Coxsackie B2 Virus Infection Causing Multiorgan Failure and Cardiogenic Shock in a 42-Year-Old Man

Infections from coxsackie B2 viruses often cause viral myocarditis and, only rarely, multisystem organ impairment. We present the unusual case of a 42-year-old man in whom coxsackie B2 virus infection caused multiorgan infection, necessitating distal pancreatectomy, splenectomy, renal dialysis, and venoarterial extracorporeal membrane oxygenation with mechanical ventilation. In addition, the patient had a rapid-eye-movement sleep-related conduction abnormality that caused frequent sinus pauses of longer than 10 s, presumably due to myocarditis from the coxsackievirus infection. He recovered after permanent pacemaker placement and was discharged from the hospital. We discuss our aggressive supportive care and the few other reports of multiorgan impairment from coxsackieviruses

Central Nervous System Strategy for Roche Pharmaceuticals

Roche is the fifth largest pharmaceutical and biotechnology company in the world with $52B in sales during 2013 and 4.9% market share in the pharmaceutical industry. Its main competitors include Novartis, Pfizer, Johnson & Johnson, Sanofi, Merck & Co., and GlaxoSmithKline. Roche’s mission is to develop treatments for medical needs that have gone unmet and to create more efficient treatment options through cutting edge research. The Central Nervous System market segment makes up 19.6% of total industry sales and includes products treating such ailments as depression, epilepsy, psychosis, and Alzheimer’s disease. Though historically Roche has been a market leader in this segment, in recent years its Share of Market (SOM) has declined. Alzheimer’s disease is a progressive degenerative illness that causes memory loss, personality changes, loss of mobility, and death. Currently 35MM people, word wide, are suffering from the disease. The greatest predictors of Alzheimer’s disease are age and genetics. Therefore the number of people infected with the disease is expected to increase dramatically in the coming years as the global populate ages. Currently there are five FDA approved treatments for the disease, however they are ineffective as the best possible outcome is an increase in life expectancy of only 12 months. The objective of this undergraduate research project is to recommend a central nervous system corporate strategy for Roche, which would involve the development of a new drug to treat Alzheimer’s disease. This strategy would help Roche to retain or even strengthen its SOM against competitors

Regulation and Function of PP2A-B56delta and its Pathological Variants

B56δ is a regulatory subunit of protein phosphatase PP2A, which is responsible for the majority of phosphoserine and phosphothreonine dephosphorylation within a cell. PPP2R5D-Related Developmental Disorder is characterized by intellectual disability, autism-spectrum disorder, hypotonia, and epilepsy and is caused by de novo single nucleotide changes in PPP2R5D, the gene that encodes B56δ, resulting in missense mutations (i.e. E198K, E420K, etc.). Yet, the molecular mechanisms impacted by these variants are unknown. To investigate these mechanisms as described in Chapters 2 and 3, we generated HEK293 cells harboring a single nucleotide change in the endogenous locus of PPP2R5D to recapitulate two pathogenic variants: E198K and E420K. Employing quantitative proteomic and phosphoproteomic approaches, we investigated global protein and phosphorylation changes in wild type-, heterozygous E198K- and heterozygous E420K-cell lines. These analyses revealed both unique and common changes in the E198K and E420K variants versus wild type cells in various signaling cascades. Based on mass spectrometry and western blot data, neither the E198K nor E420K mutation impacts the expression of PPP2R5D. However, we find that the variants bind less PP2A catalytic proteins, suggesting partial loss of PP2A holoenzyme assembly or reduced stability of the complex. The E420K and E198K variants also showed reduced activity compared to wild type in an in vitro dephosphorylation assay. Over- representation analysis of the E420K phosphoproteomic data revealed enrichment of the Protein Kinase B (AKT/PKB) consensus sequence. Hyperphosphorylation of AKT-mTOR pathway components such as RPS6 was also evident in western and LC-MS/MS analyses of the E420K variant. While RPS6 is also hyperphosphorylated in the E198K variant, activation of the AKT-mTOR pathway was not evident, suggesting that this variant results in a similar phenotype through convergent signaling pathways. Intriguingly, our data indicate ERK-dependent activation of mTORC1 in both E198K and E420K variant cells, suggesting ERK/MAPK-mediated activation of mTORC1 as key signaling alterations in PPP2R5D-variant cells. These studies reveal molecular pathways that could be therapeutically targeted in PPP2R5D-Related Developmental Disorder. Finally in Chapter 4, we investigate the interaction between B56δ and Oxidative Resistance 1 (OXR1), a poorly characterized protein shown to be implicated in a various neurological diseases

The Death Dignity Demands: The Eighth Amendment Requires Incarcerated People Decide Their Method of Execution

Recently, there have been a number of incarcerated people on death-row challenging their method of execution and proposing an alternative: usually, firing squad. Courts are hesitant to grant this request for a number of reasons, including the rare use of the firing squad. But there is substantial evidence this method is the most humane. Additionally, it appears incarcerated people think so, which is why so many in recent years chose—or petitioned for—death by firing squad rather than lethal injection or electrocution. As pharmaceutical companies halt their drugs’ distribution to prisons, prisons are forced to come up with their own—often more dangerous and less humane—drug cocktails, or revert back to the use of the electric chair, which has led to many botched and painful executions. Questions about the humaneness of execution methods the United States has used for more than fifty years are once again being raised. Already, there are some states, including Alabama and South Carolina, who allow for incarcerated people to petition for a method of execution other than the standard, and the United States Supreme Court recently ruled that incarcerated people can file a 42 U.S.C. § 1983 petition to receive an execution method their state does not currently provide. While this mid-point is a step in the right direction, many of these petitions for alternative methods of execution are denied; some of those incarcerated people who petitioned and were denied another method ended up experiencing painful, inhumane deaths. Society’s interest in humaneness demands serious consideration on widespread availability of the firing squad as a method of execution for incarcerated people on death row. This Note will specifically argue that the Eighth Amendment demands an incarcerated person’s right to choose how he dies

The Effect of Perceived Level of Social Support on the Fear of Falling

Background: Perhaps the most prevalent cause of anxiety among the elderly is the fear of falling (FOF), considering that a fall can lead to serious complications and the decline of health. Kumar et al. found that subjects with a FOF usually have less social support. Therefore, increased social support could possibly decrease the FOF, thus decreasing the likelihood of a fall overall. The purpose of this study is to examine the relationship between the amount of perceived social support one receives and the FOF among people ages 60 and up. Methods: In order to measure FOF and social support among participants, the Falls Efficacy Scale-International and the Multidimensional Scale of Perceived Social Support were administered to forty-three individuals ages 60 and older either living in assisted living facilities, independently or with a loved one. Both scales have been shown to be both valid and reliable. Results: Overall, this population did not yield significant results for FOF vs. social support; however, many significant results were found regarding important social and physical factors

Treatment of Iron Tailings at the Forecariah Guinea Mine - Guinea Conakry

Forecariah Guinea Mine SA (FGMSA) in Guinea - Conakry mines and processes Iron ore. About 0.5 Mt of tailings material has already been generated with additional 4000 tons generated daily. This paper presents a re-treatment technology for the Iron tailings obtained from the processing plant of FGMSA. Metallurgical tests were carried out on the tailings to determine which process route gives the most satisfactory result in terms of recovery and cost. Two representative samples (FCOPD-01 and FCDOP-02), taking from the tailings, were investigated. Particle Size Distribution (PSD) and chemical composition of various size fractions of representative samples of the tailings were performed. Dense Medium Separation (DMS) and Magnetic Separation (WHIMS) were also performed on a number of size fractions. The initial chemical composition of the various size fractions shows that the highest Fe grades were present in the +1 mm fractions at 58.8% and 58.6% for FCOPD-01 and FCOPD-02 respectively. The PSD of the tailings also indicated a mass yield of 77.9% for the +1 mm fraction and 22.1% for the -1 mm fraction. Contaminant Oxides, such as Al2O3 and SiO2 tend to be higher in the finer size fractions (-1 mm) of both samples. Result from the DMS analysis performed on the (-4 +0.5) mm fraction shows an underflow mass yields of 45.98% with Fe grade of 65.55% and overflow mass yield of 53.08% with Fe grade of just 13.5%. Magnetic separation (WHIMS) results on the (-4 +0.5) mm samples also gave varied mass yield and Fe grade at different magnetic intensities (3000 Gauss, 6000 Gauss and 10,000 Gauss). However, the highest Fe mass yield and grade produced from the magnetic separation were 18.10% and 50.8% respectively. The results show that DMS technique has the potential to re-treat the tailings at FGMSA. Keywords: Treatment, Iron ore, Tailings, Magnetic separation, Dense Medium Separatio

Acute reperfusion intramyocardial hemorrhage leads to regional chronic iron deposition in the heart

Intramyocardial hemorrhage commonly occurs in large reperfused myocardial infarctions. However, its long-term fate remains unexplored. We hypothesized that acute reperfusion intramyocardial hemorrhage leads to chronic iron deposition