of a discontinuation of TNFi therapy due to ineffectiveness.

Structure-activity relationships of flavanones, flavanone glycosides, and flavones in anti-degranulation activity in rat basophilic leukemia RBL-2H3 cells.

The incidence of type I allergies, which are associated with mast cell degranulation and local inflammation, is increasing, and new treatments are needed. To date, structure-activity relationships of flavonoids in their degranulation-inhibiting activity have not been systematically characterized. In the current study, the degranulation-inhibiting activity of a series of flavonoids was evaluated. The following three observations were made: (1) the activity disappears when a sugar moiety is introduced into the A ring of the flavanone; (2) the activity depends on the number of hydroxyl groups on the B ring; (3) the activity is markedly enhanced when a double bond is introduced into the C ring. The information obtained in the current study may guide the development of a therapy for type I allergies.

Structure-activity relationship of flavanone. Anti-degranulation activity of 7-O-substituted hesperetin.

A series of 7-O-substituted hesperetins was evaluated for degranulation-inhibiting activity in rat basophil leukaemia cells. 7-O-Methyl and 7-O-ethyl hesperetin exhibited potent anti-degranulation activity compared with the original hesperetin.

Endovascular aneurysm repair for an abdominal aortic aneurysm and a left ruptured common iliac artery aneurysm in a patient with hepatocellular carcinoma: report of a case.

We performed an endovascular aneurysm repair (EVAR) for an abdominal aortic aneurysm (AAA) and a ruptured common iliac artery aneurysm (rCIAA) in a patient complicated by severe liver dysfunction due to obstructive jaundice resulting from hepatocellular carcinoma (HCC). A 68-year-old male presented with acute lower abdominal pain. Abdominal computed tomography (CT) showed a 4.5-cm infrarenal AAA, a 6.0-cm left rCIAA with retroperitoneal hematoma and a 13-cm mass in the liver, which was suspected to be HCC. His laboratory data showed severe liver dysfunction. An emergency EVAR was done under local anesthesia because of his liver dysfunction. He was transferred to another hospital without any complications.

Bolus ingestion of individual branched-chain amino acids alters plasma amino acid profiles in young healthy men.

Physiological conditions in humans affect plasma amino acid profiles that might have potential for medical use. Because the branched-chain amino acids (BCAAs) leucine, isoleucine and valine are used as medicines and supplements, we investigated the acute effects of individual BCAAs (10-90 mg/kg body weight) or mixed BCAAs ingested as a bolus on plasma amino acid profiles in young healthy men. Plasma leucine levels rapidly increased and peaked around 30 min after leucine ingestion. Concentrations of plasma isoleucine, valine and phenylalanine subsequently decreased after ingestion, and those of methionine and tyrosine tended to decrease. The effects of ingested leucine on other plasma amino acids were biphasic, being higher at lower doses (10-20 mg/kg body weight). Isoleucine or valine intake also caused corresponding plasma amino acid concentrations to rapidly elevate, and peaks at 30-40 min after ingestion were much higher than that of plasma leucine after leucine ingestion. However, the increase in plasma isoleucine and valine concentrations essentially did not affect those of other plasma amino acids. The rate of decline among peak plasma BCAA concentrations was the highest for leucine, followed by isoleucine and valine. Oral mixed BCAAs promoted the decline in plasma isoleucine and valine concentrations. These results suggest that plasma leucine is a regulator of the plasma concentrations of BCAAs, methionine and aromatic amino acids.

Engineering tumors with 3D scaffolds.

Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.

The sleep-enhancing effect of valerian inhalation and sleep-shortening effect of lemon inhalation.

We examined the effects of odorant inhalation on the sleep-wake states in rats. Odorants used in the experiment were clove, jasmine, lavender, lemon, peppermint, pine, rose, sandalwood, valerian, and ylang-ylang. Valerian and rose inhalation significantly prolonged the pentobarbital-induced sleeping time, whereas lemon inhalation significantly shortened it. The effect of valerian inhalation was markedly noticeable. In the anosmic rats, a significant effect of odorants on the pentobarbital sleep time was not seen. Electroencephalographic studies on natural sleep revealed that rose inhalation did not exert any significant effect on sleep, but a significant shortening in sleep latency and a significant prolonging in total sleep time were observed with valerian inhalation, whereas a significant prolonging in sleep latency was observed with lemon inhalation. Such effects of valerian and lemon inhalation were not admitted in anosmic rats. gamma-Aminobutyric acid (GABA) transaminase assay indicates that valerian inhalation decreases the activity of the enzyme and enhances GABA activity. Although valerian has been reported to exert a good effect for sleep as a medicine for internal use, the present study is the first medical report suggesting that the inhalation of valerian may enhance the sleep. On the other hand, the present results may suggest the possibility that lemon inhalation may cause a worsening of insomnia symptoms.

Prior intraperitoneal injection of rat recombinant IL-6 increases hypothalamic IL-6 contents in subsequent forced swim stressor in rats.

BACKGROUND: Cytokines do not only mediate responses to infection, but are also involved in behavioral and physiological responses to psychological stressors. IL-6 has received special attention in relation to the development of posttraumatic stress disorders and depression. OBJECTIVE: We tested effects of prior injection of rat recombinant IL-6 (rrIL-6) on behaviors induced by the forced swim (FS) stressor, and central and peripheral responses of IL-6 to FS. METHODS: Rats were injected intraperitoneally with either rrIL-6 (250 ng/0.5 ml) or equal-volume sterile saline twice within an interval of 24 h. One hour after each injection, the rats were exposed to FS or remained at the home cage (control). RESULTS: Injection of rrIL-6 did not affect immobility, swimming or climbing behaviors during FS compared with the saline control. Although FS was not a significant factor for hypothalamic and midbrain IL-6 mRNA and plasma IL-6 responses, FS with prior administration of rrIL-6 significantly increased hypothalamic IL-6 contents in response to FS compared with the saline injection-FS condition. CONCLUSIONS: Our results suggested that stressor alone had no influence on plasma IL-6 levels and IL-6 mRNA expression levels in midbrain and hypothalamus, but administration of rrIL-6 followed by FS significantly increased hypothalamic IL-6. Our results support the notion that the interaction between IL-6 and stressor might have implications for the pathophysiology of IL-6-induced depressive symptoms.

Effects of single and repeated prolonged stress on mu-opioid receptor mRNA expression in rat gross hypothalamic and midbrain homogenates.

This study tested the hypothesis that stress-induced opioid peptides may have stimulative and inhibitive influence on mu opioid receptor (MOR) mRNA expression and hypothalamus. Several studies have investigated the effects of stress on MOR mRNA expression in rat brain, but almost none compared the response to single versus repeated stresses. Here, we examined the effects of single and repeated stress on MOR mRNA expression in different rat brain regions using reverse transcriptase-polymerase chain reaction (RT-PCR). Following a single episode of restraint stress for 4 h (1R) or 4 h per day on 2 (2R) or 3 (3R) consecutive days, the hypothalamus and midbrain were removed immediately and MOR mRNA levels in both regions were determined by RT-PCR. Blood samples were also collected for simultaneous measurement of serum adrenocorticotropic hormone (ACTH) and corticosterone (CS). MOR mRNA expression was significantly higher in both regions in the 2R group, whereas expression levels in the 3R group did not differ from controls. In the 1R group, hypothalamic MOR expression was equivalent to that in controls, but expression was significantly higher in the midbrain. Serum ACTH levels were significantly higher only in the 1R group, whereas serum CS was significantly higher in both the 1R and 3R groups. Our findings indicate that the influence of restraint stress on MOR mRNA expression in the hypothalamus is different than in the midbrain region in rats. Endogenous opioid peptides released in response to stress may paradoxically have an effect on the HPA axis.

Effects of single and repeated restraint stresses on the expression of beta(1)-adrenoceptor mRNA in the rat hypothalamus and midbrain.

We examined the effects of single and repeated restraint stresses on the expression of beta(1)-adrenoceptor mRNA in the rat midbrain and hypothalamus using reverse transcriptase-polymerase chain reaction (RT-PCR). After the rats had been restrained for 4 h (single stress), or for 4 h per day during 2 or 3 consecutive days, the hypothalamus and midbrain were removed immediately and beta(1)-adrenoceptor mRNA levels in these regions were determined by RT-PCR. Single stress significantly decreased the mRNA level in the hypothalamus, but the mRNA level was near control levels after 2 and 3 days of stress. In the midbrain, single stress had no effect on the mRNA level, but 2 days of stress significantly increased it.