Optimal patient selection for anticoagulant therapy in sepsis: an evidence-based proposal from Japan.

Selecting an appropriate target population is essential to maximize survival benefits of anticoagulant therapy against sepsis. Our meta-analysis of three populations with sepsis and nationwide observational study in Japan showed that anticoagulants improved mortality only in sepsis-induced disseminated intravascular coagulation (DIC) but not in non-DIC. This divergent effect was physiologically explained by host-protective immune responses of local thrombosis, which are mandatory in the early stage of sepsis. Meanwhile, the lack of definitive evidence for survival benefit provided by several trials of sepsis-induced DIC indicated that this condition was probably not the best target of anticoagulants. Our multicenter cohort study including only patients with sepsis-induced DIC showed a survival benefit from recombinant thrombomodulin only in patients with high disease severity. Thus, we believe that the population with sepsis and DIC and high disease severity is the optimal target for anticoagulant therapy. Anticoagulant therapy without appropriate target selection should be avoided because of the increased risk of bleeding with no survival benefit.

Dynamic Stretching does not Change the Stiffness of the Muscle-Tendon Unit.

The purpose of this study was to identify changes in ankle range of motion and passive mechanical properties of the muscle-tendon unit after dynamic stretching. 12 healthy subjects participated in this study. Displacement of the muscle-tendon junction was measured using ultrasonography while the ankle was passively dorsiflexed at 1°/sec to its maximal dorsiflexion angle. Passive torque was also measured using an isokinetic dynamometer. Measurements were conducted pre-intervention, immediately after the intervention and 5, 10, 15 and 30 min post-intervention. The dynamic stretching consisted of four 30-s periods of ankle dorsiflexion and plantarflexion. Ankle range of motion was significantly increased immediately (from 18.3±1.8° to 21.4±1.7°) and 10 min (20.9±1.9°) after dynamic stretching, but this change disappeared within 15 min. However, stiffness of the muscle-tendon unit and displacement of the muscle-tendon junction at the submaximal dorsiflexion angle did not differ between the experimental conditions. These results demonstrate that dynamic stretching by contracting an antagonist muscle group increases ankle range of motion temporarily without changing the passive mechanical properties of the muscle-tendon unit. The increased range of motion of the ankle after dynamic stretching might be caused by enhanced stretch tolerance.

Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials.

UNLABELLED: ESSENTIALS: Most anticoagulant therapy has failed to demonstrate a survival benefit in the overall sepsis population. We conducted separate meta-analyses of anticoagulant therapy in three different populations. Survival benefit was observed only in the septic disseminated intravascular coagulation (DIC) population. Further randomized controlled trials should focus on specific populations with septic DIC. BACKGROUND: Although many preclinical trials have indicated the effectiveness and safety of anticoagulant therapy as an adjuvant therapy against sepsis, there is little evidence to support its effectiveness to reduce mortality in the overall population with sepsis in clinical situations. However, several studies suggested that specific anticoagulant therapy may potentially reduce mortality in patients with sepsis-induced disseminated intravascular coagulation (DIC). OBJECTIVE: We investigated whether the survival benefit of anticoagulant therapy might pertain to the coagulopathic population with sepsis. METHODS: We conducted separate meta-analyses of randomized controlled trials for anticoagulant therapy in three different populations: (i) overall population with sepsis, (ii) population with sepsis-induced coagulopathy, and (iii) population with sepsis-induced DIC. We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials comparing anticoagulant therapy with placebo or no intervention in sepsis patients. We measured all-cause mortality as the primary outcome and bleeding complications as the secondary outcome. RESULTS: We analyzed 24 trials enrolling 14 767 patients. There were no significant reductions in mortality in the overall sepsis population and the population with sepsis-induced coagulopathy. Otherwise, we observed significant reductions in mortality (risk ratio 0.72, 95% confidence interval 0.62-0.85) in the population with sepsis-induced DIC. As adverse events, bleeding complications tended to increase similarly with anticoagulant therapy in all three populations. CONCLUSION: Although associated with an increased risk of bleeding, anticoagulant therapy resulted in no survival benefits in the overall sepsis population and even the population with sepsis-induced coagulopathy; beneficial effects on mortality were observed only in the population with sepsis-induced DIC.

Exercise characteristics influence femoral cross-sectional geometry: a magnetic resonance imaging study in elite female athletes.

UNLABELLED: The associations between mid-femoral cross-sectional geometry and exercise characteristics were investigated in female athletes. The effects on bone geometry for weight-bearing sports with low-to-high-impact were greater than those for non-impact weight-bearing sports, whereas low-impact or high-strain-magnitude/low-strain-rate sports had less of an effect on bone geometry compared with higher-impact sports. INTRODUCTION: Many previous studies have investigated tibial geometry in athletes; however, few studies have examined the associations between femoral cross-sectional geometry and exercise characteristics. The aim of this study was to investigate these relationships using magnetic resonance imaging (MRI) at the femoral mid-shaft. METHODS: One hundred and fifty-three female elite athletes, aged 18-34 years, were classified into five groups based on the characteristics of their sports. Sports were considered non-impact (n = 27), low- or moderate-impact (n = 39), odd-impact (n = 38), high-strain-magnitude/low-strain-rate (n = 10), or high-impact (n = 39). Bone geometrical parameters, including cortical area, periosteal perimeter, and moment of inertia (bone strength index), were determined using MRI images. RESULTS: Higher-impact groups displayed bone expansion, with significantly greater periosteal perimeters, cortical areas (~37.3%), and minimum moments of inertia (I(min,) ~92.3%) at the mid-femur than non- and low-impact groups. After adjusting for age, height, and weight, the cortical area and I(min) of the low-impact and high-strain-magnitude/low-strain-rate groups were also significantly greater than those of the non-impact group. CONCLUSIONS: Higher-impact sports with high strain rates stimulated periosteal bone formation and improved bone geometry and strength indices at the femoral mid-shaft. Although our results indicate that weight-bearing sports are beneficial even if they are low impact, the effects of lower-impact or high-strain-magnitude/low-strain-rate sports on bone geometry were less pronounced than the effects of higher-impact sports at the femoral mid-shaft.

Spatiotemporal expression patterns of doublesex and mab-3 related transcription factor 1 in the chicken developing gonads and Mullerian ducts.

Sex of birds is genetically determined by the inheritance of sex chromosomes (ZZ for male and ZW for female), and the Z-linked gene named doublesex and mab-3 related transcription factor 1 (DMRT1) is a candidate sex-determining gene in avian species. However, the mechanisms underlying sex determination in birds are not yet understood, and the expression patterns of the DMRT1 protein in urogenital tissues have not been identified. In the current study, we used immunohistochemistry to investigate the detailed expression patterns of the DMRT1 protein in the urogenital systems (including Müllerian ducts) in male and female chicken embryos throughout embryonic development. Gonadal somatic cells in the male indifferent gonads showed stronger expressions of DMRT1 compared with those in the female indifferent gonads well before the presumptive period of the sex determination, and Sertoli cells forming testicular cords expressed DMRT1 in the testes after sex determination. Germ cells expressed DMRT1 equally in males and females after sex determination. The expression was continuous in males, but in females it gradually disappeared from the germ cells in the central part of the cortex of the left ovary toward both edges. The DMRT1 was also detected in the tubal ridge, which is a precursor of the Müllerian duct, and at the mesenchyme and outermost coelomic epithelium of the Müllerian duct in both sexes. Strong expression was observed in the males, but it was restricted to coelomic epithelium after the regression of the duct started. Thus, we observed the detailed spatiotemporal expression patterns of DMRT1 in the developing chicken urogenital systems throughout embryonic development, suggesting its various roles in the development of urogenital tissues in the chicken embryo.

Decrements in stiffness are restored within 10 min.

The purpose of this study was to clarify the temporal course of stiffness in the muscle-tendon unit after stretching. In 11 male participants, displacement of the myotendinous junction on the gastrocnemius medialis muscle was measured ultrasonographically during the passive-dorsiflexion test, with the ankle was passively dorsiflexed at 1 °/s to the end of the range of motion. Passive torque, representing resistance to stretch, was also measured using an isokinetic dynamometer. On 4 different days, passive-dorsiflexion tests were performed before and immediately, 5, 10 or 15 min after stretching, which comprised dorsiflexion to end range of motion and holding that position for 1 min, 5 times. As a result, end range of motion and passive torque at end range of motion were significantly increased after stretching (P<0.05) as compared with each previous value. Although stiffness of the muscle-tendon unit was significantly decreased immediately and 5 min after stretching (P<0.05), this change recovered within 10 min. These results suggest that static stretching for 5 min results in significantly increased range of motion over 30 min, but significant decreases in stiffness of the muscle-tendon unit returned to baseline levels within 5-10 min.

Viscoelasticity of the muscle-tendon unit is returned more rapidly than range of motion after stretching.

The purpose of this study was to clarify the time course of the viscoelasticity of gastrocnemius medialis muscle and tendon after stretching. In 11 male participants, displacement of the myotendinous junction on the gastrocnemius medialis muscle was measured ultrasonographically during the passive dorsiflexion test, in which the ankle was passively dorsiflexed at a speed of 1°/s to the end of the range of motion (ROM). Passive torque, representing resistance to stretch, was also measured using an isokinetic dynamometer. On five different days, passive dorsiflexion tests were performed before and 0, 15, 30, 60 or 90 min after stretching, which consisted of dorsiflexion to end ROM and holding that position for 1 min, five times. As a result, end ROM was significantly increased at 0, 15 and 30 min (P<0.05 each) after stretching as compared with each previous value. Passive torque at end ROM was also significantly increased after stretching. Although the stiffness of the muscle-tendon unit was significantly decreased immediately after stretching (P<0.05), this shift recovered within 15 min. These results showed that the retention time of the effect of stretching on viscoelasticity of the muscle-tendon unit was shorter than the retention time of the effect of stretching on end ROM.

Adolescent exercise associated with long-term superior measures of bone geometry: a cross-sectional DXA and MRI study.

OBJECTIVE: To investigate whether childhood sports participation, particularly weight-bearing sports, has any effect on bone mineral content (BMC), areal bone mineral density (aBMD) and bone geometric characteristics in middle-aged postmenopausal women. Design/ SETTING: In this cross-sectional comparison of two groups, 46 middle-aged women (mean age, 60.2 (SD 5.6) years; range, 52-73 years) were grouped according to sport participation during growth: weight-bearing sports, including high-impact weight-bearing activities; and low-impact non-weight-bearing sports or no participation. MAIN OUTCOME MEASURES: Dual energy X-ray absorptiometry (DXA)-measured BMC, aBMD in the lumbar spine and femur. Magnetic resonance imaging (MRI) determined bone geometric characteristics in the femur, such as femoral mid-diaphyseal cross-sectional area, periosteal and endosteal perimeters and maximum and minimum second moment of area. RESULTS: Postmenopausal middle-aged women with participation in weight-bearing sports during junior high to high school (12-18 years old) displayed significantly greater BMC in both lumbar spine and femoral neck regions, and also significantly greater femoral mid-diaphyseal bone cross-sectional area, periosteal perimeter and maximum and minimum second moment of area than the non-weight-bearing sports group. CONCLUSIONS: Adolescent weight-bearing exercise exerts preservational effects on femoral mid-diaphyseal size and shape, while DXA-measured BMC effectively identified the same tendency. Weight-bearing exercise in youth affects bone, and these effects may be preserved as BMC, geometric and structural advantages even after 40 years.

Minimum level of jumping exercise required to maintain exercise-induced bone gains in female rats.

SUMMARY: This study determines the minimum level of exercise required to maintain 8 weeks of jumping exercise-induced bone gains in rats. It was found that the minimum level of exercise required for maintaining the different exercise-induced bone gains varied between 11% and 18% of the initial exercise intensity. INTRODUCTION: This study ascertains the minimum level of follow-up exercise required to maintain bone gains induced by an 8-week jumping exercise in rats. METHODS: Twelve groups of 12-week old rats (n = 10 rats per group) were given either no exercise for 8 (8S) or 32 weeks (32S), or received 8 weeks of standard training program (8STP) that consisted of 200 jumps per week, given at 40 jumps per day for 5 days per week, followed by 24 weeks of exercise at loads of either 40 or 20 or 10 jumps per day, for either 5, or 3, or 1 day/week. Bone mass, strength, and morphometric properties were measured in the right tibia. Data were analyzed using one-way analyses of variance. RESULTS: Bone mass, strength, mid-shaft periosteal perimeter and cortical area were significantly (p < 0.05) higher in the rats given 8STP than that in the 8S group. The minimal level of exercise required to maintain the bone gains was 31, 36, 25, and 21 jumps per week for mass, strength, periosteal perimeter and cortical area, respectively. CONCLUSIONS: Eight weeks of jumping exercise-induced bone gains could be maintained for a period of 24 weeks with follow-up exercise consisting of 11% to 18% of the initial exercise load.

Full suspension mountain bike improves off-road cycling performance.

AIM: The purpose of the present study was to determine the effects of suspension systems on the cycling performance of cyclists during off-road bicycling. METHODS: Eight elite male cyclists (67.8+/-5.8 ml/min/kg of (.-)VO(2max)) performed 30-minute riding tests on bicycles with 2 different suspension setups: front suspension (FS) and front and rear suspension (FRS). Heart rate, blood lactate concentration, pedaling power, cadence, cycling velocity, and completed distance during the trial were measured creatin kinase (CK), lactic dehydrogenase (LDH) and glutamic-oxaloacetic transaminase (GOT) were measured before and after the trials. RESULTS: The average cadence during the trial was significantly higher (p<0.05) with the FRS (73.6+/-6.1 rpm) than the FS (70.2+/-6.2 rpm). Subjects rode significantly faster (p<0.05) on FRS (24.1+/-2.6 km/h) than FS bikes (22.9+/-2.4 km/h), although no significant difference was observed in pedaling power (240.7+/-26.6 W vs 242.2+/-28.8 W, FS vs FRS, respectively). Serum creatin kinase increased significantly (p<0.05) at 24 h after the trial when cyclists exercised with the FS bike. CONCLUSIONS: We conclude that the FRS improved cycling performance over rough terrain. FRS might therefore be more suitable for cross-country mountain bike races.

Maintenance of bone mass and mechanical properties after short-term cessation of high impact exercise in rats.

Abstract. The effects of cessation of high-impact exercise on bone mass in female Wistar rats was assessed. Fifty 10-week old rats were randomly divided into five groups (n = 10): 4 weeks jump-exercise (4JEX), 4 weeks sedentary control (4S), 8 weeks jump-exercise (8JEX), 4 weeks jump-exercise followed by 4 weeks sedentary (4JEX4S) and 8 weeks sedentary control (8S). The rats were jumped trained 40 times/session, 5 days/week. After 4 weeks or 8 weeks the mass and breaking force in tibia and cross-sectional areas of the tibia were measured. The tibia in the 4JEX and 8JEX groups had significantly greater fat-free dry weight and maximum loads at the fracture tests than those in the 4S and 8S groups. The tibia of 4JEX and 8JEX also had significantly larger cortical area without a significant change in the medullary area at the cross-sectional analysis. Bone mass acquired in 4JEX4S group was retained after cessation of exercise. The results indicate that high-impact jump-exercise, which is osteotropic, leads to an increased cortical bone with enhanced periosteal bone formation, which is also, however, maintained after cessation of exercise. It is therefore suggested that high-impact jump-exercise may provide greater safety margin against disuse-related or/and age-related bone loss and skeletal fragility later in life.

Effect of high-impact and low-repetition training on bones in ovariectomized rats.

This study was designed to investigate the effect of high-impact and low-repetition jump training on bones in ovariectomized (OVX) rats. Forty female Wistar rats were sham-operated (sham) or OVX at the age of 11 weeks. The rats were divided randomly into the following four groups: sham-sedentary (SS; n = 10), sham-exercised (SE; n = 10), OVX-sedentary (OS; n = 10), and OVX-exercised (OE; n = 10). The rats started the jump training at the age of 12 weeks. The jump-training protocol was 10 times/day, 5 days/week and the jumping-height was 40 cm. After 8 weeks of training, the mass and breaking force in the tibia and ulna, cross-sectional areas of diaphysis in the tibia, and serum bone turnover markers were measured. The jump training significantly increased the fat-free dry weight, ash weight, and ultimate breaking force in the tibia. The rate of increase in these parameters was similar in both the sham and the OVX groups. On the other hand, in the ulna, there were no significant changes in the ultimate breaking force. The jump training significantly increased the periosteal perimeter and cortical area, although the increase in these parameters in OE compared with OS was lower than that in SE compared with SS. The jump training significantly increased serum osteocalcin in the OVX groups, as well as in the sham groups. These results suggest that high-impact and low-repetition training had beneficial effects on bone formation and bone biomechanical properties in OVX rats, as well as in sham rats.

A basic class I chitinase expression in winged bean is up-regulated by osmotic stress.

We isolated a cDNA for basic class I chitinase (ChitiWb1). ChitiWb1 cDNA encodes a protein that consists of 315 amino acid residues and has a signal peptide. Northern blot analysis indicated that the class I chitinase mRNA in leaves and cultured cells of winged bean was increased by treatments with NaCl, KCl, CaCl2, mannitol or saccharose, but not with abscisic acid. Thus, class I chitinase expression was shown to be up-regulated by osmotic stress.

Exercise and mechanical loading increase periosteal bone formation and whole bone strength in C57BL/6J mice but not in C3H/Hej mice.

To identify the genes, and the mechanisms that account for the 53% higher peak bone density in C3H/HeJ (C3H) mice compared with C57BL/6J (B6) mice, we are performing quantitative trait locus and phenotypic analyses. The phenotypic studies revealed differences in bone formation and resorption, and showed that hindlimb immobilization (by sciatic neurectomy) caused a greater increase in endosteal resorption in the tibiae of B6 compared with C3H mice. The current studies were intended to examine the hypothesis that the bones of C3H mice are less sensitive to mechanical loading than the bones of B6 mice. To increase mechanical loading, 9-week-old female B6 and C3H mice (n = 10-13 mice/group) were subjected to a jumping exercise (20 jumps/day, 5 days/week, to heights of 20-30 cm) for a total of 4 weeks. Control mice did not jump. Osteocalcin, alkaline phosphatase (ALP) activity, and IGF-I were measured in serum. The left tibiae were used for histomorphometry (ground cross-sections prepared at the tibiofibular junction) and the right tibiae and femora were used for determinations of bone breaking strength (3-point bending). The results of these studies revealed (1) significant effects of both mouse strain (B6 and C3H) and the jumping exercise on tibial strength; (2) an exercise-dependent increase in serum IGF-I in C3H, but not B6 mice; and (3) no effects on serum ALP or osteocalcin. The histomorphometric analyses showed no effect of exercise on C3H tibiae, but significant exercise-dependent increases in total bone area, periosteal perimeter, periosteal mineral apposition rate (MAR), and periosteal bone formation (P < 0.02 for each) in B6 tibiae. There were no effects of exercise on periosteal resorption or any endosteal measurement in either C3H or B6 mice. Since the jumping exercise was designed to cause a two-three fold increase in muscular-skeletal loading at the tibio-fibular junction, and the calculated stress (g/mm2) at this sampling site was only 16% greater for B6 compared with C3H mice, we had anticipated that both strains of mice would show exercise-dependent increases in periosteal bone formation, with a greater response in the B6 mice. The lack of a response in the C3H tibiae demonstrates that the bones of C3H mice are less sensitive to mechanical loading (and unloading) than the bones of B6 mice.

[Primary Sjögren's syndrome presenting as unconsciousness associated with IgA-lambda M-protein].

We describe the case of a 43-year-old woman who presented with primary Sjögren's syndrome (SS) which manifestated as unconsciousness due to M protein. A diagnosis of SS was made based on a ten-year history of dryness, a Shirmer test, and the histological findings of labial biopsy. A rouleaux formation was observed and serum protein electrophoresis revealed a monoclonal spike of 4.0 gm/dl in the gamma-region, which was characterized as IgA-lambda. Biopsy of the minor salivary glands showed marked polyclonal lymphoproliferation with lymphoid follicles, including both T cells and B cells as revealed by immunohistological staining. Therefore, the patient had a lymphoproliferative lesion of the minor salivary glands, which is also known as pseudolymphoma. We conclude that fainting associated with marked M protein may be manifestation of SS. Such cases should be followed carefully since the subsequent neoplastic transformation of pseudolymphomas have been previously reported.

Five jumps per day increase bone mass and breaking force in rats.

The effects of jump training on bone morphological and mechanical properties were investigated in immature bones of female Fischer 344 rats. Five-week-old rats were divided into control or five jump-trained groups comprised of 5-, 10-, 20-, 40-, and 100-jump groups, representing the number of jumps per day. The rats were jump-trained 5 days/week for 8 weeks, and the height of jump was increased to 40 cm progressively. The femur and tibia in the 5-jump group had significantly greater fat-free dry weights per body weight and maximum loads at the fracture tests than those in the control group. The tibia in the 5-jump group also had significantly larger cortical area at the cross-sectional analysis. Although a slight tendency toward increase according to the number of jumps per day was observed, there were few differences in bone morphological and mechanical parameters among the 10-, 20-, and 40-jump groups. The present results indicate that a large number of strains per day is not necessary for bone hypertrophy to develop in rats.

Expression of endothelial nitric oxide synthase in human eccrine clear cells.

Nitric oxide is generated from L-arginine by nitric oxide synthase (NOS), which has at least three isoforms; endothelial-type NOS (eNOS) and brain-type NOS (bNOS) are constitutive enzymes, and inducible-type NOS (iNOS) is expressed after stimulation. Studies by the avidin-biotin immunocomplex method, revealed eNOS immunoreactivity exclusively in the human eccrine clear cells. No eNOS immunoreactivity was observed in the eccrine dark cells or myoepithelial cells. No staining of iNOS or bNOS was observed in the eccrine gland. These findings indicate that NO plays a physiological part in the production and/or excretion of sweat in the human skin eccrine gland.