Structures of triterpenoids from the leaves of Lansium domesticum

Journal of Natural Medicines - From the methanolic extract of the leaves of Lansium domesticum, three new onoceranoid-type triterpenoids, lansium acids X–XII and a new cycloartane-type...     

Carbon dioxide insufflation during colorectal endoscopic submucosal dissection for patients with obstructive ventilatory disturbance

Purpose

Carbon dioxide (CO₂) insufflation reduces abdominal pain and discomfort after endoscopic procedures; however, there is no previous study focusing the safety of CO₂ insufflation for patients with obstructive ventilatory disturbance. Here, we investigated the safety of CO₂ insufflation during colorectal endoscopic submucosal dissection (ESD) for patients with obstructive disturbance.

Methods

Between January 2010 and January 2013, colorectal ESD was performed using CO₂ insufflation for 385 consecutive patients. End-tidal CO₂ (EtCO₂) and transcutaneous oxygen saturation (SpO₂) were consecutively measured from the time before insertion of the colonoscope to the end of ESD. Patients were monitored by two nurses during the procedure and controlled for clinical symptoms of hypercapnia such as apnea or a depressed level of consciousness. According to their respiratory function, patients were stratified into a normal group and an obstructive disturbance group. We retrospectively compared EtCO₂ and SpO₂ during the procedures and the incidence of symptoms related to CO₂ retention between the two groups.

Results

The obstructive disturbance group consisted of 77 patients. There were similar changes of EtCO₂ in the obstructive disturbance group and normal group and no significant rise in EtCO_2. The maximum EtCO₂ level in any patient was <60 mmHg. In the obstructive disturbance group, there were no symptoms associated with CO₂ retention. There were no significant differences in the median SpO₂ between both groups and no prolonged drop of SpO₂.

Conclusions

CO₂ insufflation during colorectal ESD is safe for patients with obstructive ventilatory disturbance.     

Investigation of inflammation inducing substances in PM2.5 particles by an elimination method using thermal decomposition

The substances associated with PM2.5‐induced inflammatory response were investigated using an elimination method. PM2.5 were heated at temperatures of 120, 250, and 360°C. The results demonstrated microbial substances such as LPS and b‐glucan, and chemicals including BaP, 1,2‐NQ, and 9,10‐PQ were reduced drastically in PM2.5 heated at 120°C. On the other hand, DBA, 7,12‐BAQ, and BaP‐1,6‐Q were not noticeably reduced. Most of these substances had disappeared in PM2.5 heated at 250°C and 360°C. Metals (eg, Fe, Cu, Cr, Ni) in PM2.5 exhibited a slight thermo‐dependent increase. RAW264.7 macrophages with or without NAC were exposed to unheated PM2.5, oxidative stress‐related and unrelated inflammatory responses were induced. PM2.5‐induced lung inflammation in mice is caused mainly by thermo‐sensitive substances (LPS, b‐glucan, BaP, 1,2‐NQ, 9,10‐PQ, etc.). Also, a slight involvement of thermo‐resistant substances (DBA, 7,12‐BAQ, BaP‐1,6‐Q, etc.) and transition metals was observed. The thermal decomposition method could assist to evaluate the PM2.5‐induded lung inflammation.     

Peripheral blood lymphocyte telomere length as a predictor of response to immunosuppressive therapy in childhood aplastic anemia

Predicting the response to immunosuppressive therapy could provide useful information to help the clinician define treatment strategies for patients with aplastic anemia. In our current study, we evaluated the relationship between telomere length of lymphocytes at diagnosis and the response to immunosuppressive therapy in 64 children with aplastic anemia, using flow fluorescence in situ hybridization. Median age of patients was ten years (range 1.5–16.2 years). Severity of the disease was classified as very severe in 23, severe in 21, and moderate in 20 patients. All patients were enrolled in multicenter studies using antithymocyte globulin and cyclosporine. The response rate to immunosuppressive therapy at six months was 52% (33 of 64). The probability of 5-year failure-free survival and overall survival were 56% (95% confidence interval (CI): 41–69%) and 97% (95%CI: 87–99%), respectively. Median telomere length in responders was −0.4 standard deviation (SD) (−2.7 to +3.0 SD) and −1.5 SD (−4.0 to +1.6 (SD)) in non-responders (P<0.001). Multivariate analysis showed that telomere length shorter than −1.0 SD (hazard ratio (HR): 22.0; 95%CI: 4.19–115; P<0.001), platelet count at diagnosis less than 25×10⁹/L (HR: 13.9; 95%CI: 2.00–96.1; P=0.008), and interval from diagnosis to immunosuppressive therapy longer than 25 days (HR: 4.81; 95%CI: 1.15–20.1; P=0.031) were the significant variables for poor response to immunosuppressive therapy. Conversely to what has been found in adult patients, measurement of the telomere length of lymphocytes at diagnosis is a promising assay in predicting the response to immunosuppressive therapy in children with aplastic anemia.     

First-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy

The current treatment approach for severe aplastic anemia in children is based on studies performed in the 1980s, and updated evidence is required. We retrospectively compared the outcomes of children with acquired severe aplastic anemia who received immunosuppressive therapy within prospective trials conducted by the Japanese Childhood Aplastic Anemia Study Group or who underwent bone marrow transplantation from an HLA-matched family donor registered in the Japanese Society for Hematopoietic Cell Transplantation Registry. Between 1992 and 2009, 599 children (younger than 17 years) with severe aplastic anemia received a bone marrow transplant from an HLA-matched family donor (n=213) or immunosuppressive therapy (n=386) as first-line treatment. While the overall survival did not differ between patients treated with immunosuppressive therapy or bone marrow transplantation [88% (95% confidence interval: 86–90) versus 92% (90–94)], failure-free survival was significantly inferior in patients receiving immunosuppressive therapy than in those undergoing bone marrow transplantation [56% (54–59) versus 87% (85–90); P<0.0001]. There was no significant improvement in outcomes over the two time periods (1992–1999 versus 2000–2009). In multivariate analysis, age <10 years was identified as a favorable factor for overall survival (P=0.007), and choice of first-line immunosuppressive therapy was the only unfavorable factor for failure-free survival (P<0.0001). These support the current algorithm for treatment decisions, which recommends bone marrow transplantation when an HLA-matched family donor is available in pediatric severe aplastic anemia.     

From the Cover: Form of an evolutionary tradeoff affects eco-evolutionary dynamics in a predator–prey system

Evolution on a time scale similar to ecological dynamics has been increasingly recognized for the last three decades. Selection mediated by ecological interactions can change heritable phenotypic variation (i.e., evolution), and evolution of traits, in turn, can affect ecological interactions. Hence, ecological and evolutionary dynamics can be tightly linked and important to predict future dynamics, but our understanding of eco-evolutionary dynamics is still in its infancy and there is a significant gap between theoretical predictions and empirical tests. Empirical studies have demonstrated that the presence of genetic variation can dramatically change ecological dynamics, whereas theoretical studies predict that eco-evolutionary dynamics depend on the details of the genetic variation, such as the form of a tradeoff among genotypes, which can be more important than the presence or absence of the genetic variation. Using a predator–prey (rotifer–algal) experimental system in laboratory microcosms, we studied how different forms of a tradeoff between prey defense and growth affect eco-evolutionary dynamics. Our experimental results show for the first time to our knowledge that different forms of the tradeoff produce remarkably divergent eco-evolutionary dynamics, including near fixation, near extinction, and coexistence of algal genotypes, with quantitatively different population dynamics. A mathematical model, parameterized from completely independent experiments, explains the observed dynamics. The results suggest that knowing the details of heritable trait variation and covariation within a population is essential for understanding how evolution and ecology will interact and what form of eco-evolutionary dynamics will result.Evolutionary dynamics, changes in intraspecific genotype frequency over generations, can have a time scale similar to that of ecological dynamics (1–3). Selection mediated by ecological interactions causes evolutionary dynamics, and evolution of traits, in turn, changes ecological interactions. Thus, understanding population dynamics needs to take account of the feedbacks between trait evolution and ecological interactions (i.e., eco-evolutionary feedbacks). These feedbacks have increasingly attracted ecologists’ attention since Pimentel (4) proposed genetic feedback as a mechanism regulating animal populations (e.g., refs. 5–11). This integration of evolutionary biology and ecology has important implications in both basic and applied problems in biology (12–17).Empirical studies have shown that rapid evolution can affect many ecological interactions, including predator–prey (18–20), host–parasite (21), herbivore–plant (22), competitive interactions (23), and interactions with abiotic environments (24–27). Previous empirical studies on eco-evolutionary feedbacks have usually compared the dynamics of populations with and without genetic variation, but recent theoretical models predicted that not only the presence or absence of genetic variation (28–30) but also the form of the evolutionary tradeoff among genotypes is important in generating qualitatively different dynamics (31–35). Indeed, the forms of evolutionary tradeoffs within populations are known to be remarkably variable in plants and microbes (36–38). Thus, there should be various eco-evolutionary dynamics depending on the form of evolutionary tradeoffs existing in wild populations. Nevertheless, to our knowledge, no empirical study has directly demonstrated the theoretically predicted effects of the evolutionary tradeoff on eco-evolutionary dynamics, and it is still unclear how different forms of an evolutionary tradeoff in real organisms can result in different eco-evolutionary dynamics.Here, using a predator–prey (rotifer–algal) system cultured in continuous flow-through microcosms (chemostats), we examined how different forms of an evolutionary tradeoff between defense and growth in algal prey (Chlorella vulgaris) affect the population dynamics of the predator–prey system and the evolutionary changes in the clonal frequency of the algal prey. Experimental studies using laboratory microcosms have been a powerful approach in exploring eco-evolutionary dynamics and testing theoretical predictions because of the constant environment and simple community structure (39–41). We used two different pairs of algal clones originally obtained from the University of Texas (UTEX) algal collection that showed different forms of a fitness tradeoff between antipredator defense and competitive ability to obtain the resource limiting population growth in the experimental system (inorganic nitrogen). Each pair of algal clones was cultured with an obligately asexual lineage of rotifer predators (Brachionus calyciflorus). Population dynamics of the predators and prey and clonal frequency changes in the algal pair were observed in long-term chemostat runs. We recorded evolutionary dynamics (genotype frequency change) by using an allele-specific quantitative PCR (AsQ-PCR) technique based on microsatellite DNA that allowed us to measure the relative abundance of algal clones (42). We also developed a mathematical model for the experimental system, based on a model of Jones and Ellner (43), parameterized the model using data from separate experiments, and compared the model’s predictions to the observed population and genotype dynamics.     

Hepatitis C drugs: The end of the pegylated interferon era and the emergence of all-oral,interferon-free antiviral regimens: A concise review

Between 2001 and 2011, the standard of care for chronic hepatitis C virus (HCV) infection was a combination of pegylated interferon (PEGIFN) and ribavirin (RBV). In May 2011, boceprevir and telaprevir, two first-generation NS3/4A protease inhibitors, were approved in combination with PEG-IFN and RBV for 24 to 48 weeks in hepatitis C virus genotype 1 infections. In December 2013, simeprevir, a second-generation NS3/4A protease inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotype 1, while sofosbuvir, a NS5B nucleotide polymerase inhibitor, was approved for use with PEG-IFN and RBV for 12 weeks in genotypes 1 and 4, as well as with RBV alone for 12 weeks in genotype 2 and for 24 weeks in genotype 3. Sofosbuvir combined with simeprevir or an NS5A replication complex inhibitor (ledipasvir or daclatasvir) with or without RBV for 12 weeks in genotype 1 resulted in a sustained virological response >90%, irrespective of previous treatment history or presence of cirrhosis. Similarly impressive sustained virological response rates have been shown with ABT-450/r (ritonavir-boosted NS3/4A protease inhibitor)-based regimens in combination with other direct-acting antiviral agent(s) with or without RBV for 12 weeks in genotype 1. The optimal all-oral interferon-free antiviral regimen likely entails a combination of an NS5B nucleotide polymerase inhibitor with either a second-generation NS3/4A protease inhibitor or an NS5A replication complex inhibitor with or without RBV. Further research is needed to determine the role of resistance testing, clarify the optimal follow-up duration post-treatment, and evaluate the antiviral efficacy and safety in difficult-to-cure patient populations.     

Prognostic impact of lipid contents on the target lesion in patients with drug eluting stent implantation

We sought to determine the morphologic predictors of major adverse cardiac events (MACEs) after successful percutaneous coronary intervention (PCI) with drug-eluting stents (DES), using integrated backscatter intravascular ultrasound (IB-IVUS). Conventional IVUS and IB-IVUS were performed in 260 consecutive patients who underwent PCI with DES. Three-dimensional analyses were performed to determine plaque volume and the volume of each plaque component (lipid, fibrous, and calcification). Patients were divided into two groups according to the median lipid volume (LV) in the target lesion. MACEs were defined as death, nonfatal myocardial infarction, and any repeat revascularization. The median follow-up interval was 1285 days. MACEs were observed in 64 patients (24.6 %). Patients having a larger LV compared with their counterparts had worse long-term clinical outcomes regarding mortality (3.8 vs. 0 %, P = 0.02) and MACEs (31.5 vs. 17.7 %, P = 0.008) by log-rank test. After adjustment for confounders, large LV (odds ratio 1.95, 95 % confidence interval 1.14–3.33, P = 0.02) was significantly and independently associated with MACEs. The assessment of coronary plaque characteristics in the target lesion may be useful to predict long-term outcome following successful coronary intervention.     

Identification of predictive factors for response to intravenous immunoglobulin treatment in children with immune thrombocytopenia

Acute immune thrombocytopenia (ITP) is a common benign bleeding disorder of variable etiology characterized by isolated thrombocytopenia. Intravenous immunoglobulin (IVIG) treatment is generally given as an initial treatment to pediatric patients with ITP, but markers predictive of the response to IVIG remain poorly defined. We retrospectively evaluated whether clinical and laboratory findings before treatment could predict response to IVIG and progression to chronic ITP in Japanese children with ITP. Between April 1997 and December 2011, a total of 49 children with newly diagnosed ITP were initially treated with IVIG. Their medical records were retrospectively reviewed. In multivariate analyses, lower white blood cell (WBC) count was the only unfavorable factor for response to IVIG and progression to chronic ITP. Patients with WBC count <7.0 × 10⁹/L had a lower probability of thrombocytopenia-free survival (41 vs. 77 %, P = 0.003) and a higher rate of progression to chronic ITP (29 vs. 6 %, P = 0.040) than those with WBC count ≥7.0 × 10⁹/L. These results suggest that ITP with lower WBC count may represent a distinct subgroup requiring initial treatment other than IVIG.