A lymphoma patient with Cytomegalovirus retinitis and post‐autologous hematopoietic cell transplantation immune reconstitution uveitis: A case report and review of the literature

Cytomegalovirus (CMV) retinitis in hematologic malignancies in the absence of hematopoietic cell transplant (HCT) is uncommon. We report a case of a 54‐year‐old woman with peripheral T‐cell lymphoma who develops CMV retinitis and subsequently undergoes an autologous HCT, with eventual development of immune reconstitution uveitis. We further reviewed the PubMed literature on CMV retinitis in patients with lymphoma. We describe that CMV retinitis in patients with lymphoma has variable clinical presentations, may occur at any time during the course of the disease and chemotherapy, and is associated with significant morbidity.     

Maribavir,brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections

Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation. Therapeutic antiviral options [(val)ganciclovir, foscarnet, cidofovir] are still limited and can expose to severe toxicities. Moreover, prolonged antiviral drug exposure and ongoing viral replication are key factors in the development of antiviral drug resistance. After many years of few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period characterized by a series of phase III clinical trials incorporating three novel agents: maribavir, brincidofovir, and letermovir. This article summarizes the current state of the prevention and treatment of CMV infections as well as data of investigational drugs in clinical development.     

熊果酸对K562/ADR细胞多药耐药基因1 mRNA和P-糖蛋白表达影响及机制研究

目的研究熊果酸对多药耐药基因1 (MDR1) mRNA和P-糖蛋白(P-gp)表达的影响及机制。方法空白组给予0. 5%二甲基亚砜(DMSO),核因子-κB(NF-κB)激动剂组给予5μmol·L^-1阿霉素,NF-κB抑制剂组给予25μmol·L^-1吡咯烷二硫代氨基甲酸盐(PDTC),实验组单独或联合激动剂或抑制剂给予5,10,25,50μmol·L^-1熊果酸。培养48 h后,用逆转录聚合酶链式反应(RT-PCR)检测MDR1 mRNA水平,用Western blot法测定P-糖蛋白和核蛋白P65的表达水平。结果与空白组比较,5,10,25,50μmol·L^-1熊果酸分别使MDR1 mRNA的表达下调了7. 41%,15. 58%,28. 75%和44. 21%(IC50=66. 04μmol·L^-1),P-糖蛋白的表达下调了23. 36%,37. 23%,43. 07%和64. 23%(IC50=26. 27μmol·L^-1)。与空白组相比,5,10,25,50μmol·L^-1熊果酸分别使P65的表达下调了13. 73%,28. 92%,44. 07%和56. 77%(IC50=34. 07μmol·L^-1),且熊果酸和PDTC在5～50μmol·L^-1均能明显抑制阿霉素诱导的P65的表达,差异均有统计学意义(均P <0. 05)。结论熊果酸可显著抑制K562/ADR细胞MDR1 mRNA和P-糖蛋白的表达,且对抗阿霉素的诱导作用;其机制可能是通过抑制MDR1 mRNA和P-糖蛋白的上游调控信号通路NF-κB位点核蛋白P65的表达;减少NF-κB的核转位,从而抑制NF-κB活性并干扰MDR1基因转录,最终导致MDR1 mRNA及P-糖蛋白表达量的下调。     

Cytomegalovirus Infection Incidence and Risk Factors Across Diverse Hematopoietic Cell Transplantation Platforms Using a Standardized Monitoring and Treatment Approach: A Comprehensive Evaluation from a Single Institution

Human cytomegalovirus (CMV) infection and disease remains a significant cause of morbidity and mortality for hematopoietic cell transplantation (HCT) recipients. Disruption of or weak reconstitution of virus-specific cellular immune function, such as with certain HCT approaches, poses significant risk for CMV-related complications. The incidence of and risk factors for CMV infection and the nature of CMV disease were evaluated retrospectively among 356 consecutive HCT recipients transplanted at the National Institutes of Health using all graft sources, including bone marrow, peripheral blood stem cell (PBSC), and umbilical cord blood (UCB), and a range of in vivo and ex vivo approaches for graft-versus-host disease (GVHD) prophylaxis. The cumulative incidence of CMV infection was higher for CMV-seropositive recipients at 33%, regardless of donor CMV serostatus. Patients transplanted with CMV-seropositive donors had a significantly shorter duration of antiviral therapy. Among graft sources UCB was associated with the highest cumulative incidence of CMV infection at 65% and significantly longer treatment duration at a median of 36days, whereas PBSC HCT was associated with the lowest incidence at 26% and the shortest CMV treatment duration at a median of 21days. There were significant differences in the cumulative incidence of CMV infection by T cell manipulation strategy when systemic steroids were included as a risk-modifying event. Over one-third of CMV infections occurred in the setting of systemic steroid administration. CMV disease occurred in 5% of HCT recipients, with 70% of cases in the setting of treatment for GVHD. Although factors related to serostatus, graft source, and GVHD prophylaxis were associated with varied CMV infection incidence, unplanned post-HCT corticosteroid therapy contributed greatly to the incidence of both CMV infection and disease across HCT approaches, highlighting this post-HCT intervention as a key time to potentially tailor the approach to monitoring, preemptive therapy, and even prophylaxis.     

The bacterial aetiology of pleural empyema. A descriptive and comparative metagenomic study

ObjectivesThe view of pleural empyema as a complication of bacterial pneumonia is changing because many patients lack evidence of underlying pneumonia. To further our understanding of pathophysiological mechanisms, we conducted in-depth microbiological characterization of empyemas in clinically well-characterized patients and investigated observed microbial parallels between pleural empyemas and brain abscesses.MethodsCulture-positive and/or 16S rRNA gene PCR-positive pleural fluids were analysed using massive parallel sequencing of the 16S rRNA and rpoB genes. Clinical details were evaluated by medical record review. Comparative analysis with brain abscesses was performed using metagenomic data from a national Norwegian study.ResultsSixty-four individuals with empyema were included. Thirty-seven had a well-defined microbial aetiology, while 27, all of whom had community-acquired infections, did not. In the latter subset, Fusobacterium nucleatum and/or Streptococcus intermedius was detected in 26 patients, of which 18 had additional facultative and/or anaerobic species in various combinations. For this group, there was 65.5% species overlap with brain abscesses; predisposing factors included dental infection, minor chest trauma, chronic obstructive pulmonary disease, drug abuse, alcoholism and diabetes mellitus. Altogether, massive parallel sequencing yielded 385 bacterial detections, whereas culture detected 38 (10%) and 16S rRNA gene PCR/Sanger-based sequencing detected 87 (23%).ConclusionsA subgroup of pleural empyema appears to be caused by a set of bacteria not normally considered to be involved in pneumonia. Such empyemas appear to have a similar microbial profile to oral/sinus-derived brain abscesses, supporting spread from the oral cavity, potentially haematogenously. We suggest reserving the term ‘primary empyema’ for these infections.     

AMPK activity is required for the induction of anhydrobiosis in a tardigrade Hypsibius exemplaris,and its potential up‐regulator is PP2A

The anhydrobiotic tardigrade, Hypsibius exemplaris, was previously considered to require de novo gene expression and protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activity for successful anhydrobiosis. These indicate that H. exemplaris has signal transduction systems responding to desiccation stress, with the involvement of phosphorylation events. To this end, we carried out time‐series phosphoproteomics of H. exemplaris exposed to mild desiccation stress and detected 48 phosphoproteins with significant differential regulations. Among them, immediate and successive reduction of phosphorylation levels of AMP‐activated protein kinase (AMPK) was observed. The subsequent chemical genetic approach showed that AMPK was activated during the preconditioning stage for anhydrobiosis, and inhibition of its activity impaired successful anhydrobiosis. As PP2A is known to dephosphorylate AMPK in other organisms, we suggested that decreased phosphorylation levels of AMPK upon mild desiccation stress were caused by dephosphorylation by PP2A. Accordingly, phosphoproteomics of animals pre‐treated with the PP1/PP2A inhibitor cantharidic acid (CA) lacked the decrease in phosphorylation levels of AMPK. These observations suggest that AMPK activity is required for successful anhydrobiosis in H. exemplaris, and its phosphorylation state is possibly regulated by PP2A.     

Immune phenotype predicts new onset diabetes after kidney transplantation

Few data are available concerning immune factors involved in the occurrence of new onset diabetes after transplantation (NODAT). Our objective was to determine an immune profile associated with the subsequent development of NODAT. The secondary objective was to build a predictive model of NODAT. We studied a prospective cohort of incident kidney transplant patients to determine whether pre-transplant immune characteristics could be associated with the occurrence of NODAT. 818 patients were included. We observed a significant inverse correlation between BMI and recent thymic emigrants (RTE) % at transplant time (p < 0.001). 177 (17.3%) of 677 non-diabetic patients experienced NODAT in the first year post-transplant. In multivariate analysis, age, body mass index (BMI), use of Tacrolimus, use of anti-thymocyte globulins (ATG), higher B cell count, and lower recent thymic emigrants (RTE) % were associated with NODAT. A differential effect of immune profile was observed in ATG-treated patients and non-ATG-treated patients. B cell count predicts NODAT only in non-ATG-treated patients whereas lower RTE% was associated with NODAT only in ATG-treated patients. Tacrolimus sparing and B cell depletion may efficiently prevent NODAT in selected patients. We identified an immune profile associated with the occurrence of post-transplant diabetes. Further studies should better precise the exact mechanisms involved in this association. Trial registration NCT02843867, registered July 8, 2016 – retrospectively registered https://clinicaltrials.gov/ct2/show/record/NCT02843867.     

虫草素联合谷氨酰胺对LPS诱导的脓毒症大鼠炎症失衡及肝肺病理变化的影响

目的　研究虫草素（cordycepin,Cop）联合谷氨酰胺（glutamine,Gln）对脂多糖（lipopolysaccharides,LPS）诱导的脓毒症大鼠炎症失衡和肝肺病理变化的影响及其可能机制。 方法　将大鼠按体重随机分为5组：对照组、模型组（LPS组）、LPS+Cop组、LPS+Gln组和LPS+Cop+Gln组,腹腔注射LPS（5 mg/kg）诱导建立脓毒症大鼠模型。ELISA检测外周血中炎症因子IL-6、TNF-α、IL-1β和IL-10的含量;HE染色观察肝肺组织的病理损伤情况;TUNEL染色观察肝肺组织的细胞凋亡情况;Western blot检测肝肺组织中Caspase-3表达水平及NF-κB p65的磷酸化情况 。 结果　LPS+Cop组、LPS+Gln组和LPS+Cop+Gln组均能逆转LPS诱导的促炎因子（IL-6、TNF-α、IL-1β）的高表达和抗炎因子（IL-10）的低表达（P<0.05）,减轻病理损伤,抑制细胞凋亡（P<0.05）,降低凋亡蛋白Caspase-3高表达（P<0.05）,下调NF-κB p65的磷酸化水平（P<0.05）。 结论　在LPS诱导的脓毒症大鼠模型中,虫草素联合谷氨酰胺能有效改善其炎症失衡和肝肺病理变化。