Bone lesions in elderly multiple myeloma

We investigated the incidence of bone lesions in elderly cases of multiple myeloma (MM) and the course of those lesions, and also evaluated the relationships of skeletal symptoms with prognostic factors, and prognosis. The subjects were 146 patients, aged 65 years or more (median age 74, range 65-97 year), who were admitted to 11 institutions between January, 1988 and December, 1997. They consisted of 64 men and 82 women. The disease type was IgG type in 88 patients, IgA type in 37 patients, Bence-Jones (BJ) type in 17 patients, IgD type in three patients, and non-secretory type in one patient. Bone lesions in elderly MM patients were compared with those in 65 non-elderly MM patients. Skeletal symptoms were noted in 104 patients, and bone pain in 75 patients at the time of diagnosis. The bone lesions were evaluated as only osteolytic lesions in 26 patients, osteolytic lesions + osteoporosis in 23 patients, only osteoporosis in 2 patients and pathologic bone fractures in 53 patients. The occurrence rate of osteoporosis plus osteolytic lesion was higher in elderly patients (63.5%) than that in non-elderly patients (NE-MM group) (28.3%) (p < 0.0001). The bone lesions were most often observed in lumbar vertebrae (58.7%), cranial bone (56.7%), thoracic vertebrae (40.4%) and ribs (27.9%). The occurrence rate of bone lesion in lumbar vertebrae was higher in elderly patients (58.7%) than that in non-elderly patients (22.6%) (p < 0.0001). The life activities were limited in 71 patients because of the bone lesions. The relationship between the prognostic factors of MM and bone lesions was evaluated. There was a significant difference in the serum Ca level between patients with and without bone pain (P < 0.0001) and between those with and without pathologic bone fracture (P < 0.01). There was a significant difference in the appearance rate of plasma cells in the bone marrow between the patients with and without bone lesions (P < 0.05), between those with and without bone pain (P < 0.01), and between those with and without pathologic fracture (P < 0.05). There was a significant difference in the serum beta 2-microglobulin level between the patients with and without bone pain, and between those with and without pathologic fracture. There were no significant differences in survival times between elderly MM patients with and without bone lesions, bone pain and pathological bone fractures, while significant differences of survival times were found between non-elderly MM patients with and without bone lesions, bone pain and pathological bone fractures (P < 0.05, each). These data suggest that there are some differences in bone lesions between elderly and non-elderly MM patients.     

Rhythmic adenosine triphosphate release from the cyanobacterial circadian clock protein KaiC revealed by real-time monitoring of bioluminescence using firefly luciferase

The cyanobacterial circadian clock is composed of three clock proteins, KaiA, KaiB and KaiC. This KaiABC clock system can be reconstituted in vitro in the presence of adenosine triphosphate (ATP) and Mg²⁺, and shows circadian rhythms in the phosphorylation level and ATPase activity of KaiC. Previously, we found that ATP regulates a complex formation between KaiB and KaiC, and KaiC releases ATP from KaiC itself (PLoS One, 8, 2013, e80200). In this study, we examined whether the ATP release from KaiC shows any rhythms in vitro. We monitored the release of ATP from wild-type and ATPase motif mutants of KaiC as a bioluminescence in real time using a firefly luciferase assay in vitro and obtained the following results: (a) ATP release from KaiC oscillated even without KaiA and KaiB although period of the oscillation was not 24 hr; (b) ATP was mainly released from the N-terminal domain of KaiC; and (c) the ATP release was enhanced and suppressed by KaiB and KaiA, respectively. These results suggest that KaiC can generate basal oscillation as a core clock without KaiA and KaiB, whereas these two proteins contribute to adjusting and stabilizing the oscillation.     

Inflammatory responses in cuff-induced atherosclerosis in rabbits

Cuff-treatment of the rabbit carotid artery produced a diffuse intimal thickening which resembled early lesions of atherosclerosis. A limited amount of focal endothelial damage occurred first (0.5 h), leukocytes infiltrated the subendothelium and extensive endothelial denudation occurred at 24 h. At 3 days, the regenerating endothelium covered the denuded area, and the media was edematous. At 7 days proliferation of intimal cells became visible. Maximum intimal thickening occurred at 3 weeks. Daily injection of dexamethasone (0.01-10 mg/kg i.m.) and ticlopidine (1-100 mg/kg i.m.) dose-dependently attenuated the intimal thickening. Indomethacin had little effect. Inflammatory exudate from zymosan-activated air pouch induced chemotaxis of rat smooth muscle cells (SMC) in vitro. Similar chemotactic activity was observed with leukotriene B4 (LTB4) but not with the other lipoxygenase products tested. The exudate contained reasonable amounts of LTB4, which would account for its chemotactic activity. Dexamethasone inhibited the chemotaxis by the exudate and proliferation of SMC. These results are discussed in relation to the mechanism of atherogenesis. It is concluded that leukocytes play a major role in cuff-induced intimal thickening, and that their products cause endothelial denudation and SMC chemotaxis. Involvement of platelet aggregation in atherogenesis is also suggested.     

Differential effects of FK506 and methotrexate on inflammatory cytokine levels in rat adjuvant-induced arthritis

OBJECTIVE: To investigate the effects of prophylactic and therapeutic treatments with FK506 (tacrolimus), an immunosuppressive drug that specifically inhibits T cell activation, and methotrexate (MTX) on inflammatory cytokines, tumor necrosis factor (TNF)-a, interleukin (IL)-1beta, and IL-6 levels in rat adjuvant-induced arthritis (AIA). METHODS: AIA was induced in female Lewis rats. Arthritis was assessed by hindpaw swelling. TNF-a, IL-1beta, and IL-6 levels in paw extracts were determined by ELISA. To assess the effects on cytokine levels, rats were treated prophylactically with FK506 (3 mg/kg) or MTX (0.1 mg/kg) from day 1 to day 17, and therapeutically with FK506 (5 mg/kg) or MTX (1 mg/kg) from day 15 to day 17 (3-day treatment) or day 15 to 20 (6-day treatment) by oral administration. RESULTS: TNF-a, IL-1beta, and IL-6 levels in paw tissue were found to significantly increase between day 15 and day 21 after adjuvant injection, when the arthritis was in a developed stage. Prophylactic treatment with FK506 and MTX suppressed arthritis and reduced the levels of those inflammatory cytokines. FK506 caused a marked reduction of TNF-a and IL-1beta levels in paw tissue even in short-term (3-day) therapeutic treatment. It reduced all levels of TNF-a, IL-1beta, and IL-6 in paws in 6-day therapeutic treatment. In contrast, therapeutic treatment with MTX affected neither TNF-a or IL-6 levels in paws. MTX reduced IL-1beta levels only in the 6-day treatment. CONCLUSION: FK506 is more effective than MTX in reducing elevated levels of inflammatory cytokines TNF-a, IL-1beta, and IL-6 in established stages of AIA. Our findings suggest that inhibition of T cell activation results in a rapid reduction of inflammatory cytokine levels even after the arthritis is established in AIA.     

Fenofibrate,a peroxisome proliferator-activated receptor alpha activator,suppresses experimental autoimmune myocarditis by stimulating the interleukin-10 pathway in rats

Experimental autoimmune myocarditis (EAM) in rats is an animal model of human giant cell myocarditis and postmyocarditis dilated cardiomyopathy. As the heart consumes large amounts of energy, heart diseases such as myocarditis and dilated cardiomyopathy are associated with abnormal fatty acid metabolism. Peroxisome proliferator-activated receptor alpha (PPARalpha) is a regulator of the oxidative degradation of fatty acids. To investigate the role of PPARalpha in EAM, fenofibrate (a PPARalpha activator) was administered to rats with EAM for 4 weeks. Reductions in the ratios of both ventricular weight to body weight and the area of inflammatory lesions to the total area of heart sections were observed in fenofibrate-treated rats when compared with controls. Fenofibrate ameliorated changes in serum albumin and sialic acid, which are markers of inflammation. Cardiac expression of interleukin-10 (IL-10) mRNA was more pronounced in the fenofibrate group than in the control group (1.3 +/- 0.2 vs 0.7 +/- 0.1; p < 0.01), and the area of intact myocardium correlated with the IL-10 mRNA level (p = 0.0297, r = 0.620). We suggest that PPARalpha activators may prevent the progression of myocarditis through increased expression of the gene encoding the anti-inflammatory cytokine IL-10, although the mechanisms involved remain to be determined.     

Worksite Wellness for the Primary and Secondary Prevention of Cardiovascular Disease in Japan: The Current Delivery System and Future Directions

In the Japanese workplace, employers are required to provide annual health checkups for workers in accordance with the “Industrial Safety and Health Law,” which also mandates that an occupational physician be assigned to companies employing at least 50 workers. The annual medical examination includes testing for the early detection of cardiovascular risk factors such as hypertension, dyslipidemia, diabetes, and the metabolic syndrome. This approach has successfully contributed to the extremely low incidence of coronary artery disease among Japanese workers. However, problems such as poor health and the low rate of participation in health checkups among small-scale companies still persist. Furthermore, although most wellness delivery systems in Japan employ strategies targeting high-risk individuals, instituting a strategy addressing the broader population irrespective of screening may be effective in reducing disease risk in the overall population. As a future direction, we should therefore develop practical methods for implementing a population strategy.