Aim
To investigate the in vivo metabolic effects of treatment with BPR0912, a novel and potent peripheral cannabinoid receptor 1 (CB1R) antagonist, on both normal mice and diet‐induced obese (DIO) ...mice.
Methods
The acute peripheral effects of BPR0912 administration on gastrointestinal transit and energy metabolism in normal mice were investigated. The effects of chronic BPR0912 treatment were compared with those of rimonabant using DIO mice. Alterations to body weight and biochemical and metabolic variables were determined.
Results
Acute treatment with BPR0912 did not alter food intake or energy metabolism, but efficiently reversed CB1R‐mediated gastrointestinal delay. Chronic treatment of DIO mice with BPR0912 showed that BPR0912 exerts a food intake‐independent mechanism, which contributes to weight loss. Genes involved in β‐oxidation and thermogenesis were upregulated in white adipose tissue (WAT) in addition to increased lipolytic activity, whereas Ucp1 expression was induced in brown adipose tissue (BAT) and body temperature was elevated. Expression of the β2‐adrenoceptor was specifically elevated in both WAT and BAT in a manner dependent on the BPR0912 dose. Lastly, chronic BPR0912 treatment was more efficacious than rimonabant in reducing hepatic triglycerides in DIO mice.
Conclusion
BPR0912 exhibits significant in vivo efficacy in inducing food intake‐independent weight loss in DIO mice, while tending to reduce their hepatic steatosis. The thermogenic effects of BPR0912, as well as its modulation of protein and gene expression patterns in WAT and BAT, may enhance its efficacy as an anti‐obesity agent. The results of the present study support the benefits of the use of peripheral CB1R antagonists to combat metabolic disorders.
This study investigated the in vitro susceptibilities of methicillin-resistant
Staphylococcus aureus
(MRSA) to nine antimicrobial agents in Taiwan. A total of 1,725 isolates were obtained from 20 ...hospitals throughout Taiwan from 2006 to 2010. The minimum inhibitory concentrations (MICs) of the nine agents were determined by the agar dilution method. The MICs of mupirocin and tyrothricin were determined for 223 MRSA isolates collected from 2009 to 2010. For vancomycin, 99.7 % were susceptible; however, 30.0 % (
n
= 517) exhibited MICs of 2 μg/ml and 0.3 % (
n
= 6) demonstrated intermediate susceptibility (MICs of 4 μg/ml). Nearly all isolates (≥99.9 %) were susceptible to teicoplanin, linezolid, and daptomycin. The MIC
90
values were 2 μg/ml for ceftobiprole and 1 μg/ml for nemonoxacin. The MIC
90
values of mupirocin and tyrothricin were 0.12 and 4 μg/ml, respectively. MIC creep was noted for daptomycin during this period, but not for vancomycin, teicoplanin, linezolid, or tigecycline. For isolates with vancomycin MICs of 2 μg/ml, the MIC
90
values were 2 μg/ml for teicoplanin, 0.5 μg/ml for daptomycin, and 0.5 μg/ml for tigecycline. Those values were four- to eight-fold higher than those among isolates with vancomycin MICs of 0.5 μg/ml (2, 0.06, and 0.12 μg/ml, respectively). Of the nine MRSA isolates exhibiting non-susceptibility to vancomycin (
n
= 6), teicoplanin (
n
= 1), daptomycin (
n
= 2), or tigecycline (
n
= 1), all had different pulsotypes, indicating the absence of intra-hospital or inter-hospital spread. The presence of a high proportion of MRSA isolates with elevated MICs (2 μg/ml) and MIC creep of daptomycin might alert clinicians on the therapy for serious MRSA infections in Taiwan.
Objectives
Supplementation of high protein oral nutrition shakes supplemented with β-hydroxy-β-methylbutyrate (HP-HMB) has been shown to improve muscle mass, muscle strength, and physical performance ...in older adults, but the roles of HP-HMB supplementation on the intramuscular adiposity remained unknown. This 12-week randomized controlled trial evaluated the changes of muscle mass, muscle strength, physical performance and intramuscular adiposity among community-dwelling pre-frail older persons.
Methods
This was an open-label, parallel group, randomized controlled trail that enrolled 70 community-dwelling pre-frail older persons without active or uncontrolled conditions, disability or dementia. The intervention group was provided with two services of HP HMB (Ensure® Plus Advance containing 3g HMB) per day for 12 weeks, and the control group was provided with professional nutritional counselling for sufficient protein intake. All participants received functional assessments, laboratory tests and magnetic resonance imaging (MRI) of the dominant leg before and after study. Intramuscular adipose tissue (IMAT) and the mid-thigh cross-sectional area (CSA) of muscle were obtained by MRI, and the IMAT-to-CSA ratio was calculated to evaluate intramuscular adiposity.
Results
Overall, 62 participants (mean age: 71.1±3.8 years, 69.4% female) completed the study (HP-HMB group: 29, control group: 33) and comparisons of baseline characteristics between groups were not statistically different. For the primary outcome, HP-HMB group showed significant improvements in the CSA of mid-thigh muscle (mean increase of CSA: 149.1±272.3 for HMB group vs −22.9±309.1 mm
2
for control group, P=0.045). The improvement of MNA-SF was borderline (0.28±0.75 vs. −0.15±0.94, P=0.064), but serum levels of Vit D were significantly increased in the HMB group (3.83±8.18 vs. −1.30±4.81 ng/mL, P=0.002). Moreover, the body weight and BMI were significantly increased in the HMB group (1.10±1.18 vs. 0.24±1.13 kg, P=0.005; 0.56±0.68 vs. 0.22±0.47 kg/m
2
, P=0.019). In particular, the IMAT-to-CSA ratio was reduced in the HMB group (−0.38±1.21 vs. −0.02±2.56 %, P=0.06). Using the generalized estimating equation, we found that SPPB score in chair rise test was significantly improved (β=0.71, 95% C.I.0.09–1.33, P=0.026).
Conclusions
The 12-week supplementation with high protein oral nutrition shake supplemented with 3g HMB per day significantly increased muscle mass, as well as nutritional status and physical performance, and ameliorated the intramuscular adiposity of pre-frail older persons. Further study is needed to explore the long-term benefits of HP-HMB supplementation on muscle and metabolic health for older adults.
We aimed to determine the effect of dementia and Parkinson's disease on one, three and 12-month mortality following surgery for fracture of the hip in elderly patients from an Asian population.
Using ...a random sample of patients taken from the Taiwan National Health Insurance Research Database, this retrospective cohort study analyzed the data on 6626 elderly patients who sustained a fracture of the hip between 1997 and 2012 who had ICD-9 codes within the general range of hip fracture (820.xx). We used Cox regression to estimate the risk of death associated with dementia, Parkinson's disease or both, adjusting for demographic, clinical, treatment, and provider factors.
Among 6626 hip fracture patients, 10.20% had dementia alone, 5.60% had Parkinson's disease alone, and 2.67% had both. Corresponding one-year mortality rates were 15.53%, 11.59%, and 15.82%, compared with 9.22% for those without neurological illness. Adjusted hazard ratio for one-year mortality was 1.45 (95% confidence intervals (CI) 1.17 to 1.79) for those with dementia, and 1.57 (95% CI 1.07 to 2.30) with both dementia and Parkinson's disease versus patients with neither. There was no significant association with death for Parkinson's disease alone. Age, male gender and comorbidities were also associated with a higher risk of mortality.
Dementia, with or without Parkinson's disease, is an independent predictor of mortality following surgery for fractures of the hip. Age, male gender and comorbidities also increase the risk of death. Parkinson's disease alone has no significant effect. Cite this article: Bone Joint J 2018;100-B:1220-6.
Cd3As2 is a candidate three-dimensional Dirac semimetal which has exceedingly high mobility and nonsaturating linear magnetoresistance that may be relevant for future practical applications. We ...report magnetotransport and tunnel diode oscillation measurements on Cd3As2, in magnetic fields up to 65 T and temperatures between 1.5 and 300 K. We find that the nonsaturating linear magnetoresistance persists up to 65 T and it is likely caused by disorder effects, as it scales with the high mobility rather than directly linked to Fermi surface changes even when approaching the quantum limit. From the observed quantum oscillations, we determine the bulk three-dimensional Fermi surface having signatures of Dirac behavior with a nontrivial Berry phase shift, very light effective quasiparticle masses, and clear deviations from the band-structure predictions. In very high fields we also detect signatures of large Zeeman spin splitting (g~16).
Preclinical mouse models suggest that the gut microbiome modulates tumor response to checkpoint blockade immunotherapy; however, this has not been well-characterized in human cancer patients. Here we ...examined the oral and gut microbiome of melanoma patients undergoing anti-programmed cell death 1 protein (PD-1) immunotherapy (
= 112). Significant differences were observed in the diversity and composition of the patient gut microbiome of responders versus nonresponders. Analysis of patient fecal microbiome samples (
= 43, 30 responders, 13 nonresponders) showed significantly higher alpha diversity (
< 0.01) and relative abundance of bacteria of the Ruminococcaceae family (
< 0.01) in responding patients. Metagenomic studies revealed functional differences in gut bacteria in responders, including enrichment of anabolic pathways. Immune profiling suggested enhanced systemic and antitumor immunity in responding patients with a favorable gut microbiome as well as in germ-free mice receiving fecal transplants from responding patients. Together, these data have important implications for the treatment of melanoma patients with immune checkpoint inhibitors.
The Migdal effect in a dark-matter-nucleus scattering extends the direct search experiments to the sub-GeV mass region through electron ionization with sub-keV detection thresholds. In this paper, we ...derive a rigorous and model-independent "Migdal-photoabsorption" relation that links the sub-keV Migdal process to photoabsorption. This relation is free of theoretical uncertainties as it only requires the photoabsorption cross section as the experimental input. Validity of this relation is explicitly checked in the case of xenon with a state-of-the-art atomic calculation that is well benchmarked by experiments. The predictions based on this relation for xenon, argon, semiconductor silicon, and germanium detectors are presented and discussed.
Summary
Background: Primary percutaneous coronary intervention (PCI) in patients with ST‐elevation myocardial infarction (STEMI) significantly reduces mortality and morbidity, particularly when ...door‐to‐balloon (D2B) time is < 90 min. We sought to minimize preventable delays by instituting an on‐site cardiology team‐based approach in the emergency department (ED).
Methods: The on‐site group comprised 146 consecutive patients with STEMI undergoing primary PCI after implementation of the on‐site strategy. This new patient care model was compared with the conventional care administered before instituting the on‐site cardiology team‐based strategy in ED, which included 90 patients (interim group) receiving primary PCI at a catheterization room in the same building as the ED, and 147 patients (pre‐on‐site group) undergoing primary PCI at a catheterization room two blocks away from the ED.
Results: Median D2B time decreased from 107 min in the pre‐on‐site group to 72 min in the interim group, and to 47 min in the on‐site group, respectively (p < 0.001). The percentage of D2B times < 90 min increased from 34% to 78% and 96%, respectively among the three groups (p < 0.001). Hospitalization costs were significantly reduced in the on‐site and interim vs. pre‐on‐site groups ($5944, $5999, and $6581, respectively; p = 0.008). In‐hospital mortality did not differ significantly among the three groups (4.8%, 2.2%, and 6.1%, respectively; p = 0.387).
Conclusions: Institution of an on‐site cardiology team‐based approach in the ED significantly reduces D2B time in STEMI patients eligible for primary PCI.
HLJ1 (DNAJB4), a DNAJ/Hsp40 chaperone, has emerged as a novel prognostic marker in lung cancers; however, the molecular contribution and functionality in neoplastic diseases remain to be established. ...This study demonstrated that HLJ1 inhibits epithelial-mesenchymal transition in vitro and reduces lung cancer metastasis in vivo. Using shRNA silencing and ectopic expression of HLJ1, we found that HLJ1 not only suppresses catalytic activity of Src but also downregulates the formation of oncogenic complexes associated with the EGFR, FAK and STAT3 signaling pathways. A screen of specimens from HLJ1-knockout mice and lung cancer patients validated that HLJ1 expression is inversely correlated with Src activity. Mechanistically, HLJ1 protein directly bound to catalytic and protein-binding domains of Src through its amino acid Y172 and the P301/P304 motif. Following Src-induced HLJ1 phosphorylation at Y172, HLJ1-Src interaction was elevated, resulting in Src inhibition and malignancy suppression. Interestingly, both Src-binding regions also occurred in other DNAJB family members and contributed to anti-invasive activities of DNAJB proteins. We conclude that HLJ1 is an endogenous Src inhibitor that can suppress cancer metastasis through complex interacting mechanisms. This HLJ1-Src complex might provide a promising molecular model for developing new anticancer strategies.
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