Severity and Treatment of Alcohol Withdrawal in Elderly Versus Younger Patients

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65425/1/j.1530-0277.1994.tb00903.x.pd

Environmental influences on familial discordance of phenotype in people with homocystinuria: a case report

<p>Abstract</p> <p>Introduction</p> <p>Non-heritable factors may have an influence on the clinical expression of monogenic inherited metabolic diseases.</p> <p>Case presentation</p> <p>This is a case report of a man whose mother had been diagnosed late in childhood with pyridoxine responsive homocystinuria with lens dislocation and neurodevelopmental delay. These severe complications were not observed in her son who was pyridoxine unresponsive but who had been treated appropriately since early infancy.</p> <p>Conclusion</p> <p>The phenotype of people with homocystinuria can be discordant within a family, with variability in metabolic and clinical expression depending upon both the genotype and therapeutic interventions. Offspring of people with homocystinuria should be screened in early infancy and, if positive, treated appropriately whether they have pyridoxine responsive or unresponsive disease.</p

Functional analysis of recurrent CDC20 promoter variants in human melanoma

Small nucleotide variants in non-coding regions of the genome can alter transcriptional regulation, leading to changes in gene expression which can activate oncogenic gene regulatory networks. Melanoma is heavily burdened by non-coding variants, representing over 99% of total genetic variation, including the well-characterized TERT promoter mutation. However, the compendium of regulatory non-coding variants is likely still functionally under-characterized. We developed a pipeline to identify hotspots, i.e. recurrently mutated regions, in melanoma containing putatively functional non-coding somatic variants that are located within predicted melanoma-specific regulatory regions. We identified hundreds of statistically significant hotspots, including the hotspot containing the TERT promoter variants, and focused on a hotspot in the promoter of CDC20. We found that variants in the promoter of CDC20, which putatively disrupt an ETS motif, lead to lower transcriptional activity in reporter assays. Using CRISPR/Cas9, we generated an indel in the CDC20 promoter in human A375 melanoma cell lines and observed decreased expression of CDC20, changes in migration capabilities, increased growth of xenografts, and an altered transcriptional state previously associated with a more proliferative and less migratory state. Overall, our analysis prioritized several recurrent functional non-coding variants that, through downregulation of CDC20, led to perturbation of key melanoma phenotypes

Downstream rounding rate of pebbles in the Himalaya

Sediment grains are progressively rounded during their transport down a river. For more than a century, Earth scientists have used the roundness of pebbles within modern sediment, and of clasts within conglomerates, as a key metric to constrain the sediment's transport history and source area(s). However, the current practices of assessment of pebble roundness are mainly qualitative and based on time-consuming manual measurement methods. This qualitative judgement provides the transport history only in a broad sense, such as classifying distance as “near” or “far”. In this study, we propose a new model that quantifies the relationship between roundness and the transport distance. We demonstrate that this model can be applied to the clasts of multiple lithologies including modern sediment, as well as conglomerates, deposited by ancient river systems. We present field data from two Himalayan catchments in Nepal. We use the normalized isoperimetric ratio (IRn), which relates a pebble's area (A) to its perimeter (P), to quantify roundness. The maximum analytical value for IRn is 1, and IRn is expected to increase with transport distance. We propose a non-linear roundness model based on our field data, whereby the difference between a grain's IRn and the maximum value of 1 decays exponentially with transport distance, mirroring Sternberg's model of mass loss or size reduction by abrasion. This roundness model predicts an asymptotic behaviour for IRn, and the distance over which IRn approaches the asymptote is controlled by a rounding coefficient. Our field data suggest that the roundness coefficient for granite pebbles is 9 times that of quartzite pebbles. Using this model, we reconstruct the transport history of a Pliocene paleo-river deposit preserved at the base of the Kathmandu intermontane basin. These results, along with other sedimentary evidence, imply that the paleo-river was much longer than the length of the Kathmandu Basin and that it must have lost its headwaters through drainage capture. We further explore the extreme rounding of clasts from Miocene conglomerate of the Siwalik zone and find evidence of sediment recycling.</p

Location matters:Valuing firm-specific nonmarket risk in the global mining industry

Research summary Using collective action and social movement theory, we investigate the potential incentives and ability of stakeholders to engage in collective action that can increase firm-specific nonmarket risk of mining companies. We argue that proximity to the nearest environmentally sensitive water source increases the probability that local stakeholders will take collective actions that impose material costs on the focal mine. We hypothesize that stock markets recognize this nonmarket risk and apply a discount on announcements related to mines located near such areas, and that these risks are moderated by the type of mineral, the nature of the water source, and the strength of host country institutions. Using a unique data set and an event study method, we find support for most of our arguments. Managerial summary We argue that mines located near environmentally sensitive water sources are subject to nonmarket risks arising from the potential collective actions of local stakeholders and their allies. Stakeholder mobilization can impose material costs on a mine in the form of delays, regulatory hurdles, and closure. We find that stock markets recognize these nonmarket risks and apply a discount on announcements by mining companies whose mines are located near environmentally sensitive water sources, particularly rivers. However, we also find that investor reaction is stronger in countries with strong institutions that support collective action. Thus, nonmarket risk management is important even in countries that are typically characterized by low political and institutional risks. We discuss the degree to which these results can be generalized beyond mining