Parkinson\u27s Disease, Amantadine Hydrochloride Therapy and Dopa Metabolites

In an attempt to clarify the effect of amantadine hydrochloride therapy in Parkinson\u27s disease, dopa metabolites were measured in the urine of 15 patients who were taking this medication. The results indicated that patients on amantadine therapy had lower urinary levels of epinephrine plus norepinephrine than either normal individuals or parkinsonian patients not receiving amantadine. Patients who developed livedo reticularis during amantadine therapy showed a small but significant increase in urinary dopamine levels and a similar decrease in dopac levels, when compared to other patients on amantadine who did not develop livedo reticularis

Genomic mapping of RNA polymerase II reveals sites of co-transcriptional regulation in human cells

BACKGROUND: Transcription by RNA polymerase II is regulated at many steps including initiation, promoter release, elongation and termination. Accumulation of RNA polymerase II at particular locations across genes can be indicative of sites of regulation. RNA polymerase II is thought to accumulate at the promoter and at sites of co-transcriptional alternative splicing where the rate of RNA synthesis slows. RESULTS: To further understand transcriptional regulation at a global level, we determined the distribution of RNA polymerase II within regions of the human genome designated by the ENCODE project. Hypophosphorylated RNA polymerase II localizes almost exclusively to 5' ends of genes. On the other hand, localization of total RNA polymerase II reveals a variety of distinct landscapes across many genes with 74% of the observed enriched locations at exons. RNA polymerase II accumulates at many annotated constitutively spliced exons, but is biased for alternatively spliced exons. Finally, RNA polymerase II is also observed at locations not in gene regions. CONCLUSION: Localizing RNA polymerase II across many millions of base pairs in the human genome identifies novel sites of transcription and provides insights into the regulation of transcription elongation. These data indicate that RNA polymerase II accumulates most often at exons during transcription. Thus, a major factor of transcription elongation control in mammalian cells is the coordination of transcription and pre-mRNA processing to define exons

Intergenerational justice of what: welfare, resources or capabilities?

An important aspect of intergenerational justice concerns the specification of a 'currency of advantage' that can be used to evaluate distributive outcomes across time. Environmental theorists have introduced several innovative currencies of justice in recent years, such as ecological space and critical natural capital. However they have often downplayed the application of established currencies (such as welfare, resources or capabilities) to issues of futurity. After exploring the merits of a number of rival currencies, it is argued that the currency of 'capabilities to function' provides a promising basis for a theory of justice that takes seriously the rights and duties of intergenerational justice

Exon expression profiling reveals stimulus-mediated exon use in neural cells

Exon centric microarrays were used to resolve the calcium-modulated gene expression response into transcript-level an exon-level regulation

NQO1-Bioactivatable Therapeutics as Radiosensitizers for Cancer Treatment

Developing cancer therapeutics that radiosensitize in a tumor-selective manner remains an ideal. We developed a novel means of radiosensitization, exploiting NAD(P)H:Quinone Oxidoreductase 1 (NQO1) overexpression, and lowered catalase expression in solid human tumors using NQO1-bioactivatable drugs. Non-small cell lung (NSCLC), pancreatic (PDAC), prostate, and breast cancers overexpress NQO1. Ionizing radiation (IR) creates a spectrum of DNA lesions, including lethal DNA double-strand breaks (DSBs), and mutagenic but rarely lethal altered DNA bases and DNA single-strand breaks (SSBs). NQO1-bioactivatable drugs (e.g., β-lapachone and deoxynyboquiones) also promote abasic DNA lesions and SSBs. These hyperactivate poly (ADP-ribose) polymerase 1 (PARP1) and dramatically increase calcium release from the endoplasm reticulum (ER). Exposure of human cancer cells overexpressing NQO1 to NQO1-bioactivatable drugs immediately following IR, therefore, hyperactivates PARP1 synergistically, which in turn depletes NAD+ and ATP, inhibiting DSB repair. Ultimately, this leads to cell death. Combining IR with NQO1-bioactivatable drugs allows for a reduction in drug dose. Similarly, a lower IR dose can be used in combination with the drug, reducing the effects of IR on normal tissue. The combination treatment is effective in preclinical animal models with NSCLC, prostate, and head and neck xenografts, indicating that clinical trials are warranted

Low-dose aspirin for the prevention of preterm delivery in nulliparous women with a singleton pregnancy (ASPIRIN): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Preterm birth remains a common cause of neonatal mortality, with a disproportionately high burden in low-income and middle-income countries. Meta-analyses of low-dose aspirin to prevent pre-eclampsia suggest that the incidence of preterm birth might also be decreased, particularly if initiated before 16 weeks of gestation. METHODS: ASPIRIN was a randomised, multicountry, double-masked, placebo-controlled trial of low-dose aspirin (81 mg daily) initiated between 6 weeks and 0 days of pregnancy, and 13 weeks and 6 days of pregnancy, in nulliparous women with an ultrasound confirming gestational age and a singleton viable pregnancy. Participants were enrolled at seven community sites in six countries (two sites in India and one site each in the Democratic Republic of the Congo, Guatemala, Kenya, Pakistan, and Zambia). Participants were randomly assigned (1:1, stratified by site) to receive aspirin or placebo tablets of identical appearance, via a sequence generated centrally by the data coordinating centre at Research Triangle Institute International (Research Triangle Park, NC, USA). Treatment was masked to research staff, health providers, and patients, and continued until 36 weeks and 7 days of gestation or delivery. The primary outcome of incidence of preterm birth, defined as the number of deliveries before 37 weeks\u27 gestational age, was analysed in randomly assigned women with pregnancy outcomes at or after 20 weeks, according to a modified intention-to-treat (mITT) protocol. Analyses of our binary primary outcome involved a Cochran-Mantel-Haenszel test stratified by site, and generalised linear models to obtain relative risk (RR) estimates and associated confidence intervals. Serious adverse events were assessed in all women who received at least one dose of drug or placebo. This study is registered with ClinicalTrials.gov, NCT02409680, and the Clinical Trial Registry-India, CTRI/2016/05/006970. FINDINGS: From March 23, 2016 to June 30, 2018, 14 361 women were screened for inclusion and 11 976 women aged 14-40 years were randomly assigned to receive low-dose aspirin (5990 women) or placebo (5986 women). 5780 women in the aspirin group and 5764 in the placebo group were evaluable for the primary outcome. Preterm birth before 37 weeks occurred in 668 (11·6%) of the women who took aspirin and 754 (13·1%) of those who took placebo (RR 0·89 [95% CI 0·81 to 0·98], p=0·012). In women taking aspirin, we also observed significant reductions in perinatal mortality (0·86 [0·73-1·00], p=0·048), fetal loss (infant death after 16 weeks\u27 gestation and before 7 days post partum; 0·86 [0·74-1·00], p=0·039), early preterm delivery (\u3c34 \u3eweeks; 0·75 [0·61-0·93], p=0·039), and the incidence of women who delivered before 34 weeks with hypertensive disorders of pregnancy (0·38 [0·17-0·85], p=0·015). Other adverse maternal and neonatal events were similar between the two groups. INTERPRETATION: In populations of nulliparous women with singleton pregnancies from low-income and middle-income countries, low-dose aspirin initiated between 6 weeks and 0 days of gestation and 13 weeks and 6 days of gestation resulted in a reduced incidence of preterm delivery before 37 weeks, and reduced perinatal mortality. FUNDING: Eunice Kennedy Shriver National Institute of Child Health and Human Development