Pharmacological Preconditioning with Diazoxide in the Experimental Hypothermic Circulatory Arrest Model

Background: Hypothermic circulatory arrest includes a remarkable risk for neurological injury. Diazoxide, a mitochondrial adenosine triphosphate-dependent potassium ion (K+ATP) channel opener, is known to have cardioprotective effects. We assessed its efficacy in preventing ischemic injury in a clinically relevant animal model.Methods: Eighteen piglets were randomized into a diazoxide group (n = 9) and a control group (n = 9). Animals underwent 60 minutes of hypothermic circulatory arrest at 18 degrees C. Diazoxide (5 mg/kg + 10 mL NaOH + 40 mL NaCl) was infused during the cooling phase. Metabolic and hemodynamic data were collected throughout the experiment. After 24-hour follow-up, whole brain, heart, and kidney biopsy specimens were collected for analysis.Results: Cerebellar Cytochrome-C and caspase-3 activation was higher in the control group (P = .02 and P = .016, respectively). Antioxidant activity tended to be higher in the diazoxide group (P = .099). Throughout the experiment, the oxygen consumption ratio was higher in the control animals (P-g = .04), as were the lactate levels (P-g = .02). Cardiac function tended to be better in diazoxide-treated animals.Conclusion: Diazoxide might confer neuroprotective effect as implied by the immunohistochemical analysis of the brain. Additionally, the circulatory effects of diazoxide were beneficial, supporting its neuroprotective effect

DNA damage by lipid peroxidation products: implications in cancer, inflammation and autoimmunity

Oxidative stress and lipid peroxidation (LPO) induced by inflammation, excess metal storage and excess caloric intake cause generalized DNA damage, producing genotoxic and mutagenic effects. The consequent deregulation of cell homeostasis is implicated in the pathogenesis of a number of malignancies and degenerative diseases. Reactive aldehydes produced by LPO, such as malondialdehyde, acrolein, crotonaldehyde and 4-hydroxy-2-nonenal, react with DNA bases, generating promutagenic exocyclic DNA adducts, which likely contribute to the mutagenic and carcinogenic effects associated with oxidative stress-induced LPO. However, reactive aldehydes, when added to tumor cells, can exert an anticancerous effect. They act, analogously to other chemotherapeutic drugs, by forming DNA adducts and, in this way, they drive the tumor cells toward apoptosis. The aldehyde-DNA adducts, which can be observed during inflammation, play an important role by inducing epigenetic changes which, in turn, can modulate the inflammatory process. The pathogenic role of the adducts formed by the products of LPO with biological macromolecules in the breaking of immunological tolerance to self antigens and in the development of autoimmunity has been supported by a wealth of evidence. The instrumental role of the adducts of reactive LPO products with self protein antigens in the sensitization of autoreactive cells to the respective unmodified proteins and in the intermolecular spreading of the autoimmune responses to aldehyde-modified and native DNA is well documented. In contrast, further investigation is required in order to establish whether the formation of adducts of LPO products with DNA might incite substantial immune responsivity and might be instrumental for the spreading of the immunological responses from aldehyde-modified DNA to native DNA and similarly modified, unmodified and/or structurally analogous self protein antigens, thus leading to autoimmunity

Pohjoissuomalaisten BRCA1/2-alttiusmutaation kantajanaisten syöpäseulonta:takautuva seurantatutkimus vuosilta 1992–2016

Tiivistelmä JOHDANTO: Oulun yliopistollisen sairaalan perinnöllisyyspoliklinikan ja gynekologisen onkologian yhteisprojektina on ollut 1990-luvulta lähtien tavoittaa perinnöllistä rinta- ja munasarjasyöpäalttiutta kantavia sukuja. Selvitimme BRCA1/2-alttiusmutaation toteamisen jälkeen kantajanaisten seurantatapahtumat. MENETELMÄT: Tutkimme vuosina 1992–2016 alttiusmutaatiovastauksen saaneiden naisten mutaatiokirjoa, syöpäsairastavuutta, seurantaa ja riskiä pienentäviä toimenpiteitä Pohjois-Suomessa. Tarkemmat tiedot hankittiin henkilöistä, jotka eivät olleet sairastaneet rinta- tai munasarjasyöpää ennen mutaatiovastausta. Tutkimus toteutettiin takautuvana rekisteritutkimuksena, jonka aineisto kerättiin sairauskertomuksista. TULOKSET: BRCA1-mutaatio oli 63 naisella (54 %) ja BRCA2-mutaatio 54:llä (46 %). Tarkemmin tarkastelluista henkilöistä valtaosa osallistui seurantatutkimuksiin. Mutaatiovastauksen jälkeen kuudella todettiin rintasyöpä ja kahdella munasarjasyöpä. Riskiä pienentävä munasarjojen poistoleikkaus oli mastektomiaa suositumpi. PÄÄTELMÄT: Tutkimus on ensimmäinen pohjoissuomalaisia BRCA1/2-sukuja kartoittava julkaisu. Suurin osa alttiusmutaatioista oli perustajamutaatioita. Seurantojen toteutuminen vaihteli paljon, mutta on sittemmin yhtenäistynyt kansallisten suositusten ansiosta

Randomized trial of single agent paclitaxel given weekly versus every three weeks and with peroral versus intravenous steroid premedication to patients with ovarian cancer previously treated with platinum

The aim of this study was to evaluate the efficacy and toxicity of paclitaxel given at the same dose intensity and administered weekly (arm A) or every 3 weeks (arm B), and to assess the safety of intravenous steroids versus standard peroral premedication. Two hundred and eight patients with advanced ovarian cancer previously treated with no more than one platinum-containing regimen were randomized to receive either a weekly infusion of paclitaxel or an infusion every 3 weeks. The median delivered dose intensity was 77.6 mg/m(2)/week in the weekly arm, and 72.7 mg/m(2)/week in the every 3 weeks arm. WHO grade 3-4 hematological and non-hematological toxicity occurred more frequently in arm B. No difference in number of severe events of hypersensitivity, response rate, time to progression or survival between arms was observed. Weekly paclitaxel at a dose of 67 mg/m(2)/week was found to have a better safety profile and seemed to be as effective as the equivalently dosed schedule every 3 weeks. Intravenous steroids are a safe alternative to oral steroids