Lipoxygenases and Poly(ADP-Ribose) Polymerase in Amyloid Beta Cytotoxicity

The 12/15-lipoxygenase(s) (LOX), poly(ADP-ribose) polymerase (PARP-1) activity and mitochondrial apoptosis inducing factor (AIF) protein in the amyloid β (Aβ) toxicity were investigated in PC12 cells that express either wild-type (APPwt) or double Swedish mutation (APPsw) forms of human Aβ precursor protein. Different levels of Aβ secretion and free radicals formation characterize these cells. The results demonstrated a relationship between the Aβ levels and LOX protein expression and activity. High Aβ concentration in APPsw cells correlated with a significant increase in free radicals and LOX activation, which leads to translocation of p65/NF-κB into the nucleus. An increase in AIF expression in mitochondria was observed concurrently with inhibition of PARP-1 activity in the nuclear fraction of APPsw cells. We suggested that AIF accumulation in mitochondria may be involved in adaptive/protective processes. However, inhibition of PARP-1 may be responsible for the disturbances in transcription and DNA repair as well as the degeneration of APP cells. Under conditions of increased nitrosative stress, evoked by the nitric oxide donor, sodium nitroprusside (SNP, 0.5 mM), 70–80% of all cells types died after 24 h, significantly more in APPsw cells. There was no further significant change in mitochondrial AIF level and PARP-1 activity compared to corresponding non-treated cells. Only one exception was observed in PC12 control, where SNP significantly inhibits PARP-1 activity. Moreover, SNP significantly activated gene expression for 12/15-LOX in all types of investigated cells. Inhibitors of all LOX isoforms and specific inhibitor of 12-LOX enhanced the survival of cells that were subjected to SNP. We conclude that the LOX pathways may play a role in Aβ toxicity and in nitrosative-stress-induced cell death and that inhibition of these pathways offers novel protective strategies

Конференции

STUDY QUESTION: What is the cost-effectiveness of in vitro fertilization(IVF) with conventional ovarian stimulation, single embryotransfer (SET) and subsequent cryocycles or IVF in a modified natural cycle (MNC) compared with intrauterine insemination with controlled ovarian hyperstimulation (IUI-COH) as a first-line treatment in couples with unexplained subfertility and an unfavourable prognosis on natural conception?. SUMMARY ANSWER: Both IVF strategies are significantly more expensive when compared with IUI-COH, without being significantly more effective. In the comparison between IVF-MNC and IUI-COH, the latter is the dominant strategy. Whether IVF-SET is cost-effective depends on society's willingness to pay for an additional healthy child. WHAT IS KNOWN ALREADY: IUI-COH and IVF, either after conventional ovarian stimulation or in a MNC, are used as first-line treatments for couples with unexplained or mild male subfertility. As IUI-COH is less invasive, this treatment is usually offered before proceeding to IVF. Yet, as conventional IVF with SET may lead to higher pregnancy rates in fewer cycles for a lower multiple pregnancy rate, some have argued to start with IVF instead of IUI-COH. In addition, IVF in the MNC is considered to be a more patient friendly and less costly form of IVF. STUDY DESIGN, SIZE, DURATION: We performed a cost-effectiveness analysis alongside a randomized noninferiority trial. Between January 2009 and February 2012, 602 couples with unexplained infertility and a poor prognosis on natural conception were allocated to three cycles of IVF-SET including frozen embryo transfers, six cycles of IVF-MNC or six cycles of IUI-COH. These couples were followed until 12 months after randomization. PARTICIPANTS/MATERIALS, SETTING, METHODS: We collected data on resource use related to treatment, medication and pregnancy from the case report forms. We calculated unit costs from various sources. For each of the three strategies, we calculated the mean costs and effectiveness. Incremental cost-effectiveness ratios (ICER) were calculated for IVF-SET compared with IUI-COH and for IVF-MNC compared with IUI-COH. Nonparametric bootstrap resampling was used to investigate the effect of uncertainty in our estimates. MAIN RESULTS AND THE ROLE OF CHANCE: There were 104 healthy children (52%) born in the IVF-SET group, 83 (43%) the IVF-MNC group and 97 (47%) in the IUI-COH group. The mean costs per couple were (sic)7187 for IVF-SET, (sic)8206 for IVF-MNC and (sic)5070 for IUI-COH. Compared with IUI-COH, the costs for IVF-SET and IVF-MNC were significantly higher (mean differences (sic)2117; 95% CI: (sic)1544-(sic)2657 and (sic)3136, 95% CI: (sic)2519-(sic)3754, respectively). The ICER for IVF-SET compared with IUI-COH was (sic)43 375 for the birth of an additional healthy child. In the comparison of IVF-MNC to IUI-COH, the latter was the dominant strategy, i.e. more effective at lower costs. LIMITATIONS, REASONS FOR CAUTION: We only report on direct health care costs. The present analysis is limited to 12 months. WIDER IMPLICATIONS OF THE FINDINGS: Since we found no evidence in support of offering IVF as a first-line strategy in couples with unexplained and mild subfertility, IUI-COH should remain the treatment of first choice

A Tale of Switched Functions: From Cyclooxygenase Inhibition to M-Channel Modulation in New Diphenylamine Derivatives

Cyclooxygenase (COX) enzymes are molecular targets of nonsteroidal anti-inflammatory drugs (NSAIDs), the most used medication worldwide. However, the COX enzymes are not the sole molecular targets of NSAIDs. Recently, we showed that two NSAIDs, diclofenac and meclofenamate, also act as openers of Kv7.2/3 K+ channels underlying the neuronal M-current. Here we designed new derivatives of diphenylamine carboxylate to dissociate the M-channel opener property from COX inhibition. The carboxylate moiety was derivatized into amides or esters and linked to various alkyl and ether chains. Powerful M-channel openers were generated, provided that the diphenylamine moiety and a terminal hydroxyl group are preserved. In transfected CHO cells, they activated recombinant Kv7.2/3 K+ channels, causing a hyperpolarizing shift of current activation as measured by whole-cell patch-clamp recording. In sensory dorsal root ganglion and hippocampal neurons, the openers hyperpolarized the membrane potential and robustly depressed evoked spike discharges. They also decreased hippocampal glutamate and GABA release by reducing the frequency of spontaneous excitatory and inhibitory post-synaptic currents. In vivo, the openers exhibited anti-convulsant activity, as measured in mice by the maximal electroshock seizure model. Conversion of the carboxylate function into amide abolished COX inhibition but preserved M-channel modulation. Remarkably, the very same template let us generating potent M-channel blockers. Our results reveal a new and crucial determinant of NSAID-mediated COX inhibition. They also provide a structural framework for designing novel M-channel modulators, including openers and blockers

A review of estimating population exposure to sea-level rise and the relevance for migration

This review analyses global or near-global estimates of population exposure to sea-level rise (SLR) and related hazards, followed by critically examining subsequent estimates of population migration due to this exposure. Our review identified 33 publications that provide global or near-global estimates of population exposure to SLR and associated hazards. They fall into three main categories of exposure, based on definitions in the publications: (i) the population impacted by specified levels of SLR; (ii) the number of people living in floodplains that are subject to coastal flood events with a specific return period; and (iii) the population living in low-elevation coastal zones. Twenty of these 33 publications discuss connections between population migration and SLR. In our analysis of the exposure and migration data, we consider datasets, analytical methods, and the challenges of estimating exposure to SLR followed by potential human migration. We underscore the complex connections among SLR, exposure to its impacts, and migration. Human mobility to and from coastal areas is shaped by diverse socioeconomic, demographic, institutional, and political factors; there may be 'trapped' populations as well as those who prefer not to move for social, cultural, and political reasons; and migration can be delayed or forestalled through other adaptive measures. While global estimates of exposed and potentially migrating populations highlight the significant threats of SLR for populations living in low-lying areas at or near coastlines, further research is needed to understand the interactions among localised SLR and related hazards, social and political contexts, adaptation possibilities, and potential migration and (im)mobility decision-making

Mindaugas e Radvilas

Desde 1920, quando enviou uma delegação pela primeira vez aos Jogos Olímpicos, o Brasil já foi representado por 2.111 atletas. Parte deles nasceu fora do país e é brasileira nata, por questões de ancestralidade familiar, ou naturalizada. Este texto discorre sobre Radvilas Gorauskas, que nasceu na Lituânia, imigrou para o Brasil no fim da década de 1940 e atuou como pivô pela seleção brasileira de basquete nos Jogos Olímpicos de Munique, em 1972. Refere-se ainda a Mindaugas, irmão de Radvilas, também nascido na Lituânia e atleta da seleção brasileira de basquete, por meio de quem a história do membro olímpico da família pode ser resgatada. O objetivo desse artigo é recuperar a memória da carreira esportiva de Radvilas, contextualizando todo o processo de deslocamento e a imigração desencadeada pela Segunda Guerra Mundial da família Gorauskas. O método utilizado baseia-se nas narrativas biográficas, e a entrevista com Mindaugas é a principal referência para a realização do trabalho, além de objetos biográficos trazidos pelo entrevistado. Conclui-se que a recuperação de um universo informativo é possível quando um narrador ainda vivo compartilha suas memórias. A entrevista com Mindaugas revelou dados pouco ou nada conhecidos não apenas sobre o processo migratório da família Gorauskas para o Brasil, como também do basquetebol das décadas de 1960 e 1970

Pooling job physical exposure data from multiple independent studies in a consortium study of carpal tunnel syndrome

Pooling data from different epidemiological studies of musculoskeletal disorders (MSDs) is necessary to improve statistical power and to more precisely quantify exposure–response relationships for MSDs. The pooling process is difficult and time-consuming, and small methodological differences could lead to different exposure–response relationships. A subcommittee of a six-study research consortium studying carpal tunnel syndrome: (i) visited each study site, (ii) documented methods used to collect physical exposure data and (iii) determined compatibility of exposure variables across studies. Certain measures of force, frequency of exertion and duty cycle were collected by all studies and were largely compatible. A portion of studies had detailed data to investigate simultaneous combinations of force, frequency and duration of exertions. Limited compatibility was found for hand/wrist posture. Only two studies could calculate compatible Strain Index scores, but Threshold Limit Value for Hand Activity Level could be determined for all studies. Challenges of pooling data, resources required and recommendations for future researchers are discussed

Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation

The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted

The M-OVIN study: does switching treatment to FSH and / or IUI lead to higher pregnancy rates in a subset of women with world health organization type II anovulation not conceiving after six ovulatory cycles with clomiphene citrate - a randomised controlled trial

Background: Clomiphene citrate (CC) is first line treatment in women with World Health Organization (WHO) type II anovulation and polycystic ovary syndrome (PCOS). Whereas 60% to 85% of these women will ovulate on CC, only about one half will have conceived after six cycles. If women do not conceive, treatment can be continued with gonadotropins or intra-uterine insemination (IUI). At present, it is unclear for how many cycles ovulation induction with CC should be repeated, and when to switch to ovulation induction with gonadotropins and/or IUI. Methods/Design: We started a multicenter randomised controlled trial in the Netherlands comparing six cycles of CC plus intercourse or six cycles of gonadotrophins plus intercourse or six cycles of CC plus IUI or six cycles of gonadotrophins plus IUI. Women with WHO type II anovulation who ovulate but did not conceive after six ovulatory cycles of CC with a maximum of 150 mg daily for five days will be included. Our primary outcome is birth of a healthy child resulting from a pregnancy that was established in the first eight months after randomisation. Secondary outcomes are clinical pregnancy, miscarriage, multiple pregnancy and treatment costs. The analysis will be performed according to the intention to treat principle. Two comparisons will be made, one in which CC is compared to gonadotrophins and one in which the addition of IUI is compared to ovulation induction only. Assuming a live birth rate of 40% after CC, 55% after addition of IUI and 55% after ovulation induction with gonadotrophins, with an alpha of 5% and a power of 80%, we need to recruit 200 women per arm (800 women in total). An independent Data and Safety Monitoring Committee has criticized the data of the first 150 women and concluded that a sample size re-estimation should be performed after including 320 patients (i.e. 80 per arm). Discussion: The trial will provide evidence on the most effective, safest and most cost effective treatment in women with WHO type II anovulation who do not conceive after six ovulatory cycles with CC with a maximum of 150 mg daily for five days. This evidence could imply the need for changing our guidelines, which may cause a shift in large practice variation to evidence based primary treatment for these women.Marleen J Nahuis, Nienke S Weiss, Fulco van der Veen, Ben Willem J Mol, Peter G Hompes, Jur Oosterhuis, Nils B Lambalk, Jesper MJ Smeenk, Carolien AM Koks, Ron JT van Golde, Joop SE Laven, Ben J Cohlen, Kathrin Fleischer, Angelique J Goverde, Marie H Gerards, Nicole F Klijn, Lizka CM Nekrui, Ilse AJ van Rooij, Diederik A Hoozemans, and Madelon van Wely