Medical care costs of patients with rheumatoid arthritis during the prebiologics period in Japan: a large prospective observational cohort study

Our objective was to describe outpatient medical care costs of patients with rheumatoid arthritis (RA) in the prebiologics period in Japan. The outpatient costs of 6,771 RA patients (17,666 patient years) who were enrolled in an observational cohort study at the Institute of Rheumatology, Rheumatoid Arthritis (IORRA), in Tokyo, Japan, were calculated from the billing records dated from 2000 to 2004. Associations between outpatient costs and variables such as age, RA duration, RA disease activities, and disability levels were assessed. The average outpatient cost gradually increased (+7.7% in 4 years) from 271,498 JPY per year in 2000 to 292,417 JPY per year in 2004. Medications accounted for approximately 50% of total outpatient costs, which increased 29.6% during the 4 years. The outpatient costs increased in association with aging, longer RA duration, higher Disease Activity Score of 28 Joints (DAS28), and higher Japanese version of Health Assessment Questionnaire (J-HAQ) score. Generalized linear regression analysis revealed that both DAS28 and J-HAQ scores were the most significant factors associated with outpatient costs (p < 0.001). Outpatient costs for patients with RA increased year after year over the 4-year period under observation in Japan. Medical costs were higher with increasing RA disease activity and disability levels.     

Raloxifene prevents cardiac hypertrophy and dysfunction in pressure-overloaded mice

17beta-estradiol reduces myocardial hypertrophy and left ventricular mass, suggesting that the selective estrogen receptor modulator raloxifene may have similar effects. However, it is not clear whether raloxifene inhibits both cardiac hypertrophy and dysfunction. We used transverse aortic-banded mice to produce pressure-overload cardiac hypertrophy and used neonatal rat ventricular cardiomyocytes to investigate the cellular mechanisms of raloxifene on cardiac hypertrophy. Left ventricular mass and fractional shortening of mice hearts were measured by transthoracic echocardiography. Protein synthesis of cardiomyocytes was evaluated by incorporation of [3H]leucine into cardiomyocytes exposed to angiotensin II. Phosphorylation of mitogen-activated protein (MAP) kinase was also observed in cardiomyocytes. Raloxifene prevented increases in left ventricular mass and decreases of fractional shortening at 4 weeks after aortic banding. Pretreatment with raloxifene before angiotensin II stimulation inhibited the increase in [3H]leucine incorporation into neonatal rat cardiomyocytes in a concentration-dependent manner. This inhibition was partially but not significantly attenuated by N(G)-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase, and completely abolished by ICI182780, an estrogen receptor antagonist. Although the phosphorylation of p38 MAP kinase, c-Jun N-terminal kinase (JNK), or extracellular signal-regulated protein kinase (ERK) in cardiomyocytes was significantly increased by angiotensin II stimulation as compared with the control, pretreatment with raloxifene attenuated p38 MAP kinase phosphorylation, but neither JNK nor ERK phosphorylation. We conclude that raloxifene inhibits cardiac hypertrophy and dysfunction and that the inhibition of p38 MAP kinase phosphorylation after the stimulation of estrogen receptors may be involved in the cellular mechanisms of this agent.     

Does long-term medication with a proton pump inhibitor induce a tolerance to H<Subscript>2</Subscript> receptor antagonist?

Background Previous reports suggest that complete tolerance to H₂ receptor antagonists (H₂RAs) in patients with regular H₂RA medication may be due to hypergastrinemia-increased histamine synthesis or upregulation of H₂ receptors. As proton pump inhibitors (PPIs) have been reported to induce hypergastrinemia (similar to H₂RAs), patients receiving long-term medication with PPIs may show tolerance to preanesthetic H₂RA. Therefore, we studied the efficacy of an H₂RA, roxatidine, in patients receiving long-term PPI medication. Methods Effects of H₂RA in 15 surgical patients receiving a regular PPI for more than 4 weeks (PPI+H₂RA group) were compared with those in 30 patients not receiving regular PPIs or H₂RAs (None+H₂RA group and None+None group, n = 15 each). Oral roxatidine was given to both PPI+H₂RA and None+H₂RA group patients as an anesthetic premedication, while it was not given to None+None group patients. Gastric volume and pH were measured after induction of anesthesia. Results Gastric pH and volume (ml) in the PPI+H₂RA group (5.79 ± 1.61 and 9.1 ± 16.7, respectively) were both similar to those in the None+H₂RA group (5.54 ± 2.20 and 9.7 ± 10.8, respectively) but were significantly higher (gastric pH) and lower (volume) than in the None+None group (2.29 ± 1.84 and 29.3 ± 22.8, respectively, P < 0.01). Conclusions These data suggest that long-term PPI medication may not induce a tolerance to H₂RAs.     

EDI results of Japanese and German women and possible sociocultural explanations

The goal of this study was to compare data for women with bulimia nervosa and for a healthy control group both in Japan and Germany. These data were obtained using the Eating Disorder Inventory (EDI‐2). In Germany, EDI‐2 data and BMI values were collected from 102 nurses in training, 57 female medical students, and 29 patients with bulimia nervosa. In Japan, data were gathered from 243 female ‘short college’ students and 20 patients with bulimia nervosa. The Japanese non‐clinical control group showed significantly higher values on nearly all EDI scales than the German control group. They had a markedly higher drive for thinness, though their BMI values were lower. When the German and the Japanese bulimia nervosa patients were compared, the Japanese patients also showed higher values than their German counterparts on three EDI scales, but these differences were negligible. It is suggested that sociocultural factors in Japan, in particular a significant dependency on social norms, may contribute to the high EDI values. Copyright © 2005 John Wiley & Sons, Ltd and Eating Disorders Association.     

Influence of TNF gene polymorphisms in Japanese patients with NASH and simple steatosis

BACKGROUND/AIMS: Tumor necrosis factor (TNF) is considered to play a role in the second hit of non-alcoholic steatohepatitis (NASH). To clarify the effects of TNF in NASH we investigated TNF gene polymorphisms that might influence TNF production were investigated. METHODS: We analyzed 102 patients with non-alcoholic fatty liver disease (NAFLD; 36 with simple steatosis and 66 with NASH) and 100 control subjects. The serum level of soluble TNF receptor (sTNFR)-2 was measured. The TNF-alpha promoter region positions -1031, -863, -857, -308, and -238 and the TNF-beta gene Nco1 polymorphism site were investigated. RESULTS: The level of sTNFR-2 was significantly higher in NASH patients than in those with simple steatosis or control subjects. In the analysis of TNF gene polymorphisms, there were no significant deviations between the group of all NAFLD patients and the control subjects. The carrier frequencies of polymorphisms at positions -1031C and -863A were significantly higher in patients with NASH than in those with simple steatosis. In the multivariate analysis, TNF-alpha promoter polymorphisms proved to be significant independent factors distinguishing NASH from simple steatosis. CONCLUSIONS: TNF polymorphisms, which influence TNF production, might be associated with the progression of NAFLD.     

Effect of cardiac resynchronization therapy in isolated ventricular noncompaction in adults: follow-up of four cases

Background: An isolated ventricular noncompaction (IVNC) is an unclassified cardiomyopathy and, despite the increasing awareness of and interest in this disorder, the role of cardiac resynchronization therapy (CRT) remains obscure. Objective: The purpose of this study was to clarify the long‐term effect of CRT on IVNC in adult patients. Methods: Four cases of IVNC were included in this study. Before the CRT device was implanted, all four patients (54 ± 16‐year‐old, 4 males) presented with symptomatic congestive heart failure. Echocardiography revealed their systolic dysfunction and their left ventricular ejection fraction (LVEF) was 21 ± 8%. There was also mechanical dyssynchrony observed between the LV septum and free wall area. The QRS duration was “narrow” (112 and 120 ms) in two patients. One patient had been resuscitated from ventricular fibrillation (VF) and two had nonsustained ventricular tachycardia (VT). A CRT defibrillator (CRT‐D) was implanted in three patients with VT/VF and a CRT pacemaker (CRT‐P) in a patient without VT/VF. The LV lead was positioned in a lateral branch of the coronary sinus where a thickened noncompacted wall existed. Results: During the follow‐up period (28 ± 23 months), their congestive heart failure had improved in terms of the cardiothoracic ratio on the chest X‐ray, B‐type natriuretic peptide level, LV systolic dimension, and LVEF. No episodes of defibrillation shocks were observed. Conclusion: CRT may improve the prognosis and quality‐of‐life in patients with an IVNC with mechanical dyssynchrony.     

Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration

The periosteum is now widely recognized as a homeostatic and therapeutic target for actions of sex steroids and intermittent PTH administration. The mechanisms by which estrogens suppress but PTH promotes periosteal expansion are not known. In this report, we show that intermittent PTH(1-34) promotes differentiation of periosteal osteoblast precursors as evidenced by the stimulation of the expression or activity of alkaline phosphatase as well as of targets of the bone morphogenetic protein 2 (BMP-2) and Wnt pathways. In contrast, 17beta-estradiol (E2) had no effect by itself. However, it attenuated PTH- or BMP-2-induced differentiation of primary periosteal osteoblast progenitors. Administration of intermittent PTH to ovariectomized mice induced rapid phosphorylation of the BMP-2 target Smad1/5/8 in the periosteum. A replacement dose of E2 had no effect by itself but suppressed PTH-induced phosphorylation of Smad1/5/8. In contrast to its effects to stimulate periosteal osteoblast differentiation, PTH promoted and subsequently suppressed proliferation of periosteal osteoblast progenitors in vitro and in vivo. E2 promoted proliferation and attenuated the antiproliferative effect of PTH. Both hormones protected periosteal osteoblasts from apoptosis induced by various proapoptotic agents. These observations suggest that the different effects of PTH and estrogens on the periosteum result from opposing actions on the recruitment of early periosteal osteoblast progenitors. Intermittent PTH promotes osteoblast differentiation from periosteum-derived mesenchymal progenitors through ERK-, BMP-, and Wnt-dependent signaling pathways. Estrogens promote proliferation of early osteoblast progenitors but inhibit their differentiation by osteogenic agents such as PTH or BMP-2.     

日本血吸虫虫卵毛蚴中带信号序列基因的全长cDNA序列分析

目的 对带有信号序列的日本血吸虫虫卵毛蚴基因的全长cDNA序列进行分析。方法 根据日本血吸虫虫卵毛蚴中带信号序列的cDNA片段序列设计合成基因特异性引物。以虫卵的第一链全长cDNA为模板，采用套式PCR，快速扩增带信号序列的虫卵毛蚴cDNA的5’、3’末端片段，将特异性扩增片段进行TA克隆与序列分析。将每个带信号序列的虫卵毛蚴cDNA片段序列与其5’、3’末端片段序列进行比对和拼接，构建每个带信号序列的虫卵毛蚴基因的完整全长cDNA序列，对部分带信号序列虫卵毛蚴基因的信号序列所对应的基因组序列结构进行分析。结果 本研究分析了30个带有信号序列的cDNA片段，其中16个片段的5’、3’末端cDNA序列被成功扩增，并测定了它们的DNA序列，通过序列比对和拼接，获得了该16个虫卵毛蚴基因的全长cDNA序列。对开放阅读框演绎的氨基酸序列进行分析，发现基因SjP4001与SjP1531的信号肽序列完全相同，而基因SjP3742和SjP1183的信号肽氨基酸序列甚为相似，从而进一步证明不同的基因可拥有相同或相似的信号肽。基因组序列分析表明，基因SjP1183的信号肽基因序列与成熟肽基因序列通过交替拼接（alternative splicing）方式进行拼接；而基因SjP4001、SjP1531、SjP3742的信号肽基因序列与成熟肽基因序列之间可能是通过转移拼接的方式进行拼接。结论 确定了16个带有信号序列的虫卵毛蚴基因的全长cDNA序列，虫卵毛蚴基因可通过交替拼接方式或转移拼接方式获得信号肽序列。     

Acute onset of ulcerative colitis following an operation for sigmoid colon cancer

We describe a case of ulcerative colitis (UC) where clinical symptoms began abruptly within a few weeks after colon resection. The patient, a 44-year-old woman, was first referred to our hospital for the treatment of colon cancer. During the past several years, she had not had any inflammatory bowel disease-like clinical symptoms, such as frequent diarrhea or abdominal discomfort. Before the operation, both macroscopic and microscopic examination revealed that no remarkable inflammatory change was associated with the cancer in any area of her colon. At 10 days after the operation, she started to complain of frequent watery diarrhea. Two weeks after the operation, she was readmitted to our hospital because of frequent bloody diarrhea, fever, and abdominal discomfort. Based on endoscopic and histological examinations, she was diagnosed as having severe UC and was treated with hyperalimentation, predonisolone, mesalazine, and granulocyte apheresis. However, she did not respond to this combination therapy. At 45 days after the first operation, owing to sudden onset hemorrhagic shock, she underwent a second colectomy. The resected specimen of the entire colon showed severe pancolitis, and histological examination revealed severe inflammatory changes in the lamina propria together with crypt distortion, all of which were consistent with UC.     

Four-year efficacy of cardiac resynchronization therapy on exercise tolerance and disease progression: the importance of performing atrioventricular junction ablation in patients with atrial fibrillation.

OBJECTIVES: The goal of this study was to investigate the effects of cardiac resynchronization therapy (CRT) in heart failure patients with permanent atrial fibrillation (AF) and the role of atrioventricular junction (AVJ) ablation. BACKGROUND: Cardiac resynchronization therapy has been proven effective in heart failure patients with sinus rhythm (SR). However, little is known about the effects of CRT in heart failure patients with permanent AF. METHODS: Efficacy of CRT on ventricular function, exercise performance, and reversal of maladaptive remodeling process was prospectively compared in 48 patients with permanent AF in whom ventricular rate was controlled by drugs, thus resulting in apparently adequate delivery of biventricular pacing (>85% of pacing time), and in 114 permanent AF patients, who had undergone AVJ ablation (100% of resynchronization therapy delivery). The clinical and echocardiographic long-term outcomes of both groups were compared with those of 511 SR patients treated with CRT. RESULTS: Both SR and AF groups showed significant and sustained improvements of all assessed parameters (model p < 0.001 for all parameters). However, within the AF group, only patients who underwent ablation showed a significant increase of ejection fraction (p < 0.001), reverse remodeling effect (p < 0.001), and improved exercise tolerance (p < 0.001); no improvements were observed in AF patients who did not undergo ablation. CONCLUSIONS: Heart failure patients with ventricular conduction disturbance and permanent AF treated with CRT showed large and sustained long-term (up to 4 year) improvements of left ventricular function and functional capacity, similar to patients in SR, only if AVJ ablation was performed.