Cytotoxic drug sensitivity of Epstein-Barr virus transformed lymphoblastoid B-cells.

BACKGROUND: Epstein-Barr virus (EBV) is the causative agent of immunosuppression associated lymphoproliferations such as post-transplant lymphoproliferative disorder (PTLD), AIDS related immunoblastic lymphomas (ARL) and immunoblastic lymphomas in X-linked lymphoproliferative syndrome (XLP). The reported overall mortality for PTLD often exceeds 50%. Reducing the immunosuppression in recipients of solid organ transplants (SOT) or using highly active antiretroviral therapy in AIDS patients leads to complete remission in 23-50% of the PTLD/ARL cases but will not suffice for recipients of bone marrow grafts. An additional therapeutic alternative is the treatment with anti-CD20 antibodies (Rituximab) or EBV-specific cytotoxic T-cells. Chemotherapy is used for the non-responding cases only as the second or third line of treatment. The most frequently used chemotherapy regimens originate from the non-Hodgkin lymphoma protocols and there are no cytotoxic drugs that have been specifically selected against EBV induced lymphoproliferative disorders. METHODS: As lymphoblastoid cell lines (LCLs) are well established in vitro models for PTLD, we have assessed 17 LCLs for cytotoxic drug sensitivity. After three days of incubation, live and dead cells were differentially stained using fluorescent dyes. The precise numbers of live and dead cells were determined using a custom designed automated laser confocal fluorescent microscope. RESULTS: Independently of their origin, LCLs showed very similar drug sensitivity patterns against 29 frequently used cytostatic drugs. LCLs were highly sensitive for vincristine, methotrexate, epirubicin and paclitaxel. CONCLUSION: Our data shows that the inclusion of epirubicin and paclitaxel into chemotherapy protocols against PTLD may be justified

Using big data from health records from four countries to evaluate chronic disease outcomes: a study in 114 364 survivors of myocardial infarction

Aims: to assess the international validity of using hospital record data to compare long-term outcomes in heart attack survivors. Methods and results: we used samples of national, ongoing, unselected record sources to assess three outcomes: cause death; a composite of myocardial infarction (MI), stroke, and all-cause death; and hospitalized bleeding. Patients aged 65 years and older entered the study 1 year following the most recent discharge for acute MI in 2002–11 [n = 54 841 (Sweden), 53 909 (USA), 4653 (England), and 961 (France)]. Across each of the four countries, we found consistent associations with 12 baseline prognostic factors and each of the three outcomes. In each country, we observed high 3-year crude cumulative risks of all-cause death (from 19.6% [England] to 30.2% [USA]); the composite of MI, stroke, or death [from 26.0% (France) to 36.2% (USA)]; and hospitalized bleeding [from 3.1% (France) to 5.3% (USA)]. After adjustments for baseline risk factors, risks were similar across all countries [relative risks (RRs) compared with Sweden not statistically significant], but higher in the USA for all-cause death [RR USA vs. Sweden, 1.14 (95% confidence interval 1.04–1.26)] and hospitalized bleeding [RR USA vs. Sweden, 1.54 (1.21–1.96)]. Conclusion: the validity of using hospital record data is supported by the consistency of estimates across four countries of a high adjusted risk of death, further MI, and stroke in the chronic phase after MI. The possibility that adjusted risks of mortality and bleeding are higher in the USA warrants further study

Functional loss of IKBE leads to NF-KB deregulation in aggressive chronic lymphocytic leukemia

NF-?B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-?B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I?B?, a negative regulator of NF-?B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I?B? protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I?B? loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-?B deregulation during lymphomagenesis. <br/

Short-Term Antibiotic Treatment Has Differing Long-Term Impacts on the Human Throat and Gut Microbiome

Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer. However, the long-term consequences of this treatment on the human indigenous microbiota are relatively unexplored. Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat and in the lower intestine. The bacterial compositions in samples collected over a four-year period were monitored by analyzing the 16S rRNA gene using 454-based pyrosequencing and terminal-restriction fragment length polymorphism (T-RFLP). While the microbial communities of untreated control subjects were relatively stable over time, dramatic shifts were observed one week after antibiotic treatment with reduced bacterial diversity in all treated subjects in both locations. While the microbiota of the different subjects responded uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic decline in Actinobacteria in both throat and feces immediately after treatment. Although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance

Differential Effects of Antibiotic Therapy on the Structure and Function of Human Gut Microbiota

The human intestinal microbiota performs many essential functions for the host. Antimicrobial agents, such as antibiotics (AB), are also known to disturb microbial community equilibrium, thereby having an impact on human physiology. While an increasing number of studies investigate the effects of AB usage on changes in human gut microbiota biodiversity, its functional effects are still poorly understood. We performed a follow-up study to explore the effect of ABs with different modes of action on human gut microbiota composition and function. Four individuals were treated with different antibiotics and samples were taken before, during and after the AB course for all of them. Changes in the total and in the active (growing) microbiota as well as the functional changes were addressed by 16S rRNA gene and metagenomic 454-based pyrosequencing approaches. We have found that the class of antibiotic, particularly its antimicrobial effect and mode of action, played an important role in modulating the gut microbiota composition and function. Furthermore, analysis of the resistome suggested that oscillatory dynamics are not only due to antibiotic-target resistance, but also to fluctuations in the surviving bacterial community. Our results indicated that the effect of AB on the human gut microbiota relates to the interaction of several factors, principally the properties of the antimicrobial agent, and the structure, functions and resistance genes of the microbial community

Characteristics and outcomes in patients with a prior myocardial infarction treated with extended dual antiplatelet therapy with ticagrelor 60 mg: findings from ALETHEIA, a multi-country observational study

Background Guidelines recommend extended dual antiplatelet therapy, including ticagrelor 60 mg twice daily, in high-risk post-myocardial infarction (MI) patients who have tolerated 12 months and are not at high bleeding risk. The real-world utilization and bleeding and ischaemic outcomes associated with long-term ticagrelor 60 mg in routine clinical practice have not been well described. Methods Register and claims data from the USA (Optum Clinformatics, IBM MarketScan, and Medicare) and Europe (Sweden, Italy, UK, and Germany) were extracted. Patients initiating ticagrelor 60 mg ≥12 months after MI, meeting eligibility criteria for the PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin – Thrombolysis in Myocardial Infarction 45) 54 trial, were included. The cumulative incidence of the composite of MI, stroke, or all-cause mortality and that of bleeding requiring hospitalization were calculated. Meta-analyses were performed to combine estimates from each source. Results A total of 7035 patients treated with ticagrelor 60 mg met eligibility criteria. Median age was 67 years and 29% were females; 12% had a history of multiple MIs. The majority (95%) had been treated with ticagrelor 90 mg prior to initiating ticagrelor 60 mg. At 12 months from initiation of ticagrelor 60 mg, the cumulative incidence [95% confidence interval (CI)] of MI, stroke, or mortality was 3.33% (2.73–4.04) and was approximately three-fold the risk of bleeding (0.96%; 0.69–1.33). Conclusions This study provides insights into the use of ticagrelor 60 mg in patients with prior MI in clinical practice. Observed event rates for ischaemic events and bleeding generally align with those in the pivotal trials, support the established safety profile of ticagrelor, and highlight the significant residual ischaemic risk in this population

Targeting the IGF-1R signaling and mechanisms for epigenetic gene silencing in human multiple myeloma

Multiple myeloma (MM) is a B cell malignancy characterized by the expansion of clonal plasmablast/plasma cells within the bone-marrow. It is well established that the bone-marrow microenvironment has a pivotal role in providing critical cytokines and cell–cell interactions to support the growth and survival of the MM tumor clone. The pathogenesis of MM is, however, only fragmentarily understood. Detailed genomic analysis reveals a heterogeneous and complex pattern of structural and numerical chromosomal aberrations. In this review we will discuss some of the recent results on the functional role and potential clinical use of the IGF-1R, one of the major mediators of growth and survival for MM. We will also describe some of our results on epigenetic gene silencing in MM, as it may indeed constitute a novel basis for the understanding of tumor initiation and maintenance in MM and thus may change the current view on treatment strategies for MM

Prevalence of Myocardial Infarction With Obstructive and Non-Obstructive Coronary Arteries in a Middle-Aged Population With Chronic Airflow Limitation: A Cross-Sectional Study

Josefin Sundh,1 Magnus Ekström,2 Anders Blomberg,3 Eva Lindberg,4 Andrei Malinovschi,5 Anna-Carin Olin,6 C Magnus Sköld,7,8 Kjell Torén,6 Per Wollmer,6 Carl Johan Östgren,9,10 Tomas Jernberg11,12 1Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, Sweden; 2Lund University, Faculty of Medicine, Department of Clinical Sciences Lund, Respiratory Medicine, Allergology and Palliative Medicine, Lund, Sweden; 3Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden; 4Department of Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, Uppsala, Sweden; 5Department of Medical Sciences, Clinical Physiology, Uppsala University, Uppsala, Sweden; 6Occupational and Environmental Medicine, School of Public Health and Community Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; 7Respiratory Medicine Unit, Department of Medicine Solna and Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; 8Department of Respiratory Medicine and Allergy, Karolinska University Hospital, Stockholm, Sweden; 9Department of Translational Medicine, Lund University, Malmö, Sweden; 10Centre of Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; 11Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden; 12Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, SwedenCorrespondence: Josefin Sundh, Department of Respiratory Medicine, Faculty of Medicine and Health, Örebro University, Örebro, 701 82, Sweden, Tel +46702349517, Email [email protected]; [email protected]: Myocardial infarctions (MIs) can occur in underlying obstructive coronary artery disease (MI-CAD) or in non-obstructive coronary arteries (MINOCA). The primary objectives of the study were to investigate the prevalence of MI-CAD and MINOCA in people with CAL, and to explore if CAL is an independent risk factor for MI-CAD and MINOCA. Secondary objectives were to explore these research questions stratified by sex and by smoking history.Patients and Methods: Cross-sectional analysis of the population-based Swedish CArdioPulmonary bioImage Study (SCAPIS) of people aged 50– 64 years. CAL was defined as a post-bronchodilator ratio of forced expiratory volume in one second and forced vital capacity below 0.70. MI-CAD was defined as a self-reported MI with coronary computed tomography angiography findings of previous revascularization or at least one significant coronary stenosis (> 50%), and MINOCA as self-reported MI with no previous revascularization and no significant coronary stenosis.Results: In total, 1735 (8.3%) of 20,882 included participants had CAL. MI-CAD was more common than MINOCA both in people with (2.8 vs 0.6%) and without CAL (1.2 vs 0.3%). Compared with those without CAL, people with CAL had an almost doubled independent risk of both MI-CAD ([adjusted OR] 1.72; [95% CI] 1.22– 2.42) and MINOCA (1.99; 1.02– 3.86). In men, CAL was associated with increased risk of MINOCA (2.63; 1.23– 5.64), and in women with increased risk for MI-CAD (3.43; 1.68– 1.26).Conclusion: Middle-aged people with CAL have an almost doubled risk of both MI-CAD and MINOCA, compared with people without CAL. In contrast to people without CAL, the risk of MINOCA is increased in men and the risk of MI-CAD is increased in women. In a clinical context, both MI types should be considered in CAL.Keywords: coronary atherosclerosis, COPD, smoking, se

Flexor Hallucis Longus tendon rupture in RA-patients is associated with MTP 1 damage and pes planus

<p>Abstract</p> <p>Background</p> <p>To assess the prevalence of and relation between rupture or tenosynovitis of the Flexor Hallucis Longus (FHL) tendon and range of motion, deformities and joint damage of the forefoot in RA patients with foot complaints.</p> <p>Methods</p> <p>Thirty RA patients with painful feet were analysed, their feet were examined clinically for the presence of pes planus and range of motion (ROM), radiographs were scored looking for the presence of forefoot damage, and ultrasound examination was performed, examining the presence of tenosyovitis or rupture of the FHL at the level of the medial malleolus. The correlation between the presence or absence of the FHL and ROM, forefoot damage and pes planus was calculated.</p> <p>Results</p> <p>In 11/60(18%) of the feet, a rupture of the FHL was found. This was associated with a limited motion of the MTP1-joint, measured on the JAM (χ²= 10.4, p = 0.034), a higher prevalence of pes planus (χ²= 5.77, p = 0.016) and a higher prevalence of erosions proximal at the MTP-1 joint (χ²= 12.3, p = 0.016), and joint space narrowing of the MTP1 joint (χ²= 12.7, p = 0.013).</p> <p>Conclusion</p> <p>Rupture of the flexor hallucis longus tendon in RA-patients is associated with limited range of hallux motion, more erosions and joint space narrowing of the MTP-1-joint, as well as with pes planus.</p

Phylogeographic analysis reveals multiple international transmission events have driven the global emergence of Escherichia coli O157:H7

This work was supported by: Scotland by Food Standards Scotland [Grant Number FS102029] and University of Aberdeen; New Zealand, Institute of Environmental Science and Research; Canada, the Public Health Agency of Canada; United States, United States Department of AgriculturePeer reviewedPostprin