CD19嵌合抗原受体T细胞治疗后细胞因子释放综合征的诊治进展

CD19嵌合抗原受体T细胞疗法是治疗B细胞血液肿瘤的新兴免疫疗法，并取得了较好的疗效。随着其使用的增加，免疫效应细胞相关细胞因子释放综合征的发生率也相应升高，迫切需要对其精确机制和治疗进行进一步的临床研究。文章总结了细胞因子释放综合征的机制、临床表现、分级系统、治疗以及管理策略。     

Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice

The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins, such as glycoprotein 120 (gp120), are considered to be responsible for the HIV-associated distal sensory neuropathy. Accumulating evidences suggest that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. Here, we demonstrated that perineural application of X4 gp120 from HIV-1 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. In in vitro cell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB- or MN-treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB-treated cultured Schwann cells. Similar to gp120 IIIB or MN, perineural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore, the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB-treated mice. Thus, the present study newly defines that Schwann cell-derived CXCL1, secreted in response to X4 gp120 exposure, is responsible for macrophage infiltration into peripheral nerves, and is thereby associated with pain-like behaviors in mice. We propose herein that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.     

Lipocalin-2 mediates HIV-1 induced neuronal injury and behavioral deficits by overriding CCR5-dependent protection

People living with HIV (PLWH) continue to develop HIV-associated neurocognitive disorders despite combination anti-retroviral therapy. Lipocalin-2 (LCN2) is an acute phase protein that has been implicated in neurodegeneration and is upregulated in a transgenic mouse model of HIV-associated brain injury. Here we show that LCN2 is significantly upregulated in neocortex of a subset of HIV-infected individuals with brain pathology and correlates with viral load in CSF and pro-viral DNA in neocortex. However, the question if LCN2 contributes to HIV-associated neurotoxicity or is part of a protective host response required further investigation. We found that the knockout of LCN2 in transgenic mice expressing HIVgp120 in the brain (HIVgp120tg) abrogates behavioral impairment, ameliorates neuronal damage, and reduces microglial activation in association with an increase of the neuroprotective CCR5 ligand CCL4. In vitro experiments show that LCN2 neurotoxicity also depends on microglia and p38 MAPK activity. Genetic ablation of CCR5 in LCN2-deficient HIVgp120tg mice restores neuropathology, suggesting that LCN2 overrides neuroprotection mediated by CCR5 and its chemokine ligands. RNA expression of 168 genes involved in neurotransmission reveals that neuronal injury and protection are each associated with genotype- and sex-specific patterns affecting common neural gene networks. In conclusion, our study identifies LCN2 as a novel factor in HIV-associated brain injury involving CCR5, p38 MAPK and microglia. Furthermore, the mechanistic interaction between LCN2 and CCR5 may serve as a diagnostic and therapeutic target in HIV patients at risk of developing brain pathology and neurocognitive impairment.     

Development of a platform-based approach for the clinical production of HIV gp120 envelope glycoprotein vaccine candidates

Preclinical development of vaccine candidates is an important link between the discovery and manufacture of vaccines for use in human clinical trials. Here, an exploratory clinical study utilizing multiple gp120 envelope proteins as vaccine antigens was pursued, which required a harmonized platform development approach for timely and efficient manufacture of the combined HIV vaccine product.Development of cell lines, processes, and analytical methods was initiated with a transmitted founder envelope protein (CH505TF), then applied to produce three subsequent gp120 Env (envelope) variants. Cell lines were developed using the commercially available Freedom CHO DG44 kit (Life Technologies). The fed-batch cell culture production process was based on a commercially-available medium with harmonized process parameters across the variants. A platform purification process was developed utilizing a mixed mode chromatography capture step, with ceramic hydroxyapatite and ion exchange polishing steps. A suite of analytical methods was developed to establish and monitor the Quality Target Profile (QTP), release and long-term stability testing of the vaccine products.The platform development strategy was successfully implemented to produce four gp120 envelope protein variants. In some cases, minor changes to the platform were required to optimize for a particular variant; however, baseline conditions for the processes (cell line type, media & feed system, chromatography resins, and analytical approaches) remained constant, leading to successful transfer and manufacture of all four proteins in a cGMP facility.This body of work demonstrates successful pursuit of a platform development approach to manufacture important vaccine candidates and can be used as a model for other vaccine glycoproteins, such as HIV gp140 trimers or other viral glycoproteins with global health implications.Clinical trial identifier.NCT03220724, NCT03856996.     

浅析持续改进120院前急救工作

医疗急救水平是衡量城市现代化程度、社会发展的重要标志之一，本文通过分析目前红河州120在院前急救中的存在问题，提出了应对措施，为进一步提高本地区120院前急救工作效率，提供了一定的依据。     

120急救中心院前急救患者的疾病谱探析

目的分析鹤岗市人民医院120急救中心院前急救患者的疾病谱特点。方法随机选取本院120急救中心院前急救患者1000例,分析患者在性别、年龄、疾病分布、死亡情况等方面的特点及其内在联系。结果各个年龄段的男女比例差异显著,P0.05,具有统计学意义。根据院前急救疾病谱,因受创伤而急救的患者比重最大,其次为脑血管疾病、心血管疾病、消化系统疾病等,创伤、脑血管疾病、心血管疾病等男女患者所占比重具有显著差异,P0.05,具有统计学意义。结论鉴于创伤、脑血管疾病、心血管疾病、呼吸系统疾病等是急救中心院前急救常见病症,医院在医疗设备的配置、人员的配备和培训上应给予重视,提高急救处理水平。     

Reduced or painful jaw movement after collision-related injuries: a population-based study

BACKGROUND: The authors report the incidence of and factors associated with reduced and/or painful jaw movement after motor vehicle collisions that resulted in whiplash-associated disorders (WADs). METHODS: All adults filing collision-related personal injury claims during an 18-month period in Saskatchewan, Canada, were evaluated via questionnaire to determine demographic characteristics, precollision health (including jaw pain), collision parameters and collision-related symptoms, including reduced and/or painful jaw movement and injury-related neck pain. The authors excluded patients who were hospitalized for more than two days and those who sustained injuries as a pedestrian, bicyclist or motorcyclist. In determining incidence rates, the authors also excluded those who had had jaw pain before the collision. RESULTS: The incidence of reduced and/or painful jaw movement was 14.9 percent (n = 1,158), and it was higher in subjects with WADs (15.8 percent) than in those without WADs (4.7 percent; relative risk = 3.36, 95 percent confidence interval, 2.36 to 4.78). Within the WAD injuries, multivariable logistic regression revealed that the onset of reduced and/or painful jaw movement was associated with female sex; age < 50 years; having hit one's head in the collision; and postinjury symptoms of difficulty swallowing, ringing in the ears, dizziness or unsteadiness, and more intense neck pain. Collision parameters, such as head position at the time of the crash and headrest use and type, were not associated with onset of jaw symptoms. CONCLUSIONS: Reduced or painful jaw movement was more common in people with WADs than in those with other collision-related injuries. Among those with WADs, reduced or painful jaw movement was more common in women and younger people. CLINICAL IMPLICATIONS: Reduced or painful jaw movement is an important aspect of WADs, and more studies are needed to determine how to best assess and treat this problem.     

Metabolic syndrome: pathogenesis, medical care and dental implications

BACKGROUND: The dental literature contains little information about metabolic syndrome (MetS) and its dental implications. TYPES OF STUDIES REVIEWED: The authors conducted a MEDLINE search for the period 2000 through 2005, using the term "metabolic syndrome" to define its pathophysiology, medical treatment and dental implications. RESULTS: MetS is the co-occurrence of abdominal obesity, hyper-triglyceridemia, reduced high-density lipoprotein cholesterol levels, hypertension and impaired fasting glucose, which results from consumption of a high-calorie diet and decreased levels of physical activity superimposed on the appropriate genetic setting. Components of MetS synergistically promote the development of atherosclerosis, resulting in myocardial infarction and stroke. CLINICAL IMPLICATIONS: Deteriorating oral health status is associated with worsening of the atherogenic profile. Tooth loss often results in chewing difficulties because of inadequate occlusive surfaces and may lead to alterations in food selection and dietary quality. This, in turn, adversely affects body composition and nutritional status, both of which are related to vascular health. Dentists should develop treatment plans that preserve and restore the dentition, thus ensuring maximum masticatory efficiency and affording patients the optimum opportunity to consume food that will not foster atherogenesis.