Pattern of Serum Cytokine Expression and T-Cell Subsets in Sickle Cell Disease Patients in Vaso-Occlusive Crisis

The pathogenesis of sickle vaso-occlusive crisis (VOC) in sickle cell disease (SCD) patients involves the accumulation of rigid sickle cells and the stimulation of an ongoing inflammatory response, as well as the stress of infections. The immune response, via cytokine imbalances and deregulated T-cell subsets, also has been proposed to contribute to the development of VOC. In this study, a panel of high-sensitivity cytokine kits was used to investigate cytokines in the sera of SCD patients in VOC. The results were compared primarily with those for stable SCD patients and secondarily with those for normal healthy people who served as controls. The cytokines studied included interleukin-2 (IL-2), IL-4, and IL-10. Lymphocyte subsets of patients with VOC were also studied and were compared with those of both control groups (20 stable patients without crisis [SCD group] and 20 normal healthy controls [NHC]). The VOC group was notable for remarkably elevated levels of IL-4, among the three cytokines tested, compared with those for the SCD and NHC groups. Patients with VOC also differed from stable SCD patients and NHC by having notably lower IL-10 levels, as well as the lowest ratio of CD4⁺ to CD8⁺ T cells (0.7). The patterns of the proinflammatory cytokine IL-2 did not differ between VOC and stable SCD patients, but NHC had significantly lower IL-2 levels than both the VOC and SCD groups. Our results demonstrate coexisting levels, both high and low, of TH1- and TH2-type cytokines, as well as diminished levels of T-cell subsets in VOC. These results are discussed in an effort to better understand the importance of the immune system profile in the pathogenesis of sickle cell VOC. Since the possibility that a cytokine imbalance is implicated in the pathogenesis of sickle cell crisis has been raised, our results should prompt further investigation of the host immune response in terms of TH1 and TH2 balance in sickle cell crisis.Sickle cell disease (SCD) is a chronic, incurable condition presenting primarily as anemia (sickle cell anemia [SCA]) in people homozygous for hemoglobin S (HbS). This abnormal hemoglobin, resulting from the replacement of glutamic acid at position 6 of the β-globin chain by valine, is responsible for erythrocyte distortion and fragility in these patients, as well as for thrombosis, fever, splenomegaly, joint pain, lethargy, and weakness. Sickle cell crises refer to the sudden attacks of pain, at various levels of severity, that occur during the lifetime of the patient with sickle cell disease (1, 3). Of these, the painful vaso-occlusive crisis (VOC) is the most common and is characterized by fever, leukocytosis, joint effusions, and tenderness, which occur in about 50% of patients at initial presentation (2), as well as by susceptibility to infection. It is a medical emergency and an acute crisis state. Patients in a state of well-being between these episodes are referred to as “steady-state” SCD patients.The sequence of pathophysiological events that lead to the sickle cell VOC is not well understood. Several authors (8, 13, 27, 28) have outlined a sequence of steps occurring in the microcirculation that culminate in this painful sickle cell crisis. Polymerization of HbS, decreased blood red cell flexibility, microvascular occlusion, hypoxia of tissue involved with the occluded microvascular network, and tissue damage triggering painful stimuli have been mentioned (26), although the precise dynamics of these events and their interrelationships are poorly understood. Tissue ischemia due to vascular occlusion causing infarctive tissue damage, which in turn initiates secondary inflammatory responses, has also been mentioned (3, 4). Ischemic events produced by the occlusion of both large and small blood vessels are stressful and involve intricate interactions between red blood cells, the endothelium, and leukocytes (7). These interactions are known to be regulated by cytokines secreted by T cells as well as by adhesion molecules, and consequently, the immune response is implicated in the initiation and development of the sickle cell crisis. Indeed, studies now show that immune subsets are operative in sickle cell disease (9, 14, 16, 25), and the susceptibility of sickle cell disease patients in crisis to infections that specifically require the help of T cells to be cleared, such as Salmonella enterica serovar Typhimurium osteomyelitis (14), is suggestive.CD4⁺ T cells, subdivided based on their associated cytokines, play a crucial role in inflammatory responses and the elimination of infection. TH1 cells provide immunity against intracellular pathogens by secreting the cytokines interleukin-2 (IL-2), IL-12, and gamma interferon (IFN-γ), whereas commitment to the TH2 lineage programs the clearance of extracellular pathogens and the secretion of cytokines such as IL-10, IL-4, and IL-13. This balance of TH1/TH2 cytokine responses is believed to play an important role in coordinating an effective immune response, even under inflammatory conditions, although very limited data exist on their roles in sickle cell VOC.This study thus hypothesizes that the balance between TH1- and TH2-type cytokines might explain the differences in clinical outcomes in sickle cell disease. It was undertaken with patients with SCD in VOC in Zaria, Nigeria, a town in the zone of sickle cell endemicity of West Africa (17). The study analyzed numerical values for CD3⁺, CD4⁺, and CD8⁺ T cells and levels of selected serum cytokines in patients in VOC, and it compared these values with those obtained for steady-state SCD patients and unaffected hemoglobin AA homozygotes who served as normal healthy controls (NHC). This was done in an effort to understand if any imbalance in the immune response is important in the pathogenesis of sickle cell disease.     

DC-SIGN interacts with Mycobacterium leprae but sequence variation in this lectin is not associated with leprosy in the Pakistani population

The C-type lectin DC-SIGN is involved in early interactions between human innate immune cells and a variety of pathogens. Here we sought to evaluate whether DC-SIGN interacts with the leprosy bacillus, Mycobacterium leprae, and whether DC-SIGN genetic variation influences the susceptibility and/or pathogenesis of the disease. A case-control study conducted in a cohort of 272 individuals revealed no association between DC-SIGN variation and leprosy. However, our results clearly show that DC-SIGN recognizes M. leprae, indicating that mycobacteria recognition by this lectin is not as narrowly restricted to the Mycobacterium tuberculosis complex as previously thought. Altogether, our results provide further elucidation of M. leprae interactions with the host innate immune cells and emphasize the importance of DC-SIGN in the early interactions between the human host and the infectious agents.     

Herpes zoster vaccination among adults aged 60 years or older in the United States, 2007: Uptake of the first new vaccine to target seniors

Background

Approximately one million new cases of shingles (herpes zoster [HZ]), a severely painful and debilitating disease caused by reactivation of varicella-zoster virus (VZV), occur in the United States each year. HZ incidence increases with age, especially after age 50. A vaccine to prevent HZ and its sequelae was licensed in May 2006 for those aged 60 years or older, making it the first new vaccine targeted to this age group in many years. In October 2006 the Advisory Committee on Immunization Practices (ACIP) recommended HZ vaccination of persons aged ≥60 years; these recommendations were published in 2008. We examined HZ vaccination coverage among persons aged ≥60 years in the U.S. in 2007, and evaluated factors affecting the uptake of HZ vaccine in this population.

Methods

Data from the 2007 National Immunization Survey-Adult (NIS-Adult) restricted to individuals aged ≥60 years were analyzed using SUDAAN software to estimate national HZ vaccination coverage, and reasons for not receiving the HZ vaccine. We used multivariable logistic regression analysis to identify factors independently associated with HZ vaccination.

Results

Of 3662 respondents, 1.9% (95% confidence interval = 1.3%, 2.8%) reported having received the HZ vaccine. A total of 72.9% of respondents were unaware of the HZ vaccine but 77.8% stated that they would accept HZ vaccination if their doctor recommended it. Of the remaining 556 respondents, key reasons reported for not accepting HZ vaccine included ‘vaccination not needed’ (34.8%), ‘not at risk’ (12.5%), and ‘don’t trust in doctors or medicine’ (9.5%).

Conclusions

Soon after its availability in the United States, coverage among adults recommended to receive the HZ vaccine was low. Our data provide evidence that the lack of patient awareness and of physician recommendations were barriers to vaccine uptake.     

急性粘连性肠梗阻病人手术适应证及手术时机的探讨

目的：探讨急性粘连性肠梗阻病人的手术时机,以提高手术治疗效果。方法：回顾性分析我院1998～2008年手术治疗的61粘连性肠梗阻病例的临床资料,其中7例行腹腔镜粘连松解术。术中使用2～3支医用几丁糖凝胶以防止肠粘连。结果：本组手术治疗61例,非手术治疗95例。手术治疗患者中痊愈55例（88．2％）,二次手术5例（10％）,三次手术1例（2％）。术后肺部感染2例,切口感染3例,肠瘘2例,经保守治疗痊愈。1例死于感染性休克合并多器官功能衰竭综合征。结论：在非手术治疗前提下,粘连性肠梗阻病人手术时机宜把握在24～48h。对粘连性肠梗阻病人应采取因人而异的个体化原则,重在密切观察病情的演变和有效的非手术治疗。术中应用医用几丁糖凝胶可以减少肠粘连,防止复发。     

CTX-M-15-producing Escherichia coli clinical isolates in Cairo (Egypt), including isolates of clonal complex ST10 and clones ST131, ST73, and ST405 in both community and hospital settings

In Egypt, little is known about the genetic background of Escherichia coli isolates harboring extended-spectrum β-lactamase (ESBL). Five hundred twenty Enterobacteriaceae were prospectively collected (May 2007-August 2008) at the Theodor Bilharz Research Institute (Cairo). Among the collected Enterobacteriaceae, 56% (n=291) were E. coli and 32% (n=165) Klebsiella pneumoniae. A total of 16% (n=3) of all isolates were ESBL, 19% (n=55) of the E. coli and 14% (n=23) of the K. pneumoniae. The proportion of E. coli ESBL producers did not differ significantly between in and outpatients (20% vs. 17%) but was significantly different for non-E. coli ESBL producers (18.5% vs. 1.2%: p=0.0001). The majority of E. coli ESBL producers (75%) was isolated from urine. All the ESBL-producing Enterobacteriaceae available for molecular study (n=74) produced CTX-M-15. Among the CTX-M-15-producing E. coli isolates; 40% belonged to phylogenetic group A, 32% to D, and 26% to B2. ERIC-2 PCR profiles were obtained for all these E. coli isolates and multilocus sequence typing for those belonging to group B2. Genotyping analyses showed strain diversity; however, some clusters had profiles indistinguishable from that of previously published clones. Multilocus sequence typing showed that 75% of E. coli group B2 belonged to clone ST131. This indicates that a new country in Africa is adversely affected by clones of E. coli-producing CTX-M-15.