Experimental Study of Amphibolite-Basalt (SiO2-AlO3-CaO-Fe2O3) Glasses for Glass-Ceramic Materials Production.

The paper presents research on multicomponent glasses obtained from natural and secondary raw materials, i.e., basalt, amphibolite, and cullet. The raw materials were used as potential sets to produce mineral fibres or glass-ceramic materials. FTIR spectroscopy and XRD studies were carried out to identify the composition of the phase type in the glass sets. The results were supported by SEM-EDS microstructural studies of the obtained materials. The ability of the melts to crystallize and their basic properties required in producing mineral fibres, i.e., the hardness and the acidity modulus, were also determined. In the glass samples after the crystallization process, the spectroscopic studies revealed an increase in the half-width of the band at 1200-800 cm-1 and splitting at the values of about 870 cm-1 and 970 cm-1. These changes probably indicate the formation of pyroxene-type crystalline phases. Moreover, based on the XRD results, it was confirmed that the obtained materials were fully amorphous. After annealing at 800 °C for 2 h, the materials show a small proportion of crystalline phases. For the materials annealed at higher temperatures, clear peaks from the crystalline phases were represented mainly by pyroxenes. The proportion of crystalline phases in the samples was also found to rise with increasing temperature, and the hardness values for the basalt glasses and glasses after crystallization rose from 753 to 946 HV0.05. Such an effect positively affects the properties of the obtained glass-ceramic materials based on the proposed sets. However, in the case of mineral fibres, crystallization at early 2 h at 800 °C can be a disadvantageous feature from the point of view of their application because crystalline phases can lead to fibre damage after a short period of operation; this will be confirmed in this study.

Experimental vs. Theoretical Viscosity Determination of Aluminosilicate Glasses.

The paper presents the results of studies on the viscosity of the glass mass in various temperature ranges, determining the basic technological parameter, very important from the point of view of melting and forming. For this purpose, six sets based on natural raw materials such as basalt, dolomite, and amphibolite, modified with different amounts of float glass cullet, were melted. The melting process was carried out in an electric furnace at the temperature of 1450 °C for 2 h. Using the dilatometric method, high-temperature microscopy and theoretical calculation methods, the viscosity of the produced glasses was determined in various temperature ranges. Comparative analyses of the employed methods were carried out. The significance of the applied calculation methods for aluminosilicate glasses depending on the basic chemical composition of the glasses was presented. The relationship between the manner of incorporating amphoteric ions Al3+, Fe3+ and Mg2+ into the glass structure and the change in viscosity in the temperature range corresponding to the working point range at 104 [dPa·s] viscosity and the relaxation range-Tg temperature at 1013 [dPa·s] viscosity was justified. It was justified that in order to plot the viscosity curve with the correct slope in the forming range for aluminosilicate glasses, it is appropriate to use the two-point method based on the fixed viscosity points of 104 [dPa·s] and 1013 [dPa·s].

Synergy between health technology assessments and clinical guidelines for multiple sclerosis.

Decision-making for reimbursement and clinical guidelines (CGs) serves different purposes although the decision-criteria and required evidence largely overlap. This study aimed to assess similarities and discrepancies between health technology assessment (HTA) reports as compared to CGs for multiple sclerosis (MS) medicines. All HTA reports and corresponding CGs for MS from the UK, France, Germany, the Netherlands, Poland, Sweden, and the European Union were assessed to identify synergies in recommendations for MS medicines (approved 1995-2020). A content analysis of HTA reports and CGs was performed to identify similarities and discrepancies in wording of treatment recommendations across documents. We assessed 132 HTA reports and 9 CGs for 16 MS treatments. Final recommendations for reimbursement and inclusion in CGs were mostly similar (90%), albeit with considerable differences in treatment lines and subindications. Since 2010, HTA reports refer to the use of CGs in 42% (55/132) and to consultations with clinicians in 43% (57/132) of cases. Six of nine CGs referred to HTA reports and two referred to HTA consultations, in one case having a formal relation to the HTA organization. CGs referenced pharmacoeconomic studies (4/9) for costs and cost-effectiveness. To date, not all new HTA recommendations for MS treatments are included in CGs. Some synergy exists between treatment recommendations in HTA reports and CGs, although discrepancies were seen in timelines and in recommended treatment lines and subindications. More stakeholder dialogue and/or consultation of each other's publications may further improve synergy, facilitate transparency, and enhance patient access.

The Effect of Pr Doping Contents on the Structural, Microstructure and Dielectric Properties of BaBi2Nb2O9 Aurivillius Ceramics.

Aurivillius BaBi2Nb2O9 and Ba1-xPrxBi2Nb2O9 ceramics were successfully synthesized by a simple solid state reaction method. Ceramics were prepared from reactants: Nb2O5, Bi2O3, BaCO3 and Pr2O3. The microstructure, structure, chemical composition, and dielectric properties of the obtained materials were examined. Dielectric properties were investigated in a wide range of temperatures (T = 20-500 °C) and frequencies (f = 0.1 kHz-1 MHz). The obtained ceramic materials belong to the group of layered perovskites, crystallizing in a tetragonal structure with the space group I4/mmm. Modification of the barium niobate compound with praseodymium ions influenced its dielectric properties and introducing a small concentration of the dopant ion causes a slight increase in the value of electric permittivity and shifts its maximum towards higher temperatures.

Application of Statistical Methods in Predicting the Properties of Glass-Ceramic Materials Obtained from Inorganic Solid Waste.

This paper uses mathematical methods as the basic tool at the stage of experiment planning. The importance of research programming applications was shown using the theory of experiments and the STATISTICA software. The method of experiment planning used in the case of studying the properties of a mixture, depending on its composition, features considerable complexity. The aim of the statistical analysis was to determine the influence of variable chemical composition of waste materials on selected properties of glass-ceramic materials. A statistical approach to multicomponent systems, such as ceramic sets, enables the selection of appropriate amounts of raw materials through the application of 'a plan for mixtures'. To utilize the raw waste materials, e.g., slags from a solid waste incinerator, fly or bottom ashes, in the modeling of new materials, a mathematical relationship was developed, which enables estimating, based on the waste chemical composition, selected technological and practical properties of the glass so as to obtain a material featuring the required technological-practical parameters. For the obtained glasses, a comparative analysis of the experimentally and computationally determined properties was carried out: transformation temperature, liquidus temperature, density, and thermal expansion coefficient. The obtained high theoretical approximation (at the level of determination correlation coefficient R2 > 0.8) confirms the suitability of the polynomial model for mixtures for applications in the design of new glass-ceramic products.

Influence of Sandblasting and Chemical Etching on Titanium 99.2-Dental Porcelain Bond Strength.

The metal-ceramic interface requires proper surface preparation of both metal and ceramic substrates. This process is complicated by the differences in chemical bonds and physicochemical properties that characterise the two materials. However, adequate bond strength at the interface and phase composition of the titanium-bioceramics system is essential for the durability of dental implants and improving the substrates' functional properties. In this paper, the authors present the results of a study determining the effect of mechanical and chemical surface treatment (sandblasting and etching) on the strength and quality of the titanium-low-fusing dental porcelain bond. To evaluate the strength of the metal-ceramic interface, the authors performed mechanical tests (three-point bending) according to EN ISO 9693 standard, microscopic observations (SEM-EDS), and Raman spectroscopy studies. The results showed that depending on the chemical etching medium used, different bond strength values and failure mechanisms of the metal-ceramic system were observed. The analyzed samples met the requirements of EN ISO 9693 for metal-ceramic systems and received strength values above 25 MPa. Higher joint strength was obtained for the samples after sandblasting and chemical etching compared to the samples subjected only to sandblasting.

Assessment of significant benefit for orphan medicinal products by European regulators may support subsequent relative effectiveness assessments by health technology assessment organizations.

To maintain orphan drug status at the time of market authorization, orphan medicinal products (OMPs) need to be assessed for all criteria, including significant benefit, by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). Subsequently, health technology assessment (HTA) organizations evaluate the same OMPs in their relative effectiveness assessments (REAs). This review investigates the similarities and differences between the two frameworks for six HTA organizations, including the European Network for HTA. We discuss differences between both assessment frameworks within five domains (clinical evidence used, patient population, intervention, comparators, and outcome measures) for all drugs. Five illustrative cases studies were selected for a qualitative review.

Structural and microstructural aspects of asbestos-cement waste vitrification.

The main goal of the work was to evaluate the vitrification process of asbestos-cement waste (ACW). A mixture of 50 wt% ACW and 50 wt% glass cullet was melted in an electric furnace at 1400 °C for 90 min and then cast into a steel mold. The vitrified product was subjected to annealing. Optical microscopy, scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) were used to evaluate the effects of the vitrification. The chemical constitution of the material before and after the vitrification process was also analyzed. It was found that the vitrified product has an amorphous structure in which the components of asbestos-cement waste are incorporated. MIR spectroscopy showed that the absorption bands of chrysotile completely disappeared after the vitrification process. The results of the spectroscopic studies were confirmed by X-ray studies - no diffraction reflections from the chrysotile crystallographic planes were observed. As a result of the treatment, the fibrous asbestos construction, the main cause of its pathogenic properties, completely disappeared. The vitrified material was characterized by higher resistance to ion leaching in an aquatic environment than ACW and a smaller volume of nearly 72% in relation to the apparent volume of the substrates. The research has confirmed the high effectiveness of vitrification in neutralizing hazardous waste containing asbestos and the FT-IR spectroscopy was found to be useful to identify asbestos varieties and visualizing changes caused by the vitrification process. The work also presents the current situation regarding the utilization of asbestos-containing products.

HTA IN CENTRAL-EASTERN-SOUTHERN EUROPE: FINDING ITS WAY TO HEALTH POLICY.

The number of publications on health technology assessment (HTA) from Central, Eastern, and Southern Europe (CESE countries) is still low compared with the north and west of Europe. It is not surprising, as the idea of HTA originated from high-income Western economies and was afterward adopted by the south-eastern part of Europe, which mostly consists of middle-income countries. These CESE countries, with less capacity and experience with HTA processes, must deal with even tougher decisions on financing health technologies than north-western Europe. There may even be a lack of confidence to open discussions on their specific needs for HTA.

SOME ADDITIONAL THOUGHTS ON FORTHCOMING AMENDMENTS TO HTA IN POLAND.

In reference to the article A Decade of Health Technology Assessment in Poland by I. Lipska et al. (1), I would like to provide you with some comments and additional information on the changes in reimbursement policies in the Polish healthcare system currently taking place, which is likely to lead to increased number of health technology assessments (HTAs) of medical devices (MDs).

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation. This is an update of a review previously published in 2009 and 2015. OBJECTIVES: To compare the effect of home-based and supervised centre-based cardiac rehabilitation on mortality and morbidity, exercise-capacity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease. SEARCH METHODS: We updated searches from the previous Cochrane Review by searching the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid), Embase (Ovid), PsycINFO (Ovid) and CINAHL (EBSCO) on 21 September 2016. We also searched two clinical trials registers as well as previous systematic reviews and reference lists of included studies. No language restrictions were applied. SELECTION CRITERIA: We included randomised controlled trials, including parallel group, cross-over or quasi-randomised designs) that compared centre-based cardiac rehabilitation (e.g. hospital, gymnasium, sports centre) with home-based programmes in adults with myocardial infarction, angina, heart failure or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two review authors independently screened all identified references for inclusion based on pre-defined inclusion criteria. Disagreements were resolved through discussion or by involving a third review author. Two authors independently extracted outcome data and study characteristics and assessed risk of bias. Quality of evidence was assessed using GRADE principles and a Summary of findings table was created. MAIN RESULTS: We included six new studies (624 participants) for this update, which now includes a total of 23 trials that randomised a total of 2890 participants undergoing cardiac rehabilitation. Participants had an acute myocardial infarction, revascularisation or heart failure. A number of studies provided insufficient detail to enable assessment of potential risk of bias, in particular, details of generation and concealment of random allocation sequencing and blinding of outcome assessment were poorly reported.No evidence of a difference was seen between home- and centre-based cardiac rehabilitation in clinical primary outcomes up to 12 months of follow up: total mortality (relative risk (RR) = 1.19, 95% CI 0.65 to 2.16; participants = 1505; studies = 11/comparisons = 13; very low quality evidence), exercise capacity (standardised mean difference (SMD) = -0.13, 95% CI -0.28 to 0.02; participants = 2255; studies = 22/comparisons = 26; low quality evidence), or health-related quality of life up to 24 months (not estimable). Trials were generally of short duration, with only three studies reporting outcomes beyond 12 months (exercise capacity: SMD 0.11, 95% CI -0.01 to 0.23; participants = 1074; studies = 3; moderate quality evidence). However, there was evidence of marginally higher levels of programme completion (RR 1.04, 95% CI 1.00 to 1.08; participants = 2615; studies = 22/comparisons = 26; low quality evidence) by home-based participants. AUTHORS' CONCLUSIONS: This update supports previous conclusions that home- and centre-based forms of cardiac rehabilitation seem to be similarly effective in improving clinical and health-related quality of life outcomes in patients after myocardial infarction or revascularisation, or with heart failure. This finding supports the continued expansion of evidence-based, home-based cardiac rehabilitation programmes. The choice of participating in a more traditional and supervised centre-based programme or a home-based programme may reflect local availability and consider the preference of the individual patient. Further data are needed to determine whether the effects of home- and centre-based cardiac rehabilitation reported in the included short-term trials can be confirmed in the longer term and need to consider adequately powered non-inferiority or equivalence study designs.

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: Cardiovascular disease is the most common cause of death globally. Traditionally, centre-based cardiac rehabilitation programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation. This is an update of a review originally published in 2009. OBJECTIVES: To compare the effect of home-based and supervised centre-based cardiac rehabilitation on mortality and morbidity, health-related quality of life, and modifiable cardiac risk factors in patients with heart disease. SEARCH METHODS: To update searches from the previous Cochrane review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 9, 2014), MEDLINE (Ovid, 1946 to October week 1 2014), EMBASE (Ovid, 1980 to 2014 week 41), PsycINFO (Ovid, 1806 to October week 2 2014), and CINAHL (EBSCO, to October 2014). We checked reference lists of included trials and recent systematic reviews. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared centre-based cardiac rehabilitation (e.g. hospital, gymnasium, sports centre) with home-based programmes in adults with myocardial infarction (MI), angina, heart failure or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the eligibility of the identified trials and data were extracted by a single author and checked by a second. Authors were contacted where possible to obtain missing information. MAIN RESULTS: Seventeen trials included a total of 2172 participants undergoing cardiac rehabilitation following an acute MI or revascularisation, or with heart failure. This update included an additional five trials on 345 patients with heart failure. Authors of a number of included trials failed to give sufficient detail to assess their potential risk of bias, and details of generation and concealment of random allocation sequence were particularly poorly reported. In the main, no difference was seen between home- and centre-based cardiac rehabilitation in outcomes up to 12 months of follow up: mortality (relative risk (RR) = 0.79, 95% confidence interval (CI) 0.43 to 1.47, P = 0.46, fixed-effect), cardiac events (data not poolable), exercise capacity (standardised mean difference (SMD) = -0.10, 95% CI -0.29 to 0.08, P = 0.29, random-effects), modifiable risk factors (total cholesterol: mean difference (MD) = 0.07 mmol/L, 95% CI -0.24 to 0.11, P = 0.47, random-effects; low density lipoprotein cholesterol: MD = -0.06 mmol/L, 95% CI -0.27 to 0.15, P = 0.55, random-effects; systolic blood pressure: mean difference (MD) = 0.19 mmHg, 95% CI -3.37 to 3.75, P = 0.92, random-effects; proportion of smokers at follow up (RR = 0.98, 95% CI 0.79 to 1.21, P = 0.83, fixed-effect), or health-related quality of life (not poolable). Small outcome differences in favour of centre-based participants were seen in high density lipoprotein cholesterol (MD = -0.07 mmol/L, 95% CI -0.11 to -0.03, P = 0.001, fixed-effect), and triglycerides (MD = -0.18 mmol/L, 95% CI -0.34 to -0.02, P = 0.03, fixed-effect, diastolic blood pressure (MD = -1.86 mmHg; 95% CI -0.76 to -2.95, P = 0.0009, fixed-effect). In contrast, in home-based participants, there was evidence of a marginally higher levels of programme completion (RR = 1.04, 95% CI 1.01 to 1.07, P = 0.009, fixed-effect) and adherence to the programme (not poolable). No consistent difference was seen in healthcare costs between the two forms of cardiac rehabilitation. AUTHORS' CONCLUSIONS: This updated review supports the conclusions of the previous version of this review that home- and centre-based forms of cardiac rehabilitation seem to be equally effective for improving the clinical and health-related quality of life outcomes in low risk patients after MI or revascularisation, or with heart failure. This finding, together with the absence of evidence of important differences in healthcare costs between the two approaches, supports the continued expansion of evidence-based, home-based cardiac rehabilitation programmes. The choice of participating in a more traditional and supervised centre-based programme or a home-based programme should reflect the preference of the individual patient. Further data are needed to determine whether the effects of home- and centre-based cardiac rehabilitation reported in these short-term trials can be confirmed in the longer term. A number of studies failed to give sufficient detail to assess their risk of bias.

Fidelity consequences of the impaired interaction between DNA polymerase epsilon and the GINS complex.

DNA polymerase epsilon interacts with the CMG (Cdc45-MCM-GINS) complex by Dpb2p, the non-catalytic subunit of DNA polymerase epsilon. It is postulated that CMG is responsible for targeting of Pol ɛ to the leading strand. We isolated a mutator dpb2-100 allele which encodes the mutant form of Dpb2p. We showed previously that Dpb2-100p has impaired interactions with Pol2p, the catalytic subunit of Pol ɛ. Here, we present that Dpb2-100p has strongly impaired interaction with the Psf1 and Psf3 subunits of the GINS complex. Our in vitro results suggest that while dpb2-100 does not alter Pol ɛ's biochemical properties including catalytic efficiency, processivity or proofreading activity - it moderately decreases the fidelity of DNA synthesis. As the in vitro results did not explain the strong in vivo mutator effect of the dpb2-100 allele we analyzed the mutation spectrum in vivo. The analysis of the mutation rates in the dpb2-100 mutant indicated an increased participation of the error-prone DNA polymerase zeta in replication. However, even in the absence of Pol ζ activity the presence of the dpb2-100 allele was mutagenic, indicating that a significant part of mutagenesis is Pol ζ-independent. A strong synergistic mutator effect observed for transversions in the triple mutant dpb2-100 pol2-4 rev3Δ as compared to pol2-4 rev3Δ and dpb2-100 rev3Δ suggests that in the presence of the dpb2-100 allele the number of replication errors is enhanced. We hypothesize that in the dpb2-100 strain, where the interaction between Pol ɛ and GINS is weakened, the access of Pol δ to the leading strand may be increased. The increased participation of Pol δ on the leading strand in the dpb2-100 mutant may explain the synergistic mutator effect observed in the dpb2-100 pol3-5DV double mutant.

Monohydroxylated metabolites of the K2 synthetic cannabinoid JWH-073 retain intermediate to high cannabinoid 1 receptor (CB1R) affinity and exhibit neutral antagonist to partial agonist activity.

K2 and several similar purported "incense products" spiked with synthetic cannabinoids are abused as cannabis substitutes. We hypothesized that metabolism of JWH-073, a prevalent cannabinoid found in K2, contributes to toxicity associated with K2 use. Competition receptor binding studies and G-protein activation assays, both performed by employing mouse brain homogenates, were used to determine the affinity and intrinsic activity, respectively, of potential monohydroxylated (M1, M3-M5) and monocarboxylated (M6) metabolites at cannabinoid 1 receptors (CB1Rs). Surprisingly, M1, M4 and M5 retain nanomolar affinity for CB1Rs, while M3 displays micromolar affinity and M6 does not bind to CB1Rs. JWH-073 displays equivalent efficacy to that of the CB1R full agonist CP-55,940, while M1, M3, and M5 act as CB1R partial agonists, and M4 shows little or no intrinsic activity. Further in vitro investigation by Schild analysis revealed that M4 acts as a competitive neutral CB1R antagonist (K(b)∼40nM). In agreement with in vitro studies, M4 also demonstrates CB1R antagonism in vivo by blunting cannabinoid-induced hypothermia in mice. Interestingly, M4 does not block agonist-mediated responses of other measures in the cannabinoid tetrad (e.g., locomotor suppression, catalepsy or analgesia). Finally, also as predicted by in vitro results, M1 exhibits agonist activity in vivo by inducing significant hypothermia and suppression of locomotor activity in mice. In conclusion, the present study indicates that further work examining the physiological effects of synthetic cannabinoid metabolism is warranted. Such a complex mix of metabolically produced CB1R ligands may contribute to the adverse effect profile of JWH-073-containing products.

Home-based versus centre-based cardiac rehabilitation.

BACKGROUND: The burden of cardiovascular disease world-wide is one of great concern to patients and health care agencies alike. Traditionally centre-based cardiac rehabilitation (CR) programmes are offered to individuals after cardiac events to aid recovery and prevent further cardiac illness. Home-based cardiac rehabilitation programmes have been introduced in an attempt to widen access and participation. OBJECTIVES: To determine the effectiveness of home-based cardiac rehabilitation programmes compared with supervised centre-based cardiac rehabilitation on mortality and morbidity, health-related quality of life and modifiable cardiac risk factors in patients with coronary heart disease. SEARCH STRATEGY: We updated the search of a previous review by searching the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2007, Issue 4), MEDLINE, EMBASE and CINAHL from 2001 to January 2008. We checked reference lists and sought advice from experts. No language restrictions were applied. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared centre-based cardiac rehabilitation (e.g. hospital, gymnasium, sports centre) with home-based programmes, in adults with myocardial infarction, angina, heart failure or who had undergone revascularisation. DATA COLLECTION AND ANALYSIS: Studies were selected independently by two reviewers, and data extracted by a single reviewer and checked by a second one. Authors were contacted where possible to obtain missing information. MAIN RESULTS: Twelve studies (1,938 participants) met the inclusion criteria. The majority of studies recruited a lower risk patient following an acute myocardial infarction (MI) and revascularisation. There was no difference in outcomes of home- versus centre-based cardiac rehabilitation in mortality risk ratio (RR) was1.31 (95% confidence interval (C) 0.65 to 2.66), cardiac events, exercise capacity standardised mean difference (SMD) -0.11 (95% CI -0.35 to 0.13), as well as in modifiable risk factors (systolic blood pressure; diastolic blood pressure; total cholesterol; HDL-cholesterol; LDL-cholesterol) or proportion of smokers at follow up or health-related quality of life. There was no consistent difference in the healthcare costs of the two forms of cardiac rehabilitation. AUTHORS' CONCLUSIONS: Home- and centre-based cardiac rehabilitation appear to be equally effective in improving the clinical and health-related quality of life outcomes in acute MI and revascularisation patients. This finding, together with an absence of evidence of difference in healthcare costs between the two approaches, would support the extension of home-based cardiac rehabilitation programmes such as the Heart Manual to give patients a choice in line with their preferences, which may have an impact on uptake of cardiac rehabilitation in the individual case.

Home based versus centre based cardiac rehabilitation: Cochrane systematic review and meta-analysis.

OBJECTIVE: To compare the effect of home based and supervised centre based cardiac rehabilitation on mortality and morbidity, health related quality of life, and modifiable cardiac risk factors in patients with coronary heart disease. DESIGN: Systematic review. DATA SOURCES: Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, Medline, Embase, CINAHL, and PsycINFO, without language restriction, searched from 2001 to January 2008. REVIEW METHODS: Reference lists checked and advice sought from authors. Included randomised controlled trials that compared centre based cardiac rehabilitation with home based programmes in adults with acute myocardial infarction, angina, or heart failure or who had undergone coronary revascularisation. Two reviewers independently assessed the eligibility of the identified trials and extracted data independently. Authors were contacted when possible to obtain missing information. RESULTS: 12 studies (1938 participants) were included. Most studies recruited patients with a low risk of further events after myocardial infarction or revascularisation. No difference was seen between home based and centre based cardiac rehabilitation in terms of mortality (relative risk 1.31, 95% confidence interval 0.65 to 2.66), cardiac events, exercise capacity (standardised mean difference -0.11, -0.35 to 0.13), modifiable risk factors (weighted mean difference systolic blood pressure (0.58 mm Hg, -3.29 mm Hg to 4.44 mm Hg), total cholesterol (-0.13 mmol/l, -0.31 mmol/l to 0.05 mmol/l), low density lipoprotein cholesterol (-0.15 mmol/l, -0.31 mmol/l to 0.01 mmol/l), or relative risk for proportion of smokers at follow-up (0.98, 0.73 to 1.31)), or health related quality of life, with the exception of high density lipoprotein cholesterol (-0.06, -0.11 to -0.02) mmol/l). In the home based participants, there was evidence of superior adherence. No consistent difference was seen in the healthcare costs of the two forms of cardiac rehabilitation. CONCLUSIONS: Home and centre based forms of cardiac rehabilitation seem to be equally effective in improving clinical and health related quality of life outcomes in patients with a low risk of further events after myocardial infarction or revascularisation. This finding, together with the absence of evidence of differences in patients' adherence and healthcare costs between the two approaches, supports the further provision of evidence based, home based cardiac rehabilitation programmes such as the "Heart Manual." The choice of participating in a more traditional supervised centre based or evidence based home based programme should reflect the preference of the individual patient.

Characterization of human hepatic and extrahepatic UDP-glucuronosyltransferase enzymes involved in the metabolism of classic cannabinoids.

Tetrahydrocannabinol (Delta(9)-THC), the primary psychoactive ingredient in marijuana, is subject to cytochrome P450 oxidation and subsequent UDP-glucuronosyltransferase (UGT)-dependent glucuronidation. Many studies have shown that CYP2C9 and CYP3A4 are the primary enzymes responsible for these cytochrome P450-dependent oxidations, but little work has been done to characterize phase II metabolic pathways. In this study, we test the hypothesis that there are specific human UGTs responsible for classic cannabinoid metabolism. The activities of 12 human recombinant UGTs toward classic cannabinoids [cannabinol (CBN), cannabidiol (CBD), (-)-Delta(8)-THC, (-)-Delta(9)-THC, (+/-)-11-hydroxy-Delta(9)-THC (THC-OH), and (-)-11-nor-9-carboxy-Delta(9)-THC (THC-COOH)] were evaluated using high-performance liquid chromatography-tandem mass spectrometry and labeling assays. Despite activity by UGT1A1, 1A3, 1A8, 1A9, 1A10, and 2B7 toward CBN, CBD, THC-OH, and THC-COOH, only selected UGTs demonstrate sufficient activity for further characterization of steady-state kinetics. CBN was the most recognized substrate as evidenced by activities from hepatic UGT1A9 and extrahepatic UGT1A7, UGT1A8, and UGT1A10. These results may reflect the introduction of an aromatic ring to Delta(9)-THC, leading to favorable pi stacking with phenylalanines in the UGT active site. Likewise, oxidation of Delta(9)-THC to THC-OH results in UGT1A9 and UGT1A10 activity toward the cannabinoid. Further oxidation to THC-COOH surprisingly leads to a loss in metabolism by UGT1A9 and UGT1A10, while creating a substrate recognized by UGT1A1 and UGT1A3. The resulting glucuronide of THC-COOH is the main metabolite found in urine, and thus these hepatic enzymes play a critical role in the metabolic clearance of cannabinoids. Taken together, glucuronidation of cannabinoids depends on upstream processing including enzymes such as CYP2C9 and CYP3A4.

Identification of hydroxywarfarin binding site in human UDP glucuronosyltransferase 1a10: phenylalanine90 is crucial for the glucuronidation of 6- and 7-hydroxywarfarin but not 8-hydroxywarfarin.

Recent studies show that the extrahepatic human UDP-glucuronosyltransferase (UGT)1A10 is capable of phase II glucuronidation of several major cytochrome P450 metabolites of warfarin (i.e., 6-, 7-, and 8-hydroxywarfarin). This study expands on this finding by testing the hypothesis that the UGT1A10 F(90)-M(91)-V(92)-F(93) amino acid motif is important for proper recognition and conjugation of hydroxywarfarin derivatives. Site-directed mutagenesis studies demonstrate that F(90) is critical for 6- and 7-hydroxywarfarin glucuronidation based on the complete loss of enzymatic activity toward these substrates. In contrast, V92A and F93A mutants lead to higher rates of substrate turnover, have minimum changes in K(m) values, and demonstrate substrate inhibition kinetics. A completely different activity profile is observed in the presence of 8-hydroxywarfarin. No change in either activity or affinity is observed with F90A when compared with wild type, whereas F93A and V92A mutants show increases in V(max) (3- and 10-fold, respectively) and minimum changes in K(m). Liquid chromatographytandem mass spectrometry studies show that enzymatic products produced by mutants are identical to wild-type products produced in the presence of 6-, 7-, and 8-hydroxywarfarin. Because F(90) is not critical for the glucuronidation of 8-hydroxywarfarin, there is likely another, different amino acid responsible for binding this compound. In addition, an inhibitory binding site may be formed in the presence of 6- and 7-hydroxywarfarin. This new knowledge and continued characterization of the hydroxywarfarin binding site(s) for UGT1A10 will help elucidate the molecular mechanism of hydroxywarfarin glucuronidation and potentially result in more effective anticoagulant therapies.

Glucuronidation of monohydroxylated warfarin metabolites by human liver microsomes and human recombinant UDP-glucuronosyltransferases.

Our understanding of human phase II metabolic pathways which facilitate detoxification and excretion of warfarin (Coumadin) is limited. The goal of this study was to test the hypothesis that there are specific human hepatic and extrahepatic UDP-glucuronosyltransferase (UGT) isozymes, which are responsible for conjugating warfarin and hydroxylated metabolites of warfarin. Glucuronidation activity of human liver microsomes (HLMs) and eight human recombinant UGTs toward (R)- and (S)-warfarin, racemic warfarin, and major cytochrome P450 metabolites of warfarin (4'-, 6-, 7-, 8-, and 10-hydroxywarfarin) has been assessed. HLMs, UGT1A1, 1A8, 1A9, and 1A10 showed glucuronidation activity toward 4'-, 6-, 7-, and/or 8-hydroxywarfarin with K(m) values ranging from 59 to 480 microM and V(max) values ranging from 0.03 to 0.78 microM/min/mg protein. Tandem mass spectrometry studies and structure comparisons suggested glucuronidation was occurring at the C4'-, C6-, C7-, and C8-positions. Of the hepatic UGT isozymes tested, UGT1A9 exclusively metabolized 8-hydroxywarfarin, whereas UGT1A1 metabolized 6-, 7-, and 8-hydroxywarfarin. Studies with extrahepatic UGT isoforms showed that UGT1A8 metabolized 7- and 8-hydroxywarfarin and that UGT1A10 glucuronidated 4'-, 6-, 7-, and 8-hydroxywarfarin. UGT1A4, 1A6, 1A7, and 2B7 did not have activity with any substrate, and none of the UGT isozymes evaluated catalyzed reactions with (R)- and (S)-warfarin, racemic warfarin, or 10-hydroxywarfarin. This is the first study identifying and characterizing specific human UGT isozymes, which glucuronidate major cytochrome P450 metabolites of warfarin with similar metabolic rates known to be associated with warfarin metabolism. Continued characterization of these pathways may enhance our ability to reduce life-threatening and costly complications associated with warfarin therapy.

Phenylalanine(90) and phenylalanine(93) are crucial amino acids within the estrogen binding site of the human UDP-glucuronosyltransferase 1A10.

Human UDP-glucuronosyltransferase 1A10 has been identified as the major isoform involved in the biotransformation of a wide range of phenolic substrates, including native estrogens and their oxidized metabolites. Our recent studies point to the F(90)-M(91)-V(92)-F(93) amino acid motif of UGT1A10, which was identified using photoaffinity labeling followed by LC-MS/MS analysis, as a key determinant of the binding of phenolic substrates. In this report, we have evaluated the role of F(90), V(92), and F(93) in the recognition of estrogens by UGT1A10 using site-directed mutagenesis. Kinetic studies using five mutants revealed that F(90) and F(93) are critical residues for the recognition of all estrogen substrates. The substitution of F(90) with alanine totally abolished the activity of this enzyme toward all the estrogens investigated. Overall, sequential removal for the aromatic ring (F to L) and of the hydrophobic chain (F to A and V to A) from amino acids 90, 92, and 93 effectively alters estrogen recognition. This demonstrates that individual features of the native and hydroxylated estrogens determine the specific binding properties of the compound within the binding site of the human UGT1A10 and the mutants. The resulting activities are completely abolished, unchanged, increased, or decreased depending on the structures of both the mutant and the substrate. The novel identification of UGT1A10 as the major isoform involved in the glucuronidation of all estrogens and the discovery of the importance of the FMVF motif in the binding of steroids will help to elucidate the molecular mechanism of glucuronidation, resulting in the design of more effective estrogen-based therapies.