CARDIOPROTECTIVE ACTIONS OF ATP-SENSITIVE K⁺ CHANNEL OPENERS (CROMAKALIM, PINACIDIL AND NICORANDIL) IN CARDIAC PURKINJE FIBERS

Effects of ATP-dependent K⁺ channel openers on the action potentials and the contractile force in canine cardiac Purkinje fibers were examined. Cromakalim and pinacidil (0.3 to 10 μM), and nicorandil (0.3 to 1 mM) shortened both the 50% and 90% action potential durations (APD), and decreased the contractile force, in a concentration and frequency-dependent manner. These responses were reversible. The APD shortening and the negative inotropic effect induced by a switch of stimulation frequency (from 0.5 to 3 Hz) were potentiated by application of the openers. Other action potential parameters were unaffected, but the resting potential of relatively less negative voltage was hyperpolarized. These effects were potently antagonized by glibenclamide (a selective blocker of ATP-sensitive K⁺ channel). Under the calcium overload condition, the K⁺ channel openers abolished a delayed afterdepolarization and recovered the contractile force. These results suggest that the ATP-sensitive K⁺ channel openers increase the K⁺ conductance and simultaneously may possess cardioprotective actions to reduce the cellular Ca²⁺ level in calcium overloaded cells

A strategy to predict the global warming gas from stock farming —Potential scaling law of the released methane from livestock—

This work examines a scaling approach to predict the amount of methane released from the daily activity of livestock on farms. The subject animals are ruminants, i.e. having rumen or a ruminant stomach, that generates methane through digestion processes via several microbial fermentation steps. The produced methane is mixed into their breathing and released into the atmosphere. Existing data on methane released from various kinds of ruminant livestock were correlated as a power function of an animal’s weight, with an exponent near 0.92. This value is larger than a value of 0.75 which was related to the general metabolism rates for various animals. These differences may be explained by structure differences of the digestive organs or, more precisely, the difference in the relative length of the small intestine against animal size. Smaller animals have relatively longer small intestines, suggesting that the digestive activity in their stomachs is relatively less-active with less methane production as compared to larger animals. Validity of these structurally-dependent hypothesis was examined and a scaling law is proposed. The derived scaling law can then be used to estimate the release of global warming gas from various kinds of livestock and help to consider reduction strategies to decrease this emitted methane

USE-DEPENDENT BLOCK AND RECOVERY OF NA⁺ CHANNELS BY CLASS IC ANTIARRHYTHMIC DRUGS (FLECAINIDE AND ETHACIZIN) IN CANINE VENTRICULAR MUSCLE

Electrophysiological effects of flecainide and ethacizin (class Ic antiarrhythmic drugs) were examined using conventional microelectrode techniques. Flecainide significantly depressed the maximum rate of depolarization (⩒max) at 3x10⁻⁶M, and depolarized the resting potential (RP) at 10⁻⁵M, in a concentration-dependent manner. Ethacizin depressed ⩒max at 10⁻⁶M, and depolarized RP at 10⁻⁵M, significantly. However, both drugs did not affect the effective refractory period (ERP) nor the action potential duration (75% repolarization, APD₇₅). Both also had no effect on the action potential amplitude (APA). On the other hand, the drugs caused a use (or rate)-dependent block of ⩒max, and their time constants of onset of inhibition (at 3 Hz) were slow ; 6.3±1.2　msec (n=10) in the presence of flecainide (10⁻⁵M), and 6.0±1.6 msec (n=6) in the presence of ethacizin (10⁻⁵M). The time constants of the recovery were also so late : 12.2±2.5 sec (n=3) for flecainide (10⁻⁵M), and 27.1±13.3 sec (n=3) for ethacizin (2x10⁻⁶M), These results indicate that both antiarrhythmic drugs, flecainide and ethacizin, have no effect on APD₇₅ and ERP, but possess the characteristics for very slow kinetics of the use-dependent block and the recovery for fast Na⁺ channels of cardiac muscles. Ethacizin produces slower kinetics for the Na⁺ channels than flecainide

X-linked inhibitor of apoptosis protein mediates neddylation by itself but does not function as a NEDD8–E3 ligase for caspase-7

AbstractX-linked inhibitor of apoptosis protein (XIAP) is a potent antagonist of caspases, and functions as a ubiquitin–E3 ligase by itself and for caspases. Recently, NEDD8, a ubiquitin-like modifier, has been suggested to be used for modification of caspase-7 mediated by XIAP. However, it is not clear whether caspase-7 is a bona fide target for NEDD8. Here we showed that no neddylation of caspase-7 but that of XIAP itself was observed under the conditions in which caspase-7 was modified with ubiquitin. These results reveal that XIAP does not function as a NEDD8–E3 ligase for caspase-7 in vivo.Structured summary of protein interactionsNEDD8 physically interacts with Caspase-7 by pull down (View interaction)XIAP physically interacts with NEDD8 by anti-bait coimmunoprecipitation (View interaction

Free Flap Blood Flow Evaluated Using Two-Dimensional Laser Speckle Flowgraphy

Objective. We investigated the efficiency of laser speckle flowgraphy for evaluating blood flow in free flaps used for plastic surgery. Methods. We measured blood flow using a visual laser meter capable of providing two-dimensional color graphic representations of flow distribution for a given area using a dynamic laser speckle effect. Using laser speckle flowgraphy, we examined the blood flow of 20 free flaps applied following the excision of head and neck tumors. Results. After anastomosis of the feeding and draining blood vessels and sewing the flap, musculocutaneous (MC) flaps showed significantly lower blood flow than jejunal or omental flaps (P < .05). The ratio of blood flow decrease from the edge to the center was significantly greater in MC flaps than in jejunal or omental flaps (P < .001). Conclusion. Laser speckle flowgraphy is useful for the perioperative measurement of blood flow in free flaps used in plastic surgery. This method is a highly useful, practical, and reliable tool for assessing cutaneous blood flow and is expected to be applicable to several clinical fields

Verification of Implant Surface Modification by a Novel Processing Method

Metals have been used clinically as biomaterials, especially in the orthopaedic and dental fields. Metals used as implants wear at contact surfaces, producing metal particles and metal ions that may be harmful. Newly developed metal implants and methods of implant surface modification are currently under scrutiny. We evaluated the use of electrolytic in-process dressing (ELID) as a surface finishing method for metal implants. Metal implants processed using the ELID method (ELID group) or not processed (Non-ELID group) were inserted surgically into rabbit femurs. The rabbits were sacrificed postoperatively over a 24-week period. We assessed the concentrations of the cytokines, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α, the resistance to implant pull-out, and histopathology at the implant site. There was no significant difference between the groups regarding the cytokine concentrations or implant pull-out resistance. Many particles indicating wear around the implant were noted in the Non-ELID group (n=10) but not the ELID group (n=13), while a fibrous membrane adhering to the every implant was noted in the ELID group. The formation of a fibrous membrane rather than metal particles in the ELID group may indicate improved biocompatibility, and it suggests that ELID may prevent corrosion in the areas of contact

Peroxisome proliferator-activated receptor α (PPARα) mRNA expression in human hepatocellular carcinoma tissue and non-cancerous liver tissue

<p>Abstract</p> <p>Background</p> <p>Peroxisome proliferator-activated receptor α (PPARα) regulates lipid metabolism in the liver. It is unclear, however, how this receptor changes in liver cancer tissue. On the other hand, mouse carcinogenicity studies showed that PPARα is necessary for the development of liver cancer induced by peroxisome proliferators, and the relationship between PPARα and the development of liver cancer have been the focus of considerable attention. There have been no reports, however, demonstrating that PPARα is involved in the development of human liver cancer.</p> <p>Methods</p> <p>The subjects were 10 patients who underwent hepatectomy for hepatocellular carcinoma. We assessed the expression of PPARα mRNA in human hepatocellular carcinoma tissue and non-cancerous tissue, as well as the expression of target genes of PPARα, carnitine palmitoyltransferase 1A and cyclin D1 mRNAs. We also evaluated glyceraldehyde 3-phosphate dehydrogenase, a key enzyme in the glycolytic system.</p> <p>Results</p> <p>The amounts of PPARα, carnitine palmitoyltransferase 1A and glyceraldehyde 3-phosphate dehydrogenase mRNA in cancerous sections were significantly increased compared to those in non-cancerous sections. The level of cyclin D1 mRNA tends to be higher in cancerous than non-cancerous sections. Although there was a significant correlation between the levels of PPARα mRNA and cyclin D1 mRNA in both sections, however the correlation was higher in cancerous sections.</p> <p>Conclusion</p> <p>The present investigation indicated increased expression of PPARα mRNA and mRNAs for PPARα target genes in human hepatocellular carcinoma. These results might be associated with its carcinogenesis and characteristic features of energy production.</p

Kidney outcomes associated with haematuria and proteinuria trajectories among patients with IgA nephropathy in real-world clinical practice: The Japan Chronic Kidney Disease Database

Aim: Among patients with Immunoglobulin A (IgA) nephropathy, we aimed to identify trajectory patterns stratified by the magnitude of haematuria and proteinuria using repeated urine dipstick tests, and assess whether the trajectories were associated with kidney events. Methods: Using a nationwide multicentre chronic kidney disease (CKD) registry, we analysed data from 889 patients with IgA nephropathy (mean age 49.3 years). The primary outcome was a sustained reduction in eGFR of 50% or more from the index date and thereafter. During follow-up (median 49.0 months), we identified four trajectories (low-stable, moderate-decreasing, moderate-stable, and high-stable) in both urine dipstick haematuria and proteinuria measurements, respectively. Results: In haematuria trajectory analyses, compared to the low-stable group, the adjusted hazard ratios (HRs) (95% confidence interval [CI]) for kidney events were 2.59 (95% CI, 1.48-4.51) for the high-stable, 2.31 (95% CI, 1.19-4.50) for the moderate-stable, and 1.43 (95% CI, (0.72-2.82) for the moderate-decreasing groups, respectively. When each proteinuria trajectory group was subcategorized according to haematuria trajectories, the proteinuria group with high-stable and with modest-stable haematuria trajectories had approximately 2-times higher risk for eGFR reduction ≥50% compared to that with low-stable haematuria trajectory. Conclusion: Assessments of both haematuria and proteinuria trajectories using urine dipstick could identify high-risk IgA nephropathy patients.journal articl

Periodontal Tissue Regeneration Using Fibroblast Growth Factor -2: Randomized Controlled Phase II Clinical Trial

Background: The options for medical use of signaling molecules as stimulators of tissue regeneration are currently limited. Preclinical evidence suggests that fibroblast growth factor (FGF)-2 can promote periodontal regeneration. This study aimed to clarify the activity of FGF-2 in stimulating regeneration of periodontal tissue lost by periodontitis and to evaluate the safety of such stimulation. Methodology/Principal Findings: We used recombinant human FGF-2 with 3% hydroxypropylcellulose (HPC) as vehicle and conducted a randomized double-blinded controlled trial involving 13 facilities. Subjects comprised 74 patients displaying a 2- or 3-walled vertical bone defect as measured ?3 mm apical to the bone crest. Patients were randomly assigned to 4 groups: Group P, given HPC with no FGF-2; Group L, given HPC containing 0.03% FGF-2; Group M, given HPC cotaining 0.1% FGF-2; and Group H, given HPC Containing 0.3% FGF-2. Each patient underwent flap operation during which we administered 200 μL of the appropriate investigational drug to the bone defect. Before and for 36 weeks following administration, patients underwent periodontal tissue inspections and standardized radiography of the region under investigation. As a result, a significant difference (p = 0.021) in rate of increase in alveolar bone height was identified between Group P (23.92%) and Group H (58.62%) at 36 weeks. The linear increase in alveolar bone height at 36 weeks in Group P and H was 0.95 mm and 1.85 mm, respectively (p = 0.132). No serious adverse events attribute to the investigational drug were identified. Conclusions: Although no statistically significant differences were noted for gains in clinical attachment level and alveolar bone gain for FGF-2 groups versus Group P, the significant difference in rate of increase in alveolar bone height (p = 0.021) between Groups P and H at 36 weeks suggests that some efficacy could be expected from FGF-2 in stimulating regeneration of periodontal tissue in patients with periodontitis

Prediction of DAS28-ESR remission at 6 months by baseline variables in patients with rheumatoid arthritis treated with etanercept in Japanese population

We tried to determine which baseline variables are responsible for remission induction at 6 months in unselected rheumatoid arthritis (RA) patients of Japanese population treated with etanercept. One hundred forty-one patients with RA who were administered etanercept were registered. Thirty-four patients were started on etanercept monotherapy, 60 patients on cotherapy with methotrexate (MTX) (MTX cotherapy), and 47 patients on cotherapy with other non-MTX nonbiologic disease-modifying antirheumatic drugs (DMARDs) (non-MTX cotherapy). None of the patients were treated with both MTX and non-MTX nonbiologic DMARDs at entry. Outcome was set as achievement of disease activity score 28 (DAS28)-ESR remission at 6 months. We examined association of gender, DAS at baseline, MTX cotherapy at baseline, non-MTX cotherapy at baseline, and prednisolone use at baseline with achievement of remission at 6 months by logistic regression analysis. All subjects were classified as having high (N = 109) or moderate disease activity (N = 32) at entry. One hundred twenty out of 141 patients (85.1%) continued treatment with etanercept at 6 months. Continuation rate was statistically higher in MTX cotherapy (93.3%) compared with etanercept monotherapy (73.5%), and tended to be higher than with non-MTX cotherapy (85.1%). Logistic regression analysis identified that MTX cotherapy at entry and moderate disease activity at entry were independent variables for remission induction at 6 months. Accordingly, DAS28-ESR at 6 months was significantly lower with MTX cotherapy as compared with etanercept monotherapy or non-MTX cotherapy. To a lesser extent, DAS28-ESR with non-MTX cotherapy at 6 months was lower than with etanercept monotherapy. In this study of unselected patients, use of MTX and moderate disease activity at entry were associated with higher likelihood of response to etanercept. Non-MTX nonbiologic DMARDs may be an alternative in RA patients administrated etanercept who are intolerant to MTX