TLIF术式在布氏杆菌性脊柱炎病人中的临床疗效及安全性分析

目的 对比分析单纯后路内固定+一期经腰椎间孔病椎间病灶清除(TLIF)与经典的前后联合手术在布氏杆菌性脊柱炎患者中的临床疗效及安全性。 方法 对我院2015年1月至2017年12月收治的93例布病性脊柱炎患者的临床资料进行分析。按手术方式分为观察组(45例)和对照组(48例)。对两组患者的基础数据、临床指标、术前术后各项指标水平以及术后并发症、植骨治愈情况。 结果 观察组与对照组基础数据比较,差异无统计学意义(P>0.05)。观察组患者的手术时间、住院天数、术中出血量及术后下床时间均明显低于对照组(P<0.01)。两组患者术后3个月的ODI、VAS、CRP、ESR及Cobb角均明显低于术前(P<0.05);术后3个月,观察组患者的ODI、VAS、CRP、ESR及Cobb角均明显低于对照组(P<0.05)。观察组术后并发症发生率(4.4%)明显低于对照组(25.0%)(Χ²=7.674,P<0.01)。 结论 TLIF治疗布氏杆菌性脊柱炎患者的临床疗效突出,安全性较好,更有利于患者术后身体的恢复。     

From the Cover: A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs

The recent success of antibody–drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.Microtubule-targeting agents such as the taxanes and the vinca alkaloids represent a successful class of anticancer drugs (1). Vinblastine, for example, is a microtubule-destabilizing agent (MDA) that is widely used in combination therapy for the treatment of childhood and adult malignancies (2). The broad clinical application of MDAs, however, is hampered by their severe adverse effects (3). This problem has been very recently addressed by the use of antibody–drug conjugate (ADC) approaches, which have revived interest in the development of highly potent MDAs for therapeutic use (4–6).For several important MDAs, the molecular mechanism of action on tubulin and microtubules has so far remained elusive. Rhizoxin, for example, is a potent MDA that has been investigated in phase 2 clinical trials, but for reasons poorly understood, it has demonstrated only very limited clinical efficacy (7). At the molecular level, it is well established that rhizoxin interferes with the binding of vinblastine to tubulin; however, the exact location of its binding site has been a matter of debate (8–10). Interestingly, biochemical and mutagenesis data suggest that the structurally unrelated MDA maytansine (9, 11), which is part of an ADC that was recently approved by the FDA for the treatment of advanced breast cancer (11, 12), and the phase 1 drug PM060184 (13, 14) (Fig. 1A) share a common tubulin-binding site with rhizoxin (9, 13, 14). These two latter drugs have also been reported to interfere with the binding of vinblastine; however, as for rhizoxin, the exact binding sites and modes of action of maytansine and PM060184 have not been elucidated (9, 14–16).Open in a separate windowFig. 1.Structure of the tubulin–rhizoxin F complex. (A) Chemical structures of rhizoxin F, maytansine, and PM060184. (B) Overall view of the T₂R-TTL–rhizoxin F complex. Tubulin (gray), RB3 (light green), and TTL (violet) are shown in ribbon representation; the MDA rhizoxin F (orange) and GDP (cyan) are depicted in spheres representation. As a reference, the vinblastine structure (yellow, PDB ID no. 1Z2B) is superimposed onto the T₂R complex. (C) Overall view of the tubulin–rhizoxin F interaction in two different orientations. The tubulin dimer with bound ligand (α-tubulin-2 and β-tubulin-2 of the T₂R-TTL–rhizoxin F complex) is shown in surface representation. The vinblastine structure is superimposed onto the β-tubulin chain to highlight the distinct binding site of rhizoxin F. All ligands are in sphere representation and are colored in orange (rhizoxin F), cyan (GDP), and yellow (vinblastine). (D) Close-up view of the interaction observed between rhizoxin F (orange sticks) and β-tubulin (gray ribbon). Interacting residues of β-tubulin are shown in stick representation and are labeled.To establish the exact tubulin-binding site of rhizoxin, maytansine, and PM060184 and to clarify their specific interactions with the protein, we have investigated the structures of the corresponding ligand–tubulin complexes by X-ray crystallography. Our data reveal a new tubulin-binding site and pharmacophore for small molecules, and binding to this site is associated with a distinct molecular mechanism for the inhibition of microtubule formation.     

Psychiatric Diagnoses and Psychosocial Needs of Outpatient Deaf Children and Adolescents

Deaf youth may be more vulnerable to psychiatric disorders but very little research data is available. The current study identified prevalence rates of psychiatric disorders and examined the psychosocial needs and strengths of deaf youth aged 4–17 receiving specialized outpatient mental health services for the deaf. Compared to hearing peers, deaf youth had greater rates of attention deficit hyperactivity disorder, conduct, autism-spectrum and bipolar disorders and spent three times longer in treatment than their hearing peers. In the deaf subsample, moderate-severe risk was found in social functioning (33.3 %) and suicidal behavior (14 %). Deaf youth had moderate to severe impairment in social relationships (54.8 %), school functioning (42.9 %). Over one-third of deaf youth had impaired family relationships, living situation, communication, judgment and physical health. Deaf youth present with higher rates of certain clinical disorders and have deficits in multiple life domains that may impact functioning and create a longer treatment course.     

Human macrophage and dendritic cell-specific silencing of high-mobility group protein B1 ameliorates sepsis in a humanized mouse model

Hypersecretion of cytokines by innate immune cells is thought to initiate multiple organ failure in murine models of sepsis. Whether human cytokine storm also plays a similar role is not clear. Here, we show that human hematopoietic cells are required to induce sepsis-induced mortality following cecal ligation and puncture (CLP) in the severely immunodeficient nonobese diabetic (NOD)/SCID/IL2Rγ^−/− mice, and siRNA treatment to inhibit HMGB1 release by human macrophages and dendritic cells dramatically reduces sepsis-induced mortality. Following CLP, compared with immunocompetent WT mice, NOD/SCID/IL2Rγ^−/− mice did not show high levels of serum HMGB1 or murine proinflammatory cytokines and were relatively resistant to sepsis-induced mortality. In contrast, NOD/SCID/IL2Rγ^−/− mice transplanted with human hematopoietic stem cells [humanized bone marrow liver thymic mice (BLT) mice] showed high serum levels of HMGB1, as well as multiple human but not murine proinflammatory cytokines, and died uniformly, suggesting human cytokines are sufficient to induce organ failure in this model. Moreover, targeted delivery of HMGB1 siRNA to human macrophages and dendritic cells using a short acetylcholine receptor (AchR)-binding peptide [rabies virus glycoprotein (RVG)-9R] effectively suppressed secretion of HMGB1, reduced the human cytokine storm, human lymphocyte apoptosis, and rescued humanized mice from CLP-induced mortality. siRNA treatment was also effective when started after the appearance of sepsis symptoms. These results show that CLP in humanized mice provides a model to study human sepsis, HMGB1 siRNA might provide a treatment strategy for human sepsis, and RVG-9R provides a tool to deliver siRNA to human macrophages and dendritic cells that could potentially be used to suppress a variety of human inflammatory diseases.Sepsis is an important cause of mortality in intensive-care units, with more than 750,000 individuals developing severe sepsis in North America annually and a mortality rate varying between 35 and 50% (1, 2). The pathogenesis of sepsis includes countless disturbances of the host immune system starting with a harmful, infection-triggered exaggerated inflammatory cascade that results in tissue injury and rapidly leads to massive apoptosis of immune cells (2, 3). This is followed by a secondary immune paralysis phase accompanied by uncontrolled growth of bacteria and tissue damage. Although therapy to suppress the immediate cytokine response, such as treatment with TNF and IL-1β antibodies, have failed in clinical trials (4–6), it has now come to be recognized that, at least in animal models, high-mobility group protein 1 (HMGB1), which is secreted from macrophages and dendritic cells (DCs) but not lymphocytes late in the disease, acts as a master regulator of late and sustained cytokine storm, up-regulating many cytokines including TNF-α, IL-6, IL-1β, and IL-8 (reviewed in refs. 7–11). In fact, injection of mice with HMGB1 is enough to induce the lethal organ damage seen in sepsis (12), whereas treatment with neutralizing HMGB1 antibody can rescue mice and rats from experimental sepsis (13, 14). However, although HMGB1 is also secreted in human sepsis (12), its role in sepsis pathogenesis or the impact of its neutralization on human cells remain unclear.RNA interference can be used to silence virtually any gene, including multiple genes, as long as a way can be found to introduce small interfering (si)RNAs into relevant cell types in vivo without toxicity. Several advances have been made in developing methods to deliver siRNA in vivo to different cell types, most successfully to the liver cells (reviewed in refs. 15–17). A lipid-like nanoparticle called C12-200, which had been developed for liver-specific delivery of siRNA, was recently also shown to deliver siRNA to murine monocytes, and silencing C-C chemokine receptor type 2 (CCR2) in monocytes using this reagent was effective in reducing atherosclerosis, islet transplantation and tumors (18). Whether this reagent also targets human DCs and monocytes/macrophages is unclear. We have reported previously that a short 29-aa peptide derived from the rabies virus glycoprotein (RVG), fused to 9R residues (RVG-9R), can deliver siRNA to murine macrophages and brain cells by specific binding to its ligand acetylcholine receptor (AchR) (19, 20). Because AchR is also expressed on human macrophages and DCs (21) and also because the acetylcholine-binding site on the α7 subunit is highly conserved, we reasoned that RVG-9R might also be used to target human macrophages and DCs. In this study, we validate this hypothesis in vitro, as well as in vivo, using human hematopoietic stem cell–engrafted nonobese diabetic NOD/SCID/IL2Rγ^−/− mice that lack mouse innate and adaptive immune systems (22). More importantly, we also show that silencing human HMGB1 using this delivery reagent in this mouse model substantially reduces human lymphocyte apoptosis and cytokine storm and protects mice from sepsis-induced mortality.     

An insight into the sialotranscriptome of Triatoma matogrossensis, a kissing bug associated with fogo selvagem in South America

Triatoma matogrossensis is a Hemiptera that belongs to the oliveirai complex, a vector of Chagas' disease that feeds on vertebrate blood in all life stages. Hematophagous insects' salivary glands (SGs) produce potent pharmacologic compounds that counteract host hemostasis, including anticlotting, antiplatelet, and vasodilatory molecules. Exposure to T. matogrossensis was also found to be a risk factor associated with the endemic form of the autoimmune skin disease pemphigus foliaceus, which is described in the same regions where Chagas' disease is observed in Brazil. To obtain a further insight into the salivary biochemical and pharmacologic diversity of this kissing bug and to identify possible allergens that might be associated with this autoimmune disease, a cDNA library from its SGs was randomly sequenced. We present the analysis of a set of 2,230 (SG) cDNA sequences, 1,182 of which coded for proteins of a putative secretory nature.     

A prospective study of central venous catheters placed in a tertiary care Emergency Department: indications for use, infectious complications, and natural history

Despite successful efforts to improve overall central line-associated bloodstream infections (CLABSI) rates, little is known about CLABSI rates or even central venous catheter insertion practices in the Emergency Department. We sought to determine the baseline CLABSI rate for Emergency Department-inserted central venous catheters and to describe indications for placement, duration of use, and the natural history of these devices.