Persistent inflammation is well known to promote the progression of arthropathy. mesenchymal stem cells (MSCs) have been shown to possess anti-inflammatory properties and tissue differentiation potency. Although the experience so far with the intraarticular administration of mesenchymal stem cell (MSC) to induce cartilage regeneration has been disappointing, MSC implantation is now being attempted using various surgical techniques. Meanwhile, prevention of osteoarthritis (OA) progression and pain control remain important components of the treatment of early-stage OA. We prepared a shoulder arthritis model by injecting monoiodoacetate (MIA) into a rat shoulder, and then investigated the intraarticular administration of MSC from the aspects of the cartilage protective effect associated with their anti-inflammatory property and inhibitory effect on central sensitization of pain. When MIA was administered in this rat shoulder arthritis model, anti-Calcitonin Gene Related Peptide (CGRP) was expressed in the joint and C5 spinal dorsal horn. Moreover, expression of A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS5), a marker of joint cartilage injury, was similarly elevated following MIA administration. When MSC were injected intraarticularly after MIA, the expression of CGRP in the spinal dorsal horn was significantly deceased, indicating suppression of the central sensitization of pain. The expression of ADAMTS 5 in joint cartilage was also significantly inhibited by MSC administration. In contrast, a significant increase in the expression of TNF-α stimulated gene/protein 6 (TSG-6), an anti-inflammatory and cartilage protective factor shown to be produced and secreted by MSC intraarticularly, was found to extend to the cartilage tissue following MSC administration. In this way, the intraarticular injection of MSC inhibited the central sensitization of pain and increased the expression of the anti-inflammatory and cartilage protective factor TSG-6. As the least invasive conservative strategies possible are desirable in the actual clinical setting, the intraarticular administration of MSC, which appears to be effective for the treatment of pain and cartilage protection in early-stage arthritis, may achieve these aims.
OBJECTIVE -To clarify whether stiffness and impaired blood flow in lower-leg arteries are associated with severity of coronary artery calcification among asymptomatic diabetic patients.RESEARCH DESIGN AND METHODS -We enrolled 102 asymptomatic type 2 diabetic patients with no history of cardiovascular complications consecutively admitted to our hospital. Agatston coronary artery calcium (CAC) score, as a marker of coronary artery calcification, was obtained using electron-beam computed tomography. Total flow volume and resistive index, as an index of vascular resistance, at the popliteal artery were evaluated using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging. Brachial-ankle pulsewave velocity (PWV), as an index of distensibility in the lower-extremity arteries, was also measured using an automatic device.RESULTS -When the patients were grouped according to CAC scores of 0 -10 (n ϭ 54), 11-100 (n ϭ 25), and Ͼ100 (n ϭ 23), those with the highest scores, which is considered to show possible coronary artery disease, showed the highest brachial-ankle PWV (P Ͻ 0.001) and resistive index (P Ͻ 0.001) and the lowest total flow volume (P Ͻ 0.001) among the groups. Simple linear regression analyses showed that both brachial-ankle PWV (r ϭ 0.508, P Ͻ 0.001) and resistive index (r ϭ 0.500, P Ͻ 0.001) were positively correlated and total flow volume (r ϭ Ϫ0.528, P Ͻ 0.001) was negatively correlated with the log-transformed CAC score. Receiver operator characteristic curve analyses indicated that 1,800 cm/s for brachial-ankle PWV, 1.03 for resistive index, and 70 ml/min for total flow volume were diagnostic values for identifying patients with the highest scores.CONCLUSIONS -Quantitatively assessed stiffness and impaired blood flow in lower-leg arteries may help identify diabetic patients with possible coronary artery disease. Diabetes Care 27:2409 -2415, 2004A therosclerotic coronary artery disease (CAD) is a major cause of mortality and morbidity among diabetic patients (1). It is desirable to identify subjects with coronary atherosclerosis before the onset of angina pectoris or myocardial infarction. When atherosclerotic plaques are at an advanced stage, calcified deposits in the coronary arteries are found more frequently and in greater amounts (2). A number of studies (3) have documented the usefulness of electron-beam computed tomography (EBCT) for the detection and evaluation of the extent of coronary calcified atherosclerotic lesions in asymptomatic patients before the development of life-threatening cardiac complications. The reliability of EBCT in the detection of calcified deposits in coronary arteries has been confirmed by histomorphometric analysis of dissected coronary vessels from autopsied hearts (4). Moreover, diabetic patients show twofold prevalence of extensive coronary artery calcification compared with nondiabetic subjects as evaluated by EBCT (5). Calcified lesions of arterial walls can be classified as either intimal atherosclerotic calcification or medial arterial calcifica...
The purpose of the role of antioxidant enzymes and mitochondria in the developmental mechanism of steroid-associated osteonecrosis in the femur. In the present study Japanese white rabbits (mean weight 3.5kg) were injected into the gluteus with methylprednisolone (MP) 20mg/kg, and killed after 3 days (MP3 group), 5 days (MP5 group), and 14 days (MP14 group) (n=3 each). As a Control group (C group) Japanese white rabbits not administered MP were used. In experiment 1, the expression of the antioxidant enzymes Superoxide dismutade (SOD) and catalase was compared in liver, kidney, heart, humerus, and femur in C group, and the presence/absence of mitochondria transcription factor A (TFAM) expression was determined by Western blotting (WB) and used to evaluate the number of mitochondria and their function. In experiment 2, the presence/absence of necrosis was determined by immunohistochemistry, while changes in the expression of SOD, catalase, and TFAM in the femur after steroid administration were determined by Western blotting (WB). In experiment 1, intense expression of all of SOD, catalase, and TFAM was found in the liver, kidney, and heart as compared to the humerus and femur. In experiment 2, the expression of all of SOD, catalase, and TFAM in MP3 and MP5 groups was decreased on WB as compared with C group, while in MP14 group a tendency to improvement was seen. Accordingly, steroid-associated mitochondrial injury and redox failure are concluded to be important elements implicated in the pathogenesis of osteonecrosis.
OBJECTIVE -To clarify the prevalence and major risk factors of reduced flow volume in lower extremities with normal ankle-brachial index (ABI) in Japanese patients with type 2 diabetes.RESEARCH DESIGN AND METHODS -We recruited 208 consecutive type 2 diabetic patients and 33 age-matched nondiabetic subjects (control group) admitted to our hospital. Thirty-two of the patients had low ABI (Ͻ0.90) and intermittent claudication (peripheral arterial disease [PAD] group), and 176 patients had normal ABI (Ͼ0.9) (non-PAD group). We evaluated flow volume and resistive index, as an index of arterial resistance to blood flow, at the popliteal artery using gated two-dimensional cine-mode phase-contrast magnetic resonance imaging.RESULTS -Simple linear regression analysis showed a negative correlation between resistive index and total flow volume in the non-PAD group (r ϭ Ϫ0.714, P Ͻ 0.001). We defined the means Ϯ 2 SD of these parameters in the control group as the normal range; abnormal resistive index was Ͼ1.017, and abnormal flow volume was Ͻ50.8 ml/min. The non-PAD group was divided according to the levels of these parameters: 80 patients had both normal resistive index and normal flow volume (normal group); of 96 patients with higher resistive index, 63 had normal flow volume (borderline group) and 33 had reduced flow volume (reduced group). Multiple regression analysis demonstrated that the major risk factors for reduced flow volume were age, hypertension, and diabetic nephropathy (r 2 ϭ 0.303, P Ͻ 0.001).CONCLUSIONS -The prevalence of patients without PAD with reduced flow volume in the lower extremities was 16% (n ϭ 33) and comparable with that of patients with PAD with intermittent claudication (n ϭ 32), suggesting that increase in arterial resistance to blood flow may be one of the major causes of lower extremity arterial disease in Japan. Diabetes Care 26:1764 -1769, 2003P eripheral arterial disease (PAD), which is usually caused by atherosclerotic occlusive lesions of the lower leg arteries, reduces flow volume to the lower limb during exercise or at rest (1). To aid in identifying patients at high risk of PAD, the ankle-brachial index (ABI) is generally used (2). However, patients with diabetes (3) or renal failure (4) have rigid or calcified lower leg arteries, rendering the arteries incompressible and causing a falsely elevated ABI. Although a negative ABI does not exclude PAD, an abnormal ABI is extremely useful in predicting an increase in cardiovascular mortality in epidemiological studies. Low ABI is closely associated with increased risk of death from myocardial infarction (5-7). In contrast, we previously reported that increased arterial resistance to blood flow because of increased arterial wall stiffness limits flow volume in the lower-extremity arteries in diabetic patients, although they have a normal ABI (non-PAD) (8). Some patients without PAD had critically reduced flow volume in the lower extremities and were considered at high risk for foot lesions. Although the existence of this condition is re...
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