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The Influence Of Methotrexate On The Cardiovascular System Of The Albino Rat

The medical historian, looking backward to our own times from some point still in the future, may well single out the years 19H8 and 1958 as important markers in the fight against human cancer. Lederle Laboratories, a Division of American Cyanamid Company (8), developed methotrexate in 19H8 and the second date stands out as the year when Creech and his associates first described their successful application of regional perfusion - a technique of blocking off circulation around a tumor while an anti-cancer drug is introduced into the blood vessels of the isolated region (2). Although of limited use, regional perfusion or infusion with methotrexate and leucovorin (citrovorum factor) therapy has been called the most significant advancement in cancer chemotherapy in the past fifteen years. The previous statement assumes a greater force when it is noted that the production of a cancer drug is one thing while its utilization presents a problem in itself (2), Thus it happened that the full value of methotrexate was not realized for nearly a decade while the best methods of using it were being explored. The perfusion technique permitted a higher concentration of the drug to be delivered to the tumor area while minimizing undesirable systemic side effects. The relationship between the mode of action of drugs used to treat cancer has caused many investigators to wonder what this dreadful disease is. Is it a chronic virus infection as some scientists believe? Or is it caused by any one of a number of other factors, or combination of factors: a defective immunity, a mutated gene, a distorted enzyme pattern, a hormonal imbalance, an environmental poison, a breakdown of organs and systems which enable us to withstand stress or a perverted allergic-like immunity which destroys normal body cells and tissues? Whatever it is, the change from non-cancer to cancer takes place in a world all but hidden from man - a world so minute that it cannot even be viewed by an electron microscope. Against such a background of death, hope and imperfect knowledge, the word challenge seems wholly inadequate to describe the task confronting the scientist. Some of the lines of attack are as follows: (a) the action of chemical molecules which are deliberately designed to block a specific chemical reaction within cancer cells; (b) chemicals that prevent cell division; (c) substances that imitate the effects of X-ray and (d) substances which compete with vitamins and hormones in cell metabolism or destroy bacteria and other primitive cells

Infrared algorithm development for ocean observations

Efforts continue under this contract to develop algorithms for the computation of sea surface temperature (SST) from MODIS infrared retrievals. This effort includes radiative transfer modeling, comparison of in situ and satellite observations, development and evaluation of processing and networking methodologies for algorithm computation and data accession, evaluation of surface validation approaches for IR radiances, and participation in MODIS (project) related activities. Efforts in this contract period have focused on radiative transfer modeling, evaluation of atmospheric correction methodologies, involvement in field studies, production and evaluation of new computer networking strategies, and objective analysis approaches

Infrared algorithm development for ocean observations with EOS/MODIS

Efforts continue under this contract to develop algorithms for the computation of sea surface temperature (SST) from MODIS infrared retrievals. This effort includes radiative transfer modeling, comparison of in situ and satellite observations, development and evaluation of processing and networking methodologies for algorithm computation and data accession, evaluation of surface validation approaches for IR radiances, and participation in MODIS (project) related activities. Efforts in this contract period have focused on radiative transfer modeling and evaluation of atmospheric path radiance efforts on SST estimation, exploration of involvement in ongoing field studies, evaluation of new computer networking strategies, and objective analysis approaches

Mesoscale ocean variability signal recovered from altimeter data in the SW Atlantic Ocean: a comparison of orbit error correction in three Geosat data sets

Orbit error is one of the largest sources of uncertainty in studies of ocean dynamics using satellite altimeters. The sensitivity of GEOSAT mesoscale ocean variability estimates to altimeter orbit precision in the SW Atlantic is analyzed using three GEOSAT data sets derived from different orbit estimation methods: (a) the original GDR data set, which has the lowest orbit precision, (b) the GEM-T2 set, constructed from a much more precise orbital model, and (c) the Sirkes-Wunsch data set, derived from additional spectral analysis of the GEM-T2 data set. Differences among the data sets are investigated for two tracks in dynamically dissimilar regimes of the Southwestern Atlantic Ocean, by comparing: (a) distinctive features of the average power density spectra of the sea height residuals and (b) space-time diagrams of sea height residuals. The variability estimates produced by the three data sets are extremely similar in both regimes after removal of the time-dependent component of the orbit error using a quadratic fit. Our results indicate that altimeter orbit precision with appropriate processing plays only a minor role in studies of mesoscale ocean variability.Erro orbital tem sido a principal fonte de incerteza no processamento de dados altimétricos. Recentes conjuntos de dados, baseados em modelos de predição orbital mais avançados c em novas metodologias de correção de erro, já foram capazes de reduzir o erro orbital de ate uma ordem de magnitude em comparação com os GDRs originais. Ncslc trabalho nós avaliamos os resultados dessas melhores eslimativas na descrição da variabilidade "meso- escalar" na parte sudoeste do oceano Atlântico Sul. Comparamos resultados obtidos cm tres conjuntos de dados: os GDRs originais c os conjuntos de dados GEM-T2 c Sirkes-Wunsch. Para garantir a "sensibilidade" das estimativas dc variabilidade mcso-cscalar quanto às mudanças na precisão orbital, utilizamos as mesmas "correções ambientais" c o mesmo método dc processamento de dados no tratamento dos três conjuntos dc dados. Para investigar as possíveis diferenças entre os valores de variabilidade meso-escalar produzidos pelos tres conjuntos dc dados utilizamos as características espectrais dos residuais de "amplitude do mar" obtidas antes c depois da remoção do erro orbital "dependente" do tempo. O fato da componente mcso-cscalar do espectro quase não ter sido afetada pela remoção do maior comprimento de onda do sinal (o que corresponde principalmente ao erro orbital) sugere que muito pouco do sinal meso-escalar foi realmente removido através deste processo. Um "pico" menor no espectro da "faixa" B confirma uma variabilidade oceânica local menor com respeito à faixa A. Uma análise mais profunda demonstra que, após a remoção do erro orbital, os residuais de amplitude do mar são incrivelmente similares entre os três conjuntos de dados para uma determinada faixa. Tal resultado sugere que a precisão orbital contribui apenas parcialmente para o estudo da variabilidade meso-escalar oceânica. Esta conclusão só é válida se o erro orbital dependente do tempo puder ser removido sem se remover simultaneamente uma porção excessiva do sinal meso-escalar. Nossos resultados sugerem que estudos de variabilidade mesoescalar não requerem dados dc órbita altimótrica extremamente precisos. Além disso, apesar deste trabalho só analisar dados do GEOSAT do oceano Atlântico Sul, acredita-se que tal resultado possa ser extrapolado para outras regiões do mar. Isto é devido às características espectrais do erro orbital dependente do tempo c à possibilidade de remoção deste erro sem remoção de grande parle do sinal meso-escalar oceânico. Estes resultados, contudo, não significam que não se deva tentar obter valores orbitais mais precisos. Pelo contrário, tal melhoramento pode ser capaz de levar à eliminação dc algumas das limitações atualmente existentes na utilização dc dados altimétricos. Por exemplo, estimativas dc órbita do GEOSAT mais precisas nos permitiriam estudar a variabilidade oceânica cm larga escala e, através de uma melhor compreensão do geoide, nos auxiliariam no estudo da circulação oceânica "meso e largoescalar" geral

Lessons from the Use of Ranked Choice Voting in American Presidential Primaries

Grounded in experience in 2020, both major political parties have reasons to expand use of ranked choice voting (RCV) in their 2024 presidential primaries. RCV may offer a ‘win-win’ solution benefiting both the parties and their voters. RCV would build on both the pre-1968 American tradition of parties determining a coalitional presidential nominee through multiple ballots at party conventions and the modern practice of allowing voters to effectively choose their nominees in primaries. Increasingly used by parties around the world in picking their leaders, RCV may allow voters to crowd-source a coalitional nominee. Most published research about RCV focuses on state and local elections. In contrast, this article analyzes the impact on voters, candidates, and parties from five state Democratic parties using RCV in party-run presidential nomination contests in 2020. First, it uses polls and results to examine how more widespread use of RCV might have affected the trajectory of contests for the 2016 Republican nomination. Second, it contrasts how more than three million voters in the 2020 Democratic presidential primaries backed withdrawn candidates with the low rate of such wasted votes for withdrawn candidates in the states with RCV ballots. Finally, it concludes with an examination of how RCV might best interact with the parties’ current rules and potential changes to those rules

Effect of HIV-1-related protein expression on cardiac and skeletal muscles from transgenic rats

<p>Abstract</p> <p>Background</p> <p>Human immunodeficiency virus type 1 (HIV-1) infection and the consequent acquired immunodeficiency syndrome (AIDS) has protean manifestations, including muscle wasting and cardiomyopathy, which contribute to its high morbidity. The pathogenesis of these myopathies remains partially understood, and may include nutritional deficiencies, biochemical abnormalities, inflammation, and other mechanisms due to viral infection and replication. Growing evidence has suggested that HIV-1-related proteins expressed by the host in response to viral infection, including Tat and gp120, may also be involved in the pathophysiology of AIDS, particularly in cells or tissues that are not directly infected with HIV-1. To explore the potentially independent effects of HIV-1-related proteins on heart and skeletal muscles, we used a transgenic rat model that expresses several HIV-1-related proteins (e.g., Tat, gp120, and Nef). Outcome measures included basic heart and skeletal muscle morphology, glutathione metabolism and oxidative stress, and gene expressions of atrogin-1, muscle ring finger protein-1 (MuRF-1) and Transforming Growth Factor-β₁(TGFβ₁), three factors associated with muscle catabolism.</p> <p>Results</p> <p>Consistent with HIV-1 associated myopathies in humans, HIV-1 transgenic rats had increased relative heart masses, decreased relative masses of soleus, plantaris and gastrocnemius muscles, and decreased total and myosin heavy chain type-specific plantaris muscle fiber areas. In both tissues, the levels of cystine (Cyss), the oxidized form of the anti-oxidant cysteine (Cys), and Cyss:Cys ratios were significantly elevated, and cardiac tissue from HIV-1 transgenic rats had altered glutathione metabolism, all reflective of significant oxidative stress. In HIV-1 transgenic rat hearts, MuRF-1 gene expression was increased. Further, HIV-1-related protein expression also increased atrogin-1 (~14- and ~3-fold) and TGFβ₁(~5-fold and ~3-fold) in heart and plantaris muscle tissues, respectively.</p> <p>Conclusion</p> <p>We provide compelling experimental evidence that HIV-1-related proteins can lead to significant cardiac and skeletal muscle complications independently of viral infection or replication. Our data support the concept that HIV-1-related proteins are not merely disease markers, but rather have significant biological activity that may lead to increased oxidative stress, the stimulation of redox-sensitive pathways, and altered muscle morphologies. If correct, this pathophysiological scheme suggests that the use of dietary thiol supplements could reduce skeletal and cardiac muscle dysfunction in HIV-1-infected individuals.</p

No effect of arm exercise on diaphragmatic fatigue or ventilatory constraint in Paralympic athletes with cervical spinal cord injury

Cervical spinal cord injury (CSCI) results in a decrease in the capacity of the lungs and chest wall for pressure, volume, and airflow generation. We asked whether such impairments might increase the potential for exercise-induced diaphragmatic fatigue and mechanical ventilatory constraint in this population. Seven Paralympic wheelchair rugby players (mean ± SD peak oxygen uptake = 16.9 ± 4.9 ml·kg–1·min–1) with traumatic CSCI (C5–C7) performed arm-crank exercise to the limit of tolerance at 90% of their predetermined peak work rate. Diaphragm function was assessed before and 15 and 30 min after exercise by measuring the twitch transdiaphragmatic pressure (Pdi,tw) response to bilateral anterolateral magnetic stimulation of the phrenic nerves. Ventilatory constraint was assessed by measuring the tidal flow volume responses to exercise in relation to the maximal flow volume envelope. Pdi,tw was not different from baseline at any time after exercise (unpotentiated Pdi,tw = 19.3 ± 5.6 cmH2O at baseline, 19.8 ± 5.0 cmH2O at 15 min after exercise, and 19.4 ± 5.7 cmH2O at 30 min after exercise; P = 0.16). During exercise, there was a sudden, sustained rise in operating lung volumes and an eightfold increase in the work of breathing. However, only two subjects showed expiratory flow limitation, and there was substantial capacity to increase both flow and volume (<50% of maximal breathing reserve). In conclusion, highly trained athletes with CSCI do not develop exercise-induced diaphragmatic fatigue and rarely reach mechanical ventilatory constraint

Receptor protein tyrosine phosphatases control Purkinje neuron firing

Spinocerebellar ataxias (SCA) are a genetically heterogeneous family of cerebellar neurodegenerative diseases characterized by abnormal firing of Purkinje neurons and degeneration. We recently demonstrated the slowed firing rates seen in several SCAs share a common etiology of hyper-activation of the Src family of non-receptor tyrosine kinases (SFKs). However, the lack of clinically available neuroactive SFK inhibitors lead us to investigate alternative mechanisms to modulate SFK activity. Previous studies demonstrate that SFK activity can be enhanced by the removal of inhibitory phospho-marks by receptor-protein-tyrosine phosphatases (RPTPs). In this Extra View we show that MTSS1 inhibits SFK activity through the binding and inhibition of a subset of the RPTP family members, and lowering RPTP activity in cerebellar slices with peptide inhibitors increases the suppressed Purkinje neuron basal firing rates seen in two different SCA models. Together these results identify RPTPs as novel effectors of Purkinje neuron basal firing, extending the MTSS1/SFK regulatory circuit we previously described and expanding the therapeutic targets for SCA patients

Agulhas ring dynamics from TOPEX/POSEIDON satellite altimeter data

The transfer of warm water from the Indian Ocean into the South Atlantic subtropical gyre takes place in the form of rings and filaments formed when the Agulhas Current retroflects south of Africa between 15 and 25E. A survey of the rings formed from September 1992 until December 1995 in the Retroflection region was carried out using TOPEX/POSEIDON altimeter data. A two-layer model was used to estimate the upper layer thickness from the altimeter-derived sea-surface height anomaly data. An objective analysis scheme was used to construct a map of upper layer thickness every ten days. Seventeen rings and their trajectories were identified using these maps. The shedding of rings from the Agulhas Current was neither continuous nor periodic, and for long periods there is no formation of rings. Several rings remained in the region for more than a year and, at any given time, 2 to 6 rings coexisted in the region east of the Walvis Ridge. The results showed that the number of rings translating simultaneously in this region is larger during the first half of each year. The upper layer transport of the Agulhas Current in the Retroflection region was computed and a close association between high variations in transport and ring shedding was found. Rings translated WNW at translation speeds ranging from 5 to 16 km day−1 following formation. The values of available potential energy computed for the rings place them among the most energetic rings observed in the world oceans, with values of up to 70 × 1015 J. Transport computations indicate that each ring contributes in the average approximately 1 Sv of Agulhas Current waters to the Benguela Current