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Internet-delivered cognitive-behavioral treatment is effective for insomnia. However, little is known about the beneficial effects of support. Recently we demonstrated that motivational support moderately improved the effects of Internet-delivered treatment for insomnia. In the present study, we tested whether depressive symptoms at baseline moderate the effect of support on Internet-delivered treatment for insomnia. We performed a multilevel intention-to-treat analysis on 262 participants in a randomized controlled trial. We found that baseline depressive symptoms moderated the effect of support on sleep efficiency, total sleep time, and sleep onset latency (but not on wake after sleep onset, number of nightly awakenings, or the Insomnia Severity Index). This means that for these variables, people with high levels of depressive symptoms benefit from support, whereas people with low levels of depressive symptoms improve regardless of support. The data show that baseline depression severity plays an important role in the way Internet treatments need to be delivered. These findings open up opportunities to personalize the support offered in Internet-delivered treatments. © 2014

Health effects of the Chernobyl disaster: illness or illness behavior? A comparative general health survey in two former Soviet regions.

Results are described of a general health survey (n = 3044) that was conducted 6.5 years after the Chernobyl accident in 1986 in a seriously contaminated region in Belarus and a socioeconomically comparable, but unaffected, region in the Russian Federation. The purpose of the study was to investigate whether there are differences in the general health status of the inhabitants of the two regions that may be attributed to the Chernobyl disaster. A broad-based population sample from each of these regions was studied using a variety of self-report questionnaires. A subsample (n = 449) was further examined with a standardized physical and psychiatric examination. The results show significantly higher scores on the self-report questionnaires and higher medical service utilization in the exposed region. No significant differences were observed in global clinical indices of health. Although there were trends for some disorders to be more prevalent in the exposed region, none of these could be directly attributed to exposure to ionizing radiation. The results of this study suggest that the Chernobyl disaster had a significant long-term impact on psychological well-being, health-related quality of life, and illness behavior in the exposed population

Delayed Lithium Reintoxication in a Case of Severe Multidrug Intoxication:A Case Study

The authors present a case of severe multidrug intoxication following massive ingestion of lithium, nortriptyline, aripiprazole, lorazepam, and temazepam. After initial treatment, serum lithium levels decreased significantly. However, 28 hours post ingestion, recurrent elevated lithium levels were observed, and serum lithium level increased 0.71 mmol/L in 12 hours. The intensivist consulted a hospital pharmacist about this. After administering clearance-inducing therapy using continuous venovenous hemodialysis, the lithium level was reduced to a long-lasting nontoxic level. The occurrence of secondary elevation in lithium levels exceeding the toxic limit in cases of massive ingestion of lithium tablets, whether in combination with anticholinergic drugs, should be anticipated. Close monitoring and prompt initiation of clearance-inducing therapy can improve clinical outcomes.</p

Особливості скульптури поверхні зерен мінералів у паласитах

Наведено результати растрових електронно-мікроскопічних досліджень скульптури поверхні зерен мінералів із паласитів. Показано, що тонкі скульптурні особливості на поверхні зерен є чутливим індикатором фізико-хімічних умов утворення та еволюції паласитів у космосі й на Землі.The results of the scanning electron microscopic study of surface sculpture of mineral grains from pallasites are given. It is shown that the fine sculpture features belong to a sensitive indicator of physico-chemical conditions of pallasites formation and evolution in space and on the Earth

Cost-utility of a visiting service for older widowed individuals: Randomised trial

Background. Despite a growing understanding of the effectiveness of bereavement interventions and the groups that benefit most from them, we know little about the cost-effectiveness of bereavement interventions. Methods. We conducted a cost-utility analysis alongside a randomized clinical trial on a visiting service for older widowed individuals (n = 110) versus care as usual (CAU; n = 106). The visiting service is a selective bereavement intervention that offers social support to lonely widows and widowers by a trained volunteer. Participants were contacted 6-9 months post-loss. Eleven percent of all contacted persons responded and eight percent participated in the trial. The primary outcome measure was quality adjusted life years (QALYs) gained (assessed with the EQ-5D), which is a generic measure of health status. Costs were calculated from a societal perspective excluding costs arising from productivity losses. Using the bootstrap method, we obtained the incremental cost utility ratio (ICUR), projected these on a cost-utility plane and presented as an acceptability curve. Results. Overall, the experimental group demonstrated slightly better results against slightly higher costs. Whether the visiting service is acceptable depends on the willingness to pay: at a willingness to pay equal to zero per QALY gained, the visiting service has a probability of 31% of being acceptable; beyond €20,000, the visiting service has a probability of 70% of being more acceptable than CAU. Conclusion. Selective bereavement interventions like the visiting service will not produce large benefits from the health economic point of view, when targeted towards the entire population of all widowed individuals. We recommend that in depth analyses are conducted to identify who benefits most from this kind of interventions, and in what subgroups the incremental cost-utility is best. In the future bereavement interventions are then best directed to these groups. Trial registration. Controlled trials ISRCTN17508307. © 2008 Onrust et al; licensee BioMed Central Ltd

Titin circular RNAs create a back-splice motif essential for SRSF10 splicing

Background: Titin (TTN), the largest protein in humans, forms the molecular spring that spans half of the sarcomere to provide passive elasticity to the cardiomyocyte. Mutations that disrupt the TTN transcript are the most frequent cause of hereditary heart failure. We showed before that TTN produces a class of circular RNAs (circRNAs) that depend on RBM20 to be formed. In this study we show that the backsplice junction formed by this class of circRNAs creates a unique motif, which binds SRSF10 to enable it to regulate splicing. Furthermore, we show that one of these circRNAs (cTTN1) distorts both localization of and splicing by RBM20. Methods: We calculated genetic constraint of the identified motif in 125.748 exomes collected from the gnomAD database. Furthermore, we focused on the highest expressed RBM20-dependent circRNA in the human heart, which we named cTTN1. We used shRNAs directed to the backsplice junction to induce selective loss of cTTN1 in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM). Results: Human genetics suggests reduced genetic tolerance of the generated motif, indicating that mutations in this motif might lead to disease. RNA immunoprecipitation confirmed binding of circRNAs with this motif to SRSF10. Selective loss of cTTN1 in hiPSC-CM induced structural abnormalities, apoptosis and reduced contractile force in engineered heart tissue. In line with its SRSF10 binding, loss of cTTN1 caused abnormal splicing of important cardiomyocyte SRSF10 targets like MEF2A and CASQ2. Strikingly, loss of cTTN1 also caused abnormal splicing of TTN itself. Mechanistically, we show that loss of cTTN1 distorts both localization of and splicing by RBM20. Conclusions: We demonstrate that circRNAs formed from the TTN transcript are essential for normal splicing of key muscle genes by enabling splice regulators RBM20 and SRSF10. This shows that the TTN transcript also has regulatory roles, besides its well-known signaling and structural function. In addition, we demonstrate that the specific sequence created by the backsplice junction of these circRNAs has important functions. This highlights the existence of functionally important sequences that cannot be recognized as such in the human genome, but provides a yet unrecognized source for functional sequence variation

Novel in silico-designed estradiol analogues are cytotoxic to a multidrug-resistant cell line at nanomolar concentrations

PURPOSE : 2-Methoxyestradiol (2ME) is a promising anticancer agent that disrupts the integrity and dynamics of the spindle network. In order to overcome the pharmacokinetic constraints of this compound, a panel of sulphamoylated estradiol analogues were in silico-designed by our laboratory. In this study, we analysed the potential of each analogue to induce cell death on a panel of cancer cell lines. Moreover, the mechanism of action of the most effective compounds was determined. METHODS : Cytotoxicity screening of the compounds and intermediates was performed on five different cancer cell lines to determine IG50 values. An in vitro tubulin polymerization assay was done to determine the effect of the drugs on tubulin polymerization while their intracellular effects on the microtubule network were assessed by immunofluorescence microscopy. RESULTS : IG50 calculations showed that the sulphamoylated analogues induce cytotoxicity at nanomolar concentrations in all cell lines, including the P-glycoprotein pump overexpressing multidrug-resistant uterine sarcoma cell line. The non-sulphamoylated compounds were only cytotoxic at micromolar ranges, if at all. The sulphamoylated compounds inhibited pure tubulin polymerization in a dose-dependent manner and induced microtubule destruction in cells after 24-h exposure. CONCLUSION : Results revealed that the novel sulphamoylated 2ME derivatives have potential as anti-cancer drugs, possibly even against chemoresistant cancer cells. These compounds disrupt the intracellular microtubule integrity which leads to mitotic block of the cells.The Research Development Programme of the University of Pretoria (RDP AOV840), the South African Medical Association (SAMA), the National Research Foundation (NRF Project # 86475, N00465, N00375, N00591), the Research Committee of the Faculty of Health Sciences, University of Pretoria (RESCOM), CANSA (AOV741, AOW228) and the Medical Research Council (MRC AOW110).http://link.springer.com/journal/2802016-02-28hb201

BRCA1/2 mutation testing in breast cancer patients: a prospective study of the long-term psychological impact of approach during adjuvant radiotherapy

This study assessed psychological distress during the first year after diagnosis in breast cancer patients approached for genetic counseling at the start of adjuvant radiotherapy and identified those vulnerable to long-term high distress. Of the approached patients some chose to receive a DNA test result (n = 58), some were approached but did not fulfill criteria for referral (n = 118) and some declined counseling and/or testing (n = 44). The comparative group consisted of patients not eligible for genetic counseling (n = 182) and was therefore not approached. Patients actively approached for genetic counseling showed no more long-term distress than patients not eligible for such counseling. There were no differences between the subgroups of approached patients. Predictors for long-term high distress or an increase in distress over time were pre-existing high distress and a low quality of life, having children, and having no family members with breast cancer. It is concluded that breast cancer patients can be systematically screened and approached for genetic counseling during adjuvant radiotherapy without imposing extra psychological burden. Patients vulnerable to long-term high distress already displayed high distress shortly after diagnosis with no influence of their medical treatment on their level of distress at long-term

High transcript levels of vitamin D receptor are correlated with higher mRNA expression of human beta defensins and IL-10 in mucosa of HIV-1-exposed seronegative individuals

RESUMEN: La vitamina D (VitD) es un inmunomodulador endógena que podría proteger de la infección por VIH-1 la reducción de la activación inmune y la inducción de la expresión de VIH-1 anti-péptidos. Para establecer una correlación entre VitD y resistencia natural a la infección VIH-1, un estudio de casos y controles utilizando sangre y mucosa muestras de 58 VIH-1 expuesto, pero seronegativos (HESN) individuos , 43 VIH-1 seropositivos (SP) y 59 no controles sanos -exposed (HCS) se llevó a cabo. La concentración VitD en el plasma se determinó por ELISA, y de ARNm de unidades relativas (RU) de VDR, IL-10 , TGF-β, TNF-α e IL-1β en las células mononucleares de sangre periférica (PBMCs), oral y genital mucosa se cuantificó por QRT-PCR. mRNA niveles de humana beta -defensin (HBD) -2 y -3 se informó anteriormente y utilizados para correlaciones. Significativamente más altos niveles de VitD se encontraron en plasma, así como mayor mRNA RU de VDR en PBMCs, y en genital mucosa de HESN en comparación con HC. Además, superior mRNA RU de TNF-α, IL-1β y IL-10 , e inferior mRNA RU de TGF-β se encontraron en PBMC de HESNs en comparación con HC. También se observó mayor IL-10 mRNA RU en genital mucosa de HESNs en comparación con HC, y los ARNm de los niveles de TNF-α en oral y genital mucosa de SPs estábamos más alta en comparación con HESNs. Por otra parte, las correlaciones positivas entre VDR y la IL-10 mRNA RU en PBMCs y genital mucosa encontrados de HESNs. Por último, HBD-2 y HBD-3 ARNm RU fueron positivamente correlacionadas con VDR mRNA expresión en forma oral mucosa de HESNs. Estos resultados sugieren que los altos niveles de VitD y su receptor están asociadas con resistencia natural a la infección por VIH-1. Sobre regulación de los anti-inflamatoria IL-10 , y la inducción de anti-VIH-1 defensinas en la mucosa podría ser parte de los mecanismos implicados en esta asociación. Sin embargo, se necesitan más estudios para definir las asociaciones causales.ABSTRACT: Vitamin D (VitD) is an endogenous immunomodulator that could protect from HIV-1 infection reducing immune activation and inducing the expression of anti-HIV-1 peptides. To establish a correlation between VitD and natural resistance to HIV-1 infection, a case-control study using blood and mucosa samples of 58 HIV-1-exposed but seronegative (HESN) individuals, 43 HIV-1 seropositives (SPs) and 59 non-exposed healthy controls (HCs) was carried out. The VitD concentration in plasma was determined by ELISA, and mRNA relative units (RU) of VDR, IL-10, TGF-β, TNF-α and IL-1β in peripheral blood mononuclear cells (PBMCs), oral and genital mucosa was quantified by qRT-PCR. mRNA levels of human beta-defensin (HBD) -2 and -3 were previously reported and used for correlations. Significantly higher levels of VitD were found in plasma as well as higher mRNA RU of VDR in PBMCs, and in genital mucosa from HESN compared to HCs. In addition, higher mRNA RU of TNF-α, IL-1β and IL-10, and lower mRNA RU of TGF-β were found in PBMC from HESNs compared to HCs. We also observed higher IL-10 mRNA RU in genital mucosa of HESNs compared to HCs, and the mRNA levels of TNF-α in oral and genital mucosa of SPs were higher compared to HESNs. Furthermore, positive correlations between VDR and IL-10 mRNA RU in PBMCs and genital mucosa of HESNs were found. Finally, HBD-2 and HBD-3 mRNA RU were positively correlated with VDR mRNA expression in oral mucosa from HESNs. These results suggest that high levels of VitD and its receptor are associated with natural resistance to HIV-1 infection. Up-regulation of the anti-inflammatory IL-10, and the induction of anti-HIV-1 defensins in mucosa might be part of the mechanisms involved in this association. However, further studies are required to define causal associations