Hyperglycemia induces mixed M1/M2 cytokine profile in primary human monocyte-derived macrophages

Hyperglycaemia is a key factor in diabetic pathology. Macrophages are essential regulators of inflammation which can be classified into two major vectors of polarisation: classically activated macrophages (M1) and alternatively activated macrophages (M2). Both types of macrophages play a role in diabetes, where M1 and M2-produced cytokines can have detrimental effects in development of diabetes-associated inflammation and diabetic vascular complications. However, the effect of hyperglycaemia on differentiation and programming of primary human macrophages was not systematically studied. We established a unique model to assess the influence of hyperglycaemia on M1 and M2 differentiation based on primary human monocyte-derived macrophages. The effects of hyperglycaemia on the gene expression and secretion of prototype M1 cytokines TNF-alpha and IL-1beta, and prototype M2 cytokines IL-1Ra and CCL18 were quantified by RT-PCR and ELISA. Hyperglycaemia stimulated production of TNF-alpha, IL-1beta and IL-1Ra during macrophage differentiation. The effect of hyperglycaemia on TNF-alpha was acute, while the stimulating effect on IL-1beta and IL-1Ra was constitutive. Expression of CCL18 was supressed in M2 macrophages by hyperglycaemia. However the secreted levels remained to be biologically significant. Our data indicate that hyperglycaemia itself, without additional metabolic factors induces mixed M1/M2 cytokine profile that can support of diabetes-associated inflammation and development of vascular complications.     

Area postrema syndrome as initial manifestation in neuromyelitis optica spectrum disorder patients: A retrospective study

BackgroundArea postrema syndrome (APS) is recognized as a core feature in neuromyelitis optica (NMO) diagnosis. Isolated APS can occur at NMO onset and frequently results in a delay of diagnosis, along with devastating secondary neurologic deficits. To date, few studies have characterized APS-onset neuromyelitis optica spectrum disorder (APSO-NMOSD).ObjectiveWe aimed to describe the clinical and radiologic features of patients with APSO-NMOSD who are initially misdiagnosed in a cohort of patients from Zhengzhou, China.Materials and methodsWe identified 15 patients who presented with APS as an initial manifestation, based on the 2015 international consensus diagnostic criteria for NMOSD, and reviewed their demographic, clinical, laboratory, and magnetic resonance imaging (MRI) data.ResultFifteen patients (3 men, 12 women) aged 14–50 years old were included in our study. All patients presented with APS that included intractable nausea, vomiting, or hiccups (INVH) as the initial manifestation; many experienced a delay in diagnosis. Serum AQP4 was positive in eleven patients and myelin oligodendrocyte glycoprotein (MOG) in one patient. All patients had a linear medullary lesion or a linear medulla-spinal lesion on sagittal MRI. An “inverted V sign” on axial medulla oblongata images, representing a lesion involving the area postrema, was noted in seven patients in this study.ConclusionsAPS can occur as a sole and initial manifestation of NMOSD, often leading to misdiagnosis in the early process of disease. Identifying patients with an “inverted V” sign and a linear medullary lesion upon MRI examination can help to quickly identify APS patients and avoid further diagnostic delays.     

Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants

BackgroundVaccinating pregnant women may prevent invasive Group B Streptococcus (GBS) disease in their young infants. In a low-middle income setting, we sought to determine an association between natural maternal antibody responses and the development of invasive GBS disease.MethodsWe undertook a matched case-control study in Johannesburg, South Africa. Maternal and infant antibody concentrations were compared between serotype-specific Ia and III GBS cases and well-baby controls in which the mother was colonized with the same serotype.ResultsThe median maternal serotype Ia and III antibody concentrations (in μg/mL) were 0.05 (IQR: 0.02–0.24; n = 27) and 0.14 (IQR: 0.08–0.33; n = 29) in cases, and 0.29 (IQR: 0.06–1.60; n = 43) and 0.29 (IQR: 0.13–0.58; n = 31) in homotypic controls, respectively. A smaller proportion of cases as compared to homotypic controls had higher serotype Ia and III maternal antibody concentrations. Using Bayesian modeling, we demonstrated that the risk of invasive GBS disease was less than 10% with maternal antibody concentrations ≥6 μg/mL and ≥3 μg/mL for serotypes Ia and III, respectively.ConclusionsMaternal capsular antibody concentrations are associated with the risk of invasive GBS disease in infants. In a low-middle income setting with a high burden of invasive disease, we have demonstrated a sero-correlate of protection for GBS serotypes Ia and III which could facilitate vaccine licensure.     

Population Pharmacokinetics of Voriconazole and Optimization of Dosage Regimens Based on Monte Carlo Simulation in Patients With Liver Cirrhosis

Because voriconazole metabolism is highly influenced by liver function, the dose regimen of voriconazole should be carefully assessed in patients with liver cirrhosis. We aimed to identify significant factors associated with plasma concentrations. Blood samples were collected from patients with liver cirrhosis who received voriconazole, and voriconazole concentrations were determined. One-compartment model with first-order absorption and elimination appropriately characterized the in vivo process of voriconazole. The typical population value of voriconazole clearance (CL) was 1.45 L/h and the volume of distribution (V) was 132.12 L. The covariate analysis identified that CYP2C19 gene phenotype and Child-Pugh classification were strongly associated with CL and body weight had a significant influence on V. The results of the Monte Carlo simulation suggested that CYP2C19 gene phenotype was a critical factor for determining voriconazole dosage in patients with liver cirrhosis. The extensive metabolizer patients with Aspergillus fumigatus infections could be treated effectively with a recommended dose of 75 mg twice daily in mild to moderate liver cirrhosis and 100 mg once daily in moderate severe liver cirrhosis. However, the recommended dosage for Candida albicans infections patients was not achieved in present study.     

套管针在血液透析患者人工血管内瘘使用中的效果观察

目的　对比观察透析用套管针与普通钢针（16G）在人工血管内瘘（arteriovenous graft,AVG）穿刺使用中的效果。方法　选取2018年1月至2021年1月在广州医科大学附属第五医院血液透析中心使用AVG作为血管通路进行维持性血液透析治疗患者30例,其中男18例、女12例,年龄（40.2±5.1）岁,每例前10次采用套管针穿刺,后10次采用钢针穿刺,采用自身对照。观察患者在2种穿刺针穿刺治疗过程中的疼痛感、肘部活动度、动静脉压力、皮下血肿发生例数、指压止血时间。计量资料采用独立样本t检验,计数资料采用Fisher精确概率法。结果　套管针及16G钢针上机血流速度稳定后动脉压及透析后3 h的动脉压值［（-50±18）mmHg（1 mmHg=0.133 kPa）比（-70±22）mmHg及（-55±21）mmHg比（-76±23）mmHg］、静脉压值［（105±15）mmHg比（140±22）mmHg及（108±16）mmHg比（145±23）mmHg］比较,差异均有统计学意义（均P<0.05）。套管针与16G钢针肘部活动度［（2.33±0.61）分比（1.25±0.53）分］、指压止血时间［（7.08±2.11）min比（12.12±3.15）min］比较,差异均有统计学意义（均P<0.05）;穿刺时疼痛感比较差异无统计学意义（P>0.05）。结论　使用套管针进行AVG穿刺行血液透析治疗,可提高患者的舒适度和安全性,获取更好的血流量及血管通畅性,降低皮下血肿以及远期并发症的发生率,从而达到提高患者生活质量的目的。     

Development of a performance standard for physiotherapists delivering exercise and mobilisation to the critically ill: A modified Delphi consensus study

BackgroundThe provision of early mobilisation to critically ill patients has the potential to improve long term outcomes, but, is complex to deliver. There is minimal literature detailing the training and expertise required to deliver these interventions safely and effectively.ObjectiveThe objective of this study was to determine the key elements of a performance standard for assessment of physiotherapists delivering exercise and mobilisation interventions to the critically ill.MethodThis is a modified eDelphi expert consensus study. Fifty-one physiotherapists from Australia and New Zealand with relevant clinical, educational, or research experience were included on the expert panel. Background information and the initial pool of items were developed from review of relevant literature. Five survey rounds were administered across two study phases to determine the elements, performance criteria, and assessment scale of the performance standard. Items were modified, amalgamated, and added based upon panel comments.ResultsConsensus was achieved for 69 mandatory, and two supplementary performance criteria which were arranged under 15 elements encompassing knowledge, assessment, analysis, intervention, and professional behaviours. A 3-point rating scale was selected to assess item achievement and global performance.ConclusionBinational expert consensus was reached to define the assessment criteria for physiotherapists delivering exercise and mobilisation interventions to the critically ill. This standard can be utilised in clinical, educational, and research practice environments to guide training, assessment, and skill recognition in critical care physiotherapy.     

UNC45A-related osteo-oto-hepato-enteric syndrome in a Chinese neonate

Unexplained diarrhea and cholestasis are common clinical phenotypes in newborns, indicating there is only a little common genetic basis for these conditions. However, it has been reported that defects in the UNC45A gene can lead to osteo-oto-hepato-enteric syndrome. However, to date, only 10 patients with this syndrome have been reported in 2 studies; therefore, there is still a lack of analysis regarding the correlation between disease phenotype and genotype. Trio-whole exome sequencing was conducted using DNA samples from a newborn with congenital diarrhea and cholestasis from a Chinese Han family. The UNC45A variants were verified using Sanger sequencing. In addition, we applied a crystal structure model to analyze the potential hazards associated with the variants. The plasmids were constructed in vitro and transfected into human 293T cells for Western blot (WB) analysis. After the mutant protein was fused with the Green Fluorescent Protein label, intracellular localization was observed using laser confocal microscopy. The gene detection results showed that the UNC45A gene of the newborn examined in the present study harbored the compound heterozygous variants p.Arg819Ter, and p.Leu237Pro; this was confirmed via Sanger sequencing. Analysis of the Leu237Pro crystal structure model suggested that this variant may decrease local structural stability and affect protein function. The Western blot and laser confocal microscopy observation results suggested that the Leu237Pro mutation leads to reduced protein expression, while the Arg819Ter mutation completely inhibits the expression of the protein. The compound heterozygous variants of UNC45A (p.Arg819Ter and p.Leu237Pro) may be pathogenic factors of congenital diarrhea and cholestasis in this neonatal patient. Therefore, UNC45A deficiency should be considered when intractable diarrhea and cholestasis occur in newborns.     

Risk of pancreatic cancer after acute pancreatitis: A population-based matched cohort study

BackgroundWe investigated the short- and long-term risks of pancreatic cancer after the diagnosis of acute pancreatitis.MethodsThis population-based matched-cohort study used data from the Korean National Health Insurance Service database. Patients with acute pancreatitis (n = 25,488) were matched with the control group (n = 127,440) based on age, sex, body mass index, smoking status, and diabetes. We estimated the hazard ratios for developing pancreatic cancer in both groups using Cox regression analysis.ResultsDuring a median follow-up of 5.4 years, pancreatic cancer developed in 479 patients (1.9%) in the acute pancreatitis group and 317 patients (0.2%) in the control group. Compared with the control group, the risk of pancreatic cancer in the acute pancreatitis group was very high within the first 2 years, which gradually decreased over time. The hazard ratio for the risk of developing pancreatitis was 8.46 (95% confidence interval, 5.57–12.84) at 1–2 years, and then decreased to 3.62 (95% confidence interval, 2.26–4.91) at 2–4 years. However, even after 8–10 years, the hazard ratio was still statistically significantly increased to 2.80 (95% confidence interval, 1.42–5.53). After 10 years, there was no significant difference in the risk of pancreatic cancer between the two groups.ConclusionsThe risk of pancreatic cancer increases rapidly after acute pancreatitis diagnosis, gradually declines after 2 years, and remains elevated for up to 10 years. Further studies are needed to determine the long-term effects of acute pancreatitis on the risk of pancreatic cancer.