Sero-epidemiological analysis of the risk of virus infections for childhood leukaemia

Virus infections have been thought to be involved in the development of childhood leukaemia. In order to address this issue we determined, in a case-control study, the prevalence of antibodies to viruses infecting blood or bone-marrow cells [Epstein-Barr virus (EBV), human herpes virus type 6 (HHV-6), parvovirus B19] as well as to the human virus known for its tumour-suppressive properties, the adeno-associated virus type 2 (AAV-2), in the sera of 121 children with leukaemia in Germany, and in 197 control individuals, hospitalized for other reasons, and matched for age and gender to the cases. In addition, we developed a questionnaire to be answered by the children's parents, in order to gain information on previous infections of the children as well as to calculate for factors which may influence serological findings. Comparative determination of the prevalence of antibodies against AAV-2, B-19 or HHV-6 revealed no significant differences in cases and controls. However, antibodies to EBV were more frequently found in children with leukaemia younger than 6 years of age (age at the time of diagnosis of leukaemia) than in controls. Apparently, infection with AAV-2 has no protective effect in childhood leukaemia, in contrast to results observed for other malignancies. Similarly, and in accordance with results on leukaemia in adults, we found no indication of a protective effect of infection with the parvovirus B-19. The data suggest that EBV, which is known to be involved in various lymphomas, may play a role in the development of childhood leukaemia in young children. © 1996 Wiley-Liss, Inc.     

Impact of single-room contact precautions on acquisition and transmission of vancomycin-resistant enterococci on haematological and oncological wards,multicentre cohort-study,Germany, January−December 2016

BackgroundEvidence supporting the effectiveness of single-room contact precautions (SCP) in preventing in-hospital acquisition of vancomycin-resistant enterococci (haVRE) is limited.AimWe assessed the impact of SCP on haVRE and their transmission.MethodsWe conducted a prospective, multicentre cohort study in German haematological/oncological departments during 2016. Two sites performed SCP for VRE patients and two did not (NCP). We defined a 5% haVRE-risk difference as non-inferiority margin, screened patients for VRE, and characterised isolates by whole genome sequencing and core genome MLST (cgMLST). Potential confounders were assessed by competing risk regression analysis.ResultsWe included 1,397 patients at NCP and 1,531 patients at SCP sites. Not performing SCP was associated with a significantly higher proportion of haVRE; 12.2% (170/1,397) patients at NCP and 7.4% (113/1,531) patients at SCP sites (relative risk (RR) 1.74; 95% confidence interval (CI): 1.35–2.23). The difference (4.8%) was below the non-inferiority margin. Competing risk regression analysis indicated a stronger impact of antimicrobial exposure (subdistribution hazard ratio (SHR) 7.46; 95% CI: 4.59–12.12) and underlying disease (SHR for acute leukaemia 2.34; 95% CI: 1.46–3.75) on haVRE than NCP (SHR 1.60; 95% CI: 1.14–2.25). Based on cgMLST and patient movement data, we observed 131 patient-to-patient VRE transmissions at NCP and 85 at SCP sites (RR 1.76; 95% CI: 1.33–2.34).ConclusionsWe show a positive impact of SCP on haVRE in a high-risk population, although the observed difference was below the pre-specified non-inferiority margin. Importantly, other factors including antimicrobial exposure seem to be more influential.     

Treatment of blepharospasm and Meige’s syndrome with abo- and onabotulinumtoxinA: long-term safety and efficacy in daily clinical practice

Journal of Neurology - Thirty years after their approval, botulinum toxin injections still are the first-line therapy for blepharospasm. The aim of our study was to analyze long-term data...     

Comparison of immune reconstitution between anti-T-lymphocyte globulin and posttransplant cyclophosphamide as acute graft-versus-host disease prophylaxis in allogeneic myeloablative peripheral blood stem cell transplantation

Anti-T-cell lymphocyte globulin (ATLG) and posttransplant cyclophosphamide (PTCy) are now widely used strategies to prevent graft-versus-host disease (GVHD) after allogeneic stem cell transplantation. Data comparing immune reconstitution (IR) between ATLG and PTCy is scarce. This retrospective study conducted at the University Medical Center Hamburg-Eppendorf (UKE) compares PTCy (n=123) and ATLG (n=476) after myeloablative allogeneic peripheral blood stem cell transplant. Detailed phenotypes of T, B natural killer (NK), natural killer T (NKT) cells were analyzed by multicolor flow at day 30, 100 and 180 posttransplant. Incidence of infections, viral reactivations, GVHD and relapse were collected. Neutrophil engraftment was significantly delayed in the PTCy group (median day 12 vs. day 10, P<0.001) with a high incidence of infection before day+100 in the PTCy arm but a higher Epstein-Barr virus reactivation in the ATLG arm and comparable cytomegalovirus reactivation. Overall incidence of acute GVHD was similar but moderate/severe chronic GVHD was seen more often after PTCy (44% vs. 38%, P=0.005). ATLG resulted in a faster reconstitution of CD8+ T, NK, NKT and gdT cells while CD4 T cells and B cells reconstituted faster after PTCy. Similar reconstitution was observed for T-regulatory cells and B cells. Non-relapse mortality relapse incidence, disease-free survival, and overall survival did not differ significantly between both arms. Even though differences in IR were related to a decreased incidence of infection and moderate/severe cGVHD in the ATLG group they had no impact on any of the other long-term outcomes. However, it remains undetermined which regimen is better as GVHD prophylaxis.     

IFITM3 Interacts with the HBV/HDV Receptor NTCP and Modulates Virus Entry and Infection

The Na⁺/taurocholate co-transporting polypeptide (NTCP, gene symbol SLC10A1) is both a physiological bile acid transporter and the high-affinity hepatic receptor for the hepatitis B and D viruses (HBV/HDV). Virus entry via endocytosis of the virus/NTCP complex involves co-factors, but this process is not fully understood. As part of the innate immunity, interferon-induced transmembrane proteins (IFITM) 1–3 have been characterized as virus entry-restricting factors for many viruses. The present study identified IFITM3 as a novel protein–protein interaction (PPI) partner of NTCP based on membrane yeast-two hybrid and co-immunoprecipitation experiments. Surprisingly, IFITM3 knockdown significantly reduced in vitro HBV infection rates of NTCP-expressing HuH7 cells and primary human hepatocytes (PHHs). In addition, HuH7-NTCP cells showed significantly lower HDV infection rates, whereas infection with influenza A virus was increased. HBV-derived myr-preS1 peptide binding to HuH7-NTCP cells was intact even under IFITM3 knockdown, suggesting that IFITM3-mediated HBV/HDV infection enhancement occurs in a step subsequent to the viral attachment to NTCP. In conclusion, IFITM3 was identified as a novel NTCP co-factor that significantly affects in vitro infection with HBV and HDV in NTCP-expressing hepatoma cells and PHHs. While there is clear evidence for a direct PPI between IFITM3 and NTCP, the specific mechanism by which this PPI facilitates the infection process remains to be identified in future studies.     

Modifications in fMRI Representation of Mental Rotation Following a 6 Week Graded Motor Imagery Training in Chronic CRPS Patients

Complex regional pain syndrome (CRPS) is a neuropathic pain condition that is difficult to treat. For behavioral interventions, graded motor imagery (GMI) showed relevant effects, but underlying neural substrates in patient groups have not been investigated yet. A previous study investigating differences in the representation of a left/right hand judgment task demonstrated less recruitment of subcortical structures, such as the putamen, in CRPS patients than in healthy controls. In healthy volunteers, the putamen activity increased after a hand judgment task training. In order to test for longitudinal effects of GMI training, we investigated 20 CRPS patients in a wait-list crossover design with 3 evaluation time points. Patients underwent a 6 week GMI treatment and a 6 week waiting period in a randomized group assignment and treatment groups were evaluated by a blinded rater. When compared to healthy matched controls at baseline, CRPS patients showed less functional activation in areas processing visual input, left sensorimotor cortex, and right putamen. Only GMI treatment, but not the waiting period showed an effect on movement pain and hand judgment task performance. Regression analyses revealed positive associations of movement pain with left anterior insula activation at baseline. Right intraparietal sulcus activation change during GMI was associated with a gain in performance of the hand judgment task. The design used here is reliable for investigating the functional representation of the hand judgment task in an intervention study.PerspectiveTwenty chronic CRPS patients underwent a 6 week GMI intervention in a randomized wait-list crossover design. functional MRI was tested pre and post for the hand lateralization task which improved over GMI but not over WAITING. Performance gain was positively related to right parietal functional MRI activation.     

Next-generation sequencing in X-linked intellectual disability

X-linked intellectual disability (XLID) is a genetically heterogeneous disorder with more than 100 genes known to date. Most genes are responsible for a small proportion of patients only, which has hitherto hampered the systematic screening of large patient cohorts. We performed targeted enrichment and next-generation sequencing of 107 XLID genes in a cohort of 150 male patients. Hundred patients had sporadic intellectual disability, and 50 patients had a family history suggestive of XLID. We also analysed a sporadic female patient with severe ID and epilepsy because she had strongly skewed X-inactivation. Target enrichment and high parallel sequencing allowed a diagnostic coverage of >10 reads for ~96% of all coding bases of the XLID genes at a mean coverage of 124 reads. We found 18 pathogenic variants in 13 XLID genes (AP1S2, ATRX, CUL4B, DLG3, IQSEC2, KDM5C, MED12, OPHN1, SLC9A6, SMC1A, UBE2A, UPF3B and ZDHHC9) among the 150 male patients. Thirteen pathogenic variants were present in the group of 50 familial patients (26%), and 5 pathogenic variants among the 100 sporadic patients (5%). Systematic gene dosage analysis for low coverage exons detected one pathogenic hemizygous deletion. An IQSEC2 nonsense variant was detected in the female ID patient, providing further evidence for a role of this gene in encephalopathy in females. Skewed X-inactivation was more frequently observed in mothers with pathogenic variants compared with those without known X-linked defects. The mutation rate in the cohort of sporadic patients corroborates previous estimates of 5–10% for X-chromosomal defects in male ID patients.     

Dual-field-of-view high-spectral-resolution lidar: Simultaneous profiling of aerosol and water cloud to study aerosol–cloud interaction

Aerosol–cloud interaction (ACI) is complex and difficult to be well represented in current climate models. Progress on understanding ACI processes, such as the influence of aerosols on water cloud droplet formation, is hampered by inadequate observational capability. Hitherto, high-resolution and simultaneous observations of diurnal aerosol loading and cloud microphysical properties are challenging for current remote-sensing techniques. To overcome this conundrum, we introduce the dual-field-of-view (FOV) high-spectral-resolution lidar (HSRL) for simultaneously profiling aerosol and water cloud properties, especially water cloud microphysical properties. Continuous observations of aerosols and clouds using this instrument, verified by the Monte Carlo simulation and coincident observations of other techniques, were conducted to investigate the interactions between aerosol loading and water cloud microphysical properties. A case study over Beijing highlights the scientific potential of dual-FOV HSRL to become a significant contributor to the ACI investigations. The observed water cloud profiles identify that due to air entrainment its vertical structure is not perfectly adiabatic, as assumed by many current retrieval methods. Our ACI analysis shows increased aerosol loading led to increased droplet number concentration and decreased droplet effective radius—consistent with expectations—but had no discernible increase on liquid water path. This finding supports the hypothesis that aerosol-induced cloud water increase caused by suppressed rain formation can be canceled out by enhanced evaporation. Thus, these observations obtained from the dual-FOV HSRL constitute substantial and significant additions to understanding ACI process. This technique is expected to represent a significant step forward in characterizing ACI.

Aerosol–cloud interaction (ACI) is a crucial aspect of atmospheric research and one of the primary sources of uncertainties in climate predictions (1–3). To assess the credibility of climate projections, it is imperative to improve our understanding of how aerosols interact with clouds (4–6). It has been well known that aerosols can serve as cloud condensation nuclei (CCN) to form cloud droplets, which can further influence the initiation of precipitation (7). However, quantifying the impact of natural and anthropogenic aerosols on the growth and the evolution of water clouds is still challenging (8, 9). The short lifetime, high temporal variability, and complex vertical structure of water cloud layers lead to a major difficulty for ACI studies (3, 10, 11). Despite the advances in the characterization of ACI by ground-based measurements (12–21), satellite retrieved products (22–25), and airborne in situ measurements (26–28), uncertainties remain in the effects of the aerosols on the water cloud properties. The reason for this gap in our knowledge is closely linked to the inadequate observations of the water cloud microphysical properties under various aerosol conditions (3). Current satellites can estimate cloud properties but not the typical aerosol nucleation region beneath clouds (22–25). Moreover, they also bring challenges for ACI studies that the typical revisit time of satellite-based sensors is much longer than the temporal scales of cloud variability (29, 30). Quintessential ground-based remote-sensing techniques for retrieving cloud properties, such as the cloud radar and the microwave radiometer, cannot provide simultaneous aerosol observations for ACI studies. Therefore, ground-based measurements commonly combine those with other remote-sensing or in situ aircraft instruments for characterizing aerosol loading beneath clouds (12–20). However, given the high variability of clouds, differences in perspective or mismatched sampling in space and time would raise uncertainty and bias in the characterization of ACI (15).Lidar, a powerful tool for profiling optical properties of aerosols and clouds, has been widely used in atmospheric studies (31–33). Yet, further progress with lidar-based techniques for ACI studies is hampered by limited observations of the water cloud microphysical properties, mainly due to the difficulties of quantifying the multiple scattering within water clouds (34). The multiple scattering has a significant impact on the water cloud observations of the extinction as well as the depolarization ratio, which is related to the receiver field of view (FOV). In brief, a retrieval of water cloud microphysical properties for lidar-based techniques relies on utilizing different receiver FOVs to provide the necessary observations for characterizing the multiple-scattering effect caused by the water droplets (34, 35). The first multiple-FOV lidars were aimed at investigating the multiple-scattering effect and measured Mie scattering by water droplets (36). However, a complicated behavior of the Mie phase function makes the quantifying of the multiple scattering become an arduous task. It naturally leads to the use of Raman scattering of atmospheric nitrogen, which has an isotropic phase function practically in the backward direction, to allow developing a feasible algorithm for the retrieval of water cloud microphysical properties (35). Moreover, the dual-FOV Raman lidar technique for profiling cloud properties has been experimentally demonstrated (37). With this technique in conjunction with an incoherent Doppler lidar, the ACI findings have been obtained with an ACI index versus vertical air motion (21, 38). However, nitrogen Raman signals are so weak that the observations are usually restricted to nighttime hours, and the signal has to be averaged over tens of minutes to deliver reliable lidar products, while the typical temporal scale of cloud variability is much shorter than that (29). Recently, a dual-FOV polarization lidar technique was reported, which continued and further developed the concept of the dual-FOV Mie lidar (39). However, to assess ACI this method requires a priori assumptions about the lidar ratio and subadiabatic cloud conditions. The impact of the a priori assumptions on the aerosol and cloud retrievals has been widely discussed (10, 40, 41). In general, all existing multiple-FOV lidar-based techniques have their advantages and also limitations.To overcome this conundrum, a dual-FOV high-spectral-resolution lidar (HSRL) technique for profiling aerosol and cloud properties simultaneously is introduced here. It provides lateral observations of aerosols and clouds with high vertical and temporal resolutions during daytime and nighttime. Neither assumptions on thermodynamic conditions nor lidar ratio are required. This work benefited from the range-resolved observations of water clouds with high resolution, revealing that the observed profiles of low-level water cloud microphysical properties are not perfectly adiabatic as assumed by many current retrievals (42–46). Furthermore, the ACI analysis supports the hypothesis that aerosol-induced water decrease by enhanced evaporation can cancel out the increase caused by suppressed rain formation (6, 47), while most current global general circulation models (GCMs) suggest that increased aerosol loading typically causes increased cloud water content (19, 48). Thus, these observations obtained from the dual-FOV HSRL can constitute a substantial and significant addition to our understanding of ACI studies. We believe that this versatile system will not only benefit the quality monitoring of aerosol and cloud properties but also serve as a powerful tool for ACI studies.