The recipient side of TRALI – the role of patient neutrophils

Transfusion‐related acute lung injury (TRALI) is a serious and potentially fatal complication of blood transfusions. The fact that TRALI has been the top cause of transfusion‐related mortalities in the USA over the last 3 years (2004–06) [ 1 ] provides irrefutable evidence of the clinical significance of this syndrome. From this perspective, its importance in transfusion complications surpasses that of blood‐borne viruses and bacterial infections. Despite this, we still do not clearly understand the pathophysiology and pathogenesis of TRALI. This paper presents a TRALI patient or recipient perspective by discussing how thorough serological investigations can be utilized to provide evidence that patient neutrophils are the target cell and to identify the implicated donation/s when there are multiple associated donations.     

Evidence behind the pathophysiology of TRALI

Transfusion-related acute lung injury (TRALI) is a serious transfusion complication that may lead to significant morbidity and mortality. This has driven a significant research effort focused on understanding why and how TRALI develops. The ultimate goal must be prevention or at least mitigation of the clinical consequences of TRALI. The underlying pathophysiology of TRALI is presently best described by two hypotheses which are not mutually exclusive. These are the antibody mediated TRALI mechanism and the two-event or priming TRALI mechanism. One of the key initial findings in TRALI research was the frequent presence of leucocyte antibodies in associated blood products, providing strong evidence for an antibody driven pathogenesis. In contrast, the two-event mechanism proposed that these transfused antibodies activated neutrophils that had first been primed by the patient’s clinical condition. Together, data from haemovigilance programs, clinical reports and experimental findings have led several countries to introduce TRALI risk-reduction strategies. These include either limiting the transfusion of plasma from female donors or, screening female donors for the presence of leucocyte antibodies. Both approaches are justified by adoption of the immune mechanism as the prime driver of the pathogenesis of TRALI. TRALI incidence has gratifyingly been reduced by these measures. Nevertheless, TRALI cases persist and they remain a major concern because of continuing significant morbidity and mortality. While the majority of earlier TRALI research has focused on the role of antibodies in TRALI, evidence for the role of non-antibody factors in TRALI is now growing, based on an increasing number of in vitro, ex vivo and in vivo models. This review aims to present data from such models, which are the foundation for our current understanding of the pathophysiology behind antibody mediated and non-antibody mediated TRALI.     

Recent insights into the Smith-Lemli-Opitz syndrome

The Smith–Lemli–Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation disorder caused by an inborn error of post-squalene cholesterol biosynthesis. Deficient cholesterol synthesis in SLOS is caused by inherited mutations of 3β-hydroxysterol-Δ7 reductase gene ( DHCR7 ). DHCR7 deficiency impairs both cholesterol and desmosterol production, resulting in elevated 7DHC/8DHC levels, typically decreased cholesterol levels and, importantly, developmental dysmorphology. The discovery of SLOS has led to new questions regarding the role of the cholesterol biosynthesis pathway in human development. To date, a total of 121 different mutations have been identified in over 250 patients with SLOS who represent a continuum of clinical severity. Two genetic mouse models have been generated which recapitulate some of the developmental abnormalities of SLOS and have been useful in elucidating the pathogenesis. This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS.     

Recent insights into the varying activity of estrogens

Recent advances have added substantially to our understanding of the biology of estrogens. Estrogens are no longer considered to differ only in potency. Two estrogens can have similar effects in one tissue and very different effects in another. Additionally, an estrogen can have different effects in different tissues. It is now recognized that there are at least two estrogen receptors, ER-alpha and ER-beta, and that it is quite likely that estrogens also work through non-genomic mechanisms. The development of new methods of chromatographic separation has aided substantially in our ability to characterize the composition of Premarin, including the identification of estradiene, the fourth-most abundant estrogen in Premarin. Recent studies have contributed to our understanding of the unique profile of Delta(8,9) dehydroestrone sulfate, another of the Premarin estrogens. It was found that Delta(8,9) dehydroestrone sulfate is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine and bone preservation parameters. However, it displayed little or no efficacy, at the dose studied, on other peripheral parameters normally affected by classical estrogens. Increasing knowledge of the unique profiles of the Premarin components, as well as their complex interaction, will help to increase our understanding of the clinical profile of Premarin.     

阿霉素诱导心肌细胞死亡机制

阿霉素是目前最为有效的抗肿瘤药物之一,其主要的严重副作用是累积性、剂量依赖性的心肌毒性反应,可进一步发展成不可逆性心肌损伤,最终导致充血性心力衰竭.心肌细胞凋亡和坏死被认为是阿霉素诱导心肌病变发展过程中的主要因素,自我吞噬和细胞老化等其他细胞死亡方式也参与此过程.阿霉素诱导心肌细胞死亡的机制可能包括:氧化应激以及由此发...     

Recent insights into SARS-CoV-2 omicron variant

The SARS-CoV-2 omicron variant (B.1.1.529) was first identified in Botswana and South Africa, and its emergence has been associated with a steep increase in the number of SARS-CoV-2 infections. The omicron variant has subsequently spread very rapidly across the world, resulting in the World Health Organization classification as a variant of concern on 26 November 2021. Since its emergence, great efforts have been made by research groups around the world that have rapidly responded to fill our gaps in knowledge for this novel variant. A growing body of data has demonstrated that the omicron variant shows high transmissibility, robust binding to human angiotensin-converting enzyme 2 receptor, attenuated viral replication, and causes less severe disease in COVID-19 patients. Further, the variant has high environmental stability, high resistance against most therapeutic antibodies, and partial escape neutralisation by antibodies from convalescent patients or vaccinated individuals. With the pandemic ongoing, there is a need for the distillation of literature from primary research into an accessible format for the community. In this review, we summarise the key discoveries related to the SARS-CoV-2 omicron variant, highlighting the gaps in knowledge that guide the field's ongoing and future work.     

TTID risk in the Latin America and Caribbean: recommendations to improve safety

Transfusion-Transmitted Diseases (TTD) have been a persistent risk since the onset of transfusion medicine. In Latin America and the Caribbean countries (LACC), prevention of TTD requires special and different care in comparison with the in United States and European countries, due to the still persistent high prevalence of replacement donors, specific geographic location, topography, and climate, genetic and cultural and socio-economic status of the population. These factors result in different distribution patterns of the infections, which together with the migration have changed the donor profile. According to the Pan American Health Organization (PAHO) reports, the screening of HIV, HBV, HCV and T. pallidum has increased in LACC since 2005, significantly reducing the risk of transmission. However these results have not yet reached the established aim in 1998, of analyzing 100% of blood units for these pathogens. The strategies recommended for the LACC should be based on the following points: a) the establishment of national blood transfusion services, b) blood collection from volunteer donors, c) high quality monitoring of TTD and emerging transfusion-transmitted infections (ETTI) in all blood units, d) implementation of effective quality assurance systems and e) the rational use of blood components and alternatives to transfusion.     

Recent insights into the molecular pathogenesis of pheochromocytoma and paraganglioma

Pheochromocytomas and paragangliomas are rare tumors derived from chromaffin cells. These tumors can arise in the context of hereditary cancer syndromes such as von Hippel-Lindau disease, multiple endocrine neoplasia type 2, and neurofibromatosis 1. Recent studies indicate that germ line mutations of genes encoding specific succinate dehydrogenase (SDH) subunits also predispose individuals to pheochromocytomas and paragangliomas. This review focuses on the genetics of these tumors and suggests a possible link between familial pheochromocytomas/paraganglioma genes and control of neuronal apoptosis during embryological development.     

Recent insights into the role of Toll-like receptors in viral infection

Toll‐like receptors (TLRs) have a central role in innate immunity as they detect conserved pathogen‐associated molecular patterns (PAMPs) on a range of microbes, including viruses, leading to innate immune activation and orchestration of the adaptive immune response. To date, a large number of viruses have been shown to trigger innate immunity via TLRs, suggesting that these receptors are likely to be important in the outcome to viral infection. This suggestion is supported by the observation that many viruses have evolved mechanisms not only to evade the innate immune system, but also to subvert it for the benefit of the virus. In this review we will discuss earlier evidence, mainly from knock‐out mice studies, implicating TLRs in the innate immune response to viruses, in light of more recent clinical data demonstrating that TLRs are important for anti‐viral immunity in humans.     

109例产后出血孕妇及新生儿高危因素的相关性分析

目的：探讨产后出血孕妇发生出血现象的高危影响因素及对新生儿的影响,进而为孕妇产后出血的预防和治疗提供有效的方法和措施。方法：统计我院2008年7月至2015年8月产妇产后24 h之内输血量(包括红细胞悬液1 U按200 mL计算和新鲜冰冻血浆)超过1600 mL的患者109例,对其出现产后出血问题的相关因素进行分析研究。结果：产妇年龄、妊娠次数、剖宫产再孕、胎盘因素、新生儿体重及母乳喂养情况等因素均与产后出血的发生存在着密切的联系。结论：对于存在高危因素的患者应采取科学性、针对性的预防措施,减少术中出血量,做到合理用血,科学用血,尽可能地将母婴所受伤害降到最低。     

Murine MPS I: insights into the pathogenesis of Hurler syndrome

Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disease resulting from deficiency of the lysosomal enzyme α-L-iduronidase. A murine model which shows complete deficiency in α-L-iduronidase activity has been developed and shows phenotypic features similar to severe MPS I in humans. Here we report on the long-term clinical, biochemical, and pathological course of MPS I in mice with emphasis on the skeletal and central nervous system (CNS) manifestations. Affected mice show a progressive clinical course with the development of coarse features, altered growth characteristics and a shortened life span. Progressive lysosomal accumulation is seen in all tissues. Skeletal manifestations represent the earliest clinical finding in MPS I mice with histologic analysis of growth plate and cortical bone revealing evidence that significant early pathology is present. Analysis of the CNS has revealed the novel finding of progressive neuronal loss within the cerebellum. In addition, brain tissue from MPS I mice shows increased levels of GM₂ and GM₃ gangliosides. This murine model clearly shows phenotypic and pathologic features which mimic those seen in severe human MPS I and should be an invaluable tool for the study of the pathogenesis of generalized storage disorders.     

New insights into the molecular mechanism of interleukin-10-mediated immunosuppression

Interleukin-10 (IL-10) is an important immunomodulatory cytokine, which has attracted much attention because of its anti-inflammatory properties. It reduces antigen presentation and inhibits T cell activation. IL-10-treated myeloid cells lose their ability to respond toward the endotoxin lipopolysaccharide (LPS) with the production of several proinflammatory mediators. Thereby, IL-10 limits excessive inflammatory reactions in response to endotoxin as it occurs in colitis or endotoxin shock. Mice can be tolerized toward endotoxin shock when pretreated with a sublethal dose of LPS. This can be mimicked in vitro as LPS desensitization, resulting in a similar LPS hyporesponsiveness as observed with IL-10 pretreatment. However, an early block in LPS signaling characterizes LPS desensitization, whereas IL-10 seems to target late events. Controversial reports have been published where IL-10 would interfere with the induction of proinflammatory mediators, and little is known about the molecular mechanisms behind the anti-inflammatory activities of IL-10. Some recent publications have tried to gain more insight into the molecular mechanism of IL-10 by gene-expression profiling and functional studies in myeloid-derived cells. These results are reviewed here and compared with the progress that has been made to understand the induction of endotoxin tolerance by LPS itself.     

Blood transfusion services in countries that joined the EU in the last years: Czech Republic

The Czech Republic is a country in the middle of Europe with 10·3 million inhabitants and 80 000 km². It became a European Union (EU) member in 2004. Blood transfusion service is disperse, hospital based. Blood is collected mostly from voluntary non‐remunerated blood donors and the country is self‐sufficient in blood components and plasma for fractionation. Predeposit autologeous programme is popular and covers around 4·5% of red cells needs. Donor population is stable and relatively safe. Total of 21 HIV positive donors have been detected during last 20 years, the incidence of hepatitis in blood donors is decreasing being below 0·10 pro mille for hepatitis B virus and below 0·20 pro mille for hepatitis C virus in 2005. European standards have been accepted and implemented during last 15 years; safety (quality) and general availability being the priorities. Donor selection, blood collection, processing and testing comply with EU directives. Producers of blood components (blood establishments) are under control of the state authority (State Institute for Drug Control). Recommendations based on expert opinion are available for clinical use of blood. Adverse effects of treatment are followed and investigated. Costs of blood components and plasma products are covered by general health insurance.