Effect of cumulative dose of brentuximab vedotin maintenance in relapsed/refractory classical Hodgkin lymphoma after autologous stem cell transplant: an analysis of real-world outcomes

Sixteen cycles of Brentuximab vedotin (BV) after autologous stem cell transplant (ASCT) in high-risk relapsed/refractory classical Hodgkin lymphoma demonstrated an improved 2-year progression-free survival (PFS) over placebo. However, most patients are unable to complete all 16 cycles at full dose due to toxicity. This retrospective, multicenter study investigated the effect of cumulative maintenance BV dose on 2-year PFS. Data were collected from patients who received at least one cycle of BV maintenance after ASCT with one of the following high-risk features: primary refractory disease (PRD), extra-nodal disease (END), or relapse 75% of the planned total cumulative dose, cohort 2 with 51-75% of dose, and cohort 3 with ≤50% of dose. The primary outcome was 2-year PFS. A total of 118 patients were included. Fifty percent had PRD, 29% had RL<12, and 39% had END. Forty-four percent of patients had prior exposure to BV and 65% were in complete remission before ASCT. Only 14% of patients received the full planned BV dose. Sixty-one percent of patients discontinued maintenance early and majority of those (72%) were due to toxicity. The 2-year PFS for the entire population was 80.7%. The 2-year PFS was 89.2% for cohort 1 (n=39), 86.2% for cohort 2 (n=33), and 77.9% for cohort 3 (n=46) (P=0.70). These data are reassuring for patients who require dose reductions or discontinuation to manage toxicity

Cardioversion in patients with newly diagnosed non-valvular atrial fibrillation: observational study using prospectively collected registry data

OBJECTIVE To investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation. DESIGN Observational study using prospectively collected registry data (Global Anticoagulant Registry in the FIELD-AF-GARFIELD-AF). SETTING 1317 participating sites in 35 countries. PARTICIPANTS 52 057 patients aged 18 years and older with newly diagnosed atrial fibrillation (up to six weeks' duration) and at least one investigator determined stroke risk factor. MAIN OUTCOME MEASURES Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between patients who received direct current cardioversion and those who had pharmacological cardioversion. Overlap propensity weighting with Cox proportional hazards models was used to evaluate the effect of cardioversion on clinical endpoints (all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding), adjusting for baseline risk and patient selection. RESULTS 44 201 patients were included in the analysis comparing cardioversion and no cardioversion, and of these, 6595 (14.9%) underwent cardioversion at baseline. The propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (95% confidence interval 0.63 to 0.86) from baseline to one year follow-up and 0.77 (0.64 to 0.93) from one year to two year follow-up. Of the 6595 patients who had cardioversion at baseline, 299 had a follow-up cardioversion more than 48 days after enrolment. 7175 patients were assessed in the analysis comparing type of cardioversion: 2427 (33.8%) received pharmacological cardioversion and 4748 (66.2%) had direct current cardioversion. During one year follow-up, event rates (per 100 patient years) for all cause mortality in patients who received direct current and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively. OBJECTIVE To investigate the clinical outcomes of patients who underwent cardioversion compared with those who did not have cardioverson in a large dataset of patients with recent onset non-valvular atrial fibrillation. DESIGN Observational study using prospectively collected registry data (Global Anticoagulant Registry in the FIELD-AF-GARFIELD-AF). SETTING 1317 participating sites in 35 countries. PARTICIPANTS 52 057 patients aged 18 years and older with newly diagnosed atrial fibrillation (up to six weeks' duration) and at least one investigator determined stroke risk factor. MAIN OUTCOME MEASURES Comparisons were made between patients who received cardioversion and those who had no cardioversion at baseline, and between patients who received direct current cardioversion and those who had pharmacological cardioversion. Overlap propensity weighting with Cox proportional hazards models was used to evaluate the effect of cardioversion on clinical endpoints (all cause mortality, non-haemorrhagic stroke or systemic embolism, and major bleeding), adjusting for baseline risk and patient selection. RESULTS 44 201 patients were included in the analysis comparing cardioversion and no cardioversion, and of these, 6595 (14.9%) underwent cardioversion at baseline. The propensity score weighted hazard ratio for all cause mortality in the cardioversion group was 0.74 (95% confidence interval 0.63 to 0.86) from baseline to one year follow-up and 0.77 (0.64 to 0.93) from one year to two year follow-up.Of the 6595 patients who had cardioversion at baseline, 299 had a follow-up cardioversion more than 48 days after enrolment. 7175 patients were assessed in the analysis comparing type of cardioversion: 2427 (33.8%) received pharmacological cardioversion and 4748 (66.2%) had direct current cardioversion. During one year follow-up, event rates (per 100 patient years) for all cause mortality in patients who received direct current and pharmacological cardioversion were 1.36 (1.13 to 1.64) and 1.70 (1.35 to 2.14), respectively. CONCLUSION In this large dataset of patients with recent onset non-valvular atrial fibrillation, a small proportion were treated with cardioversion. Direct current cardioversion was performed twice as often as pharmacological cardioversion, and there appeared to be no major difference in outcome events for these two cardioversion modalities. For the overall cardioversion group, after adjustments for confounders, a significantly lower risk of mortality was found in patients who received early cardioversion compared with those who did not receive early cardioversion. STUDY REGISTRATION ClinicalTrials.gov NCT01090362

Neurofilament depletion improves microtubule dynamics via modulation of Stat3/stathmin signaling

In neurons, microtubules form a dense array within axons, and the stability and function of this microtubule network is modulated by neurofilaments. Accumulation of neurofilaments has been observed in several forms of neurodegenerative diseases, but the mechanisms how elevated neurofilament levels destabilize axons are unknown so far. Here, we show that increased neurofilament expression in motor nerves of pmn mutant mice, a model of motoneuron disease, causes disturbed microtubule dynamics. The disease is caused by a point mutation in the tubulin-specific chaperone E (Tbce) gene, leading to an exchange of the most C-terminal amino acid tryptophan to glycine. As a consequence, the TBCE protein becomes instable which then results in destabilization of axonal microtubules and defects in axonal transport, in particular in motoneurons. Depletion of neurofilament increases the number and regrowth of microtubules in pmn mutant motoneurons and restores axon elongation. This effect is mediated by interaction of neurofilament with the stathmin complex. Accumulating neurofilaments associate with stathmin in axons of pmn mutant motoneurons. Depletion of neurofilament by Nefl knockout increases Stat3-stathmin interaction and stabilizes the microtubules in pmn mutant motoneurons. Consequently, counteracting enhanced neurofilament expression improves axonal maintenance and prolongs survival of pmn mutant mice. We propose that this mechanism could also be relevant for other neurodegenerative diseases in which neurofilament accumulation and loss of microtubules are prominent features

Chlamydia trachomatis paralyses neutrophils to evade the host innate immune response.

Chlamydia trachomatis, an obligate intracellular human pathogen, is a major cause of sexually transmitted diseases. Infections often occur without symptoms, a feature that has been attributed to the ability of the pathogen to evade the host immune response. We show here that C. trachomatis paralyses the host immune system by preventing the activation of polymorphic nuclear leukocytes (PMNs). PMNs infected with Chlamydia fail to produce neutrophil extracellular traps and the bacteria are able to survive in PMNs for extended periods of time. We have identified the secreted chlamydial protease-like activating factor (CPAF) as an effector mediating the evasion of the innate immune response since CPAF-deficient Chlamydia activate PMNs and are subsequently efficiently killed. CPAF suppresses the oxidative burst and interferes with chemical-mediated activation of neutrophils. We identified formyl peptide receptor 2 (FPR2) as a target of CPAF. FPR2 is cleaved by CPAF and released from the surface of PMNs. In contrast to previously described subversion mechanisms that mainly act on already activated PMNs, we describe here details of how Chlamydia actively paralyses PMNs, including the formation of neutrophil extracellular traps, to evade the host's innate immune response

Medicinal used plants from India: analysis of the essential oils of Sphaeranthus indicus flowers, roots and stems with leaves

The essential oils of flowers, roots and herb (stems with leaves) of Sphaeranthus indicus Kurz. (Asteraceae) from southern India were investigated by gas chromatographic-spectroscopic (GC-FID and GC-MS) and olfactoric methods to identify those compounds responsible for the characteristic odor as well as partly for the folk medicinal use of this plant. More than 95 volatiles were found to be constituents of the three essential S. indicus oils with following composition of main components: flower oil: β-eudesmol (21.4%), 2,5-dimethoxy-p-cymene (16.2%), β-caryophyllene (7.8%), τ-cadinol (7.2%). caryophyllene oxide (6.9%) and α-eudesmol (4.5%); root oil: 2,5-dimethoxy-pcymene (28.3%), τ-cadinol (25.3%), (2)-arteannuic alcohol (10.1 %), β-maaliene (3.9%) and caryophyllene oxide (3.1%); herb oil: 2,5-dimethoxy-p-cymene (27.0%), τ-cadinol (12.5%), β-eudesmol (9.1 %), α-eudesmol (7.0%) and caroyphyllene oxide (4.7%). In addition, the odor impressions of the samples are described and the possible use of the essential Sphaeranthus indicus oils in medicinal, cosmetic and food flavoring discussed

Medicinal used plants from India: analysis of the essential oils of Sphaeranthus indicus flowers, roots and stems with leaves

The essential oils of flowers, roots and herb (stems with leaves) of Sphaeranthus indicus Kurz. (Asteraceae) from southern India were investigated by gas chromatographic-spectroscopic (GC-FID and GC-MS) and olfactoric methods to identify those compounds responsible for the characteristic odor as well as partly for the folk medicinal use of this plant. More than 95 volatiles were found to be constituents of the three essential S. indicus oils with following composition of main components: flower oil: β-eudesmol (21.4%), 2,5-dimethoxy-p-cymene (16.2%), β-caryophyllene (7.8%), τ-cadinol (7.2%). caryophyllene oxide (6.9%) and α-eudesmol (4.5%); root oil: 2,5-dimethoxy-pcymene (28.3%), τ-cadinol (25.3%), (2)-arteannuic alcohol (10.1 %), β-maaliene (3.9%) and caryophyllene oxide (3.1%); herb oil: 2,5-dimethoxy-p-cymene (27.0%), τ-cadinol (12.5%), β-eudesmol (9.1 %), α-eudesmol (7.0%) and caroyphyllene oxide (4.7%). In addition, the odor impressions of the samples are described and the possible use of the essential Sphaeranthus indicus oils in medicinal, cosmetic and food flavoring discussed.</jats:p