A limited number of studies have reported associations of markers of liver injury, including elevated concentrations of aspartate aminotransferase (AST) and alanine aminotransferase (ALT), with ...prospective risk of type 2 diabetes. However, only one study has adjusted for a detailed measure of insulin sensitivity (insulin sensitivity index S(i)), which is important given associations of obesity and S(i) with nonalcoholic fatty liver disease (NAFLD). Our objective was to investigate the associations of elevated AST and ALT with incident type 2 diabetes among 906 participants in the Insulin Resistance Atherosclerosis Study who were nondiabetic at baseline. S(i) and acute insulin response (AIR) were measured directly from the frequently sampled intravenous glucose tolerance test among black, Hispanic, and non-Hispanic white participants aged 40-69 years. After 5.2 years, 148 individuals had developed type 2 diabetes. Baseline AST and ALT were positively correlated with fasting insulin (r = 0.22 and r = 0.35, respectively), waist circumference (r = 0.18 and r = 0.34), and fasting glucose (r = 0.13 and r = 0.29) and inversely with S(i) (r = -0.18 and r = -0.30; all P < 0.0001). In separate logistic regression models adjusting for age, sex, ethnicity, clinical center, and alcohol consumption, participants in the highest quartiles (Q4) of AST and ALT were at significantly increased risk of incident type 2 diabetes compared with those in the lowest three quartiles (Q1-Q3): AST: odds ratio (OR) 1.73 (95% CI 1.17-2.57); ALT: OR 2.32 (1.36-3.75). After further adjustment for smoking, waist circumference, triglyceride, HDL, impaired glucose tolerance, S(i), and AIR, both AST and ALT remained significantly associated with incident type 2 diabetes: AST, Q4 vs. Q1-Q3: OR 1.98 (1.23-3.17); ALT, Q4 vs. Q1-Q3: OR 2.00 (1.22-3.28). There were no interactions of sex, ethnicity, obesity, impaired glucose tolerance, or S(i) with AST or ALT in the prediction of type 2 diabetes. When entered into the same model with adjustment for demographic variables, both C-reactive protein and ALT independently predicted type 2 diabetes. In addition, AST and ALT were positively associated with incident type 2 diabetes after excluding former and moderate to heavy drinkers. In conclusion, AST and ALT independently predict type 2 diabetes. Baseline elevations of these markers may reflect NAFLD or related pathologies.
The activity of vinorellbine, a new semisynthetic vinca alkaloid, was evaluated against a battery of human tumor xenografts derived from adult and pediatric CNS malignancies.
Tumors included adult ...high-grade gliomas (D-54 MG, D-245 MG), childhood high-grade gliomas (D-212 MG, D-456 MG), medulloblastomas (D-341 MED, D-487 MED), ependymomas (D-612 EP, D-528 EP), and a mismatch repair-deficient procarbazine-resistant glioma D-245 MG (PR). Tumors were grown subcutaneously in athymic nude mice and vinorelbine was administered at a dose of 11 mg/kg on days 1, 5, and 9. Additionally, vinorelbine was also administered in combination with BCNU against D-54 MG.
Vinorelbine produced statistically significant growth delays in D-456 MG, D-245 MG, and D-245 MG (PR). No statistically significant growth delays were observed in D-54 MG, D-487 MED, D-212 MG, D-528 EP, D-341 MED or D-612 EP. The antitumor effects of the vinorelbine/BCNU combination were additive. Growth delays observed in the procarbazine-resistant line D-245 MG (PR) were greater than twofold the delays seen in the parent line (D-245 MG). Vincristine was equally potent against D-245 MG and D-245 MG (PR). Taxol demonstrated little activity against D-245 MG but produced 32- and 18-day growth delays in D245 MG (PR).
These studies indicate that vinorelbine possesses antitumor activity against several glioma tumor xenografts with marked activity in a mismatch repair deficient-tumor.
In addition to predicting cardiovascular disease (CVD) morbidity and mortality, the metabolic syndrome is strongly associated with the development of type 2 diabetes mellitus (DM), itself an ...important risk factor for CVD. Our objective was to compare the ability of various metabolic syndrome criteria (including those recently proposed by the International Diabetes Federation), markers of insulin resistance (IR) and inflammation, and impaired glucose tolerance (IGT) in the prediction of DM and to determine whether various proposed modifications to the National Cholesterol Education program (NCEP) metabolic syndrome definition improved predictive ability.
We examined 822 subjects in the Insulin Resistance Atherosclerosis Study aged 40 to 69 years who were nondiabetic at baseline. After 5.2 years, 148 individuals had developed DM. IGT, metabolic syndrome definitions, and IR markers all significantly predicted DM, with odds ratios ranging from 3.4 to 5.4 (all P<0.001), although there were no significant differences in the areas under the receiver operator characteristic (AROC) curves between the definitions. Modifying or requiring obesity, glucose, or IR components in NCEP-defined metabolic syndrome did not significantly alter the predictive ability of the definition under AROC curve criteria (all P>0.05). Similarly, although IR and inflammation variables were significantly associated with incident DM when included in multivariate models with NCEP-defined metabolic syndrome (all P<0.01), expanding the definition by adding these variables as components did not significantly alter the predictive ability of the definition under AROC curve criteria (all P>0.05).
The International Diabetes Federation and NCEP metabolic syndrome definitions predicted DM at least as well as the World Health Organization definition, despite not requiring the use of oral glucose tolerance testing or measures of IR or microalbuminuria. Modifications or additions to the NCEP metabolic syndrome definition had limited impact on the prediction of DM.
To test the hypothesis that preoperative lumbar epidural morphine improves postoperative pain control and ventilatory function after transsternal thymectomy in patients with myasthenia gravis.
The ...study design was randomized, placebo-controlled, and double-blind.
After surgery, all patients were admitted to the Neuroscience Critical Care Unit for evaluation and treatment.
All patients with myasthenia gravis who presented to the hospital for thymectomy were asked to participate in the study. Twenty patients were randomized to either the placebo or epidural morphine groups.
Patients received either epidural morphine (7 mg in 14 mL of sterile saline) or saline (14 mL) before induction of anesthesia. Supplemental iv opioids were administered intraoperatively, with need determined by the anesthesiologist.
The main outcome measures were indicators of postoperative pain (e.g., Visual Analog Pain Score, requirement for supplemental opioid administration, respiratory rate) and ventilatory function (e.g., forced vital capacity, negative inspiratory pressure).
Immediately after surgery, the Visual Analog Pain Score in the placebo group was twice as high as the score in the epidural morphine group (placebo 7.0 +/- 1.3; epidural morphine 3.5 +/- 1.2, p less than or equal to .05). During the first eight postoperative hours, the placebo group required more opioids (0.22 +/- 0.03 vs. 0.12 +/- 0.04 mg/kg morphine equivalents, p less than or equal to .06) than the epidural morphine group. Later, both groups received similar amounts of opioids. Patients receiving epidural morphine had better initial recovery of forced vital capacity (at 8 hrs: 55 +/- 6% epidural morphine vs. 34 +/- 5% placebo of preoperative value, p less than or equal to .05). Respiratory rate was lower for the first 12 postoperative hours in the epidural morphine group, without a difference in PaCO2. There was no difference between groups for the duration of postoperative intubation or ventilation.
Preoperative lumbar epidural morphine facilitates postoperative analgesia and improves initial postoperative ventilatory performance.
Organ-specific functions of tissue-resident macrophages in the steady-state heart are unknown. Here, we show that cardiac macrophages facilitate electrical conduction through the distal ...atrioventricular node, where conducting cells densely intersperse with elongated macrophages expressing connexin 43. When coupled to spontaneously beating cardiomyocytes via connexin-43-containing gap junctions, cardiac macrophages have a negative resting membrane potential and depolarize in synchrony with cardiomyocytes. Conversely, macrophages render the resting membrane potential of cardiomyocytes more positive and, according to computational modeling, accelerate their repolarization. Photostimulation of channelrhodopsin-2-expressing macrophages improves atrioventricular conduction, whereas conditional deletion of connexin 43 in macrophages and congenital lack of macrophages delay atrioventricular conduction. In the Cd11bDTR mouse, macrophage ablation induces progressive atrioventricular block. These observations implicate macrophages in normal and aberrant cardiac conduction.
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•Tissue-resident macrophages abound in the mouse and human AV nodes•Connexin 43 connects macrophages with cardiomyocytes•Macrophages modulate the electrical activity of cardiomyocytes•Macrophages assist normal AV nodal conduction
Heart-resident macrophages directly modulate the electrical properties of cardiomyocytes.
The HOPE mass spectrometer of the Radiation Belt Storm Probes (RBSP) mission (renamed the Van Allen Probes) is designed to measure the
in situ
plasma ion and electron fluxes over 4
π
sr at each RBSP ...spacecraft within the terrestrial radiation belts. The scientific goal is to understand the underlying physical processes that govern the radiation belt structure and dynamics. Spectral measurements for both ions and electrons are acquired over 1 eV to 50 keV in 36 log-spaced steps at an energy resolution Δ
E
FWHM
/
E
≈15 %. The dominant ion species (H
+
, He
+
, and O
+
) of the magnetosphere are identified using foil-based time-of-flight (TOF) mass spectrometry with channel electron multiplier (CEM) detectors. Angular measurements are derived using five polar pixels coplanar with the spacecraft spin axis, and up to 16 azimuthal bins are acquired for each polar pixel over time as the spacecraft spins. Ion and electron measurements are acquired on alternate spacecraft spins. HOPE incorporates several new methods to minimize and monitor the background induced by penetrating particles in the harsh environment of the radiation belts. The absolute efficiencies of detection are continuously monitored, enabling precise, quantitative measurements of electron and ion fluxes and ion species abundances throughout the mission. We describe the engineering approaches for plasma measurements in the radiation belts and present summaries of HOPE measurement strategy and performance.
Serotiny is the prolonged storage of seeds in closed cones or fruits held within the crown of woody plants. It is widespread throughout fireprone vegetation with a predominantly winter rainfall, ...especially in Mediterrnanean-type ecosystems (MTEs). Nonstorage is a feature of fireprone vegetation with summer-dominant rainfall or nonfireprone vegetation. Serotiny confers fitness benefits on an individual when fire return intervals fall between age to reproductive maturity and the plant life span. The level of serotiny within and between species varies greatly along a continuum indicating highly plastic responses to different environmental conditions. Here we review how and why the traits that underpin this reproductive syndrome evolved and continue to control the occurrence of species in contemporary landscapes. We documented 1345 serotinous species in fireprone regions of Australia, South Africa, the Mediterranean Basin, North America, and Asia. The length of seed storage varies from a few years (weak serotiny) to >10 years (strong serotiny), with remarkable diversity even within clades. We show how the interplay between postfire and interfire seedling recruitment dictates the expression of serotiny along a strong serotiny/nonserotiny continuum, and that, where strong serotiny is favored, the 'gene support for serotiny' builds up over successive generations. Nonserotiny is favored in the absence of fire or occurs at intervals exceeding plant longevity, but also when the fire is so frequent that only resprouters can survive. We identify 23 traits associated with serotiny/nonserotiny syndromes that are subject to both environmental and phylogenetic constraints. While all are coordinated for maximum fitness, some traits, such as protection from granivores, are only indirectly related to the fire regime. Serotiny has a long history extending back to the Triassic. The rate of serotinous-lineage proliferation has fluctuated greatly over time but peaked over the last 5 million years. Nonserotinous species have evolved from serotinous ancestors in response to increased fire frequency, or as plants migrated to fire-free habitats. We note that contemporary shifts in climate, land-use, and exploitation have had a profound, but disproportionate, effect on the conservation status and evolutionary trajectory of serotinous species in MTEs. Escalating anthropogenic impacts increase the need to understand how and why serotiny is such a prominent feature of some fireprone ecosystems. We highlight avenues for future research and argue for the use of temporally based measures of serotiny to facilitate comparisons between studies.
Polyclonal convalescent plasma may be obtained from donors who have recovered from coronavirus disease 2019 (Covid-19). The efficacy of this plasma in preventing serious complications in outpatients ...with recent-onset Covid-19 is uncertain.
In this multicenter, double-blind, randomized, controlled trial, we evaluated the efficacy and safety of Covid-19 convalescent plasma, as compared with control plasma, in symptomatic adults (≥18 years of age) who had tested positive for severe acute respiratory syndrome coronavirus 2, regardless of their risk factors for disease progression or vaccination status. Participants were enrolled within 8 days after symptom onset and received a transfusion within 1 day after randomization. The primary outcome was Covid-19-related hospitalization within 28 days after transfusion.
Participants were enrolled from June 3, 2020, through October 1, 2021. A total of 1225 participants underwent randomization, and 1181 received a transfusion. In the prespecified modified intention-to-treat analysis that included only participants who received a transfusion, the primary outcome occurred in 17 of 592 participants (2.9%) who received convalescent plasma and 37 of 589 participants (6.3%) who received control plasma (absolute risk reduction, 3.4 percentage points; 95% confidence interval, 1.0 to 5.8; P = 0.005), which corresponded to a relative risk reduction of 54%. Evidence of efficacy in vaccinated participants cannot be inferred from these data because 53 of the 54 participants with Covid-19 who were hospitalized were unvaccinated and 1 participant was partially vaccinated. A total of 16 grade 3 or 4 adverse events (7 in the convalescent-plasma group and 9 in the control-plasma group) occurred in participants who were not hospitalized.
In participants with Covid-19, most of whom were unvaccinated, the administration of convalescent plasma within 9 days after the onset of symptoms reduced the risk of disease progression leading to hospitalization. (Funded by the Department of Defense and others; CSSC-004 ClinicalTrials.gov number, NCT04373460.).
Measurement of the dense cold thermal plasma in planetary ionospheres via orbiting spacecraft is challenging because ion energies are small (0–4 eV), densities can vary by four orders of magnitude, ...composition varies with altitude, spacecraft charging varies in time and must be measured very accurately, and instrumental effects (e.g., detector dead‐time and background) can be significant. The SupraThermal And Thermal Ion Composition instrument team has recently released a new set of data products that contain density moments of the primary ion species at Mars, including those derived at periapsis, subject to the full suite of calibration factors required. This article discusses the challenges associated with deriving these densities and provides examples of the key caveats that users of the data should be aware of. A preliminary statistical study of this new data set focuses on the structure and variability of Mars' ionosphere, demonstrating that solar zenith angle effects, the crustal magnetic fields, and electron precipitation on the nightside, drive the strongest structural features, consistent with photochemical theory and previous studies. Dayside ionospheric density profiles are highly repeatable below altitudes of 200 km, marking the region where photochemistry and collisions dominate. In the upper dayside ionosphere (altitudes >300–400 km) changes in the solar wind dynamic pressure on timescales of Mars Atmosphere and Volatile EvolutioN's orbit (hr) drive the largest (factors of 1–3) variability in ionospheric density. In contrast variability in ionospheric density peaks between 150 and 250 km altitude on the nightside (factors of 1–2), consistent with electron precipitation driving ionization in this region.
Plain Language Summary
Making accurate measurements of the ions present in planetary atmospheres via orbiting spacecraft is difficult due to the large changes in conditions encountered throughout spacecraft orbits. This paper describes the techniques implemented to address the full array of difficulties associated with measuring planetary ions at Mars using measurements made by the SupraThermal And Thermal Ion Composition instrument. These techniques are used to calculate ion densities in Mars' atmosphere and we perform a preliminary investigation of this new data set, revealing several important characteristics of how ions behave in Mars' atmosphere. In particular, we find that on the dayside of the planet, there is a transition region between the upper and lower atmosphere where planetary ions behave differently. Above this transition region planetary ions are influenced by forces that arise in the space environment about Mars, while below this transition region, planetary ions are well shielded from these effects. Our results provide insight into the processes that shape Mars' atmosphere and tell us how energy is transported through the Mars system.
Key Points
The calibration challenges and caveats of ion densities derived from SupraThermal And Thermal Ion Composition observations are discussed
Solar zenith angle effects and the crustal magnetic fields drive the strongest structural features in ionospheric density
A variety of processes drive ionospheric variability throughout different regions of the Martian ionosphere
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