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"Hauser, Thomas"
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Diffuse myocardial fibrosis in patients with mitral valve prolapse and ventricular arrhythmia
ObjectiveWe aimed to investigate the association of diffuse myocardial fibrosis by cardiac magnetic resonance (CMR) T1 with complex ventricular arrhythmia (ComVA) in mitral valve prolapse (MVP).MethodsA retrospective analysis was performed on 41 consecutive patients with MVP referred for CMR between 2006 and 2011, and 31 healthy controls. Arrhythmia analysis was available in 23 patients with MVP with Holter/event monitors. Left ventricular (LV) septal T1 times were derived from Look-Locker sequences after administration of 0.2 mmol/kg gadopentetate dimeglumine. Late gadolinium enhancement (LGE) CMR images were available for all subjects.ResultsPatients with MVP had significantly shorter postcontrast T1 times when compared with controls (334±52 vs 363±58 ms; p=0.03) despite similar LV ejection fraction (LVEF) (63±7 vs 60±6%, p=0.10). In a multivariable analysis, LV end-diastolic volume, LVEF and mitral regurgitation fraction were all correlates of T1 times, with LVEF and LV end-diastolic volume being the strongest (p=0.005, p=0.008 and p=0.045, respectively; model adjusted R2=0.30). Patients with MVP with ComVA had significantly shorter postcontrast T1 times when compared with patients with MVP without ComVA (324 (296, 348) vs 354 (327, 376) ms; p=0.03) and only 5/14 (36%) had evidence of papillary muscle LGE.ConclusionsMVP may be associated with diffuse LV myocardial fibrosis as suggested by reduced postcontrast T1 times. Diffuse interstitial derangement is linked to subclinical systolic dysfunction, and may contribute to ComVA in MVP-related mitral regurgitation, even in the absence of focal fibrosis.
Journal Article
The final recollections of Charles Dickens : a novel
\"England, 1870: His health failing, his most important work all but done, Charles Dickens is readying himself for the final bed. But there is still one more story that he must tell. As a young journalist just getting his start, Dickens encountered a story that would affect him for the rest of his life. As his \"Sketches by Boz\" column is just beginning to find acclaim, young Dickens encounters the wealthy and powerful Charles Wingate. While researching the mysterious businessman, Dickens uncovers a horrific story of corruption and violence, centered on a mutilated prostitute and the murder of her lover. Dickens's investigation could wreak havoc on Wingate and, more importantly, his beautiful wife Amanda. Dickens, already betrothed to his publisher's daughter, realizes just how loveless his future marriage will be as he falls in love with Amanda--even as his story threatens to ruin the Wingates\"--Provided by publisher.
Book
Carbamates as Potential Prodrugs and a New Warhead for HDAC Inhibition
We designed and synthesized carbamates of the clinically-approved HDAC (histone deacetylase) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in order to validate our previously-proposed hypothesis that these carbamates might serve as prodrugs for hydroxamic acid containing HDAC inhibitors. Biochemical assays proved our new compounds to be potent inhibitors of histone deacetylases in vitro, and they also showed antiproliferative effects in leukemic cells. These results, as well as stability analysis led to the suggestion that the intact carbamates are inhibitors of histone deacetylases themselves, representing a new zinc-binding warhead in HDAC inhibitor design. This suggestion was further supported by the synthesis and evaluation of a carbamate derivative of the HDAC6-selective inhibitor bufexamac.
Journal Article
A dangerous journey : inside another year in boxing
\"A Dangerous Journey is a collection of Thomas Hauser's writing on boxing over the course of the 2018 season. He turns his award-winning investigative reporting skills on the scandal surrounding the use of illegal performance enhancing drugs in boxing today and the failures of corrupt and incompetent state athletic commissions. Hauser also takes readers into Canelo Alvarez's dressing room in the hours before and after his rematch against Gennady Golovkin, the biggest fight of the year, and offers in-depth portraits of boxing's biggest stars--past and present--as well as reflections on fight-related curiosities ranging from Ronda Rousey to David and Goliath\"-- Provided by publisher.
Book
Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies
Background: The classification of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and polyarteritis nodosa (PAN) for epidemiology studies is confusing. The existing schemes such as American College of Rheumatology (ACR) criteria, Chapel Hill Consensus Conference (CHCC) definitions and Lanham criteria produce overlapping and conflicting classifications, making it difficult to compare incidence figures. Aim: To develop a consensus method of using these criteria and definitions for epidemiological studies to permit comparison without confounding by classification. Methods: A stepwise algorithm was developed by consensus between a group of doctors interested in the epidemiology of vasculitis. The aim was to categorise patients with Wegener’s granulomatosis, microscopic polyangiitis (MPA), Churg–Strauss syndrome (CSS) and PAN into single clinically relevant categories. The ACR and Lanham criteria for CSS, and ACR criteria for Wegener’s granulomatosis were applied first, as these were considered to be the most specific. Surrogate markers for Wegener’s granulomatosis were included to distinguish Wegener’s granulomatosis from MPA. MPA was classified using the CHCC definition and surrogate markers for renal vasculitis. Finally, PAN was classified using the CHCC definition. The algorithm was validated by application to 20 cases from each centre and 99 from a single centre, followed by a paper case exercise. Results: A four-step algorithm was devised. It successfully categorises patients into a single classification. There was good correlation between observers in the paper case exercise (91.5%; unweighted κ = 0.886). Conclusion: The algorithm achieves its aim of reliably classifying patients into a single category. The use of the algorithm in epidemiology studies should permit comparison between geographical areas.
Journal Article
The baker's tale : Ruby Spriggs and the legacy of Charles Dickens
A \"historical novel that explores the rising influence of Dickens's work in mid-19th century London through the journey of a young woman's struggle against poverty and injustice\"--Dust jacket flap.
Book
The potential for histone deacetylase (HDAC) inhibitors as cestocidal drugs
Echinococcosis and cysticercosis are neglected tropical diseases caused by cestode parasites (family Taeniidae). Not only there is a small number of approved anthelmintics for the treatment of these cestodiases, but also some of them are not highly effective against larval stages, such that identifying novel drug targets and their associated compounds is critical. Histone deacetylase (HDAC) enzymes are validated drug targets in cancers and other diseases, and have been gaining relevance for developing new potential anti-parasitic treatments in the last years. Here, we present the anthelmintic profile for a panel of recently developed HDAC inhibitors against the model cestode Mesocestoides vogae (syn. M. corti).
Phenotypic screening was performed on M. vogae by motility measurements and optical microscopic observations. Some HDAC inhibitors showed potent anthelmintic activities; three of them -entinostat, TH65, and TH92- had pronounced anthelmintic effects, reducing parasite viability by ~100% at concentrations of ≤ 20 μM. These compounds were selected for further characterization and showed anthelmintic effects in the micromolar range and in a time- and dose-dependent manner. Moreover, these compounds induced major alterations on the morphology and ultrastructural features of M. vogae. The potencies of these compounds were higher than albendazole and the anthelmintic effects were irreversible. Additionally, we evaluated pairwise drug combinations of these HDAC inhibitors and albendazole. The results suggested a positive interaction in the anthelmintic effect for individual pairs of compounds. Due to the maximum dose approved for entinostat, adjustments in the dose regime and/or combinations with currently-used anthelmintic drugs are needed, and the selectivity of TH65 and TH92 towards parasite targets should be assessed.
The results presented here suggest that HDAC inhibitors represent novel and potent drug candidates against cestodes and pave the way to understanding the roles of HDACs in these parasites.
Journal Article
Rituximab versus Cyclophosphamide in ANCA-Associated Renal Vasculitis
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and renal involvement. Rates of sustained remission were high in both groups.
A standard glucocorticoid regimen plus rituximab was not superior to standard intravenous cyclophosphamide as induction therapy in patients with newly diagnosed antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and renal involvement.
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, including Wegener's granulomatosis and microscopic polyangiitis, is a multisystem autoimmune syndrome characterized by vasculitis predominantly affecting microscopic vessels and circulating autoantibodies to neutrophil cytoplasmic antigens. Renal involvement occurs in 70% of affected patients and is manifested as rapidly progressive glomerulonephritis with pauci-immune necrotizing, crescentic glomerulonephritis on biopsy. The current standard of care for ANCA-associated vasculitis is cyclophosphamide with high-dose glucocorticoids
1–4
; such regimens are effective in 70 to 90% of patients. However, cyclophosphamide is associated with leukopenia, severe infections, cancer, and ovarian failure.
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Mortality at 1 year exceeds 15%; infection and active vasculitis are . . .
Journal Article
Early mortality in systemic vasculitis: relative contribution of adverse events and active vasculitis
Objective To contrast the effect of the burden of vasculitis activity with the burden of adverse events on 1-year mortality of patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods This study assessed the outcome and adverse events in patients prospectively recruited to four European AAV clinical trials. Data on 524 patients with newly diagnosed AAV were included. The burden of adverse events was quantified using a severity score for leucopenia, infection and other adverse events, with an additional weighting for follow-up duration. A ‘combined burden of events’ (CBOE) score was generated for each patient by summing the individual scores. Vasculitis severity was quantified using the Birmingham vasculitis activity score and glomerular filtration rate (GFR). Results 1-year mortality probability was 11.1%; 59% and 14% of deaths were caused by therapy-associated adverse events and active vasculitis, respectively. Using Cox regression analysis, infection score (p<0.001), adverse event score (p<0.001), leucopenia score (p<0.001) and GFR (p=0.002) were independently associated with mortality. The risk of 1-year mortality remained low (5%) with CBOE scores less than 7, but increased dramatically with scores above this. Hazard ratio for death with a CBOE greater than 7 was 14.4 (95% CI 8.4 to 24.8). Age and GFR were independent predictors of CBOE score. Conclusions The greatest threat to patients with AAV in the first year of therapy is from adverse events rather than active vasculitis. The accumulation of adverse events, monitored using this scoring method, should prompt increased awareness that the patient is at high risk of death.
Journal Article