Residual symptoms and disease burden among patients with rheumatoid arthritis in remission or low disease activity: a systematic literature review.

OBJECTIVES: To identify, describe and summarize evidence on residual symptoms and disease burdens in rheumatoid arthritis (RA) patients qualified as being in remission or low disease activity (LDA). METHODS: A systematic literature review (SLR) was conducted according to Cochrane collaboration guidelines. The population of interest was adult patients with RA in remission or LDA. The reported outcomes of interest were any symptoms or burdens. RESULTS: Fifty-one publications were identified through an eDatabase search. Together with 17 articles found through other sources, 68 were included for full text review. The most commonly reported residual symptoms were pain (number of studies = 25), fatigue (n = 21) and morning stiffness (n = 5). Reported disease burdens included mental health (n = 15), sleep disturbances (n = 7) and work productivity (n = 5), impairment in quality of life (n = 21), and functional disability (n = 34). Substantial residual symptoms and disease burdens were found to be present in patients in remission or LDA. CONCLUSION: This is the first SLR to investigate residual symptoms and disease burdens in RA patients in remission or LDA. The results indicate that despite achieving conventional clinical targets, the disease continues to affect patients, suggesting the existence of unmet need under the current treatment paradigm.

On What Day of Illness Does the Dilatation of Coronary Arteries in Patients With Kawasaki Disease Begin?

BACKGROUND: In the present study we used echocardiography to investigate coronary artery diameter at the time of diagnosis of Kawasaki disease (KD), before the start of treatment.Methods and Results:Diameters of the right, left main, left anterior descending, and left circumflex coronary arteries were determined in 410 patients before KD treatment commenced. The maximum Z-score was considered to be the pretreatment, maximum coronary artery Z-score (preZmax). The cumulative probability of coronary arterial dilatation was analyzed using the Kaplan-Meier method. In the present study, 31 patients (7.6%) had a preZmax ≥3.0, 56 (13.7%) had a preZmax ≥2.5, and 96 (23.4%) had a preZmax ≥2.0. The cumulative probability of a preZmax ≥2.0 was >20% on Day 5 of illness, 40% on Day 7, and 70% on Day 10. The positive predictive value (PPV) of a preZmax of 2.0 was approximately 0.9 on Day 5 of illness. CONCLUSIONS: The present study demonstrates that the coronary arteries may dilate before Day 5 of illness, and that the rate of dilatation increases gradually until Day 10. Because preZmax 2.0 has high PPV after Day 5 of illness, it is a useful marker of coronary artery dilatation in the early phase of KD.

Construction and evaluation of a neurofeedback system using finger tapping and near-infrared spectroscopy.

Introduction: Neurofeedback using near-infrared spectroscopy (NIRS) has been used in patients with stroke and other patients, but few studies have included older people or patients with cognitive impairment. Methods: We constructed a NIRS-based neurofeedback system and used finger tapping to investigate whether neurofeedback can be implemented in older adults while finger tapping and whether brain activity improves in older adults and healthy participants. Our simple neurofeedback system was constructed using a portable wearable optical topography (WOT-HS) device. Brain activity was evaluated in 10 older and 31 healthy young individuals by measuring oxygenated hemoglobin concentration during finger tapping and neurofeedback implementation. Results: During neurofeedback, the concentration of oxygenated hemoglobin increased in the prefrontal regions in both the young and older participants. Discussion: The results of this study demonstrate the usefulness of neurofeedback using simple NIRS devices for older adults and its potential to mitigate cognitive decline.

N-terminal pro-brain natriuretic Peptide as a useful diagnostic marker of acute Kawasaki disease in children.

BACKGROUND: Serum N-terminal pro-brain natriuretic peptide (NTproBNP) is often elevated in patients with acute Kawasaki disease (KD), but the NTproBNP level in normal children is higher than in adults. Thus, characterization of the normal levels and cut-off values of NTproBNP according to age is warranted for proper diagnosis of acute KD in children. METHODS AND RESULTS: Six hundred and fifty-five patients aged 1 month-15 years (median, 2.9 years) were included. Patients were admitted to the NTT East Japan Sapporo Hospital between October 2007 and October 2011. Serum NTproBNP level was examined in 149 patients with KD (median, 2.1 years) and 506 control patients with acute infectious disease (median, 3.2 years). In the control group, a Z-score curve of NTproBNP was generated for each age group using least mean square-based methods. The Z-score distribution of KD patients was then compared with that of the control group. The specificity and sensitivity of NTproBNP for diagnosing acute KD were 97.8% and 47.0%, respectively, at Z-score >2.0. Additionally, simple cut-offs every 100 pg/ml according to age were established for more convenient use at the bedside. CONCLUSIONS: The Z-score curve for NTproBNP in children was characterized. A Z-score >2.0 or the cut-off for children may be used to diagnose acute KD.

Clinical characteristics and computed tomography findings in children with 2009 pandemic influenza A (H1N1) viral pneumonia.

In this article we review the clinical characteristics and computed tomography (CT) findings in children with 2009 pandemic H1N1 influenza viral pneumonia. The medical charts of 88 children with pandemic H1N1 influenza virus infection, admitted to our hospital in Japan from 10 August to 28 December 2009, were reviewed; we compared the clinical features of these children with those of 61 children admitted with seasonal influenza A during the previous 3 seasons. Of 88 patients, 53 (60%) had radiographic findings consistent with pneumonia and 34 patients underwent a chest computed tomography (CT) scan. Pneumonia was a more frequent complication in children with pandemic H1N1 influenza compared with those with seasonal influenza (60% vs 11%; p < 0.001). The predominant CT findings were unilateral or bilateral multifocal consolidation (15/34; 44%) associated with ground-glass opacities in the peribronchovascular region. The second most common CT finding was unilateral diffuse consolidation or atelectasis in 1 or more lung zones (12/34; 35%). The chest CT findings of unilateral or bilateral multifocal consolidation often associated with ground-glass opacities were commonly seen in children with pandemic H1N1 influenza viral pneumonia. Atelectasis was seen in patients who required oxygen administration.

Identification of a methotrexate-binding peptide from a T7 phage display screen using a QCM device.

An 11-mer unique peptide sequence SIFPLCNSGAL was identified as a methotrexate (MTX)-binding peptide from a T7 phage display screen using a quartz-crystal microbalance (QCM) biosensor. The synthetic peptide displayed weak interaction with MTX (K(D) 2.23x10(-5) M) using surface plasmon resonance (SPR). Interestingly, analysis of the primary amino acid sequence of the peptide identified similarities to the MTX-binding site of dihydrofolate reductase (DHFR). Our results highlight the importance of this primary sequence for the recognition of the MTX molecule.

Chiari type 1 malformation associated with central sleep apnea after high dose growth hormone (GH) therapy in a 12-year-old boy: A case report.

We describe the case of a short-statured 12-yr-old boy who developed a Chiari type 1 malformation associated with central sleep apnea after administration of high-dose GH therapy, which he had been receiving since the age of 10 yr and 4 mo. He responded well to GH therapy, and his height increased by 18.8 cm in 2 yr. At 12 yr and 4 mo of age, his mother reported that he had developed sleep apnea during the previous year and it had worsened over a month prior to presentation at our hospital. Otolaryngological examination did not reveal tonsillar or adenoidal hypertrophy. Polysomnography demonstrated severe central sleep apnea with an apnea-hypopnea index of 46.5/h. Sagittal T1-weighted magnetic resonance imaging (MRI) demonstrated herniation of the cerebellar tonsils 15 mm below the foramen magnum into the cervical spinal cord. Continuous positive airway pressure therapy initiated prior to performing neurosurgery was ineffective. Following uncomplicated foramen magnum decompression, his breathing pattern during sleep returned to normal. Sagittal MRI examination should be considered in patients who develop sleep apnea during/following administration of GH therapy.

Treatment of McLeod phenotype chronic granulomatous disease with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation.

Patients with chronic granulomatous disease (CGD) complicated by antimycotics-refractory invasive aspergillosis have an extremely poor prognosis if they cannot undergo allogeneic hematopoietic stem cell transplantation from a suitable related donor while in good clinical condition. We successfully treated a 20-year-old man with very rare McLeod phenotype CGD with reduced-intensity conditioning and unrelated-donor umbilical cord blood transplantation. We postulate that reduced-intensity conditioning-allogeneic hematopoietic stem cell transplantation is a promising therapeutic strategy for patients with CGD even if only unrelated-donor umbilical cord blood is available.

Detection of BK virus and adenovirus in the urine from children after allogeneic stem cell transplantation.

The development of hemorrhagic cystitis (HC) and urinary excretion of polyoma BK virus (BKV) and adenovirus (ADV) was investigated by polymerase chain reaction in 20 children undergoing allogeneic stem cell transplantation. Five children developed HC, and all of them excreted BKV; however, only 1 excreted ADV, suggesting that BKV is more significant cause of HC than ADV in children undergoing stem cell transplantation.

[Prognostic value of serum markers for liver fibrosis in transient abnormal myelopoiesis (TAM)].

Transient abnormal myelopoiesis (TAM) is usually a self-limiting myeloproliferative disorder observed in approximately 10% of newborn infants with Down syndrome. However, progressive liver fibrosis may occur in patients with TAM and is often lethal. We investigated the utility of the serum levels of hyaluronic acid (HA) and N-terminal peptide of III procollagen (P-III-P) as markers of liver fibrosis and indication for chemotherapy. We reviewed 4 cases of TAM retrospectively. HA levels were more than one hundred times as high as the upper limit of the normal range in 2 patients, one of whom died from gastrointestinal bleeding. His HA and P-III-P had increased up to 18,800 U/ml and 26.2 ng/ml, respectively, just before he died. Another patient's serum HA and P-III-P increased to 6,100 U/ml and 12.8 ng/ml, respectively, however his liver fibrosis resolved with low-dose cytosine arabinoside treatment after exchange transfusion during his clinical course. We suggest that serum HA is useful as a marker of liver fibrosis and a prognostic indicator for chemotherapy in patients with TAM. Early treatment including both exchange transfusion and chemotherapy should be considered for patients presenting with extremely high or an elevating tendency of their HA serum levels.

Identification and characterization of the direct interaction between methotrexate (MTX) and high-mobility group box 1 (HMGB1) protein.

BACKGROUND: Methotrexate (MTX) is an agent used in chemotherapy of tumors and autoimmune disease including rheumatoid arthritis (RA). In addition, MTX has some anti-inflammatory activity. Although dihydrofolate reductase (DHFR) is a well-known target for the anti-tumor effect of MTX, the mode of action for the anti-inflammatory activity of MTX is not fully understood. METHODOLOGY/RESULT: Here, we performed a screening of MTX-binding proteins using T7 phage display with a synthetic biotinylated MTX derivative. We then characterized the interactions using surface plasmon resonance (SPR) analysis and electrophoretic mobility shift assay (EMSA). Using a T7 phage display screen, we identified T7 phages that displayed part of high-mobility group box 1 (HMGB1) protein (K86-V175). Binding affinities as well as likely binding sites were characterized using genetically engineered truncated versions of HMGB1 protein (Al G1-K87, Bj: F88-K181), indicating that MTX binds to HMGB1 via two independent sites with a dissociation constants (KD) of 0.50±0.03 µM for Al and 0.24 ± 0.01 µM for Bj. Although MTX did not inhibit the binding of HMGB1 to DNA via these domains, HMGB1/RAGE association was impeded in the presence of MTX. These data suggested that binding of MTX to part of the RAGE-binding region (K149-V175) in HMGB1 might be significant for the anti-inflammatory effect of MTX. Indeed, in murine macrophage-like cells (RAW 264.7), TNF-α release and mitogenic activity elicited by specific RAGE stimulation with a truncated monomeric HMGB1 were inhibited in the presence of MTX. CONCLUSIONS/SIGNIFICANCE: These data demonstrate that HMGB1 is a direct binding protein of MTX. Moreover, binding of MTX to RAGE-binding region in HMGB1 inhibited the HMGB1/RAGE interaction at the molecular and cellular levels. These data might explain the molecular basis underlying the mechanism of action for the anti-inflammatory effect of MTX.

Treatment of stage IV malignant rhabdoid tumor of the kidney (MRTK) with ICE and VDCy: a case report.

The prognosis of stage IV malignant rhabdoid tumor of the kidney (MRTK) has been extremely poor. However, a combination of ICE (ifosfamide, carboplatin, and etoposide) and VDCy (vincristine, doxorubicin, and cyclophosphamide) was recently reported to be effective for metastatic MRTK. We describe a 21-month-old girl with stage IV MRTK who was successfully treated with ICE, VDCy, and radiotherapy. She remained well, without recurrence, 24 months after diagnosis. Alternating therapy with ICE and VDCy might become a standard regimen for stage IV MRTK, although further study is required to confirm its effectiveness.

Gastric antral vascular ectasia in 2-yr-old girl undergoing unrelated cord blood stem cell transplantation.

Gastrointestinal bleeding is a common complication after hematopoietic stem cell transplantation (HSCT) and is often related to acute graft-vs.-host disease (aGVHD). Gastric antral vascular ectasia (GAVE), recently recognized as a complication after HSCT, is a rare cause of severe gastrointestinal bleeding, which has only been reported in adult patients so far. We report a 2-yr-old girl who developed GAVE after unrelated cord blood stem cell transplantation (CBSCT) as treatment of intractable Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). Her conditioning regimen for CBSCT consisted of etoposide, busulfan, and cyclophosphamide. She was doing well after CBSCT without recurrence and developed only grade I aGVHD. She suddenly developed coffee ground emesis, tarry stools and severe anemia 76 days after CBSCT. As antacids were ineffective, esophagogastroduodenoscopy was performed and revealed GAVE on day 97. Endoscopic coagulation therapy was performed twice; subsequently, she needed no further transfusions and there was no clinical recurrence of GAVE.

A phylogenetic study of human respiratory syncytial viruses group A and B strains isolated in two cities in Japan from 1980-2002.

The circulation pattern and genetic evolution of respiratory syncytial virus (RSV) in Japan were examined based on 109 RSV field strains isolated over 20 seasons (1980-2002) in two cities, Sapporo and Tokyo. The second hypervariable region of the large glycoprotein (G) gene was amplified by RT-PCR and the products sequenced directly. The nucleotide sequences were compared to those representatives of RSV genotypes identified previously. Japanese group A and B isolates clustered into five and four genotypes defined previously, respectively. Another one group A and one group B genotypes, which could not be assigned to previous genotypes, were also identified. Although different genotypes usually co-circulated in each season, the isolates in proximate seasons from two communities were usually located in the same branches. Moreover, the strains with genotypes defined previously were usually isolated at the same time as each reference strain of Western countries. Several mutant group B strains with 1-20 longer amino acid G proteins were newly identified in Sapporo. These findings suggest that Japanese RSV strains underwent geographical and also temporal clustering while participating in RSV genetic evolution in a global setting. In addition, Japanese strains, especially group B, might have evolved individually in each community, sometimes changing the length of the G protein.

Genetic variability and molecular epidemiology of respiratory syncytial virus subgroup a strains in Japan determined by heteroduplex mobility assay.

We used heteroduplex mobility assay (HMA) to determine the genetic variability of 118 respiratory syncytial virus (RSV) field isolates from 19 epidemics occurring in a Japanese urban area between 1980 and 2000. Nucleotides 1 to 584 of the attachment G glycoprotein gene were amplified by reverse transcription-PCR, and the PCR amplicons were analyzed by HMA by using the earliest isolate from 1980 as the reference throughout. We also performed PCR-restriction fragment length polymorphism (RFLP) analysis and phylogenetic analysis on the same nucleotide sequence. PCR-RFLP revealed 9 patterns, whereas HMA produced 31 distinct patterns. The RFLP patterns were divided into two to seven distinct HMA genotypes. Field strains with similar degrees of G gene nucleotide differences from the reference strain often showed distinct HMA types. The RSV genetic heterogeneity detected by direct sequencing of the PCR amplicon was usually identical to HMA analysis. Analysis of the molecular epidemiology of RSV subgroup A isolates obtained by HMA showed that new RSV variants emerged with each epidemic and that previously dominant variants seldom recurred in subsequent epidemics. HMA is useful in detecting genetic variants of RSV subgroup A and has some advantages over other conventional methods.

Comparison of an immunochromatography test with multiplex reverse transcription-PCR for rapid diagnosis of respiratory syncytial virus infections.

A new commercial rapid 10-min one-step immunochromatography (IC) test, SAS RSV test, was compared to another IC test, Directigen EZ RSV, employing RT-PCR as the "gold standard" for detecting respiratory syncytial virus. Of 102 clinical samples, 79 were positive by RT-PCR, 66 (82.5%) were positive with the SAS RSV test, and 55 (69.6%) were positive with Directigen EZ RSV. The specificity of the new test was 91.3% (21 of 23), similar to that of Directigen EZ RSV (100% [23 of 23]). This test performs well enough to be used for patient care.