Drug-related problems in a general paediatric ward of a tertiary care hospital in Malaysia

International Journal of Clinical Pharmacy - Background Drug-related problems are relatively common among hospitalised patients and may be detrimental to patients and even increase healthcare...     

从免疫炎性损伤角度探讨5种清热解毒药物抗流感的机制及其临床意义

目的探讨黄芩、板蓝根、白头翁、虎杖、白花蛇舌草5种清热解毒代表药物抗流感病毒感染所致免疫炎性损伤的作用机制。方法在流感病毒亚洲甲型鼠肺适应株FM1感染小鼠后的不同时相(初期、极期、后期),采用ELISA法,动态观察清热解毒代表药物对小鼠血清肿瘤坏死因子-α(TNF-α)、白细胞介素-1(IL-1)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)、γ干扰素(IFN-γ)5种炎性细胞因子含量的影响。结果黄芩在感染后第3日可显著降低血清TNF-α、IL-1、IL-6含量,并于感染后各时相均可增加IFN-γ含量,感染后第1~5日增加IL-10含量。板蓝根在感染后第3日能显著降低血清TNF-α含量,第3~5日降低IL-6含量,并在感染后第1天升高IL-10含量,在感染后第3~5日能升高IFN-γ含量。白头翁在感染后第3日能明显降低血清TNF-α、IL-1、IL-6含量,同时显著升高IL-10含量。虎杖在感染后第1日可显著升高血清IL-10含量,在感染后第5日升高IFN-γ含量。白花蛇舌草在感染后第3日降低血清IL-6含量,在感染后第5日升高IFN-γ含量。结论黄芩的抗流感作用主要表现在流感病毒感染引起的急性外感热病的极期;板蓝根在流感病毒感染的各个时相均有一定的治疗作用;白头翁在流感病毒感染的极期可抑制炎性损伤;虎杖在感染流感病毒的初期与后期均可减少促炎性细胞因子的分泌;白花蛇舌草在流感病毒感染的极期及后期均可起到一定的抗免疫炎性损伤。各药物均具有抑制炎性损伤、防止多脏器功能衰竭、防止休克、退热和抑制促炎性细胞因子的分泌,调节机体免疫,从而减轻炎症反应的作用。     

Automated classification of depression from structural brain measures across two independent community‐based cohorts

Major depressive disorder (MDD) has been the subject of many neuroimaging case–control classification studies. Although some studies report accuracies ≥80%, most have investigated relatively small samples of clinically‐ascertained, currently symptomatic cases, and did not attempt replication in larger samples. We here first aimed to replicate previously reported classification accuracies in a small, well‐phenotyped community‐based group of current MDD cases with clinical interview‐based diagnoses (from STratifying Resilience and Depression Longitudinally cohort, ‘STRADL’). We performed a set of exploratory predictive classification analyses with measures related to brain morphometry and white matter integrity. We applied three classifier types—SVM, penalised logistic regression or decision tree—either with or without optimisation, and with or without feature selection. We then determined whether similar accuracies could be replicated in a larger independent population‐based sample with self‐reported current depression (UK Biobank cohort). Additional analyses extended to lifetime MDD diagnoses—remitted MDD in STRADL, and lifetime‐experienced MDD in UK Biobank. The highest cross‐validation accuracy (75%) was achieved in the initial current MDD sample with a decision tree classifier and cortical surface area features. The most frequently selected decision tree split variables included surface areas of bilateral caudal anterior cingulate, left lingual gyrus, left superior frontal, right precentral and paracentral regions. High accuracy was not achieved in the larger samples with self‐reported current depression (53.73%), with remitted MDD (57.48%), or with lifetime‐experienced MDD (52.68–60.29%). Our results indicate that high predictive classification accuracies may not immediately translate to larger samples with broader criteria for depression, and may not be robust across different classification approaches.     

Supratentorial Intraparenchymal Haemorrhages during Spine Surgery

Intracranial haemorrhages are rare but potentially life-threatening complications of spine surgery. Most reported cases involved subdural or cerebellar haemorrhages; supratentorial parenchymal bleeding is very uncommon. We report a 28-year-old woman who underwent resection of a thoracic Ewing''s sarcoma, and developed fatal haemorrhages around her cerebral metastases during surgery. The clinical presentations, possible pathogenesis and potential preventive measures are discussed. Patients with disseminated metastases within the neural axis are at risks of intracranial complications during spine surgery. The presence of intracranial mass lesions should be considered as a relative contraindication to intradural spine surgery.     

Identification and characterization of the constituent human serum antibodies elicited by vaccination

Most vaccines confer protection via the elicitation of serum antibodies, yet more than 100 y after the discovery of antibodies, the molecular composition of the human serum antibody repertoire to an antigen remains unknown. Using high-resolution liquid chromatography tandem MS proteomic analyses of serum antibodies coupled with next-generation sequencing of the V gene repertoire in peripheral B cells, we have delineated the human serum IgG and B-cell receptor repertoires following tetanus toxoid (TT) booster vaccination. We show that the TT⁺ serum IgG repertoire comprises ∼100 antibody clonotypes, with three clonotypes accounting for >40% of the response. All 13 recombinant IgGs examined bound to vaccine antigen with K_d ∼ 10⁻⁸–10⁻¹⁰ M. Five of 13 IgGs recognized the same linear epitope on TT, occluding the binding site used by the toxin for cell entry, suggesting a possible explanation for the mechanism of protection conferred by the vaccine. Importantly, only a small fraction (<5%) of peripheral blood plasmablast clonotypes (CD3⁻CD14⁻CD19⁺CD27⁺⁺CD38⁺⁺CD20⁻TT⁺) at the peak of the response (day 7), and an even smaller fraction of memory B cells, were found to encode antibodies that could be detected in the serological memory response 9 mo postvaccination. This suggests that only a small fraction of responding peripheral B cells give rise to the bone marrow long-lived plasma cells responsible for the production of biologically relevant amounts of vaccine-specific antibodies (near or above the K_d). Collectively, our results reveal the nature and dynamics of the serological response to vaccination with direct implications for vaccine design and evaluation.Most approved vaccines confer protection against infectious diseases by the induction of long-lived plasma cells (LLPCs), which secrete antibodies that serve to neutralize and opsonize the pathogen for many years or decades (1–3). Additionally, the generation of memory B cells (mBCs) provides both a mechanism for the rapid synthesis of affinity matured, antigen-specific antibodies following rechallenge and a means to diversify the humoral immune response to confer protection against rapidly evolving viruses or bacteria (4). Although some vaccines elicit antibody titers that remain virtually constant for many decades, for others, including the tetanus toxoid (TT) vaccine, antibody titers wane monotonically over time (5). Booster immunization triggers the rapid expansion and differentiation of cognate B cells, generating antigen-specific plasmablasts that peak in concentration in peripheral blood after 6–7 d and subsequently rapidly decline to nearly undetectable levels (6, 7). Some, but not all, of these peak-wave plasmablasts migrate to specialized niches overwhelmingly located in the bone marrow (BM) and survive as LLPCs (8), which constitute the major source of all classes of Ig in the serum (9).The establishment of serological memory following either primary or booster vaccination is not understood well (10–14). Even though antibody production is the most critical effector function of B-cell immunity, and antigen-specific antibodies in the serum play a key role in protection against pathogen challenge, technical difficulties have precluded direct determination of the identities of the mAbs that comprise the serum antibody response to vaccination. However, recent studies showing that flu vaccination elicits not only neutralizing antibodies but also antibodies that enhance infection by different flu strains (15) underscore the pressing need to develop approaches for delineating the sequences and functionalities of the serum antibodies elicited by vaccination (16).Single-cell cloning has been used to identify neutralizing antibodies encoded by mBCs or plasmablasts in peripheral blood (17). However, although extremely useful for understanding of the structural mechanisms that can lead to the blockade of pathogen infection, the interrogation of single peripheral B cells alone cannot provide information on whether antibodies encoded by single B cells are also produced as secreted IgGs from BM LLPCs, and hence whether they contribute to the serological memory induced by vaccination. A detailed understanding of the diversity of serum antibodies elicited by vaccination, their functionality (e.g., antigen affinity, epitope specificity), and their relative concentrations in the blood can provide key insights toward vaccine evaluation and development.Here, we deployed high-resolution liquid chromatography (LC) tandem MS (MS/MS) (18–20) for the molecular-level analysis of the serum IgG repertoire, combined with deep sequencing of the V gene repertoire of peripheral B lymphocyte subsets (20) and subsequent expression and characterization of representative serum antibodies, to map the dynamics of the human humoral response to vaccination in unprecedented detail. We elected to analyze the response to booster immunization of the TT vaccine because (i) it elicits a highly effective neutralizing response that is protective toward Clostridium tetani challenge; (ii) the vaccine is highly efficacious, and as a result, no deaths from tetanus intoxication have been reported in the United States for individuals who have completed at least primary immunization (21); (iii) TT has been used as a model for analyzing B-cell development following vaccination in humans (6, 22, 23); and (iv) although early serological and mAb studies had pointed to the C-terminal fragment of the toxin heavy chain [recombinant TT fragment C (rTT.C)] as the target for antibody-mediated protection (24), the precise mechanism by which antibodies elicited by the vaccine mediate neutralization has remained unclear.We show that the anti-TT serum IgG repertoire at steady state is composed of a limited number of antibody clonotypes (∼80–100) displaying uniformly high antigen affinity (low nanomolar or subnanomolar), that most of the serum repertoire postboost comprises preexisting (i.e., prevaccination) serum antibody clonotypes, and that there is only partial overlap between the peak-wave plasmablast V gene repertoire and the TT⁺ serum IgG repertoire at steady state after vaccination. We identified several serum monoclonal IgGs that bind to rTT.C, and epitope mapping revealed that all rTT.C-specific antibodies tested bind to an immunodominant linear epitope at the ganglioside-binding site of the toxin that is used for cell entry. Computational antibody docking substantiated that binding of these antibodies to the toxin blocks access to the ganglioside ligand, thus providing a possible mechanistic explanation for how the TT vaccine confers protection. These results highlight the importance of understanding the composition and dynamics of the serum antibody repertoire, together with the V gene repertoire in peripheral B lymphocytes, for the molecular understanding of vaccine function.