Search

Theories of embodied cognition suggest that a shared environment and ongoing sensorimotor interaction are central for interpersonal learning and engagement. To investigate the embodied, distributed and hence dynamically unfolding nature of social cognitive capacities, we present a novel laboratory-based coordination task: the BallGame. Our paradigm requires continuous sensing and acting between two players who jointly steer a virtual ball around obstacles towards as many targets as possible. By analysing highly resolved measures of movement coordination and gaming behaviour, game-concurrent experience ratings, semi-structured interviews, and personality questionnaires, we reveal contributions from different levels of observation on social experience. In particular, successful coordination (number of targets collected) and intermittent periods of high versus low movement coordination (variability of relation) emerged as prominent predictors of social experience. Importantly, having the same (but incomplete) view on the game environment strengthened interpersonal coordination, whereas complementary views enhanced engagement and tended to generate more complex interactive behaviour. Overall, we find evidence for a critical balance between similarity and synchrony on the one hand, and variability and difference on the other, for successful engagement in social interactions. Finally, following participant reports, we highlight how interpersonal experience emerges from specific histories of coordination that are closely related to the interaction context in both space and time. [ABSTRACT FROM AUTHOR]

In our study, we aimed to explore the profile of the high-risk subgroup of suicide attempters that used a violent means compared to suicide attempters that chose a non-violent suicide means. Therefore, we recruited a sample of inpatients with recent suicide attempts in three psychiatric hospitals in Thuringia, Germany. We used a structured clinical interview to assess the psychiatric diagnoses, sociodemographic data, and characteristics of the suicide attempt. Furthermore, we used several validated clinical questionnaires to measure suicidal ideations, suicide intent, depression severity, hopelessness, impulsivity, aggression, anger expression, and childhood trauma. We compared 41 individuals using violent means to 59 using non-violent means with univariate and multivariate statistical analyses. We found significantly (corrected for multiple comparisons) higher levels of impulsivity-related sensation-seeking in violent suicide attempters in univariate and multivariate analyses, and additionally in anger expression directed inward at an uncorrected statistical threshold. Besides that, there were no significant differences between the two groups. We assume that underlying neurocognitive mechanisms, such as impaired decision-making processes and/or differences in risk/loss assessment, could explain the higher levels of questionnaire-based sensation-seeking in subjects who use violent suicide means. Further research is needed, including neuroimaging and biochemical techniques, to gain more insight into the mechanisms underlying the choice of a suicidal means. [ABSTRACT FROM AUTHOR]

Purpose: Infectious complications are as high as 30% in elective colorectal surgery. In recent years, several studies have discussed the topic of preoperative bowel decontamination prior to colorectal surgery in order to reduce postoperative infectious complications and have found significant effects of oral antibiotic administration with a large variety of drugs used. No study has evaluated the combination of oral paromomycin and metronidazole in this context. Methods: We performed a prospective single-center study with a matched-pair retrospective cohort to evaluate postoperative infectious complications (superficial site infections, organ space abscess, anastomotic leakage) in elective colorectal surgery. Patients: A total of 120 patients were available for study inclusion; 101 gave informed consent and were included. A total of 92 patients were matched and subsequently analyzed. We could show a reduction in overall infectious complications in the intervention group (15.2% vs 30.8%, p = 0.018; odds ratio 0.333, 95% CI 0.142–0.784) as well as a reduction in superficial surgical site infections (8.7 vs 19.6%, p = 0.041, OR 0.333, 95% CI 0.121–0.917). The frequency of the other infectious complications such as intraabdominal abscesses and anastomotic leakage showed a tendency towards decreased frequencies in the intervention group (OR 0.714, 95% CI 0.235–2.169 and OR 0.571; 95% CI 0.167–1.952, respectively). Finally, the oral antibiotic administration led to an almost significantly reduced length of stay (12.24 days vs 15.25 days; p = 0.057). Conclusions: Oral paromomycin and metronidazole with intravenous ertapenem effectively reduce infectious complications in elective colorectal surgery. Trial registration: The study was registered at Clinicaltrials.gov (NCT03759886) December 17, 2018 [ABSTRACT FROM AUTHOR]

• Mobility classified mass spectrometry of glutathione capped gold core-shell particles. • Determination of chemical composition of ultra-small particles. • Extraction of structural and mechanical properties by the modified Stokes-Millikan mobility model. • Liquid to gas-phase transfer of sub-3nm particles by electrospray. [ABSTRACT FROM AUTHOR]

I expand on the implications that Candiotto’s enactive and situated account of love has for scientific research. In particular, I focus on curiosity as a common denominator of the strategies that Candiotto suggests in order to maintain desirable distance and loving relations with the concrete others that make up our world. Staying close to Candiotto’s arguments around the importance of difference and distance for the development of loving (learning) relations, as well as the central role she ascribes to prolonged and attentive engagement with environmental others (inhabiting place), I offer resources and research questions to strengthen curiosity about self and other in scientific environments. [ABSTRACT FROM AUTHOR]

Background: Treatment of active rheumatoid arthritis may necessitate a methotrexate mono- or combination therapy. As in the present case, novel side effects may occur, when escalating therapy.Case Presentation: A 63-year-old Caucasian female patient with rheumatoid arthritis on methotrexate for 8 years and on leflunomide for 6 years was admitted for weakness, edema, ascites, and petechiae of the lower legs. Comorbidities included a urinary tract infection, metabolic syndrome with obesity, type-2 diabetes without necessity for insulin or oral antidiabetics, and non-alcoholic fatty liver disease. Laboratory results showed acute liver failure, oliguric acute kidney injury, thrombocytopenia, and schistocyte-positive, Coombs-negative hemolytic anemia. On admission, her ADAMTS13 activity was decreased, and her leflunomide plasma level was elevated (120 μg/l). Due to severe hypoalbuminemia, an intravascular hypovolemia, and severe metabolic alcalosis with hypokalemia were found. For the newly diagnosed thrombotic microangiopathy, leflunomide and methotrexate were discontinued, and 4 units of fresh-frozen plasma were given. Steroid therapy was administered for 5 days, until thrombotic thrombocytopenic purpura was excluded. Intravenous human albumin, oral vitamin K, and cholestyramine were administered for liver failure and leflunomide overdosage, respectively. Liver biopsy revealed a non-alcoholic fatty liver disease transforming into liver cirrhosis. After 2 weeks, our patient was discharged. However, within 3 weeks after discharge, our patient was rehospitalized for a relapse of acute liver failure, urinary tract infection, and influenza. Leflunomide and methotrexate were not reintroduced before or thereafter. Over a period of 11 months after discharge, her thrombotic microangiopathy subsided, and her renal and liver function fully recovered.Conclusions: Under a combination of leflunomide and methotrexate, liver toxicity and, for the first time, thrombotic microangiopathy occurred as side effects. Non-alcoholic fatty liver disease may have predisposed for the drug-induced liver toxicity. [ABSTRACT FROM AUTHOR]

The presence of electrochemical reactions occurring in an electrospray processes at the point where the current enters the liquid is discussed since the early 1990's. This current transfer to the liquid results in oxidation or reduction of either electrolyte species in the liquid sprayed or of the electrode material in contact with the liquid. As a result, new chemical species are generated. These products of the electrochemical reaction might be detected as altered species in mass spectra; they might be volatile and not recognized at all or accumulate on the electrode surface and cause cross contamination later on. In other cases, it might happen that the products of the electrochemical reactions are the only detectable species formed from an otherwise nondetectable analyte. An electrospray setup in which electrochemical reactions do not interfere with the analyte under investigation excludes the electrochemical reaction as source of sample contamination and sample altering and may serve as reference setup for experiments focused on the electrochemical reaction itself. We present a simple and inexpensive current coupling approach and specify operation conditions for which any impact of the electrochemical reaction on the sample under investigation is inherently excluded. On the basis of a practical example, we show the impact of the electrochemical reaction on sample composition and demonstrate the benefit of using the proposed current coupling method. Because of the obvious benefit of this method and its simple realization, it has the potential to be employed as standard feeding approach, especially for electrosprays operated at small flow rates. [ABSTRACT FROM AUTHOR]

Electrospraying is a highly attractive method for generation of small particles and also for measurement applications of particles in suspensions. In the cone jet mode, the particle generation rate increases with decreasing flow rate. For applications in the field of aerosol technology flow rates of less than 10µl/h are attractive as particle sizes of less than 200nm can be obtained in this flow rate range. At the same time generation frequency of drops reaches the values required for size measurements by Scanning Mobility Particle Sizers (SMPS). A special challenge in operation of electrosprays at small flow rates is the change of liquid composition due to mass transfer processes between the Taylor cone and the surrounding gas phase. Typically used organic solvents such as alcohols, acetone or acetonitrile evaporate fast (or even evaporate completely) and mixtures containing such volatile species will change their composition significantly due to evaporation from the Taylor cone. Based on key experiments we show a) that the evaporating solvent can be reduced by as much as a factor of 20 by controlling the gas phase saturation. This allows spraying volatile solvents such as e.g. methanol at flow rates down to less than 1µl/h and makes the attractive sub-10µl/h flow rate range accessible to quite volatile solvents as well. b) that changes in the liquid composition by not considering the mass transfer (evaporation) problem lead to significant differences in liquid properties between the feed liquid and the Taylor cone. For example, an increase of surface tension by a factor of 2 is observed for water and t-butanol feed liquid. c) that employing a saturated sheath gas flow allows for very effective manipulation of the solvent composition in the Taylor cone. Based on water as feed liquid we show that a sufficient amount of organic solvent is easily transferred to the Taylor cone liquid from the gas phase to allow spraying the water without electron scavenging gases. Measurement results of the Taylor cone liquid composition are in good agreement with predictions by the presented new model describing the mass transfer between the Taylor cone and the surrounding gas phase. The efficiency of the mass transfer, the predictability of the process and the opportunity of comparably quick changes of the Taylor cone liquid by changing the gas phase saturation state result in a powerful tool for the entire field of electrospraying at low rates. [ABSTRACT FROM AUTHOR]

In central nervous system (CNS) synapses, action potential-evoked neurotransmitter release is principally mediated by CaV2.1 calcium channels (CaV2.1) and is highly dependent on the physical distance between CaV2.1 and synaptic vesicles (coupling). Although various active zone proteins are proposed to control coupling and abundance of CaV2.1 through direct interactions with the CaV2.1 a1 subunit C-terminus at the active zone, the role of these interaction partners is controversial. To define the intrinsic motifs that regulate coupling, we expressed mutant CaV2.1 a1 subunits on a CaV2.1 null background at the calyx of Held presynaptic terminal. Our results identified a region that directly controlled fast synaptic vesicle release and vesicle docking at the active zone independent of CaV2.1 abundance. In addition, proposed individual direct interactions with active zone proteins are insufficient for CaV2.1 abundance and coupling. Therefore, our work advances our molecular understanding of CaV2.1 regulation of neurotransmitter release in mammalian CNS synapses. [ABSTRACT FROM AUTHOR]

Although azanucleoside DNA-hypomethylating agents ( HMAs) are routinely used for the treatment of myelodysplastic syndrome/acute myeloid leukaemia ( MDS/ AML), very few outcome predictors have been established. Expression of the β-like globin gene locus is tightly regulated by DNA methylation, is HMA-sensitive in vitro, and fetal haemoglobin (HbF) expression is under study as a potential biomarker for response of MDS patients to azacitidine. We determined HbF expression in 16 MDS and 36 AML patients receiving decitabine ( DAC). Pre-treatment HbF was already elevated (>1·0% of total haemoglobin) in 7/16 and 12/36 patients, and HbF was induced by DAC in 81%/54% of MDS/ AML patients, respectively. Elevated pre-treatment HbF was associated with longer median overall survival ( OS): 26·6 vs. 8·6 months for MDS (hazard ratio [ HR] 8·56, 95% confidence interval [ CI] 1·74-42·49, P = 0·008, with similarly longer progression-free and AML-free survival), and 10·0 vs. 2·9 months OS for AML ( HR 3·01, 95% CI 1·26-7·22, P = 0·014). In a multivariate analysis, the prognostic value of HbF was retained. Time-dependent Cox models revealed that the prognostic value of treatment-induced HbF induction was inferior to that of pre-treatment HbF. In conclusion, we provide first evidence for in vivo HbF induction by DAC in MDS/ AML, and demonstrate prognostic value of elevated pre-treatment HbF, warranting prospective, randomized studies. [ABSTRACT FROM AUTHOR]

The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95). [ABSTRACT FROM AUTHOR]

Introduction: Clostridium difficile infection (CDI) is the most common cause of health-care-associated infectious diarrhea. Recurrence rates are as high as 20-30% after standard treatment with metronidazole or vancomycin, and appear to be reduced for patients treated with fidaxomicin. According to the literature, the risk of CDI recurrence increases after the second relapse to 30-65%. Accurate data for Germany are not yet available. Methods: Based on the research database of arvato health analytics (Munich, Germany), a secondary data analysis for the incidence, treatment characteristics and course of CDI was performed. The database included high granular accounting information of about 1.46 million medically insured patients covering the period 2006-2013, being representative for Germany. The analysis was based on new-onset CDI in 2012 in patients which either received outpatient antibiotic therapy for CDI or were hospitalized. Results: The ICD-10 coded incidence of CDI in 2012 was 83 cases per 100,000 population. Overall mortality rates within the follow-up period of 1 year were 13.5% in inpatients with primary diagnosis of CDI, compared to 24.3% in inpatients with secondary diagnosis of CDI ( P < 0.001), and 7.1% in outpatients ( P < 0.001). In the median, patients with secondary diagnosis of CDI remained significantly longer hospitalized (24 vs. 9 days, P < 0.001). First recurrence of CDI was observed in 18.2% of cases with index events. There was a significantly increased risk to suffer a second and third recurrence, reaching 28.4% ( P < 0.001), and 30.2% ( P = 0.017), respectively. Antibiotic therapy of CDI in outpatients was performed mainly with metronidazole (in 90.8% of index events, 60.0% of first recurrences, and 43.5% of second recurrences). Conclusion: The reported incidence of CDI in Germany is higher than noted previously. The recurrence rates do increase with the number of relapses, but are lower than reported in the literature, despite dominance of metronidazole treatment in outpatients. Funding: MSD Sharp & Dohme GmbH, Haar, Germany. [ABSTRACT FROM AUTHOR]

The term epigenetics is defined as heritable changes in gene expression that are not due to alterations of the DNA sequence. In the last years, it has become more and more evident that dysregulated epigenetic regulatory processes have a central role in cancer onset and progression. In contrast to DNA mutations, epigenetic modifications are reversible and, hence, suitable for pharmacological interventions. Reversible histone methylation is an important process within epigenetic regulation, and the investigation of its role in cancer has led to the identification of lysine methyltransferases and demethylases as promising targets for new anticancer drugs. In this review, we describe those enzymes and their inhibitors that have already reached the first stages of clinical trials in cancer therapy, namely the histone methyltransferases DOT1L and EZH2 as well as the demethylase LSD1. [ABSTRACT FROM AUTHOR]

Background: Plastic stents used for the treatment of biliary obstruction will become occluded over time due to microbial colonization and formation of biofilms. Treatment of stent-associated cholangitis is often not effective because of inappropriate use of antimicrobial agents or antimicrobial resistance. We aimed to assess the current bacterial and fungal etiology of stent-associated biofilms, with particular emphasis on antimicrobial resistance. Methods: Patients with biliary strictures requiring endoscopic stent placement were prospectively enrolled. After the retrieval of stents, biofilms were disrupted by sonication, microorganisms were cultured, and isolates were identified by matrix-associated laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry and/or biochemical typing. Finally, minimum inhibitory concentrations (MICs) were determined for various antimicrobial agents. Selected stents were further analyzed by fluorescence in situ hybridization (FISH). Results: Among 120 patients (62.5% males, median age 64 years) with biliary strictures (35% malignant, 65% benign), 113 double pigtail polyurethane and 100 straight polyethylene stents were analyzed after a median indwelling time of 63 days (range, 1–1274 days). The stent occlusion rate was 11.5% and 13%, respectively, being associated with a significantly increased risk of cholangitis (38.5% vs. 9.1%, P<0.001). Ninety-five different bacterial and 13 fungal species were detected; polymicrobial colonization predominated (95.8% vs. 4.2%, P<0.001). Enterococci (79.3%), Enterobacteriaceae (73.7%), and Candida spp. (55.9%) were the leading pathogens. Candida species were more frequent in patients previously receiving prolonged antibiotic therapy (63% vs. 46.7%, P = 0.023). Vancomycin-resistant enterococci accounted for 13.7%, extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae with co-resistance to ciprofloxacin accounted for 13.9%, and azole-resistant Candida spp. accounted for 32.9% of the respective isolates. Conclusions: Enterococci and Candida species play an important role in the microbial colonization of biliary stents. Therefore, empirical antimicrobial treatment of stent-associated cholangitis should be guided toward enterococci, Enterobacteriaceae, streptococci, anaerobes, and Candida. To determine causative pathogens, an accurate microbiological analysis of the extracted stent(s) may be helpful. [ABSTRACT FROM AUTHOR]

In a study of elderly AML patients treated with the hypomethylating agent decitabine (DAC), we noted a surprisingly favorable outcome in the (usually very unfavorable) subgroup with two or more autosomal monosomies (MK2+) within a complex karyotype (Lübbert et al., Haematologica 97:393-401, 2012). We now analyzed 206 myelodysplastic syndrome (MDS) patients (88 % of 233 patients randomized in the EORTC/GMDSSG phase III trial 06011, 61 of them with RAEBt, i.e. AML by WHO) with cytogenetics informative for MK status.. Endpoints are the following: complete/partial (CR/PR) and overall response rate (ORR) and progression-free (PFS) and overall survival (OS). Cytogenetic subgroups are the following: 63 cytogenetically normal (CN) patients, 143 with cytogenetic abnormalities, 73 of them MK-negative (MK-), and 70 MK-positive (MK+). These MK+ patients could be divided into 17 with a single autosomal monosomy (MK1) and 53 with at least two monosomies (MK2+). ORR with DAC in CN patients: 36.1 %, in MK- patients: 16.7 %, in MK+ patients: 43.6 % (MK1: 44.4 %, MK2+ 43.3 %). PFS was prolonged by DAC compared to best supportive care (BSC) in the CN (hazard ratio (HR) 0.55, 99 % confidence interval (CI), 0.26; 1.15, p = 0.03) and MK2+ (HR 0.50; 99 % CI, 0.23; 1.06, p = 0.016) but not in the MK-, MK+, and MK1 subgroups. OS was not improved by DAC in any subgroup. In conclusion, we demonstrate for the first time in a randomized phase III trial that high-risk MDS patients with complex karyotypes harboring two or more autosomal monosomies attain encouraging responses and have improved PFS with DAC treatment compared to BSC. [ABSTRACT FROM AUTHOR]

In the first randomized trial of older patients with myelodysplastic syndrome/acute myeloid leukemia (adaptive randomization) to receive treatment with intravenous decitabine (5‐day schedule) either alone or in combination with the oral histone deacetylase (HDAC) inhibitor valproic acid (7‐day schedule), Issa and colleagues do not detect an improved response rate or overall survival with the combined treatment. The various factors potentially affecting clinical outcome in studies combining decitabine or 5‐azacytidine with valproic acid or other HDAC inhibitors are discussed. [ABSTRACT FROM AUTHOR]

Treatment outcomes for older patients with acute myeloid leukemia (AML) have remained dismal. This randomized, phase 2 trial in AML patients not considered suitable for intensive induction therapy compared low-dose cytarabine (LDAC) with or without volasertib, a highly potent and selective inhibitor of polo-like kinases. Eighty-seven patients (median age 75 years) received LDAC 20 mg twice daily subcutaneously days 1-10 or LDAC + volasertib 350 mg IV days 1 + 15 every 4 weeks. Response rate (complete remission and complete remission with incomplete blood count recovery) was higher for LDAC + volasertib vs LDAC (31.0% vs 13.3%; odds ratio, 2.91; P = .052). Responses in the LDAC + volasertib arm were observed across all genetic groups, including 5 of 14 patients with adverse cytogenetics. Median event-free survival was significantly prolonged by LDAC + volasertib compared with LDAC (5.6 vs 2.3 months; hazard ratio, 0.57; 95% confidence interval, 0.35-0.92; P = .021); median overall survival was 8.0 vs 5.2 months, respectively (hazard ratio, 0.63; 95% confidence interval, 0.40-1.00; P = .047). LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events; there was no increase in the death rate at days 60 + 90. This study was registered at www.clinicaltrials.gov as #NCT00804856. [ABSTRACT FROM AUTHOR]

Abstract: After a single patient was transferred to Leipzig University Hospital from a hospital in Rhodes, Greece, the hospital experienced the largest outbreak due to a KPC-2-producing Klebsiella pneumoniae (KPC-2-KP) strain thus far observed in Germany. Ninety patients hospitalised between July 2010 and October 2012 were affected. In an attempt to eliminate KPC-2-KP from their digestive tracts, 14 consecutive patients (16%) were treated with a short course (7 days) of selective digestive decontamination (SDD), employing colistin (1 million units q.i.d.) and gentamicin (80mg q.i.d.) as oral solutions, and applying colistin/gentamicin gel (0.5g) to the oral cavity. In a retrospective analysis, these 14 SDD patients were compared with the remaining 76 patients harbouring KPC-2-KP. KPC-2-KP carrier status was followed in all 14 SDD patients by submitting stool samples to KPC-specific PCR. The mean follow-up period was 48 days (range 12–103 days). Successful elimination of KPC-2-KP was defined as a minimum of three consecutive negative PCR test results separated by ≥48h each. Decolonisation of KPC-2-KP was achieved in 6/14 patients (43%) after a mean of 21 days (range 12–40 days), but was also observed in 23/76 (30%) of the non-SDD controls (P =0.102). SDD treatment resulted in the development of secondary resistance to colistin (19% increase in resistance rate) and gentamicin (45% increase) in post-treatment isolates. In the control group, no secondary resistance occurred. We conclude that the SDD protocol applied in this study was not sufficiently effective for decolonisation and was associated with resistance development. [Copyright &y& Elsevier]

Primary sensory afferents of the dorsal root and trigeminal ganglia constantly transmit sensory information depicting the individual’s physical and chemical environment to higher brain regions. Beyond the typical trigeminal stimuli (e.g. irritants), environmental stimuli comprise a plethora of volatile chemicals with olfactory components (odorants). In spite of a complete loss of their sense of smell, anosmic patients may retain the ability to roughly discriminate between different volatile compounds. While the detailed mechanisms remain elusive, sensory structures belonging to the trigeminal system seem to be responsible for this phenomenon. In order to gain a better understanding of the mechanisms underlying the activation of the trigeminal system by volatile chemicals, we investigated odorant-induced membrane potential changes in cultured rat trigeminal neurons induced by the odorants vanillin, heliotropyl acetone, helional, and geraniol. We observed the dose-dependent depolarization of trigeminal neurons upon application of these substances occurring in a stimulus-specific manner and could show that distinct neuronal populations respond to different odorants. Using specific antagonists, we found evidence that TRPA1, TRPM8, and/or TRPV1 contribute to the activation. In order to further test this hypothesis, we used recombinantly expressed rat and human variants of these channels to investigate whether they are indeed activated by the odorants tested. We additionally found that the odorants dose-dependently inhibit two-pore potassium channels TASK1 and TASK3 heterologously expressed In Xenopus laevis oocytes. We suggest that the capability of various odorants to activate different TRP channels and to inhibit potassium channels causes neuronal depolarization and activation of distinct subpopulations of trigeminal sensory neurons, forming the basis for a specific representation of volatile chemicals in the trigeminal ganglia. [ABSTRACT FROM AUTHOR]

Background: Alveolar echinococcosis (AE) is an endemic parasitic zoonosis in Germany. In most cases, the liver is the primary organ affected. Case presentation: A 59-year old female patient presented with increasing exertional dyspnea and unintentional weight loss. A computed tomography (CT) scan showed a left-sided chylous pleural effusion and multiple intrahepatic masses with infiltration of the diaphragm and the pleura. The findings were initially misinterpreted as hepatocellular carcinoma (HCC) with infiltrating growth. Liver biopsy of one of the masses showed no evidence of malignancy, but an amorphous necrosis of unclear origin. HCC was further ruled out by magnetic resonance imaging (MRI). However, MRI findings were highly suspicious for hepatothoracic dissemination and complications due to AE. Typical histologic findings in a repeated and more specific examination of the liver tissue and a positive serology for echinococcosis confirmed the diagnosis of AE. As the hepatic and pulmonary manifestations were considered inoperable in a curative matter, an anti-parasitic treatment with albendazole was initiated. A video-assisted thoracoscopic surgery (VATS) with removal of the chylous effusion as well as a talc pleurodesis was performed to relieve the patient from dyspnea. Two months later, the patient was asymptomatic and a positron emission tomography (PET)-CT-scan with [18 F] fluoro-2-deoxy-d-glucose (FDG) showed a remarkable diminution of the hepatic manifestation. Conclusions: This case demonstrates a rare presentation of alveolar echinococcosis with a focus on pulmonary symptoms, emphasizing the importance of evaluation for pulmonary involvement in patients with AE and respiratory symptoms. [ABSTRACT FROM AUTHOR]

We present a calculation of the perturbative quark-to-quark transverse parton disthbution function at next-to-next-to-leading order based on a gauge invariant operator definition. We demonstrate for the first time that such a defimtion works beyond the first nontrivial order. We extract from our calculation the coefficient functions relevant for a next-to-next-to-next-to-leading logarithmic QT resummation in a large class of processes at hadron colliders. [ABSTRACT FROM AUTHOR]

Electrostatic precipitation (ESP) probably is the most energy efficient way to remove particles from gas streams. Even after more than a century of industrial application and scientific research, there is still work to do. Changing demands and new technological developments are creating new fields of application for ESP. On the other hand, a number of gaps in basic scientific understanding of ESP still need to be filled. Here, an overview of recent findings and developments is given. [ABSTRACT FROM AUTHOR]

We have piloted a low-dose schedule of 5-azacytidine followed by donor lymphocyte infusions (DLIs) in patients with relapse of AML or chronic myelomonocytic leukemia (CMMoL) after allografting. Of the 26 patients (median age 62 years, range 28–75) with relapsed AML (n=24) or CMMoL (n=2), 11 (42%) had poor-risk cytogenetics. Twenty-three patients had received fludarabine-based reduced-toxicity conditioning regimens, and three had received conventional myeloablative conditioning. Patients received 5-azacytidine s.c., at a total daily dose of 100 mg, on days 1–3, to be followed by DLI on day 10, with the next course of treatment to be started on day 22. A total of 60 courses of 5-azacytidine were administered, with a median of 2 courses (range: 1–10). In 44 courses, 5-azacytidine was followed by DLI, and thus 19/26 (73%) patients received at least one course of this combined treatment. Clinically relevant neutropenic infections not associated with progressive disease developed in four patients, one of them succumbing to sepsis. Only two patients developed de novo acute GvHD after the combination of 5-azacytidine and DLI. Overall, 66% of the patients benefited from this treatment, with continued CRs achieved in 4 (16%) patients, lasting a median of 525 days (range: 450+ to 820+), and a 50% rate of temporary disease control with stable mixed chimerism (median duration 72 days). The median survival from the start of 5-azacytidine treatment was 136 days (range: 23 to 873+), with an estimated 2-year survival probability of 16%. In conclusion, this non-intensive outpatient regimen of 5-azacytidine followed by DLI is feasible, with a very low aGVHD rate. Objective responses, including continuous complete donor chimerism, occurred also in patients with poor-risk cytogenetics. [ABSTRACT FROM AUTHOR]

Focuses on the questions regarding the mechanisms mediating a regional, inactivating promoter methylation of the p15/INK4B gene in myelodysplastic syndromes. Genetic alterations of tumor suppressors; Expression of p15 in normal hematopoiesis; Accounts on the number of cases without blast expansion.

Novel, non-intensive treatment options in older MDS/AML patients planned for allografting, with the goal of down-staging the underlying disease and bridging time to transplantation, are presently being developed. 5-azacytidine and decitabine (DAC) are of particular interest, as they can be given repetitively, with very limited non-hematologic toxicity and result in responses both in MDS and AML even at low doses. We describe 15 consecutive patients (median age 69 years, range 60–75 years) with MDS (n=10) or AML (n=5) who all received first-line treatment with DAC and subsequent allografting (from sibling donor in four patients, unrelated donor in 11) after reduced-intensity conditioning with the FBM regimen. Successful engraftment was attained in 14/15 patients, all of whom achieved a CR, with a median duration of 5 months (range 1+ to 51+). Six of these 14 patients are alive (4 with complete donor chimerism), 8 have died either from relapse (n=4) or treatment-related complications while in CR (n=4). We conclude that allografting after low-dose DAC and subsequent conditioning with FBM is feasible, with no unexpected toxicities and appears as a valid alternative to standard chemotherapy (‘InDACtion instead of induction’) in elderly patients with MDS/AML. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the therapeutic effects of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV) infection..

Spatially resolved rocking curve imaging has been used to analyze laterally overgrown silicon layers grown by liquid phase epitaxy. We were able to study both the overgrown layer as well as the strain fluctuations of the Si substrate underneath by means of a tabletop xray topographic setup. The strainfield analysis reveals relative changes of the lattice parameter up to 3.5×106in the silicon substrate underneath the overgrown layer in particular regions and a down bending of both wings of the epitaxial overgrown layers. © 2009 WILEYVCH Verlag GmbH & Co. KGaA, Weinheim [ABSTRACT FROM AUTHOR]

Abstract: Cathepsins have long been regarded enzymes that are primarily involved in general protein turnover within lysosomes. However, more recently, their differential cell and tissue distributions suggest that at least some of them participate in specific cellular processes. Cathepsin S (CATS) is mainly expressed in cells of mononuclear phagocytotic origin and plays a major role in the MHC-II-mediated antigen presentation. Although a central role for CATS in brain function has also been suggested, its localization and regulation in the central nervous system are still poorly understood. In the present study we investigated the regional and cellular expression of CATS in normal, aging and pathological mouse brain. Our studies show that CATS is expressed throughout the adult mouse brain, in particular in microglial cells. In aged mice, CATS protein expression increases in these cells. In addition, it became apparent that in old mice a larger number of neuronal cells stained positive for this protease. At the subcellular level, CATS immunostaining accumulated in granules, indicating a lysosomal localization. In a transgenic mouse model of amyotrophic lateral sclerosis expressing mutant superoxide dismutase 1 (SOD1), CATS transcript and protein levels were significantly upregulated in spinal cord and lower brain regions displaying neuronal degeneration. The majority of strongly immunopositive cells in these regions exhibited microglial morphology. These results suggest that CATS participates in inflammatory processes accompanying aging and pathologies of the CNS. [Copyright &y& Elsevier]

Epigenetic deregulation plays an important role in cancer development. The great interest in epigenetics in hematology and oncology results from the fact that epigenetic, in contrast to genetic, alterations are, in principle, amenable to pharmacological reversal. Epigenetically active drugs currently within clinical trials include histone deacetylase inhibitors (HDACi) and DNA methyltransferase (DNMT) inhibitors. The first treatment approved by the Food and Drug Administration for the treatment of myelodysplastic syndromes (MDS) was the DNMT-inhibitor 5-azacytidine. Currently, two out of three drugs FDA approved for MDS therapy, 5-azacytidine and 5-aza-2′-deoxycytidine, are epigenetically active drugs. Recent clinical trials investigate new dosing schedules, routes of administration, and combination regimens. Several structurally distinct HDACi have been developed. Available data is mostly restricted to phase I trials. The largest experience in MDS and acute myeloid leukemia exists with the anticonvulsant valproic acid. This review summarizes the existing clinical experience on HDACi and DNMT inhibitors [ABSTRACT FROM AUTHOR]

Abstract: For the determination of adsorption isotherms of dissolved components from supercritical fluids, an experimental equipment has been constructed. It consists of a fluid preparation and two chromatographic units with UV detector and pressure expansion. The equipment allows the performance of peak experiments (injecting samples onto an empty column) as well as perturbation experiments (perturbing the equilibrium in a saturated column). Adsorption isotherms of α- and δ-tocopherol on two unmodified silica gels were determined at a temperature of 313.15K and pressures of 16.1, 20.0, and 26.1MPa, respectively. Fluid phase was CO2 with 2-propanol (weight fraction 0.05) as modifier. Parameters of a cubic Hill isotherm were fitted to the data. Ideal adsorbed solution theory (IAST) was applied for prediction of mixture adsorption. Applicability of IAST was tested with perturbation chromatographic experiments using different mixtures. All isotherms show anti-Langmuir behaviour (concave shaped isotherms). These results agree with literature data. Competitive adsorption was successfully predicted by means of the IAS theory. [Copyright &y& Elsevier]

Abstract: Rocking curve imaging is based on measuring a series of Bragg-reflection digital topographs by monochromatic parallel-beam synchrotron radiation in order to quantify local crystal lattice rotations within a large surface area with high angular and high spatial resolution. In this paper we apply the method to map local lattice tilts in two distinct semiconductor sample types with lattice misorientations up to and with spatial resolution from 30  down to 1 . We analyse the measured surface-tilt data volumes for samples with almost smoothly varying specific misoriented defect formation in GaAs wafers and for an inherent subsurface grain structure of epitaxial lateral overgrowth wings in GaN. Back-projected tilt maps and histograms provide both local and global characteristics of the microcrystallinity. [Copyright &y& Elsevier]

During the last 10 years, three European phase II studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2′-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase II study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French–American–British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukaemia. Decitabine showed a rather low toxicity profile in this elderly patient group. In conclusion, low-dose decitabine is an active drug for the treatment of MDS patients, even for those older than 75 years with bad prognostic characteristics. [ABSTRACT FROM AUTHOR]

The myelodysplastic syndromes have, since their first recognition decades ago, been considered notoriously difficult with regard to their proper classification, determination of prognosis, and optimal treatment. With the advent of the French–American–British (FAB) classification, now aided but not superseded by the World Health Organization classification, distinct biological entities have been delineated, which in turn are very useful for stratification to different, established and experimental treatment modalities. However, precise subclassification of different types of myelodysplastic syndrome (MDS) is only possible with hematopathological studies based on the analysis of peripheral blood, bone marrow smear, and bone marrow biopsy, backed by appropriate clinical information. Bone marrow cytogenetics are also essential for any risk stratification since they still provide the second most powerful prognostic parameter after bone marrow blast enumeration. This paper will review the most important aspects of hematopathological diagnostics in MDS, risk scoring, and their application to the inclusion and stratification of patients into the European Organization for Research and Treatment of Cancer (EORTC)/German MDS Study Group Phase III multicenter trial of low-dose decitabine in patients more than 60 years old with high-risk MDS. Emphasis is placed on itemizing the broad spectrum of cytologic and histologic stigmata defining the myelodysplastic categories that are to be considered in this study. [ABSTRACT FROM AUTHOR]

Abstract: The prognosis of lung cancer is very much limited by the difficulties of diagnosing early stage disease amenable to surgery. Thus, novel diagnostic and therapeutic approaches are urgently needed for this common type of cancer. Recently, epigenetic alterations of tumor cells have been defined for a multitude of tissues and genes. Thus, promoter hypermethylation of tumor suppressor genes, and other targets of neoplasia-associated methylation disturbances, have become the most frequent recurrent alteration in solid tumors and hematologic neoplasia. In lung cancer, several sets of genes including the tumor suppressor gene p16, the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), E-cadherin and retinoic acid receptor beta have been shown to be frequently methylated and inactivated. Distinct methylation patterns can provide molecular distinctions between different histologic subtypes of lung cancer. Gene hypermethylation in lung cancer is an early event associated with exposure to tobacco-specific carcinogens. Highly sensitive detection of hypermethylated DNA in sputum and peripheral blood offers a powerful tool for detecting lung cancer at an early stage. Epigenetic alterations in cancer, as opposed to genetic lesions, are potentially reversible. Thus, hypermethylation has been studied as a therapeutic target for agents which revert this epigenotype. The most advanced drugs to inhibit methylation are two azanucleosides, decitabine and its ribonucleoside analogue 5-azacytidine. In vitro, demethylating agents given at low doses reactivate tumor suppressor genes, and in mouse models, the development of lung cancer can be retarded. This effect is more powerful when histone acetylation, as a second epigenetic silencing mechanism, is also inhibited pharmacologically (HDAC inhibitors). Clinical trials of both groups of agents have been performed, and novel demethylating agents which are not incorporated into DNA offer further perspectives for epigenetic therapy of lung cancer and other malignancies. [Copyright &y& Elsevier]

The method called ‘rocking-curve imaging’ (RCI) has recently been developed to visualize lattice imperfections in large crystals such as semiconductor wafers with high spatial resolution. The method is based on a combination of X-ray rocking-curve analysis and digital X-ray diffraction topography. In this article, an extension of the method is proposed by which dislocation densities in large-scale samples (semiconductor wafer crystals) can be quantified and their variation across the sample surface determined in an instrumentally simple way. Results from a nearly dislocation-free S-doped InP crystal and a semi-insulating GaAs are presented; both display a clearly non-random distribution of dislocations. [ABSTRACT FROM AUTHOR]

The demethylating agents 5-aza-2′-deoxycytidine (decitabine, DAC) and 5-azacytidine at low doses induce hematologic and cytogenetic remissions in a subset of patients with MDS. It is unclear whether the correction of neutropenia involves differentiation of abnormal granulocyte precursors, or emergence of normal granulopoiesis. A previous study in three MDS patients, analyzing a differentiating activity of GM-CSF, had shown heterogenous granulocyte responses. The objective of our study was to determine the ratio of clonal and nonclonal peripheral blood granulocytes in MDS patients treated with DAC using FISH analysis. In two patients with initial severe neutropenia, an informative cytogenetic marker, complete normalization of peripheral blood neutrophils and a bone marrow cytogenetic response following DAC, >90% of the cells contributing to neutrophil normalization lacked this clonal marker. In one of them, an early and transient increase in clonal neutrophils was compatible also with a modest differentiating effect upon the dysplastic granulocyte precursors, whereas in a third patient, resistant to re-treatment with DAC, no expansion of either granulocyte population occurred. In the responders, leukocyte nadirs following DAC appeared less pronounced after conversion to normal cytogenetics. In conclusion, restoration of nonclonal hematopoiesis may be the predominant effect of DAC both in early and late stages of treatment, at least in patients achieving a hematologic and cytogenetic response. [Copyright &y& Elsevier]

5-Aza-2′-deoxycytidine, a DNA-hypomethylating agent, can induce clinical remissions in patients with high-risk myelodysplastic syndromes (MDS). During treatment an increase in platelet count is frequently the first positive event to be seen. In this study, we analyzed the platelet response of patients with high-risk MDS on low-dose 5-aza-2′-deoxycytidine therapy. We evaluated 162 from the 170 patients entered in three consecutive Phase II studies. One hundred twenty-six of them were thrombocytopenic at start of the therapy. All patients had an IPSS risk score of Intermediate I or higher. A rise in platelet count preceded a good trilineage response. In 58% of the thrombocytopenic patients a platelet response was already seen after one cycle of therapy. During therapy 69% of the patients with a low platelet count showed a response. Due to disease progression the final response rate was 63% in thrombocytopenic patients. No correlation was found between the platelet response and either the presence or absence of an adequate number of megakaryocytes or serum thrombopoietin levels. However, platelet response strongly predicted for overall survival (P<0.0001).5-Aza-2′-deoxycytidine has a clinically significant, often long lasting, effect on the platelet count in a substantial number of high-risk MDS patients. [Copyright &y& Elsevier]

Differences in mosaicity between lysozyme crystals grown inside and outside a homogeneous magnetic field of 2.4 T and with and without agarose gel were investigated by X-ray diffraction rocking-curve measurements. High angular resolution was achieved using an Si(113) four-reflection Bartels monochromator. The results show that (i) all crystals were highly perfect, (ii) the mosaicities were clearly anisotropic and (iii) the mosaicities varied more strongly within each group of crystals (grown under identical conditions) than the average values across groups. In particular, the effect of the magnetic field on crystal mosaicity was found to be very small. Finally, the spatial distribution of mosaic blocks inside a protein crystal was visualized with a novel diffraction technique using a high spatial resolution two-dimensional CCD detector [ABSTRACT FROM AUTHOR]

Myelodysplastic syndrome (MDS) is a clonal disorder characterized by ineffective hematopoiesis, which can lead to either fatal cytopenias or acute myelogenous leukemias (AML). During the last 15 years, important progress has been made in the understanding of the biology and prognosis of MDS. Risk-adapted treatment strategies were established due to the high median age (60-75 years) of MDS patients and the individual history of the disease (number of cytopenias, cytogenetic changes, transfusion requirements). The use of allogeneic bone marrow transplantation for MDS patients currently offers the only potentially curative treatment, but this form of therapy is not available for the ‘typical’ MDS patient who is >60 years of age. The development of small molecules directed against specific molecular targets with minimal adverse effects is the hope for the future. Innovative uses of immunomodulatory agents and the optimizing of cytotoxic treatment should continue to help in the treatment of MDS.The Hematology Journal (2004) 5, 1-8. doi:10.1038/sj.thj.6200335 [ABSTRACT FROM AUTHOR]

Frequent genetic alterations in hematopoietic neoplasias (chromosomal translocations, point mutations, etc.) have provided biologic targets for the development of effective novel therapies. A rapidly increasing body of knowledge provides evidence also for multiple epigenetic alterations in these disorders, which can complement or even precede genetic aberrations. Gene inactivation (‘silencing’) of tumor suppressor and growth inhibitory genes (e.g. the cyclin-dependent kinase inhibitors p16, p15, p21) is frequently mediated by DNA methylation of gene promoters. The acetylation state of histones (functionally linked to the DNA methylation state by the methylcytosine binding protein 2, recruiting histone deacetylases) provides a second major epigenetic silencing mechanism. Therapeutic reversal strategies are being developed for acute leukemias, myelodysplastic syndromes and malignant lymphomas. Since the discovery of the DNA methyltransferase (Dnmt) inhibitory activity of two azanucleosides (5-azacytidine, 5-aza-2'-deoxycytidine/decitabine) even at doses with minimal nonhematologic toxicity, both have been clinically studied in several myeloid neoplasias, particularly in elderly patients unable to tolerate aggressive treatment. Further development of agents counteracting aberrant methylation is directed at more targeted approaches, for example, antisense molecules against Dnmts. Histone deacetylases (HDACs) can be inhibited by numerous compounds (sodium phenylbutyrate, valproic acid, novel compounds such as depsipeptide), which have entered the clinical arena in similar indications as Dnmt inhibitors. Impressive effects of HDAC inhibition in acute promyelocytic leukemia models (PML/RARA expression) translate the finding of HDAC recruitment by this chimeric transcription factor to its target genes. The recent discovery of recruitment by PML/RARA also of Dnmt activity to the retinoic acid receptor-beta promoter makes it an interesting candidate for Dnmt inhibitors. Studies combining a ‘re-expressor’ strategy with inhibitors of Dnmts and HDACs are underway. Thus, resensitization to biological agents such as retinoids, colony-stimulating factors and other differentiation inducers may be envisioned.Oncogene (2003) 22, 6489-6496. doi:10.1038/sj.onc.1206814 [ABSTRACT FROM AUTHOR]

The continuous separation of R(-)-ibuprofen and S(+)-ibuprofen by supercritical fluid simulated moving bed chromatography has been developed. First, experiments were performed at a low concentration level. Therefore, a starting set of operating parameters was calculated using the “triangle theory,” which has been developed in the frame of equilibrium theory. Subsequently, the feed concentration was increased. A dynamic simulation program, based on a plug flow model with axial dispersion and linear mass transfer resistance, was used to predict the effect of operating variables on the process performance. Adsorption isotherms were determined with the elution by a characteristic point method. The experimental results were compared both with the model predictions based on the triangle theory and with the results of simulations. [ABSTRACT FROM AUTHOR]

Decitabine (5-aza-2′-deoxycytidine) acts as a powerful demethylating agent in vitro. Clinically, low-dose decitabine ameliorates cytopenias including induction of trilineage responses in ≈50% of patients with high-risk myelodysplastic syndrome (MDS). We examined the incidence and kinetics of cytogenetic responses to decitabine in these patients. Of 115 successfully karyotyped patients, 61 (53%) had clonal chromosomal abnormalities prior to treatment. Major cytogenetic responses were observed in 19 patients (31% of those with abnormal cytogenetics, 17% of all patients by intention-to-treat) after a median of three courses (range, 2–6) until best cytogenetic response. Progressive decrease of the abnormal clone over time was also determined using fluorescence in situ hybridization (FISH) analysis in two patients. Median duration of cytogenetic responses was 7·5 months (range, 3–15). Analysis of response by the International Prognostic Scoring System (IPSS) cytogenetic risk groups revealed three out of five cytogenetic responses (60%) in the IPSS ‘low-risk’ group, 6 out of 30 with ‘intermediate risk’ (20%) and 10 out of 26 in the ‘high-risk’ group (38%). Median survival in these cytogenetic subgroups was 30, 8 and 13 months respectively. The relative risk of death in patients achieving a major cytogenetic response was 0·38 (95% confidence interval 0·17–0·88) compared with patients in whom the cytogenetically abnormal clone persisted (P = 0·0213). In conclusion, repeated courses of low-dose decitabine induce cytogenetic remissions in a substantial number of elderly MDS patients with pre-existing chromosomal abnormalites; these are associated with improved survival compared with patients in whom the cytogenetically abnormal clone persists. Patients with ‘high-risk’ chromosomal abnormalities may particularly benefit from this treatment. [ABSTRACT FROM AUTHOR]

Summary Diabetes insipidus (DI) in patients with acute myeloid leukaemia (AML) and chromosome 3q alterations (EVI1/PRDM3/MECOM overexpression) constitutes a poorly understood paraneoplasia. A 44‐year‐old patient presented with clinical and morphological features of this syndrome but, surprisingly, disclosed the rare translocation t(1;2)(p36;p21), with massive PRDM16 overexpression. WGS and RNA sequencing suggest enhancer hijacking of the ZFP36L2 enhancer region as underlying mechanism. Methylome alterations were similar to those in EVI1/PRDM3/MECOM AML, indicating converging pathways. The patient was successfully allografted, she is in complete remission 14 months later. We conclude that t(1;2)(p36;p21), with massive PRDM16 overexpression, can result in a faithful genocopy of EVI1/PRDM3/MECOM AML, including DI. [ABSTRACT FROM AUTHOR]

Summary: This study compared decitabine exposure when administered IV (DEC‐IV) at a dose of 20 mg/m2 for 5‐days with orally administered decitabine with cedazuridine (DEC‐C), as well as the clinical efficacy and safety of DEC‐C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC‐IV or oral DEC‐C (days 1–5 in a 28‐day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC‐C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5‐day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC‐C were consistent with those previously observed with DEC‐IV. Next‐generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC‐C in patients with AML. [ABSTRACT FROM AUTHOR]

The objective of this study is to examine the comparative effectiveness of vancomycin and metronidazole in a confirmatory analysis of event-free survival (EFS) after initial infection in patients with Clostridioides difficile from a German multicentre cohort study. The IBIS multicentre cohort enrolled patients with an index episode of C. difficile infection between August 2017 and September 2020. The primary endpoint was EFS, defined as response to treatment with metronidazole or vancomycin within 10 days of initiation, absence of recurrence and death from any cause up to 90 days post-treatment. A Cox proportional hazards model with inverse probability of treatment weighting was used to investigate the comparative effectiveness of this outcome. Additionally, subgroup analyses were performed based on severe and non-severe infections. Of the 489 patients included, 118 (24%) received initial treatment with metronidazole and 371 (76%) with vancomycin. Of these, 78/118 (66.1%) and 247/371 (66.6%), respectively, responded to treatment within 10 days, neither developed a recurrence nor died within 90 days and thus achieved the outcome of EFS. In the subgroup of non-severe infections, 74/293 patients (25.3%) received metronidazole, and 219/293 (74.7%) received vancomycin. Of these, 33/74 (44.6%) metronidazole patients and 150/219 (68.5%) vancomycin patients survived event free. The Cox proportional hazards model revealed differences in EFS for the overall population and both subgroups (reference metronidazole: all severity levels: hazard ratio [HR] 0.46, [95% CI, 0.33 – 0.65]; non-severe: HR 0.39; [95% CI, 0.24 – 0.60]; severe: HR 0.52; [95% CI, 0.28 – 0.95]). Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared with metronidazole across all severity levels. [ABSTRACT FROM AUTHOR]

This study investigates the prevalence and evaluates the prognostic implications of acute kidney injury (AKI) in COVID-19 patients, with a novel emphasis on the evaluation of serum uromodulin (sUmod) as a potential kidney-specific biomarker. A cohort of hospitalised COVID-19 patients (n = 378) was examined for AKI using standard criteria. In addition to traditional urinary biomarkers, sUmod levels were analysed. Univariable and multivariable regression models were employed to evaluate the association of sUmod and AKI and in-hospital mortality. Levels of sUmod were significantly lower in patients with CKD (91.8 ± 60.7 ng/ml) compared to patients with normal kidney function (204.7 ± 91.7 ng/ml; p < 0.001). 151 patients (40.0%) presented with AKI at the time of hospital admission or developed an AKI during hospitalization. 116 patients (76.8%) had an AKI already at the time of hospital admission. COVID-19 patients with AKI had significantly lower levels of sUmod compared to patients without AKI during hospitalisation (124.8 ± 79.5 ng/ml) vs 214.6 ± 92.3 ng/ml; p < 0.001). The in-hospital mortality rate in this cohort of COVID-19 patients was 15.3%. Patients with AKI had a higher probability for in-hospital death (OR 5.6, CI 1.76 to 17.881, p = 0.004). Patients who died during hospital stay, had significantly lower sUmod levels (129.14 ± 89.56 ng/ml) compared to patients surviving hospitalisation (187.71 ± 96,64 ng/ml; p < 0.001). AKI is frequently associated with COVID-19 in hospitalized patients. Serum uromodulin may emerge as a promising biomarker for AKI in COVID-19 patients. Further research is warranted to explore its clinical application and refine risk stratification in this patient population. [ABSTRACT FROM AUTHOR]