Effects of a psychosocial intervention programme combined with exercise in community-dwelling older adults with chronic pain: A randomized controlled trial.

BACKGROUND: Although researchers have recommended exercise training and psychosocial intervention to manage chronic pain, an effective intervention for Japanese community-dwelling older adults with chronic pain has not been established. This randomized controlled trial examined whether exercise training combined with psychosocial intervention more effectively improves pain, psychological status and physical activity than does exercise training alone in this population. METHODS: We randomized 128 older adults with chronic pain to either an intervention group (n = 64) involving exercise training combined with psychosocial intervention, or a control group (n = 64) involving only exercise training. Exercise training comprised weekly 60-min sessions for 12 weeks. Psychosocial intervention involved changing participants' focus on pain using self-management education and cognitive behavioural therapy, and participants recorded their daily pain intensity and step counts. Pain intensity, psychological status and physical activity were assessed before and 12 weeks after the intervention. RESULTS: A time-by-group interaction emerged for psychological status (p = 0.003) and physical activity (p < 0.001), both favouring the intervention group. The intervention group also showed greater improvement in pain intensity at 12 weeks than did the control group (p = 0.007). CONCLUSIONS: Exercise training combined with psychosocial intervention improves key outcome indicators more effectively than does exercise training alone in older adults with chronic pain. SIGNIFICANCE: Although research has shown that combined exercise and psychosocial intervention is optimal for managing chronic pain, our study is the first, to the best of our knowledge, to test a specific intervention of this type in community-dwelling older adults with chronic pain in Japan.

The influence of aging on the effectiveness of heat stress in preventing disuse muscle atrophy.

This study examined the aging effect on disuse muscle atrophy prevention using heat stress. Wistar rats aged 7 and 60 weeks were divided into three groups as follows: control, immobilized (Im), and immobilized and heat stressed (ImH). Heat stress was given by immersing the hindlimbs in hot water (42 °C) for 60 min, once in every 3 days and the gastrocnemius (GAS) and soleus (SOL) muscles were extracted after 14 days. Muscle-fiber types were classified using ATPase staining. Heat shock protein 70 (HSP70) was assessed through Western blotting. In GAS muscle of both groups and SOL muscle of 7-week-old rats, the fiber diameter of each muscle type in the ImH group significantly increased compared with that in the Im group. However, this could not be observed in the SOL muscle of the 60-week-old rats. The increased percentage of type-I fibers and variability of types I and II muscle-fiber diameter were evident in the SOL muscle of the 60-week rats. HSP70 was significantly elevated in the ImH group compared with in the Im group in both muscle types of both age groups. Thus, effectiveness of heat stress in the prevention of disuse muscle atrophy appears unsatisfactory in aging muscle fibers.

Effect of continuous passive motion initiated after the onset of arthritis on inflammation and secondary hyperalgesia in rats.

This study investigated the effect of continuous passive motion (CPM) initiated after the onset of arthritis in rats. Rats were injected with 3 % kaolin/carrageenan in the knee joint and randomized to the control, immobilization (IM), or CPM group. The knee joints of the IM and CPM groups were immobilized with a cast for 56 days. In the CPM group, CPM exercise was administered for 60 min/day (6 times/week). Joint transverse diameter and pressure pain threshold (PPT) were assessed as indicators of inflammation, and paw withdrawal response (PWR) was assessed as indicator of secondary hyperalgesia. Central sensitization was analyzed by measuring calcitonin gene-related peptide (CGRP) expression levels in the spinal dorsal horn. In the CPM group, the PPT was significantly increased compared with the IM group from 14 to 35 days, and PWR was significantly decreased from 14 to 56 days. Additionally, CGRP expression in the super facial layer (I-II) of the spinal dorsal horn (L4-5) in the CPM group was significantly decreased compared with the IM group. Our study found the CPM initiated after the onset of arthritis promoted the recovery of inflammation and mitigated secondary hyperalgesia.

Heat treatment inhibits skeletal muscle atrophy of glucocorticoid-induced myopathy in rats.

The purpose of this study was to investigate the influence of heat treatment on glucocorticoid (GC)-induced myopathy. Eight-week-old Wistar rats were randomly assigned to the control, Dex, and Dex + Heat groups. Dexamethasone (2 mg/kg) was injected subcutaneously 6 days per week for 2 weeks in the Dex and Dex + Heat group. In the Dex + Heat group, heat treatment was performed by immersing hindlimbs in water at 42 °C for 60 min, once every 3 days for 2 weeks. The extensor digitorum longus muscle was extracted following 2 weeks of experimentation. In the Dex + Heat group, muscle fiber diameter, capillary/muscle fiber ratio, and level of heat shock protein 72 were significantly higher and atrogene expression levels were significantly lower than in the Dex group. Our results suggest that heat treatment inhibits the development of GC-induced myopathy by decreasing atrogene expression and increasing angiogenesis.

Hyperglycemia inhibits recovery from disuse-induced skeletal muscle atrophy in rats.

The purpose of this study was to evaluate the effects of hyperglycemia on skeletal muscle recovery following disuse-induced muscle atrophy in rats. Wistar rats were grouped as streptozotocin-induced diabetic rats and non-diabetic rats. Both ankle joints of each rat were immobilized to induce atrophy of the gastrocnemius muscles. After two weeks of immobilization and an additional two weeks of recovery, tail blood and gastrocnemius muscles were isolated. Serial cross sections of muscles were stained for myosin ATPase (pH 4.5) and alkaline phosphatase activity. Serum insulin and muscle insulin-like growth factor-1 (IGF-1) levels were also measured. Serum insulin levels were significantly reduced in the diabetic rats compared to the non-diabetic controls. The diameters of type I, IIa, and IIb myofibers and capillary-to-myofiber ratio in the isolated muscle tissue were decreased after immobilization in both treatments. During the recovery period, these parameters were restored in the non-diabetic rats, but not in the diabetic rats. In addition, muscle IGF-1 levels after recovery increased significantly in the non-diabetic rats, but not in the diabetic rats. We conclude that decreased levels of insulin and IGF-1 and impairment of angiogenesis associated with diabetes might be partly responsible for the inhibition of regrowth in diabetic muscle.

Sensory hyperinnervation and increase in NGF, TRPV1 and P2X3 expression in the epidermis following cast immobilization in rats.

BACKGROUND: Cast immobilization is known to induce pain in humans and experimental animal models; however, the detailed mechanisms underlying this pain have yet to be elucidated. Recently, several lines of evidence have indicated that morphological changes in sensory innervation and changes in the expression of pain-related molecules in the epidermis are related to certain painful conditions. The aim of the present study was to temporally investigate the histological changes in the glabrous skin of the rat hind paw after 1, 2 and 4 weeks of ankle joint immobilization by casting. METHODS: The von Frey test and the plantar test were performed to examine noxious sensitivity of the skin. Immunohistochemical methods were used to assess sensory nerve fibre profiles and to examine the expression of the nerve growth factor (NGF), transient receptor potential vanilloid 1 (TRPV1) and P2X3 in the epidermis. RESULTS: Cast immobilization produced a time-dependent increase in mechanical and thermal sensitivity. In the plantar skin of immobilized rats, both myelinated A fibres and unmyelinated C fibres were increased. NGF, TRPV1 and P2X3 expression levels in the epidermis were also increased. Although the level of NGF expression did not display a meaningful change throughout the immobilization period, other changes became remarkable, depending on the period of immobilization. CONCLUSIONS: The time course of the increase in peripheral nerve fibres and in the expression of TRPV1 and P2X3 paralleled the development of hypersensitivity, which suggests that histological changes of the skin following cast immobilization may have some relation to the resulting hypersensitivity.

Hindlimb suspension does not influence mechanical sensitivity, epidermal thickness, and peripheral nerve density in the glabrous skin of the rat hind paw.

Our aim was to investigate the influence of microgravity on the sensitivity of the skin to mechanical stimulation, epidermal thickness, peripheral nerve density in the upper dermis, and serum levels of a stress marker in a rat hindlimb suspension (HS) model. Thirty 8-week-old male Wistar rats were randomly divided into 3 groups: HS, n=10; sham HS, n=10; control, n=10. The suspension system was attached to rat tails in both the HS and sham-HS groups, but the hindlimbs were suspended only in the HS group. The HS and sham-HS groups were treated for 4 weeks. In behavioral tests using von-Frey filaments (n=5 in each group), mechanical hypersensitivity developed in the HS and sham HS groups. Serum corticosterone levels increased significantly in the HS and sham HS groups compared to the control group, and no changes in epidermal thickness or peripheral nerve density were observed immediately after the removal of HS (n=5 in each group). These data indicated that the mechanical hypersensitivity observed in the HS group was not caused by microgravity or inactivity, but rather by restraint stress. We suggest that microgravity does not affect skin sensitivity and histology in these animals. Unit of Physical Therapy and Occupational Therapy Sciences, Nagasaki University Graduate School of Biochemical Sciences, Nagasaki-shi, Japan.

Changes in hind paw epidermal thickness, peripheral nerve distribution and mechanical sensitivity after immobilization in rats.

This study was designed to investigate histological changes in skin tissue accompanying immobilization-induced hypersensitivity. Changes in mechanical sensitivity, epidermal thickness, and peripheral nerve profiles in the upper dermis were examined in glabrous skin of rat hind paw after 1, 2, and 4 weeks of ankle joint immobilization by plaster casts. Induction of mechanical hypersensitivity was confirmed after 2 and 4 weeks of joint immobilization. Epidermal thinning and increase in peripheral nerve profiles were observed in skin tissues in immobilized rats. The time course of epidermal thinning and increase in peripheral nerve profiles were similar closely to that of hypersensitivity, with significant differences between the immobilized and control rats after 2 weeks of immobilization, which became even more remarkable at 4 weeks of immobilization. These findings suggest that joint immobilization by cast induces epidermal thinning and increases peripheral nerve profiles in the upper dermis and that these changes might be partly responsible for immobilization-induced hypersensitivity.

The clinical significance of splice variants and subcellular localisation of survivin in non-small cell lung cancers.

Survivin is a member of the inhibitor of apoptosis protein family. Survivin has splice variants with different biological functions associated with tumorigenesis. We investigated 134 non-small cell lung cancers (NSCLCs) to study the clinical significance of wild-type survivin, survivin-2B, and survivin-deltaEx3. Real-time PCR analyses were performed for their gene expressions. The subcellular localisation of survivin proteins was evaluated by immunohistochemistry. The Ki-67 proliferation index and the apoptotic index were also evaluated. The survivin-deltaEx3 gene expression was significantly higher in stage II-III than in stage I (P=0.0174), and significantly correlated with the nuclear pan-survivin expression (P<0.0001). The Ki-67 index was significantly higher in wild-type survivin-positive tumours (P<0.0001), survivin-deltaEx3-positive tumours (P<0.0001), and tumours with positive expression of the nuclear pan-survivin (P=0.0047). In contrast, the apoptotic index was significantly lower only in wild-type survivin-positive tumours (P<0.0001). Thus, the wild-type survivin gene expression was associated with apoptotic inhibition and tumour proliferation. Furthermore, the survivin-deltaEx3 gene expression was strongly associated with tumour proliferation, especially in advanced stage NSCLCs. In contrast, the survivin-2B gene expression did not correlate with tumour proliferation or tumour apoptosis.

Evaluations of biomarkers associated with 5-FU sensitivity for non-small-cell lung cancer patients postoperatively treated with UFT.

The sensitivity to 5-fluorouracil (5-FU) has been reported to be associated with target molecule thymidylate synthase (TS), fluoropyrimidine-metabolising enzymes such as orotate phosphoribosyltransferase (OPRT), and dihydropyrimidine dehydrogenase (DPD). We performed an immunohistochemical study on the clinical significance of TS, OPRT, and DPD expression using 151 resected non-small-cell lung cancer (NSCLC) patients postoperatively treated with a combination of tegafur and uracil (UFT). Eighty-two carcinomas were TS-positive, 105 carcinomas were OPRT-positive, 68 carcinomas were DPD-positive. No correlation was observed in the HSCORE between the TS and OPRT expression (r=0.203), between the TS and DPD expression (r=0.098), or between the OPRT and DPD expression (r=0.074). Regarding the survival of NSCLC patients treated with UFT, the 5-year survival rate of patients with TS-negative tumours was significantly higher than that with TS-positive tumours (P=0.0133). The 5-year survival rate of patients with OPRT-positive stage II to III tumours was significantly higher than that with OPRT-negative stage II to III tumours (P=0.0145). In addition, the 5-year survival rate of patients with DPD-negative tumours was also significantly higher than that with DPD-positive tumours (P=0.0004). A Cox multivariate regression analysis revealed the TS status (hazard ratio 2.663; P=0.0003), OPRT status (hazard ratio 2.543; P=0.0005), and DPD status (hazard ratio 2.840; P<0.0001) to all be significant prognostic factors for the survival of resected NSCLC patients postoperatively treated with UFT.

MRP-1/CD9 gene transduction regulates the actin cytoskeleton through the downregulation of WAVE2.

Motility-related protein-1 (MRP-1/CD9) is involved in cell motility. We studied the change in the actin cytoskeleton, and the expression of actin-related protein (Arp) 2 and Arp3 and the Wiskott-Aldrich syndrome protein (WASP) family according to MRP-1/CD9 gene transduction into HT1080 cells. The frequency of cells with lamellipodia was significantly lower in MRP-1/CD9-transfected HT1080 cells than in control HT1080 cells (P<0.0001). MRP-1/CD9 gene transduction affected the subcellular localization of Arp2 and Arp3 proteins. Furthermore, MRP-1/CD9 gene transduction induced a downregulation of WAVE2 expression (P<0.0001). However, no difference was observed in the expression of Arp2, Arp3 or other WASPs. A neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited downregulation of WAVE2 in MRP-1/CD9-transfected HT1080 cells (P<0.0001), and reversed the morphological effects of MRP-1/CD9 gene transduction. Furthermore, downregulation of WAVE2 by transfection of WAVE2-specific small interfering RNA (siRNA) mimicked the morphological effects of MRP-1/CD9 gene transduction and suppressed cell motility. However, transfection of each siRNA for Wnt1, Wnt2b1 or Wnt5a did not affect WAVE2 expression. Transfection of WAVE2-specific siRNA also did not affect expressions of these Wnts. These results indicate that MRP-1/CD9 regulates the actin cytoskeleton by downregulating of the WAVE2, through the Wnt-independent signal pathway.

[Early and late results and problems of coronary artery bypass grafting in patients over 80-year-old].

This study evaluated the validity of coronary artery bypass grafting (CABG) in patients over 80-year-old investigating the early and late result, patient's opinion to the surgery, and change of activities of daily living scale. From July 1993 to September 2002, consecutive 94 patients over 80-year-old were performed CABG in our institution. The group consisted of 43 female patients, and mean age of 82.6 years. Of these patients, 36 were operated conventional CABG (CABG group) and 58 patients were operated with off-pump CABG (OPCAB) group. There were no significant differences between 2 groups in preoperative characteristics except for anemia and hypertension. Operative results, including mortality, number of distal anastomoses, operative time had no significant differences between 2 groups. But maximum CK-MB fraction was higher in CABG group. There were 4 operative deaths, indicating operative mortality was 4.3%. Late results showed overall survival rate at 3 years was 81.1% and cardiac event free survival rate at 3 years was 88.8%. Questionnaire revealed over 80% patients were satisfied with the surgery but less than 40% patients felt activities of daily living (ADL) scale was improved. Operative results of CABG in octogenarians were satisfied, but more efforts to remain patient's high ADL were mandatory.

Rational design, discovery, and synthesis of a novel series of potent growth hormone secretagogues.

In the joint experimental and computational efforts reported here to obtain novel chemical entities as growth hormone secretagogues (GHSs), a small database of peptides and non-peptides known to have GHS activity was used to generate and assess a 3D pharmacophore for this activity. This pharmacophore was obtained using a systematic and efficient procedure, "DistComp", developed in our laboratory. The 3D pharmacophore identified was then used to search 3D databases to explore chemical structures that could be novel GHSs. A number of these were chosen for synthesis and assessment of their ability to release growth hormone (GH) from rat pituitary cells. Among the compounds tested, those with a benzothiazepin scaffold were discovered with micromolar activity. To facilitate lead optimization, a second program, a site-dependent fragment QSAR procedure was developed. This program calculates a library of chemical and physical properties of "fragments" or chemical components in a known pharmacophore and determines which, if any, of these properties are important for the observed activity. The combined use of the 3D pharmacophore and the results of the site-dependent fragment QSAR analysis led to the discovery and synthesis of a novel series of potent GHSs, a number of which had nanomolar in vitro activity.

Production of (4)(double Lambda)H hypernuclei.

An experiment demonstrating the production of double-Lambda hypernuclei in (K(-),K(+)) reactions on (9)Be was carried out at the D6 line in the BNL alternating-gradient synchrotron. The technique was the observation of pions produced in sequential mesonic weak decay, each pion associated with one unit of strangeness change. The results indicate the production of a significant number of the double hypernucleus (4)(double Lambda)H and the twin hypernuclei (4)(Lambda)H and (3)(Lambda)H. The relevant decay chains are discussed and a simple model of the production mechanism is presented. An implication of this experiment is that the existence of an S = -2 dibaryon more than a few MeV below the double Lambda mass is unlikely.

Activated astrocytes with glycogen accumulation in ischemic penumbra during the early stage of brain infarction: immunohistochemical and electron microscopic studies.

Brain infarction was induced in rats by injection of microspheres through the right internal carotid artery, and structural changes in the astrocytes were observed during the early period following the infarction. Necrotic foci, varying in size and shape, were found in the right hemisphere. After immunohistochemical staining for GFAP, GFAP-positive astrocytes in the perinecrotic area known as the ischemic penumbra had distinctly increased in number and size with elongation of cytoplasmic processes 3 days after infarction. Electron microscopic observation revealed that glycogen granules had markedly accumulated in the cytoplasm of astrocytes located in the ischemic penumbra 3 and 5 days after infarction. Seven days after infarction, however, the glycogen granules disappeared from the astrocytes. Intermediate filaments increasingly appeared in the protoplasmic astrocytes after 3 days and were abundant in the activated and hypertrophied astrocytes after 7 days. As a result of our present study, we conclude that: (1) the function of glucose uptake from blood vessels was not impaired in the astrocytes under hypoxic conditions; (2) the astrocytes actively ingested blood glucose through the endothelial cells and accumulated it as glycogen for activation of their functions, and the cell volume increased under hypoxic conditions; (3) the depression of energy metabolism and the decrease in the uptake of energy sources in the nerve cells promoted glycogen accumulation in the astrocytes under hypoxic conditions; (4) intermediate filaments (GFAP filaments) increased in number, coincident with the activation and enlargement of the astrocytes; and (5) protoplasmic astrocytes were transformed into fibrous astrocytes in the ischemic penumbra of the brain infarction.

Observation of spin-orbit splitting in lambda single-particle states.

The spin-orbit splitting of Lambda single-particle states in (13)(Lambda)C was measured. The 13C(K-,pi(-))(13)(Lambda)C reaction was used to excite both the 1/2(-) and 3/2(-) states simultaneously, which have predominantly 12C(0(+)) x p(Lambda) configuration. gamma rays from the states to the ground state were measured in coincidence with the pi(-)'s, by which ls splitting was found to be 152+/-54(stat)+/-36(syst) keV. The value is 20-30 times smaller than exhibited by the ls splitting in the nuclear shell model. This value gives us new insight into the YN interaction.

In vivo effects of apoptosis in asthma examined by a murine model.

BACKGROUND: One of the characteristic features of bronchial asthma is the accumulation of various inflammatory cells, predominantly eosinophils, at the subepithelial region beneath the basement membrane of the airway. Apoptosis is a form of physiological cell death, through which the cellular contents including biologically active substances are kept in the cell membrane and are removed without their harmful effects. So, attempts were made to clarify whether the induction of apoptosis is beneficial in asthma by using a murine model with ovalbumin (OA) as responsible allergen. METHODS: A/J mice, which are genetically predisposed to be hyperresponsive to acetylcholine, were immunized with OA and alum, accompanied by OA inhalation for 2 weeks, during which some of the mice were also treated with either anti-Fas monoclonal antibody or sham control hamster IgG intranasally. Airway responsiveness to acetylcholine was then analyzed by measuring airway resistance with a body plethysmograph box. Apoptosis was assessed by propidium iodide and TUNEL staining. RESULTS: Inhalation of OA increased both airway responsiveness to acetylcholine and the number of cells, mostly eosinophils, infiltrated into the airway. Administration of anti-Fas antibody induced apoptosis in the infiltrated eosinophils and abolished augmentation of airway hyperresponsiveness caused by OA inhalation. CONCLUSION: Induction of apoptosis in proinflammatory cells including eosinophils at the airway may have a beneficial effect on suppressing airway hyperresponsiveness.

Platelet-derived growth factor is involved in the augmentation of airway responsiveness through remodeling of airways in diesel exhaust particulate-treated mice.

BACKGROUND: Thickening of the region adjacent to the basement membrane is a key component of the remodeling of the asthmatic airway and is caused by collagen deposition in the region. OBJECTIVE: We sought to clarify the role of platelet-derived growth factor (PDGF), a competence factor of fibroblast, in the enhanced airway responsiveness and remodeling in a murine model. METHODS: Diesel exhaust particulates (DEPs) were administered intranasally every other day for 2 weeks with or without anti-PDGF-beta neutralizing antibody or goat IgG. Pulmonary function was then analyzed by using whole-body plethysmography before and after acetylcholine inhalation. RESULTS: Anti-PDGF-beta neutralizing antibody significantly inhibited both the elevation of airway resistance elicited by 1.25 and 2.5 mg/mL acetylcholine and the increase in the airway wall thickening induced by DEPs. In addition, bronchoalveolar lavage fluid cell analysis revealed that anti-PDGF-beta neutralizing antibody did not affect cellular infiltration at the airways. CONCLUSION: PDGF plays an important role in the process of remodeling brought about by DEP exposure in mice.

Effects of short duration stretching on disuse muscle atrophy in immobilized rat soleus muscles.

The purpose of this study was to determine whether short duration stretching is ameliorating for disuse muscle atrophy in immobilized rat soleus muscles. Eighteen male Wistar rats (age, 8 weeks; weight, 311.0 ± 35.6 g) were divided randomly into control (n=3) and experimental (n=15) groups. Bilateral ankles of each rat in the experimental group were fixed in full planter flexion with a plaster cast. After the experimental groups rats were immobilized for 4 weeks, animals were divided into three groups: immobilization alone (group I, n=3), stretch training for 30 min/day for 1 or 3 weeks after remobilization (group S, n=6), and spontaneous recovery (non stretch training) for 1 or 3 weeks after remobilization (group NS, n=6). At the end of the experimental periods, the soleus muscle was extracted from hindlimb, and the frozen sections were stained with myofibrillar adenosine triphosphatase. After 1 week of remobilization, the means of the muscle fiber diameters for type I fibers in group S had increased significantly compared with group NS, but those for type II fibers in group S did not significantly differ from that for group NS. After 3 weeks of remobilization, the means of the muscle fiber diameters for types I and II fibers in group S had increased significantly compared with group NS. No difference in the fiber type distribution were observed between the experimental group. Our findings suggest that short duration stretching induces recovery from disuse muscle atrophy after joint fixation.

Effects of treadmill exercise on muscle fibers in mice with steroid myopathy.

We studied the effect of treadmill exercise on muscle fibers in mice with experimental steroid myopathy. Frozen sections of the extensor digitorum longus (EDL) and soleus (SOL) muscles were stained with hematoxylin-eosin, and the muscle fiber diameters measured. In the EDL, muscle fiber diameters in the steroid groups decreased significantly compared with those in the control groups; moreover, muscle fiber diameters in the exercise groups increased significantly compared with those in the non-exercise groups, whereas the diameters in the SOL did not differ. We speculate that treadmill exercise may prevent corticosteroid-induced muscle fiber atrophy.