52 research outputs found
Manganese causes neurotoxic iron accumulation via translational repression of Amyloid Precursor Protein (APP) and H-Ferritin
For more than 150 years, it is known that occupational overexposure of manganese (Mn) causes movement disorders resembling Parkinson's disease (PD) and PDâlike syndromes. However, the mechanisms of Mn toxicity are still poorly understood. Here, we demonstrate that Mn doseâ and timeâdependently blocks the protein translation of amyloid precursor protein (APP) and heavyâchain Ferritin (HâFerritin), both iron homeostatic proteins with neuroprotective features. APP and HâFerritin are postâtranscriptionally regulated by iron responsive proteins, which bind to homologous iron responsive elements (IREs) located in the 5âČâuntranslated regions (5âČâUTRs) within their mRNA transcripts. Using reporter assays, we demonstrate that Mn exposure repressed the 5âČâUTRâactivity of APP and HâFerritin, presumably via increased iron responsive proteinsâiron responsive elements binding, ultimately blocking their protein translation. Using two specific Fe2+âspecific probes (RhoNoxâ1 and IPâ1) and ion chromatography inductively coupled plasma mass spectrometry (ICâICPâMS), we show that loss of the protective axis of APP and HâFerritin resulted in unchecked accumulation of redoxâactive ferrous iron (Fe2+) fueling neurotoxic oxidative stress. Enforced APP expression partially attenuated Mnâinduced generation of cellular and lipid reactive oxygen species and neurotoxicity. Lastly, we could validate the Mnâmediated suppression of APP and HâFerritin in two rodent in vivo models (C57BL6/N mice and RjHan:SD rats) mimicking acute and chronic Mn exposure. Together, these results suggest that Mnâinduced neurotoxicity is partly attributable to the translational inhibition of APP and HâFerritin resulting in impaired iron metabolism and exacerbated neurotoxic oxidative stress
Organ complications after CD19 CAR T-cell therapy for large B cell lymphoma: a retrospective study from the EBMT transplant complications and lymphoma working party.
We investigated â„ grade 3 (CTC-AE) organ toxicities for commercial CD19 chimeric antigen receptor T cell (CAR-T cell) products in 492 patients (Axi-Cel; n = 315; Tisa-Cel; n = 177) with Large B-cell Lymphoma in the European Society for Blood and Marrow Transplantation (EBMT) CAR-T registry. The incidence of â„ grade 3 organ toxicities during the first 100 days after CAR-T was low and the most frequent were: renal (3.0%), cardiac (2.3%), gastro-intestinal (2.3%) and hepatic (1.8%). The majority occurred within three weeks after CAR-T cell therapy. Overall survival was 83.1% [79.8-86.5; 95% CI] at 3 months and 53.5% [49-58.4; 95% CI] at one year after CAR-T. The most frequent cause of death was tumour progression (85.1%). Non-relapse mortality was 3.1% [2.3-4.1; 95% CI] at 3 months and 5.2% [4.1-6.5; 95% CI] at one year after CAR-T. The most frequent causes of non-relapse mortality were cell-therapy-related toxicities including organ toxicities (6.4% of total deaths) and infections (4.4% of total deaths). Our data demonstrates good safety in the European real-world setting
Measuring the capability to raise revenue process and output dimensions and their application to the Zambia revenue authority
The worldwide diffusion of the good governance agenda and new public management has triggered a renewed focus on state capability and, more specifically, on the capability to raise revenue in developing countries. However, the analytical tools for a comprehensive understanding of the capability to raise revenue remain underdeveloped. This article aims at filling this gap and presents a model consisting of the three process dimensions âinformation collection and processingâ, âmerit orientationâ and âadministrative accountabilityâ. âRevenue performanceâ constitutes the fourth capability dimension which assesses tax administrationâs output. This model is applied to the case of the Zambia Revenue Authority. The dimensions prove to be valuable not only for assessing the how much but also the how of collecting taxes. They can be a useful tool for future comparative analyses of tax administrationsâ capabilities in developing countries.Die weltweite Verbreitung der Good-Governance- und New-Public-Management-Konzepte hat zu einer zunehmenden Konzentration auf staatliche LeistungsfĂ€higkeit und, im Besonderen, auf die LeistungsfĂ€higkeit der Steuererhebung in EntwicklungslĂ€ndern gefĂŒhrt. Allerdings bleiben die analytischen Werkzeuge fĂŒr ein umfassendes VerstĂ€ndnis von LeistungsfĂ€higkeit unterentwickelt. Dieser Artikel stellt hierfĂŒr ein Modell vor, das die drei Prozess-Dimensionen âSammeln und Verarbeiten von Informationenâ, âLeistungsorientierung der Mitarbeiterâ und âVerantwortlichkeit der Verwaltungâ beinhaltet. âEinnahmeperformanzâ ist die vierte Dimension und erfasst den Output der Steuerverwaltung. Das mehrdimensionale Modell wird fĂŒr die Analyse der LeistungsfĂ€higkeit der Steuerbehörde Zambias (Zambia Revenue Authority) genutzt. Es erweist sich nicht nur fĂŒr die Untersuchung des Wieviel, sondern auch des Wie des Erhebens von Steuern als wertvoll. Die vier Dimensionen können in Zukunft zur umfassenden und vergleichenden Analyse der LeistungsfĂ€higkeit verschiedener Steuerverwaltungen in EntwicklungslĂ€ndern genutzt werden
Current incidence, severity, and management of veno-occlusive disease/sinusoidal obstruction syndrome in adult allogeneic HSCT recipients:an EBMT Transplant Complications Working Party study
The current incidence, diagnostic policy, management, and outcome of VOD/SOS at EBMT centers were studied. All centers that had performed allogeneic HSCTs in adult patients within one defined year were invited to the study. Seventy-one centers participated with a total of 2886 allogeneic transplantations and 93 cases of VOD/SOS in 2018. The cumulative incidence of VOD/SOS at day 21 was 1.8% and at day 100 2.4%. Of 67 cases with detailed data, 52 were classical and 15 (22%) late onset (>day 21). According to the EBMT criteria, 65/67 patients had at least two VOD/SOS risk factors. The severity grades were: mild 0, moderate 3, severe 29, very severe 35. Fifty-four patients were treated with defibrotide. VOD/SOS resolved in 58% of the patients, 3/3 with moderate, 22/28 with severe, and 12/33 with very severe grade (p < 0.001). By day 100, 57% of the patients were alive; 3/3 with moderate, 22/29 with severe, and 13/35 with very severe VOD/SOS (p = 0.002). In conclusion, the incidence of VOD/SOS was low. Severe and very severe grades dominated. Very severe grade predicted poor outcome compared to severe grade further supporting the concept of early diagnosis and treatment to avoid a dismal outcome. [Figure not available: see fulltext.]</p
Rituximab retherapy in patients with relapsed aggressive B cell and mantle cell lymphoma
Neither effective salvage regimens nor the outcome and response to retherapy with rituximab containing chemotherapy have been defined for rituximab pre-treated patients with relapsing aggressive lymphoma. We report here a single-centre retrospective outcome analysis of second-line immunochemotherapy with rituximab. In 28 patients with relapsed or refractory diffuse large B cell lymphomas, first-line immunochemotherapy had induced objective responses in 18 patients. Nine of 28 patients responded to rituximab containing salvage therapy, leading to a median overall survival of 243Â days after start of second immunochemotherapy. Long-term disease free survivors (1,260 and 949Â days) were restricted to the group of twelve patients that had received allogeneic stem cell transplantation as consolidation therapy. In 21 patients with relapsed mantle cell lymphomas (MCL), 19 patients had reached remissions with first-line therapy. Of those, 16 patients experienced responses to salvage therapy with a median overall survival of 226Â days. Noteworthy, none of patients with initial non-responding disease reached a remission with second immunochemotherapy. Seven patients with MCL stayed free from progression after high-dose therapy with autologous or allogeneic stem cell transplantation in two and five cases, respectively. In summary, responses to repeated immunotherapy with rituximab were observed in approximately one third and two thirds of initially responding patients with aggressive B cell lymphoma and mantle cell lymphoma, respectively, but not in primarily refractory disease. Lasting remissions were achieved only by high-dose chemotherapy with stem cell transplantation
Validation of the transplant conditioning intensity (TCI) index for allogeneic hematopoietic cell transplantation
The intensity of the conditioning regimen given before allogeneic hematopoietic cell transplantation (allo-HCT) can vary substantially. To confirm the ability of the recently developed transplant conditioning intensity (TCI) score to stratify the preparative regimens of allo-HCT, we used an independent and contemporary patient cohort of 4060 transplant recipients with acute myeloid leukemia meeting inclusion criteria from the discovery study (allo-HCT in first complete remission, matched donor), but who were allografted in a more recent period (2018â2021) and were one decade older (55â75 years, median 63.4 years), we assigned them to a TCI category (low n = 1934, 48%; intermediate n = 1948, 48%, high n = 178, 4%) according to the calculated TCI score ([1â2], [2.5â3.5], [4â6], respectively), and examined the validity of the TCI category in predicting early non-relapse mortality (NRM), 2-year NRM and relapse (REL). In the unadjusted comparison, the TCI index provided a significant risk stratification for d100 and d180 NRM, NRM and REL risk. In the multivariate analysis adjusted for significant variables, there was an independent association of TCI with early NRM, NRM and REL. In summary, we confirm in contemporary treated patients that TCI reflects the conditioning regimen related morbidity and anti-leukemic efficacy satisfactorily and across other established prognostic factors.</p
Short term non-invasive ventilation post-surgery improves arterial blood-gases in obese subjects compared to supplemental oxygen delivery - a randomized controlled trial
<p>Abstract</p> <p>Background</p> <p>In the immediate postoperative period, obese patients are more likely to exhibit hypoxaemia due to atelectasis and impaired respiratory mechanics, changes which can be attenuated by non-invasive ventilation (NIV). The aim of the study was to evaluate the duration of any effects of early initiation of short term pressure support NIV vs. traditional oxygen delivery via venturi mask in obese patients during their stay in the PACU.</p> <p>Methods</p> <p>After ethics committee approval and informed consent, we prospectively studied 60 obese patients (BMI 30-45) undergoing minor peripheral surgery. Half were randomly assigned to receive short term NIV during their PACU stay, while the others received routine treatment (supplemental oxygen via venturi mask). Premedication, general anaesthesia and respiratory settings were standardized. We measured arterial oxygen saturation by pulse oximetry and blood gas analysis on air breathing. Inspiratory and expiratory lung function was measured preoperatively (baseline) and at 10 min, 1 h, 2 h, 6 h and 24 h after extubation, with the patient supine, in a 30 degrees head-up position. The two groups were compared using repeated-measure analysis of variance (ANOVA) and t-test analysis. Statistical significance was considered to be P < 0.05.</p> <p>Results</p> <p>There were no differences at the first assessment. During the PACU stay, pulmonary function in the NIV group was significantly better than in the controls (p < 0.0001). Blood gases and the alveolar to arterial oxygen partial pressure difference were also better (p < 0.03), but with the addition that overall improvements are of questionable clinical relevance. These effects persisted for at least 24 hours after surgery (p < 0.05).</p> <p>Conclusion</p> <p>Early initiation of short term NIV during in the PACU promotes more rapid recovery of postoperative lung function and oxygenation in the obese. The effect lasted 24 hours after discontinuation of NIV. Patient selection is necessary in order to establish clinically relevant improvements.</p> <p>Trial Registration#</p> <p>DRKS00000751; <url>http://www.germanctr.de</url></p
Measuring the Capability to Raise Revenue: Process and Output Dimensions and Their Application to the Zambia Revenue Authority
Relevance of target cell-induced apoptosis as mechanism of resistance against natural killer cells
First lacustrine varve chronologies from Mexico: impact of droughts, ENSO and human activity since AD 1840 as recorded in maar sediments from Valle de Santiago
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