Long-Term Efficacy of Pulmonary Rehabilitation in Patients with Occupational Respiratory Diseases

Background: Pulmonary rehabilitation is a well-recognized treatment option in chronic obstructive lung disease improving exercise performance, respiratory symptoms and quality of life. In occupational respiratory diseases, which can be rather cost-intensive due to the compensation needs, very little information is available. Objectives: This study aims at the evaluation of the usefulness of pulmonary rehabilitation in patients with occupational respiratory diseases, partly involving complex alterations of lung function and of the sustainability of effects. Methods: We studied 263 patients with occupational respiratory diseases (asthma, silicosis, asbestosis, chronic obstructive pulmonary disease) using a 4-week inpatient rehabilitation program and follow-up examinations 3 and 12 months later. The outcomes evaluated were lung function, 6-min walking distance (6MWD), maximum exercise capacity (Wmax), skeletal muscle strength, respiratory symptoms, exacerbations and associated medical consultations, quality of life (SF-36, SGRQ), anxiety/depression (HADS) and Medical Research Council and Baseline and Transition Dyspnea Index scores. Results: Compared to baseline, there were significant (p < 0.05) improvements in 6MWD, Wmax and muscle strength immediately after rehabilitation, and these were maintained over 12 months (p < 0.05). Effects were less pronounced in asbestosis. Overall, a significant reduction in the rate of exacerbations by 35%, antibiotic therapy by 27% and use of health care services by 17% occurred within 12 months after rehabilitation. No changes were seen in the questionnaire outcomes. Conclusions: Pulmonary rehabilitation is effective even in the complex settings of occupational respiratory diseases, providing sustained improvement of functional capacity and reducing health care utilization. Copyright (C) 2012 S. Karger AG, Base

Income Shocks, Inequality, and Democracy

In this paper, motivated by contradictory evidence on the effect of income on democracy, we investigate the hypothesis that it is income shocks – major income fluctuations relative to the trend – rather than marginal year‐on‐year variation in income levels that lead to non‐trivial changes in the quality of political institutions. Empirical results provide support for this hypothesis, and show how income inequality plays a crucial role in the effects of economic shocks on democracy. In particular, negative income shocks reveal a positive effect on democracy in countries with high inequality, and vice versa

The 'one-pot' preparation of substituted benzofurans

A simple one-pot procedure has been elaborated for the preparation of substituted benzofurans starting from halogenated phenols, and this method has been applied successfully to the total synthesis of dehydrotremetone, a natural product of White Snakeroot

The nomenclature and application of the names Euphorbia candelabrum Welw. and Euphorbia ingens in tropical Africa

During the last 40 years, one of the most widespread and conspicuous succulent trees in East and north‐east Africa has been referred to as Euphorbia candelabrum Kotschy or as E. candelabrum Trémaux ex Kotschy. This name is a later homonym of E. candelabrum Welw., and consequently it is illegitimate. The species to which the name E. candelabrum Kotschy has been widely applied is shown to be conspecific with E. ingens, which occurs from southern Ethiopia to subtropical South Africa.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152821/1/tax12091_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152821/2/tax12091.pd

Is an Individual Prediction of Maximal Work Rate by 6-Minute Walk Distance and Further Measurements Reliable in Male Patients with Different Lung Diseases?

Background: In patients with chronic lung diseases, the work rate forendurance training is calculated by the maximal work rate (W-max).Because the assessment bears side effects, a prediction by easieraccessible tests would be of practical use. Objective: We addressed thereliability of predicting W-max on the basis of the 6-min walk distance(6MWD) test and a set of further parameters in patients with differentlung diseases. Methods: Baseline data of a longitudinal study including6MWD, W max, peripheral muscle force, lung function, fat-free mass anddyspnea (Modified Medical Research Council score) of 255 men withoccupational lung diseases (104 asthma, 69 asbestosis, 42 silicosis, 40 chronic obstructive pulmonary disease) were evaluated

Reconstructive periodontal therapy with simultaneous ridge augmentation. A clinical and histological case series report

Treatment of intrabony periodontal defects with a combination of a natural bone mineral (NBM) and guided tissue regeneration (GTR) has been shown to promote periodontal regeneration in intrabony defects. In certain clinical situations, the teeth presenting intrabony defects are located at close vicinity of the resorbed alveolar ridge. In these particular cases, it is of clinical interest to simultaneously reconstruct both the intrabony periodontal defect and the resorbed alveolar ridge, thus allowing insertion of endosseous dental implants. The aim of the present study was to present the clinical and histological results obtained with a new surgical technique designed to simultaneously reconstruct the intrabony defect and the adjacently located resorbed alveolar ridge. Eight patients with chronic advanced periodontitis displaying intrabony defects located in the close vicinity of resorbed alveolar ridges were consecutively enrolled in the study. After local anesthesia, mucoperiosteal flaps were raised, the granulation tissue removed, and the roots meticulously scaled and planed. A subepithelial connective tissue graft was harvested from the palate and sutured to the oral flap. The intrabony defect and the adjacent alveolar ridge were filled with a NBM and subsequently covered with a bioresorbable collagen membrane (GTR). At 11–20 months (mean, 13.9 ± 3.9 months) after surgery, implants were placed, core biopsies retrieved, and histologically evaluated. Mean pocket depth reduction measured 3.8 ± 1.7 mm and mean clinical attachment level gain 4.3 ± 2.2 mm, respectively. Reentry revealed in all cases a complete fill of the intrabony component and a mean additional vertical hard tissue gain of 1.8 ± 1.8 mm. The histologic evaluation indicated that most NBM particles were surrounded by bone. Mean new bone and mean graft area measured 17.8 ± 2.8% and 32.1 ± 8.3%, respectively. Within their limits, the present findings indicate that the described surgical approach may be successfully used in certain clinical cases to simultaneously treat intrabony defects and to reconstruct the resorbed alveolar ridge

Predicting effective pro-apoptotic antileukaemic drug combinations using cooperative dynamic BH3 profiling

The BH3-only apoptosis agonists BAD and NOXA target BCL-2 and MCL-1 respectively and co-operate to induce apoptosis. On this basis, therapeutic drugs targeting BCL-2 and MCL-1 might have enhanced activity if used in combination. We identified anti-leukaemic drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism using the technique of dynamic BH3 profiling, whereby cells were primed with drugs to discover whether this would elicit mitochondrial outer membrane permeabilisation in response to BCL-2-targeting BAD-BH3 peptide or MCL-1-targeting MS1-BH3 peptide. We found that a broad range of anti-leukaemic agents–notably MCL-1 inhibitors, DNA damaging agents and FLT3 inhibitors–sensitise leukaemia cells to BAD-BH3. We further analysed the BCL-2 inhibitors ABT-199 and JQ1, the MCL-1 inhibitors pladienolide B and torin1, the FLT3 inhibitor AC220 and the DNA double-strand break inducer etoposide to correlate priming responses with co-operative induction of apoptosis. ABT-199 in combination with pladienolide B, torin1, etoposide or AC220 strongly induced apoptosis within 4 hours, but the MCL-1 inhibitors did not co-operate with etoposide or AC220. In keeping with the long half-life of BCL-2, the BET domain inhibitor JQ1 was found to downregulate BCL-2 and to prime cells to respond to MS1-BH3 at 48, but not at 4 hours: prolonged priming with JQ1 was then shown to induce rapid cytochrome C release when pladienolide B, torin1, etoposide or AC220 were added. In conclusion, dynamic BH3 profiling is a useful mechanism-based tool for understanding and predicting co-operative lethality between drugs sensitising to BCL-2 antagonism and drugs sensitising to MCL-1 antagonism. A plethora of agents sensitised cells to BAD-BH3-mediated mitochondrial outer membrane permeabilisation in the dynamic BH3 profiling assay and this was associated with effective co-operation with the BCL-2 inhibitory compounds ABT-199 or JQ1

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

BH3-only proteins are dispensable for apoptosis induced by pharmacological inhibition of both MCL-1 and BCL-XL.

The impressive selectivity and efficacy of BH3 mimetics for treating cancer has largely been limited to BCL-2 dependent hematological malignancies. Most solid tumors depend on other anti-apoptotic proteins, including MCL-1, for survival. The recent description of S63845 as the first specific and potent MCL-1 inhibitor represents an important therapeutic advance, since MCL-1 is not targeted by the currently available BH3 mimetics, Navitoclax or Venetoclax, and is commonly associated with chemoresistance. In this study, we confirm a high binding affinity and selectivity of S63845 to induce apoptosis in MCL-1-dependent cancer cell lines. Furthermore, S63845 synergizes with other BH3 mimetics to induce apoptosis in cell lines derived from both hematological and solid tumors. Although the anti-apoptotic BCL-2 family members in these cell lines interact with a spectrum of pro-apoptotic BH3-only proteins to regulate apoptosis, these interactions alone do not explain the relative sensitivities of these cell lines to BH3 mimetic-induced apoptosis. These findings necessitated further investigation into the requirement of BH3-only proteins in BH3 mimetic-mediated apoptosis. Concurrent inhibition of BCL-XL and MCL-1 by BH3 mimetics in colorectal HCT116 cells induced apoptosis in a BAX- but not BAK-dependent manner. Remarkably this apoptosis was independent of all known BH3-only proteins. Although BH3-only proteins were required for apoptosis induced as a result of BCL-XL inhibition, this requirement was overcome when both BCL-XL and MCL-1 were inhibited, implicating distinct mechanisms by which different anti-apoptotic BCL-2 family members may regulate apoptosis in cancer

MCL-1 is a prognostic indicator and drug target in breast cancer

Analysis of publicly available genomic and gene expression data demonstrates that MCL1 expression is frequently elevated in breast cancer. Distinct from other pro-survival Bcl-2 family members, the short half-life of MCL-1 protein led us to investigate MCL-1 protein expression in a breast cancer tissue microarray and correlate this with clinical data. Here, we report associations between high MCL-1 and poor prognosis in specific subtypes of breast cancer including triple-negative breast cancer, an aggressive form that lacks targeted treatment options. Deletion of MCL-1 in the mammary epithelium of genetically engineered mice revealed an absolute requirement for MCL-1 in breast tumorigenesis. The clinical applicability of these findings was tested through a combination of approaches including knock-down or inhibition of MCL-1 to show triple-negative breast cancer cell line dependence on MCL-1 in vitro and in vivo. Our data demonstrate that high MCL-1 protein expression is associated with poor outcome in breast cancer and support the therapeutic targeting of MCL-1 in this disease