Evaluation of human herpesvirus-8 viremia and antibody positivity in patients with HIV infection with human herpesvirus-8-related diseases.

Human herpesvirus-8 (HHV-8) viremia is associated with refractory conditions in patients infected with HIV-1. Therefore, we evaluated the factors related to plasma HHV-8-DNA. Participants included patients infected with HIV-1 who visited our hospital. Plasma HHV-8-DNA levels were measured using real-time polymerase chain reaction, and anti-HHV-8 antibodies were assessed through enzyme immunoassays using multiple antigens (K8.1, ORF59, ORF65, and LANA). Factors related to plasma HHV-8-DNA were examined using Fisher's exact test or Mann-Whitney U test. The study involved 36 patients infected with HIV-1, of whom 19 were histologically diagnosed with Kaposi's sarcoma (KS), two had multicentric Castleman's disease (MCD), and 15 did not exhibit HHV-8-related disease. Before the introduction of antiretroviral therapy (ART), plasma HHV-8-DNA was detected in 44% (7/16) of patients with KS and in 9% (1/11) of patients without HHV-8-related disease. Among patients with KS, elevated plasma HHV-8-DNA levels (≥0.05 copies/µL) correlated with the presence of CDC category C diseases other than KS (p = 0.0337), anti-HHV-8 antibody negativity (p = 0.0337), anemia (p = 0.0474), and thrombocytopenia (p = 0.0146). Following ART initiation, the percentage of patients positive for plasma HHV-8-DNA decreased from 44% (7/16) to 6% (1/17), and the percentage of patients positive for anti-HHV-8 antibodies increased from 44% (7/16) to 88% (15/17). Finally, plasma HHV-8-DNA positivity and anti-HHV-8 antibody negativity were observed in two patients with MCD. Our findings suggest that insufficient production of anti-HHV-8 antibodies was associated with HHV-8 viremia, and that anti-HHV-8 antibody production was recovered with ART; thus, indicating the possibility of involvement of humoral immunity in suppressing HHV-8 viremia.

[CD5-positive diffuse large B-cell lymphoma with gastrointestinal infiltration presenting with protein-losing enteropathy].

Protein-losing enteropathy is rarely associated with malignant lymphoma. This report describes the case of a 67-year-old man with diffuse large B-cell lymphoma (DLBCL) and concomitant protein-losing enteropathy who was admitted to our hospital for evaluation of watery diarrhea, edema, and abdominal fullness. On admission, the patient reported a history of weight gain. Subsequent examination showed ascites, hepatosplenomegaly, and hypoalbuminemia. Notably, 99mTc-labeled human serum albumin scintigraphy revealed protein loss from the intestine, and the patient was diagnosed with protein-losing enteropathy. Endoscopy revealed erosive and edematous hyperplasia of the gastric-colonic mucosa, and histopathological evaluation of a biopsy specimen showed proliferation of CD20+ and CD5+ tumor cells. Thus, the diagnosis of DLBCL was histopathologically confirmed. Lymphomatous infiltration of the bone marrow was observed; however, no lymphadenopathy was detected. Based on these findings, the patient was diagnosed with protein-losing enteropathy associated with gastrointestinal infiltration of CD5+ DLBCL. Hypoalbuminemia and diarrhea improved following the initiation of R-CHOP regimen. The DLBCL showed a favorable response to treatment, and gastrointestinal lesions and hepatosplenomegaly improved, along with the resolution of protein-losing enteropathy.

Metabolic state switches between morning and evening in association with circadian clock in people without diabetes.

AIMS/INTRODUCTION: Understanding morning-evening variation in metabolic state is critical for managing metabolic disorders. We aimed to characterize this variation from the viewpoints of insulin secretion and insulin sensitivity, including their relevance to the circadian rhythm. MATERIALS AND METHODS: A total of 14 and 10 people without diabetes were enrolled, and underwent a 75-g oral glucose tolerance test (OGTT) and hyperinsulinemic-euglycemic clamp study, respectively. Participants completed the OGTT or hyperinsulinemic-euglycemic clamp at 08.00 hours and 20.00 hours in random order. Before each study, hair follicles were collected. In mice, phosphorylation levels of protein kinase B were examined in the liver and muscle by western blotting. RESULTS: Glucose tolerance was better at 08 .00 hours, which was explained by the higher 1-h insulin secretion on OGTT and increased skeletal muscle insulin sensitivity on hyperinsulinemic-euglycemic clamp. Hepatic insulin sensitivity, estimated by the hepatic insulin resistance index on OGTT, was better at 20.00 hours. The 1-h insulin secretion and hepatic insulin resistance index correlated significantly with Per2 messenger ribonucleic acid expression. The change (evening value - morning value) in the glucose infusion rate correlated significantly with the change in non-esterified fatty acid, but not with clock gene expressions. The change in non-esterified fatty acid correlated significantly with E4bp4 messenger ribonucleic acid expression and the change in cortisol. In mice, phosphorylation of protein kinase B was decreased in the liver and increased in muscle in the beginning of the active period as, expected from the human study. CONCLUSIONS: Glucose metabolism in each tissue differed between the morning and evening, partly reflecting lipid metabolism, clock genes and cortisol levels. Deeper knowledge of these associations might be useful for ameliorating metabolic disorders.

Liver-specific dysregulation of clock-controlled output signal impairs energy metabolism in liver and muscle.

The liver is the major organ maintaining metabolic homeostasis in animals during shifts between fed and fasted states. Circadian oscillations in peripheral tissues including the liver are connected with feeding-fasting cycles. We generated transgenic mice with hepatocyte specific E4BP4, D-box negative regulator, overexpression. Liver-specific E4BP4 overexpression was also achieved by adenoviral gene transfer. Interestingly, hepatic E4BP4 overexpression induced marked insulin resistance, that was rescued by DBP, a competing D-box positive regulator, overexpression. At basal conditions hepatocyte E4BP4 transgenic mice exhibited increased gluconeogenesis with reduced AKT phosphorylation in liver. In muscle, AKT phosphorylation was impaired after insulin stimulation. Such muscle insulin resistance was associated with elevated free fatty acid flux from the liver and reduced fatty acid utilization as an energy source during the inactive phase. E4BP4, one of the clock-controlled output genes, are key metabolic regulators in liver adjusting liver and muscle metabolism and insulin sensitivity in the feeding-fasting cycles. Its tuning is critical for preventing metabolic disorders.

Virus-infected peripheral blood plasmablasts in a patient with severe fever with thrombocytopenia syndrome.

Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne viral hemorrhagic disease with a high fatality rate. It is caused by the SFTS virus and is endemic in East Asian countries such as China, South Korea, and Japan. Previous studies have shown that plasmablasts appear transiently in peripheral blood during the acute phase of SFTS, but do not specify the characteristics of these plasmablasts. In this report, we describe the features of peripheral blood plasmablasts in a patient with SFTS. Immunohistochemical and immunofluorescence staining detected a small number of atypical lymphocytes expressing the SFTS virus antigen among peripheral leukocytes in a blood sample. The phenotype of the virus-infected cells was CD27+, CD38+, MUM1+, and CD138+, which is consistent with that of plasmablasts. This novel study demonstrates that plasmablasts in the peripheral blood of patients with SFTS are targets of the SFTS virus.

[Acute thrombocytopenia after obinutuzumab administration in a patient with relapsed follicular lymphoma].

A 64-year-old woman was admitted to our hospital because of relapsed follicular lymphoma. Obinutuzumab (OBZ) and bendamustine (GB) therapy was administered for her lymphoma, and thrombocytopenia requiring platelet transfusion was observed after the first course. Although the dose of bendamustine had been reduced, her thrombocytopenia was observed again after the second course. Complete remission of her lymphoma was achieved after 4 courses of GB therapy, and the patient was switched to OBZ maintenance therapy. Nevertheless, thrombocytopenia was observed again during the maintenance therapy with OBZ alone. Observing the platelet count that changed over time after OBZ administration in detail, the platelet count started to decrease 1 hour after the end of OBZ administration, decreased to half after 6 hours, reached the lowest value 4 days after administration, and gradually recovered from 10 days after administration. Although OBZ administration-associated thrombocytopenia is a relatively common complication, acute thrombocytopenia up to 24 hours after administration is rare. However, as in this case, thrombocytopenia may progress in an extremely short time after administration, and it is necessary for clinicians to pay attention to OBZ treatment.

Adrenomedullin has a cytoprotective role against endoplasmic reticulum stress for pancreatic ß-cells in autocrine and paracrine manners.

AIMS/INTRODUCTION: Pancreatic ß-cells are sensitive to endoplasmic reticulum (ER) stress, which has a major role in the context of ß-cell death. Adrenomedullin (ADM) has been shown to exert a cytoprotective effect under various pathophysiological conditions. Several studies have suggested that thiazolidinediones have protective effects on ß-cells. During the course to elucidate the molecular mechanisms by which pioglitazone prevents ß-cell death, ADM emerged as a candidate. Here, we studied the regulation of ADM expression, including the effects of pioglitazone, and its role in pancreatic islets. MATERIALS AND METHODS: We analyzed ADM expression in islet cell lines treated with pioglitazone. The effects of ER stress on ADM and ADM receptor expressions were investigated by analyzing thapsigargin-treated MIN6 cells and islets isolated from Wfs1-/- and db/db mice. To study the anti-apoptotic effect of ADM, ER stress-exposed MIN6 cells were treated with ADM peptides or transfected with ADM expression plasmid. RESULTS: Pioglitazone increased the production and secretion of ADM in islets through peroxisome-proliferator activated receptor-γ-dependent mechanisms. Thapsigargin treatment increased expressions of both ADM and ADM receptor, composed of Ramp2, Ramp3 and Crlr, in MIN6 cells. ADM and ADM receptor expressions were also increased in isolated islets from Wfs1-/- and db/db mice. ADM peptides and ADM overexpression protected MIN6 cells from thapsigargin-induced apoptosis. CONCLUSIONS: ER stress stimulates ADM production and secretion in islets. ADM signaling might protect ß-cells from ER stress-induced apoptosis, and might be one of the self-protective mechanisms. ß-Cell protection by pioglitazone is partly through induction of ADM. ADM-based therapy could be a novel strategy for treating diabetes.

Transient Appearance of Plasmablasts in the Peripheral Blood of Japanese Patients With Severe Fever With Thrombocytopenia Syndrome.

Atypical lymphocytes in the peripheral blood in patients with severe fever with thrombocytopenia syndrome (SFTS) have not been well examined. In this study, we analyzed counts and characteristics of atypical lymphocytes in 7 patients with SFTS. Atypical lymphocytes resembled plasma cells morphologically and appeared in the peripheral blood of all patients 4-8 days after onset of disease. Among these lymphocytes flow cytometry showed a CD19+CD38+CD138-/+ phenotype, and immunohistochemical staining revealed a CD79a+CD38+CD138-/+CD27+ phenotype. From our observations, atypical lymphocytes transiently that appeared in the peripheral blood during the acute phase of SFTS were considered to be plasmablasts.

Role of TEM-1 ß-Lactamase in the Predominance of Ampicillin-Sulbactam-Nonsusceptible Escherichia coli in Japan.

We investigated the epidemiology and resistance mechanisms of ampicillin-sulbactam-nonsusceptible Escherichia coli, focusing on the role of the TEM-1 ß-lactamase. We collected all nonduplicate E. coli clinical isolates at 10 Japanese hospitals during December 2014 and examined their antimicrobial susceptibility, ß-lactamases, TEM-1 transferability, TEM-1 ß-lactamase activity, outer membrane protein profile, membrane permeability, and clonal genotypes. Among the 329 isolates collected, 95 were ampicillin-sulbactam nonsusceptible. Of these ampicillin-sulbactam-nonsusceptible isolates, ß-lactamases conferring resistance to sulbactam, such as AmpC, were present in 33%. Hyperproduction of sulbactam-susceptible ß-lactamases, TEMs with a strong promoter, were rare (5%). The remaining 59 isolates (62%) had only sulbactam-susceptible ß-lactamases, including TEM-1 with a wild-type promoter (n = 28), CTX-Ms (n = 13), or both (n = 17). All 45 transconjugants from 96 donors with TEM-1 had higher ampicillin-sulbactam MICs (4 to 96 mg/liter) than the recipient (2 mg/liter). In donors with only TEM-1, TEM-1 activity correlated with the 50% inhibitory concentration of sulbactam and ampicillin-sulbactam MICs. The decreased membrane permeation of sulbactam was associated with an increased ampicillin-sulbactam MIC. The reduced permeation was partly attributable to deficient outer membrane proteins, which were observed in 57% of the ampicillin-sulbactam-nonsusceptible isolates with only TEM-1 and a wild-type promoter. Sequence type 131 (ST131) was the most common clonal type (52%). TEM-1 with a wild-type promoter primarily contributed to ampicillin-sulbactam nonsusceptibility in E. coli, with the partial support of other mechanisms, such as reduced permeation. Conjugative TEM-1 and the clonal spread of ST131 may contribute to the prevalence of Japanese ampicillin-sulbactam-nonsusceptible isolates.

Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts ß-cell Function.

In Wfs1-/-Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in ß-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in ß-cell priming for insulin release by regulating ß-cell metabolism and gene expressions. Because ER stress is also involved in the ß-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.

Comparison of Geriatric Nutritional Risk Index scores on physical performance among elderly patients with chronic obstructive pulmonary disease.

OBJECTIVES: The Geriatric Nutritional Risk Index (GNRI) is a new prognostic indicator for nutritional status-related complications and mortality among the elderly. Here we aimed to compare 6-min walk distance (6MWD) between high and low GNRI groups for patients with COPD. METHODS: We enrolled 63 elderly men with COPD. These subjects were divided into two groups based on their GNRI scores: high GNRI group (≥92 points; n = 44) and low GNRI group (n = 19); we compared 6MWD between these groups. RESULTS: The subjects' characteristics between the high and the low GNRI groups were similar, except for BMI and serum albumin levels. 6MWD were significantly lower in the low GNRI group (279.5 ± 112.3 m versus 211.1 ± 125.3 m; p = 0.03). CONCLUSIONS: The GNRI has a more close relation with exercise tolerance and may be a useful nutritional assessment scale for elderly patients with COPD.

Long-term Effect of Home Nursing Intervention on Cost and Healthcare Utilization for Patients with Chronic Obstructive Pulmonary Disease: A Retrospective Observational Study.

PURPOSE: The present study aimed to examine the long-term effects of a home nursing intervention on healthcare utilization and costs among patients with chronic obstructive pulmonary disease (COPD). DESIGN: A 3-year retrospective study. METHODS: Eleven COPD patients who had received home nursing intervention after hospital discharge were enrolled. We retrospectively investigated their healthcare utilization and costs for 1 year before the intervention and during 2 years of the intervention. FINDINGS: The number and length of hospitalizations decreased gradually from the pre-intervention period through the second year. The number of hospital and home nursing visits increased from the pre-intervention period through the first and second years. The hospitalization costs were decreased by approximately half from the pre-intervention period through the first year and from the first year through the second year. The total medical cost did not change significantly. CONCLUSIONS AND CLINICAL RELEVANCE: Our home nursing intervention decreased the number and length of hospitalizations and the hospitalization costs; however, it did not affect the total medical cost. It is possible that the continuation of home nursing interventions may decrease the number of hospitalizations, number of home nursing visits, and the total medical cost by maintaining the health condition of patients.

Safety and efficacy of peramivir for influenza treatment.

OBJECTIVE: This report presents a review of the efficacy and safety of peramivir, a neuraminidase inhibitor that was granted Emergency Use Authorization by the US Food and Drug Administration (FDA) from October 23, 2009 to June 23, 2010 during the 2009 H1N1 pandemic. METHODS: Literature was accessed via PubMed (January 2000-April 2014) using several search terms: peramivir; BCX-1812; RWJ 270201; H1N1, influenza; antivirals; and neuraminidase inhibitors. The peramivir manufacturers, Shionogi and Co Ltd and BioCryst Pharmaceuticals, were contacted to obtain unpublished data and information presented at recent scientific meetings. Information was obtained from the Centers for Disease Control and Prevention (CDC) and from US FDA websites. English-language and Japanese-language reports in the literature were reviewed and selected based on relevance, along with information from the CDC, US FDA, and the drug manufacturers. RESULTS: We obtained eleven clinical trial reports of intravenous peramivir, two of which described comparisons with oseltamivir. Seven of nine other recently reported published studies was a dose-response study. Clinical reports of critically ill patients and pediatric patients infected with pandemic H1N1 described that early treatment significantly decreased mortality. Peramivir administered at 300 mg once daily in adult patients with influenza significantly reduces the time to alleviation of symptoms or fever compared to placebo. It is likely to be as effective as other neuraminidase inhibitors. CONCLUSION: Although peramivir shows efficacy for the treatment of seasonal and pH1N1 influenza, it has not received US FDA approval. Peramivir is used safely and efficiently in hospitalized adult and pediatric patients with suspected or laboratory-confirmed influenza. Peramivir might be a beneficial alternative antiviral treatment for many patients, including those unable to receive inhaled or oral neuraminidase inhibitors, or those requiring nonintravenous drug delivery.

[Risk factors for the onset of aspiration pneumonia among stroke patients in the recovery stage].

AIM: Post-stroke aspiration pneumonia is one of the most common complications among stroke patients. Although the onset of aspiration pneumonia is caused by a disruption of the balance between invasion (the type and amount of oral flora and aspiration) and host resistance (the protective airway reflex and immune function), several previous studies have focused on invasion, such as aspiration and dysphagia. In this study, we examined the importance of the host resistance to aspiration pneumonia among stroke patients with dysphagia. METHODS: The study subjects included 76 stroke patients (mean age, 74.7±8.4 years) with dysphagia chosen from 175 stroke patients who were newly admitted to four rehabilitation hospitals. We divided the subjects into two groups based on the onset of pneumonia during the period of admission and compared their status. RESULTS: Ten patients (13.2%) developed pneumonia at the hospital, and all of the affected patients were over 65 years old. Significant differences existed between the two groups with respect to the gender, activity level, albumin level, nutrition method and severity of dysphagia (p<0.05). CONCLUSIONS: Our study revealed that recumbency, malnutrition, tube feeding, severe dysphagia and female sex were risk factors for pneumonia. In particular, dysphagia was closely associated with aspiration pneumonia. Moreover, host resistance factors, such as recumbency and malnutrition, also play important roles in the development of aspiration pneumonia.

Quantitative trait locus that determines the cross-sectional shape of the femur in SAMP6 and SAMP2 mice.

UNLABELLED: We segregated a QTL on chromosome 11 that affects femoral cross-sectional shape during growth by generating a congenic strain and an additional 16 subcongenic strains of the senescence-accelerated mouse strain, SAMP6. The QTL region was narrowed down to a 10.0-Mbp region. INTRODUCTION: Genetic background is known to affect bone characteristics. However, little is known about how polymorphic genes modulate bone shape. In a previous study using SAMP2 and SAMP6 mice, we reported a quantitative trait locus (QTL) on chromosome (Chr) 11 that had significant linkage to peak relative bone mass in terms of cortical thickness index (CTI) in male mice. We named it Pbd1. Here we aimed to clarify the effects of Pbd1 on skeletal phenotype in male mice and to narrow down the QTL region. MATERIALS AND METHODS: We generated a congenic strain named P6.P2-Pbd1(b), carrying a 39-cM SAMP2-derived Chr11 interval on a SAMP6 genetic background. Sixteen subcongenic strains with smaller overlapping intervals on the SAMP6 background were generated from P6.P2-Pbd1(b) to narrow the region of interest. The effects of Pbd1 on bone properties were determined. Gene expression analysis of all candidate genes in Pbd1 was performed using real-time RT-PCR. RESULTS: The CTI of strain P6.P2-Pbd1(b) at 16 wk was higher than that of SAMP6. This was not caused by differences in cortical thickness but by cross-sectional shape. Morphological analysis by microCT revealed that the femoral cross-sectional shape of P6.P2-Pbd1(b) (and the other subcongenic strains with higher CTI or bone area fraction [BA/TA]) was more compressed anteroposteriorly than that of SAMP6, which was associated with superior mechanical properties. This feature was formed during bone modeling up to 16 wk of age. Subcongenic strains with a higher CTI showed significant increases in endocortical mineral apposition rate and significant reductions in periosteal mineral apposition rate at 8 wk compared with those of the SAMP6. The Pbd1 locus was successfully narrowed down to a 10.0-Mbp region, and the expression analysis suggested a candidate gene, Cacng4. CONCLUSIONS: The Pbd1 affects femoral cross-sectional shape by regulating the rate of endocortical and periosteal bone formation of the femur during postnatal growth.

Consistency of low bone density across bone sites in SAMP6 laboratory mice.

The development of bone densitometry has made it clear that there are discrepancies in bone density at various measurement sites in a given individual. This study examined the consistency of bone density measurements across various sites in a strain of laboratory mouse (senescence-accelerated mouse; SAM). A systemic evaluation of the bone density was performed by dual-energy X-ray absorptiometry (DXA) on SAMP6 (P6) mice, a strain with low peak bone density, as measured by microphotodensitometry of the femoral bones, whereas the SAMP2 (P2) and SAMR1 (R1) strains have high peak bone density. We modified Jilka's method to more comprehensively measure the whole body and additional regions of interest (ROIs; head, right foreleg, left foreleg, right hindleg, left hindleg, spine, and tail). The age-related changes in the total (whole-body) BMD showed a common pattern among the strains studied, and the peak value was seen at 4 months old. P6 showed the lowest peak BMD. A detailed comparison of the bone density between P6 and P2 at the age of 4 months revealed significantly lower regional BMD values for P6 in all seven ROIs. The strain difference in BMD could not be attributed to a difference in size. In conclusion, P6 mice showed low bone density not only in their femurs but also in the subregions and over their entire body. This strain can be potentially useful in the investigation of the genetic basis of senile osteoporosis.

A congenic mouse and candidate gene at the Chromosome 13 locus regulating bone density.

Previously, we identified two significant quantitative trait loci (QTLs) specifying the peak relative bone mass (bone mass corrected for bone size) on chromosomes (Chrs) 11 and 13 by interval mapping in two mouse strains, SAMP2 and SAMP6. The latter strain is an established murine model of senile osteoporosis and exhibits a significantly lower peak relative bone mass than SAMP2 mice. We recently designated the Chr 13 locus as Pbd2 (Peak bone density 2) and constructed a congenic strain, P6.P2-Pbd2(b), which carried a single genomic interval from the Chr 13 of SAMP2 on a SAMP6-derived osteoporotic background. In this study, we have constructed a congenic strain, P2.P6-Pbd2(a), carrying a SAMP6-derived susceptible interval on a SAMP2-derived resistance background. This congenic strain had a lower bone density than the background strain, SAMP2, based on three measurement methods, each utilizing a different principle for evaluating bone density: MD, DXA, and pQCT. Next, a candidate gene approach was used to find polymorphisms of Bmp6 (bone morphogenetic protein 6). The CAG trinucleotide repeat numbers in exon 1 of this gene differ among SAM strains. We found an association of CAG repeat length with relative peak bone mass in mice.

The aniracetam metabolite 2-pyrrolidinone induces a long-term enhancement in AMPA receptor responses via a CaMKII pathway.

The present study was conducted to assess the effect of aniracetam and its metabolites, such as 2-pyrrolidinone, p-anisic acid, and anisamide butyrate, on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, heteromerically formed of GluR1,2 (GluR1 and GluR2), GluR1,3 (GluR1 and GluR3), and GluR1,2,3 (GluR1, GluR2, and GluR3), expressed in Xenopus oocytes. 2-Pyrrolidinone potentiated kainate-evoked currents through GluR1,2,3 channels in a bell-shaped dose-dependent manner at concentrations ranged from 1 nM to 300 microM, with a maximal effect at 100 microM. The potentiation was long-lasting, reaching approximately 180% of basal levels 60 min after 5-min treatment with 2-pyrrolidinone at 100 microM. 2-Pyrrolidinone (100 microM) potentiated GluR1,3 channel currents as observed in GluR1,2,3, but instead it depressed GluR1,2 currents. Aniracetam and p-anisic acid potentiated GluR1,2,3 channel currents, but to a lesser extent, each about 130 and 103% of basal levels 60 min after treatment at 100 microM. In contrast, anisamide butyrate had no potentiating effect on the currents. Potentiation of GluR1,2,3 channel currents obtained with 2-pyrrolidinone was inhibited by KN-93, a selective inhibitor of calcium/calmodulin-dependent protein kinase (CaMKII), while it was not affected by GF109203X, a selective inhibitor of protein kinase C or H-89, a selective inhibitor of cAMP-dependent protein kinase. The results of the present study suggest that 2-pyrrolidinone persistently enhances activity of the Ca2+-permeable AMPA receptors, GluR1,3 and GluR1,2,3, by interacting with CaMKII.