Impacts of an Ammonia Leak on the Cabin Atmosphere of the International Space Station

Toxic chemical release into the cabin atmosphere is one of the three major emergency scenarios identified on the International Space Station (ISS). The release of anhydrous ammonia, the coolant used in the U.S. On-orbit Segment (USOS) External Active Thermal Control Subsystem (EATCS), into the ISS cabin atmosphere is one of the most serious toxic chemical release cases identified on board ISS. The USOS Thermal Control System (TCS) includes an Internal Thermal Control Subsystem (ITCS) water loop and an EATCS ammonia loop that transfer heat at the interface heat exchanger (IFHX). Failure modes exist that could cause a breach within the IFHX. This breach would result in high pressure ammonia from the EATCS flowing into the lower pressure ITCS water loop. As the pressure builds in the ITCS loop, it is likely that the gas trap, which has the lowest maximum design pressure within the ITCS, would burst and cause ammonia to enter the ISS atmosphere. It is crucial to first characterize the release of ammonia into the ISS atmosphere in order to develop methods to properly mitigate the environmental risk. This paper will document the methods used to characterize an ammonia leak into the ISS cabin atmosphere. A mathematical model of the leak was first developed in order to define the flow of ammonia into the ISS cabin atmosphere based on a series of IFHX rupture cases. Computational Fluid Dynamics (CFD) methods were then used to model the dispersion of the ammonia throughout the ISS cabin and determine localized effects and ventilation effects on the dispersion of ammonia. Lastly, the capabilities of the current on-orbit systems to remove ammonia were reviewed and scrubbing rates of the ISS systems were defined based on the ammonia release models. With this full characterization of the release of ammonia from the USOS TCS, an appropriate mitigation strategy that includes crew and system emergency response procedures, personal protection equipment use, and atmosphere monitoring and scrubbing hardware can be established

Transdifferentiating Astrocytes Into Neurons Using ASCL1 Functionalized With a Novel Intracellular Protein Delivery Technology

Cellular transdifferentiation changes mature cells from one phenotype into another by altering their gene expression patterns. Manipulating expression of transcription factors, proteins that bind to DNA promoter regions, regulates the levels of key developmental genes. Viral delivery of transcription factors can efficiently reprogram somatic cells, but this method possesses undesirable side effects, including mutations leading to oncogenesis. Using protein transduction domains (PTDs) fused to transcription factors to deliver exogenous transcription factors serves as an alternative strategy that avoids the issues associated with DNA integration into the host genome. However, lysosomal degradation and inefficient nuclear localization pose significant barriers when performing PTD-mediated reprogramming. Here, we investigate a novel PTD by placing a secretion signal sequence next to a cleavage inhibition sequence at the end of the target transcription factor–achaete scute homolog 1 (ASCL1), a powerful regulator of neurogenesis, resulting in superior stability and nuclear localization. A fusion protein consisting of the amino acid sequence of ASCL1 transcription factor with this novel PTD added can transdifferentiate cerebral cortex astrocytes into neurons. Additionally, we show that the synergistic action of certain small molecules improves the efficiency of the transdifferentiation process. This study serves as the first step toward developing a clinically relevant in vivo transdifferentiation strategy for converting astrocytes into neurons

European mtDNA Variants Are Associated With Differential Responses to Cisplatin, an Anticancer Drug: Implications for Drug Resistance and Side Effects.

Background: Cisplatin, a powerful antitumor agent, causes formation of DNA adducts, and activation of apoptotic pathways. Presently, cisplatin resistance develops in up to 70% of patients but the underlying molecular mechanism(s) are unclear and there are no markers to determine which patients will become resistant. Mitochondria play a significant role not only in energy metabolism but also retrograde signaling (mitochondria to nucleus) that modulates inflammation, complement, and apoptosis pathways. Maternally inherited mitochondrial (mt) DNA can be classified into haplogroups representing different ethnic populations that have diverse susceptibilities to diseases and medications. Methods: Transmitochondrial cybrids, where all cell lines possess identical nuclear genomes but either the H (Southern European) or J (Northern European) mtDNA haplogroups, were treated with cisplatin and analyzed for differential responses related to viability, oxidative stress, and expression levels of genes associated with cancer, cisplatin-induced nephrotoxicity and resistance, apoptosis and signaling pathways. Results: The cisplatin-treated-J cybrids showed greater loss of cell viability along with lower levels of reactive oxygen species and mitochondrial membrane potential compared to cisplatin-treated-H cybrids. After cisplatin treatment, J cybrids showed increased gene expression of BAX, CASP3, and CYP51A, but lower levels of SFRP1 compared to untreated-J cybrids. The cisplatin-treated-H cybrids had elevated expression of CDKN1A/P21, which has a role in cisplatin toxicity, compared to untreated-H cybrids. The cisplatin-treated H had higher transcription levels of ABCC1, DHRS2/HEP27, and EFEMP1 compared to cisplatin-treated-J cybrids. Conclusions: Cybrid cell lines that contain identical nuclei but either H mtDNA mitochondria or J mtDNA mitochondria respond differently to cisplatin treatments suggesting involvement of the retrograde signaling (from mitochondria to nucleus) in the drug-induced cell death. Varying toxicities and transcription levels of the H vs. J cybrids after cisplatin treatment support the hypothesis that mtDNA variants play a role in the expression of genes affecting resistance and side effects of cisplatin

Accelerometry and physical activity questionnaires - a systematic review

Abstract Background The aim of this study is to review accelerometer wear methods and correlations between accelerometry and physical activity questionnaire data, depending on participant characteristics. Methods We included 57 articles about physical activity measurement by accelerometry and questionnaires. Criteria were to have at least 100 participants of at least 18 years of age with manuscripts available in English. Accelerometer wear methods were compared. Spearman and Pearson correlation coefficients between questionnaires and accelerometers and differences between genders, age categories, and body mass index (BMI) categories were assessed. Results In most investigations, requested wear time was seven days during waking hours and devices were mostly attached on hips with waist belts. A minimum of four valid days with wear time of at least ten hours per day was required in most studies. Correlations (r = Pearson, ρ = Spearman) of total questionnaire scores against accelerometer measures across individual studies ranged from r = 0.08 to ρ = 0.58 (P < 0.001) for men and from r = −0.02 to r = 0.49 (P < 0.01) for women. Correlations for total physical activity among participants with ages ≤65 ranged from r = 0.04 to ρ = 0.47 (P < 0.001) and from r = 0.16 (P = 0.02) to r = 0.53 (P < 0.01) among the elderly (≥65 years). Few studies investigated stratification by BMI, with varying cut points and inconsistent results. Conclusion Accelerometers appear to provide slightly more consistent results in relation to self-reported physical activity among men. Nevertheless, due to overall limited consistency, different aspects measured by each method, and differences in the dimensions studied, it is advised that studies use both questionnaires and accelerometers to gain the most complete physical activity information

Preventing Teen Relationship Abuse and Sexual Assault through Bystander Training: Intervention Outcomes for School Personnel

The purpose of the current study was to examine the impact of exposure to Bringing in the Bystander—High School Curriculum (BITB-HSC) on school personnel, which included a seven session classroom curriculum for ninth through twelfth graders (student curriculum), a bystander training workshop for school personnel (school personnel workshop), and reading materials (handout). We examined how exposure to these various BITB-HSC intervention components was associated with school personnel’s knowledge and bystander efficacy, intentions, and barriers specific to student relationship abuse (RA) and sexual assault (SA). Participants were 488 school personnel from 12 high schools in upper New England who completed the 4-month follow-up survey that assessed for intervention exposure (284 participants completed both the baseline and follow-up survey). Whereas 53% of participants were exposed to no intervention components, the other half of the sample were exposed to a combination of intervention components. Higher baseline knowledge and reactive bystander intentions were associated with subsequent exposure to both the student curriculum and the handout, and fewer barriers to bystander action predicted exposure to the school personnel workshop. Exposure to the school personnel workshop, student curriculum, and handout was associated with subsequent greater knowledge, exposure to the student curriculum predicted reactive bystander intentions, and exposure to the handout predicted higher reactive bystander intentions and bystander efficacy. Findings suggest that despite challenges with engagement, exposure to the BITB-HSC components may be a useful tool in improving school personnel’s responses to RA and SA among high school students

Short courses of antibiotics for children and adults with bronchiectasis (Review)

BackgroundBronchiectasis is an important cause of respiratory morbidity in both developing and developed countries. Antibiotics are considered standard therapy in the treatment of this condition but it is unknown whether short courses (four weeks or less) are efficacious.ObjectivesTo determine whether short courses of antibiotics (i.e. less than or equal to four weeks) for treatment of acute and stable state bronchiectasis, in adults and children, are efficacious when compared to placebo or usual care.Search methodsThe Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), MEDLINE, EMBASE, OLDMEDLINE, CINAHL, AMED and PsycINFO and handsearching of respiratory journals and meeting abstracts were performed by the Cochrane Airways Group up to February 2011.Selection criteriaOnly randomised controlled trials were considered. Adults and children with bronchiectasis (defined clinically or radiologically) were included. Patients with cystic fibrosis were excluded.Data collection and analysisTwo review authors independently reviewed the titles, abstracts and citations to assess eligibility for inclusion. Only one study fulfilled the inclusion criteria and thus meta-analysis could not be performed.Main resultsThe single eligible study showed a small benefit, when compared to placebo, of four weeks of inhaled antibiotic therapy in adults with bronchiectasis and pseudomonas in their sputum. There were no studies in children and no studies on oral or intravenous antibiotics.Authors\u27 conclusionsThere is insufficient evidence in the current literature to make reasonable conclusions about the efficacy of short course antibiotics in the management of adults and children with bronchiectasis. Until further evidence is available, adherence to current treatment guidelines is recommended

Characterization of Actions Taken During the Delivery of Medication Therapy Management: A Time-and-Motion Approach

OBJECTIVES: To characterize actions performed by pharmacists and support staff during provision of medication therapy management (MTM) and to compare actions performed according to practice characteristics. METHODS: A purposeful sample of 7 MTM practices (2 call centers and 5 community practices) was identified and visited by investigators. Pharmacists and support staff were observed during their routine provision of MTM. Investigators characterized "major" (e.g., preparation for a comprehensive medication review) and "minor" (i.e., specific steps in overarching major action) actions with the use of a time-and-motion approach. RESULTS: A total of 32 major and 469 minor actions were observed. Practices were characterized as Later Maturity Level or Early Maturity Level on the basis of their self-reported MTM appointment volume, self-assessment of the extent of integration of chronic care model principles, and payer mix. Later Maturity Level practices were more likely to deliver follow-up medication therapy reviews and comprehensive medication reviews (CMRs) as opposed to targeted medication reviews (TMRs) and to receive physician referrals for MTM. Later Maturity Level practices were also more likely to use paid interns than pharmacy rotation students. CMR activities observed at Later Maturity Level practices lasted a median of 30.8 minutes versus 20.3 minutes for CMR activities at Early Maturity Level practices. Similarly, TMR activities observed at Later Maturity Level practices were longer: a median of 31.0 minutes versus 12.3 minutes. At Later Maturity Level practices, pharmacists spent a greater proportion of time providing patient education, while support staff spent a greater proportion of time on tasks such as capturing demographics and introducing or explaining MTM. CONCLUSION: MTM activities were longer at Later Maturity Level practices, and these practices were more likely to use paid pharmacy interns and to receive physician referrals for MTM. This work provides a foundation for future research

Abnormal structural and functional brain connectivity in gray matter heterotopia

available in PMC 2013 June 01Purpose:  Periventricular nodular heterotopia (PNH) is a malformation of cortical development associated with epilepsy and dyslexia. Evidence suggests that heterotopic gray matter can be functional in brain malformations and that connectivity abnormalities may be important in these disorders. We hypothesized that nodular heterotopia develop abnormal connections and systematically investigated the structural and functional connectivity of heterotopia in patients with PNH. Methods:  Eleven patients were studied using diffusion tensor tractography and resting-state functional connectivity MRI with bold oxygenation level–dependent (BOLD) imaging. Fiber tracks with a terminus within heterotopic nodules were visualized to determine structural connectivity, and brain regions demonstrating resting-state functional correlations to heterotopic nodules were analyzed. Relationships between these connectivity results and measures of clinical epilepsy and cognitive disability were examined. Key Findings:  A majority of heterotopia (69%) showed structural connectivity to discrete regions of overlying cortex, and almost all (96%) showed functional connectivity to these regions (mean peak correlation coefficient 0.61). Heterotopia also demonstrated connectivity to regions of contralateral cortex, other heterotopic nodules, ipsilateral but nonoverlying cortex, and deep gray matter structures or the cerebellum. Patients with the longest durations of epilepsy had a higher degree of abnormal functional connectivity (p = 0.036). Significance:  Most heterotopic nodules in PNH are structurally and functionally connected to overlying cortex, and the strength of abnormal connectivity is higher among patients with the longest duration of epilepsy. Along with prior evidence that cortico-cortical tract defects underlie dyslexia in this disorder, the current findings suggest that altered connectivity is likely a critical substrate for neurologic dysfunction in brain malformations.National Institutes of Health (U.S.) (NIH/NINDS R01 NS073601)National Institutes of Health (U.S.) (NIH/NINDS K23 NS049159)Epilepsy Foundation of AmericaHarvard University (William F. Milton Fund

Restoring Ureagenesis in Hepatocytes by CRISPR/Cas9-mediated Genomic Addition to Arginase-deficient Induced Pluripotent Stem Cells.

Urea cycle disorders are incurable enzymopathies that affect nitrogen metabolism and typically lead to hyperammonemia. Arginase deficiency results from a mutation in Arg1, the enzyme regulating the final step of ureagenesis and typically results in developmental disabilities, seizures, spastic diplegia, and sometimes death. Current medical treatments for urea cycle disorders are only marginally effective, and for proximal disorders, liver transplantation is effective but limited by graft availability. Advances in human induced pluripotent stem cell research has allowed for the genetic modification of stem cells for potential cellular replacement therapies. In this study, we demonstrate a universally-applicable CRISPR/Cas9-based strategy utilizing exon 1 of the hypoxanthine-guanine phosphoribosyltransferase locus to genetically modify and restore arginase activity, and thus ureagenesis, in genetically distinct patient-specific human induced pluripotent stem cells and hepatocyte-like derivatives. Successful strategies restoring gene function in patient-specific human induced pluripotent stem cells may advance applications of genetically modified cell therapy to treat urea cycle and other inborn errors of metabolism