Using a large set of plant gene sequences we compared individual introns to their flanking exons. Both Zea mays and Arabidopsis thaliana introns are U-rich but display no apparent bias for A. We ...identified fifteen 11-mer U-rich motifs as frequent elements of maize introns, and these are virtually absent from exons. By mutagenesis, we show that the single U-rich motif in the Bronze2 intron of maize plays a key role in intron processing in vivo.
The beta-carboline FG7142 is a partial inverse agonist at benzodiazepine receptors. We have shown previously that a single dose of this drug causes an upregulation of cortical beta-adrenoceptor ...numbers in mouse cerebral cortex. This rise was seen seven days, but not 15-30 min or 24 h after FG7142 administration. We now report that two weeks pretreatment with the tricyclic antidepressant desipramine prevented the beta-adrenoceptor upregulation after a single dose of FG7142, although desipramine alone did not alter beta-adrenoceptor number. We also studied the effects of desipramine pretreatment on other pharmacological effects of FG7142 to see which of these effects might be related to the beta-adrenoceptor changes. Desipramine pretreatment caused a small, but significant, decrease in the depression of locomotor activity, but no change in the hypothermic action of FG7142. The possibility that upregulation of beta-adrenoceptors by FG7142 may be related to the behavioural actions of this compound is discussed.
Oleanane has been reported in Upper Cretaceous and Tertiary source rocks and their related oils and has been suggested as a marker for flowering plants. Correspondence of oleanane concentrations ...relative to the ubiquitous microbial marker 17 alpha-hopane with angiosperm diversification (Neocomian to Miocene) suggests that oleanane concentrations in migrated petroleum can be used to identify the maximum age of unknown or unavailable source rock. Rare occurrences of pre-Cretaceous oleanane suggest either that a separate lineage leads to the angiosperms well before the Early Cretaceous or that other plant groups have the rarely expressed ability to synthesize oleanane precursors
PURPOSETo report the case of an adult female who presented on different occasions with recurrent uveitis provoked by initiating therapy of two recently approved agents, dabrafenib and pembrolizumab, ...for treatment of metastatic melanoma. OBSERVATIONSA 61 year old female presented with bilateral anterior uveitis after initiating therapy with dabrafenib for advanced metastatic melanoma. Her symptoms resolved and exam improved with oral and topical steroid therapy. Months later, she was started on pembrolizumab and transitioned off dabrafenib. Within days of starting pembrolizumab, she developed recurrent bilateral uveitis. This responded to escalating doses of topical and oral corticosteroid therapy and resolved following discontinuation of pembrolizumab. Nine months later, our patient received her third dose of pembrolizumab due to further progression of melanoma and within three days developed blurry vision, photophobia and subsequent ophthalmologic exam demonstrated bilateral panuveitis. CONCLUSIONS AND IMPORTANCEDabrafenib and pembrolizumab therapy have both previously been associated with uveitis. Here, we document a case of a woman who developed acute uveitis in response to beginning therapy with dabrafenib and then later developed acute uveitis soon after initiating pembrolizumab. To our knowledge, this is the first time this uncommon side-effect has been reported in the same patient after receiving sequential targeted agents and checkpoint inhibitors.
Abstract
Background
The determinants of coronavirus disease 2019 (COVID-19) disease severity and extrapulmonary complications (EPCs) are poorly understood. We characterized relationships between ...severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNAemia and disease severity, clinical deterioration, and specific EPCs.
Methods
We used quantitative and digital polymerase chain reaction (qPCR and dPCR) to quantify SARS-CoV-2 RNA from plasma in 191 patients presenting to the emergency department with COVID-19. We recorded patient symptoms, laboratory markers, and clinical outcomes, with a focus on oxygen requirements over time. We collected longitudinal plasma samples from a subset of patients. We characterized the role of RNAemia in predicting clinical severity and EPCs using elastic net regression.
Results
Of SARS-CoV-2–positive patients, 23.0% (44 of 191) had viral RNA detected in plasma by dPCR, compared with 1.4% (2 of 147) by qPCR. Most patients with serial measurements had undetectable RNAemia within 10 days of symptom onset, reached maximum clinical severity within 16 days, and symptom resolution within 33 days. Initially RNAemic patients were more likely to manifest severe disease (odds ratio, 6.72 95% confidence interval, 2.45–19.79), worsening of disease severity (2.43 1.07–5.38), and EPCs (2.81 1.26–6.36). RNA loads were correlated with maximum severity (r = 0.47 95% confidence interval, .20–.67).
Conclusions
dPCR is more sensitive than qPCR for the detection of SARS-CoV-2 RNAemia, which is a robust predictor of eventual COVID-19 severity and oxygen requirements, as well as EPCs. Because many COVID-19 therapies are initiated on the basis of oxygen requirements, RNAemia on presentation might serve to direct early initiation of appropriate therapies for the patients most likely to deteriorate.
Measurement of severe acute respiratory syndrome coronavirus 2 RNA from the plasma of patients with coronavirus disease 2019, using digital polymerase chain reaction, can predict disease severity, clinical deterioration, and extrapulmonary complications and may help guide patient triage and management.
Purpose The objective of this study was to investigate the effects of polymer type and storage relative humidity (RH) on the crystallization kinetics of felodipine from amorphous solid dispersions. ...Methods Crystallization of the model drug felodipine from amorphous solid dispersion samples containing poly(vinyl pyrrolidone) (PVP) and hypromellose acetate succinate (HPMCAS) were evaluated. Samples at three different drug-polymer weight ratios (10, 25, and 50 wt. % polymer) were prepared and stored at six different RHs (0%, 32%, 52% or 66%, 75%, 86%, and 93%). Periodically, the fraction of the drug that had crystallized from the samples was quantified using powder X-ray diffractometry (PXRD). Results Felodipine crystallization rates from PVP-containing dispersions were found to be very sensitive to changes in storage RH, while crystallization rates from HPMCAS-containing dispersions were not. PVP and HPMCAS were similar in terms of their ability to inhibit crystallization at low RH, but when the storage RH was increased to 75% or above, felodipine crystallization from PVP-containing solid dispersions proceeded much faster. It is hypothesized that this trend was caused by moisture-induced drug-polymer immiscibility in PVP-felodipine system. For PVP-containing solid dispersion samples stored at 75% RH and above, crystallization of the model drug felodipine seemed to approach a kinetic plateau, whereby a fraction of the drug still remained amorphous even after storage for 500 days or more. Conclusions The physical stability of solid dispersions as a function of RH is highly dependent on the polymer used to form the solid dispersion, with PVP-containing dispersions being much less physically stable at high RH than HPMCAS-containing dispersions.
Radio bubbles in clusters of galaxies Dunn, R. J. H.; Fabian, A. C.; Taylor, G. B.
Monthly notices of the Royal Astronomical Society,
12/2005, Volume:
364, Issue:
4
Journal Article
Peer reviewed
Open access
We extend our earlier work on cluster cores with distinct radio bubbles, adding more active bubbles, i.e. those with GHz radio emission, to our sample and also investigating ‘ghost bubbles’, i.e. ...those without GHz radio emission. We have determined k, which is the ratio of the total particle energy to that of the electrons radiating between 10 MHz and 10 GHz. Constraints on the ages of the active bubbles confirm that the ratio of the energy factor, k, to the volume filling factor, f, lies within the range 1 ≲k/f≲ 1000. On the assumption that there is pressure equilibrium between the radio-emitting plasma and the surrounding thermal X-ray gas, none of the radio lobes has equipartition between the relativistic particles and the magnetic field. A Monte Carlo simulation of the data led to the conclusion that there are not enough bubbles present in the current sample to be able to determine the shape of the population. An analysis of the ghost bubbles in our sample showed that on the whole they have higher upper limits on k/f than the active bubbles, especially when compared with those in the same cluster. A study of the Brightest 55 (B55) cluster sample shows that 17, possibly 20, clusters required some form of heating as they have a short central cooling time, tcool≤ 3 Gyr, and a large central temperature drop, Tcentre/Touter < 1/2. Of these, between 12 (70 per cent) and 15 (75 per cent) contain bubbles. This indicates that the duty cycle of bubbles is large in such clusters and that they can play a major role in the heating process.
The objective of this study was to investigate the phase behavior of amorphous solid dispersions composed of a hydrophobic drug and a hydrophilic polymer following exposure to elevated relative ...humidity. Infrared (IR) spectroscopy, differential scanning calorimetry (DSC) and moisture sorption analysis were performed on five model systems (nifedipine−poly(vinylpyrrolidone) (PVP), indomethacin−PVP, ketoprofen−PVP, droperidol−PVP, and pimozide−PVP) immediately after production of the amorphous solid dispersions and following storage at room temperature and elevated relative humidity. Complete miscibility between the drug and the polymer immediately after solid dispersion formation was confirmed by the presence of specific drug−polymer interactions and a single glass transition (T g) event. Following storage at elevated relative humidity (75−94% RH), nifedipine−PVP, droperidol−PVP, and pimozide−PVP dispersions formed drug-rich and polymer-rich amorphous phases prior to crystallization of the drug, while indomethacin−PVP and ketoprofen−PVP dispersions did not. Drug crystallization in systems exhibiting amorphous−amorphous phase separation initiated earlier (<6 days at 94% RH) when compared to systems that remained miscible (≥46 days at 94% RH). Evidence of moisture-induced amorphous−amorphous phase separation was observed following storage at as low as 54% RH for the pimozide−PVP system. It was concluded that, when an amorphous molecular level solid dispersion containing a hydrophobic drug and hydrophilic polymer is subjected to moisture, drug crystallization can occur via one of two routes: crystallization from the plasticized one-phase solid dispersion, or crystallization from a plasticized drug-rich amorphous phase in a two-phase solid dispersion. In the former case, the polymer is still present in the same phase as the drug, and can inhibit crystallization to a greater extent than the latter scenario, where the polymer concentration in the drug phase is reduced as a result of the amorphous−amorphous phase separation. The strength of drug−polymer interactions appears to be important in influencing the phase behavior.
Interaction between maternal obesity, intrauterine environment and adverse clinical outcomes of newborns has been described.
Using statewide birth certificate data, this retrospective, ...matched-control cohort study compared paired birth weights and complications of infants born to women before and after Roux-en-Y gastric bypass surgery (RYGB) and to matched obese non-operated women in several different groups. Women who had given birth to a child before and after RYGB (group 1; n=295 matches) and women with pregnancies after RYGB (group 2; n=764 matches) were matched to non-operated women based on age, body mass index (BMI) prior to both pregnancy and RYGB, mother's race, year of mother/s birth, date of infant births and birth order. In addition, birth weights of 13 143 live births before and/or after RYGB of their mothers (n=5819) were compared (group 3).
Odds ratios (ORs) for having a large-for-gestational-age (LGA) neonate were significantly less after RYGB than for non-surgical mothers: ORs for groups 1 and 2 were 0.19 (0.08-0.38) and 0.33 (0.21-0.51), respectively. In contrast, ORs in all three groups for risk of having a small for gestational age (SGA) neonate were greater for RYGB mothers compared to non-surgical mothers (ORs were 2.16 (1.00-5.04); 2.16 (1.43-3.32); and 2.25 (1.89-2.69), respectively). Neonatal complications were not different for group 1 RYGB and non-surgical women for the first pregnancy following RYGB. Pregnancy-induced hypertension and gestational diabetes were significantly lower for the first pregnancy of mothers following RYGB compared to matched pregnancies of non-surgical mothers.
Women who had undergone RYGB not only had lower risk for having an LGA neonate compared to BMI-matched mothers, but also had significantly higher risk for delivering an SGA neonate following RYGB. RYGB women were less likely than non-operated women to have pregnancy-related hypertension and diabetes.
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