POBOLJŠANJE ZBRINJAVANJA BOLESNIKA S RIJETKIM BOLESTIMA U HRVATSKOJ - TEMELJENO NA PROTOKOLU ZA HEREDITARNI ANGIOEDEM

Rare diseases affect up to 6%-8% of the population and pose a challenge to healthcare professionals and healthcare system. Hereditary angioedema is a rare life-threatening, debilitating disease characterized by recurrent edema attacks. It is essential to establish the diagnosis as quickly as possible. The Healthcare Network was created in o der to prevent mistreatment of hereditary angioedema. This study evaluated the usefulness of the Hospital Information System and the Healthcare Network in urgent management of hereditary angioedema. The Instructions for Hereditary Angioedema that contain information on the diagnosis, instructions for treatment, preventive measures prior to a dental procedure, endoscopy or surgery under general anesthesia, available regimens and storage location in the Hospital, specialist’s telephone number in emergency, and name of the family member to be contacted, were implemented in the Hospital Information System, Šibenik General Hospital as a protocol for urgent management. Data on the treatment before and after implementation of the Instructions for Hereditary Angioedema were compared. Comparing medical decisions before and after implementing the Instructions for Hereditary Angioedema in the Hospital Information System revealed that following implementation of the Instructions, correct therapy was administered more often (p=0.006, Fisher exact test) and shortterm prophylaxis applied more often before medical procedures (p=0.011, Fisher exact test). Healthcare Network raised the physician awareness of this disabling and potentially fatal disease, led to accurate diagnosis and timely treatment, enabled short hospital stay, prompt recovery, and reduced absenteeism from work due to hereditary angioedema. With specific modifications, it could also be extrapolated to other rare diseases.Rijetke bolesti su izazov zdravstvenim stručnjacima i sustavima. Smatra se da 6-8 % populacije boluje od rijetkih bolesti. Nasljedni angioedem (HAE) jedna je od rijetkih bolesti, karakterizirana ponavljajućim napadima oteklina (edema) različitih dijelova tijela te se vrlo često ne dijagnosticira pravodobno, a težina ponavljajućih napadaja se pogoršava i za život je opasno stanje. Bitno je posumnjati na rijetku bolest i postaviti dijagnozu što je brže moguće. Ova je probna studija procijenila korisnost implementacije podataka o bolesnicima s HAE u Bolnički informacijski sustav (BIS) Opće bolnice Šibenskokninske županije kao i primjenu protokola za hitno zbrinjavanje i formiranje mreže zdravstvene zaštite (MZZ). Upute u BIS-u za HAE sadrže podatke o dijagnozi HAE-a, upute za liječenje, preventivne mjere prije stomatološkog, endoskopskog ili kirurškog postupka (pod lokalnom/općom anestezijom); popis raspoloživih lijekova u hitnoći i mjesto njihove pohrane u bolnici; telefonski broj specijalista u hitnoći te ime člana obitelji (kontakt osoba). Podatci o liječenju prije primjene uputa za HAE uspoređeni su s podatcima prikupljenima u razdoblju nakon provedbe implementacije novog sustava. Uspoređujući medicinske odluke prije i nakon implementacije uputa za HAE u BIS-u, pravilna je terapija bila češće primijenjena (p =0,006, Fisherov test), kao i kratkotrajna profi laksa prije medicinskih postupaka (p = 0,011, Fisherov test). Uspostava MZZ pospješuje informiranost medicinskog osoblja, pravilan odabir liječenja i zbrinjavanje bolesnika s HAE. Omogućuje brži oporavak, kraći boravak u bolnici i smanjenje radne odsutnosti bolesnika s HAE. Temeljem ove studije otvara se mogućnost primjene MZZ i za druge rijetke bolesti

Technoeconomical evaluation of black liquorgasification processes

Godkänd; 2000; 20091123 (andbra

FcεR1-mediated mast cell reactivity is amplified through prolonged Toll-like receptor-ligand treatment.

BACKGROUND: Mast cell-derived mediators mediate several of the pathological features of asthma. Microbial infections induce asthma exacerbations in which the contribution of mast cells remains incomprehensible. PRINCIPAL FINDINGS: In this study we have investigated the characteristic expression pattern of Toll-like receptors (TLRs) 1-9 and the effect of TLR ligand treatment on IgE-receptor mediated mast cell reactivity. For the studies we employed in vitro differentiated connective tissue like mast cells (CTLMC) and mucosal like mast cells (MLMC) from mice. Both phenotypes were treated for 24 h or 96 h with ligands for TLR1/2, TLR2/6, TLR3 and TLR4, before activation with IgE and antigen. Prolonged exposure (96 h) with TLR-ligands promoted mast cell reactivity following IgE-receptor activation. TLR4 activation with LPS generated the most pronounced effect, with an enhanced degranulation and secretion of leukotrienes, cytokines and chemokines, in both CTLMC and MLMC. The effect of LPS was mediated through a Myd88-dependent pathway and the increased effect involved JNK-dependent pathway. CONCLUSION: We find that prolonged exposure of mast cells to pathogens/TLR-ligands modulates their effector responses by priming them for increased release of several inflammatory mediators when subsequently activated by IgE-receptors. These data suggest that infections might exaggerate the severity of allergic reactions such as in asthma, by enhancing mediator release from mast cells

Pre-treatment with TLR agonists increase FcεRI-mediated degranulation in CTLMC and MLMC.

<p>Cells were treated with different TLRs agonists for 24 h (<i>A</i> and <i>C</i>) or 96 h (<i>B</i> and <i>D</i>) and were sensitized with IgE followed by antigen. Degranulation was determined by measuring the release of β-hexosaminidase in duplicates. The release was calculated as a percentage of total β-hexosaminidase content released following activation. Results are represented as the mean ±SEM for 5 independent experiments. *p<0.05, **p<0.01 significantly different from the respective controls.</p

Pre-treatment with LPS did not increase FcεRI-mediated degranulation and leukotrienes release in MyD88−/− MLMC. MLMCs were treated with different LPS for 96 h and were sensitized with IgE followed by antigen.

<p>Degranulation was determined by measuring the release of β-hexosaminidase in duplicates. The release was calculated as a percentage of total β-hexosaminidase content released following activation (A). CysLT and LTB₄ also exhibited the similar pattern as measured in the culture supernatant by ELISA (B and C). Results are represented as the mean ±SEM for 5 independent experiments. *p<0.05, **p<0.01 significantly different from the respective controls.</p

MAPK activation induced by LPS or IgE cross-linking.

<p>(<i>A</i>) MLMC were treated with LPS (1 µg/ml) for 96 h, IgE cross-linking (IgE-XL) or combination with LPS and IgE-XL (10 min). Phosphorylation of ERK, p38 MAPK and JNK was detected by phosphospecific antibodies against the respective kinases by Western blot with reference to the total kinases present in whole cell lysate. <i>Lane 1</i>: Control resting cells; <i>Lane 2</i>: control cells with IgE-XL; <i>Lane 3</i>: LPS treated cells; <i>Lane 4</i>: LPS treated cells exposed to IgE-XL (<i>B</i>) To explore the role of MAPKs involved in LPS triggered induction of degranulation from activated mast cells following IgE-XL, MLMC were preincubated with JNK inhibitor SP 600125 (1 µM), ERK inhibitor PD 98059 (1 µM) and p38 MAPK inhibitor SB 203580 (10 µM) in presence and absence of LPS (1 µg/ml) for 96 h. The cells were then sensitized challenged with IgE for 90 min and further treated with antigen for 30 min. Supernatants were collected in duplicates to evaluate β-hexosaminidase activity. Release was calculated as a percentage of total β-hexosaminidase. Results are presented as the mean ± SEM for 5 independent experiments. **p<0.01.</p

Pre-treatment with TLR agonists increase leukotriene products in CTLMC and MLMC.

<p>Cells were treated with different TLRs agonists for 24 h (<i>A</i>, <i>C</i>, <i>E</i>, <i>G</i>) and 96 h (<i>B</i>, <i>D</i>, <i>F</i>, <i>H</i>), CTMLC (<i>A</i>, <i>B</i>, <i>E</i>, <i>F</i>) and MLMC (<i>C</i>, <i>D</i>, <i>G</i>, <i>H</i>) were sensitized with IgE by antigen. CysLT and LTB₄ were measured in the culture supernatant by ELISA in duplicates. Results are represented as the mean ±SEM for 5 independent experiments. *p<0.05, **p<0.01 significantly different from the control cells without IgE receptor cross-linking.</p

IgE-receptor induced pro-inflammatory cytokine and chemokine production by mast cells are enhanced upon pre-treatment with TLRs agonists.

<p>CTLMC (<i>A</i>,<i>C</i>,<i>E</i>) and MLMC (<i>B</i>,<i>D</i>,<i>F</i>) were treated for 96 h with different TLR agonists and then sensitized with IgE followed by antigen for 6 h. Culture supernatants were analysed for the presence of IL-6 (<i>A</i>,<i>B</i>), MIP-1α (<i>C</i>,<i>D</i>) and MCP-1 (E,F) by Luminex in duplicates. Data are mean ± SEM and representative of 5 independent experiments. *p<0.05, **p<0.01 significantly different from the respective controls.</p

Sequences of TLR and β-actin primer pairs.

<p>Sequences of TLR and β-actin primer pairs.</p