High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis diffuse large cell lymphoma: an Intergruppo Italiano Linfomi randomized trial

Background and Objectives. Poor prognosis diffuse large cell lymphoma (DLCL) responds poorly to standard chemotherapy. Randomized studies comparing high-dose chemotherapy with autologous stem-cell transplantation (ASCT) against standard chemotherapy have produced conflicting results. Dose-dense chemotherapy with granulocyte colony-stimulating factor (G-CSF) support seems to hold promise. The purpose of this multicenter, randomized trial was to compare failure-free and overall survival in patients with poor prognosis DLCL treated with high-dose sequential (HDS) chemotherapy followed by ASCT or an outpatient dose-dense chemotherapy regimen (MegaCEOP). Design and Methods. Between 1996 and 2001, 130 DLCL patients, aged <= 60 years, with intermediate-high or high-risk disease, according to the International Prognostic Index score, and/or bone marrow involvement were enrolled. Sixty were randomized to HDS chemotherapy plus high-dose mitoxantrone and melphalan with ASCT (arm A) and 66 to the MegaCEOP regimen (6-8 courses of an escalated dose of cyclophosphamide and epirubicin plus vincristine and prednisone with G-CSF every 2-weeks) (arm B); 4 patients were considered ineligible. Results. The complete remission rate was 59% in arm A and 70% in arm B (p=0.18). After a median follow-up of 78 months, the 6-year failure-free survival was 45% in arm A and 48% in arm B (hazard ratio=1.15, 95% confidence intervals =0.72-1.84, p=0.56). The 5-year overall survival was 49% in arm A and 63% in arm B (hazard ratio=1.67, 95% confidence interval=0.98-2.85, p=0.06). Two cases of secondary acute myeloid leukemia were observed after treatment in group A. Interpretations and Conclusions. HDS and ASCT as initial therapy for patients with poor-prognosis DLCL does not provide a benefit over that of outpatient dose-dense MegaCEOP chemotherapy

Quantification of radial arterial pulse characteristics change during exercise and recovery

It is physiologically important to understand the arterial pulse waveform characteristics change during exercise and recovery. However, there is a lack of a comprehensive investigation. This study aimed to provide scientific evidence on the arterial pulse characteristics change during exercise and recovery. Sixty-five healthy subjects were studied. The exercise loads were gradually increased from 0 to 125 W for female subjects and to 150 W for male subjects. Radial pulses were digitally recorded during exercise and 4-min recovery. Four parameters were extracted from the raw arterial pulse waveform, including the pulse amplitude, width, pulse peak and dicrotic notch time. Five parameters were extracted from the normalized radial pulse waveform, including the pulse peak and dicrotic notch position, pulse Area, Area1 and Area2 separated by notch point. With increasing loads during exercise, the raw pulse amplitude increased significantly with decreased pulse period, reduced peak and notch time. From the normalized pulses, the pulse Area, pulse Area1 and Area2 decreased, respectively, from 38 ± 4, 61 ± 5 and 23 ± 5 at rest to 34 ± 4, 52 ± 6 and 13 ± 5 at 150-W exercise load. During recovery, an opposite trend was observed. This study quantitatively demonstrated significant changes of radial pulse characteristics during different exercise loads and recovery phases

The Mitochondrial Ca(2+) Uniporter: Structure, Function, and Pharmacology.

Mitochondrial Ca(2+) uptake is crucial for an array of cellular functions while an imbalance can elicit cell death. In this chapter, we briefly reviewed the various modes of mitochondrial Ca(2+) uptake and our current understanding of mitochondrial Ca(2+) homeostasis in regards to cell physiology and pathophysiology. Further, this chapter focuses on the molecular identities, intracellular regulators as well as the pharmacology of mitochondrial Ca(2+) uniporter complex

Pulmonary Tuberculosis and Delay in Anti-Tuberculous Treatment Are Important Risk Factors for Chronic Obstructive Pulmonary Disease

OBJECTIVE: Tuberculosis (TB) remains the leading cause of death among infectious diseases worldwide. It has been suggested as an important risk factor of chronic obstructive pulmonary disease (COPD), which is also a major cause of morbidity and mortality. This study investigated the impact of pulmonary TB and anti-TB treatment on the risk of developing COPD. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used the National Health Insurance Database of Taiwan, particularly the Longitudinal Health Insurance Database 2005 to obtain 3,176 pulmonary TB cases and 15,880 control subjects matched in age, sex, and timing of entering the database. MAIN OUTCOME MEASURES: Hazard ratios of potential risk factors of COPD, especially pulmonary TB and anti-TB treatment. RESULTS: The mean age of pulmonary TB cases was 51.9±19.2. The interval between the initial study date and commencement of anti-TB treatment (delay in anti-TB treatment) was 75.8±65.4 days. Independent risk factors for developing COPD were age, male, low income, and history of pulmonary TB (hazard ratio 2.054 [1.768-2.387]), while diabetes mellitus was protective. The impact of TB persisted for six years after TB diagnosis and was significant in women and subjects aged >70 years. Among TB patients, delay in anti-TB treatment had a dose-response relationship with the risk of developing COPD. CONCLUSIONS: Some cases of COPD may be preventable by controlling the TB epidemic, early TB diagnosis, and prompt initiation of appropriate anti-TB treatment. Follow-up care and early intervention for COPD may be necessary for treated TB patients

Ectopic Catalase Expression in Mitochondria by Adeno-Associated Virus Enhances Exercise Performance in Mice

Oxidative stress is thought to compromise muscle contractility. However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise. One possible explanation may relate to the inability of the supplemented antioxidants to effectively eliminate excessive free radicals at the site of generation. Here, we tested whether delivering catalase to the mitochondria, a site of free radical production in contracting muscle, could improve treadmill performance in C57Bl/6 mice. Recombinant adeno-associated virus serotype-9 (AV.RSV.MCAT) was generated to express a mitochondria-targeted catalase gene. AV.RSV.MCAT was delivered to newborn C57Bl/6 mouse circulation at the dose of 1012 vector genome particles per mouse. Three months later, we observed a ∼2 to 10-fold increase of catalase protein and activity in skeletal muscle and the heart. Subcellular fractionation western blot and double immunofluorescence staining confirmed ectopic catalase expression in the mitochondria. Compared with untreated control mice, absolute running distance and body weight normalized running distance were significantly improved in AV.RSV.MCAT infected mice during exhaustive treadmill running. Interestingly, ex vivo contractility of the extensor digitorum longus muscle was not altered. Taken together, we have demonstrated that forced catalase expression in the mitochondria enhances exercise performance. Our result provides a framework for further elucidating the underlying mechanism. It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease

Frequency of the C9orf72 hexanucleotide repeat expansion in patients with amyotrophic lateral sclerosis and frontotemporal dementia: a cross-sectional study.

We aimed to accurately estimate the frequency of a hexanucleotide repeat expansion in C9orf72 that has been associated with a large proportion of cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)