[Angioimmunoblastic T-cell lymphoma after immune checkpoint inhibitor-combined chemotherapy for lung cancer].

A 68-year-old male patient with lung adenocarcinoma, who was treated with chemotherapy and immune checkpoint inhibitors (ICIs), developed lymphadenopathy during treatment. His para-aortic lymph nodes increased to 2.0 cm in diameter. Both inguinal lymph nodes were 1.5 cm in diameter, and multiple hepatic masses appeared. After the ICI readministration, both inguinal lymph nodes increased to 2.0 cm in diameter, but the para-aortic lymph nodes and hepatic masses remained. Angioimmunoblastic T-cell lymphoma (AITL) diagnosis was established after the right inguinal lymph node biopsy, which was accompanied by an infiltration of Epstein-Barr virus (EBV)-encoded small ribonucleic acid-positive B-cells. After the ICI discontinuation, the inguinal lymph nodes decreased to 1.5 cm in diameter, but the para-aortic lymph nodes remained, and hepatic masses increased. Hepatic lesions were possibly lung cancer metastasis. The ICI administration and EBV reactivation were potentially associated with AITL development in the present case. The natural shrinkage of lymphoma after the ICI cessation implied the immunological mechanism like that of the methotrexate-related lymphoproliferative disease.

Familial Background Factors And Their Association With Non-Organic Visual Loss.

PURPOSE: To identify new types of clinical findings that could be used to diagnose and treat non-organic visual loss (NOVL). METHODS: This study retrospectively examined the records of 191 patients diagnosed with NOVL at the Kato Eye Clinic. Clinical characteristics, including uncorrected visual acuity (UCVA) and complaints of vision loss, were compared in 125 of 191 patients with NOVL and control subjects with organic refractive errors, identified during annual school health checks. If available, familial background data for the NOVL patients were compared with data from a mass population study. Familial background data included the presence of siblings, and whether the mother worked outside the home. RESULTS: Patients with NOVL were more likely to be younger and female (P=0.02, and P<0.001, respectively). UCVA was statistically similar in the better eyes of the NOVL and control subjects (P=0.60), even though the NOVL patients were much more likely to be emmetropic (P<0.001). Complaints of vision loss were significantly more common in the patients with NOVL than in the control subjects (P=0.001). There was no significant difference in the presence of siblings between the subjects in the mass population study and the patients with NOVL (P=0.38), but the NOVL patients were significantly more likely to have a mother who did not work outside the home (P=0.01). CONCLUSION: Patients with NOVL tended to be younger, female and to complain more often of vision loss, compared to control subjects with organic refractive errors. Familial background factors, including the presence of siblings or a mother working outside the home, seemed not to be associated with the pathogenesis of NOVL, compared to subjects in a mass population study.

Immuno-pillar chip: a new platform for rapid and easy-to-use immunoassay.

We present a new rapid and easy-to-use immunoassay chip which we have named the immuno-pillar chip. It has hydrogel pillars, fabricated inside a microchannel, with many antibody molecules immobilized onto 1 µm diameter polystyrene beads. To evaluate the chip performance, we applied it to the sandwich assay of C-reactive protein (CRP), α-fetoprotein (AFP) and prostate-specific antigen (PSA), a cardiac and inflammation marker, tumors and prostate cancer markers, respectively. For detection of disease markers, we confirmed the chip provides rapid analysis (total assay time of about 4 min) with high sensitivity, it is easy-to-use (no special skills are needed), and it uses small volumes of the sample and reagent (0.25 µL each). Moreover, multiplex assay for three biomarkers was also possible. Additionally, the immuno-pillar chip has a big advantage of having hardly any influence on the assay results even if the introduction quantities of the sample or reagents are different.

Human basophils and cytokines/chemokines.

Basophils comprise the smallest population in human peripheral blood leukocytes. The role of basophils in the pathogenesis of allergic diseases has long been obscure, although their accumulation and activation in tissues have suggested their potential importance. Recent advances in the field of basophil biology have indicated that cytokines and chemokines are the primary regulators of basophil functions. In addition, various functions of these cells seem differently modulated. The evidence strongly supports the notion that basophils exposed to these substances and allergens will behave as unique effector cells that presumably play proinflammatory roles in type I allergic reactions.

Blocking antibody is generated in allergic rhinitis patients during specific immunotherapy using standardized Japanese cedar pollen extract.

BACKGROUND: Japanese cedar pollen is by far the most important cause of allergic rhinitis in Japan. In this study, we assessed the induction of blocking antibody during specific immunotherapy (SIT) using a recently standardized allergen extract from Japanese cedar pollen. METHODS: Basophils from nonallergic subjects were passively sensitized with serum samples prepared from pollinosis patients before and after SIT; all patients showed good clinical efficacy. The cells were then stimulated with the standardized allergen, and histamine release was measured. In most experiments, the basophil stimulation buffer contained 1% serum. RESULTS: Pollinosis patients' sera obtained both before and after SIT showed essentially similar sensitizing capacity for basophils. Basophil degranulation in response to a relatively low concentration of pollen extract was effectively suppressed by addition of post-SIT serum samples, indicating the presence of blocking antibody. The blocking antibody was IgG, and its potency varied widely among the donor patients. CONCLUSIONS: The standardized allergen extract from Japanese cedar pollen is useful not only for clinical application in SIT, but also for testing for induction of blocking antibody during SIT.

Enhancement of basophil apoptosis by olopatadine and theophylline.

Regulation of basophil survival is an important aspect in the pathogenesis of allergic inflammation associated with local accumulation of basophils. However, pharmacologic modulation of basophil survival is largely unknown except for the apoptosis-enhancing effect of glucocorticoids. We tested the effects of two anti-allergic and anti-asthmatic drugs, olopatadine and theophylline, on basophil survival. Basophils were highly purified from normal human peripheral blood. Apoptosis was analyzed by flow cytometry using annexin V staining or another staining method that detected alterations in the mitochondrial transmembrane potential. In addition to the conventional method using annexin V, basophil apoptosis was successfully established by analysis of the mitochondrial transmembrane potential. Olopatadine decreased the number of live basophils, and they induced apoptosis of basophils during culture. The decline in live basophils was induced by olopatadine even when low doses of IL-3 were included in the culture medium. Theophylline also affected basophil apoptosis and induced a decrease in the number of live basophils. Basophil apoptosis was enhanced by both olopatadine and theophylline. This effect may partly explain the pharmacologic basis of why these drugs are effective on allergic diseases.

IgE- and FcepsilonRI-mediated enhancement of surface CD69 expression in basophils: role of low-level stimulation.

Surface-expressed CD69 is a recently recognized activation marker for basophils and is reported to be strongly induced in vitro by IL-3. In this study, we investigated whether IgE- and high-affinity receptor for IgE (FcepsilonRI)-dependent stimuli can affect basophil CD69 expression. Highly purified basophils were cultured for 24 h in the presence of anti-FcepsilonRI alpha-chain mAb, CRA-1 and IL-3, and surface CD69 expression was analyzed by flow cytometry. CRA-1 mAb at 1 ng/ml or lower concentrations, levels too low to provoke direct histamine release, dose-dependently enhanced surface CD69 expression in the presence of IL-3, although low-dose CRA-1 mAb failed to induce CD69 expression in the absence of IL-3. Recombinant Der f 2 at 10 to 100 pg/ml enhanced CD69 levels in the presence of IL-3 in basophils from mite-sensitive subjects. These results suggest that allergens may influence basophil CD69 expression even when the levels of the antigens are too low to trigger direct degranulation. Upregulated CD69 expression on locally accumulated basophils in bronchial asthma may be attributed at least in part to a combination of local cytokines, especially IL-3, plus exposure to low levels of IgE-crosslinking allergens.

Three cases of ortho-phthalaldehyde-induced anaphylaxis after laryngoscopy: detection of specific IgE in serum.

BACKGROUND: Ortho-phthalaldehyde (OPA) has recently been used as a disinfectant for various medical apparatuses. OPA is not generally recognized as a potential allergen. CASE SUMMARY: Subsequent to our recent report describing a patient presenting with OPA-induced anaphylaxis following laryngoscopy, we experienced two more such cases. In all three cases, the basophil histamine release test was useful for identifying the allergen as OPA. OPA-specific IgE was successfully detected in the serum of the patients by ELISA. DISCUSSION: Physicians and co-medical workers need to be aware of potential allergens to which patients may be exposed during routine medical procedures.

Involvement of NMDA receptor mechanisms in the modulation of serotonin release in the lateral parabrachial nucleus in the rat.

Microdialysis was employed to investigate whether N-methyl-d-asparatate (NMDA) glutamate receptor mechanisms are involved in the modulation of serotonin (5-hydoxytryptamine, 5-HT) release in the region of the lateral parabrachial nucleus (LPBN) in freely moving rats. Perfusion of NMDA (10 and 50 microM) through the microdialysis probe significantly enhanced extracellular concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the LPBN area. Local perfusion of the NMDA antagonist dizocilpine (MK801, 10 and 50 microM) did not change the basal 5-HT and 5-HIAA levels in the LPBN area. MK801 (10 microM) administered together with NMDA antagonized the stimulant effect of NMDA (10 microM). The intake of 0.3M NaCl and water induced by subcutaneous injections of the diuretic furosemide (FURO, 10 mg/kg) and the angiotensin converting enzyme inhibitor captopril (CAP, 5 mg/kg) produced significant increases in the 5-HT and 5-HIAA concentrations in the LPBN area. The increased levels of 5-HT and 5-HIAA caused by the combined treatment with FURO and CAP were attenuated by perfusion of MK801 (10 microM). These results indicate the participation of NMDA receptors in the control of 5-HT release in the LPBN area.

Expression and function of toll-like receptors in human basophils.

We investigated the expression and function of a panel of Toll-like receptors (TLRs) in human basophils. Basophil preparations constitutively expressed TLR2, TLR4, TLR9 and TLR10 mRNAs (TLR4 > TLR2 >> TLR9, TLR10). Although TLR mRNA expression in basophils was generally less prominent compared with those in neutrophils and monocytes, basophils expressed significantly higher levels of TLR2 and TLR4 mRNA than eosinophils. Various TLR ligands (Pam3Cys-Ser-Lys4, poly I:C, lipopolysaccharide, R-848, CpG DNA) were tested, but none affected the expression level of adhesion molecule CD11b or the viability of freshly purified basophils. On the other hand, when basophils were pretreated with interferon-gamma before stimulation with TLR ligands, only the TLR4 ligand, lipopolysaccharide, upregulated CD11b expression. However, the surface levels of TLR2 and TLR4 on the interferon-gamma-treated basophils showed no obvious changes. These results suggest that TLR4 on basophils may be involved in the pathogenesis of infection-induced exacerbation of allergic inflammation by modulating basophil functions.

GABAergic systems in the nucleus tractus solitarius regulate noradrenaline release in the subfornical organ area in the rat.

Previous studies have shown that catecholaminergic neurons in the nucleus tractus solitarius (NTS) with ascending projections to the subfornical organ (SFO) are highly sensitive to gamma-aminobutyric acid (GABA). To clarify the role of the GABAergic system in the NTS in the regulation of the activity of noradrenergic NTS projections to the SFO, the present study was carried out to investigate the effects of local administration (50 nl) of GABA, the GABA(A) agonist muscimol, the GABA(B) agonist baclofen, the GABA(A) antagonist bicuculline or the GABA(B) antagonist phaclofen into the NTS on the release of noradrenaline (NA) in the region of the SFO using microdialysis techniques in rats under urethane anesthesia. Microinjections of GABA (10(-4) - 10(-2) M) into the region of the NTS significantly decreased the NA release in the SFO area. Injections of either muscimol (10(-4) - 10(-2) M) or baclofen (10(-5) - 10(-3) M) into the NTS region significantly attenuated the NA release in the SFO area. Injections of bicuculline (10(-5) and 10(-4) M), but not phaclophen (10(-6) - 10(-4) M), into the NTS region significantly enhanced the NA release in the SFO area, suggesting that the GABAergic system in the NTS may tonically inhibit the NA release in the SFO area through a GABA(A) receptor mechanism. Neither injection of these drugs in any of the doses used in this study into the NTS region caused any significant changes in the NA release in the sites away from the SFO. Injections of vehicle (50 nl) into the NTS region had no significant effect on the NA release in either the SFO area or the sites away from the SFO. These results suggest that the GABAergic system in the NTS may serve to decrease the release of NA in the SFO area and the two types of GABA receptors are involved in the modulation of the NA release.

The action of the A1 noradrenergic region on the activity of subfornical organ neurons in the rat.

Electrical stimulation of the A1 noradrenergic region of the ventrolateral medulla produced synatic excitation (n = 19, 9%), inhibition (n = 5, 2%) or no effect (n = 184, 89%) in the activity of a total of 208 neurons in the subfornical organ (SFO) in male rats under urethane anesthesia. Almost all (n = 18) of the excitatory responses (n = 19) were blocked by microiontophoretically-applied phentolamine, an alpha-adrenergic antagonist, but not by timolol, a beta-adrenergic antagonist. The inhibitory response of all the neurons (n = 5) tested was prevented by iontophoretically applied timolol, but not by phentolamine. Approximately a half (n = 9) of SFO neurons that demonstrated the excitatory response to A1 region stimulation exhibited an increase in neuronal activity in response to hemorrhage (10 ml/kg b.w.t.), while remaining neurons (n = 10) were unresponsive. Hemorrhage did not cause any change in the activity of all the neurons (n = 5) that demonstrated the inhibitory response to A1 region stimulation. These results suggest that the medullary inputs to approximately 10% of SFO neurons tested are mediated by alpha-adrenergic excitatory and beta-adrenergic inhibitory pathways, and imply that a part of the excitatory pathways may transmit the peripheral baroreceptor information.

Effects of type of cognitive demand on bilateral advantage in interhemispheric processing.

The relationship between cognitive task demand and effect of bilateral advantage (BLA) was examined. In Experiment 1, the task demand based upon visual stimulus complexity was manipulated. One-digit and two-digit numbers were presented in the left, right or both visual fields tachistoscopically and subjects were requested to identify the numbers. The results showed no BLA, although a right visual field advantage was demonstrated. In Experiment 2, cognitive demand in terms of memory was manipulated. Subjects were asked to recall one-digit numbers that were presented successively once, three and five times in the left, right or the both visual fields. The results did not show any sign of BLA in the recall of numbers. In Experiment 3, a greater memory load task was given than that in Experiment 2, where two-digit numbers were presented successively (once, three and five times). Subjects were asked to recall the numbers. The results showed a significant BLA in the recall of numbers, i.e., the correct numbers in the correct temporal positions. These results strongly suggest that a benefit of redundant bilateral visual fields presentation is shown only in a highly cognitively demanding task, especially when it involves phonological memory loads.

Color of computer display frame in work performance, mood, and physiological response.

The effects of the color of a personal computer screen on work performance, psychological mood, and autonomic response were investigated. 24 subjects were asked to perform visual tasks presented on the computer display. Three types of computer monitor, which were colored red, blue, or beige, were employed to present visual cognitive tasks. The mood measure, the Japanese Stress Arousal Check List, and heart rate measurement were administered before and after work on each color of computer monitor. Analysis of a low-demand task (Exp. 1) showed that the red computer monitor reduced visual task performance compared to that with the blue, while the blue monitor decreased visual task performance on a high-demand task (Exp. 2). The color of the monitor did not affect mood or heart rate. Based on these findings, the effect of the color of environmental cues on work was discussed.