Methylation of hMLH1 promoter correlates with the gene silencing with a region-specific manner in colorectal cancer

Microsatellite instability is present in over 80% of the hereditary non-polyposis colorectal carcinoma and about 15–20% of the sporadic cancer. Microsatellite instability is caused by the inactivation of the mismatch repair genes, such as primarily hMLH1, hMSH2. To study the mechanisms of the inactivation of mismatch repair genes in colorectal cancers, especially the region-specific methylation of hMLH1 promoter and its correlation with gene expression, we analysed microsatellite instability, expression and methylation of hMLH1 and loss of heterozygosity at hMLH1 locus in these samples. Microsatellite instability was present in 17 of 71 primary tumours of colorectal cancer, including 14 of 39 (36%) mucinous cancer and three of 32 (9%) non-mucinous cancer. Loss of hMLH1 and hMSH2 expression was detected in nine and three of 16 microsatellite instability tumours respectively. Methylation at CpG sites in a proximal region of hMLH1 promoter was detected in seven of nine tumours that showed no hMLH1 expression, while no methylation was present in normal mucosa and tumours which express hMLH1. However, methylation in the distal region was observed in all tissues including normal mucosa and hMLH1 expressing tumours. This observation indicates that methylation of hMLH1 promoter plays an important role in microsatellite instability with a region-specific manner in colorectal cancer. Loss of heterozygosity at hMLH1 locus was present in four of 17 cell lines and 16 of 54 tumours with normal hMLH1 status, while loss of heterozygosity was absent in all nine cell lines and nine tumours with abnormal hMLH1 status (mutation or loss of expression), showing loss of heterozygosity is not frequently involved in the inactivation of hMLH1 gene in sporadic colorectal cancer

Spontaneous and deliberate future thinking: A dual process account

© 2019 Springer Nature.This is the final published version of an article published in Psychological Research, licensed under a Creative Commons Attri-bution 4.0 International License. Available online at: https://doi.org/10.1007/s00426-019-01262-7.In this article, we address an apparent paradox in the literature on mental time travel and mind-wandering: How is it possible that future thinking is both constructive, yet often experienced as occurring spontaneously? We identify and describe two ‘routes’ whereby episodic future thoughts are brought to consciousness, with each of the ‘routes’ being associated with separable cognitive processes and functions. Voluntary future thinking relies on controlled, deliberate and slow cognitive processing. The other, termed involuntary or spontaneous future thinking, relies on automatic processes that allows ‘fully-fledged’ episodic future thoughts to freely come to mind, often triggered by internal or external cues. To unravel the paradox, we propose that the majority of spontaneous future thoughts are ‘pre-made’ (i.e., each spontaneous future thought is a re-iteration of a previously constructed future event), and therefore based on simple, well-understood, memory processes. We also propose that the pre-made hypothesis explains why spontaneous future thoughts occur rapidly, are similar to involuntary memories, and predominantly about upcoming tasks and goals. We also raise the possibility that spontaneous future thinking is the default mode of imagining the future. This dual process approach complements and extends standard theoretical approaches that emphasise constructive simulation, and outlines novel opportunities for researchers examining voluntary and spontaneous forms of future thinking.Peer reviewe

Acute camptocormia induced by olanzapine: a case report

<p>Abstract</p> <p>Introduction</p> <p>Camptocormia refers to an abnormal posture with flexion of the thoraco-lumbar spine which increases during walking and resolves in supine position. This symptom is an increasingly recognized feature of parkinsonian and dystonic disorders, but may also be caused by neuromuscular diseases. There is recent evidence that both central and peripheral mechanisms may be involved in the pathogenesis of camptocormia. We report a case of acute onset of camptocormia, a rare side effect induced by olanzapine, a second-generation atypical anti-psychotic drug with fewer extra-pyramidal side-effects, increasingly used as first line therapy for schizophrenia, delusional disorders and bipolar disorder.</p> <p>Case presentation</p> <p>A 73-year-old Caucasian woman with no history of neuromuscular disorder, treated for chronic delusional disorder for the last ten years, received two injections of long-acting haloperidol. She was then referred for fatigue. Physical examination showed a frank parkinsonism without other abnormalities. Routine laboratory tests showed normal results, notably concerning creatine kinase level. Fatigue was attributed to haloperidol which was substituted for olanzapine. Our patient left the hospital after five days without complaint. She was admitted again three days later with acute back pain. Examination showed camptocormia and tenderness in paraspinal muscles. Creatine kinase level was elevated (2986 UI/L). Magnetic resonance imaging showed necrosis and edema in paraspinal muscles. Olanzapine was discontinued. Pain resolved quickly and muscle enzymes were normalized within ten days. Risperidone was later introduced without significant side-effect. The camptocormic posture had disappeared when the patient was seen as an out-patient one year later.</p> <p>Conclusions</p> <p>Camptocormia is a heterogeneous syndrome of various causes. We believe that our case illustrates the need to search for paraspinal muscle damage, including drug-induced rhabdomyolysis, in patients presenting with acute-onset bent spine syndrome. Although rare, the occurrence of camptocormia induced by olanzapine must be considered.</p

Durability monitoring of long-lasting insecticidal (mosquito) nets (LLINs) in Madagascar: physical integrity and insecticidal activity

Abstract Background Long-lasting insecticidal mosquito nets (LLINs) are highly effective for malaria prevention. However, it is also clear that durability monitoring is essential to predict when, post-distribution, a net population, no longer meets minimum WHO standards and needs to be replaced. Following a national distribution campaign in 2013, we tracked two durability indicators, physical integrity and bio-efficacy at six and 12 months post-distribution. While the loss of net integrity during this period was in line with expectations for a one-year net life, bio-efficacy results suggested that nets were losing insecticidal effect faster than expected. The rate of bio-efficacy loss varied significantly between different net brands. Methods We tested 600 randomly selected LLINs, 200 from each of three net brands. Each brand came from different eco-epidemiological zones reflecting the original distribution scheme. Fabric integrity (size and number of holes) was quantified using the proportional hole index (pHI). A subsample of the nets, 134 new nets, 150 at six months and 124 at 12 months, were then tested for bio-efficacy using the World Health Organization (WHO) recommended method. Results Three net types, Netprotect®, Royalsentry® and Yorkool®, were followed. After six months, 54%, 39% and 45%, respectively, showed visible loss of integrity. The median pHI by type was estimated to be one, zero and one respectively. The percentage of damaged nets increased after 12 months such that 83.5%, 74% and 68.5%, had holes. The median pHI for each brand of nets was 47.5, 47 and 23. No significant difference in the estimated pHI at either six or 12 months was observed. There was a statistically significant difference in the proportion of hole size category between the three brands (χ 2 = 15.761, df = 4, P = 0.003). In cone bio-assays, mortality of new Yorkool® nets was surprisingly low (48.6%), mortality was 90.2% and 91.3% for Netprotect® and Royalsentry® (F (2, 131) = 81.59, P < 0.0001), respectively. At 12 month use, all tested nets were below the WHO threshold for replacement. Conclusion These findings suggest that there is a need for better net quality control before distribution. More frequent replacement of LLINs is probably not an option programmatically. Regardless of prior approval, LLIN durability monitoring for quality assessment as well as net loss following distribution is necessary to improve malaria control efforts

Fitness Ranking of Individual Mutants Drives Patterns of Epistatic Interactions in HIV-1

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Reviewing progress: 7 Year Trends in Characteristics of Adults and Children Enrolled at HIV Care and Treatment Clinics in the United Republic of Tanzania.

To evaluate the on-going scale-up of HIV programs, we assessed trends in patient characteristics at enrolment and ART initiation over 7 years of implementation. Data were from Optimal Models, a prospective open cohort study of HIV-infected (HIV+) adults (>=15 years) and children (<15 years) enrolled from January 2005 to December 2011 at 44 HIV clinics in 3 regions of mainland Tanzania (Kagera, Kigoma, Pwani) and Zanzibar. Comparative statistics for trends in characteristics of patients enrolled in 2005--2007, 2008--2009 and 2010--2011 were examined. Overall 62,801 HIV+ patients were enrolled: 58,102(92.5%) adults, (66.5% female); 4,699(7.5%) children.Among adults, pregnant women enrolment increased: 6.8%, 2005--2007; 12.1%, 2008--2009; 17.2%, 2010--2011; as did entry into care from prevention of mother-to-child HIV transmission (PMTCT) programs: 6.6%, 2005--2007; 9.5%, 2008--2009; 12.6%, 2010--2011. WHO stage IV at enrolment declined: 27.1%, 2005--2007; 20.2%, 2008--2009; 11.1% 2010--2011. Of the 42.5% and 29.5% with CD4+ data at enrolment and ART initiation respectively, median CD4+ count increased: 210cells/muL, 2005--2007; 262cells/muL, 2008--2009; 266cells/muL 2010--2011; but median CD4+ at ART initiation did not change (148cells/muL overall). Stavudine initiation declined: 84.9%, 2005--2007; 43.1%, 2008--2009; 19.7%, 2010--2011.Among children, median age (years) at enrolment decreased from 6.1(IQR:2.7-10.0) in 2005--2007 to 4.8(IQR:1.9-8.6) in 2008--2009, and 4.1(IQR:1.5-8.1) in 2010--2011 and children <24 months increased from 18.5% to 26.1% and 31.5% respectively. Entry from PMTCT was 7.0%, 2005--2007; 10.7%, 2008--2009; 15.0%, 2010--2011. WHO stage IV at enrolment declined from 22.9%, 2005--2007, to 18.3%, 2008--2009 to 13.9%, 2010--2011. Proportion initiating stavudine was 39.8% 2005--2007; 39.5%, 2008--2009; 26.1%, 2010--2011. Median age at ART initiation also declined significantly. Over time, the proportion of pregnant women and of adults and children enrolled from PMTCT programs increased. There was a decline in adults and children with advanced HIV disease at enrolment and initiation of stavudine. Pediatric age at enrolment and ART initiation declined. Results suggest HIV program maturation from an emergency response

Global-scale climate impact functions: the relationship between climate forcing and impact

Although there is a strong policy interest in the impacts of climate change corresponding to different degrees of climate change, there is so far little consistent empirical evidence of the relationship between climate forcing and impact. This is because the vast majority of impact assessments use emissions-based scenarios with associated socio-economic assumptions, and it is not feasible to infer impacts at other temperature changes by interpolation. This paper presents an assessment of the global-scale impacts of climate change in 2050 corresponding to defined increases in global mean temperature, using spatially-explicit impacts models representing impacts in the water resources, river flooding, coastal, agriculture, ecosystem and built environment sectors. Pattern-scaling is used to construct climate scenarios associated with specific changes in global mean surface temperature, and a relationship between temperature and sea level used to construct sea level rise scenarios. Climate scenarios are constructed from 21 climate models to give an indication of the uncertainty between forcing and response. The analysis shows that there is considerable uncertainty in the impacts associated with a given increase in global mean temperature, due largely to uncertainty in the projected regional change in precipitation. This has important policy implications. There is evidence for some sectors of a non-linear relationship between global mean temperature change and impact, due to the changing relative importance of temperature and precipitation change. In the socio-economic sectors considered here, the relationships are reasonably consistent between socio-economic scenarios if impacts are expressed in proportional terms, but there can be large differences in absolute terms. There are a number of caveats with the approach, including the use of pattern-scaling to construct scenarios, the use of one impacts model per sector, and the sensitivity of the shape of the relationships between forcing and response to the definition of the impact indicator

Predictors of linkage to care following community-based HIV counseling and testing in rural Kenya

Despite innovations in HIV counseling and testing (HCT), important gaps remain in understanding linkage to care. We followed a cohort diagnosed with HIV through a community-based HCT campaign that trained persons living with HIV/AIDS (PLHA) as navigators. Individual, interpersonal, and institutional predictors of linkage were assessed using survival analysis of self-reported time to enrollment. Of 483 persons consenting to follow-up, 305 (63.2%) enrolled in HIV care within 3 months. Proportions linking to care were similar across sexes, barring a sub-sample of men aged 18–25 years who were highly unlikely to enroll. Men were more likely to enroll if they had disclosed to their spouse, and women if they had disclosed to family. Women who anticipated violence or relationship breakup were less likely to link to care. Enrolment rates were significantly higher among participants receiving a PLHA visit, suggesting that a navigator approach may improve linkage from community-based HCT campaigns.Vestergaard Frandse

Dose reduction to normal tissues as compared to the gross tumor by using intensity modulated radiotherapy in thoracic malignancies

BACKGROUND AND PURPOSE: Intensity modulated radiotherapy (IMRT) is a powerful tool, which might go a long way in reducing radiation doses to critical structures and thereby reduce long term morbidities. The purpose of this paper is to evaluate the impact of IMRT in reducing the dose to the critical normal tissues while maintaining the desired dose to the volume of interest for thoracic malignancies. MATERIALS AND METHODS: During the period January 2002 to March 2004, 12 patients of various sites of malignancies in the thoracic region were treated using physical intensity modulator based IMRT. Plans of these patients treated with IMRT were analyzed using dose volume histograms. RESULTS: An average dose reduction of the mean values by 73% to the heart, 69% to the right lung and 74% to the left lung, with respect to the GTV could be achieved with IMRT. The 2 year disease free survival was 59% and 2 year overall survival was 59%. The average number of IMRT fields used was 6. CONCLUSION: IMRT with inverse planning enabled us to achieve desired dose distribution, due to its ability to provide sharp dose gradients at the junction of tumor and the adjacent critical organs

Mining a Sea of Data: Deducing the Environmental Controls of Ocean Chlorophyll

Chlorophyll biomass in the surface ocean is regulated by a complex interaction of physiological, oceanographic, and ecological factors and in turn regulates the rates of primary production and export of organic carbon to the deep ocean. Mechanistic models of phytoplankton responses to climate change require the parameterization of many processes of which we have limited knowledge. We develop a statistical approach to estimate the response of remote-sensed ocean chlorophyll to a variety of physical and chemical variables. Irradiance over the mixed layer depth, surface nitrate, sea-surface temperature, and latitude and longitude together can predict 83% of the variation in log chlorophyll in the North Atlantic. Light and nitrate regulate biomass through an empirically determined minimum function explaining nearly 50% of the variation in log chlorophyll by themselves and confirming that either light or macronutrients are often limiting and that much of the variation in chlorophyll concentration is determined by bottom-up mechanisms. Assuming the dynamics of the future ocean are governed by the same processes at work today, we should be able to apply these response functions to future climate change scenarios, with changes in temperature, nutrient distributions, irradiance, and ocean physics