Effects of treprostinil sodium in a monocrotaline-induced rat model of pulmonary hypertension

"May 2005"Dissertations, Academic -- University of Missouri--Columbia -- microbiology (Medicine).Includes bibliographical references.Vita.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file.Thesis (M.S.) University of Missouri-Columbia 2005.Treprostinil is a prostacyclin analog currently used in the treatment of pulmonary hypertension. Although clinical studies show treprostinil to be a successful therapy for pulmonary hypertension, little information exists concerning the effects of treprostinil treatment in vivo. The purpose of this study is to elucidate the effects of treprostinil on right ventricular systolic pressure (RVSP), right ventricular hypertrophy and vascular remodeling in a rat model of MCT-induced pulmonary hypertension. Male, Sprague-Dawley rats were randomized to one of four treatment groups; control, monocrotaline (MCT) only, MCT with treprostinil treatment (MCT/TRE), and treprostinil treatment only (TRE). At the beginning of the experiment, rats received a one-time subcutaneous dose of MCT (60 mg/kg) or saline. Rats were then administered either treprostinil or placebo for 28-days. After 28-days of treprostinil treatment, we recorded RVSP and right ventricular size. In addition, paraffin embedded left whole lung tissues were used for morphometric analysis and right whole lung tissues were snap frozen in liquid nitrogen for protein analysis. As expected, MCT exposure caused a significant increase in RVSP and right ventricular hypertrophy. Morphometric analyses also indicated that MCT-exposure led to medial wall thickening of the pulmonary vasculature. Neither low-dose (10 ng/kg/min) nor high-dose (150 ng/kg/min) treprostinil therapy attenuated elevations of RVSP and right ventricular hypertrophy in pulmonary hypertensive rats. In addition, there was no attenuation of medial wall thickening when MCT-exposed rats also received treprostinil treatment. Finally, treprostinil significantly lowered PPAR-[gamma] protein expression in MCT-exposed rats. In conclusion, we demonstrated that increases in RVSP, right ventricular hypertrophy and vascular remodeling associated with MCT-induced pulmonary hypertension are not attenuated with treprostinil therapy. Additionally, we found that treprostinil attenuated the induction of PPAR-[gamma] protein levels in whole lung homogenates of MCT-exposed rats. Although we have not yet established that PPAR-[gamma] is an important therapeutic target for pulmonary hypertension, we speculate that further investigation of its role could reveal a mechanism in which PGI₂ elicits its effects on the pulmonary vasculature

Impact of the COVID-19 pandemic on tuberculosis control in Indonesia:a nationwide longitudinal analysis of programme data

BACKGROUND: The impact of the COVID-19 pandemic on tuberculosis control in high-burden countries has not been adequately assessed. We aimed to estimate the impact of the COVID-19 pandemic on the national tuberculosis programme in Indonesia, in association with indicators of human development and health-system capacity across all 514 districts in 34 provinces. METHODS: We did a nationwide longitudinal analysis to compare tuberculosis case notification, treatment coverage, and mortality rates in Indonesia before (2016-19) and during (2020-21) the COVID-19 pandemic. The following outcomes were assessed: the district-level quarterly reported tuberculosis case notification rate (number of all reported tuberculosis cases per 100 000 population), treatment coverage (proportion of tuberculosis patients who started treatment), and all-cause mortality rate in patients with tuberculosis (number of reported deaths per 100 000 population). District-level data on COVID-19 incidence and deaths, health-system capacity, and human development and sociodemographics were also analysed. Multilevel linear spline regression was done to assess quarterly time trends for the three outcomes. FINDINGS: During the COVID-19 pandemic, the tuberculosis case notification rate declined by 26% (case notification rate ratio 0·74, 95% CI 0·72-0·77) and treatment coverage declined by 11% (treatment coverage ratio 0·89, 95% CI 0·88-0·90), but there was no significant increase in all-cause mortality (all-cause mortality rate ratio 0·97, 95% CI 0·91-1·04) compared with the pre-pandemic period. In the second year of the pandemic, we observed a partial recovery of the case notification rate from Q1 to Q4 of 2021, a persistent decrease in treatment coverage, and a decrease in the all-cause mortality rate from Q2 of 2020 to Q4 of 2021. The multivariable analysis showed that the reduction in the tuberculosis case notification rate was associated with a higher COVID-19 incidence rate (adjusted odds ratio 3·1, 95% CI 1·1-8·6, for the highest compared with the lowest group) and fewer GeneXpert machines for tuberculosis diagnosis (3·1, 1·0-9·4, for the lowest compared with the highest group) per 100 000 population. The reduction in tuberculosis treatment coverage was associated with higher COVID-19 incidence (adjusted odds ratio 11·7, 95% CI 1·5-93·4, for the highest compared with the lowest group), fewer primary health centres (10·6, 4·1-28·0, for the lowest compared with the middle-high group), and a very low number of doctors (0·3, 0·1-0·9, for the low-middle compared with the lowest group) per 100 000 population. No factors were shown to be significantly associated with all-cause mortality. INTERPRETATION: The COVID-19 pandemic adversely and unevenly affected the national tuberculosis programme across Indonesia, with the greatest impacts observed in districts with the lowest health-system capacity. These disruptions could lead to an escalation in tuberculosis transmission in the coming years, warranting the need for intensified efforts to control tuberculosis and strengthen local health systems. FUNDING: Wellcome Africa Asia Programme Vietnam. TRANSLATION: For the Bahasa translation of the abstract see Supplementary Materials section.</p

Locking bandwidth of two laterally coupled semiconductor lasers subject to optical injection

We report here for the first time (to our knowledge), a new and universal mechanism by which a two-element laser array is locked to external optical injection and admits stably injection-locked states within a nontrivial trapezoidal region. The rate equations for the system are studied both analytically and numerically. We derive a simple mathematical expression for the locking conditions, which reveals that two parallel saddle-node bifurcation branches, not reported for conventional single lasers subject to optical injection, delimit the injection locking range and its width. Important parameters are the linewidth enhancement factor, the laser separation, and the frequency offset between the two laterally-coupled lasers; the influence of these parameters on locking conditions is explored comprehensively. Our analytic approximations are validated numerically by using a path continuation technique as well as direct numerical integration of the rate equations. More importantly, our results are not restricted by waveguiding structures and uncover a generic locking behavior in the lateral arrays in the presence of injection

Defining binding efficiency and specificity of auxins for SCF(TIR1/AFB)-Aux/IAA co-receptor complex formation.

Structure-activity profiles for the phytohormone auxin have been collected for over 70 years, and a number of synthetic auxins are used in agriculture. Auxin classification schemes and binding models followed from understanding auxin structures. However, all of the data came from whole plant bioassays, meaning the output was the integral of many different processes. The discovery of Transport Inhibitor-Response 1 (TIR1) and the Auxin F-Box (AFB) proteins as sites of auxin perception and the role of auxin as molecular glue in the assembly of co-receptor complexes has allowed the development of a definitive quantitative structure-activity relationship for TIR1 and AFB5. Factorial analysis of binding activities offered two uncorrelated factors associated with binding efficiency and binding selectivity. The six maximum-likelihood estimators of Efficiency are changes in the overlap matrixes, inferring that Efficiency is related to the volume of the electronic system. Using the subset of compounds that bound strongly, chemometric analyses based on quantum chemical calculations and similarity and self-similarity indices yielded three classes of Specificity that relate to differential binding. Specificity may not be defined by any one specific atom or position and is influenced by coulomb matrixes, suggesting that it is driven by electrostatic forces. These analyses give the first receptor-specific classification of auxins and indicate that AFB5 is the preferred site for a number of auxinic herbicides by allowing interactions with analogues having van der Waals surfaces larger than that of indole-3-acetic acid. The quality factors are also examined in terms of long-standing models for the mechanism of auxin binding

Interactions between Surround Suppression and Interocular Suppression in Human Vision

Several types of suppression phenomena have been observed in the visual system. For example, the ability to detect a target stimulus is often impaired when the target is embedded in a high-contrast surround. This contextual modulation, known as surround suppression, was formerly thought to occur only in the periphery. Another type of suppression phenomena is interocular suppression, in which the sensitivity to a monocular target is reduced by a superimposed mask in the opposite eye. Here, we explored how the two types of suppression operating across different spatial regions interact with one another when they simultaneously exert suppressive influences on a common target presented at the fovea. In our experiments, a circular target grating presented to the fovea of one eye was suppressed interocularly by a noise pattern of the same size in the other eye. The foveal stimuli were either shown alone or surrounded by a monocular annular grating. The orientation and eye-of-origin of the surround grating were varied. We found that the detection of the foveal target subjected to interocular suppression was severely impaired by the addition of the surround grating, indicating strong surround suppression in the fovea. In contrast, when the interocular suppression was released by superimposing a binocular fusion ring onto both the target and the dichoptic mask, the surround suppression effect was found to be dramatically decreased. In addition, the surround suppression was found to depend on the contrast of the dichoptic noise with the greatest surround suppression effect being obtained only when the noise contrast was at an intermediate level. These findings indicate that surround suppression and interocular suppression are not independent of each other, but there are strong interactions between them. Moreover, our results suggest that strong surround suppression may also occur at the fovea and not just the periphery

Study of e+e−→ppˉe^+e^- \rightarrow p\bar{p} in the vicinity of ψ(3770)\psi(3770)

Using 2917 $\rm{pb}^{-1}$ of data accumulated at 3.773~$\rm{GeV}$, 44.5~$\rm{pb}^{-1}$ of data accumulated at 3.65~$\rm{GeV}$ and data accumulated during a $\psi(3770)$ line-shape scan with the BESIII detector, the reaction $e^+e^-\rightarrow p\bar{p}$ is studied considering a possible interference between resonant and continuum amplitudes. The cross section of $e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}$, $\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p})$, is found to have two solutions, determined to be ($0.059\pm0.032\pm0.012$) pb with the phase angle $\phi = (255.8\pm37.9\pm4.8)^\circ$ ($<$0.11 pb at the 90% confidence level), or $\sigma(e^+e^-\rightarrow\psi(3770)\rightarrow p\bar{p}) = (2.57\pm0.12\pm0.12$) pb with $\phi = (266.9\pm6.1\pm0.9)^\circ$ both of which agree with a destructive interference. Using the obtained cross section of $\psi(3770)\rightarrow p\bar{p}$, the cross section of $p\bar{p}\rightarrow \psi(3770)$, which is useful information for the future PANDA experiment, is estimated to be either ($9.8\pm5.7$) nb ($<17.2$ nb at 90% C.L.) or $(425.6\pm42.9)$ nb

A role for the fusogen eff-1 in epidermal stem cell number robustness in Caenorhabditis elegans

Developmental patterning in Caenorhabditis elegans is known to proceed in a highly stereotypical manner, which raises the question of how developmental robustness is achieved despite the inevitable stochastic noise. We focus here on a population of epidermal cells, the seam cells, which show stem cell-like behaviour and divide symmetrically and asymmetrically over post-embryonic development to generate epidermal and neuronal tissues. We have conducted a mutagenesis screen to identify mutants that introduce phenotypic variability in the normally invariant seam cell population. We report here that a null mutation in the fusogen eff-1 increases seam cell number variability. Using time-lapse microscopy and single molecule fluorescence hybridisation, we find that seam cell division and differentiation patterns are mostly unperturbed in eff-1 mutants, indicating that cell fusion is uncoupled from the cell differentiation programme. Nevertheless, seam cell losses due to the inappropriate differentiation of both daughter cells following division, as well as seam cell gains through symmetric divisions towards the seam cell fate were observed at low frequency. We show that these stochastic errors likely arise through accumulation of defects interrupting the continuity of the seam and changing seam cell shape, highlighting the role of tissue homeostasis in suppressing phenotypic variability during development.Funding: Some C. elegans strains were provided by the CGC, which is funded by NIH Office of Research Infrastructure Programs (P40 OD010440). This work was funded by the European Research Council (ROBUSTNET-639485

Serum Fetuin-A in hemodialysis: a link between derangement of calcium-phosphorus homeostasis and progression of atherosclerosis?

BACKGROUND: Fetuin A, a circulating inhibitor of ectopic calcification, is downregulated in hemodialysis and has been shown to predict cardiovascular mortality in this setting. The association of altered calcium-phosphorus with serum fetuin A levels is still a matter of debate. Although carotid intima-media thickness (cIMT) is a strong predictor of major cardiovascular events, its association with serum fetuin A levels is poorly defined. STUDY DESIGN: Cohort study. PARTICIPANTS &amp; SETTINGS: 174 uremic patients on long-term hemodialysis therapy enrolled in 4 university hospitals. PREDICTORS: Serum fetuin A levels at the beginning of the study (T0) and after 12 months (T12). OUTCOMES: Progression of atherosclerosis assessed by means of cIMT measurements at 24 months (T24); cardiovascular morbidity and mortality at 36 months. RESULTS: Serum fetuin A concentrations at T0 and T12 were 282.3 +/- 79.4 and 290.0 +/- 92.2 microg/mL, respectively. Mean T0 and T24 cIMT values were 1.02 +/- 0.2 and 1.06 +/- 0.2 mm, respectively (P &lt; 0.001). Fatal and nonfatal cardiovascular disease occurred in 36 and 86 patients by 36 months, respectively. In multivariate logistic regression, higher calcium-phosphorus product was associated with lower serum fetuin A level (odds ratio, 0.96; 95% confidence interval [CI], 0.93 to 1.00; P = 0.02). Multiple regression analysis showed that T0 serum fetuin A level was associated with T24 cIMT (P = 0.01) after adjustments for age, cholesterol level, high-sensitivity C-reactive protein level, previous cardiovascular events, and T0 cIMT. In a multivariate Cox regression analysis, cardiovascular mortality was independently associated with a 1-tertile lower T0 serum fetuin A level, and a 1-tertile higher T0 cIMT value was independently associated with greater cardiovascular mortality (hazard ratio, 0.45; 95% CI, 0.15 to 0.65; P = 0.007 and hazard ratio, 10.00; 95% CI, 3.16 to 31.73; P &lt; 0.001, respectively) after adjustment for age and previous cardiovascular events. LIMITATION: Length of follow-up. CONCLUSION: Calcium-phosphorus product in hemodialysis patients inversely correlated with serum fetuin A level, which, in turn, was associated inversely with progression of atherosclerotic lesions and cardiovascular mortality in this study population