Glycans are an essential structural component of immunoglobulin G (IgG) that modulate its structure and function. However, regulatory mechanisms behind this complex posttranslational modification are ...not well known. Previous genome-wide association studies (GWAS) identified 29 genomic regions involved in regulation of IgG glycosylation, but only a few were functionally validated. One of the key functional features of IgG glycosylation is the addition of galactose (galactosylation), a trait which was shown to be associated with ageing. We performed GWAS of IgG galactosylation (N=13,705) and identified 16 significantly associated loci, indicating that IgG galactosylation is regulated by a complex network of genes that extends beyond the galactosyltransferase enzyme that adds galactose to IgG glycans. Gene prioritization identified 37 candidate genes. Using a recently developed CRISPR/dCas9 system we manipulated gene expression of candidate genes in the
IgG expression system. Upregulation of three genes,
and
, changed the IgG glycome composition, which confirmed that these three genes are involved in IgG galactosylation in this
expression system.
Procjenjuje se da u svijetu od astme boluje više od 300 milijuna ljudi. Uočljiv je porast prevalencije astme, kao i troškova zbrinjavanja ove bolesti. Glavni patogenetski mehanizam u astmi je ...kronična upala u dišnim putovima. Ova spoznaja preusmjerila je liječenje astme sa simptomatskog k temeljnomu, protuupalnom liječenju. U svrhu što učinkovitijeg zbrinjavanja astme diljem svijeta rabe se globalne smjernice za liječenje astme. Najčešće se rabe smjernice Globalne inicijative za astmu (GINA), zadnji put revidirane 2012. godine. Inhalacijski kortikosteroidi (IKS) danas su najučinkovitiji lijekovi u liječenju astme. Prema smjernicama IKS su u monoterapiji prvi izbor temeljnog liječenja trajne astme za sve dobne skupine. Novi pripravci inhalacijskih kortikosteroida s vrlo sitnim česticama lijeka osiguravaju distribuciju lijeka i u male dišne putove, što može pridonijeti boljoj kontroli astme.
Bronhoskopija je jedna od glavnih dijagnostičkih procedura u plućnim bolestima. U novije se vrijeme počinje sve više rabiti i u dijagnostici infektivnih bolesti donjega dišnog sustava. Bronhoskopskom ...dijagnostikom u infektivnim bolestima pluća najviše se koristimo radi utvrđivanja uzročnika upale u imunokompromitiranih bolesnika, bolesnika na mehaničkoj ventilaciji i u onih s izvanbolničkom pneumonijom u kojih primjena empirijske antibiotske terapije nije uspjela. Ograničenje vrijednosti materijala uzetog bronhoskopski jest mogućnost njegove kontaminacije prilikom postupka bronhoskopije. Zbog toga su razvijene sofisticiranije tehnike kojima se to pokušava smanjiti. Najčešće upotrebljavane tehnike jesu ispiranje bronha (tzv. minilavat), uzimanje obriska zaštićenom četkicom, transbronhalna biopsija i transbronhalna odnosno transtrahealna iglena aspiracija. Za bakteriološko uzorkovanje najpogodniji su minilavat zahvaćenog područja plućnog parenhima i zaštićeno četkanje bronha (najmanja mogućnost kontaminacije), a transbronhalna biopsija za dijagnosticiranje određenih mikrobioloških uzročnika poput intracelularnih patogena i gljiva. Moguće komplikacije bronhoskopije jesu hipoksemija, krvarenje (kod transbronhalne biopsije i uzimanja obriska četkicom), pneumotoraks (kod transbronhalne biopsije i rjeđe kod uzimanja obriska četkicom) ili širenje infekcije. Također, prilikom izvođenja postupka mogu nastupiti poremećaj srčanog ritma ili hipotenzija u bolesnika na mehaničkoj ventilaciji (zbog dodatnog povišenja ekspiratornoga pozitivnog tlaka). Unatoč tomu pažljiv odabir bolesnika te odabir prikladnog načina uzimanja uzorka uz tehničku vještinu bronhoskopičara daju velik doprinos pri točnoj dijagnostici, a time i liječenju teških upala pluća.
Low back pain (LBP) is a common debilitating condition which aetiology and pathogenesis are poorly understood. We carried out a first so far analysis of associations between LBP and plasma IgG ...N-glycome in a sample of 4511 twins from TwinsUK database assessed for LBP, lumbar disc degeneration (LDD) as its possible cause, and IgG-glycan levels. Using weighted correlation network analysis, we established a correlation between LBP and glycan modules featured by glycans that either promote or block antibody-dependent cell-mediated cytotoxicity (ADCC). The levels of four glycan traits representing two of those modules were statistically significantly different in monozygotic twins discordant for LBP. Also, the trend to higher prevalence of systemic inflammatory disorders was shown for twins with low level of fucosylated glycans and high level of non-fucosylated glycans. Core fucosylation of IgG is a "safety switch" reducing ADCC, thus our results suggest the involvement of ADCC and associated inflammation in pathogenesis of LBP. No correlation between LDD scores and glycans was found assuming that the inflammation may not be a part of LDD. These data provide a new insight into understanding the complex pathophysiology of LBP and suggest glycan levels as a possible biomarker for inflammation-related subtypes of LBP.
Several studies have suggested that idiopathic pulmonary fibrosis (IPF) may be related to repeated aspiration of gastric contents over long periods of time. We aimed to investigate differences ...between pH measured directly in the lung, and biomarkers of acute inflammation in patients with newly diagnosed IPF and in patients with newly diagnosed GERD.
All subjects (N=61) underwent collection of medical history, physical examination, pulmonary function testing, bronchoscopy, endoscopy, arterial blood gas analyses, and biochemical testing.
Previously diagnosed GERD was found in 56.7%, typical symptoms of reflux in 80%, and Helicobacter pylori in gastric biopsy specimens in 76.6% of the cases. pH in peripheral branches of bronchi in the cases was 5.32 ± 0.44 and was 6.27 ± 0.31 (p<0.001) in the control group. The average values of LDH, ALP, and CRP in bronchoalveolar aspirate and in serum, as well as TNF-alpha in bronchoalveolar aspirate, were significantly higher in IPF patients.
The more acidic environment in the bronchoalveolar aspirate of the IPF subjects could contribute to the development or progression of IPF, possibly via changes in local metabolism or by damaging local cells and tissue. However, further studies with larger numbers of patients are required to clarify the role of gastric fluid aspiration in IPF pathogenesis. Our preliminary work has identified inflammatory biomarkers LDH, ALP, and TNF-alpha as potentially important in the pathologic processes in IPF. Further research is needed to determine their importance in clinical intervention and patient care.
Delayed diagnosis and treatment of tuberculosis increase both the severity of the disease and the duration of infectivity. A number of studies have addressed the issue of health system delays in the ...treatment of tuberculosis, but mostly in countries with a high or low incidence of the disease. Our understanding of delay is quite limited in settings with an intermediate burden of tuberculosis. We explore the duration and factors associated with delays in the Croatian health system which has free health care and a sufficient network of health services providing tuberculosis diagnosis and care.
A total of 241 consecutive adults with culture-confirmed pulmonary tuberculosis were interviewed in seven randomly selected Croatian counties and their medical records were evaluated. A health system delay was defined as the number of days from the first consultation with a physician to the initiation of anti-tuberculosis treatment. A long delay was defined as a period exceeding the median delay, while an extreme delay was considered to be above the 75th percentile delay.
The median health system delay was 15 days while the 75th percentile was 42 days (the 5th and 95th percentile being 1 and 105 days respectively). Almost 30% of tuberculosis patients remained undiagnosed for more than 30 days after the initial health care visit. Female patients (p = 0.005), patients with a negative sputum smear (p = 0.002) and patients having symptoms other than the usual ones (0.027) were found to be in significant correlation with a long delay. In a multivariate model, a long delay remained associated with the same variables (p = 0.008, p = 0.003, and p = 0.037, respectively).A significant association was demonstrated between both the female gender (p = 0.042) and a negative sputum smear (p < 0.001) and extreme delay, while only a negative sputum smear (p < 0.001) remained significant in the multivariate analysis.
Our findings suggest that some groups of tuberculosis patients experienced a health system delay. In such a setting where tuberculosis incidence is decreasing, which leads to a lack of physician experience and expertise, training in tuberculosis is required. Such measure may be useful in reducing the number of missed opportunities for tuberculosis diagnosis.
Protein glycosylation is the most common epiproteomic modification involved in numerous physiological and pathological processes. Previous studies reported strong associations between human plasma
N
...-glycans and age, prompting us to evaluate the potential application of this biological phenomenon in the field of forensics. Blood from 526 blood donors from different parts of Croatia was collected on bloodstain cards during the period 2004–2007 and stored at 4°C for 6–9 years. Glycosylation profiles of the bloodstains were analysed using hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC) and divided into 38 glycan groups (GP1-GP38). A statistically significant correlation between
N
-glycan profiles of bloodstains and chronological age was found and a statistical model that can be used for the age prediction was designed (Age = 75.59 – 5.15 × (GP4)
2
+ 17.07 × GP6 – 5.30 × (GP10)
2
– 16.56 × GP16 + 20.07 × GP20 – 7.54 × (GP20)
2
+ 16.47 × GP22). This model explains 47.78 % of the variation in age, with a prediction error of 9.07 years. Our findings demonstrate that analysing the
N
-glycan profile could be a new tool in forensics, offering an approximate human age estimation from dried bloodstains found at a crime scene.
Sve veći broj prikupljenih činjenica o prirodnom tijeku astme potvrđuje upalu, hiperreaktivnost, remodeliranje i ireverzibilno slabljenje plućne funkcije kao linearni slijed zbivanja tijekom dužeg ...vremena u većine bolesnika s astmom. Pravodobna i dugotrajna primjena inhalacijskih kortikosteroida kao najsnažnijih protuupalnih lijekova učinkovito kontrolira simptome te prevenira remodeliranje i ireverzibilni gubitak plućne funkcije. Liječenje usmjereno samo nestanku simptoma i poboljšanju plućne funkcije često ne osigurava optimalnu kontrolu astme. Terapijske odluke treba temeljiti na pokazateljima koji uzimaju u obzir različite aspekte kontrole te izravno ili neizravno daju uvid u razinu upalne reakcije u dišnim putovima bolesnika. Loša kontrola astme odražava neprimjereno liječenje, tj. neadekvatno liječenje upale u dišnim putovima. To je u znatnoj mjeri posljedica neopravdano skromnih očekivanja bolesnika i neprimjereno niskih ciljeva liječenja. Potpuna kontrola astme uz adekvatnu primjenu temeljnih lijekova, u odgovarajućoj dozi i dovoljno dugo, ostvariv je cilj liječenja u većine bolesnika.
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