SARS-CoV-2 Antibodies in Breast Milk After Vaccination Romero Ramírez, Dolores Sabina; Lara Pérez, María Magdalena; Carretero Pérez, Mercedes ...
Pediatrics (Evanston),
11/2021, Letnik:
148, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Passive and active immunity transfer through human milk (HM) constitutes a key element in the infant's developing immunity. Certain infectious diseases and vaccines have been described to induce ...changes in the immune components of HM.
We conducted a prospective cohort single-institution study from February 2 to April 4, 2021. Women who reported to be breastfeeding at the time of their coronavirus disease 2019 (COVID-19) vaccination were invited to participate. Blood and milk samples were collected on day 14 after their second dose of the vaccine. Immunoglobulin G (IgG) antibodies against nucleocapsid protein as well as IgG, immunoglobulin M and immunoglobulin A (IgA) antibodies against the spike 1 protein receptor-binding domain against severe acute respiratory syndrome coronavirus 2 (anti-SARS-CoV-2 RBD-S1) were analyzed in both serum and HM samples.
Most of the participants (ie, 94%) received the BNT162b2 messenger RNA COVID-19 vaccine. The mean serum concentration of anti-SARS-CoV-2 RBD-S-IgG antibodies in vaccinated individuals was 3379.6 ± 1639.5 binding antibody units per mL. All vaccinated study participants had anti-SARS-CoV-2 RBD-S1-IgG, and 89% of them had anti-SARS-CoV-2 RBD-S-IgA in their milk. The antibody concentrations in the milk of mothers who were breastfeeding 24 months were significantly higher than in mothers with breastfeeding periods <24 months (
< .001).
We found a clear association between COVID-19 vaccination and specific immunoglobulin concentrations in HM. This effect was more pronounced when lactation periods exceeded 23 months. The influence of the lactation period on immunoglobulins was specific and independent of other variables.
Aims/hypothesis
Inflammation contributes to pancreatic beta cell dysfunction in type 2 diabetes. Toll-like receptor (TLR)-2 and -4 ligands are increased systemically in recently diagnosed type 2 ...diabetes patients, and TLR2- and TLR4-deficient mice are protected from the metabolic consequences of a high-fat diet. Here we investigated the role of macrophages in TLR2/6- and TLR4-mediated effects on islet inflammation and beta cell function.
Methods
Genetic and pharmacological approaches were used to determine the effects of TLR2/6 and TLR4 ligands on mouse islets, human islets and purified rat beta cells. Islet macrophages were depleted and sorted by flow cytometry and the effects of TLR2/6- and TLR4-activated bone-marrow-derived macrophages (BMDMs) on beta cell function were assessed.
Results
Macrophages contributed to TLR2/6- and TLR4-induced islet
Il1a
/
IL1A
and
Il1b
/
IL1B
mRNA expression in mouse and human islets and IL-1β secretion from human islets. TLR2/6 and TLR4 ligands also reduced insulin gene expression; however, this occurred in a non-beta cell autonomous manner. TLR2/6- and TLR4-activated BMDMs reduced beta cell insulin secretion partly via reducing
Ins1
,
Ins2
, and
Pdx1
mRNA expression. Antagonism of the IL-1 receptor and neutralisation of IL-6 completely reversed the effects of activated macrophages on beta cell gene expression.
Conclusions/interpretation
We conclude that islet macrophages are major contributors to islet IL-1β secretion in response to TLR2/6 and TLR4 ligands. BMDMs stimulated with TLR2/6 and TLR4 ligands reduce insulin secretion from pancreatic beta cells, partly via IL-1β- and IL-6-mediated decreased insulin gene expression.
Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with ...activating mutations in the mitogen-activated kinase pathway gene,
, and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein.
We use organoid culture combined with CRISPR/Cas9 genome engineering to sequentially introduce genetic alterations associated with serrated CRC and which regulate the stem cell niche, senescence and DNA mismatch repair.
Targeted biallelic gene alterations were verified by DNA sequencing. Organoid growth in the absence of niche factors was assessed, as well as analysis of downstream molecular pathway activity. Orthotopic engraftment of complex organoid lines, but not
alone, quickly generated adenocarcinoma in vivo with serrated features consistent with human disease. Loss of the essential DNA mismatch repair enzyme, Mlh1, led to microsatellite instability. Sphingolipid metabolism genes are differentially regulated in both our mouse models of serrated CRC and human CRC, with key members of this pathway having prognostic significance in the human setting.
We generate rapid, complex models of serrated CRC to determine the contribution of specific genetic alterations to carcinogenesis. Analysis of our models alongside patient data has led to the identification of a potential susceptibility for this tumour type.
Multiple sclerosis (MS) is the most common autoimmune inflammatory disease of the central nervous system in Europe, often causing severe physical, cognitive and emotional impairments. Currently, it ...is unclear whether the healthcare provisions of people with MS (PwMS) are in line with the recommendations for treatment based on guidelines or patients' needs. The main objectives of the study are as follows: (a) to investigate how well PwMS are treated; and (b) to develop a needs-oriented, patient-centred care model.
This mixed-methods study focuses on adult PwMS living in Lower Saxony, a federal state in Germany. The qualitative study comprises focus groups with PwMS, physicians and people involved in the healthcare process as well as a future workshop. The quantitative study comprises a cross-sectional online survey and addresses the patient-relevant outcomes and needs, as previously determined by literature searches and focus groups. It will be administered to all PwMS who are insured by the statutory health insurance company involved in the project (n~7,000). The survey data will be linked to the longitudinal secondary data from the statutory health insurance company and data from the German MS registry where available. The linked and single data sources will be statistically analysed.
By comprehensively comparing the current healthcare provisions with the needs and requirements of PwMS, the strengths and weaknesses of the overall healthcare process and provision of assistive devices can be identified. The barriers and facilitators of the health service providers and their impact on daily life will be explored (qualitative analyses). Reliable recommendations for improvements will be given based on a study population drawn from the largest statutory health insurance company in Lower Saxony (quantitative analyses). However, the inherent advantages and limitations of the qualitative and quantitative research approaches need to be considered.
The study is registered at German Clinical Trials Register DRKS00021741.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pattern recognition receptors are central to the responsiveness of various eukaryotic cell types when they encounter pathogen-associated molecular patterns. IFN-gamma is a cytokine that is elevated ...in humans and other animals with bacterial infection and enhances the LPS-induced production of antibacterial mediators by macrophages. Mice lacking the pattern recognition receptor, TLR4, respond very poorly to stimulation by LPS, but administration of IFN-gamma has been described as restoring apparent sensitivity to this stimulatory ligand. In this study, we show that IFN-gamma primes murine macrophages stimulated by crude LPS preparations to produce the antibacterial mediator NO, a proportion of which is independent of TLRs 2 and 4. This response is lost in tlr4-/- IFN-gamma-primed murine macrophages when the LPS preparation is highly purified. NO is also induced if chemically synthesized muramyl dipeptide, an intermediate in the biosynthesis of peptidoglycan, is used to stimulate macrophages primed with IFN-gamma. This is absolutely dependent on the presence of a functional nucleotide oligomerization domain-2 (NOD-2) protein. IFN-gamma increases NOD-2 expression and dissociates this protein from the actin cytoskeleton within the cell. IFN-gamma priming of macrophages therefore reveals a key proinflammatory role for NOD-2. This study also shows that the effect of IFN-gamma in restoring inflammatory responses to gram-negative bacteria or bacterial products in mice with defective TLR4 signaling is likely to be due to a response to peptidoglycan, not LPS.
An international team spanning 19 sites across 18 biopharmaceutical and in vitro diagnostics companies in the United States, Europe, and China, along with one regulatory agency, was formed to compare ...the precision and robustness of imaged CIEF (ICIEF) for the charge heterogeneity analysis of the National Institute of Standards and Technology (NIST) mAb and a rhPD‐L1‐Fc fusion protein on the iCE3 and the Maurice instruments. This information has been requested to help companies better understand how these instruments compare and how to transition ICIEF methods from iCE3 to the Maurice instrument. The different laboratories performed ICIEF on the NIST mAb and rhPD‐L1‐Fc with both the iCE3 and Maurice using analytical methods specifically developed for each of the molecules. After processing the electropherograms, statistical evaluation of the data was performed to determine consistencies within and between laboratory and outlying information. The apparent isoelectric point (pI) data generated, based on two‐point calibration, for the main isoform of the NIST mAb showed high precision between laboratories, with RSD values of less than 0.3% on both instruments. The SDs for the NIST mAb and the rhPD‐L1‐Fc charged variants percent peak area values for both instruments are less than 1.02% across different laboratories. These results validate the appropriate use of both the iCE3 and Maurice for ICIEF in the biopharmaceutical industry in support of process development and regulatory submissions of biotherapeutic molecules. Further, the data comparability between the iCE3 and Maurice illustrates that the Maurice platform is a next‐generation replacement for the iCE3 that provides comparable data.
BRAF(V600E) mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC ...have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF(V600E) CRC.
We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF(V600E) CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF(V600E) CRC.
Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF(V600E) GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.
We have established a novel GEMM to interrogate BRAF(V600E) CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.
DOI: 10.1002/elps.202100348
The back cover picture shows the iCE3 and Maurice instruments used to demonstrate the comparability of the instruments for measuring charge heterogeneity in mAbs and ...fusion proteins by icIEF. Also shown is a representative electropherogram of the fusion protein obtained on the instruments. Previous studies evaluating icIEF for measuring charge heterogeneity have utilized mAbs; however, this study included a fusion protein to demonstrate additional capabilities of the method. The instruments were confirmed to be comparable by 19 labs across the globe.
Anxiety disorders are the most common psychiatric illnesses in children,
1
–
3
but most children with anxiety disorders do not receive treatment.
4
,
5
Several studies have documented the safety and ...efficacy of drug therapy for children with obsessive–compulsive disorder, but there have been few studies of drug therapy for children with more prevalent anxiety disorders.
6
,
7
Social phobia, separation anxiety disorder, and generalized anxiety disorder in children cause substantial distress and interfere with academic as well as social functioning.
1
,
2
,
8
,
9
Childhood anxiety disorders also foreshadow psychiatric illness later in life. Specifically, these disorders predict an increase by a factor . . .
Three experiments investigated the influence of level of construal (i.e., the interpretation of actions in terms of their meaning or their details) on different stages of face memory. We employed a ...standard multiple-face recognition paradigm, with half of the faces inverted at test. Construal level was manipulated prior to recognition (Experiment 1), during study (Experiment 2) or both (Experiment 3). The results support a general advantage for high-level construal over low-level construal at both study and at test, and suggest that matching processing style between study and recognition has no advantage. These experiments provide additional evidence in support of a link between semantic processing (i.e., construal) and visual (i.e., face) processing. We conclude with a discussion of implications for current theories relating to both construal and face processing.
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