Glycosidase activity in the excretory-secretory products of the liver fluke, Fasciola hepatica

Fasciola hepatica secretes proteolytic enzymes and other molecules that are essential for host penetration and migration. This mixture may include enzymes required for the degradation of supramucosal gels, which defend epithelial surfaces against pathogen entry. These contain hydrated mucins that are heavily glycosylated. Excretory-secretory products (ES) from F. hepatica were examined for a range of glycosidase activities, using synthetic 4-methylumbelliferyl glycosides as substrates. The ES product contained at least 8 different glycosidase activities, the most abundant of which were β-N- acetylhexosaminidase, β-galactosidase and β-glucosidase. Alpha-fucosidase, β-glucuronidase, α-galactosidase, α-mannosidase and neuraminidase were also present. β-N- acetylhexosaminidase and β-galactosidase were present in multiple isoforms (at least 4), whereas β-glucosidase appeared to exist as one isoenzyme with a pI <3.8. All three enzymes had acidic pH optima (4.5-5.0). Ovine small intestinal mucin was degraded by ES at pH 4.5 or 7.0, with or without active cathepsin L, the major protease found in F. hepatica ES. The ability of F. hepatica ES to degrade mucin in the presence or absence of active cathepsin L suggests that cathepsin L is not essential for mucin degradation. The abundance of β-galactosidase and β-hexosaminidase in ES supports a role for these enzymes in mucin degradation

Reductions in cardiovascular, cerebrovascular, and respiratory mortality following the national Irish smoking ban: Interrupted time-series analysis

Copyright @ 2013 Stallings-Smith et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Background: Previous studies have shown decreases in cardiovascular mortality following the implementation of comprehensive smoking bans. It is not known whether cerebrovascular or respiratory mortality decreases post-ban. On March 29, 2004, the Republic of Ireland became the first country in the world to implement a national workplace smoking ban. The aim of this study was to assess the effect of this policy on all-cause and cause-specific, non-trauma mortality. Methods: A time-series epidemiologic assessment was conducted, utilizing Poisson regression to examine weekly age and gender-standardized rates for 215,878 non-trauma deaths in the Irish population, ages ≥35 years. The study period was from January 1, 2000, to December 31, 2007, with a post-ban follow-up of 3.75 years. All models were adjusted for time trend, season, influenza, and smoking prevalence. Results: Following ban implementation, an immediate 13% decrease in all-cause mortality (RR: 0.87; 95% CI: 0.76-0.99), a 26% reduction in ischemic heart disease (IHD) (RR: 0.74; 95% CI: 0.63-0.88), a 32% reduction in stroke (RR: 0.68; 95% CI: 0.54-0.85), and a 38% reduction in chronic obstructive pulmonary disease (COPD) (RR: 0.62; 95% CI: 0.46-0.83) mortality was observed. Post-ban reductions in IHD, stroke, and COPD mortalities were seen in ages ≥65 years, but not in ages 35-64 years. COPD mortality reductions were found only in females (RR: 0.47; 95% CI: 0.32-0.70). Post-ban annual trend reductions were not detected for any smoking-related causes of death. Unadjusted estimates indicate that 3,726 (95% CI: 2,305-4,629) smoking-related deaths were likely prevented post-ban. Mortality decreases were primarily due to reductions in passive smoking. Conclusions: The national Irish smoking ban was associated with immediate reductions in early mortality. Importantly, post-ban risk differences did not change with a longer follow-up period. This study corroborates previous evidence for cardiovascular causes, and is the first to demonstrate reductions in cerebrovascular and respiratory causes

Unmeasured improvement work: the lack of routinely collected, service-related data in NHS endoscopy units in England involved in "modernisation"

Contains fulltext : 70532.pdf (publisher's version ) (Open Access)BACKGROUND: The availability of routinely collected service-related endoscopy data from NHS endoscopy units has never been quantified. METHODS: This retrospective observational study asked 19 endoscopy units to submit copies of all in-house, service-related endoscopy data that had been routinely collected by the unit - Referral numbers, Activity, Number of patients waiting and Number of lost slots. Nine of the endoscopy units had previously participated in the Modernising Endoscopy Services (MES) project during 2003 to redesign their endoscopy services. These MES sites had access to additional funding and data collection software. The other ten (Control sites) had modernised independently. All data was requested in two phases and corresponded to eight specific time points between January 2003 and April 2006. RESULTS: Only eight of 19 endoscopy units submitted routinely collected, service-related data. Another site's data was collected specifically for the study. A further two units claimed to routinely collect service-related data but did not submit any to the study. The remaining eight did not collect any service-related endoscopy data routinely and liaised with their Trust for data. Of the eight sites submitting service-related data, only three were MES project sites. Of these three, the data variables collected were limited and none collected the complete set of endoscopy data variables requested. Of the other five sites, two collected all four endoscopy data types. Data for the three MES project sites went back as far as January 2003, whilst the five Control sites were only able to submit data from December 2003 onwards. CONCLUSION: There was a lack of service-related endoscopy data routinely collected by the study sites, especially those who had participated in the MES project. Without this data, NHS endoscopy services cannot have a true understanding of their services, cannot identify problems and cannot measure the impact of any changes. With the increasing pressures placed on NHS endoscopy services, the need to effectively inform redesign plans is paramount. We recommend the compulsory collection of service-related endoscopy data by all NHS endoscopy units using a standardised format with rigorous guidelines

The Importance of pH in Regulating the Function of the Fasciola hepatica Cathepsin L1 Cysteine Protease

The helminth parasite Fasciola hepatica secretes cathepsin L cysteine proteases to invade its host, migrate through tissues and digest haemoglobin, its main source of amino acids. Here we investigated the importance of pH in regulating the activity and functions of the major cathepsin L protease FheCL1. The slightly acidic pH of the parasite gut facilitates the auto-catalytic activation of FheCL1 from its inactive proFheCL1 zymogen; this process was ∼40-fold faster at pH 4.5 than at pH 7.0. Active mature FheCL1 is very stable at acidic and neutral conditions (the enzyme retained ∼45% activity when incubated at 37°C and pH 4.5 for 10 days) and displayed a broad pH range for activity peptide substrates and the protein ovalbumin, peaking between pH 5.5 and pH 7.0. This pH profile likely reflects the need for FheCL1 to function both in the parasite gut and in the host tissues. FheCL1, however, could not cleave its natural substrate Hb in the pH range pH 5.5 and pH 7.0; digestion occurred only at pH≤4.5, which coincided with pH-induced dissociation of the Hb tetramer. Our studies indicate that the acidic pH of the parasite relaxes the Hb structure, making it susceptible to proteolysis by FheCL1. This process is enhanced by glutathione (GSH), the main reducing agent contained in red blood cells. Using mass spectrometry, we show that FheCL1 can degrade Hb to small peptides, predominantly of 4–14 residues, but cannot release free amino acids. Therefore, we suggest that Hb degradation is not completed in the gut lumen but that the resulting peptides are absorbed by the gut epithelial cells for further processing by intracellular di- and amino-peptidases to free amino acids that are distributed through the parasite tissue for protein anabolism

Modified mallampati classification as a clinical predictor of peroral esophagogastroduodenoscopy tolerance

<p>Abstract</p> <p>Background</p> <p>Unsedated esophagogastroduodenoscopy (EGD) is simpler and safer than sedated EGD; however, approximately 40% of patients cannot tolerate it. Early identification of patients likely to poorly tolerate unsedated EGD is valuable for improving compliance. The modified Mallampati classification (MMC) has been used to evaluate difficult tracheal intubation and laryngoscope insertion. We tried to assess the efficacy of MMC to predict the tolerance of EGD in unsedated patients.</p> <p>Methods</p> <p>Two hundred patients who underwent an unsedated diagnostic EGD were recruited. They were stratified according to the view of the oropharynx as either MMC class I + II (good view) or class III + IV (poor view). EGD tolerance was assessed in three ways: gag reflex by endoscopist assessment, patient satisfaction by interview, and the degree of change in vital signs.</p> <p>Results</p> <p>MMC was significantly correlated to gag reflex (<it>P </it>< 0.001), patient satisfaction (<it>P </it>= 0.028), and a change of vital signs (<it>P </it>= 0.024). Patients in the poor view group had a 3.87-fold increased risk of gag reflex (<it>P </it>< 0.001), a 1.78-fold increased risk of unsatisfaction (<it>P </it>= 0.067), and a 1.96-fold increased risk of a change in vital signs (<it>P </it>= 0.025) compared to those in the good view group.</p> <p>Conclusions</p> <p>MMC appears to be a clinically useful predictor of EGD tolerance. Patients with poor view of oropharynx by MMC criteria may be candidates for sedated or transnasal EGD.</p

Pulmonary Arterial Stent Implantation in an Adult with Williams Syndrome

We report a 38-year-old patient who presented with pulmonary hypertension and right ventricular dysfunction due to pulmonary artery stenoses as a manifestation of Williams syndrome, mimicking chronic thromboembolic pulmonary hypertension. The patient was treated with balloon angioplasty and stent implantation. Short-term follow-up showed a good clinical result with excellent patency of the stents but early restenosis of the segments in which only balloon angioplasty was performed. These stenoses were subsequently also treated successfully by stent implantation. Stent patency was observed 3 years after the first procedure

Immigrant status and increased risk of heart failure: the role of hypertension and life-style risk factors

<p>Abstract</p> <p>Background</p> <p>Studies from Sweden have reported association between immigrant status and incidence of cardiovascular diseases. The nature of this relationship is unclear. We investigated the relationship between immigrant status and risk of heart failure (HF) hospitalization in a population-based cohort, and to what extent this is mediated by hypertension and life-style risk factors. We also explored whether immigrant status was related to case-fatality after HF.</p> <p>Methods</p> <p>26,559 subjects without history of myocardial infarction (MI), stroke or HF from the community-based Malmö Diet and Cancer (MDC) cohort underwent a baseline examination during 1991-1996. Incidence of HF hospitalizations was monitored during a mean follow-up of 15 years.</p> <p>Results</p> <p>3,129 (11.8%) subjects were born outside Sweden. During follow-up, 764 subjects were hospitalized with HF as primary diagnosis, of whom 166 had an MI before or concurrent with the HF. After adjustment for potential confounding factors, the hazard ratios (HR) for foreign-born were 1.37 (95% CI: 1.08-1.73, <it>p </it>= 0.009) compared to native Swedes, for HF without previous MI. The results were similar in a secondary analysis without censoring at incident MI. There was a significant interaction (<it>p </it>< 0.001) between immigrant status and waist circumference (WC), and the increased HF risk was limited to immigrants with high WC. Although not significant foreign-born tended to have lower one-month and one-year mortality after HF.</p> <p>Conclusions</p> <p>Immigrant status was associated with long-term risk of HF hospitalization, independently of hypertension and several life-style risk factors. A significant interaction between WC and immigrant status on incident HF was observed.</p

Assessment of pre-industrial to present-day anthropogenic climate forcing in UKESM1

Quantifying forcings from anthropogenic perturbations to the Earth system (ES) is important for understanding changes in climate since the pre-industrial (PI) period. Here, we quantify and analyse a wide range of present-day (PD) anthropogenic effective radiative forcings (ERFs) with the UK's Earth System Model (ESM), UKESM1, following the protocols defined by the Radiative Forcing Model Intercomparison Project (RFMIP) and the Aerosol and Chemistry Model Intercomparison Project (AerChemMIP). In particular, quantifying ERFs that include rapid adjustments within a full ESM enables the role of various chemistry–aerosol–cloud interactions to be investigated. Global mean ERFs for the PD (year 2014) relative to the PI (year 1850) period for carbon dioxide (CO2), nitrous oxide (N2O), ozone-depleting substances (ODSs), and methane (CH4) are 1.89 ± 0.04, 0.25 ± 0.04, −0.18 ± 0.04, and 0.97 ±  0.04 W m−2, respectively. The total greenhouse gas (GHG) ERF is 2.92 ± 0.04 W m−2. UKESM1 has an aerosol ERF of −1.09 ± 0.04 W m−2. A relatively strong negative forcing from aerosol–cloud interactions (ACI) and a small negative instantaneous forcing from aerosol–radiation interactions (ARI) from sulfate and organic carbon (OC) are partially offset by a substantial forcing from black carbon (BC) absorption. Internal mixing and chemical interactions imply that neither the forcing from ARI nor ACI is linear, making the aerosol ERF less than the sum of the individual speciated aerosol ERFs. Ozone (O3) precursor gases consisting of volatile organic compounds (VOCs), carbon monoxide (CO), and nitrogen oxides (NOx), but excluding CH4, exert a positive radiative forcing due to increases in O3. However, they also lead to oxidant changes, which in turn cause an indirect aerosol ERF. The net effect is that the ERF from PD–PI changes in NOx emissions is negligible at 0.03 ± 0.04 W m−2, while the ERF from changes in VOC and CO emissions is 0.33 ± 0.04 W m−2. Together, aerosol and O3 precursors (called near-term climate forcers (NTCFs) in the context of AerChemMIP) exert an ERF of −1.03 ± 0.04 W m−2, mainly due to changes in the cloud radiative effect (CRE). There is also a negative ERF from land use change (−0.17 ± 0.04 W m−2). When adjusted from year 1850 to 1700, it is more negative than the range of previous estimates, and is most likely due to too strong an albedo response. In combination, the net anthropogenic ERF (1.76 ± 0.04 W m−2) is consistent with other estimates. By including interactions between GHGs, stratospheric and tropospheric O3, aerosols, and clouds, this work demonstrates the importance of ES interactions when quantifying ERFs. It also suggests that rapid adjustments need to include chemical as well as physical adjustments to fully account for complex ES interactions

Identification of molecular mechanisms for cellular drug resistance by combining drug activity and gene expression profiles

Acquired drug resistance is a major problem in cancer treatment. To explore the genes involved in chemosensitivity and resistance, 10 human tumour cell lines, including parental cells and resistant subtypes selected for resistance against doxorubicin, melphalan, teniposide and vincristine, were profiled for mRNA expression of 7400 genes using cDNA microarray technology. The drug activity of 66 cancer agents was evaluated on the cell lines, and correlations between drug activity and gene expression were calculated and ranked. Hierarchical clustering of drugs based on their drug–gene correlations yielded clusters of drugs with similar mechanism of action. Genes correlated with drug sensitivity and resistance were imported into the PathwayAssist software to identify putative molecular pathways involved. A substantial number of both proapoptotic and antiapoptotic genes such as signal transducer and activator of transcription 1, mitogen-activated protein kinase 1 and focal adhesion kinase were found to be associated to drug resistance, whereas genes linked to cell cycle control and proliferation, such as cell division cycle 25A and signal transducer of activator of transcription 5A, were associated to general drug sensitivity. The results indicate that combined information from drug activity and gene expression in a resistance-based cell line panel may provide new knowledge of the genes involved in anticancer drug resistance and become a useful tool in drug development