Bone marrow failure syndromes and refractory cytopenia of childhood

__Abstract__ Hematopoiesis, or blood cell production, is sustained through hematopoietic stem cells, which are self-renewing cells that reside in the bone marrow, and that are capable of producing daughter cells that proliferate and mature to provide all adult blood effector cells, including erythrocytes or red blood cells, leukocytes or white blood cells, and thrombocytes or platelets. Erythrocytes are the most numerous cell types in the blood, and have as main task to transport oxygen through the lungs to peripheral tissues; leukocytes are responsible for elimination of bacteria and viruses, and thrombocytes for blood clotting. Hematopoiesis can be subdivided into myelopoiesis and lymphopoiesis. Myelopoiesis comprises the generation of granulocytes, monocytes, mast cells, mega- karyocytes (the precursors of thrombocytes), and erythrocytes. Lymphopoiesis encompasses the generation of B cells, T cells, and NK cells; collectively referred to as lymphocytes. Although recent insights suggest that cell fate determination during hematopoiesis is more plastic than previously thought, the classic, hierarchical model of determination of hematopoietic cell lineages is depicted in Figure 1 (adapted from Orkin and Zon

Onset of bronchodilation with fluticasone/formoterol combination versus fluticasone/salmeterol in an open-label, randomized study

Introduction: The inhaled corticosteroid, fluticasone propionate (fluticasone), and the long-acting beta2-agonist, formoterol fumarate (formoterol), have been combined in a single aerosol inhaler (fluticasone/formoterol). In a randomized, open-label study, fluticasone/formoterol showed similar efficacy to fluticasone/salmeterol after 12 weeks of treatment. This post-hoc analysis compared the onset of bronchodilation with the two treatments. Methods: Adults with mild-to-moderatesevere persistent asthma were randomized to fluticasone/formoterol (100/10 or 250/10 μg twice daily [b.i.d.]) or fluticasone/salmeterol (100/50 or 250/50 μg b.i.d.) for 12 weeks. The onset of bronchodilation (the first post-dose time point at which the forced expiratory volume in 1 second [FEV1] was ≥12% greater than the pre-dose value), responder rates (the proportion of patients achieving bronchodilation), and changes in FEV1 were assessed at days 0 (baseline) and 84. Results: Fluticasone/formoterol (n = 101) provided more rapid onset of bronchodilation than fluticasone/salmeterol (n = 101) over the first 120 min post-dose on days 0 (hazard ratio [HR] = 1.47 [95% CI 1.05–2.05]) and 84 (HR = 1.77 [95% CI 1.14–2.73]). The odds of a patient achieving bronchodilation within 5 min of dosing were almost four-times higher with fluticasone/formoterol than with fluticasone/salmeterol on day 0 (odds ratio [OR] = 3.97 [95% CI 1.96–8.03]) and almost 10-times higher on day 84 (OR = 9.58 [95% CI 2.14–42.90]); the odds of achieving bronchodilation within 120 min post-dose were approximately twofold higher with fluticasone/formoterol on both days. The overall percentage increase in least-squares (LS) mean FEV1 during the 120-min post-dose period was significantly greater with fluticasone/formoterol than fluticasone/salmeterol on days 0 (LS mean treatment difference: 4.70% [95% CI 1.57–7.83]; P = 0.003) and 84 (2.79% [95% CI 0.65–4.93]; P = 0.011). Conclusion: These analyses showed that fluticasone/formoterol provided a faster onset of bronchodilation than fluticasone/salmeterol, which was maintained over 12 weeks of treatment. This benefit may facilitate treatment adherence among patients with asthma

Human telomere disease due to disruption of the CCAAT box of the TERC promoter

Mutations in the coding region of telomerase complex genes can result in accelerated telomere attrition and human disease. Manifestations of telomere disease include the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia, acute myeloid leukemia, liver cirrhosis, and pulmonary fibrosis. Here, we describe a mutation in the CCAAT box (GCAAT) of the TERC gene promoter in a family in which multiple members had typical features of telomeropathy. The genetic alteration in this critical regulatory sequence resulted in reduced reporter gene activity and absent binding of transcription factor NF-Y, likely responsible for reduced TERC levels, decreased telomerase activity, and short telomeres. This is the first description of a pathogenic mutation in the highly conserved CCAAT box and the first instance of a mutation in the promoter region of TERC producing a telomeropathy. We propose that current mutation-screening strategies should include gene promoter regions for the diagnosis of telomere diseases. This clinical trial was registered at www.clinicaltrials.gov as #NCT00071045. (Blood. 2012;119(13):3060-3063

Perineal wound closure using gluteal turnover flap or primary closure after abdominoperineal resection for rectal cancer: study protocol of a randomised controlled multicentre trial (BIOPEX-2 study)

BACKGROUND: Abdominoperineal resection (APR) for rectal cancer is associated with high morbidity of the perineal wound, and controversy exists about the optimal closure technique. Primary perineal wound closure is still the standard of care in the Netherlands. Biological mesh closure did not improve wound healing in our previous randomised controlled trial (BIOPEX-study). It is suggested, based on meta-analysis of cohort studies, that filling of the perineal defect with well-vascularised tissue improves perineal wound healing. A gluteal turnover flap seems to be a promising method for this purpose, and with the advantage of not having a donor site scar. The aim of this study is to investigate whether a gluteal turnover flap improves the uncomplicated perineal wound healing after APR for rectal cancer. METHODS: Patients with primary or recurrent rectal cancer who are planned for APR will be considered eligible in this multicentre randomised controlled trial. Exclusion criteria are total exenteration, sacral resection above S4/S5, intersphincteric APR, biological mesh closure of the pelvic floor, collagen disorders, and severe systemic diseases. A total of 160 patients will be randomised between gluteal turnover flap (experimental arm) and primary closure (control arm). The total follow-up duration is 12 months, and outcome assessors and patients will be blinded for type of perineal wound closure. The primary outcome is the percentage of uncomplicated perineal wound healing on day 30, defined as a Southampton wound score of less than two. Secondary outcomes include time to perineal wound closure, incidence of perineal hernia, the number, duration and nature of the complications, re-interventions, quality of life and urogenital function. DISCUSSION: The uncomplicated perineal wound healing rate is expected to increase from 65 to 85% by using the gluteal turnover flap. With proven effectiveness, a quick implementation of this relatively simple surgical technique is expected to take place. TRIAL REGISTRATION: The trial was retrospectively registered at Clinicaltrials.gov NCT04004650 on July 2, 2019

‘Cognitive closure’ in the Netherlands: mortgage securitization in a hybrid European political economy

There is a strong case that mortgage-backed securities were at the root of the 2007 – 09 financial crisis. Even though geographers have convincingly demonstrated that loan origination is strongly locally rooted and that the fallout from the subprime mortgage crisis clearly had spatially circumscribed effects, securitization is still generally perceived as a universal, private, and purely market-based financial technique. In this paper we use a description of the securitization chain in the Netherlands to contest these perceptions. Building on and adding to Thomas Wainwright’s analysis of securitization in the UK, we first argue that securitization in the Netherlands has taken a form which reflects Dutch corporatist institutional arrangements, implying that both geography and states do matter for the supposedly aspatial process of securitization. Second, we argue that the Dutch state has been very much implicated in the construction of the securitization market in the Netherlands. Third, we suggest that this can best be seen as an effect of ‘cognitive closure’ rather than of ‘regulatory capture’: that is, Dutch pro-banking regulation is not so much an effect of bankers hijacking regulators but, rather, more the result of bankers seducing regulators with their stories. This paper is a detailed case study of the workings of financialization and adds to the growing body of work which seeks to analyze the different ‘varieties of financialization’ and the variegated geographies of the financial crisis.