Inter-ictal assay of peripheral circulating inflammatory mediators in migraine patients under adjunctive cervical non-invasive vagus nerve stimulation (nVNS): A proof-of-concept study

Objective

To assay peripheral inter-ictal cytokine serum levels and possible relations with non-invasive vagus nerve stimulation (nVNS) responsiveness in migraineurs.

Glycine‐modified growth hormone secretagogues identified in seized doping material

A number of unknown pharmaceutical preparations seized by Danish customs authorities were submitted for liquid chromatography–high resolution mass spectrometry (LC–HRMS) analysis. Comparison with reference standards unequivocally identified the content of the powders as analogs of the growth hormone secretagogues GHRP‐2 (Pralmorelin), GHRP‐6, Ipamorelin, and modified growth hormone releasing factor (modified GRF 1–29), which can be used as performance‐enhancing substances in sports. In all cases, the detected modification involved the addition of an extra glycine amino acid at the N‐terminus, and analytical methods targeting growth hormone secretagogues should hence be updated accordingly.     

多肽药物专家共识

中国生化制药工业协会多肽分会日前召开多肽药物专家共识研讨会,专家们就中国多肽药物发展现状,发展重点方向及对相关部门的建议达成共识。     

依达拉奉辅助亚低温对重型颅脑创伤的血清细胞因子及凝血功能的影响

目的探讨依达拉奉辅助亚低温治疗对重型颅脑创伤（TBI）患者的凝血功能及神经生长因子（NGF）、降钙素基因相关肽（CGRP）的影响。 方法选取沧州市中心医院神经外三科自2018年8月至2019年8月收治的62例重型TBI患者，按随机数字表法分为观察组（31例）和对照组（31例）。对照组患者给予亚低温治疗，观察组患者在亚低温治疗基础上给予依达拉奉辅助治疗14 d。比较2组患者的神经功能缺损评分和疗效，观察治疗前后患者的脑内凝血功能以及血清内NGF、CGRP含量的变化。 结果观察组患者的临床治疗有效率显著高于对照组（P<0.05）。观察组患者采用依达拉奉辅助亚低温治疗后颅内水肿面积显著降低，大脑中动脉平均血流速度明显升高，美国国立卫生研究院卒中量表评分水平显著下降，巴塞尔指数评定量表评分和GCS评分显著增高，差异有统计学意义（P<0.05）。观察组患者采用依达拉奉辅助亚低温治疗后NGF、CGRP水平明显升高，血浆D-二聚体、纤维蛋白原、凝血酶原时间、凝血酶原时间国际标准比值、活化部分凝血活酶时间、凝血酶时间显著下降，抗凝血酶显著上升，差异均有统计学意义（P<0.05）。 结论依达拉奉辅助亚低温治疗重型TBI的临床治疗效果较好，安全性较高，可有效恢复患者的凝血功能，促进NGF、CGRP表达。     

Synthetic conjugate peptide Fba-Met6 (MP12) induces complement-mediated resistance against disseminated Candida albicans

The fungal genus Candida includes common commensals of the human mucosal membranes, and the most prevalently isolated species, C. albicans, poses a threat of candidemia and disseminated infection associated with an unacceptably high mortality rate and an immense $4 billion burden (US) yearly. Nevertheless, the demand for a vaccine remains wholly unfulfilled and increasingly pressing. We developed a double-peptide construct that is feasible for use in humans with the intention of preventing morbid infection by targeting epitopes derived from fructose bisphosphate aldolase (Fba) and methionine synthase (Met6) which are expressed on the C. albicans cell surface. To test the applicability of the design, we vaccinated mice via the intramuscular (IM) route with the conjugate denoted Fba-Met6 MP12 and showed that the vaccine enhanced survival against a lethal challenge. Because overall endpoint IgG1 and IgG2a antibody titers were robust and these mouse subclasses are associated with protective functionality, we investigated the potential of Fba and Met6 specific antibodies to facilitate the well-defined anti-Candida response by complement, which opsonizes fungi for degradation by primary effectors. Notably, reductions in the fungal burdens and enhanced survival were both abrogated in MP12-vaccinated mice that were pre-challenge dosed with cobra venom factor (CVF), a complement depleting factor. Altogether, we demonstrated that complement is relevant to MP12-based protection against disseminated C. albicans, delineating that a novel, multivalent targeted vaccine against proteins on the surface of C. albicans can enhance the natural response to infection.     

The emerging role of ultrasound in detecting interstitial lung disease in patients with rheumatoid arthritis

ObjectiveTo investigate the potential role of US in the detection of ILD in a cohort of patients with RA.MethodsPatients with diagnosis of RA were consecutively enrolled. All patients underwent pulmonary examination, laboratory data, DLCO measure, chest HRCT and radiographs, and US examination. A healthy group was included as control group. US was performed according the 14-intercostal space scanning protocol using the following semiquantitative scale [0 = normal (≤ 5 B-lines); 1 = slight (≥ 6 and ≤ 15 B-lines); 2 = moderate, (≤ 16 and ≥ 30 B-lines); 3 = severe (≥ 30 B-lines)].ResultsA total of 74 RA patients and 74 healthy controls were included. Thirty of 74 patients (40.5%) showed US signs of ILD with respect to the healthy controls (3 subjects, 4.1%) (P < 0.001); whereas HRCT showed ILD in 27 (36.4%) of 74 patients. Among the 30 patients that showed US findings of ILD, 17 (56.6%) were asymptomatic from respiratory view-point. The sensitivity and specificity of US were 92% and 89% respectively. A positive correlation between US and HRCT findings were found (P < 0.001) whereas no correlation was found with chest radiographs and DLCO findings. Positive association between US findings and DAS28-ESR, anti-CCP and RF (P < 0.01 for each respectively) was found. Feasibility, represented by the mean time spent to perform the pulmonary US assessment was 7.8 minutes (± SD 1.2, range 6 to 10 minutes).ConclusionsOur results support the potential of US in detect accurately ILD in patients with RA and provide a rationale to consider it as a friendly screening tool to be implemented in early phases of the disease.     

Methodological advances in the design of peptide-based vaccines

The tremendous advances in genomics, recombinant DNA technology, bioengineering and nanotechnology, in conjunction with the development of high-end computations, have been instrumental in the process of rational design of peptide-based vaccines. The use of peptide vaccines was limited owing to their inherent instability when systemically administered; however, advanced formulation techniques have been developed for their systemic delivery, thereby overcoming their degradation, clearance, cellular uptake and off-target effects. With the rise of sophisticated immunological predictors and experimental techniques, several methodological advances have occurred in this field. This review examines contemporary methods to identify and optimize epitopes, engineer their immunogenic properties and develop their safe and efficient delivery into the host.     

Current update on imaging for pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (panNEN) are a heterogeneous group of tumors with differing pathological, genetic, and clinical features. Based on clinical findings, they may be categorized into functioning and nonfunctioning tumors. Adoption of the 2017 World Health Organization classification system, particularly its differentiation between grade 3, well-differentiated pancreatic neuroendocrine tumors (panNET) and grade 3, poorly-differentiated pancreatic neuroendocrine carcinomas (panNEC) has emphasized the role imaging plays in characterizing these lesions. Endoscopic ultrasound can help obtain biopsy specimen and assess tumor margins and local spread. Enhancement patterns on computed tomography (CT) and magnetic resonance imaging (MRI) may be used to classify panNEN. Contrast enhanced MRI and diffusion-weighted imaging have been reported to be useful for characterization of panNEN and quantifying metastatic burden. Current and emerging radiotracers have broadened the utility of functional imaging in evaluating panNEN. Fluorine-18 fluorodeoxyglucose positron emission tomography (PET)/CT and somatostatin receptor imaging such as Gallium-68 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid–octreotate PET/CT may be useful for improved identification of panNEN in comparison to anatomic modalities. These new techniques can also play a direct role in optimizing the selection of treatment for individuals and predicting tumor response based on somatostatin receptor expression. In addition, emerging methods of radiomics such as texture analysis may be a potential tool for staging and outcome prediction in panNEN, however further investigation is required before clinical implementation.     

Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma

Background/objectivesPancreatic ductal adenocarcinoma (PDAC) is frequently heralded by an impairment of glucose homeostasis. Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein alpha (FAP) are aminopeptidases that regulate several bioactive peptides involved in glucoregulation, and are frequently dysregulated in cancer. The present study analyzes blood plasma levels and the quantity and localization of DPP-IV and FAP in PDAC tissues.MethodsDPP-IV and FAP concentration and enzymatic activity were evaluated in the plasma from 93 PDAC, 39 type 2 diabetes mellitus (T2DM) and 29 control subjects, and in matched paired non-tumorous and tumor tissues from 48 PDAC patients. The localization of DPP-IV and FAP was determined using immunohistochemistry and catalytic histochemistry.ResultsThe enzymatic activity and concentration of DPP-IV was higher in PDAC tumor tissues compared to non-tumorous pancreas. DPP-IV was expressed in cancer cells and in the fibrotic stroma by activated (myo)fibroblasts including DPP-IV⁺FAP⁺ cells. FAP was expressed in stromal cells and in some cancer cells and its expression was increased in the tumors. Plasmatic DPP-IV enzymatic activity, and in particular the ratio between DPP-IV enzymatic activity and concentration in PDAC with recent onset DM was higher compared to T2DM. In contrast, the plasmatic FAP enzymatic activity was lower in PDAC compared to T2DM and controls and rose after tumor removal.ConclusionsDPP-IV-like enzymatic activity is upregulated in PDAC tissues. PDAC patients with recent onset diabetes or prediabetes have increased plasmatic DPP-IV enzymatic activity. These changes may contribute to the frequently observed association of PDAC and recent onset impairment of glucoregulation.