Rodent models of complement activation-related pseudoallergy: Inducers, symptoms, inhibitors and reaction mechanisms

Complement activation-related pseudoallergy (CARPA) is a hypersensitivity reaction to intravenous administration of nanoparticle-containing medicines (nanomedicines). This review focuses on CARPA in rodent models: rats, mice, guinea pigs and rabbits. Information on all aspects of hypersensitivity reactions caused by known complement activators (zymosan, cobra venom factor) and different nanomedicines (liposomes, other drug carrier nanocarriers) in these species has been compiled and analyzed, trying to highlight the similarities and differences. What is most common in all species' reactions to i.v. complement activators, liposomes and other nanoparticles is a dose-dependent hemodynamic and cardiopulmonary disturbance manifested in acute, reversible rise or fall of blood pressure and respiratory distress that can lead to shock. Other symptoms include heart rate changes, leukopenia followed by leukocytosis, thrombocytopenia, hemoconcentration due to fluid extravasation (rise of hematocrit) and rise of plasma thromboxane B2. The results of a recent rat study are detailed, which show that rats are 2-3 orders of magnitude less sensitive to liposome-induced CARPA than pigs or hypersensitive humans. It is concluded that CARPA can be studied in rodent models, but they do not necessarily mimic the human reactions in terms of symptom spectrum and sensitivity. © 2015 by De Gruyter

Cardiopulmonary and hemodynamic changes in complement activation-related pseudoallergy

Complement activation-related pseudoallergy (CARPA) is a frequent side effect of intravenous therapies with nanoparticle-containing drugs and biologicals that are recognized by the immune system as foreign. It is an acute infusion reaction dominated by cutaneous and hemodynamic changes, most significantly a cardiopulmonary distress involving major pulmonary hypertension, systemic hypotension and arrhythmias. Because CARPA is unpredictable by conventional allergy tests and it may be life threatening, it can represent a major barrier to the safe therapeutic application of many modern medicines, including liposomal drugs and monoclonal antibodies. This review summarizes and updates the facts and opens questions regarding this phenomenon, with particular focus on its porcine model

A kalcium tranziens kialakulásának mechanizmusa működő szívben = Development of the calcium transient in the beating heart

Kutatásaink a ciklikus intracelluláris kalciumion koncentráció (Ca2+i) változásait kialakító transzport folyamatok felderítésére irányultak normál és kardiomiopátiás szívben. A mért primer jel a Ca2+i tranziens volt, melynek kvantitív analízisére matematikai modellt fejlesztettünk ki. Ennek segítségével lehetővé vált a rianodin csatorna és a SERCA2a kinetikai paramétereinak kiszámítása. Megfigyeléseink szerint a posztiszkémiás szívben a tartósan megemelkedett Ca2+i szint kontraktúrát, valamint a PLA2 aktiválásával membrán degradációt okoz. Ezek a károsodások hő-sokk előkezeléssel részlegesen kivédhetők. További megfigyelésünk szerint a diabéteszes és toxikus kardiomiopátia Ca2+i felszabadulási és szekvesztrációs zavarokat okoz, valamint a nukleáris poli(ADP-ribóz)polimeráz enzim gátlásával a toxikus kardiomiopátia ezen hatásai a Ca2+i homeosztázisra mérsékelhetők. Összefoglalva; a T038121 sz. OTKA támogatás segítségével jelentős előrelépést tettünk a myocardium Ca2+i tranziensét kialakító mechanizmusok feltérképezésében mind normál, mind patofiziológiás körülmények között. | During the grant period of 2002-2005 our research focused on the delineation of the processes responsible for the cyclic changes of the intracellular calcium concentration (Ca2+i) in the normal and diseased heart. A mathematical model was developed to allow the quantitative analysis of the observed Ca2+i signal. Using this novel mathematical approach we have calculated the kinetic parameters of the sarcoplasmic reticulum calcium release channel (RyR2) and SERCA2a. We have observed that the persistent increase in end-diastolic Ca2+i is associated with contracture of the myocardium and activation of PLA2 resulting in membrane degradation. These pathological events can be ameliorated with heat shock pretreatment. We have found that cardiomyopathy of either diabetes or toxic origin results in malfunction of Ca2+ release and sequestration. We have also shown that the disruptive effects of toxic cardiomyopathy on Ca2+i handling can be suppressed with the inhibition of the nuclear enzyme ply(ADP-ribose)polymerase. In summary; funds provided by OTKA T038121 spawned major progress in our research to delineate the processes involved in Ca2+i handling both under normal and pathological circumstances

What have we learned from two-pore potassium channels? Their molecular configuration and function in the human heart

Two-pore domain potassium channels (K2P) control excitability, stabilize the resting membrane potential below firing threshold, and accelerate repolarisation in different cells. Until now, fifteen different genes for the six K2P channel subfamily were cloned. The pore-forming part is translated from two genes and they are built up from a dimer of two two-unit transmembrane domains functioning with a wide spectrum of physiological profiles. K2P ion channels were discovered in the last two decades and gave novel opportunity to recognize the complex molecular mechanism of the potassium ion flux, and may lead to the design of individual drug targeting in the future. In this review, we summarise the structure, function, channelopathies and pharmacological silhouette of the two-pore potassium channels in the human tissues. In addition, we present the computer model of the partially reconstructed wild type K2P1/TWIK1 lacking the intracellular C and N terminal loop

Merőleges anizotrópiájú ötvözetfilmek és a mágneses szerkezet ionsugaras kialakítása = Perpendicular anisotropy multicomponent films and ion beam tailoring of their magnetic structure

A vékonyrétegek szerkezete és mágneses tulajdonságai érzékeny módon összefüggnek. A rétegtulajdonságok módosításának legfontosabb eszköze az ionimplantáció volt. Módosítottuk homogén rétegek fizikai, kémiai, és mágneses tulajdonságait, és ezzel módosítottuk a mágneses multirétegekben a rétegprofilt. Metastabil FePd a lokális környezetektől függő Fe öndiffúziós állandókat határoztunk meg. Kapcsolatot találtunk az ionsugaras keveredés és a diffúziós állandó között. Alkalmazásként periodikus laterális mágneses mintázatot hoztunk létre besugárzással, neutrontükrök feszültségmentesítésére és monokromátor tervezésére alkalmas eljárásokat dolgoztunk ki. | The structure and magnetic properties of thin films are sensitively interrelated. Physical, chemical and consequent magnetic properties of the films and their depth profile were modified in magnetic multilayers promarily by ion implantation. Three Fe self-diffusion coefficients were determined according to the local Fe-environments in metastable FePd films. A relation has been revealed between ion beam mixing rate and diffusion coefficient. As applications of the achived scientific results periodic lateral magnetic pattern was created using ion implantation and developed procedures for strain release of neutron mirrors and monochromator design

NKX2-1 New Mutation Associated With Myoclonus, Dystonia, and Pituitary Involvement

Background:NKX2-1 related disorders (also known as brain-lung-thyroid syndrome or benign hereditary chorea 1) are associated with a wide spectrum of symptoms. The core features are various movement disorders, characteristically chorea, less frequently myoclonus, dystonia, ataxia; thyroid disease; and lung involvement. The full triad is present in 50% of affected individuals. Numerous additional symptoms may be associated, although many of these were reported only in single cases. Pituitary dysfunction was ambiguously linked to NKX2-1 haploinsufficiency previously.Case Presentation: We examined two members of a family with motor developmental delay, mixed movement disorder (myoclonus, dystonia and chorea) and endocrinological abnormalities (peripheric thyroid disease, and pituitary hormone deficiencies). Dystonia predominated at the father, and myoclonus at the daughter. The father had hypogonadotropic hypogonadism, while the daughter was treated with growth hormone deficiency. Both patients had empty sella on MRI. Candidate gene analyses were negative. Exome sequencing detected a pathogenic stop variation (NM_003317:c.338G>A, p.Trp113*) in the NKX2-1 gene.Conclusions: This case study has two highlights. (1) It draws attention to possible pituitary dysfunction in brain-lung-thyroid syndrome, and provide further evidences that this might be linked to loss of function of the NKX2-1 gene. (2) It underscores the importance of considering NKX2-1 related disorders in the differential diagnosis of myoclonus dystonia