High-intensity interval training (HIIT) has recently received much attention as a new option for aerobic training. Despite its smaller time requirement, HIIT has been reported to have a greater ...effect than continuous moderate-intensity training on fat loss, especially a decrease in truncal adiposity. We therefore examined whether long-term HIIT preferentially modulates truncal adiposity rather than peripheral adiposity, especially thigh adiposity, where local muscle energy consumption increased profoundly during HIIT. We also examined the association between changes in adipose tissue distribution and serum adiponectin level. Twelve healthy male participants (28-48 years old) were assigned to a group that performed HIIT using only a leg ergometer (L-HIIT, n = 7) or to a group that performed HIIT using both leg and arm ergometers (LA-HIIT, n = 5) twice weekly for 16 weeks. The training programs consisted of 8 to 12 sets of >90% VO2 peak for 1 min, with 1 min of very light active recovery. Body composition analyses as well as aerobic fitness and measurements of serum adiponectin were performed at baseline and after intervention. A linear improvement in aerobic fitness was observed along with a decrease in leg fat (5.4 ± 1.7 vs. 5.1 ± 1.7 kg, p < 0.05) near the main working muscles during HIIT in the combined (L+LA-HIIT) group. Moreover, there was an association of decrease in leg fat or thigh adiposity with improvement in aerobic fitness in the combined group (ρ = -0.59, p < 0.05; and ρ = -0.71, p < 0.05, respectively). Visceral adiposity was decreased in L-HIIT (115 ± 45 vs. 100 ± 47 cm2, p < 0.05), however no decrease was observed in total fat or truncal fat in either group. No change was observed in serum adiponectin concentration in either group. Changes in serum adiponectin were associated with changes in visceral adiposity in the combined group (ρ = -0.72, p < 0.01). Regional rather than whole-body fat loss was observed after a 16-week HIIT program.
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Long‐term follow‐up of studies to investigate preventive effects of aspirin on arterial thrombosis indicate that aspirin reduces the incidence and mortality of some cancers in Western ...populations.
To explore the effects of aspirin on cancer incidence and mortality in the elderly Japanese.
Patients aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus (n = 14 601, 7297 in the aspirin group and 7304 in the no‐aspirin group) participated the Japanese Primary Prevention Project (JPPP), a multicenter, open‐label, randomized, parallel‐group trial. A subanalysis of JPPP was performed to analyze the incidence of newly diagnosed cancer and death related to cancer.
The cumulative incidence of newly diagnosed cancer was 5.60% (4.65‐6.64%) in the aspirin group and 4.14% (3.67‐4.66%) in the no‐aspirin group. The hazard ratio for newly diagnosed cancer was 1.24 (1.06‐1.46), and the cancer incidence was significantly higher in the aspirin group. The cumulative cancer mortality was 1.96% (1.65‐2.31%) in the aspirin group and 1.87% (1.56‐2.22%) in the no‐aspirin group, with no statistically significant difference. The Fine and Gray model suggested that the difference in the incidence of newly diagnosed cancer between the two groups decreased year by year.
Low‐dose aspirin use did not reduce the cancer incidence or cancer mortality during a 5‐year‐average study period in the elderly Japanese. The cancer incidence in the aspirin group might decrease, however, to less than that in the no‐aspirin group after the study period. Aspirin use might have led to earlier cancer diagnosis in our study.
To examine the efficacy and safety of TAS5315, an irreversible covalent Bruton's tyrosine kinase inhibitor, in Japanese patients with rheumatoid arthritis (RA) refractory to methotrexate.
In part A ...of this phase IIa double-blind study, patients were randomised to TAS5315 4 or 2 mg or placebo once daily for 12 weeks; in part B, all patients received TAS5315 for another 24 weeks. The proportion of patients meeting American College of Rheumatology criteria for 20% improvement (ACR20) at week 12 was assessed (primary endpoint).
Ninety-one patients were randomised in part A, and 84 entered part B. At week 12, 78.9% of patients achieved ACR20 in the TAS5315 combined group vs 60.0% with placebo (p=0.053), 33.3% vs 13.3% achieved ACR50 (p=0.072) and 7.0% vs 0.0% achieved ACR70 (p=0.294), respectively. More patients receiving TAS5315 than placebo had low disease activity or remission at week 12. Clinical and biomarker improvements were maintained during part B. Adverse event (AE) incidence in TAS5315 was similar to placebo in part A; common AEs with TAS5315 were nasopharyngitis (10.3%), pruritus (6.9%) and cystitis (5.2%). Over 36 weeks, nine patients experienced bleeding events of whom four and two patients recovered with drug continuation and interruption, respectively. Three patients recovered after TAS5315 discontinuation.
The primary endpoint was not achieved. TAS5315 appears to have some bleeding risks, but nevertheless demonstrated numerical differences, compared with placebo, in the improvement rates of all measures of RA disease activity. Future analysis of the risk-benefit of TAS5315 should be considered.
NCT03605251, JapicCTI-184020, jRCT2080223962.
The hemostatic activity of von Willebrand factor (vWF) is strongly dependent on its multimeric structure, with the highest activity in ‘unusually large’ multimers secreted from endothelial cells. The ...multimeric structure is regulated by a plasma protease, vWF-cleaving protease (vWF-CP, or ADAMTS-13). ADAMTS-13 mRNA is variably expressed in liver and other tissues. Because 15–25% of circulating vWF is stored in platelets, the presence and function of ADAMTS-13 in platelets are important issues. Here we report ADAMTS-13 expression in human platelets. Western blot analysis and flow cytometric analysis on permeabilized platelets revealed the presence of ADAMTS-13 protein. Real-time PCR demonstrated that ADAMTS-13 mRNA is present in platelets of six healthy volunteers, with little quantitative difference. The presence of ADAMTS-13 in platelets may imply the functional role of this enzyme in the local regulation of platelet function at the site of vascular injury or thrombus formation, and provide a useful tool for the analysis of structure and function of this enzyme.
The rapid diagnosis of pathogens and prompt initiation of appropriate antibiotic therapy are critical factors to reduce the morbidity and mortality associated with sepsis. In this study, we evaluated ...a multiplex polymerase chain reaction (PCR-M) test that detects bacteria and fungi in whole-blood specimens, comparing its features to those of a blood culture (BC). Following evaluation of the performance for sensitivity and specificity of PCR-M, 78 blood samples from 54 patients with suspected bacterial infections were evaluated. Whole-blood samples for PCR-M were collected at the same time as BC, and PCR-M results were compared with BC results. As a result, minimum sensitivity of the kit was 1–100 cfu/ml. The PCR-M test correctly identified specificity for 13 out of 14 strains blinded to the assay analyst. Of 78 blood samples examined, 56 (72%) were negative by both methods, and 22 (28%) were positive by at least one of the two methods. PCR-M detected organisms in 21 cases (27%) compared with 12 cases (15%) in BC. The correlation of positives between PCR-M and BC was 92% (11/12), and both methods identified the same organisms in these 11 cases. With higher positive rate compared with BC, PCR-M could detect and identify potentially significant microorganisms within a few hours by using a small volume of a single whole-blood sample. Early detection of microorganisms has the potential to facilitate early determination of appropriate treatment and antimicrobial selection.
Abstract The development of an effective rat model of incisional surgical site infection (SSI) has so far proven difficult. In this study, we created a novel incisional SSI model and validated it in ...terms of both macroscopic and microscopic aspects including its response to treatment using antimicrobial wound-dressing, Aquacel Ag® . Wounds were created on the dorsum of rats. 3-0 Vicryl® threads inoculated with Escherichia coli were inserted in the wound beds in the infection group ( n = 6). The wounds were closed for two days to induce infection and then opened and covered with polypropylene sheets during the study. Aquacel Ag was placed under the polypropylene sheet in the infected wounds of the Aquacel Ag group rats ( n = 6). The wounds in the control group ( n = 6) contained sterile Vicryl thread that had not been inoculated with E. coli . The macroscopic appearance, wound area, bacterial counts, and histology of each group were evaluated. The infection group demonstrated significantly lower wound healing ( p < 0.001), greater bacterial counts (median interquartile range ratings, 2.15 × 107 0.51 × 107 –53.40 × 107 vs 2.07 × 104 0.60 × 104 –4.45 × 104 CFU/g, respectively; p < 0.01), and severer histological inflammation ( p < 0.001) than the control group. The Aquacel Ag group was only able to show significantly better wound healing than the infection group ( p < 0.001). The new incisional SSI model exhibited all clinical manifestations of incisional SSI. It could be utilized to assess the effectiveness of newly developed treatments for incisional SSI.
We employ rapid-ACTH stimulation test under dexamethasone (DEX) suppression to assess the adrenal function in daily clinic. However, we have little knowledge about the excretion of urinary free ...cortisol (FF) and cortisone (FE) in pooled urine in this setting. The purpose was to examine the changes of FF and FE as well as FF/FE ratio in pooled urine after rapid-ACTH stimulation test under DEX suppression using stable isotope dilution - gas chromatography/mass spectrometry (SID-GC/MS). Pooled urine samples were collected from 8 patients (age 33-71 years) who were suspected to have primary aldsteronism. They all were finally diagnosed as having normal glucocorticoid secretion. We performed rapid-ACTH stimulation test with DEX suppression for consecutive 4 days as follows. (1) 24 hour urine samples were serially collected from 2300h on day 1 for 72 hours (Basal, DEX1mg, and DEX8mg-ACTH). (2) 1 and 8 mg DEX was given at 2300h on day 2 and 3, respectively. (3) 250μg of ACTH was given at 0900h on day 4. Urine free steroids were delivered with bismethylenedioxy-heptafluorobutyric anhydride and analyzed by SID-GC/MS (μg/day). From DEX1mg to DXE8mg-ACTH, 1) FF and FE were significantly increased (3.9±1.3 to 21.3±14.6 and 12.4±4.8 to 26.1±11.0 μg/day, respectively), but 2) FF/FE ratio significantly increased (0.32±0.05 to 0.77±0.23). These data suggested that newly synthesized cortisol by ACTH stimulation was not efficiently metabolized to cortisone.
Prevention of atherosclerotic cardiovascular diseases is an important public health priority in Japan due to an aging population.
To determine whether daily, low-dose aspirin reduces the incidence of ...cardiovascular events in older Japanese patients with multiple atherosclerotic risk factors.
The Japanese Primary Prevention Project (JPPP) was a multicenter, open-label, randomized, parallel-group trial. Patients (N = 14,464) were aged 60 to 85 years, presenting with hypertension, dyslipidemia, or diabetes mellitus recruited by primary care physicians at 1007 clinics in Japan between March 2005 and June 2007, and were followed up for up to 6.5 years, with last follow-up in May 2012. A multidisciplinary expert panel (blinded to treatment assignments) adjudicated study outcomes.
Patients were randomized 1:1 to enteric-coated aspirin 100 mg/d or no aspirin in addition to ongoing medications.
Composite primary outcome was death from cardiovascular causes (myocardial infarction, stroke, and other cardiovascular causes), nonfatal stroke (ischemic or hemorrhagic, including undefined cerebrovascular events), and nonfatal myocardial infarction. Secondary outcomes included individual end points.
The study was terminated early by the data monitoring committee after a median follow-up of 5.02 years (interquartile range, 4.55-5.33) based on likely futility. In both the aspirin and no aspirin groups, 56 fatal events occurred. Patients with an occurrence of nonfatal stroke totaled 114 in the aspirin group and 108 in the no aspirin group; of nonfatal myocardial infarction, 20 in the aspirin group and 38 in the no aspirin group; of undefined cerebrovascular events, 3 in the aspirin group and 5 in the no aspirin group. The 5-year cumulative primary outcome event rate was not significantly different between the groups (2.77% 95% CI, 2.40%-3.20% for aspirin vs 2.96% 95% CI, 2.58%-3.40% for no aspirin; hazard ratio HR, 0.94 95% CI, 0.77-1.15; P = .54). Aspirin significantly reduced incidence of nonfatal myocardial infarction (0.30 95% CI, 0.19-0.47 for aspirin vs 0.58 95% CI, 0.42-0.81 for no aspirin; HR, 0.53 95% CI, 0.31-0.91; P = .02) and transient ischemic attack (0.26 95% CI, 0.16-0.42 for aspirin vs 0.49 95% CI, 0.35-0.69 for no aspirin; HR, 0.57 95% CI, 0.32-0.99; P = .04), and significantly increased the risk of extracranial hemorrhage requiring transfusion or hospitalization (0.86 95% CI, 0.67-1.11 for aspirin vs 0.51 95% CI, 0.37-0.72 for no aspirin; HR, 1.85 95% CI, 1.22-2.81; P = .004).
Once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors.
clinicaltrials.gov Identifier: NCT00225849.
ADAMTS13 cleaves multimeric von Willebrand factor (VWF) to regulate VWF-mediated thrombus formation. To search ADAMTS13 peptide sequences binding to VWF, a λ-phage library expressing various peptides ...of ADAMTS13 on the surface was screened using VWF either immobilized or in solution under static condition. By the first screening, peptides sharing the C-terminus of spacer domain from Arg670 to Gln684 (epitope-A) were selected. To explore additional sites, peptide sequences from the first screening were synthesized and added to the second screening. Consequently, Pro618 to Glu641 (epitope-B) in the middle of spacer domain was obtained from immobilized VWF condition. Synthetic epitope-B peptide inhibited the cleavage of VWF by ADAMTS13, while the synthetic epitope-A peptide did not as efficiently as epitope-B. Elimination of four amino acids from either sides of epitope-B terminus markedly reduced the inhibitory effect. These two sites in the spacer domain may play significant roles in binding to VWF.
The development of diabetic nephropathy is considered to be associated with oxidative stress. NADPH oxidase and the receptor for advanced glycation end products (RAGE) have attracted attention as ...mechanisms of generating oxidative stress. We studied the relation between the genotypes of the NADPH p22phox C242T and RAGE G1704T polymorphisms and the development of diabetic nephropathy in type 2 diabetic patients.
Using a retrospective review of clinical data, we allocated 181 Japanese type 2 diabetic patients to one of two groups: patients without diabetic nephropathy (group N; n = 108) and patients developing diabetic nephropathy (group D; n = 73) for 10 years or more. The p22phox C242T and RAGE G1704T polymorphisms were examined by Taqman PCR methods.
The frequency of the p22phox CC genotype was significantly higher in group D than in group N (90 vs. 79%; P = 0.0427). The frequency of the RAGE GT + TT genotype was significantly higher in group D than in group N (26 vs. 13%; P = 0.0313). The frequency of the combination of p22phox CC and RAGE GT + TT genotypes was significantly higher in group D than in group N (22 vs. 8%; P = 0.0057). In multiple logistic regression analysis, systolic blood pressure, HbA(1c), triglycerides, and the combination of polymorphisms were shown to be independent variables.
These results suggest that assessment of the combination of NADPH p22phox C242T and RAGE G1704T polymorphisms may be useful in identifying the risk for developing diabetic nephropathy in type 2 diabetic patients.
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