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Eculizumab-C5 complexes express a C5a neoepitope in vivo

Friday, November 10, 2017 7:00:00 AM Etc/GMT+5

Summary of Nilsson, P. et al; Eculuzimab-C5 complexes express a C5a neoepitope in vivo: Consequences for interpretation of patient complement analyses. ScienceDirect 2017. Click here for the full article.
The complement system has obtained renewed clinical focus due to an increasing number of patients treated with eculizumab, a monoclonal antibody inhibiting cleavage of C5 into C5a and C5b for the treatment of paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS).
 
This study identifies the expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. This finding is important to evaluate whether complement inhibitory treatment is indicated and if treatment is effective. Serum was collected from 22 individuals ranging from healthy subjects to patients with genetic C5-deficiency or antiphospholipid syndrome. C5a was monitored for the diseased individuals before and after administration of eculizumab by using the Hycult Biotech C5a ELISA (HK349) and the BD C5a kit.

The results showed that the administration of eculizumab induced a false-positive c5a signal in plasma detected with BD C5a ELISA kit which was not observed in the Hycult Biotech assay. This is caused by the expression of a neoepitope which was exposed on C5 after binding to eculizumab in vivo. These data are important for interpretation of complement analyses in patients treated with eculizumab and confirms that assays used for quantification of C5a should be carefully checked for reactivity against C5 bound to eculizumab.
Posted in Scientific Publications By G. Snippe

Summary of Yamashiro, K et al; Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke. PLOS ONE 2017. Click here for the full article.

Metabolic disorders are one of the leading causes for heart disease and stroke. Increasing evidence suggests that dysbiosis is associated with metabolic diseases, but there is little known on the relation with ischemic stroke.

The aim of this study was to investigate whether the gut microbiota […] are altered in patients with ischemic stroke. Blood samples of 41 ischemic stroke patients were measured on a variety of metabolic readouts, but also cytokines and acute phase proteins were tested such as LBP (Cat. # HK315). Fecal samples were additionally used to examine the gut microbial composition with qPCR.

The results show that stroke patients had an impaired composition of the fecal bacteria and an elevated organic acid concentration. However, there were no differences in LBP concentrations, TNF-α levels and bacteremia rates between the patients with stroke and the control subjects.

Despite these findings, the data still suggests that gut dysbiosis in patients with ischemic stroke is associated with host metabolism and inflammation. Further studies are needed to determine a more predictive indicator of ischemic stroke.

Posted in Scientific Publications By G. Snippe

LPS recognition, a complex process with complex consequences

Thursday, September 21, 2017 7:50:00 AM Etc/GMT+5

LPS (lipopolysaccharide), also known as endotoxins, are large heat-resistant and resilient molecules found on the outer membrane of Gram-negative bacteria and play an important role in the structural integrity of these bacteria. LPS triggers a strong immune response as Toll-like receptors (more specifically the CD14/TLR4/MD2 receptor complex) recognize LPS. They are an essential component of Gram-negative bacteria, making LPS a relevant target for new antimicrobial agents.

LPS comprises of three parts:

  1. Lipid A: a highly conserved lipid component
  2. The core oligosaccharide: attaches directly to lipid A and common to most variants
  3. The O antigen: a repetitive glycan polymer which maintain the hydrophilic properties of the molecule.

The recognition of LPS is a complex process that starts with the binding to LBP (LPS binding protein). This protein catalyzes the monomerization of LPS and transfers it to CD14 on the cell membrane and to lipoproteins. This in turn transfers it to MD-2, a non-anchored protein that is associated with the extracellular domain of TLR4. The triggering of TLR4 initiates a signaling cascade (MyD88) for cells to secrete pro-inflammatory cytokines and nitric oxide. TLR4 is commonly found on leukocytes and dendritic cells and generates an inflammatory response when exposed to LPS that includes but is not limited to:

  • Production of cytokines such as IL’s and TNF’s
  • Activation of the alternative complement pathway
  • Activation of the coagulation cascade

These reactions can result in a physiological, pathological and clinical effects, such as fever, shock, leukopenia, hypoglycemia and even death. In the past it was thought that LPS exposure is the main cause for pathological conditions, such as sepsis and autoimmune diseases. Advancing insights demonstrate that also the host pathogen interaction plays an important role as it can cause disease due to disruption of the homeostatic state. There are many scientific publications that underline this theory with topics such as:

  • The gut microbiome in conjunction with microbial translocation
  • Periodontal disease in relation to the development of heart disease

Even though it is one of the most widely described molecules in scientific literature, its role in both homeostasis and pathology keeps expanding.

For more information on Hycult Biotech products related to the above, please take a look at the following literature:

You can also visit the products section on the Hycult Biotech website via: https://www.hycultbiotech.com/products

Posted in Scientific Publications By G. Snippe

Inflammatory markers in children with respiratory tract infection

Tuesday, August 29, 2017 4:00:00 AM Etc/GMT+5

Summary of Ahout, I et al; Prospective observational study in two Dutch hospitals to assess the performance of inflammatory plasma markers to determine disease severity of viral respiratory tract infections in children. BMJ Open 2017. Click here for the full article.

Lower respiratory tract infections (LRTIs) are a major cause of hospital admissions in children. Viruses are the most common cause and the course of these infections is unpredictable with potential fast deterioration into respiratory failure. Currently, it is difficult to improve clinical judgement on aspects such as length of hospitalization and ICU admission due to the fact that this is generally based on subjective criteria. The aim of this study was to determine whether systemic inflammatory markers can be used to predict severity of disease in children with respiratory viral infections.

Blood was collected from 104 children <3 years of age with viral LRTI in an acute setting (within 24 hours) and in the recovery phase (4-6 weeks). Plasma protein levels of SAA, SAP, PTX3, properdin and CRP were determined by ELISA to investigate potential indicators of disease severity.

The results demonstrated that plasma levels of CRP, SAP, SAA and PTX3 increased significantly during the acute phase. Properdin levels did not differ between the acute phase and the recovery phase, but it did drop significantly in patients with severe disease. SAA levels were significantly elevated in relation to disease severity. Additionally, both CRP and properdin correlated significantly with duration of hospitalization.

This study has proven the clinical relevance of plasma markers such as CRP, PTX3, SAA and properdin in children with acute viral LRTI. However, a combination of these markers significantly enhances the accuracy of identifying patients with severe disease […] and might provide additive value in clinical decision-making.

Posted in Scientific Publications By G. Snippe

Diversity of the gut microbiome in chronic fatigue syndrome

Thursday, July 20, 2017 10:09:57 AM Etc/GMT+5

Summary of Giloteaux, L et al; Reduced diversity and altered composition of the gut microbiome in individuals with ME/CFS. Microbiome 2016. Click here for the full article.

Gastrointestinal disturbances are one of the symptoms most commonly reported in patients with myalgic encephalomyelitis, also known as chronic fatigue syndrome (ME/CFS). This study assesses the microbial diversity and inflammatory status of these patients.

49 ME/CFS patients and 39 controls were tested for LBP (Cat. # HK315) as a marker for microbial translocation and I-FABP (Cat. # HK406) as a marker for gastrointestinal tract damage. The results conclude that ME/CFS patients had significantly higher plasma LPS levels than healthy individuals but that the difference in I-FABP levels was not statistically significant. Sequencing of the stool microbiota also showed lower relative abundance of Firmicutes and higher relative abundance of Proteobacteria in ME/CSF samples. It was also observed that members of the Ruminococcaeae and Bifidobacteriaceae were significantly increased in healthy individuals.

Taken together, the study suggests that ongoing damage to the gut mucosa leads to increased microbial translocation in ME/CSF, which in turn could alter antimicrobial regulators and dysregulate the innate immune system. The combination of identifying an altered commensal gut microbiota with the right inflammatory markers could lead to novel diagnostics and therapeutic strategies that would improve clinical outcome.

Posted in Scientific Publications By G. Snippe

Comparison of fecal calprotectin in infants (breast vs. formula)

Thursday, June 22, 2017 1:00:00 AM Etc/GMT+5

Summary of Asgarshirazi, M et al; Comparison of fecal calprotectin in exclusively breastfed and formula or mixed fed infants. Acta Med Iran 2017, 55:53. Click here for the full article.

Breastfeeding has been a long topic of debate for researchers and many studies are hypothesizing the benefits of mother milk. Many studies try to determine the long-term effects, while this can be controversial due to the multiple factors could impact these outcomes. The mode of feeding is likely to interfere with the intestinal behaviour during the first months of life, particularly when looking at the microflora.

This prospective cohort stuy compares fecal calprotectin levels between exclusively breastfed and formula or mixed-fed infants. 60 term newborns were enrolled in the study and their fecal calprotectin levels were measured at the age of one week and with six months using the ELISA method (Cat. # HK382). Results show that calprotectin was higher in the first month versus the six months in all infants. In exclusively breastfed infants, the mean stool calprotectin levels at the first (369 vs. 153 µg/g) and sixth month (283 vs. 114 µg/g)  were significantly higher than exclusively formula fed and mixed fed babies.

Based on the role of calprotectin in inflammation, its higher levels in exclusively breastfed infants is contrary to breast milk benefits and may be a sign of enhanced mucosal immune maturity in them. 

Posted in Scientific Publications By G. Snippe

α-defensin expression associated with risk of coronary heart disease

Wednesday, May 10, 2017 1:00:00 AM Etc/GMT+5

Summary of Maneerat, Y et al; Increased alpha-defensin expression is associated with risk of coronary heart disease: a feasible predictive inflammatory biomarker of coronary heart disease in hyperlipidemia patients. Lipids in Health and Disease 2016. Click here for the full article.

Atherosclerosis starts as an asymptomatic but progressive condition. A combination of genetics, lifestyle and other underlying (metabolic) disorders make it a life-threatening condition causing coronary heart disease (CHD) and potentially death. Polymorphonuclear neutrophils play a pivotal role in inflammation and atherogenesis as they release human neutrophil peptides (HNP) in case of an acute coronary vascular disorder. This cross-sectional study assesses the correlation between α-defensin expression and the development of CHD. It also evaluates the predictive use of this marker for evaluating CHD risk.

HNP1-3 levels were determined in hyperlipemic patients, CHD patients and health controls using an ELISA kit (Cat. # HK317). Results demonstrated that there was a trend of increased plasma HNP1-3 in hyperlipidemia and CHD patients. Furthermore, CHD patients had higher HNP1-3 levels than hyperlipidemia patients. Based on these results, α-defensin expression has potential as an inflammatory marker for predicting CHD in hyperlipidemia patients.

Posted in Scientific Publications By G. Snippe

NETs are associated with inflammation in asthma and COPD

Tuesday, April 11, 2017 1:00:00 AM Etc/GMT+5

Summary of Wright, T et al; Neutrophil extracellular traps are associated with inflammation in chronic airway disease. Respirology, April 2016. Click here for the full article.

Neutrophil extracellular traps (NETs) are created when neutrophils release granule proteins, histones and chromatin to form extracellular matrices. They represent an important strategy to immobilize and kill invading microorganisms, yet their role in respiratory disease remains unclear.

This study aimed to investigate the presence of NETs in sputum from patients with asthma and COPD, and the relationship of NETs with inflammatory phenotype and disease severity. Sputum of 44 COPD patients, 94 asthma patients and 27 healthy controls was collected and used to quantify granular proteins (α-defensins 1–3 and LL-37), gene expression and extracellular DNA. Results of the study indicate that eDNA and antimicrobial proteins accumulate in the airways in asthma and COPD. The paper further concludes that NETs and NET components are elevated in severe neutrophilic asthma and COPD, and are associated with other markers of activated innate immune responses.

 

 

 

 

 

 

 

 

 

 

Posted in Scientific Publications By G. Snippe

Complement factor H levels in miscarriage

Wednesday, March 8, 2017 2:00:00 AM Etc/GMT+5

Short summary of Savaris, R et al; Maternal plasma levels of complement Factor H in miscarriage and in normal pregnancy: A cohort study. J Reprod Immunol. 2016. Article can be downloaded here.

 

Complement plays a pivotal role in pregnancy to defend the mother and fetus from invaders. Studies also suggest that prevalence of hypocomplementemia is higher in women with recurrent pregnancy loss. Interestingly, mean levels of complement factor H (CFH) seem to increase as pregnancy progresses. However, the role of CFH in miscarriages has never been established clearly.

 

This study was set up to define “normal levels” of CFH in early pregnancy and to investigate whether there is an association between CFH and miscarriage. A total of 150 pregnant women were enrolled in the study and tested for CFH (Cat. # HK342) versus non-pregnant women as a control group. Results of the data that were generated concluded that CFH levels were not significantly different among groups. Also no relation between gestational age and CFH levels could be correlated. As a conclusion: CFH levels in plasma appear to be constant, either in pregnant or non-pregnant women.

 

 

Posted in Scientific Publications By G. Snippe

C5a is elevated in association with preterm birth

Thursday, February 9, 2017 2:30:00 AM Etc/GMT+5

Short summary of Pataky, R et al; Complement C5a is present in CSF of human newborns and is elevated in association with preterm birth. J Matern Fetal Neonatal Med. 2016. Article can be downloaded here.

 

Preterm birth is strongly associated with a phenotype that includes brain injury and long-term neurodevelopmental and psychiatric impairments. Inflammation is a major contributor to injury but the mediators and receptors involved are uncertain. The four complement pathways all result in the production of C5a, a potent anaphylatoxin that binds to receptor C5aR to induce a range of inflammatory activities. The aim of this study is to determine whether C5a is present in cerebrospinal fluid (CSF) of newborns. CSF for C5a measurement (Cat. # HK349) was obtained from 20 control infants and 17 preterm neonates. The results indicated that C5a was present in the CSF of preterm and term infants, but values were significantly higher in preterms compared with controls. The results imply evidence of a perinatal inflammatory response in CSF […] with a significant increase of C5a in preterm infants. Complement activation in the neonatal brain and its role as a potential therapeutic target in preterm brain injury warrant further study.


Posted in Scientific Publications By G. Snippe

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