Clinical results of alendronate monotherapy and combined therapy with menatetrenone (VitK2) in postmenopausal RA patients

Objectives

We aimed to evaluate the clinical efficacy of monotherapy with alendronate and combined therapy with alendronate and menatetrenone (vitamin K2 [VitK2]) in postmenopausal rheumatoid arthritis (RA) patients with osteoporosis or osteopenia.

Methods

Sixty-two postmenopausal RA patients with untreated osteoporosis or osteopenia (lumbar spine bone density ≤80 % of young adult mean [YAM]) were enrolled: 39 had abnormal serum undercarboxylated osteocalcin (ucOC) levels (>4.5 ng/mL) and received combined therapy with alendronate (35 mg/week) and VitK₂ (45 mg/day) (ALN + K group); 23 had normal ucOC levels (≤4.5 ng/mL) and received alendronate monotherapy (35 mg/week) (ALN group). The clinical results for the 57 patients in both groups were evaluated after 1-year treatment.

Results

The mean baseline/follow-up (FU) lumbar spine bone density (%YAM) values were 73.0/76.8 % (P < 0.01) in the ALN + K group and 77.0/80.3 % (P < 0.01) in the ALN group; a significant increase was shown in both groups. Mean proximal femoral bone density values at baseline/FU were 71.4/73.8 (P < 0.01) in the ALN + K group and 71.4/71.6 % (not significant; NS) in the ALN group; a significant increase was shown in the ALN + K group only. Serum ucOC levels were normalized in the ALN + K group at FU. At FU, bone metabolism markers [bone-specific alkaline phosphatase (BAP) and N-terminal cross-linked telopeptides of type I collagen] were decreased in both groups. One patient in the ALN + K group and three in the ALN group suffered new fractures.

Conclusions

Combined therapy with alendronate and VitK₂ decreases bone metabolism marker levels and serum ucOC levels, and increases lumbar spine and femoral neck bone density in postmenopausal RA patients with abnormal ucOC levels and osteoporosis or osteopenia.     

Effects of adalimumab therapy on musculoskeletal manifestations and health-related quality of life in patients with active psoriatic arthritis

Objectives

Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, was retrospectively evaluated for its effect on musculoskeletal manifestations and health-related quality of life in patients with psoriatic arthritis (PsA) during daily clinical practice.

Methods

Patients who initiated adalimumab therapy after March 2010 were followed for at least 24 weeks with the clinical outcome measures. Eleven patients, all men with a mean age of 45.4 years, had mean psoriasis durations of 16.2 and 8.4 years at baseline.

Results

After 24 weeks, 72.7, 63.6, and 45.5 % of the patients met the ACR 20, 50, and 70 response criteria, respectively, while 81.8 % achieved the PsA response criteria. Disease Activity Score using the 28-joint count and CRP declined from 3.2 ± 1.2 at baseline to 1.3 ± 0.4 at week 24 (P < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores also decreased significantly (both P values were <0.01). After 24 weeks, three out of eight dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey and Physical Component Summary were significantly improved (all P values were <0.05).

Conclusions

Adalimumab exerted its effect as early as week 4, and it was sustained until the end of the 24-week observation period in the PsA patients.     

The Strategy for Predicting Future Exacerbation of Asthma Using a Combination of the Asthma Control Test and Lung Function Test

Background. Various factors have been reported to be useful for predicting future exacerbations. Objective. This study was intended to determine a usefulness of a combination of a patient-based questionnaire, such as the Asthma Control Test (ACT) score with objective assessments, such as forced expiratory volume in 1 second (FEV₁) and/or exhaled nitric oxide (FE_NO), for predicting future exacerbations in adult asthmatics. Methods. We therefore enrolled 78 subjects with mild to moderate asthma, who were clinically stable for 3 months who all had been regularly receiving inhaled steroid treatment. All subjects underwent a routine assessment of asthma control including the ACT score, spirometry, and FE_NO, and then were followed up until a severe exacerbation occurred. The predictors of an increased risk of severe exacerbation were identified and validated using decision trees based on a classification and regression tree (CART) analysis. The properties of the developed models were the evaluated with the area under the ROC curve (AUC) (95% confidence interval [CI]). Results. The CART analysis automatically selected the variables and cut-off points, the ACT score ≤23 and FEV₁ ≤ 91.8%, with the greatest capacity for discriminating future exacerbations within one year or not. When the probalility was calculated by the likelihood ratio of a positive test (LP), the ACT score ≤23 was identified with a 60.3% probability, calculated by 1.82 of LP, whereas the combined ACT score ≤23 and the percentage of predicted FEV₁ ≤ 91.8% were identified with an 85.0% probability, calculated by an LP score of 5.43, for predicting future exacerbation. Conclusion. These results demonstrated that combining the ACT score and percentage of predicted FEV₁, but not FE_NO, can sufficiently stratify the risk for future exacerbations within one year.     

Hyper-interleukin (IL)-6-naemia in haemophagocytic lymphohistiocytosis

Clinical features in patients with haemophagocytic lymphohistiocytosis (HLH) have been demonstrated to be characterized by hypercytokinaemia. Previously, we reported the impact of high serum levels of interferon (IFN)-gamma and soluble IL-2 receptor (sIL-2R) on patient outcome; however, it was not known if serum levels of interleukin (IL)-6 also could be a prognostic factor. In a study during the active phase of disease in 25 cases of HLH in children and young adults (median age 3 years, range 0.1–23 years), we noted 12 cases which showed serum IL-6 >100 (normal <4.0) pg/ml. Five of these cases showed hyper-IL-6-naemia alone without hyper-IFN-gamma-naemia (group A) whereas seven cases showed both hyper-IL-6- and IFN-gamma-naemia (group B). Patient outcome did not differ between the patients with IL-6 >100 pg/ml and those with IL-6 <100 pg/ml, suggesting that high serum concentrations of IL-6 alone do not necessarily indicate poor prognosis in patients with HLH. Among the cases with hyper-IL-6-naemia (>100 pg/ml), underlying disorders causing haemophagocytosis were found to be different between groups A and B.     

A national survey of premedication for transfusion reactions in Japan

Background

Premedication before transfusion is commonly administered in clinical practice despite a lack of evidence for its efficacy. The aim of this study was to clarify the status of premedication and evaluate expert opinions regarding its use in Japanese medical institutions.

Carbohydrate-dependent signaling from the phosphatidylglucoside-based microdomain induces granulocytic differentiation of HL60 cells

Glycosphingolipids form glycosphingolipid signaling microdomains. Here, we report an unrecognized type of phosphatidylglucoside (PhGlc)-based lipid microdomain in HL60 cells. Treatment of cells with rGL-7, which preferentially reacts with PhGlc, induced differentiation of HL60 cells. This was manifested by the appearance of nitroblue tetrazolium-positive cells together with CD38 expression and c-Myc down-regulation. We determined the molecular mechanisms underlying early stages of signal transduction. rGL-7 treatment induced rapid tyrosine phosphorylation of Src family protein kinases Lyn and Hck. Reduction of endogenous cholesterol after application of methyl-beta-cyclodextrin suppressed rGL-7-stimulated tyrosine phosphorylation. Phosphorylated proteins and PhGlc colocalized in the Triton X-100 insoluble, light buoyant density fraction after sucrose gradient ultracentrifugation of HL60 cell lysates. This suggests PhGlc-based microdomain is involved in GL-7 signaling. Ligation of known components of microdomains, such as sphingomyelin and ganglioside GM1, with corresponding antibodies failed to induce differentiation and tyrosine phosphorylation. These results show that PhGlc constitutes a previously undescribed lipid signaling domain, and the glucose residue of PhGlc is critical for organization of the carbohydrate-dependent signaling domain involved in cellular differentiation of HL60 cells.     

A woman complicated with immune thrombocytopenic purpura, subclinical Graves disease and peripheral neuropathy 5 years after allogeneic bone marrow transplantation

A 21-year-old woman developed immune thrombocytopenia (ITP), subclinical Graves disease and peripheral neuropathy without typical chronic graft-versus-host disease (GVHD) 5 years following an allogeneic bone marrow transplantation from an HLA-identical sibling. She received high-dose intravenous immunoglobulin (IVIG) and prednisolone (PSL), which resulted in transient recovery of platelet numbers and muscle weakness. A combination of cyclosporine and PSL induced a durable response against not only the thrombocytopenia but also her high levels of thyroid stimulating antibody (TSAb), muscle weakness and sensory abnormality. The level of thyroglobulin in the donor, who had not developed Graves disease, was also elevated, indicating that late onset-subclinical Graves disease was caused by donor lymphocytes that were autoreactive to the thyroid glands.     

Is Minimally Invasive Surgery–Total Knee Arthroplasty Truly Less Invasive Than Standard Total Knee Arthroplasty? : A Quantitative Evaluation

With recent technical advancements, the number of operative manipulations in the knee joint by minimally invasive surgery–total knee arthroplasty (MIS-TKA) is now considered to be the same as that using standard TKA (S-TKA). The question still remains, however, if MIS-TKA improves recovery compared to S-TKA. We compared MIS-TKA and S-TKA patients' physical activity as measured by an accelerometer. Physical activity expressed as cumulative acceleration was significantly higher in the MIS-TKA than in the S-TKA group on postoperative days (POD1, 2, 3, 4, 5, 10, 11) (P < .05). The recovery time, defined as the number of days required to achieve cumulative acceleration of 80% of the preoperative level, was significantly shorter (P < .05) in the MIS-TKA (3.0 ± 3.3 days) group than in the S-TKA (7.0 ± 3.5 days) group. Minimally invasive surgery–total knee arthroplasty appears to allow an earlier recovery after the operation than S-TKA. Less invasion to muscle during the surgery appears to contribute to shorter convalescence.     

Decreased basal mucus secretion by Slp2-a-deficient gastric surface mucous cells

Synaptotagmin-like protein (Slp) 2-a is a putative Rab27A/B-effector protein and is implicated in intracellular membrane transport. However, the precise tissue distribution of Slp2-a protein and its functions remain largely unknown. In this study we used a specific anti-Slp2-a antibody to investigate the tissue distribution of Slp2-a in mice and found that Slp2-a is most abundantly expressed in mouse stomach. Co-immunoprecipitation experiments indicated that Slp2-a interacts with Rab27A/B in vivo. We also discovered that Slp2-a and Rab27A/B are predominantly localized at the apical region of gastric-surface mucous cells, where mucus granules are accumulated. Analysis of Slp2-a mutant mice generated by homologous recombination showed a reduced number of mucus granules, a deficiency of granule docking with the apical plasma membrane in the gastric-surface mucous cells and reduction of mucus secretion by Slp2-a-deficient gastric primary cells. Based on these results, we propose that Slp2-a is part of the mucin secretory machinery in surface mucous cells of mouse stomach.     

Adenosine kinase is a target for the prediction and prevention of epileptogenesis in mice

Astrogliosis is a pathological hallmark of the epileptic brain. The identification of mechanisms that link astrogliosis to neuronal dysfunction in epilepsy may provide new avenues for therapeutic intervention. Here we show that astrocyte-expressed adenosine kinase (ADK), a key negative regulator of the brain inhibitory molecule adenosine, is a potential predictor and modulator of epileptogenesis. In a mouse model of focal epileptogenesis, in which astrogliosis is restricted to the CA3 region of the hippocampus, we demonstrate that upregulation of ADK and spontaneous focal electroencephalographic seizures were both restricted to the affected CA3. Furthermore, spontaneous seizures in CA3 were mimicked in transgenic mice by overexpression of ADK in this brain region, implying that overexpression of ADK without astrogliosis is sufficient to cause seizures. Conversely, after pharmacological induction of an otherwise epileptogenesis-precipitating acute brain injury, transgenic mice with reduced forebrain ADK were resistant to subsequent epileptogenesis. Likewise, ADK-deficient ES cell-derived brain implants suppressed astrogliosis, upregulation of ADK, and spontaneous seizures in WT mice when implanted after the epileptogenesis-precipitating brain injury. Our findings suggest that astrocyte-based ADK provides a critical link between astrogliosis and neuronal dysfunction in epilepsy.