The cAMP and cAMP-dependent protein kinase A (PKA) signaling cascade is a ubiquitous pathway acting downstream of multiple neuromodulators. We found that the phosphorylation of phosphodiesterase-4 ...(PDE4) by cyclin-dependent protein kinase 5 (Cdk5) facilitated cAMP degradation and homeostasis of cAMP/PKA signaling. In mice, loss of Cdk5 throughout the forebrain elevated cAMP levels and increased PKA activity in striatal neurons, and altered behavioral responses to acute or chronic stressors. Ventral striatum- or D1 dopamine receptor-specific conditional knockout of Cdk5, or ventral striatum infusion of a small interfering peptide that selectively targeted the regulation of PDE4 by Cdk5, produced analogous effects on stress-induced behavioral responses. Together, our results demonstrate that altering cAMP signaling in medium spiny neurons of the ventral striatum can effectively modulate stress-induced behavioral states. We propose that targeting the Cdk5 regulation of PDE4 could be a new therapeutic approach for clinical conditions associated with stress, such as depression.
Film cooling effectiveness were studied experimentally on rows of cylindrical holes with streamwise angles of 30°, 60° and 90°, in a flat plate test facility with a zero pressure gradient. Detailed ...effectiveness and heat transfer results for a single cylindrical hole at the same inclinations have been presented in Yuen and Martinez-Botas C.H.N. Yuen, R.F. Martinez-Botas, Film cooling characteristics of a single hole at various streamwise angles: Part I. Effectiveness, Int. J. Heat Mass Transfer 46 (2003) 221–235; C.H.N. Yuen, R.F. Martinez-Botas, Film cooling characteristics of a single hole at various streamwise angles: Part II. Heat transfer coefficient, Int. J. Heat Mass Transfer 46 (2003) 237–249 with the same test facility and measurement technique. This present investigation commenced with a single row of holes with two pitch-to-diameter ratios (
p/D) of 3 and 6. It then presents and discusses the effects of introducing inline and staggered rows for each streamwise angle and pitch-to-diameter ratio. The row spacing in the inline and staggered rows is 12.5 diameters in the streamwise direction. The short but engine representative hole length (
L/D
=
4) is constant for all geometries. The blowing ratio ranges from 0.33 to 2, and the freestream Reynolds number based on the freestream velocity and hole diameter (
Re
D) was 8563. Both local values and laterally averaged ones are presented, the latter refers to the averaged value across the central hole. The current results are compared with the experimental results obtained by other researchers, the effects of the additional inline and staggered rows, and of the variations in injection angle, pitch-to-diameter ratio are described.
The objectives of the present study are to provide a consistent set of measurements in terms of effectiveness and heat transfer coefficients presented in the companion paper C.H.N. Yuen, R.F. Martinez-Botas, Film cooling characteristics of rows of round holes at various streamwise angles: Part II. Heat transfer coefficient, Int. J. Heat Mass Transfer, in press, obtained systematically with the same test facility, and to deliver a better understanding of film cooling performance. The present results also serve as a database with 105 test cases, in addition to the 21 cases presented in C.H.N. Yuen, R.F. Martinez-Botas, Film cooling characteristics of a single hole at various streamwise angles: Part I. Effectiveness, Int. J. Heat Mass Transfer 46 (2003) 221–235, for future numerical modelling.
Probing magnetic fields in giant molecular clouds is often challenging. Fortunately, recent simulations show that analysis of velocity gradients (the velocity gradient technique; VGT) can be used to ...map out the magnetic field morphology of different physical layers within molecular clouds when applied to CO isotopologues with different optical depths. Here, we test the effectiveness of the VGT in reconstructing the magnetic field structure of the molecular cloud Vela C, employing seven chemical tracers that have different optical depths, i.e., 12CO, 13CO, C18O, CS, HNC, HCO+, and HCN. Our results show good correspondence between the magnetic field morphology inferred from velocity gradients using these different molecular tracers and the magnetic field morphology inferred from BLASTPol polarization observations. We also explore the possibility of using a combination of velocity gradients for multiple chemical tracers to explain the structure of the magnetic field in molecular clouds. We search for signatures of gravitational collapse in the alignment of the velocity gradients and magnetic field and conclude that collapsing regions constitute a small fraction of the cloud.
Live streaming surgery is a developing communication platform in medicine. To maximize the technological advances that allow for the live streaming of surgery, it is crucial to have an understanding ...of the various video-capturing devices that are available and their pros and cons of implementation. Possible barriers to the widespread use of live streaming surgery include cost, concerns about patient safety and privacy, and limited understanding of the current available resources. In this article, we present the results of our literature review of techniques for live streaming of surgery as a means to inform readers and promote their implementation.
We conducted a literature review of the literature to identify previous articles indexed in PubMed and Ovid. We used the following search terms: Surgery AND Streaming, which generated 32 articles for initial review. References were reviewed within each document to find similar articles that were not captured by the initial search. The article selection criteria were peer-reviewed publications, case reports, and case series describing the use of live surgical streaming technologies.
Literature review showed enhanced surgeon interaction with viewers and improved anatomy scores with the widespread use of live streaming. Surgeons reported positive feedback and wished to engage in more sessions in the future. The largest barriers to implementation of streaming technology are video quality through the Internet and patient information protection.
Live streaming of surgery for educational purposes has not been widely accepted in surgical training programs to date. Streaming accessibility has advanced over the past 2 decades with the availability of handheld mobile devices. However, little has been done to allow for live streaming of surgery to trainees in a manner compliant with the Health Portability Insurance and Accountability Act.
Objective
To determine if the use of magnesium sulphate postdelivery reduces the risk of eclampsia in women with severe pre‐eclampsia exposed to at least 8 hours of magnesium sulphate before ...delivery.
Design
Randomised multicentre controlled trial.
Setting
Latin America.
Population
Women with severe pre‐eclampsia that had received a 4‐g loading dose followed by 1 g per hour for 8 hours as maintenance dose before delivery.
Methods
In all, 1113 women were randomised; 555 women were randomised to continue the infusion of magnesium sulphate for 24 hours postpartum and 558 were randomised to stopping the magnesium sulphate infusion immediately after delivery.
Outcome measures
Primary outcome was the incidence of eclampsia in the first 24 hours postdelivery. Secondary outcomes included maternal death, maternal complications, time to start ambulation and time to start lactation.
Results
The maternal characteristics at randomisation between the groups were not different. There were no differences in the rate of eclampsia; 1/555 (0.18%) versus 2/558 (0.35%) relative risk (RR 0.7, 95% CI 0.1–3.3; P = 0.50 or maternal complications between the groups (RR 1.0, 95% CI 0.8–1.2; P = 0.76). Time to start ambulation was significantly shorter in the no magnesium sulphate group (18.1 ± 10.6 versus 11.8 ± 10.8 hours; P = 0.0001) and time to start lactation was equally shorter in the no magnesium sulphate group (24.1 ± 17.1 versus 17.1 ± 16.8 hours; P = 0.0001).
Conclusions
Women with severe pre‐eclampsia treated with a minimum of 8 hours of magnesium sulphate before delivery do not benefit from continuing the magnesium sulphate for 24 hours postpartum.
Tweetable
No benefit of continuing magnesium sulphate postpartum in severe pre‐eclampsia exposed to this drug for a minimum of 8 hours before delivery.
Tweetable
No benefit of continuing magnesium sulphate postpartum in severe pre‐eclampsia exposed to this drug for a minimum of 8 hours prior to delivery.
BACKGROUND AND PURPOSE
The Mediterranean-style diet is widely advocated for the prevention of cardiovascular diseases (CVD). Meanwhile, blood pressure variability (BPV) is a novel risk factor for ...CVD. It is unknown whether dietary pattern plays a role in modulating BPV.
METHODS
We prospectively followed-up 274 consecutive patients with stable coronary artery disease (CAD). The Mediterranean diet score (MDS) was derived for all individuals upon recruitment, blood pressure (BP) was measured during each subsequent clinic visit and the visit-to-visit BPV was calculated. The occurrence of major adverse cardiovascular events (MACEs) and all-cause mortality was monitored.
RESULTS
After a mean follow-up of 77±12 months, 16.1% of the study population developed MACEs. About 11.3% died from all causes. Patients who developed MACEs or all-cause mortality had a greater systolic BPV compared to those who did not develop an adverse event. Patients who developed a MACE had a lower MDS and further analysis revealed those who developed a stroke had a lower MDS compared with those who did not develop a stroke, but there were no significant differences in MDS between CAD patients with or without subsequent acute coronary syndrome, cardiovascular, or all-cause mortality. After adjusting for confounding variables, a high MDS was an independent predictor for low systolic BPV (B −0.74, 95% confidence interval −1.27 to −0.21, P < 0.01) and was noted to be protective against subsequent development of stroke (hazards ratio 0.48, 95% confidence interval 0.24 to 0.94, P = 0.03).
CONCLUSIONS
Among patients with CAD, a higher MDS is associated with a lower visit-to-visit BPV and with lower stroke risk.
Primary and metastatic prostate cancers have low mutation rates and recurrent alterations in a small set of genes, enabling targeted sequencing of prostate cancer-associated genes as an efficient ...approach to characterizing patient samples (compared to whole-exome and whole-genome sequencing). For example, targeted sequencing provides a flexible, rapid, and cost-effective method for genomic assessment of patient-derived cell lines to evaluate fidelity to initial patient tumor samples.
We developed a prostate cancer-specific targeted next-generation sequencing (NGS) panel to detect alterations in 62 prostate cancer-associated genes as well as recurring gene fusions with ETS family members, representing the majority of common alterations in prostate cancer. We tested this panel on primary prostate cancer tissues and blood biopsies from patients with metastatic prostate cancer. We generated patient-derived cell lines from primary prostate cancers using conditional reprogramming methods and applied targeted sequencing to evaluate the fidelity of these cell lines to the original patient tumors.
The prostate cancer-specific panel identified biologically and clinically relevant alterations, including point mutations in driver oncogenes and ETS family fusion genes, in tumor tissues from 29 radical prostatectomy samples. The targeted panel also identified genomic alterations in cell-free DNA and circulating tumor cells (CTCs) from patients with metastatic prostate cancer, and in standard prostate cancer cell lines. We used the targeted panel to sequence our set of patient-derived cell lines; however, no prostate cancer-specific mutations were identified in the tumor-derived cell lines, suggesting preferential outgrowth of normal prostate epithelial cells.
We evaluated a prostate cancer-specific targeted NGS panel to detect common and clinically relevant alterations (including ETS family gene fusions) in prostate cancer. The panel detected driver mutations in a diverse set of clinical samples of prostate cancer, including fresh-frozen tumors, cell-free DNA, CTCs, and cell lines. Targeted sequencing of patient-derived cell lines highlights the challenge of deriving cell lines from primary prostate cancers and the importance of genomic characterization to credential candidate cell lines. Our study supports that a prostate cancer-specific targeted sequencing panel provides an efficient, clinically feasible approach to identify genetic alterations across a spectrum of prostate cancer samples and cell lines.
Abstract
Neutralization of Omicron subvariants by different bivalent vaccines has not been well evaluated. This study characterizes neutralization against Omicron subvariants in 98 individuals on ...dialysis or with a kidney transplant receiving the BNT162b2 (BA.4/BA.5) or mRNA-1273 (BA.1) bivalent COVID-19 vaccine. Neutralization against Omicron BA.1, BA.5, BQ.1.1, and XBB.1.5 increased by 8-fold one month following bivalent vaccination. In comparison to wild-type (D614G), neutralizing antibodies against Omicron-specific variants were 7.3-fold lower against BA.1, 8.3-fold lower against BA.5, 45.8-fold lower against BQ.1.1, and 48.2-fold lower against XBB.1.5. Viral neutralization was not significantly different by bivalent vaccine type for wild-type (D614G) (P = 0.48), BA.1 (P = 0.21), BA.5 (P = 0.07), BQ.1.1 (P = 0.10), nor XBB.1.5 (P = 0.10). Hybrid immunity conferred higher neutralizing antibodies against all Omicron subvariants. This study provides evidence that BNT162b2 (BA.4/BA.5) and mRNA-1273 (BA.1) induce similar neutralization against Omicron subvariants, even when antigenically divergent from the circulating variant.
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