Higher levels of IL-18 circulate during primary infection of monkeys with a pathogenic SHIV than with a nonpathogenic SHIV

We have monitored kinetics of peripheral blood Interleukin (IL)-18 level, viral RNA load, and CD4(+) T cell counts in cynomolgus and rhesus macaques following infections of various simian/human immunodeficiency viruses (SHIVs) causing differential pathogenicity. Infections of cynomolgus and rhesus macaques with pathogenic SHIVs-C2/1 and -89.6PD, respectively, induced high levels of plasma IL-18 (0.1-1 ng/ml) and enhanced apoptosis of peripheral blood T cells during primary viremia, along with a rapid decline of CD4(+) T cells and a high level of set point viral load after primary viremia (six of six cases). In contrast, infections of cynomolgus macaques with nonpathogenic SHIVs-TH09V3 and -MD14 did not cause such IL-18 elevation, showing no decline of CD4(+) T cells and no or low viral set point level following primary viremia (three of three cases). Thus, the elevation of circulating IL-18 level during primary viral infection can be a good indicator of an active pathogenic viral infection. However, the role of increased IL-18 remains to be elucidated and needs further investigation.     

Evidence that variation in the peripheral benzodiazepine receptor (PBR) gene influences susceptibility to panic disorder.

Panic disorder (PD) is the repeated sudden occurrence of panic attacks, episodes characterized by psychological symptoms. Peripheral benzodiazepine receptor (PBR) is closely associated with personality traits for anxiety tolerance, and that it holds promise as a biological marker of stressful conditions. We have performed association analyses using the polymorphism to determine the PBR in PD. We screened the subjects for sequence variations within the 5' region, the coding region (exons 2-4), and the 3' noncoding region. One novel missense variant in exon 4, derived from the nucleotide transition in codon 162 (CGT --> CAT:485G > A) resulting in an arginine-to-histidine (Arg --> His) change, was detected in these subjects. The 485G > polymorphism of the PBR gene was analyzed in 91 PD patients and 178 controls. The genotypic and allelic analyses of the 485G > A revealed significant differences between the panic patients and the comparison subjects (P = 0.021 and 0.014, respectively). The present study provides new and important evidence that variation in the PBR gene influences susceptibility to PD.     

Efficacy of golimumab for preventing large joint destruction in patients with rheumatoid arthritis as determined by the ARASHI score

Objectives: The objective of this study is to investigate the inhibitory effect of golimumab on large joint destruction in patients with rheumatoid arthritis.

Methods: We recruited 45 patients with rheumatoid arthritis and evaluated the radiographic severity of large joint destruction using the assessment of rheumatoid arthritis by scoring of large joint destruction and healing in radiographic imaging (ARASHI) score. We evaluated 450 large joints including the elbow, shoulder, hip, knee, and ankle at baseline and 52 weeks after treatment with golimumab. Rapid radiographic progression (RRP) and rapid radiographic improvement (RRI) were calculated and the correlation between large joint destruction and clinical factors was analyzed.

Results: The mean age of the study population was 61.29?±?14.71 years old, and most patients (91.1%) were female. The mean disease duration was 12.6?±?12.48 years. The cohort included patients in all clinical stages of disease as defined by the Steinbroker criteria (I:7, II:10, III:9, IV:19) as well as clinical classes 2 (n?=?18), 3 (n?=?26), and 4 (n?=?1) and the mean disease activity score-CRP (DAS28-CRP) was 4.431?±?1.044. Patients were treated with methotrexate (mean dose 6.44?±?1.78?mg/week), prednisolone (PSL) (mean dose 1.078?±?1.871?mg/d), and golimumab (44.4% of 100?mg). RRP was evident in 20% of the large joints treated with golimumab, and, therefore, golimumab was effective at inhibiting large joint destruction in 80% of joints. RRI was evident in 33.3% of large joints following golimumab treatment. We also observed that EULAR response criteria significantly correlated with the ARASHI change score at 52 weeks after treatment. The total ARASHI status score significantly correlated with the Sharp–van der Heijde score, but not with the delta total sharp score. Multiple regression analyses revealed that the total ARASHI change score was only correlated with EULAR response criteria significantly.

Conclusions: Golimumab therapy was effective at inhibiting large joint destruction of RA patients who have good clinical response, including higher improvement of the shoulder and ankle joints than other large joints.     

Chondrocyte death induced by pathological concentration of chemokine stromal cell-derived factor-1

OBJECTIVE: It had been found that the concentration of chemokine stromal cell-derived factor-1 (SDF-1) was significantly higher in synovial fluid (SF) of patients with osteoarthritis (OA; > or = 200 ng/ml) and rheumatoid arthritis (RA; > or = 700 ng/ml) compared to controls (< or = 100 ng/ml). Our aim was to determine whether the pathological concentration of SDF-1 induces chondrocyte death and to investigate mechanisms underlying such death. METHODS: Human OA chondrocytes were treated with different doses of SDF-1, or in combination with SF from patients with arthritis. Apoptotic and necrotic cells were labeled by annexin V and propidium iodide, respectively, and quantified by FACS analysis. Caspase-3 activity was quantified by a plate absorbance assay, and matrix metalloproteinase 13 mRNA levels were determined by RT-PCR. The release of high mobility group box chromatin protein 1, a specific marker of cell necrosis, and the activities of chondrocyte mitogen-activated protein kinases (MAPK) including ERK, JNK, and p38 in response to SDF-1 treatment were quantified by Western blot analysis. RESULTS: Pathological concentrations of SDF-1 (> or = 200 ng/ml) in SF or in recombinant form induced death of human chondrocytes in a necrosis-dependent manner. Chondrocyte death was inhibited by the treatment of cells with anti-CXCR4, an antibody blocking the interaction between SDF-1 and its receptor CXCR4. However, the rate of chondrocyte apoptosis and the level of caspase-3, a key apoptotic enzyme, were not affected by the treatment with anti-CXCR4. SDF-1 stimulated p38 MAPK activity in a dose- and time-dependent manner. The presence of the p38 MAPK inhibitor SB203580 during SDF-1 treatment abolished the induction of chondrocyte death by SDF-1. CONCLUSION: Our findings suggest a novel pathological mechanism by which high concentrations of SDF-1 in SF induce chondrocyte death during OA and RA.     

A case report of segmental arterial mediolysis in which computed tomography angiography was useful for diagnosis

A 48-year-old male presented to our hospital with abdominal pain. Laboratory studies showed no abnormality, the severity of his abdominal pain decreased, and the patient was discharged. Five days later, the patient visited a neighborhood clinic because of fever with a 3-day history of temperatures of approximately 38 °C. The patient was admitted to our hospital 6 days after his initial visit. Laboratory investigation revealed a C-reactive protein level of 18.2 mg/dL. Abdominal computed tomography (CT) showed an 80 × 60 mm hematoma behind the descending colon, but no extravasation was detected. Thin-slice maximum-intensity-projection images from CT angiography (CTA) showed irregular narrowing and intermittent fusiform dilatations of the left colonic artery, suggesting a vascular disease, such as segmental arterial mediolysis (SAM). Digital subtraction angiography showed local irregularity, and ‘beading and narrowing’ of the left colonic artery, similar to the findings on CTA. Left hemicolectomy was electively performed on the twenty-fifth hospital day. Histological findings were consistent with SAM. Thus, CTA was a useful modality for the early diagnosis of SAM.     

Worsening renal function,adverse clinical events and major determinants for changes of renal function in patients with atrial fibrillation: a Japanese multicenter registry substudy

Objective: To explore factors related to changing renal function and the prognostic effect of worsening renal function in patients with atrial fibrillation (AF).

Methods: The present substudy was based on the SAKURA AF Registry, a Japanese multicenter prospective observational registry that includes 3267?AF patients from 63 institutions in the Tokyo area. Worsening renal function was defined as an estimated glomerular filtration rate (eGFR) decrease equaling more than 20% of the patient’s baseline eGFR.

Results: During a median 39.3?month follow-up period, patients’ eGFR decreased annually by a mean value of 1.07?mL/min/1.73?m². Multivariable analysis showed that age ≥75?years, body weight ≤50?kg, a history of heart failure and initially preserved renal function (creatinine clearance [CrCl]?≥?60?mL/min) were significantly associated with a decrease in eGFR, whereas a history of AF ablation was associated with a maintain in eGFR. The 194 patients with worsening renal function were at significantly increased risk of death, stroke and major bleeding (adjusted hazard ratios [HRs]: 2.06, 1.97 and 2.23, respectively).

Conclusion: Age ≥75?years, body weight ≤50?kg, a history of heart failure and initially preserved renal function appear to promote renal dysfunction in patients with AF, but a history of AF ablation seems to have a favorable effect. Worsening renal function seems to increase AF patients’ risk of adverse clinical events. Renal function can decline quickly; thus, early intervention including AF ablation is warranted.     

Effectiveness of anti–folate receptor β antibody conjugated with truncated Pseudomonas exotoxin in the targeting of rheumatoid arthritis synovial macrophages

Objective

To define the distribution of folate receptor β (FRβ)–expressing cells in various tissues, including rheumatoid arthritis (RA) synovial tissues, and to verify the effects of an immunotoxin composed of an anti‐FRβ monoclonal antibody (mAb) and truncated Pseudomonas exotoxin A (PEA) on apoptosis and tumor necrosis factor α (TNFα) production by adherent synovial mononuclear cells from RA patients.

Methods

Anti‐FRβ mAb were produced by immunizing mice with FRβ‐transfected murine pre–B cells. The distribution of the FRβ antigen was examined by immunohistochemical analysis using anti‐FRβ mAb and macrophage‐specific anti‐CD163 mAb. Anti‐FRβ mAb was chemically crosslinked with truncated PEA. FRβ‐expressing macrophages were produced by the transfection of adenovirus vector containing the FRβ gene. Apoptotic cells were detected by staining with propidium iodide. TNFα was measured by enzyme‐linked immunosorbent assay.

Results

FRβ‐expressing cells were not present in peripheral blood leukocytes and their activated cells. In all of the tissues examined, most FRβ‐expressing cells were CD163+. The immunotoxin significantly induced the apoptosis of FRβ‐transfected macrophages and adherent RA synovial mononuclear cells and inhibited TNFα production by adherent RA synovial mononuclear cells.

Conclusion

We demonstrated the limited distribution of FRβ‐expressing cells in various tissues. The immunotoxin targeting FRβ‐expressing cells will provide a therapeutic tool for rheumatoid synovitis.