Effects of Passiflora nitida Kunth leaf extract on digestive enzymes and high caloric diet in rats

The present study investigated inhibition of pancreatic lipase and metabolic effects of high caloric diet in rats. The Passiflora nitida hydroethanol leaf extract (PNE) was used in in vitro assays or administered to rats to study dyslipidemia. Inhibition of lipase in vitro was studied by a spectrophotometric assay using orlistat as the positive control. The effects of PNE on reduction of postprandial triglyceride were studied by oral fat-overloading in rats. Metabolic alterations were induced using the cafeteria diet and 4 weeks post-treatment with PNE or orlistat and blood samples were collected and biochemical analyses were performed. Liver and retroperitoneal fat tissues were obtained to analyze weight and steatosis. IC₅₀ (μg/mL) values for pancreatic lipase inhibition were 21.2 ± 0.8 and 0.1 ± 0.01 for PNE and orlistat, respectively. Oral administration of lipid emulsion resulted in postprandial hypertriglyceridemia at 3 h postadministration and when rats were then administered PNE and orlistat there was decreased of triglyceride levels by 15 % compared to control. Although the energy consumption by the cafeteria diet had been higher, there was no significant weight gain observed in the study groups. The cafeteria diet resulted in a significant increase of weight in the retroperitoneal fat and hypertriglyceridemia levels that could be significantly reduced by PNE and orlistat treatment. We hypothesized that PNE administration prevented the hypertriglyceridemia in rats with a high caloric diet, possibly owing to reduction of lipid absorption and pancreatic lipase inhibition.     

High Heterogeneity of Echoviruses in Brazilian Children with Acute Gastroenteritis

Echoviruses (E) are a diverse group of viruses responsible for various pathological conditions in humans including aseptic meningitis, myocarditis, and acute flaccid paralysis. The detection and identification of echovirus genotypes in clinical samples is challenging due to its high genetic diversity. Here, we report the complete genome sequences of nine echoviruses, obtained by next-generation sequencing of 238 fecal samples from individuals with gastroenteritis in regions of Brazil. Detected viruses were classified into six genotypes: Three E1 sequences (BRA/TO-028, BRA/TO-069 and BRA/TO-236), one E3 (BRA/TO-018), one E11 (BRA/TO-086), one E20 (BRA/TO-016), two E29 (BRA/TO-030 and BRA/TO-193), and one E30 sequence (BRA/TO-032). Phylogenetic analysis indicated that the echoviruses E1 and E29 circulating in Brazil are divergent from strains circulating worldwide. The genotype diversity identified in our study may under-represent the total echovirus diversity in Brazil because of the small sample size and the restricted geographical distribution covered by the survey.     

Magnitude and duration of excess of post‐exercise oxygen consumption between high‐intensity interval and moderate‐intensity continuous exercise: A systematic review

The present systematic review examined the effect of exercise intensity (high‐intensity interval exercise [HIIE] vs. moderate‐intensity continuous exercise [MICE] vs. sprint interval exercise [SIE]) on excess post‐exercise oxygen consumption (EPOC). Twenty‐two studies were included in the final evaluation. The retrieved investigations were split into studies that analysed short‐duration (until 3 h) and long‐duration (more than 3 h) EPOC. Studies that subtracted the baseline energy expenditure (EE) were analysed separately from those that did not. Most short‐duration evaluations that subtracted baseline EE reported higher EPOC for HIIE (average of ~136 kJ) compared with MICE (average of ~101 kJ) and higher values for SIE (average of ~241 kJ) compared with MICE (average of ~151 kJ). The long‐duration evaluations resulted in greater EPOC for HIIE (average of ~289 kJ) compared with MICE (average of ~159 kJ), while no studies comparing SIE versus MICE provided appropriate values. EE from EPOC seems to be greater following HIIE and SIE compared with MICE, and long‐duration evaluations seem to present higher values than short‐duration evaluations. Additionally, more standardized methodologies are needed in order to determine the effective EPOC time following these protocols.     

Implementing a Hybrid-Collaborative Care Model: Practical Considerations for Nurse Practitioners

Access to mental health care is a considerable problem for individuals suffering from a mental illness. Of the 44.7 million adults, aged 18 or older, experiencing a mental illness in 2016 only 43.1% reported receiving treatment. Utilizing integrated and collaborative models can enhance identification and treatment for individuals in need of mental health. The purpose of this paper is threefold: (a) to describe the process of implementing hybrid-collaborative care model (hybrid-CCM) in a practice setting, (b) to discuss the similarities and differences in a hybrid-CCM when compared to a traditional collaborative care model, and (c) to discuss practical considerations for nurse practitioners fulfilling the psychiatric consultant role in a hybrid-CCM or traditional collaborative care model. Implementing collaborative care presents challenges. Understanding implementation efforts can enhance the adoption of collaborative types of care and likely enhance the effectiveness of these strategies. Nurse practitioners can serve as psychiatric consultants within these delivery models, but appropriate training should take place prior to doing so to ensure they are prepared to fulfill this role. Continuing to identify ways we can expand implementation of collaborative models or hybrid versions of collaborative care models need to be explored.     

Failure to infect rhesus monkeys with hepatitis C virus strains of genotypes 1a, 2a or 3a

The chimpanzee is the only recognized animal model for the study of hepatitis C virus (HCV). However, recently it was reported that rhesus monkeys were susceptible to HCV and developed hepatitis during infection. In the present study, we inoculated two rhesus monkeys each with HCV strain H77 (genotype 1a), strain HC-J6 (genotype 2a) or strain S52 (genotype 3a). Weekly serum samples were tested for liver enzyme values, HCV antibodies and HCV RNA. We did not find evidence of HCV infection in any of the monkeys during 24 weeks of follow-up. Our study demonstrates that rhesus monkeys are not readily infected with HCV and apparently do not represent a useful animal model for the study of HCV.     

DEVOTE 3: temporal relationships between severe hypoglycaemia,cardiovascular outcomes and mortality

Aims/hypothesis

The double-blind Trial Comparing Cardiovascular Safety of Insulin Degludec vs Insulin Glargine in Patients with Type 2 Diabetes at High Risk of Cardiovascular Events (DEVOTE) assessed the cardiovascular safety of insulin degludec. The incidence and rates of adjudicated severe hypoglycaemia, and all-cause mortality were also determined. This paper reports a secondary analysis investigating associations of severe hypoglycaemia with cardiovascular outcomes and mortality.

Methods

In DEVOTE, patients with type 2 diabetes were randomised to receive either insulin degludec or insulin glargine U100 (100 units/ml) once daily (between dinner and bedtime) in an event-driven, double-blind, treat-to-target cardiovascular outcomes trial. The primary outcome was the first occurrence of an adjudicated major adverse cardiovascular event (MACE; cardiovascular death, non-fatal myocardial infarction or non-fatal stroke). Adjudicated severe hypoglycaemia was the pre-specified secondary outcome. In the present analysis, the associations of severe hypoglycaemia with both MACE and all-cause mortality was evaluated in the pooled trial population using time-to-event analyses, with severe hypoglycaemia as a time-dependent variable and randomised treatment as a fixed factor. An investigation with interaction terms indicated that the effect of severe hypoglycaemia on the risk of MACE and all-cause mortality were the same for both treatment arms, and so the temporal association for severe hypoglycaemia with subsequent MACE and all-cause mortality is reported for the pooled population.

Results

There was a non-significant difference in the risk of MACE for individuals who had vs those who had not experienced severe hypoglycaemia during the trial (HR 1.38, 95% CI 0.96, 1.96; p = 0.080) and therefore there was no temporal relationship between severe hypoglycaemia and MACE. There was a significantly higher risk of all-cause mortality for patients who had vs those who had not experienced severe hypoglycaemia during the trial (HR 2.51, 95% CI 1.79, 3.50; p < 0.001). There was a higher risk of all-cause mortality 15, 30, 60, 90, 180 and 365 days after experiencing severe hypoglycaemia compared with not experiencing severe hypoglycaemia in the same time interval. The association between severe hypoglycaemia and all-cause mortality was maintained after adjustment for the following baseline characteristics: age, sex, HbA_1c, BMI, diabetes duration, insulin regimen, hepatic impairment, renal status and cardiovascular risk group.

Conclusions/interpretation

The results from these analyses demonstrate an association between severe hypoglycaemia and all-cause mortality. Furthermore, they indicate that patients who experienced severe hypoglycaemia were particularly at greater risk of death in the short term after the hypoglycaemic episode. These findings indicate that severe hypoglycaemia is associated with higher subsequent mortality; however, they cannot answer the question as to whether severe hypoglycaemia serves as a risk marker for adverse outcomes or whether there is a direct causal effect.

Trial registration

ClinicalTrials.gov NCT01959529

     

The contribution of black carbon to global ice nucleating particle concentrations relevant to mixed-phase clouds

Black carbon (BC) aerosol plays an important role in the Earth’s climate system because it absorbs solar radiation and therefore potentially warms the climate; however, BC can also act as a seed for cloud particles, which may offset much of its warming potential. If BC acts as an ice nucleating particle (INP), BC could affect the lifetime, albedo, and radiative properties of clouds containing both supercooled liquid water droplets and ice particles (mixed-phase clouds). Over 40% of global BC emissions are from biomass burning; however, the ability of biomass burning BC to act as an INP in mixed-phase cloud conditions is almost entirely unconstrained. To provide these observational constraints, we measured the contribution of BC to INP concentrations ([INP]) in real-world prescribed burns and wildfires. We found that BC contributes, at most, 10% to [INP] during these burns. From this, we developed a parameterization for biomass burning BC and combined it with a BC parameterization previously used for fossil fuel emissions. Applying these parameterizations to global model output, we find that the contribution of BC to potential [INP] relevant to mixed-phase clouds is ∼5% on a global average.

Black carbon (BC) is the primary light-absorbing aerosol in the atmosphere. Its short lifetime (days to weeks) relative to CO2 and methane makes it an intriguing target for near-term climate mitigation (1). Errors associated with BC climate forcing, however, obfuscate its efficacy as a climate mitigator. The largest contributions to BC’s forcing uncertainties are often attributed to its effects on clouds, in particular mixed-phase clouds [i.e., clouds containing supercooled cloud droplets and ice particles, (2)]. Efforts to reduce these uncertainties are hindered by the complexity of aerosol–cloud interactions (3). Particularly vexing is quantifying the abundance and identity of ice nucleating particles (INPs). INPs provide the only pathway for primary ice formation in mixed-phase clouds; however, they are rare [e.g., ∼1 in 106 particles are INPs at −20 °C (4)]. Despite their rarity, INPs influence mixed-phase cloud ice concentrations and precipitation and therefore alter cloud albedo and lifetime (5). Furthermore, the INP properties of aerosols, such as BC, will affect their own lifetime, vertical structure, and transport to climate-sensitive regions such as the Arctic (6). Despite its importance to the Earth’s climate and near-term climate mitigation strategies, the INP efficiency of BC relevant to mixed-phase clouds remains almost entirely unconstrained from direct observations, encumbering attempts to estimate BC’s impact on mixed-phase clouds in modeling studies (7).BC’s efficacy as an immersion-freezing INP (henceforth, INP will refer only to freezing by particles encapsulated within supercooled cloud droplets, termed immersion freezing and pertinent to mixed-phase cloud conditions) has been studied in the laboratory for decades, with starkly conflicting results. Early laboratory studies showed that acetylene and kerosene flame-generated soot can nucleate ice below −20 °C. (8, 9); after normalizing for surface area, these studies indicated that BC may be more ice active than the well-known INP mineral dust (10). Results from later laboratory studies were contradictory, suggesting that BC was not active as an INP above instrument limits of detection. These included soot aerosols from miniCAST soot generators, graphite spark generator soot, hydrocarbon flame-generated soot, and fullerene soot, as well as various lamp blacks and carbon blacks (11–15).Unfortunately, field study measurements of the contribution of BC to INP concentrations ([INP]) have also been inconclusive. For example, in-cloud measurements from the high-altitude observatory at Jungfraujoch, Switzerland saw that BC is enriched in ice-particle residuals and therefore may efficiently nucleate ice (16); later measurements at the same site, however, saw that BC is depleted in the ice phase, which suggests that BC does not play a significant role in mixed-phase cloud ice nucleation (17, 18).These contradictions in laboratory and field studies suggest that fuel type and combustion conditions determine the ice nucleation properties of BC. Such conditions prescribe BC’s physical and morphological properties as well as its coemitted and coagulated species. Major BC fuel types include fossil fuels and flammable biomass, and major combustion sources include diesel exhaust, residential fuel burning, prescribed burns, and wildfires (2). BC particles from fossil fuel combustion and anthropogenic pollution are not significant sources of INPs. For example, studies on diesel exhaust have shown that less than 1 in 109 BC particles are ice nucleation active at −30 °C (19). Furthermore, ambient [INP] in Beijing, China were relatively constant over several weeks despite BC concentrations varying by a factor of 30 and reaching values as high as 17.26 μg⋅m−3 (20).Elevated [INP] have been observed in biomass-burning smoke during laboratory and field studies (21–23); however, it is unclear from these studies if the INPs are actually BC. Some studies have shown that BC may be the dominant INP type in select biomass burning conditions. For example, soot particles were found to contribute up to 64% of the INPs in prescribed burns within a predominantly wiregrass understory (24). Furthermore, BC contributed up to 70% to [INP] in controlled laboratory burns of grasses (25). As biomass burning represents ∼40% of global BC emissions (2), BC from biomass burning could be a significant source of INP globally. In both of these studies, however, the overall ice-active fractions may be too low to influence [INP], even on the regional level (21). Thus, it remains unclear whether BC contributes to [INP] outside of thick plumes and on a global scale (26).Regional- and global-scale estimates of BC [INP] rely on models that can implement theory-based or empirical ice nucleation parameterizations. Using parameterizations based on BC INP activity from the acetylene and kerosene-burner soot studies, models have found that BC contributes ∼50% to [INP] in springtime low-level Arctic mixed-phase clouds (27), and 23 to 61% to global [INP] depending on dust loadings (28). Taking into account the aforementioned negative results, these modeling studies highlight that BC’s contribution to [INP] is poorly constrained and is estimated to vary from no contribution to being the most abundant INP globally.To assess the role of BC from biomass burning as an INP, we determined the contribution of refractory BC (rBC)-containing particles to [INP] from field measurements of both prescribed burns and wildfires using the single-particle soot photometer coupled to a continuous-flow diffusion chamber (SP2-CFDC) (29, 30). The SP2-CFDC selectively removes rBC from an aerosol stream and quantifies that effect on [INP]. From these burns, we found that rBC-containing particles contributed ≤10% to [INP]. From these results, we developed a surface-area normalized parameterization for BC INPs from biomass burning. The parameterization aligns well with other surface-area normalized parameterizations derived from laboratory proxies of BC and diesel exhaust BC (15, 19, 31). These parameterizations are over four orders of magnitude lower than the parameterization derived from acetylene and kerosene-burner soot studies and used in the aforementioned modeling studies. Assuming the INP characteristics of BC from the burns in this study can be extended to different biomass-burning fuel types and combustion conditions, this study strongly suggests that BC is not an efficient INP. Under this assumption, we assessed the global importance of BC as an INP by applying our parameterization to simulated biomass-burning aerosol from a global chemical transport model. A similar parameterization for diesel exhaust (19) was applied to simulated fossil fuel BC. From these treatments, we estimate that BC’s contribution to simulated, potential [INP] is only ∼5% on a global average.     

Identification of small-molecule antagonists that inhibit an activator: coactivator interaction

Phosphorylation of the cAMP response element binding protein (CREB) at Ser-133 in response to hormonal stimuli triggers cellular gene expression via the recruitment of the histone acetylase coactivator paralogs CREB binding protein (CBP) and p300 to the promoter. The NMR structure of the CREB:CBP complex, using relevant interaction domains called KID and KIX, respectively, reveals a shallow hydrophobic groove on the surface of KIX that accommodates an amphipathic helix in phospho (Ser-133) KID. Using an NMR-based screening approach on a preselected small-molecule library, we identified several compounds that bind to different surfaces on KIX. One of these, KG-501 (2-naphthol-AS-E-phosphate), targeted a surface distal to the CREB binding groove that includes Arg-600, a residue that is required for the CREB:CBP interaction. When added to live cells, KG-501 disrupted the CREB: CBP complex and attenuated target gene induction in response to cAMP agonist. These results demonstrate the ability of small molecules to interfere with second-messenger signaling cascades by inhibiting specific protein-protein interactions in the nucleus.