Repression of Human T-lymphotropic virus type 1 Long Terminal Repeat sense transcription by Sp1 recruitment to novel Sp1 binding sites

Human T-lymphotropic Virus type 1 (HTLV-1) infection is characterized by viral latency in the majority of infected cells and by the absence of viremia. These features are thought to be due to the repression of viral sense transcription in vivo. Here, our in silico analysis of the HTLV-1 Long Terminal Repeat (LTR) promoter nucleotide sequence revealed, in addition to the four Sp1 binding sites previously identified, the presence of two additional potential Sp1 sites within the R region. We demonstrated that the Sp1 and Sp3 transcription factors bound in vitro to these two sites and compared the binding affinity for Sp1 of all six different HTLV-1 Sp1 sites. By chromatin immunoprecipitation experiments, we showed Sp1 recruitment in vivo to the newly identified Sp1 sites. We demonstrated in the nucleosomal context of an episomal reporter vector that the Sp1 sites interfered with both the sense and antisense LTR promoter activities. Interestingly, the Sp1 sites exhibited together a repressor effect on the LTR sense transcriptional activity but had no effect on the LTR antisense activity. Thus, our results demonstrate the presence of two new functional Sp1 binding sites in the HTLV-1 LTR, which act as negative cis-regulatory elements of sense viral transcription.info:eu-repo/semantics/publishe

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Implantacja stentu do przegrody międzyprzedsionkowej u pacjentów z sercem jednokomorowym i wtórną restrykcją połączenia międzyprzedsionkowego

Background: Presence of a restrictive interatrial communication in patients with univentricular anatomy significantly affects surgical outcomes. In patients with univentricular hearts, wide open atrial communication leads to lower pulmonary artery pressure, which is one of the most important factors influencing the success of bidirectional Glenn and Fontan operations. In some patients, recurrence of restricted interatrial communication can be observed despite initially successful interventional or surgical creation of unrestrictive interatrial communication. Aim: To evaluate efficacy of stent implantation into the interatrial septum in patients with univentricular heart and a secondary restriction of interatrial communication. Methods: In 2006&#8211;2010, we created unrestrictive interatrial communication by stent implantation into the interatrial septum in 7 children with univentricular anatomy with systemic right ventricle (4 patients with hypoplastic left heart syndrome and 3 patients with mitral atresia). In all patients we diagnosed recurrent restriction of interatrial communication despite prior surgical or interventional creation of unrestrictive interatrial communication. Patient age at stent implantation was 3 to 30 months. Maximal systolic pressure gradient between the left and the right atrium was 6&#8211;29 mm Hg and left atrial pressure ranged from 20/17/19 mm Hg to 40/29/32 mm Hg. In all patients, we implanted a Palmaz-Genesis stent (length 18&#8211;29 mm) with subsequent balloon redilatation. Results: In all 7 patients, we created unrestrictive interatrial communication with mean pressure gradient reduction from 13.14 mm Hg to 0.86 mm Hg (p < 0.006). Mean interatrial communication diameter increased from 4.14 mm to 10.57 mm (p < 0.0001). Conclusions: Percutaneous stent implantation into the interatrial septum in children with univentricular heart and secondary restriction of interatrial communication is a safe and effective method. Kardiol Pol 2011; 69, 11: 1137&#8211;1141Wstęp: Restrykcyjne połączenie międzyprzedsionkowe u pacjentów z czynnościowo pojedynczą komorą znacząco wpływa na wynik leczenia chirurgicznego. W tej grupie pacjentów szerokie połączenie międzyprzedsionkowe prowadzi do obniżenia ciśnienia w tętnicy płucnej, które jest jednym z najważniejszych czynników warunkujących pomyślny przebieg zabiegu dwukierunkowego zespolenia sposobem Glenna i operacji Fontana. U niektórych osób, mimo skutecznego, interwencyjnego (zabieg Rashkinda) lub operacyjnego wytworzenia swobodnej komunikacji międzyprzedsionkowej, występuje nawrót restrykcji na poziomie przegrody międzyprzedsionkowej. Cel: Celem pracy była ocena skuteczności i bezpieczeństwa implantacji stentów do przegrody międzyprzedsionkowej u pacjentów z czynnościowo pojedynczą komorą, u których doszło do wtórnej restrykcji połączenia międzyprzedsionkowego. Metody: W latach 2006&#8211;2010 wykonano 7 zabiegów przezskórnego poszerzenia połączenia międzyprzedsionkowego z implantacją stentów. Pod względem hemodynamicznym pacjenci reprezentowali serce czynnościowo jednokomorowe, z systemową komorą prawą (4 dzieci z zespołem niedorozwoju lewego serca, 3 pacjentów z atrezją zastawki dwudzielnej). U wszystkich chorych narastanie restrykcji obserwowano mimo wcześniejszego interwencyjnego lub operacyjnego wytworzenia swobodnego połączenia międzyprzedsionkowego. Wiek dzieci w czasie implantacji stentu wynosił 3&#8211;30 miesięcy, maksymalny gradient ciśnienia na poziomie restrykcyjnego połączenia &#8212; 6&#8211;29 mm Hg, a wartość ciśnienia w lewym przedsionku &#8212; od 20/17/19 mm Hg do 40/29/32 mm Hg. Wszystkim pacjentom implantowano stenty Palmaz-Genesis (długość 18&#8211;19 mm). Wyniki: W grupie 7 pacjentów ze stentem implantowanym do przegrody międzyprzedsionkowej uzyskano obniżenie wartości gradientu lewo-prawego ze średnio 13,14 mm Hg do 0,86 mm Hg (p < 0,006). Uzyskano także poszerzenie średnicy połączenia międzyprzedsionkowego ze średnio 4,14 mm do 10,57 mm (p < 0,0001). Wnioski: Przezskórna implantacja stentu do przegrody międzyprzedsionkowej u dzieci z hemodynamicznie wspólną komorą skutecznie eliminuje wtórną restrykcję połączenia międzyprzedsionkowego, pozwalając na dekompresję lewego przedsionka; zmniejsza również konieczność dodatkowego leczenia operacyjnego. Stent implantowany do przegrody międzyprzedsionkowej może być w prosty sposób usunięty podczas kolejnego etapu leczenia operacyjnego. U pacjentów z czynnościowo pojedynczą komorą i wtórną restrykcją połączenia międzyprzedsionkowego implantacja stentu stanowi skuteczną i bezpieczną metodę terapii. Kardiol Pol 2011; 69, 11: 1137&#8211;114

Fenestration closure with Amplatzer Duct Occluder II in patients after total cavo-pulmonary connection

Introduction : Creation of a fenestration during completion of a total cavo-pulmonary connection (TCPC) has been associated with a reduction in early mortality and morbidity. However, the long-term benefits are negated by an associated limitation in exercise tolerance and the potential risks of thrombo-embolic complications. We sought to describe the safety and efficacy of an Amplatzer Duct Occluder II (ADO II) for transcatheter fenestration closure following TCPC. Material and methods : Between January 2000 and July 2014, 102 patients underwent percutaneous closure of extra-cardiac TCPC fenestrations with a range of devices. Patients in whom fenestration closure was performed with an ADO II and who had at least 6 months of follow-up were included in this study. Results : Forty-seven patients had successful fenestration occlusion with an ADO II. The mean oxygen saturation and mean systemic venous pressures increased from 84.8 ±6.1% before to 97.6 ±2.9% (p < 0.001) after and from 14.2 ±2.15 mm Hg before to 15.6 ±2.2 mm Hg after closure (p < 0.001). Eight patients developed heart failure symptoms, managed by optimization of medical therapy, with 1 patient requiring device removal to reopen the fenestration. Color Doppler transthoracic echocardiography demonstrated residual flow across the device in 18 (38%), 10 (22%), 5 (11%) and 4 (9%) patients before discharge, at 1 and 6 months, and at the latest outpatient visit, respectively. Conclusions : The ADO II can be safely and effectively used to close fenestrations in extra-cardiac type Fontan completions. Many of the design features of this device confer potential benefit in this population

A 10-year single-centre experience in percutaneous interventions for multi-stage treatment of hypoplastic left heart syndrome

AbstractObjectivesThe purpose of this paper is to report our 10 years of experience of interventional treatment of patients with hypoplastic left heart syndrome and to focus on the frequency, type, and results of percutaneous interventions during all the stages of palliation, considering the different techniques, devices, and complications.BackgroundConstant progress in surgical treatment of congenital heart defects in the last decade has significantly improved the prognosis for children with hypoplastic left heart syndrome. However, morbidity and mortality remain relatively high. Modern interventional procedures complement or occasionally replace surgical treatment.MethodsBetween January, 2001 and December, 2010, 161 percutaneous interventions were performed in 88 patients with hypoplastic left heart syndrome. Patients were divided into four groups: (a) before the first surgical treatment including hybrid approach, (b) after first-stage Norwood operation, (c) after second-stage bidirectional Glenn operation, and (d) after third-stage Fontan operation.ResultsPercutaneous interventions resulted in statistically significant changes in pulmonary artery pressures, vessel diameters, and O2saturation. Complications occurred in 4.3% of interventions and were related mainly to stent implantation in stenosed pulmonary arteries.ConclusionsPercutaneous interventions may result in haemodynamic stability and reduction in the number of operations. They may result in significant changes in pulmonary artery pressures, vessel diameters, O2saturation, with a low rate of complications, which are mainly related to stent implantation in the pulmonary arteries.</jats:sec

Characterization and prevalence of PITX2 microdeletions and mutations in axenfeld-rieger malformations

Purpose: Mutations of the homeodomain protein PITX2 produce Axenfeld-Rieger (AR) malformations of the anterior chamber, an autosomal dominant disorder accompanied by a 50% risk of glaucoma. Twenty-nine mutations of PITX2 have been described, with a mutational prevalence estimated between 10% and 60% in AR. In the current study, the possible role of altered PITX2 gene dosage in the etiology of AR was investigated. Gross gene deletions and duplications should alter PITX2 activity analogously to hypomorphic and hypermorphic mutations, respectively.Methods: Sixty-four patients with AR, iridogoniodysgenesis (IGD), iris hypoplasia (IH), or anterior segment dysgenesis (ASD) were screened for PITX2 mutations by sequencing. PITX2 gene dosage was concurrently examined in these patients by real-time quantitative PCR. Microsatellite markers were used to map 4q25 microdeletions at a contig scale, as well as for haplotype analysis in an extended AR kindred. An additional 27 patients with other assorted ocular phenotypes were evaluated by similar methods, amounting to a total of 91 cases analyzed.Results: Three novel mutations of PITX2 (4.7%) were identified among 64 patients with AR, IGD, IH, or ASD. Deletions of PITX2 were as frequent as mutations in our sample. Chromosome 4q25 microdeletions were physically mapped relative to several microsatellite markers in each patient. Cosegregation of AR and a PITX2 deletion was demonstrated in an extended kindred.Conclusions: Point mutations and gross deletions of PITX2 appear to produce an equivalent haploinsufficiency phenotype. Quantitative PCR is an efficient means of detecting causative PITX2 deletions in patients with AR and may increase the detection rate at this locus