Measurement of myocardial iron is key to the clinical management of patients at risk of siderotic cardiomyopathy. The cardiovascular magnetic resonance relaxation parameter R2* (assessed clinically ...via its reciprocal, T2*) measured in the ventricular septum is used to assess cardiac iron, but iron calibration and distribution data in humans are limited.
Twelve human hearts were studied from transfusion-dependent patients after either death (heart failure, n=7; stroke, n=1) or transplantation for end-stage heart failure (n=4). After cardiovascular magnetic resonance R2* measurement, tissue iron concentration was measured in multiple samples of each heart with inductively coupled plasma atomic emission spectroscopy. Iron distribution throughout the heart showed no systematic variation between segments, but epicardial iron concentration was higher than in the endocardium. The mean ± SD global myocardial iron causing severe heart failure in 10 patients was 5.98 ± 2.42 mg/g dry weight (range, 3.19 to 9.50 mg/g), but in 1 outlier case of heart failure was 25.9 mg/g dry weight. Myocardial lnR2* was strongly linearly correlated with lnFe (R²=0.910, P<0.001), leading to Fe=45.0×(T2*)⁻¹·²² for the clinical calibration equation with Fe in milligrams per gram dry weight and T2* in milliseconds. Midventricular septal iron concentration and R2* were both highly representative of mean global myocardial iron.
These data detail the iron distribution throughout the heart in iron overload and provide calibration in humans for cardiovascular magnetic resonance R2* against myocardial iron concentration. The iron values are of considerable interest in terms of the level of cardiac iron associated with iron-related death and indicate that the heart is more sensitive to iron loading than the liver. The results also validate the current clinical practice of monitoring cardiac iron in vivo by cardiovascular magnetic resonance of the midseptum.
Methane Oxyforming for Synthesis Gas Production York, Andrew P. E.; Xiao, Tian-cun; Green, Malcolm L. H. ...
Catalysis reviews. Science and engineering,
10/2007, Letnik:
49, Številka:
4
Journal Article
Recenzirano
This article is concerned with the reforming of methane to synthesis gas; a review of the steam reforming Rxn is presented, and the dry reforming and partial oxidation Rxns introduced. Collectively, ...these processes are known as "oxyforming." A background to oxyforming, industrial practice, and some of the most important latest developments will be presented, along with a section on the uses of synthesis gas. The current understanding of the Rxn mechanisms for the three processes and the problem of deactivation by carbon deposition will be discussed in detail. Finally, the economics of synfuel production will be addressed and compared with the production of other fuels, and the future directions and outlook for oxyforming will be forwarded. This article should allow the reader to make comparisons between these three important industrial reactions.
This aim of this statement is to report an expert consensus on the diagnosis and treatment of cardiac dysfunction in β-thalassemia major (TM). This consensus statement does not cover other ...hemoglobinopathies, including thalassemia intermedia and sickle cell anemia, in which a different spectrum of cardiovascular complications is typical. There are considerable uncertainties in this field, with a few randomized controlled trials relating to treatment of chronic myocardial siderosis but none relating to treatment of acute heart failure. The principles of diagnosis and treatment of cardiac iron loading in TM are directly relevant to other iron-overload conditions, including in particular Diamond-Blackfan anemia, sideroblastic anemia, and hereditary hemochromatosis.Heart failure is the most common cause of death in TM and primarily results from cardiac iron accumulation. The diagnosis of ventricular dysfunction in TM patients differs from that in nonanemic patients because of the cardiovascular adaptation to chronic anemia in non–cardiac-loaded TM patients, which includes resting tachycardia, low blood pressure, enlarged end-diastolic volume, high ejection fraction, and high cardiac output. Chronic anemia also leads to background symptomatology such as dyspnea, which can mask the clinical diagnosis of cardiac dysfunction. Central to early identification of cardiac iron overload in TM is the estimation of cardiac iron by cardiac T2* magnetic resonance. Cardiac T2* <10 ms is the most important predictor of development of heart failure. Serum ferritin and liver iron concentration are not adequate surrogates for cardiac iron measurement. Assessment of cardiac function by noninvasive techniques can also be valuable clinically, but serial measurements to establish trends are usually required because interpretation of single absolute values is complicated by the abnormal cardiovascular hemodynamics in TM and measurement imprecision.Acute decompensated heart failure is a medical emergency and requires urgent consultation with a center with expertise in its management. The first principle of management of acute heart failure is control of cardiac toxicity related to free iron by urgent commencement of a continuous, uninterrupted infusion of high-dose intravenous deferoxamine, augmented by oral deferiprone. Considerable care is required to not exacerbate cardiovascular problems from overuse of diuretics or inotropes because of the unusual loading conditions in TM.The current knowledge on the efficacy of removal of cardiac iron by the 3 commercially available iron chelators is summarized for cardiac iron overload without overt cardiac dysfunction. Evidence from well-conducted randomized controlled trials shows superior efficacy of deferiprone versus deferoxamine, the superiority of combined deferiprone with deferoxamine versus deferoxamine alone, and the equivalence of deferasirox versus deferoxamine.
Purpose Health related quality of life concerns factor prominently in prostate cancer management. We describe health related quality of life impact and recovery profiles of 4 commonly used operative ...treatments for localized prostate cancer. Materials and Methods Beginning in February 2000 all patients treated with open radical prostatectomy, robot assisted laparoscopic prostatectomy, brachytherapy or cryotherapy were asked to complete the UCLA-PCI questionnaire before treatment, and at 3, 6, 12, 18, 24, 30 and 36 months after treatment. Outcomes were compared across treatment types with statistical analysis using univariate and multivariate models. Results A total of 785 patients treated between February 2000 and December 2008 were included in the analysis with a mean followup of 24 months. All health related quality of life domains were adversely affected by all treatments and recovery profiles varied significantly by treatment type. Overall urinary function and bother outcomes scored significantly higher after brachytherapy and cryotherapy compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Brachytherapy and cryotherapy had a 3-fold higher rate of return to baseline urinary function compared to open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. Sexual function and bother scores were highest after brachytherapy, with a 5-fold higher rate of return to baseline function compared to cryotherapy, open radical prostatectomy and robotic assisted laparoscopic radical prostatectomy. All 4 treatments were associated with relatively transient and less pronounced impact on bowel function and bother. Conclusions In a study of sequential health related quality of life assessments brachytherapy and cryotherapy were associated with higher urinary function and bother scores compared to open radical prostatectomy and da Vinci® prostatectomy. Brachytherapy was associated with higher sexual function and bother scores compared to open radical prostatectomy, robotic assisted laparoscopic radical prostatectomy and cryotherapy.
The completion of the Plasmodium falciparum clone 3D7 genome provides a basis on which to conduct comparative proteomics studies of this human pathogen. Here, we applied a high-throughput proteomics ...approach to identify new potential drug and vaccine targets and to better understand the biology of this complex protozoan parasite. We characterized four stages of the parasite life cycle (sporozoites, merozoites, trophozoites and gametocytes) by multidimensional protein identification technology. Functional profiling of over 2,400 proteins agreed with the physiology of each stage. Unexpectedly, the antigenically variant proteins of var and rif genes, defined as molecules on the surface of infected erythrocytes, were also largely expressed in sporozoites. The detection of chromosomal clusters encoding co-expressed proteins suggested a potential mechanism for controlling gene expression.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
OBJECTIVE
To investigate the incidence of and risk factors for developing chronic renal insufficiency (CRI), proteinuria and metabolic acidosis (MA) in patients treated with radical nephrectomy (RN) ...or nephron‐sparing surgery (NSS).
PATIENTS AND METHODS
We retrospectively reviewed 749 patients (mean age 57.7 years; mean follow‐up 6.4 years) who had RN or NSS for renal tumours between July 1987 and June 2006 at our institution. The demographics and outcomes were analysed and recorded. The primary outcome variable was the development of an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2, with secondary outcomes being the development of a serum creatinine level of ≥2.0 mg/dL, MA (serum bicarbonate <22 mmol/L), and proteinuria (≥1+ on dipstick testing). Multivariate logistic regression (MV) was used to identify risk factors for developing an eGFR of <60 mL/min/1.73 m2, a creatinine level of ≥2.0 mg/dL and MA.
RESULTS
Of the 749 patients, 499 had RN and 250 NSS; there were no significant demographic differences between the groups. After surgery a significantly greater proportion of the RN than the NSS group had a low eGFR (44.7% vs 16.0%, P < 0.001), MA (12.8% vs 7.2%, P = 0.02), proteinuria (22.2% vs 13.2%, P = 0.003) and elevated creatinine (14.2% vs 8.4%, P = 0.022). MV showed that diabetes mellitus (odds ratio 8.96, P = 0.002), RN (5.32, P < 0.001), hypertension (4.55, P = 0.003), a body mass index (BMI) of ≥30 kg/m2 (3.51, P = 0.017), age ≥60 years (2.91, P = 0.015) and smoking (2.44, P = 0.014) were risk factors for developing a low eGFR; and that age ≥60 years (2.00, P = 0.019), diabetes mellitus (10, P < 0.001), hypertension (7.41, P = 0.002), smoking (5.29, P < 0.001) and RN (3.08, P < 0.001) were risk factors for developing an elevated creatinine level; and that being male (2.50, P = 0.019), age ≥60 years (3.13, P = 0.002), a BMI ≥30 (3.52, P < 0.001), RN (9.82, P < 0.001), preoperative eGFR <60 (9.71, P < 0.001) and elevated creatinine (5.9, P = 0.008) were risk factors for developing MA.
CONCLUSIONS
Patients undergoing RN had significantly greater CRI, MA and proteinuria rates than a well‐matched group undergoing NSS. In addition to RN, age ≥60 years, diabetes mellitus, hypertension and smoking were associated with progression to CRI after surgery.
Summary
Heart failure from iron overload causes 71% of deaths in thalassaemia major, yet reversal of siderotic cardiomyopathy has been reported. In order to determine the changes in myocardial iron ...during treatment, we prospectively followed thalassaemia patients commencing intravenous desferrioxamine for iron‐induced cardiomyopathy during a 12‐month period. Cardiovascular magnetic resonance assessments were performed at baseline, 3, 6 and 12 months of treatment, and included left ventricular (LV) function and myocardial and liver T2*, which is inversely related to iron concentration. One patient died. The six survivors showed progressive improvements in myocardial T2* (5·1 ± 1·9 to 8·1 ± 2·8 ms, P = 0·003), liver iron (9·6 ± 4·3 to 2·1 ± 1·5 mg/g, P = 0·001), LV ejection fraction (52 ± 7·1% to 63 ± 6·4%, P = 0·03), LV volumes (end diastolic volume index 115 ± 17 to 96 ± 3 ml, P = 0·03; end systolic volume index 55 ± 16 to 36 ± 6 ml, P = 0·01) and LV mass index (106 ± 14 to 95 ± 13, P = 0·01). Iron cleared more slowly from myocardium than liver (5·0 ± 3·3% vs. 39 ± 23% per month, P = 0·02). These prospective data confirm that siderotic heart failure is often reversible with intravenous iron chelation with desferrioxamine. Myocardial T2* improves in concert with LV volumes and function during recovery, but iron clearance from the heart is considerably slower than from the liver.
Dampening functional levels of the mitochondrial deubiquitylating enzyme Ubiquitin-specific protease 30 (USP30) has been suggested as an effective therapeutic strategy against neurodegenerative ...disorders such as Parkinson’s Disease. USP30 inhibition may counteract the deleterious effects of impaired turnover of damaged mitochondria, which is inherent to both familial and sporadic forms of the disease. Small-molecule inhibitors targeting USP30 are currently in development, but little is known about their precise nature of binding to the protein. We have integrated biochemical and structural approaches to gain novel mechanistic insights into USP30 inhibition by a small-molecule benzosulfonamide-containing compound, USP30inh. Activity-based protein profiling mass spectrometry confirmed target engagement, high selectivity, and potency of USP30inh for USP30 against 49 other deubiquitylating enzymes in a neuroblastoma cell line. In vitro characterization of USP30inh enzyme kinetics inferred slow and tight binding behavior, which is comparable with features of covalent modification of USP30. Finally, we blended hydrogen–deuterium exchange mass spectrometry and computational docking to elucidate the molecular architecture and geometry of USP30 complex formation with USP30inh, identifying structural rearrangements at the cleft of the USP30 thumb and palm subdomains. These studies suggest that USP30inh binds to this thumb–palm cleft, which guides the ubiquitin C terminus into the active site, thereby preventing ubiquitin binding and isopeptide bond cleavage, and confirming its importance in the inhibitory process. Our data will pave the way for the design and development of next-generation inhibitors targeting USP30 and associated deubiquitinylases.
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•The small-molecule benzosulfonamide USP30inh is highly potent and selective for neuronal USP30.•The inhibitor binds USP30 in a slow and tight manner and displays kinetic properties consistent with covalent attachment to USP30, despite its noncovalent design.•We identified regions within USP30 that undergo dramatic structural and conformational rearrangements by USP30inh, preventing Ub binding and decrease DUB activity.•Insights into USP30 inhibitory mechanistics will guide the development of next-generation inhibitors, which has relevance in neurodegeneration.
We describe the dynamic structural interplay between USP30 and the small-molecule benzosulfonamide-containing compound, USP30inh. The inhibitor is highly potent and selective against endogenous USP30, binding in a slow and tight manner. Upon complex formation, significant perturbations occur in the conformational dynamics of the USP30 thumb–palm cleft region, proximal to its catalytic cysteine. Inhibitor binding here would sterically clash with Ub, preventing its binding and isopeptide bond cleavage. Our results help drive the design of the next generation of USP30 inhibitors.
Changes in the frequency, duration, and severity of climate extremes are forecast to occur under global climate change. The impacts of climate extremes on forest productivity and health remain ...difficult to predict due to potential interactions with disturbance events and forest dynamics–changes in forest stand composition, density, size and age structure over time. Such interactions may lead to non-linear forest growth responses to climate involving thresholds and lag effects. Understanding how forest dynamics influence growth responses to climate is particularly important given stand structure and composition can be modified through management to increase forest resistance and resilience to climate change. To inform such adaptive management, we develop a hierarchical Bayesian state space model in which climate effects on tree growth are allowed to vary over time and in relation to past climate extremes, disturbance events, and forest dynamics. The model is an important step toward integrating disturbance and forest dynamics into predictions of forest growth responses to climate extremes. We apply the model to a dendrochronology data set from forest stands of varying composition, structure, and development stage in northeastern Minnesota that have experienced extreme climate years and forest tent caterpillar defoliation events. Mean forest growth was most sensitive to water balance variables representing climatic water deficit. Forest growth responses to water deficit were partitioned into responses driven by climatic threshold exceedances and interactions with insect defoliation. Forest growth was both resistant and resilient to climate extremes with the majority of forest growth responses occurring after multiple climatic threshold exceedances across seasons and years. Interactions between climate and disturbance were observed in a subset of years with insect defoliation increasing forest growth sensitivity to water availability. Forest growth was particularly sensitive to climate extremes during periods of high stem density following major regeneration events when average inter-tree competition was high. Results suggest the resistance and resilience of forest growth to climate extremes can be increased through management steps such as thinning to reduce competition during early stages of stand development and small-group selection harvests to maintain forest structures characteristic of older, mature stands.
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