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Presents a study which determined the effect of the hydrogen (H) implantation-induced defects on the H migration in n-type gallium arsenide. Determination of the depth scale; Effects of the deposited energy on the H migration; Indication of the dependence of the H solubilities on the annealing temperature.

Small molecule inhibitors targeting the bromodomain and extra-terminal domain (BET) family proteins have emerged as a promising class of anti-cancer drugs. Nevertheless, the clinical advancement of these agents has been significantly hampered by challenges related to their potency, oral bioavailability, or toxicity. In this study, virtual screening approaches were employed to discover novel inhibitors of the bromodomain-containing protein 4 (BRD4) by analyzing their comparable chemical structural features to established BRD4 inhibitors. Several of these compounds exhibited inhibitory effects on BRD4 activity ranging from 60 % to 70 % at 100 µM concentrations, while one compound also exhibited an 84 % inhibition of Sirtuin 2 (SIRT2) activity. Furthermore, a subset of structurally diverse compounds from the BRD4 inhibitors was selected to investigate their anti-cancer properties in both 2D and 3D cell cultures. These compounds exhibited varying effects on cell numbers depending on the specific cell line, and some of them induced cell cycle arrest in the G0/G1 phase in breast cancer (MDA-MB-231) cells. Moreover, all the compounds studied reduced the sizes of spheroids, and the most potent compound exhibited a 90 % decrease in growth at a concentration of 10 µM in T47D cells. These compounds hold potential as epigenetic regulators for future studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

In addition to the transfer across the placenta, placenta displays hormonal and xenobiotic metabolism, as well as enzymatic defense against oxidative stress. We analyzed aromatase (CYP19A1), uridine 5'-diphospho-glucuronyltransferase (UGT), glutathione-S-transferase (GST) and catalase (CAT) activities in over 70 placentas from nonsmokers stored at -80 °C from former perfusion studies. A wide interindividual variation in all activities was found. Longterm storage at -80 °C did not affect the activities. Ethoxyresorufin-O-deethylase (EROD, CYP1A1) was not detected in any of the studied placentas perfused with chemicals. Several compounds in placental perfusion changed statistically significantly the enzyme activities in placental tissue. Melamine and nicotine increased CYP19A1, melamine increased UGT and GST, PhIP with ethanol decreased CYP19A1 and increased GST, and PhIP with buprenorphine decreased CAT. Antipyrine in 100 μg/ml also changed the studied enzyme activities, but not statistically significantly. Because antipyrine is a reference compound in placental perfusions, its potential effects must be taken into account in human placental perfusion. Enzyme activities deserve further studies as biomarkers of placental toxicity. Finally, enzyme activities deserve further studies as biomarkers of placental toxicity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Diuron is a broad-spectrum phenylurea derived herbicide which is commonly used across the globe. Diuron is toxic to the reproductive system of animals and carcinogenic to rat urothelium, and recently found to be genotoxic in human cells. In in vivo, it is metabolized predominately into 3-(3,4-dichlorophenyl)-1-methyl urea (DCPMU) in humans and 3-(3, 4-dichlorophenyl)urea (DCPU) in animals. Information on diuron toxicokinetics and related toxicity in human placenta is absent. We have investigated the toxicokinetics of diuron in ex vivo human placental perfusion and in in vitro human placental microsomes and human trophoblastic cancer cells (BeWo). Diuron crossed human placenta readily in placental perfusion. Furthermore, diuron was metabolized into DCPMU in perfused placenta and in in vitro incubations using microsomes from placentas of smokers. In incubations with placental microsomes from non-smokers, and in BeWo cells, metabolism to DCPMU was detected but only with the highest used diuron concentration (100 μM). Diuron metabolism was inhibited upon addition of α-naphthoflavone, a CYP1A1 inhibitor, underscoring the role of CYP1A1 in the metabolism. In conclusion, it is evident that diuron crosses human placenta and diuron can be metabolized in the placenta to a toxic metabolite via CYP1A1. This implicates in vivo fetal exposure to diuron if pregnant women are exposed to diuron, which may result in fetotoxicity., (Copyright © 2018. Published by Elsevier B.V.)

Objective: To investigate whether parental TBI increases the overall risk for psychiatric disorders and the risk for specific psychiatric diagnoses in the children affected by parental TBI., Methods: The 1987 Finnish Birth Cohort (n = 59 476) were followed up through national registers from birth to the end of 2008. The diagnoses of cohort members and their parents were obtained from the Care Register of Health Care, provided by the National Institute of Health and Welfare., Results: During the 21-year follow-up, the likelihood for psychiatric diagnoses being assessed in psychiatric care was significantly increased in males with any mental disorder (odds ratio (OR) = 1.43), substance-use-related disorders (OR = 1.71) and behavioural and emotional disorders (OR = 1.75), and in females with disorders of psychological development (OR = 1.85)., Conclusions: Children affected by parental TBI are at increased risk for psychiatric disorders: males for externalizing disorders and females for developmental disorders. Observed gender interactions in the association between parental TBI and the psychiatric disorders of children warrant further study.

The anticancer drug doxorubicin and its liposomal formulations are in clinical use, doxorubicin also during pregnancy. However, little is known about how doxorubicin and its liposomal formulations are taken up by placental cells and whether they can cross human placenta. We therefore investigated quantitative cellular uptake and toxicity of doxorubicin and its two liposomal formulations, pH-sensitive liposomal doxorubicin (L-DOX) and commercially available pegylated liposomal doxorubicin (PL-DOX), in human placental choriocarcinoma (BeWo) cells. PL-DOX showed significantly lower cellular uptake and toxicity compared with doxorubicin and L-DOX. In preliminary studies with human placental perfusion, PL-DOX did not cross the placenta at all in 4h, whereas doxorubicin and L-DOX crossed the placenta at low levels (max 12% of the dose). Furthermore, PL-DOX did not accumulate in placental tissue while doxorubicin did (up to 70% of the dose). Surface pegylation probably explains the low placental cell and tissue uptake of PL-DOX. Formulation of doxorubicin thus seems to enable a decrease of fetal exposure., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Warfarin-associated intracerebral haemorrhage carries poor outcome due to rapid haemorrhage growth. Reversal of warfarin anticoagulation with prothrombin complex concentrate has been implemented as an acute treatment option for these subjects., Aim: We investigated whether survival of subjects with warfarin-associated intracerebral haemorrhage had improved after implementation of reversal of warfarin anticoagulation with prothrombin complex concentrate., Methods: We identified all subjects with warfarin-associated intracerebral haemorrhage during 1993-2008 among the population of Northern Ostrobothnia, Finland. From 2004 onwards, prothrombin complex concentrate was used in Oulu University Hospital, the only hospital treating intracerebral haemorrhage subjects in the region, to counteract the effect of warfarin in subjects with warfarin-associated intracerebral haemorrhage. We compared the outcomes of subjects admitted during 1993-2003 and 2004-2008 and those treated and not treated with prothrombin complex concentrate. We also explored the predictors for one-year survival of the warfarin-associated intracerebral haemorrhage subjects., Results: We identified altogether 181 subjects who had intracerebral haemorrhage while on warfarin. One-year survival was significantly (P = 0·031) higher for the 60 subjects admitted during 2004-2008 (43·3%) than for the 121 admitted before 2004 (30·6%). In multivariable analysis, prothrombin complex concentrate treatment reduced one-year case fatality (hazard ratio 0·52, 95% confidence interval 0·29-0·93). Thromboembolic complications did not occur more frequently among those treated with prothrombin complex concentrate., Conclusion: The survival of warfarin-associated intracerebral haemorrhage subjects among the population of Northern Ostrobothnia has improved likely because of introduction of prothrombin complex concentrate., (© 2012 The Authors. International Journal of Stroke © 2012 World Stroke Organization.)

Objective: Traumatic brain injury (TBI) of a parent causes significant changes in their family life and parent-children relationships. However, the number of children affected by parental TBI and the long-term consequences for these children remain unknown. We estimated the prevalence of children affected by parental TBI and investigated whether these children had greater use of psychiatric services than their peers., Methods: This a retrospective population-based register study. All 60,069 children born in Finland in 1987 were followed up through national health and social registers from 1987 to 2008., Results: During the 21-year follow-up, 1532 (2.6%) children had a parent with TBI. Overall, 22.5% of those having a parent with TBI were treated in specialized psychiatric care. Use of psychiatric care was significantly increased among those cohort members with a parent with mild [odds ratio (OR) 1.80, 95% confidence interval (CI) 1.37-2.38] or severe (OR 1.49, 95% CI 1.12-1.98) TBI compared to their peers., Conclusions: Parental TBI is associated with increased use of specialized psychiatric services by children. Adult health care services must have appropriate systems in place to address the psychosocial needs and support the welfare and development of children of patients with TBI., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The strong organoborane Lewis acid B(C6F5)3 catalyzes the polymerization of phenylsilane at elevated temperatures forming benzene and SiH4 as side-products. The resulting polymer is a branched polysilane with an irregular substitution pattern, as revealed by 2D NMR spectroscopy. Having explored the mechanism of this novel metal-free polymerization by computational chemistry methods at the DFT level, we have suggested that unusual cationic active species, namely monomer-stabilized silyl cations, propagate the polymerization. Hydride abstraction of SiH3 moiety by the catalyst in the initiation step was found to be kinetically preferred by around 9 kcal mol(-1) over activation by coordination of the monomer at the aromatic ring. The formation of linear Si-Si bonds during propagation was calculated to be less favorable than branching and ligand scrambling, which accounts for the branched and highly substituted form of the polymer that was obtained. This novel type of polymerization bears the potential for further optimization with respect to degree of polymerization and structure control for both primary as well as secondary silanes, which can be polymerized by sterically less hindered boranes., (Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Traumatic brain injuries (TBI) in subjects with craniofacial fractures are usually diagnosed by emergency room physicians. We investigated how often TBI remains unrecorded in these subjects, and whether diagnostic accuracy has improved after the implementation of new TBI guidelines., Methods: All subjects with craniofacial fractures admitted to Oulu University Hospital in 1999 and in 2007 were retrospectively identified. New guidelines for improving the diagnostic accuracy of TBI were implemented between 2000 and 2006. Clinical symptoms of TBI were gathered from notes on hospital charts and compared to the recorded diagnoses at discharge. Logistic regression was used to identify independent predictors for TBI to remain unrecorded., Results: Of 194 subjects with craniofacial fracture, 111(57%) had TBI, 40 in 1999 and 71 in 2007. Fifty-one TBIs (46%) remained unrecorded at discharge, 48 being mild and 3 moderate-to-severe. Subjects with unrecorded TBI were significantly less frequently referred to follow-up visits. Failures to record the TBI diagnosis were less frequent (29/71, 41%) in 2007 than in 1999 (22/40, 55%), but the difference was not statistically significant. The most significant independent predictor for this failure was the clinical specialty (other than neurology/neurosurgery) of the examining physician (p<0.001). The subject's alcohol intoxication did not hamper the diagnosis of TBI., Conclusions: TBIs remain frequently unrecorded in subjects with craniofacial fractures. Recording of mild TBI slightly but insignificantly improved after the implementation of new guidelines., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Obstructive sleep apnoea (OSA) carries an increased risk of ischaemic stroke, but the underlying mechanism is not clear. As right-to-left shunting can occur through a patent foramen ovale (PFO) during periods of apnoea, we investigated nocturnal changes in fibrinolytic activity and platelet function in subjects who had OSA with or without PFO and in controls. We determined plasminogen activator inhibitor 1 (PAI-1) activity and antigen and platelet activation parameters. The severity of OSA was verified by polygraphy and PFO was detected by ear oximetry. We found a higher PAI-1 activity and antigen and a lower ratio of 2,3-dinor-PGF(1α) to 2,3-dinor-TXB(2) in the subjects with OSA than in the controls. Linear regression analysis showed the apnoea-hypopnoea index (β-coefficient, 0.499; P = 0.032) and PFO (β-coefficient, 0.594; P = 0.015) to be associated independently with PAI-1 activity in the morning, while the increment in PAI-1:Ag from evening to morning was significantly associated with the presence of PFO (r(s) = 0.563, P = 0.002). Both OSA and PFO reduce fibrinolytic activity during nocturnal sleep. We hypothesize that subjects having both OSA and PFO may develop a more severe prothrombotic state during sleep than those having either OSA or PFO alone.

Many mothers use, against instructions, alcohol during pregnancy. Simultaneously mothers are exposed to a wide range of other environmental chemicals. These chemicals may also harm the developing fetus, because almost all toxic compounds can go through human placenta. Toxicokinetic effects of ethanol on the transfer of other environmental compounds through human placenta have not been studied before. It is known that ethanol has lytic properties and increases the permeability and fluidity of cell membranes. We studied the effects of ethanol on the transfer of three different environmental toxins: nicotine, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and NDMA (N-nitrosodimethylamine) in placental perfusion. We tested in human breast cancer adenocarcinoma cell line MCF-7 whether ethanol affects ABCG2/BCRP, which is also the major transporter in human placenta. We found that the transfer of ethanol is comparable to that of antipyrine, which points to passive diffusion as the transfer mechanism. Unexpectedly, ethanol had no statistically significant effect on the transfer of the other studied compounds. Neither did ethanol inhibit the function of ABCG2/BCRP. These experiments represent only the effects of acute exposure to ethanol and chronic exposure remains to be studied., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Benzo(a)pyrene (BP) is the best studied polycyclic aromatic hydrocarbon, classified as carcinogenic to humans. The carcinogenic metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), binds covalently to DNA. The key enzyme in this metabolic reaction is CYP1A1, which has also been found in placenta and human trophoblastic cells. By using human placental perfusion we confirmed that BP added to the maternal circulation in concentrations of 0.1 and 1 microM reaches fetal compartment but somewhat slower than the freely diffusible reference substance antipyrine. A well-known P-glycoprotein (ABCB1/P-gp) antagonist verapamil did not affect the transfer more than it did in the case of antipyrine, indicating that ABCB1/P-gp does not have a role in BP transfer. In one of the two placentas perfused for 6 h with the higher concentration of BP (1 microM) BPDE specific DNA adducts were found in placental tissue after the perfusion, but not before. The ability of human trophoblastic cells to activate BP to BPDE-DNA adducts was confirmed in human trophoblastic BeWo cells. This study shows that maternal exposure to BP leads to the exposure of the fetus to BP and/or its metabolites and that placenta itself can activate BP to DNA adducts., (Copyright 2010 Elsevier Ireland Ltd. All rights reserved.)

As a part of EU-project ReProTect, a comparison of the dual re-circulating human placental perfusion system was carried out, by two independent research groups. The detailed placental transfer data of model compounds [antipyrine, benzo(a)pyrene, PhIP (2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine) and IQ (2-amino-3-methylimidazo(4,5-f)quinoline] has been/will be published separately. For this project, a comparative re-analysis was done, by curve fitting the data and calculating two endpoints: AUC(120), defined as the area under the curve between time 0 and time 120 min and as t(0.5), defined as the time when the fetal to maternal concentration ratio is expected to be 0.5. The transport of the compounds from maternal to fetal circulation across the perfused placenta could be ranked in the order of antipyrine>IQ>PhIP in terms of both t(0.5) and AUC(120) by both partners. For benzo(a)pyrene the curve fitting failed. These prevalidation results give confidence for harmonization of the placental perfusion system to be used as one of the test methods in a panel for reproductive toxicology to model placental transfer in humans., (Copyright 2010 Elsevier Inc. All rights reserved.)

Microhemorrhages in the brain refer to minor chronic hemorrhages that are revealed by specific magnetic imaging techniques. Whereas microhemorrhages in the brain are a common finding in patients with a disorder of the cerebral circulation, they are surprisingly often found also in elderly persons who are considered healthy. Microhemorrhages can be regarded as a biomarker of cerebral microangiopathy. They may also offer additional diagnostic information, provide clues for the prognosis of brain diseases, and influence clinical decisions. The patient's medical history, the location, number and distribution of imaging findings have a central role in the assessment of clinical significance.

The role of paradoxical embolism through patent foramen ovale as a mechanism of cryptogenic stroke is controversial. If a venous source of emboli is relevant, prothrombotic states should be associated with patent foramen ovale and cryptogenic stroke. We assessed the occurrence of several prothrombotic states (factor V Leiden, prothrombin G20210A, deficiencies in protein S, protein C and antithrombin, lupus anticoagulant, anticardiolipin antibodies, elevated factor VIII, resistance to activated protein C) and classical risk factors for venous thrombosis in 57 adult patients with cryptogenic stroke and patent foramen ovale and in 104 matched controls. Prothrombotic states [odds ratio (OR) 2.8; 95% confidence interval (CI), 1.2-6.5; P = 0.021], migraine with aura (OR 4.4; 95% CI 1.8-10.8; P = 0.001) and classical risk factors for venous thrombosis (OR 2.5; 95% CI 1.1-5.7; P = 0.037) were independent risk factors for cryptogenic stroke. In particular factor V Leiden or prothrombin G20210A associated with cryptogenic stroke (P = 0.022) whereas other coagulation abnormalities did not (P = 0.140). Among the patients with prothrombotic states, Valsalva manoeuvre was common at onset of stroke. Our results support the possibility of paradoxical embolism behind strokes in patients with patent foramen ovale.

Epidemiological investigations have shown a linear positive correlation between the risk of haemorrhagic stroke and level of alcohol consumption. Ischaemic stroke shows a weaker relationship, which is J-shaped, suggesting that regular light-to-moderate alcohol consumption may carry a decreased risk. Case reports and case-control studies indicate that heavy recent drinking, but not heavy former drinking, increases the risk for both types of stroke. Larger amounts of alcohol are needed to trigger aneurysmal subarachnoid haemorrhage than spontaneous intracerebral haemorrhage. The increased risk caused by recent heavy drinking may be partly due to elevated systolic blood pressure, but alcohol may also provoke cerebral arterial vasospasm, as observed in animal experiments. Alcohol-induced fluctuation in haemostatic and fibrinolytic factors has not been proved to precipitate alcohol-related strokes, but may contribute to both an increase and a decrease of the risk. Subtypes of ischaemic stroke associate differently with alcohol consumption. A recent series of patients with ischaemic brain infarction showed that of the victims having a high and medium risk for cardiogenic embolism, 50% and 45% were intoxicated, respectively. This suggests that cardiogenic embolism is a significant mechanism leading to ischaemic stroke during heavy drinking of alcohol.