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Microbial Communities in Changing Aquatic Environments
No full textThe quality of aquatic ecosystems is an important public health concern [...
PTCy versus ATG as graft-versus-host disease prophylaxis in mismatched unrelated stem cell transplantation
No full textThere is an increased risk of GVHD and of non-relapse mortality (NRM) after allogeneic stem cell transplantations (alloSCT) when mismatched unrelated donors (MMUD) are used. In Europe, it is standard practice to use rabbit anti-thymocyte globulin (rATG) to reduce the high NRM and GVHD risks after MMUD alloSCT. As an alternative to rATG, post-transplantation Cyclophosphamide (PTCy) is in increasing clinical use. It is currently impossible to give general recommendations regarding preference for one method over another since comparative evidence from larger data sets is lacking. To improve the evidence base, we analyzed the outcome of rATG vs. PTCy prophylaxis in adult patients with hematologic malignancies undergoing first peripheral blood alloSCT from MMUD (9/10 antigen match) between Jan 2018 and June 2021 in the database of the European Society for Blood and Marrow Transplantation (EBMT). We performed multivariate analyses using the Cox proportional-hazards regression model. We included 2123 patients in the final analyses (PTCy, n = 583; rATG, n = 1540). p values and hazard ratios (HR) presented here are multivariate outcomes. Two years after alloSCT we found a lower NRM in the PTCy group of 18% vs. 24.9% in the rATG group; p = 0.028, HR 0.74. Overall survival in the PTCy cohort was higher with 65.7% vs. 55.7% in the rATG cohort; p < 0.001, HR 0.77. Progression-free survival was also better in the PTCy patients with 59.1% vs. 48.8% when using rATG; p = 0.001, 0.78. The incidences of chronic GVHD and acute GVHD were not significantly different between the groups. We found significantly lower NRM as well as higher survival in recipients of peripheral blood alloSCTs from MMUD receiving PTCy as compared to rATG. The results of the current analysis suggest an added value of PTCy as GVHD prophylaxis in MMUD alloSCT.
NK cells in pathogenesis of congenital cytomegalovirus infection
No full textCilj istraživanja: Prirođena infekcija citomegalovirusom (CMV) najčešća je virusna
prirođena infekcija koja može uzrokovati dugotrajne neurološke posljedice. Uloga
stanica NK u nadzoru virusa tijekom prirođene infekcije CMV-om, kao i utjecaj infekcije
na imunitet posredovan stanicama NK uglavnom su slabo istraženi. Glavni cilj ovog
istraživanja je odrediti ulogu stanica NK u nadzoru citomegalovirusa i promjene u
raznovrsnim podskupinama i funkciji stanica NK inducirane citomegalovirusnom
infekcijom u modelu prirođene infekcije.
Materijali i metode: U ovom istraživanju korišten je model prirođene infekcije, u kojem
su novookoćeni miševi inficirani MCMV-om s ciljem karakterizacije funkcionalnih,
fenotipskih i transkripcijskih promjena u stanicama NK. U istraživanju smo koristili
protočnu citometriju, transkriptomske analize te druge metode molekularne biologije.
Mehanizme odgovorne za promjene u stanicama NK nakon infekcije MCMV-om odredili
smo koristeći različite genetski modificirane miševe kojima nedostaju proupalni
medijatori ili njihovi receptori na stanicama NK. Alternativno smo inaktivaciju navedenih
tipova molekula proveli upotrebom blokirajućih protutijela.
Rezultati: Pokazali smo da infekcija novookoćenih miševa MCMV-om značajno
kompromitira fenotip, sazrijevanje i funkciju stanica NK. Upalni odgovor uzrokovao je
deregulaciju izražaja brojnih transkripcijskih faktora, što je rezultiralo dugotrajno
oslabljenom funkcijom stanica NK. Uz navedeno, utvrdili smo da perinatalna infekcija
narušava proces nastajanja stanica NK u koštanoj srži, što objašnjava navedene
dugotrajne negativne efekte infekcije na njihovu djelotvornost.
Zaključak: Ovo istraživanje pokazuje da perinatalna infekcija MCMV-om uzrokuje
dugotrajnu završnu diferencijaciju stanica NK, njihovu fenotipsku i transkripcijsku
disregulaciju, te narušava funkcionalni status stanica NK.Objectives: Congenital cytomegalovirus (CMV) infection is the most common viral
congenital infection that can cause long-term neurological sequelae. The role of NK
cells in the control of MCMV during congenital infection and the impact of infection on
NK cells in the context of immunity are not investigated. The main goal of this research
is to determine the role of NK cells in the control of MCMV during perinatal infection and
the changes in NK cell compartment and their function induced by CMV infection in the
congenital infection model.
Materials and methods: In this research, we used the congenital model of MCMV
infection, in which newborn mice are infected with MCMV, to assess the functional
phenotypic and transcriptional changes in NK cells. To address the mechanism
responsible for the changes in NK cells induced by MCMV infection, we used transgenic
mice, which lack major proinflammatory mediators or receptors on NK cells, or we used
blocking antibodies for their inactivation.
Results: We found that MCMV infection of newborns severely compromised NK cell
phenotype, maturation and functionality. Inflammatory responses to infection
dysregulated the expression of major transcription factors governing NK cell fate, such
as Eomes, resulting in impaired NK cell function. Moreover, the bone marrow's capacity
to efficiently generate new NK cells was reduced, explaining the prolonged negative
effects of perinatal infection on NK cells.
Conclusion: Results of this research show that perinatal MCMV infection induces
maturation, phenotypic change and transcriptional dysregulation of NK cells. We also
showed that perinatal MCMV infection causes functional changes in NK cells
Proton Pump Inhibitors: When, to Who and How Much? – Overview on Rational Pharmacotherapy
No full textPrevalencija neadekvatnog propisivanja inhibitora protonske pumpe (IPP) u rasponu je od 25 do 70 %, što zasigurno predstavlja značajan problem gledajući iz perspektive racionalne farmakoterapije/polipragmazije, farmakoekonomike, ali i farmakovigilancije. Kontinuirana edukacija, poznavanje aktualnih kliničkih smjernica, bolja i jasnija komunikacija (direktna i preko medicinske dokumentacije) između bolničkih specijalista, liječnika obiteljske medicine i samog bolesnika te redovita reevalvacija terapijske potrebe od neizmjerne su važnosti jer skupno rezultiraju propisivanjem lijeka u ispravnoj indikaciji, tijekom adekvatnog perioda i u potrebnoj dozi. Stoga je cilj ovog kratkog osvrta prikazati opravdane indikacije za propisivanje IPP-a, raspraviti o najčešćim zabludama i dilemama u kliničkoj praksi, evalvirati potencijalne rizike njihove neadekvatne i dugotrajne primjene, odnosno postaviti temelje za racionalniju farmakoterapiju.The prevalence of inadequate prescribing of proton pump inhibitors (PPIs) is in the range of 25-70%, which is certainly a significant problem when viewed from the perspective of rational pharmacotherapy/polypragmasia, pharmacoeconomics, but also pharmacovigilance. Continuous education, knowledge of clinical guidelines, better and clearer communication (direct and through medical records) between hospital specialists, family physicians and the patient himself, as well as regular reevaluation of the therapeutic need are of immense importance because they collectively result in prescribing the drug in the correct indication, through an adequate period and in the required dose. Therefore, the aim of this short review is to present justified indications for prescribing PPIs, discuss the most common misconceptions and dilemmas in clinical practice, evaluate the potential risks of their inadequate and long-term use, and lay the foundation for rational pharmacotherapy principles
Approach to the Psoriasis Treatment - Part Three: Non-Biologic Systemic Therapy
No full textPsorijaza je kronična imunološki posredovana bolest od koje boluje 2-5 % svjetske populacije. Većina pacijenata sa srednjim i teškim oblikom psorijaze treba sustavno liječenje. Unatoč razvoju biološke terapije, tradicionalna sustavna terapija i dalje ostaje važan izbor u liječenju psorijaze, zbog dobrih rezultata i ekonomičnosti. Najčešće korišteni tradicionalni lijekovi jesu metotreksat, ciklosporini, acitretin i fumarati. Jedna od negativnih strana tradicionalne sustavne terapije jesu moguće teške nuspojave, koje se uz redovito praćenje pacijenta mogu dobro kontrolirati.Psoriasis is a chronic immune-mediated disease that affects 2-5% of the world's population. Most patients with moderate to severe psoriasis require systemic treatment. Despite the development of biological therapy, traditional systemic drugs remain an important therapeutic option due to their efficacy and affordability. The most commonly used traditional drugs are methotrexate, ciclosporin, acitretin, and fumarate. One of the disadvantages of traditional systemic medication is the possibility of side effects, which can be successfully controlled with regular patient monitoring
Hazard assessment of nanomaterials using in vitro toxicity assays: Guidance on potential assay interferences and mitigating actions to avoid biased results
No full textThe movement towards an animal-free testing approach for risk assessment represents a key paradigm shift in
toxicology. Risk assessment of engineered and anthropogenic nanoscale materials (NM) is dependent on reliable
hazard characterization, which requires validated test methods and models, and increasingly on mechanistic
insights into the mode of action. The properties that make NMs so advantageous for a wide range of commercial
and industrial applications also pose a challenge when it comes to safety testing under in vitro and in chemico
experimental settings. Their large reactive surface area makes NMs prone to interactions with assay reagents,
readout signals, or intermediate steps of many test assays, leading to the potential for biased results and data
inconsistencies, collectively referred to as interferences. Therefore, methods and protocols developed and validated for conventional chemicals often require adaptation and checking for reliability in NMs’ toxicity assessment. This review presents the collected scientific knowledge on NMs-induced interferences for the most
common in vitro toxicity assays and methods related to cytotoxicity, oxidative stress and inflammatory response
evaluation. Our analysis of existing scientific literature showed that the challenge of NMs-induced interference
was not explicitly addressed in more than 90% of the papers published up to 2014 reporting the safety and
toxicity of NMs. In later years, increasing number of studies tackled the interference challenge in toxicity testing
of NMs, which initiated exhaustive work on standardization and validation of existing regulatory-relevant in vitro
test protocols and guidelines. Due to the specificity of the different NMs and the range of ways they can
potentially interfere with in vitro assays, interference and fit-for purpose controls should be included for each NM
type and method applied, unless label-free assays are selected. Here, we provide a decision tree to guide researchers on how to design experiments to avoid interferences during in vitro testing by taking appropriate
mitigation actions and how to include proper interference controls in their experimental design where complete
avoidance is not possible. The application of this decision tree will improve the reliability, comparability and
reusability of in vitro toxicity data on engineered NMs or ENMs, increasing the relevance of in silico hazard data
for use in risk assessment and in science-based risk governance of NMs. The approach is applicable more broadly also, to advanced materials and to hazard assessment of anthropogenic nanoscale materials such as microplastic
and tyre-wear particles
Neuro‐immune interactions in health and disease: Insights from FENS‐Hertie 2022 Winter School
No full textAbstract In a great partnership, the Federation of European Neuroscience Societies (FENS) and the Hertie Foundation organized the FENS‐Hertie 2022 Winter School on ‘Neuro‐immune interactions in health and disease’. The school selected 27 PhD students and 13 postdoctoral fellows from 20 countries and involved 14 faculty members experts in the field. The Winter School focused on a rising field of research, the interactions between the nervous and both innate and adaptive immune systems under pathological and physiological conditions. A fine‐tuned neuro‐immune crosstalk is fundamental for healthy development, while disrupted neuro‐immune communication might play a role in neurodegeneration, neuroinflammation and aging. However, much is yet to be understood about the underlying mechanisms of these neuro‐immune interactions in the healthy brain and under pathological scenarios. In addition to new findings in this emerging field, novel methodologies and animal models were presented to foment research on neuro‐immunology. The FENS‐Hertie 2022 Winter School provided an insightful knowledge exchange between students and faculty focusing on the latest discoveries in the biology of neuro‐immune interactions while fostering great academic and professional opportunities for early‐career neuroscientists from around the world
Chemically Functionalized Single-Walled Carbon Nanotubes Prevent the Reduction in Plasmalemmal Glutamate Transporter EAAT1 Expression in, and Increase the Release of Selected Cytokines from, Stretch-Injured Astrocytes in Vitro
No full textWe tested the effects of water-soluble single-walled carbon nanotubes, chemically functionalized with polyethylene glycol (SWCNT-PEG), on primary mouse astrocytes exposed to a severe in vitro simulated traumatic brain injury (TBI). The application of SWCNT-PEG in the culture media of injured astrocytes did not affect cell damage levels, when compared to those obtained from injured, functionalization agent (PEG)-treated cells. Furthermore, SWCNT-PEG did not change the levels of oxidatively damaged proteins in astrocytes. However, this nanomaterial prevented the reduction in plasmalemmal glutamate transporter EAAT1 expression caused by the injury, rendering the level of EAAT1 on par with that of control, uninjured PEG-treated astrocytes; in parallel, there was no significant change in the levels of GFAP. Additionally, SWCNT-PEG increased the release of selected cytokines that are generally considered to be involved in recovery processes following injuries. As a loss of EAATs has been implicated as a culprit in the suffering of human patients from TBI, the application of SWCNT-PEG could have valuable effects at the injury site, by preventing the loss of astrocytic EAAT1 and consequently allowing for a much-needed uptake of glutamate from the extracellular space, the accumulation of which leads to unwanted excitotoxicity. Additional potential therapeutic benefits could be reaped from the fact that SWCNT-PEG stimulated the release of selected cytokines from injured astrocytes, which would promote recovery after injury and thus counteract the excess of proinflammatory cytokines present in TBI
The “Domino effect” in MASLD: The inflammatory cascade of steatohepatitis
No full textAbstract
Metabolic dysfunction‐associated steatotic liver disease (MASLD) is an increasingly common complication of obesity, affecting over a quarter of the global adult population. A key event in the pathophysiology of MASLD is the development of metabolic‐associated steatohepatitis (MASH), which greatly increases the chances of developing cirrhosis and hepatocellular carcinoma. The underlying cause of MASH is multifactorial, but accumulating evidence indicates that the inflammatory process in the hepatic microenvironment typically follows a pattern that can be roughly divided into three stages: (1) Detection of hepatocyte stress by tissue‐resident immune cells including γδ T cells and CD4
CD8
double‐negative T cells, followed by their secretion of pro‐inflammatory mediators, most notably IL‐17A. (2) Recruitment of pro‐inflammatory cells, mostly of the myeloid lineage, and initiation of inflammation through secretion of effector‐type cytokines such as TNF, TGF‐β, and IL‐1β. (3) Escalation of the inflammatory response by recruitment of lymphocytes including Th17, CD8 T, and B cells leading to chronic inflammation, hepatic stellate cell activation, and fibrosis. Here we will discuss these three stages and how they are consecutively linked like falling domino tiles to the pathophysiology of MASH. Moreover, we will highlight the clinical potential of inflammation as a biomarker and therapeutic target for the treatment of MASLD