Caregiving centenarians: Cross-national comparison in Caregiver-Burden between the United States and Japan.

Background and Objectives: The personal distress associated with caring for a family member has been well documented; however, questions about the burden of caregiving for centenarians and cross-national differences in the caregiving context, remain unanswered.Research Design and Methods: This study includes reports by caregivers of 538 near-centenarians and centenarians in the U.S. and Japan: 234 from the Georgia Centenarian Study and 304 from the Tokyo Centenarian Study. Basic descriptive and multivariate regression analyses were conducted. Mean levels of caregiver burden and near-centenarian and centenarians' characteristics (as predictors) for caregiver burden were compared between the U.S. and Japan. The near-centenarian and centenarians' functional capacity and personality were assessed as predictors.Results: Differential predictive patterns in caregiver burden were found in the two groups. In the U.S., near-centenarian and centenarians' agreeableness and conscientiousness were negatively associated with caregiver burden; whereas the near-centenarian and centenarians' neuroticism and number of diseases were positively associated with caregiver burden. In Japan, the near-centenarian and centenarians' activities of daily living, openness, and agreeableness were negatively associated with caregiving burden. Interaction effects between functional capacity and personality, on caregiver burden were observed only in the U.S. In the U.S., higher levels of agreeableness and openness significantly changed the level of caregiver burden associated with vision problems and a greater number of diseases.Discussion and Implications: Cross-national comparative predictors of caregiving burden between the two countries emphasized that caring for centenarians should be understood in the caregiving context, as well as the social context.

Prophylactic infusion of phenylephrine is effective in attenuating the decrease in regional cerebral blood volume and oxygenation during spinal anesthesia for cesarean section.

BACKGROUND: Hypotension induced by spinal anesthesia for cesarean section causes a decrease in maternal regional cerebral blood volume and oxygenation. We used near-infrared spectroscopy to determine whether prophylactic infusion of phenylephrine attenuates these decreases. METHODS: Sixty patients undergoing bupivacaine spinal anesthesia for cesarean section were randomly divided into one of three intravenous infusion groups: saline (P0), phenylephrine 25 (P25) or 50 µg/min (P50). Mean arterial pressure, heart rate and near-infrared spectroscopy measurements were made at one-minute intervals for 20 minutes, and oxyhemoglobin, deoxy-hemoglobin and total-hemoglobin concentrations and tissue oxygenation index were determined. Mean changes in the values between baseline and each measurement time after intrathecal injection were compared. RESULTS: Significant decreases in mean arterial pressure were seen in group P0 compared to P25 and P50 (P <0.01). Heart rate decreased in a dose-dependent manner during phenylephrine infusion (P0 vs. P25 and P50, P25 vs. P50; P <0.05). Significantly higher total-hemoglobin levels were observed in the phenylephrine groups versus the P0 group (P <0.01). The largest decrease in tissue oxygenation index was found in the P50, followed by P0 and P25 groups (P0 vs. P25 and P50, P25 vs. P50; P <0.05). CONCLUSION: Prophylactic infusion of phenylephrine, especially at 25 µg/min, can effectively suppress decreases in regional cerebral blood volume and regional cerebral blood oxygenation after induction of spinal anesthesia for cesarean section.

The C-terminus of amelogenin enhances osteogenic differentiation of human cementoblast lineage cells.

BACKGROUND AND OBJECTIVES: Amelogenin proteins are the major constituent of developing extracellular enamel matrix and are believed to have an exclusively epithelial origin. Recent studies have suggested that amelogenins might induce the differentiation and maturation of various cells, including cementoblast lineage cells. However, the residues comprising the active site of amelogenin remain unclear. The purpose of this study was to identify the active site region of amelogenin by studying the effects of amelogenin fragments on the osteogenic differentiation of cementoblasts. MATERIAL AND METHODS: Amelogenin fragments lacking the C-terminus (rh163) and N-terminus (rh128) and a fragment consisting of the C-terminal region of rh174 (C11 peptide) were synthesized and purified. Human cementoblast lineage cells were cultured in osteogenic differentiation medium and treated with 0, 10, 100 or 1000 ng/mL of rh163, rh128 or C11 peptide. The mRNA levels of bone markers were examined by real-time polymerase chain reaction analysis. Alkaline phosphatase activity and calcium deposition were also determined. Mineralization was evaluated by alizarin red staining. RESULTS: The osteogenic differentiation of human cementoblast lineage cells was significantly enhanced by treatment with rh128 or C11 peptide, whereas rh163 had no significant effect as compared with untreated controls. CONCLUSIONS: The C-terminus of amelogenin promotes the osteogenic differentiation of human cementoblast lineage cells, indicating the possible utility of C11 peptide in periodontal tissue regeneration.

Development of a Cavity Disinfectant Containing Antibacterial Monomer MDPB.

An experimental cavity disinfectant (ACC) that is intended to be used for various direct and indirect restorations was prepared by adding an antibacterial monomer 12-methacryloyloxydodecylpyridinum bromide (MDPB) at 5% into 80% ethanol. The antibacterial effectiveness of ACC and its influences on the bonding abilities of resin cements were investigated. To examine the antibacterial activity of unpolymerized MDPB, the minimum inhibitory and bactericidal concentrations (MIC and MBC) were determined for Streptococcus mutans, Lactobacillus casei, Actinomyces naeslundii, Parvimonas micra, Enterococcus faecalis, Fusobacterium nucleatum, and Porphyromonas gingivalis Antibacterial activities of ACC and the commercial cavity disinfectant containing 2% chlorhexidine and ethanol (CPS) were evaluated by agar disk diffusion tests through 7 bacterial species and by MIC and MBC measurement for S. mutans The effects of ACC and CPS to kill bacteria in dentinal tubules were compared with an S. mutans-infected dentin model. Shear bond strength tests were used to examine the influences of ACC on the dentin-bonding abilities of a self-adhesive resin cement and a dual-cure resin cement used with a primer. Unpolymerized MDPB showed strong antibacterial activity against 7 oral bacteria. ACC produced inhibition zones against all bacterial species similar to CPS. For ACC and CPS, the MIC value for S. mutans was identical, and the MBC was similar with only a 1-step dilution difference (1:2). Treatment of infected dentin with ACC resulted in significantly greater bactericidal effects than CPS (P < 0.05, analysis of variance and Tukey's honest significant difference test). ACC showed no negative influences on the bonding abilities to dentin for both resin cements, while CPS reduced the bond strength of the self-adhesive resin cement (P < 0.05). This study clarified that the experimental cavity disinfectant containing 5% MDPB is more effective in vitro than the commercially available chlorhexidine solution to eradicate bacteria in dentin, without causing any adverse influences on the bonding abilities of resinous luting cements.

Denture wearing during sleep doubles the risk of pneumonia in the very elderly.

Poor oral health and hygiene are increasingly recognized as major risk factors for pneumonia among the elderly. To identify modifiable oral health-related risk factors, we prospectively investigated associations between a constellation of oral health behaviors and incident pneumonia in the community-living very elderly (i.e., 85 years of age or older). At baseline, 524 randomly selected seniors (228 men and 296 women; mean age, 87.8 years) were examined for oral health status and oral hygiene behaviors as well as medical assessment, including blood chemistry analysis, and followed up annually until first hospitalization for or death from pneumonia. During a 3-year follow-up period, 48 events associated with pneumonia (20 deaths and 28 acute hospitalizations) were identified. Among 453 denture wearers, 186 (40.8%) who wore their dentures during sleep were at higher risk for pneumonia than those who removed their dentures at night (log rank P = 0.021). In a multivariate Cox model, both perceived swallowing difficulties and overnight denture wearing were independently associated with an approximately 2.3-fold higher risk of the incidence of pneumonia (for perceived swallowing difficulties, hazard ratio [HR], 2.31; and 95% confidence interval [CI], 1.11-4.82; and for denture wearing during sleep, HR, 2.38; and 95% CI, 1.25-4.56), which was comparable with the HR attributable to cognitive impairment (HR, 2.15; 95% CI, 1.06-4.34), history of stroke (HR, 2.46; 95% CI, 1.13-5.35), and respiratory disease (HR, 2.25; 95% CI, 1.20-4.23). In addition, those who wore dentures during sleep were more likely to have tongue and denture plaque, gum inflammation, positive culture for Candida albicans, and higher levels of circulating interleukin-6 as compared with their counterparts. This study provided empirical evidence that denture wearing during sleep is associated not only with oral inflammatory and microbial burden but also with incident pneumonia, suggesting potential implications of oral hygiene programs for pneumonia prevention in the community.

Estimation of tensile force in the hamstring muscles during overground sprinting.

The purpose of this study was to identify the period of the gait cycle during which the hamstring muscles were likely injured by estimating the magnitude of tensile force in each muscle during overground sprinting. We conducted three-dimensional motion analysis of 12 male athletes performing overground sprinting at their maximal speed and calculated the hamstring muscle-tendon length and joint angles of the right limb throughout a gait cycle during which the ground reaction force was measured. Electromyographic activity during sprinting was recorded for the biceps femoris long head, semitendinosus, and semimembranosus muscles of ipsilateral limb. We estimated the magnitude of tensile force in each muscle by using the length change occurred in the musculotendon and normalized electromyographic activity value. The study found a quick increase of estimated tensile force in the biceps femoris long head during the early stance phase of the gait cycle during which the increased hip flexion angle and ground reaction force occurred at the same time. This study provides quantitative data of tensile force in the hamstring muscles suggesting that the biceps femoris long head muscle is susceptible to a strain injury during the early stance phase of the sprinting gait cycle.

Effects of enzymatic degradation after loading in temporomandibular joint.

Synovial fluid of the joint decreases friction between the cartilage surfaces and reduces cartilage wear during articulation. Characteristic changes of synovial fluid have been shown in patients with osteoarthritis (OA) in the temporomandibular joint (TMJ). OA is generally considered to be induced by excessive mechanical stress. However, whether the changes in synovial fluid precede the mechanical overloading or vice versa remains unclear. In the present study, our purpose was to examine if the breakdown of joint lubrication affects the frictional properties of mandibular condylar cartilage and leads to subsequent degenerative changes in TMJ. We measured the frictional coefficient in porcine TMJ by a pendulum device after digestion with hyaluronidase (HAase) or trypsin. Gene expressions of interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), matrix metalloproteinases (MMPs), type II collagen, and histology were examined after prolonged cyclic loading by an active pendulum system. The results showed that the frictional coefficient increased significantly after HAase (35%) or trypsin (74%) treatment. Gene expression of IL-1ß, COX-2, and MMPs-1, -3, and -9 increased significantly in enzyme-treated TMJs after cyclic loading. The increase in the trypsin-treated group was greater than that in the HAase-treated group. Type II collagen expression was reduced in both enzyme-treated groups. Histology revealed surface fibrillation and increased MMP-1 in the trypsin-treated group, as well as increased IL-1ß in both enzyme-treated groups after cyclic loading. The findings demonstrated that the compromised lubrication in TMJ is associated with altered frictional properties and surface wear of condylar cartilage, accompanied by release of pro-inflammatory and matrix degradation mediators under mechanical loading.

Development of an antibacterial root canal filling system containing MDPB.

An antibacterial monomer 12-methacryloyloxydodecylpyridinum bromide (MDPB)-containing experimental, chemically cured primer was prepared to develop a new resin-based root canal filling system. This study investigated the antibacterial effects of the MDPB-containing primer (experimental primer [EP]) against Enterococcus faecalis and assessed the in vitro bonding and sealing abilities of the filling system, consisting of EP and a Bis-GMA-based sealer resin. Antibacterial effects of EP were evaluated by contact with planktonic or adherent bacteria for 30 or 60 sec, and the viable bacterial number was counted. The antibacterial effects against E. faecalis in dentinal tubules were also assessed, according to a root canal infection model. Bonding and sealing abilities of the experimental filling system were examined by microtensile bond strength tests and leakage tests based on fluid filtration methods. Significantly greater reduction in viable bacteria in planktonic and adherent form was obtained by short-period contact with EP compared with the control primer (without MDPB) or with the proprietary (Epiphany) primer (p < .05). Significantly greater bactericidal effects of the EP inside the dentinal tubule of root, as opposed to the control primer or Epiphany primer, were confirmed according to a root canal infection model (p < .05), and 100% killing of E. faecalis could be obtained by the application of EP after irrigation with a 5% sodium hypochlorite solution. The experimental endodontic filling system demonstrated significantly greater bond strength to root dentin than Epiphany sealer system (Epiphany primer and Epiphany Root Canal Sealant; p < .05), showing formation of resin tags and a hybridized layer. Leakage tests clarified that the experimental system provided excellent sealing. This study confirmed that the MDPB-containing experimental antibacterial primer has the ability to effectively disinfect the root canal. Additionally, the experimental root canal filling system employing this primer and the Bis-GMA-based sealer resin is useful for achieving good sealing, suggesting its possible benefit for successful endodontic treatments.

Celecoxib exerts protective effects on extracellular matrix metabolism of mandibular condylar chondrocytes under excessive mechanical stress.

OBJECTIVE: Excessive mechanical stress is considered a major cause of temporomandibular joint osteoarthritis (TMJ-OA). High magnitude cyclic tensile strain (CTS) up-regulates pro-inflammatory cytokines and matrix metalloproteinases (MMPs) in chondrocytes, while selective cyclooxygenase (COX)-2 inhibition has been shown to be beneficial to cytokine-induced cartilage damage. However, the effect of selective COX-2 inhibitors on mechanically stimulated chondrocytes remains unclear. This study evaluated the effect of celecoxib, a selective COX-2 inhibitor, on extracellular matrix (ECM) metabolism of mandibular condylar chondrocytes under CTS. METHODS: Porcine mandibular chondrocytes were subjected to CTS of 0.5 Hz, 10% elongation with celecoxib for 24 h. The gene expressions of COX-2, MMPs, aggrecanase (ADAMTS), type II collagen and aggrecan were examined by real-time PCR. Also, prostaglandin E2 (PGE2) concentrations were determined using enzyme immunoassay kit. The levels of MMP and transcription factor NF-κB were measured by western blot while MMP activity was determined by casein zymography. RESULTS: The presence of celecoxib normalized the release of PGE2 and diminished the CTS-induced COX-2, MMP-1, MMP-3, MMP-9 and ADAMTS-5 gene expressions while recovered the downregulated type II collagen and aggrecan gene expressions. Concurrently, celecoxib showed inhibition of NF-κB and suppression of MMP production and activity. CONCLUSIONS: Celecoxib exerts protective effects on mandibular condylar chondrocytes under CTS stimulation by diminishing degradation and restoring synthesis of ECM.

A cross-sectional study of the plantar flexor muscle and tendon during growth.

The purpose of this study was to investigate growth changes in human plantar flexor muscle and tendons. In addition, we ascertained whether growth changes in muscle and tendon were more closely related to skeletal age than chronological age. 22 elementary school children (ESC), 19 junior high school students (JHS), and 23 young adults (ADT) men participated in this study. Maximal strain and hysteresis of tendon structures and cross-sectional area of Achilles tendon were measured using ultrasonography. In addition, skeletal age was assessed using Tanner-Whitehouse III method. Maximal strain of ESC was significantly greater than that of other groups, while no significant difference was observed between JHS and ADT. There was no difference in hysteresis among 3 groups. Relative cross-sectional area (to body mass(2/3)) of ADT was significantly smaller than that of other groups. For ESC and JHS, measured variables of muscle and tendon were significantly correlated to both chronological and skeletal ages. These results suggested that immature musculoskeletal system was protected by more extensible and larger tendon structures in ESC and only by larger tendon structures in JHS, respectively. Furthermore, there were no differences in correlation coefficient values between measured variables of muscle and tendon and chronological or skeletal ages.

Association of marine-origin n-3 polyunsaturated fatty acids consumption and functional mobility in the community-dwelling oldest old.

OBJECTIVE: To examine whether habitual dietary intake of marine-origin n-3 polyunsaturated fatty acids (MOPUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with functional mobility in the community-dwelling oldest old, 85 years or older, who are at high risk for physical disability. DESIGN: A cross-sectional study. SETTING: A community-based survey conducted at university research center or home-based. PARTICIPANTS: Four hundred seventeen (189 men, 228 women) out of 542 participants in the baseline examination of the Tokyo Oldest Old Survey on Total Health, a community-based ongoing longitudinal study among the oldest old living in the center of Japan. MEASUREMENTS: Habitual dietary intake of MOPUFA was assessed by the brief-type self-administered diet history questionnaire (BDHQ), and functional mobility was assessed by the timed up and go test. Plasma inflammatory biomarkers (C-reactive protein, interleukin-6 and tumor necrosis factor-α) were measured. We evaluated the cross-sectional association between habitual intake of MOPUFA and functional mobility using multivariate logistic regression analysis. Prior to the analysis, validation of BDHQ in this study was confirmed among 190 participants (96 men, 94 women) based on the EPA and DHA concentrations in the erythrocyte membrane phospholipids as reference. RESULTS: Moderate correlation between estimated dietary intake of EPA/DHA and concentration of EPA/DHA in the erythrocyte membrane phospholipids was obtained (Spearman's r=0.29-0.58, p<0.01). Multivariate logistic regression analysis revealed that a lower habitual intake of EPA+DHA was significantly associated with poor functional mobility in men but not in women (OR (95% CI) per 1 SD increase of EPA+DHA intake; 0.55 (0.33-0.91), 0.88 (0.59-1.32), men and women respectively). CONCLUSIONS: Habitual intake of MOPUFA was associated with functional mobility in community-dwelling oldest old men.

P2X7 receptor and cytokines contribute to extra-territorial facial pain.

The whisker pad area (WP) is innervated by the second branch of the trigeminal nerve and experiences allodynia and hyperalgesia following transection of the mental nerve (MN; the third branch of the trigeminal nerve). However, the mechanisms of this extra-territorial pain remain unclear. The ionotropic P2X(7) ATP receptor (P2X(7)) in microglia is known to potentiate, via cytokines, the perception of noxious stimuli, raising the possibility that P2X(7) and cytokines are involved in this extra-territorial pain. One day after MN transection (MNT), WP allodynia/hyperalgesia developed, which lasted for > 8 wks. Activation of microglia and up-regulation of P2X(7), membrane-bound tumor necrosis factor (TNF)-α (mTNF-α), and soluble TNF-α (sTNF-α) in the trigeminal sensory nuclear complex (TNC) were evident for up to 6 wks after MNT. Allodynia/hyperalgesia after MNT was blocked by intracisternal administration of etanercept, a recombinant TNF-α receptor (p75)-Fc fusion protein. Intracisternal A438079, a P2X(7) antagonist, also attenuated allodynia/hyperalgesia and blocked up-regulation of mTNF-α and sTNF-α in the TNC. We conclude that sTNF-α released by microglia following P2X(7) activation may be important in both the initiation and maintenance of extra-territorial pain after MNT.

P2X7 receptor in the trigeminal sensory nuclear complex contributes to tactile allodynia/hyperalgesia following trigeminal nerve injury.

BACKGROUND: The present study directly addresses the roles of the P2X(7) receptor (P2X(7)R), an ionotropic adenosine triphosphate (ATP) receptor, and cytokines in the induction of orofacial pain following chronic constriction injury (CCI) of the infraorbital nerve (IoN). METHODS: Rats were anesthetized, and ligatures of 4-0 chromic gut were tied around the IoN. A438079, a P2X(7)R antagonist or SB203580, a phosphorylated (p)-p38 mitogen-activated protein kinase (MAPK) inhibitor, was infused intrathecally into CCI-treated rats. In another group of rats, 3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP), a P2X(7) R agonist, was infused intrathecally with A438079, SB203580 or etanercept, a tumor necrosis factor (TNF)-α receptor-binding recombinant drug. RESULTS: CCI of the IoN induced tactile allodynia/hyperalgesia and up-regulation of P2X(7)R, membrane-bound TNF-α (mTNF-α) and soluble TNF-α (sTNF-α) in the trigeminal sensory nuclear complex (TNC). Tactile allodynia/hyperalgesia or up-regulation of mTNF-α and sTNF-α in the TNC following CCI of the IoN was inhibited by A438079. SB203580 also attenuated tactile allodynia/hyperalgesia or up-regulation of mTNF-α, but not the up-regulation of sTNF-α in the TNC. Treatment of rats with BzATP induced tactile allodynia/hyperalgesia and up-regulation of sTNF-α and p-p38 in the TNC. Tactile allodynia/hyperalgesia or up-regulation of sTNF-α following BzATP treatment was inhibited by SB203580 and etanercept. CONCLUSIONS: Based on these findings, phosphorylation of p38 MAPK via P2X(7)R may induce tactile allodynia/hyperalgesia, which is most likely mediated by sTNF-α released by microglia.

Antagonistic effect of flumazenil after midazolam sedation on arterial-cardiac baroreflex.

BACKGROUND: Flumazenil is generally administered to antagonise the sedative effect of midazolam. However, although flumazenil completely antagonises the sedative effect of midazolam, a few effects remain unantagonised. Hence, it is unclear whether flumazenil restores the attenuation of the arterial-cardiac baroreflex (i.e. arterial-heart rate reflex) induced by midazolam. We investigated the antagonistic effect of flumazenil administered after midazolam on cardiac baroreflex, to reveal whether complete recovery from midazolam-induced sedation by flumazenil administration is accompanied by restoration of midazolam's attenuating effects on the cardiac baroreflex. METHOD: Twelve healthy male subjects received midazolam followed by flumazenil until complete recovery from midazolam sedation. Before and during midazolam sedation, and after flumazenil administration, cardiac baroreflex function was assessed by sequence analysis and transfer function analysis between spontaneous oscillations in systolic arterial pressure and R-R interval. RESULTS: During midazolam sedation, defined by an Observer's Assessment of Alertness/Sedation scale score of 3, BIS value decreased significantly. Simultaneously, the baroreflex indices of the two analyses decreased significantly compared with baseline, suggesting attenuated cardiac baroreflex function. With complete recovery from midazolam sedation by flumazenil, indicated by an Observer's Assessment of Alertness/Sedation scale score of 5, BIS values returned to the baseline level. Simultaneously, cardiac baroreflex indices also returned to baseline levels. CONCLUSION: The present results suggest that complete recovery from midazolam sedation by flumazenil is accompanied by restoration of the attenuated cardiac baroreflex function induced by midazolam.

The effects of age on maintenance of intense neuromuscular block with rocuronium.

BACKGROUND: Increasing age is associated with a longer duration of action of neuromuscular block. The aim of this study was to determine the influence of ageing on the recovery of the post-tetanic count (PTC) from rocuronium-induced neuromuscular block. METHODS: Twenty-two younger (20-60 years) and 22 older (> 70 years) patients were enrolled in this study. After induction of anaesthesia with fentanyl and propofol, all patients initially received 1 mg/kg rocuronium and neuromuscular block were evaluated by contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation using an acceleromyograph. Subsequently, intense rocuronium-induced block was determined every 6 min using the PTC during 1.0-1.5% sevoflurane and remifentanil anaesthesia. When the first response to the PTC stimulus was detected, 0.2 mg/kg rocuronium was additionally administered, and again, spontaneous recovery of neuromuscular function was monitored until the first response to the PTC reappeared. RESULTS: Median values (range) of the times from the administration of 1 mg/kg and 0.2 mg/kg rocuronium until recovery of the first detectable PTC were significantly longer in the older [51.0 (27-100) min, P < 0.0001 and 30.0 (12-66) min, P = 0.0036, respectively] than the younger patients [31.5 (21-45) min and 18.0 (12-36) min, respectively]. CONCLUSION: The times from rocuronium injection to reappearance of the first response to PTC stimulation are approximately twofold longer and more variable in older than younger patients. Hence, the dosing interval of rocuronium should be adjusted using neuromuscular monitoring when maintaining intense neuromuscular block, especially in older patients.

Bilirubin oxidation provoked by nitric oxide radicals predicts the progression of acute cardiac allograft rejection.

Bilirubin, a strong intrinsic antioxidant, quenches free radicals produced under inflammatory conditions. The oxidized bilirubin metabolites, i.e. biopyrrins, are immediately excreted into urine and can indicate the intensity of oxidation in vivo. Our preliminary studies suggested the involvement of reactive nitrogen species (RNS) in generation of biopyrrins. However, little is known about biological significance of bilirubin oxidation by RNS. Here, we analyzed the correlation between bilirubin oxidation and nitric oxide (NO) radicals during rat acute cardiac allograft rejection. In allograft recipients, urinary biopyrrins steeply increased on day 3 prior to the increase in myocardial tissue damage marker, serum troponin-T. In contrast, no significant changes in urinary biopyrrins were evident in recipients of isografts or cyclosporine-A treated allografts. Urinary nitrotyrosine, a marker of oxidation by NO radicals also increased on day 3, while administration of a NO synthase inhibitor, N(G)-monomethyl-L-arginine apparently diminished the elevation of urinary biopyrrins as well as nitrotyrosine. Immunohistochemistry revealed enhanced local expression of heme oxygenase-1, biopyrrins and nitrotyrosine in allografts in accordance with the cellular infiltrates, suggesting that changes in urinary biopyrrins reflect the bilirubin oxidation in grafts undergoing rejection. These results indicate that locally evoked bilirubin oxidation by NO radicals can predict the progression of rejection.

Do personality characteristics predict longevity? Findings from the Tokyo Centenarian Study.

To explore whether personality influences longevity we examined the personality characteristics of centenarians. We developed a new method that compares an actual personality test score for centenarians with a predicted test score for a 100-year-old, calculated from younger controls. The participants consisted of 70 cognitively intact Japanese centenarians aged 100-106 years and 1812 elderly people aged 60-84 years, all residents of Tokyo. The NEO five factor inventory (NEO-FFI) was used to assess the "big five" personality traits: neuroticism, extraversion, openness, agreeableness, and conscientiousness. The results showed higher openness in both male and female centenarians, and higher conscientiousness and extraversion in female centenarians, as compared to controls. These results suggest that high scores in the specific personality traits conscientiousness, extraversion, and openness, are associated with longevity. We speculate that these personality traits contribute to longevity through health-related behavior, stress reduction, and adaptation to the challenging problems of the "oldest old".

Protective effect of a radical scavenger, MCI-186 on islet cell damages induced by oxidative stress.

Oxidative stress generated during islet isolation and transplantation causes islet cell damage. These oxidative injuries are mediated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). MCI-186 is an antioxidant used for clinical treatment of cerebral infarction in Japan. We examined a possible protective effect of MCI-186 on islet cells against oxidative stress. Islets isolated from Sprague-Dawley rats by collagenase P digestion were purified by density gradient centrifugation with Ficoll. Islets were treated with hydrogen peroxide (H(2)O(2); 5 to 250 micromol) in the presence or absence of MCI-186. Cell death was measured by an LDH release assay. Maximum islet cell death was observed at 250 micromol of H(2)O(2). MCI-186 inhibited islet cell death in a dose-dependent manner with significant reduction above 30 micromol. From the results observed we suggest that the antioxidant effects of MCI-186 may prove beneficial to improve the preservation of islet cells.

Interactions among mu- and delta-opioid receptors, especially putative delta1- and delta2-opioid receptors, promote dopamine release in the nucleus accumbens.

The effect of interactions among mu- and delta-opioid receptors, especially the putative delta(1)- and delta(2)-opioid receptors, in the nucleus accumbens on accumbal dopamine release was investigated in awake rats by in vivo brain microdialysis. In agreement with previous studies, perfusion of the nucleus accumbens with the mu-, delta(1)- and delta(2)-opioid receptor agonists [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin (DAMGO), [D-Pen(2,5)]-enkephalin (DPDPE) and [D-Ser(2)]Leu-enkephalin-Thr(6), respectively, significantly enhanced the extracellular amount of accumbal dopamine in a dose-related manner (5.0 nmol and 50.0 nmol). However, the highest concentration tested (50.0 nmol) of DAMGO induced a biphasic effect, i.e. a rapid onset increase lasting for 75 min followed by a slower onset gradual and prolonged increase. The mu-opioid receptor antagonist D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) (0.15 nmol) primarily reduced the DAMGO-induced second component. The delta(1)-opioid receptor antagonist (E)-7-benzylidenenaltrexone (0.15 nmol) significantly reduced the first component and abolished the second component induced by DAMGO, while the delta(2)-opioid receptor antagonist naltriben (1.5 nmol) significantly reduced only the first component. The DPDPE (50.0 nmol)-induced dopamine increase was almost completely abolished by (E)-7-benzylidenenaltrexone, but only partially reduced by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and naltriben. The [D-Ser(2)]Leu-enkephalin-Thr(6) (50.0 nmol)-induced dopamine increase was almost completely abolished by naltriben, but not at all by D-Phe-Cys-Tyr-d-Trp-Orn-Thr-Phe-Thr-NH(2) and (E)-7-benzylidenenaltrexone. The non-selective opioid receptor antagonist naloxone (0.75 and 1.5 nmol) dose-dependently reduced the effects of DAMGO, DPDPE and [D-Ser(2)]Leu-enkephalin-Thr(6) but only to about 10-25% of the control values. Moreover, perfusion with the sodium channel blocker tetrodotoxin (0.1 nmol) reduced the DAMGO-induced dopamine increase by 75%, while it almost completely abolished the increase induced by DPDPE or [D-Ser(2)]Leu-enkephalin-Thr(6). The results show that stimulation of mu-opioid receptors or, to a lesser degree, delta(1)-opioid receptors results in a large naloxone-sensitive increase and a small naloxone-insensitive increase of extracellular dopamine. It is suggested that the naloxone-insensitive component is also tetrodotoxin-insensitive. Furthermore, it is hypothesized that stimulation of mu-opioid receptors activates delta(1)-receptors, which in turn activate delta(2)-opioid receptors, thereby giving rise to a rapid onset increase of extracellular dopamine. In addition, it is hypothesized that stimulation of another group of mu-opioid receptors activates a second group of delta(1)-opioid receptors that is not coupled to delta(2)-opioid receptors and mediates a slow onset increase of extracellular dopamine. Finally, it is suggested that stimulation of delta(1)- or delta(2)-opioid receptors inhibits mu-opioid receptors involved in the slow onset increase in extracellular dopamine, whereas stimulation of delta(1)-, but not delta(2)-, opioid receptors is suggested to activate mu-opioid receptors involved in the rapid increase in extracellular dopamine.

Metabolic activation of 1alpha-hydroxyvitamin D3 in human liver microsomes.

1. 1Alpha-hydroxyvitamin D3 (1alpha-OH-D3) is a synthetic prodrug of the active form of vitamin D3, and requires the hydroxylation at the C-25 position before eliciting its biological activity. 2. 25-Hydroxylation activities for 1alpha-OH-D3 were present in both microsomal and mitochondrial fractions of human liver. 3. To determine the P450 enzyme(s) involved in microsomal 25-hydroxylation, 14 P450s (CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9-Arg, 2C9-Cys, 2C19, 2D6-Val, 2D6-Met, 2E1, 3A4, 4A11) were tested for their 25-hydroxylation activity of 1alpha-OH-D3. None catalysed the 25-hydroxylation reaction. 4. 1Alpha-OH-D3 in a high concentration (2.5 ng ml(-1)) showed small but significant inhibition of the catalytic activities of CYP2C8, 2C9-Cys, 2C19, 2D6-Val and 2E1 for their typical substrates. However, 1alpha-OH-D3 in a clinically used low concentration will not significantly affect drug metabolism catalysed by the 14 P450s tested. 5. In summary, the 25-hydroxylation activity of 1alpha-OH-D3 that localizes in the microsomal fraction appears to be attributable to a cytochrome P450 other than the microsomal forms tested in this study.