C3 Concentrations Research Articles

Pharmacokinetic and Pharmacodynamic Evaluation of Ravulizumab in Adults with Severe Coronavirus Disease 2019.

IntroductionTerminal complement amplification is hypothesized to be a key contributor to the clinical manifestations of severe coronavirus disease 2019 (COVID-19). Ravulizumab, a humanized monoclonal antibody that binds with high affinity to complement protein C5 and inhibits terminal complement activation, is being evaluated as a treatment for COVID-19-related severe pneumonia, acute lung injury, and acute respiratory distress syndrome in an ongoing phase 3 randomized controlled trial (ALXN1210-COV-305). To address the overactivation of terminal complement in severe COVID-19 compared to the diseases in which ravulizumab is currently approved, a modified dosing regimen was adopted. This analysis evaluates preliminary pharmacokinetic/pharmacodynamic data to confirm the modified dosing regimen.MethodsWeight-based ravulizumab doses were administered on days 1, 5, 10, and 15. Serum levels of ravulizumab and free C5 were measured before and after administration of ravulizumab and any time on day 22. Free C5 levels < 0.5 μg/mL indicate complete C5 inhibition. The pharmacokinetic target was defined as ravulizumab concentrations at the end of the dosing interval > 175 μg/mL, the concentration above which C5 is completely inhibited.ResultsTwenty-two patients were included in this evaluation. At baseline, mean C5 concentration was 240 ± 67 μg/mL. In all patients and at all individual timepoints after the first dose was administered, ravulizumab concentrations remained > 175 μg/mL and free C5 concentrations remained < 0.5 μg/mL.ConclusionHigh levels of baseline C5 observed in patients with severe COVID-19 contribute to the growing body of evidence that suggests this disease is marked by amplification of terminal complement activation. Data from this preliminary pharmacokinetic/pharmacodynamic evaluation of 22 patients with severe COVID-19 show that the modified ravulizumab dosing regimen achieved immediate and complete terminal complement inhibition, which can be sustained for up to 22 days. These data support the continued use of this dosage regimen in the ongoing phase 3 study.Trial RegistrationClinicalTrials.gov identifier, NCT04369469

Serum Immunoglobulin Levels, Complement Components 3 and 4, HLA-B27 Allele and Spondyloarthropathy in Patients with Non-Infectious Anterior Uveites.

To identify the relationship between serum immunoglobulin levels, complement components 3 and 4, the presence of the HLA-B27 allele and diagnosis of spondyloarthropathies in patients with non-infectious anterior uveitis. The participants were 197 patients with a non-infectious anterior uveitis. The concentrations of serum immunoglobulins, and C3 and C4 proteins of the complement were determined by turbidimetry. The personal history of suspected immunodeficiency, ophthalmological complications, arthralgia, family history of spondyloarthropathies and the presence of the HLA-B27 allele were collected. A family history of spondyloarthropathy, axial arthralgias, and ophthalmological complications were more frequent in HLA-B27 positive patients (P=.0005, P≤.0001, and P≤.0001, respectively) and in patients with spondyloarthropathy diagnoses (P≤.0001, P≤.0001, and P≤.0001, respectively). A personal history of recurrent sepsis, and gastrointestinal abnormalities was associated with the presence of the HLA-B27 allele (P≤.0001, and P=.0240, respectively) and with the diagnosis of spondyloarthropathy (P=.0492, and P=.0017, respectively). IgG decrease was observed (χ2=18.5, OR 5.03, 95% CI 2.32-10.89; P=.0001) and IgM (OR 7.13, 95% CI 1.40-36.4; P=.0128) in patients positive for the HLA-B27 allele and in patients with a diagnosis of spondyloarthropathies (P=.0364 and P=.0028, respectively). The decrease of C3 proteins (OR 4.82; CI 95% 1.35-17.11; P=.0328) and C4 (OR 9.09; CI 95% 2.13-38.88; P=.0074) were associated with a spondyloarthropathies diagnosis. Patients with non-infectious anterior uveitis, positive for the HLA-B27 allele and diagnosed with spondyloarthropathies have alterations in serum immunoglobulin levels and complement components 3 and 4, which could contribute to the perpetuation and worse clinical course of this disease.

Serum immunoglobulin levels, complement components 3 and 4, HLA-B27 allele and spondyloarthropathy in patients with non-infectious anterior uveites

ObjectiveTo identify the relationship between serum immunoglobulin levels, complement components 3 and 4, the presence of the HLA-B27 allele and diagnosis of spondyloarthropathies in patients with non-infectious anterior uveitis. Materials and methodsThe participants were 197 patients with a non-infectious anterior uveitis. The concentrations of serum immunoglobulins, C3 and C4 proteins of the complement were determined by turbidimetry. The personal history of suspected immunodeficiency, ophthalmological complications, arthralgia, family history of spondyloarthropathies and the presence of the HLA-B27 allele were collected. ResultsA family history of spondyloarthropathy, axial arthralgias, and ophthalmological complications were more frequent in HLA-B27 positive patients (P=.0005, P≤.0001, P≤.0001 respectively) and in patients with spondyloarthropathy diagnoses (P≤.0001, P≤.0001, P≤.0001 respectively). A personal history of recurrent sepsis, and gastrointestinal abnormalities was associated with the presence of the HLA-B27 allele (P≤.0001, P=.0240 respectively) and with the diagnosis of spondyloarthropathy (P=.0492, P=.0017 respectively). IgG decrease was observed (χ2=18.5, OR=5.03, 95% CI=2.32–10.89, P=.0001) and M (OR=7.13, 95% CI=1.40−36.4; P=.0128) in patients positive for the HLA-B27 allele and in patients with a diagnosis of SpA (P=.0364 and P=.0028 respectively). The decrease of C3 proteins (OR=4.82; CI 95%=1.35–17.11; P=.0328) and C4 (OR=9.09; CI 95%=2.13–38.88; P=.0074) were associated with a spondyloarthropathies diagnosis. ConclusionsPatients with non-infectious anterior uveitis, positive for the HLA-B27 allele and diagnosed with spondyloarthropathies have alterations in serum immunoglobulin levels and complement components 3 and 4, which could contribute to the perpetuation and worse clinical course of this disease.

Potentiation of Brain-Derived Neurotrophic Factor-Induced Protection of Spiral Ganglion Neurons by C3 Exoenzyme/Rho Inhibitor.

Preservation of the excitability of spiral ganglion neurons (SGN) may contribute to an improved speech perception after cochlear implantation. Thus, the application of exogenous neurotrophic factors such as the neurotrophin brain-derived neurotrophic factor (BDNF) to increase SGN survival in vitro and in vivo is a promising pharmacological approach in cochlear implant (CI) research. Due to the difficult pharmacokinetic profile of proteins such as BDNF, there is a quest for small molecules to mediate the survival of SGN or to increase the efficacy of BDNF. The C3 exoenzyme from Clostridium botulinum could be a potential new candidate for the protection and regeneration of SGN. Inhibition of the RhoA GTPase pathway which can be mediated by C3 is described as a promising strategy to enhance axonal regeneration and to exert pro-survival signals in neurons. Nanomolar concentrations of C3, its enzymatically inactive form C3E174Q, and a 26mer C-terminal peptide fragment covering amino acid 156–181 (C3156-181) potentiated the neuroprotective effect on SGN mediated by BDNF in vitro. The neuroprotective effect of C3/BDNF was reduced to the neuroprotective effect of BDNF alone after the treatment with wortmannin, an inhibitor of the phosphatidylinositol-3-kinase (PI3K).The exoenzyme C3 (wild-type and enzyme-deficient) and the C3 peptide fragment C3154–181 present novel biologically active compounds for the protection of the SGN. The exact underlying intracellular mechanisms that mediate the neuroprotective effect are not clarified yet, but the combination of BDNF (TrkB stimulation) and C3 exoenzyme (RhoA inhibition) can be used to protect SGN in vitro.

Effect of feeding a pellet diet containing high sulphur with fresh cassava root supplementation on feed use efficiency, ruminal characteristics and blood metabolites in Thai native beef cattle.

The objective of this experiment was to study the effect of feeding pellet containing high sulphur (PELFUR) diet and fresh cassava root (FCR) to Thai native beef cattle on feed use efficiency, ruminal characteristics and blood metabolites. Four male purebred Thai native beef cattle (1.5-2.0years old) with initial body weight (BW) of 150±15.0kg were allocated with a 2×2 factorial arrangement in a 4×4 Latin square design. Factor A was FCR supplementation at 15 and 20g/kg of BW. Factor B was the sulphur level in the PELFUR ration at 15 and 30g/kg of dry matter (DM). No interaction effect was found among FCR supplementation and PELFUR in terms of feed intake and nutrient intake (p>0.05). Cyanide intake was significantly increased based on FCR supplementation (p<0.05), whereas sulphur intake was increased by level addition of PELFUR levels (p<0.05). There were interaction effects among FCR supplementation and PELFUR on digestibility coefficients of DM and organic matter (OM) (p<0.05). FCR supplementation at 20g/kg BW with PELFUR 30g/kg demonstrated the highest digestibility of DM and OM. Moreover, interactions were observed between FCR and PELFUR for bacterial populations (p<0.01). The populations of bacteria were highest in FCR supplementation at 20g/kg BW with PELFUR 30g/kg at various feeding times. An interaction effect from among feeding FCR with PELFUR was found on blood thiocyanate concentrations at various feeding times (p<0.01). The highest mean values of blood thiocyanate were observed when feeding FCR at 20g/kg BW with PELFUR at 30g/kg. No interaction effect was found between FCR and PELFUR on total volatile fatty acids (VFA) and their profiles (p>0.05). However, the proportions of the total VFA at 0 and 4h post-feeding were increased when FCR at 20g/kg BW was supplemented (p<0.01). FCR at 20g/kg BW could enhance propionate (C3) at 4h post-feeding when compared with FCR at 15g/kg BW (p<0.01). Moreover, supplementation of PELFUR at 30g/kg increased the total VFA at 0 and 4h post-feeding, whereas the concentration of C3 at 4h post-feeding was enhanced (p<0.05). However, no significant changes were found for any parameters among treatments and between the main effect of FCR and PELFUR supplementation (p>0.05). In conclusion, feeding of two combinations (FCR 20g/kg BW with PELFUR 30g/kg) could promote the nutrient digestibility, the bacterial populations and the rate of disappearance of cyanide without having any adverse effect on rumen fermentation.

Complement Profiles in Patients with Amyotrophic Lateral Sclerosis: A Prospective Observational Cohort Study.

BackgroundThe complement system has been suggested to be involved in the pathophysiology of amyotrophic lateral sclerosis (ALS), a progressive motor neuron disease. In the present study, we compared levels of selected complement markers to clinical outcome in ALS patients.MethodsThis observational, explorative cohort study included 92 ALS patients, 61 neurological controls (NCs) admitted for suspected aneurysmal subarachnoid haemorrhage, and 96 neurologically healthy controls (NHCs). Peripheral blood and cerebrospinal fluid (CSF) were obtained for the measurement of ficolin-1, −2, and −3; collectin-11, MBL, MASP-3, MAP-1, C4, C3, PTX-3, and complement activation products C4c, C3bc, and sC5b-9. We recorded clinical outcomes of ALS patients for 24 to 48 months after inclusion in order to analyse the effects of the complement markers on survival time.ResultsCompared with both control groups, ALS patients exhibited increased collectin-11, C4 and sC5b-9 in plasma, as well as increased ficolin-3 in CSF. Ficolin-2 was significantly decreased in plasma of the ALS patients compared with NHCs, but not with NCs. The concentration of collectin-11, C3 and C3bc correlated negatively with the revised ALS functional rating scale (ALSFRS-R). No association was found between levels of complement markers and survival as estimated by hazard ratios.ConclusionALS patients exhibit aberrant expression of selected mediators of the lectin complement pathway as well as increased activation of the terminal complement pathway, corroborating the notion that the complement system might be involved in the pathophysiology of ALS.

Mesangial C3 deposition and serum C3 levels predict renal outcome in IgA nephropathy.

Complement activation plays an important role in the pathogenesis of IgA nephropathy (IgAN). We aimed to evaluate the relationship between mesangial C3 deposition and histologic lesions and to investigate the role of mesangial C3 deposition and serum C3 reduction in predicting renal outcome in IgAN children. We performed a retrospective cohort study in children with biopsy-proven IgAN. Mesangial C3 deposition (< 2+ vs. ≥ 2+) was detected by the immunofluorescence. Histopathologic kidney grades were determined by the Oxford classification. A decreased serum C3 concentration (hypoC3) was defined when C3 < 90mg/dl. The endpoint was composite kidney outcome with either a 30% decline in glomerular filtration rates from baseline or kidney failure during the follow-up period. A total of 98 children were analyzed. Mesangial hypercellularity (M) was an independent factor associated with mesangial C3 deposition (HR 3.267; 95% CI 1.028-10.389; P = 0.045). After a median follow-up period of 25months (interquartile range 18-36months), 6 (6.1%) children reached the endpoint. Compared with other children, a significantly higher proportion of children with composite kidney outcomes had mesangial C3 deposition ≥ 2+ and hypoC3 (3.4% versus 27.3%, P = 0.002). After adjustment for clinicopathologic risk factors, mesangial C3 deposition ≥ 2+ and hypoC3 were associated with renal outcome (HR 9.772; 95% CI 1.264-75.518; P = 0.029). Mesangial C3 deposition was associated with M in IgAN. Mesangial C3 deposition and hypoC3 were risk factors for renal outcome in children with IgAN.

Effects of plant extract supplementations or monensin on nutrient intake, digestibility, ruminal fermentation and metabolism in dairy cows

This study aimed to evaluate the effects of diet supplementation with monensin and saponins alone or combined with essential oils (EOs) on the nutrient intake and apparent digestibility, rumen fermentation parameters, microbial population, nitrogen balance, ruminal microbial protein synthesis, blood metabolites, and milk composition, yield and fatty acid profile of mid- to late-lactating Jersey cows. Eight ruminally cannulated lactating Jersey cows (average 17.6 ± 5.5 kg/day of milk yield and 100.5 ± 26.6 days of milk (mean ± SD)) were distributed in a replicated 4 × 4 Latin square design with 21-day periods (last seven days for sampling). Treatment sequences were randomly designated to cows and consisted of: (1) CON - Control, no feed additive; (2) SAP - 16 g/cow/day of a supplement based on whole-seed fenugreek powder (variety Fenucold) standardized to diosgenin, one of the major steroidal sapogenins of fenugreek (2000 mg/kg); (3) SAPEO - SAP supplement combined with a blend of natural EOs with major components of carvacrol (2500 mg/kg), cinnamaldehyde (5600 mg/kg) and limonene (3000 mg/kg); and (4) MON - Monensin, inclusion of monensin sodium in the diet at 24 mg/kg DM. Cows fed CON showed higher dry matter, organic matter, crude protein and ether extract intakes than animals fed MON, whereas higher neutral detergent fibre intake was observed in animals fed SAPEO than those fed MON (P < 0.05). Diet and time effects were observed for ruminal pH and concentration of ruminal ammonia nitrogen (P < 0.05). Cows fed SAP showed a higher relative proportion of Fibrobacter succinogenes (P = 0.04) than animals fed MON. Cows fed CON had higher net and digestible energy intakes than animals fed MON (P < 0.05). Cows fed SAPEO showed higher albumin concentrations (P = 0.04) than those fed CON, SAP, and MON. Besides, cows fed CON showed higher urea concentrations (P = 0.04) than those fed SAP and SAPEO. Higher protein and fat levels in the milk were observed in cows fed SAPEO than animals fed MON (P < 0.05). Monensin decreased the concentrations of C4:0, C6:0, C8:0, and C18:1 cis-11 milk fatty acids (P < 0.05). Monensin decreased nutrient intake to a more energetically efficient pathway but did not alter milk production, digestibility, or rumen fermentation. Saponin supplementation associated with essential oils increases milk fat and protein contents in lactating Jersey cows compared to animals fed a monensin-supplemented diet.

C3 and alternative pathway components are associated with an adverse lipoprotein subclass profile: The CODAM study

BackgroundPlasma lipoproteins contain heterogeneous subclasses. Previous studies on the associations of the complement system with lipids and lipoproteins are mainly limited to the major lipid classes, and associations of complement with lipoprotein subclass characteristics remain unknown. ObjectiveWe investigated the associations of C3 and other components of the alternative complement pathway with plasma lipoprotein subclass profile. MethodsPlasma complement concentrations (complement component 3 [C3], properdin, factor H, factor D, MASP-3, C3a, Bb), and lipoprotein subclass profile (as measured by nuclear magnetic resonance spectroscopy) were obtained in 523 participants (59.6 ± 6.9 years, 60.8% men) of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Multiple linear regression was used to investigate the associations of C3 (primary determinant) and other alternative pathway components (secondary determinants) with characteristics (particle concentration and size [main outcomes], and lipid contents [secondary outcomes]) of 14 lipoprotein subclasses, ranging from extremely large VLDL to small HDL (all standardized [std] values). ResultsParticipants with higher C3 concentrations had more circulating VLDL (stdβs ranging from 0.27 to 0.36), IDL and LDL (stdβs ranging from 0.14 to 0.17), and small HDL (stdβ = 0.21). In contrast, they had fewer very large and large HDL particles (stdβs = −0.36). In persons with higher C3 concentrations, all lipoprotein subclasses were enriched in triglycerides. Similar but weaker associations were observed for properdin, factor H, factor D, and MASP-3, but not for C3a and Bb. ConclusionsThe alternative complement pathway, and most prominently C3, is associated with an adverse lipoprotein subclass profile that is characterized by more triglyceride-enriched lipoproteins but fewer large HDL.

Legacy and emerging per- and polyfluoroalkyl substances (PFASs) in Dagang Oilfield: Multimedia distribution and contributions of unknown precursors

A systematic survey was conducted on twenty-six per- and polyfluoroalkyl substances (PFASs) in fifty-one paired samples of surface water, sediment, and soil from Dagang Oilfield, Tianjin, China. Perfluorooctanoic acid, perfluorooctane sulfonic acid, p-perfluorous nonenoxybenzenesulfonate (OBS), and 6:2 fluorotelomer sulfonamidoalkyl betaine (6:2 FTAB) were ubiquitous in the oilfield with field log Kd of 1.3–2.2, indicating a high partition potential from surface water to sediment. Total petroleum hydrocarbons (TPH) are a predictor for PFAS contamination at oilfield. The concentrations of OBS and 6:2 FTAB were higher in surface water and sediment with elevated TPH level. With total oxidizable precursor assay, unknown precursors for C2–C3 perfluoroalkyl carboxylic acids (PFCAs) (57–99 mol%) contributed more than those for C4–C12 PFCAs in the three mediums. The unknown C4-, C6-, and C8-based precursors tended to be precursors for perfluoroalkyl sulfonates at the oilfield, and C8 fluorotelomer-based precursors particularly occurred in the surface water. The concentrations of C4- and C8-based precursors were found positively correlated with TPH levels (r = 0.67–0.72, p < 0.05), while C6 precursors may also come from other sources. Further studies are necessary to clarify the mass balance and risk assessment for unknown PFASs.

A Novel Total Drug Assay for Quantification of Anti-C5 Therapeutic Monoclonal Antibody in the Presence of Abundant Target

SKY59 or RO7112689 is a humanized monoclonal antibody against complement protein C5 with pH-dependent C5-binding and neonatal Fc receptor-mediated recycling capabilities, which result in long-lasting neutralization of C5. We developed and validated a novel total drug assay for quantification of target-binding competent SKY59 in the presence of endogenous C5 in cynomolgus monkey plasma. The target-binding competent SKY59 was determined after complex formation by the addition of recombinant monkey C5 using goat anti-human IgG-heavy chain monkey-adsorbed polyclonal antibody as a capture antibody and rabbit anti-C5 monoclonal antibody (mAb) non-competing with SKY59 for detection. The total SKY59 assay was shown to be accurate and precise over the range of 0.05-3.2μg/mL as well as be tolerant to more than 400μg/mL of C5 (~ 3000-fold molar excess of target). We also developed and validated a total C5 assay, confirmed selectivity and parallelism, and verified the utility of recombinant monkey C5 for the total C5 assay as well as the total SKY59 assay. Furthermore, we used these validated methods to measure SKY59 and C5 concentrations in cynomolgus monkey plasma samples in a toxicology study. This total drug assay can be applied not only to other antibody therapeutics against shed/soluble targets when a non-competing reagent mAb is available but also for clinical studies when a reagent mAb specific for engineered Fc region on a therapeutic mAb is available.

Biomarkers of disease activity in patients with chronic spontaneous urticaria.

IntroductionPrevious studies have examined biomarkers of coagulation, inflammation and immunity in chronic spontaneous urticaria (CSU), but no recommended biomarkers for disease activity have been established yet.AimTo find the relationship between certain laboratory parameters and disease activity in patients with CSU.Material and methodsSerum concentrations of D-dimer, C-reactive protein (CRP), C3, C4, and prothrombin time (PT), activated partial thromboplastin time (aPTT) values were measured in 44 CSU patients and compared with 33 healthy controls. Correlation between biomarkers and urticaria activity score during 7 consecutive days (UAS7) was calculated.ResultsOur study included 44 CSU patients (38 females and 6 males), mean age of 50.4 years and the average disease duration of 3.1 years. Based on UAS7, 23 (52.3%) CSU patients had mild urticaria, 8 (18.2%) well-controlled, 7 (15.9%) moderate and 6 (13.6%) severe urticaria. Fourteen (31.8%) patients had elevated CRP, 21 (47.7%) had elevated D-dimer and 14 (13.6%) CSU patients had elevated C4 levels. Patients with CSU had statistically significant elevated D-dimer, CRP and PT as compared with controls (p = 0.007, p = 0.005 and p = 0.029, respectively). There was no correlation between PT, aPTT, D-dimer, CRP, C3 and disease activity. Statistically significant differences in C4 levels between patients with severe and well-controlled, mild, moderate urticaria were determined (p = 0.003).ConclusionsCRP, D-dimer, and PT may be considered as biomarkers for distinguishing patients with CSU from controls. The C4 levels correlate with disease activity and may be useful as a potential biomarker of disease activity.

Profiles of expression pattern and tissue distribution of host defense peptides genes in different chicken (Gallus gallus) breeds related to body weight.

Host defense peptides (HDPs) are an important first line of defense with antimicrobial and immunomodulatory properties. Selection for increased body weight is hypothesized to be related to reduced immune response. We studied the relationships among body weight, age, and the HDP expression patterns in intestine and immune organs. We used chickens with marked differences of body sizes. The non-selected Daweishan mini chickens showed the highest indexes of immune organs and the lowest concentrations of the plasma immune parameters C3, C4, IgA, and IgY, while the commercial Avian broiler showed the opposite results. The Daweishan mini chickens showed the highest mRNA expressions of HDP genes in small intestine followed by the semi-selected Wuding chickens. Compared with local breeds, broiler chickens showed higher mRNA expression of HDP genes in spleen, thymus, and bursa. Body weight and HDP expression levels were negatively correlated in the intestine and positively in the immune organs. Our results indicated that the HDP immune regulatory roles in small intestine acted as first line of defense in innate immunity in local breeds, and as an adaptive immunity in broiler chickens. Selection was associated with different expression expressions of HDP genes in breed-, age-, and organ-specific manners.

A robust multiplexed assay to quantify C1-inhibitor, C1q, and C4 proteins for in vitro diagnosis of hereditary angioedema from dried blood spot

Hereditary angioedema (HAE) is a rare genetic disease caused by deficiency or dysfunction of C1 esterase inhibitor (C1-INH). Plasma C1-INH activity and concentrations of C1-INH and complement components 1q and 4 (C1q, C4) are critical to the HAE diagnosis. We describe a novel multiplexed assay to simultaneously measure C1-INH, C1q, and C4 levels in dried blood spot (DBS) of HAE patients. The blood proteins were extracted from 3 mm punches of DBS samples and were subsequently digested by trypsin. The signature peptide derived from each protein was quantified by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Analyte-depleted blood was generated as a surrogate matrix for the preparation of calibration curves to overcome the interference of endogenous proteins, and the assay reproducibility was further monitored by assessing the signal of plasma transferrin as a house-keeping protein. The assay was fully validated following regulatory guideline, with a quantification range of 12.5–800 μg/mL for C1-INH and C4 and 3.13–200 μg/mL for C1q. The precision and accuracy ranged from 3.3%–9.8% and -8.2%–12.6%, respectively. All the patient samples exhibited C1-INH levels lower than normal range except the Type II patient and the C4 and C1q concentrations were as expected. Results from the DBS-based LC–MS assay were highly correlated with the ELISA data measured in plasma of the same subjects. The method described here offers unique advantages such as less invasive sampling, minimal blood processing, and easy transportation and sample storage, allowing, for the first time, C1-INH, C4, and C1q levels to be simultaneously determined in a drop of dried blood.

Иммунитет, витамины и питание

There is a relationship between nutrition and immunity. For developing countries, the problem – the protein-energy deficits, in developed and socially oriented economy – the lack of vitamins and trace elements. In Russia, various vitamins deficiency is registered in 30–90% of schoolchildren (from 20–40% to the extent of the deep deficit). Deficiency of vitamins and minerals leads to disruption of immunity raises the index of infectious diseases, autoimmune disorders. Insufficient supply of vitamins leads to a decrease in phagocytosis, proliferative activity of lymphocytes, decreased concentrations of C3 and C5 component of complement, IgG and secretory IgA, disintegrate physiological barriers. At the same time increases the concentration of pro-inflammatory cytokines. With a lack of selenium and vitamin E is possible passage of viruses from a sharp increase in virulence. The correction of micronutrient deficiencies should be combined, which implies the appointment of vitamin-mineral complexes with the inclusion of polyunsaturated fatty acids, choline. It is recommended the use of drugs, various forms of which are adapted to the age and the physiological needs of the child.

Influence of Days in Milk and Parity on Milk and Blood Fatty Acid Concentrations, Blood Metabolites and Hormones in Early Lactation Holstein Cows.

Simple SummaryAt the onset of lactation, the energy intake is not sufficient to meet the high energy requirement due to milk production increase. Consequently, body reserve is mobilized to support this negative energy balance situation. Severe negative energy balance can lead to health and production concerns. Certain blood and milk parameters could be used as indicators of lipomobilization and can thus predict the energy status in postpartum cows. Therefore, the objective of this paper was to study the influence of physiological factors that affect the energy balance, such as lactation stage and parity, on blood and milk parameters in healthy early lactation cows. Thirty-two Holstein dairy cows from five Belgian commercial farms were followed during two calving periods. This study confirms that lactation stage along with energy balance and parity significantly influence blood and milk parameters.The objective of this paper is to study the influence of physiological factors that affect the energy balance, such as lactation stage and parity, on milk yield and composition, milk and blood fatty acid concentrations, blood metabolites and hormones in healthy early lactation cows. Thirty-two Holstein dairy cows from five Belgian commercial farms were followed. The grass silage-based diets fed to cows fell within normal composition ranges typically offered to dairy cows on commercial dairy farms in the region. Milk and blood were sampled at each official milk recording and used for the determination of milk fat and protein, milk and blood fatty acids, blood metabolites and hormones concentrations. The considered period was 7 to 150 days in milk. As lactation progressed, concentrations of milk 18:0 and 18:1c9, as well as blood non-esterified fatty acids and β-hydroxybutyrate, decreased, and those of milk C4–C14, blood cholesterol, triglycerides, insulin and IGF-I increased, agreeing with the extensive mobilization of body reserves in early lactation. Lower concentrations of milk C4–C14 and 16:0 and concomitant higher concentrations of milk 18:0 and 18:1c9 suggest a larger body reserve mobilization in first parity cows compared with greater than or equal to second parity cows. This study confirms that early lactation stage along with parity significantly influence milk fatty acids, such as 18:1, and blood metabolites and hormones, such as NEFA and insulin.

Crovalimab for Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Complement C5 Polymorphism - Experience from the Phase I/II COMPOSER Study

Crovalimab for Treatment of Patients with Paroxysmal Nocturnal Hemoglobinuria and Complement C5 Polymorphism - Experience from the Phase I/II COMPOSER Study

COMPOSER Part 4: An Optimized Dosing Strategy for Crovalimab in the Treatment of Complement Inhibitor-Naïve or -Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria

COMPOSER Part 4: An Optimized Dosing Strategy for Crovalimab in the Treatment of Complement Inhibitor-Naïve or -Experienced Patients with Paroxysmal Nocturnal Hemoglobinuria

Neck adipose tissue accumulation is associated with higher overall and central adiposity, a higher cardiometabolic risk, and a pro-inflammatory profile in young adults

Neck adipose tissue (NAT) volume increases with general adiposity, with fat accumulating in different neck tissue compartments. In patients with certain malignant/benign tumours, the accumulation of NAT, and certain NAT distributions, have been associated with cardiometabolic risk (CMR). However, it is unknown whether the same relationships exist in healthy people, and whether NAT accumulation and distribution are related to the inflammatory status. In this cross-sectional study, 139 young healthy adults (68% women) underwent a computed tomography scan to quantify the volume of compartmental (i.e., subcutaneous, intermuscular and perivertebral) and total NAT at the height of vertebra C5. Anthropometric indicators were measured, and body composition determined using dual energy X-ray absorptiometry. Information on CMR factors (i.e., blood glycaemic and lipid markers, blood pressure and physical fitness) was also gathered, and a CMR score calculated. Several plasma cytokines and serum components of the innate immune system were measured to determine the inflammatory status. Compartmental and total NAT volumes were directly related to body mass index (BMI), and lean, fat, and visceral adipose tissue (VAT) masses (all, P ≤ 0.05). Larger compartmental (especially intermuscular) and total NAT volumes were directly associated with the CMR score, several CMR factors (i.e., glycaemic and lipid markers and blood pressure), and the C3, C4 and leptin concentrations. They were, however, inversely correlated with the CMR factors high density lipoprotein-cholesterol (HDL-C) and physical fitness, and with the adiponectin concentration (all P ≤ 0.05). Several of these associations remained statistically significant (P ≤ 0.05) after adjustment for BMI, body fat percentage or VAT mass. Overall, results did not change after applying false discovery rate correction. NAT volume and its distribution among different tissue compartments is associated with the CMR and inflammatory profile of young healthy adults. Total NAT volume appears to be as valuable as VAT mass in terms of predicting CMR and inflammatory status.

Immediate increase of plasma protein complement C3 in response to an acute stressor

Whereas chronic stress has immunosuppressive effects, the more immediate immunologic consequences of acute stressors are less known. We postulated that, as part of their ‘fight or flight’ response, rainbow trout would rapidly increase the efficacy of their natural immune system by means of increased concentrations of crucial plasma proteins. Plasma samples were taken from resting fish and from fish 5, 10 or 20 min after initiation of a stressful regime. Using crossed immunoelectrophoresis, we documented increases in concentrations of complement C3 and 3 other proteins within 5 min of initiation of stress. The concentration of C3 nearly doubled within 10 min of initiation of stress and had returned to near resting level by 20 min. This rapid kinetics preclude dependence on gene activation, the basis of the acute phase response. Potentiation of natural immunity, which can reasonably be expected to be selectively advantageous during or immediately after acute stressors may be one result of this increase.