Background
We have shown that testosterone administration suppresses hepcidin, stimulates iron‐dependent erythropoiesis, and increases hemoglobin and hematocrit.
Objective
We investigated whether ...testosterone‐mediated suppression of hepcidin plays an essential role in mediating testosterone's stimulatory effects on erythropoiesis.
Methods
We utilized two mouse models to elucidate the role of hepcidin as a mediator of testosterone's effects on erythropoiesis: First, we used a whole‐body hepcidin knockout (HepKO) mouse. Because testosterone's effects on hepcidin expression are mediated through androgen receptor, we also utilized a liver‐specific androgen receptor knockout mouse (L‐ArKO). Effects of 6 weeks of testosterone (50 mg/kg weekly) administration relative to vehicle on hemoglobin and hematocrit, red blood cell indices, and markers of iron stores and availability were compared between wild‐type (WT) and the two genetically modified mouse models.
Results
HepKO mice had significantly higher baseline levels of hemoglobin, hematocrit, serum and liver iron, and ferritin than WT mice. Compared to vehicle group, testosterone administration was associated with significant increases in hematocrit, hemoglobin, red cell counts, reticulocyte count, reticulocyte hemoglobin, and serum iron levels in both HepKO and WT mice. Baseline hematocrit levels did not differ between WT and L‐ArKO mice. Compared to vehicle, testosterone treatment was associated with significantly greater increase in hematocrit, hemoglobin, red cell count, reticulocyte count, reticulocyte hemoglobin, and serum iron in WT and L‐ArKO mice.
Conclusion
Although hepcidin suppression by testosterone increases iron availability and erythropoiesis, hepcidin suppression is not essential for mediating testosterone's effects on erythropoiesis in healthy mice.
Abstract Placenta accreta is a condition when the placenta is abnormally adherent to the uterus. This can result in complications like severe haemorrhage, injuries to pelvic organs, possible need for ...Caesarian hysterectomy. There is always high risk of maternal morbidity and mortality. Over the last decade there has been gradual shift towards conservative management of placenta accreta involving uterine and placental conservation, with the main aim to reduce pelvic injury and to achieve haemostasis with the aid of intervention radiology by means of Uterine Artery embolisation and use of medical chemotherapeutic agents like Methotrexate. This strategy has previously been shown to reduce morbidity and mortality in carefully selected cases of Placenta accreta. We have successfully managed a case of Placenta percreta conservatively using Uterine Artery embolisation followed by Injection methotrexate.
Performance of a prototype TORCH time-of-flight detector Bhasin, S.; Blake, T.; Brook, N.H. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/2023, Letnik:
1050
Journal Article
Recenzirano
Odprti dostop
TORCH is a novel time-of-flight detector, designed to provide charged particle identification of pions, kaons and protons in the momentum range 2–20 GeV/c over a 9.5 m flight path. A detector module, ...comprising a 10 mm thick quartz plate, provides a source of Cherenkov photons which propagate via total internal reflection to one end of the plate. Here, the photons are focused onto an array of custom-designed Micro-Channel Plate Photo-Multiplier Tubes (MCP-PMTs) which measure their positions and arrival times. The target time resolution per photon is 70 ps which, for 30 detected photons per charged particle, results in a 10–15 ps time-of-flight resolution. A 1.25 m length TORCH prototype module employing two MCP-PMTs has been developed, and tested at the CERN PS using a charged hadron beam of 8 GeV/c momentum. The construction of the module, the properties of the MCP-PMTs and the readout electronics are described. Measurements of the collected photon yields and single-photon time resolutions have been performed as a function of particle entry points on the plate and compared to expectations. These studies show that the performance of the TORCH prototype approaches the design goals for the full-scale detector.
A dynamic neural network (DNN) based robust observer for uncertain nonlinear systems is developed. The observer structure consists of a DNN to estimate the system dynamics on-line, a dynamic filter ...to estimate the unmeasurable state and a sliding mode feedback term to account for modeling errors and exogenous disturbances. The observed states are proven to asymptotically converge to the system states of high-order uncertain nonlinear systems through Lyapunov-based analysis. Simulations and experiments on a two-link robot manipulator are performed to show the effectiveness of the proposed method in comparison to several other state estimation methods.
Context
In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal ...androgens with birth weight and early life weight gain in the offspring are scarce.
Design
We evaluated 516 mother–child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959–1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI
Z
-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression.
Results
Higher maternal androgen levels associated with lower BMIz at birth (
β
= − 0.39, 95% CI: − 0.73, − 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (
β
= − 0.72, 95% CI: − 1.40, − 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (
p
= 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03).
Conclusion
Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.
A spinal cord injury (SCI) is a devastating, life-changing event that has profoundly deleterious effects on an individual's health and well-being. Dysregulation of neuromuscular, cardiometabolic, and ...endocrine organ systems following an SCI contribute to excess morbidity, mortality and a poor quality of life. As no effective treatments currently exist for SCI, the development of novel strategies to improve the functional and health status of individuals living with SCI are much needed. To address this knowledge gap, the current study will determine whether a Home-Based Multimodality Functional Recovery and Metabolic Health Enhancement Program that consists of functional electrical stimulation of the lower extremity during leg cycling (FES-LC) plus arm ergometry (AE) administered using behavioral motivational strategies, and testosterone therapy, is more efficacious than FES-LC plus AE and placebo in improving aerobic capacity, musculoskeletal health, function, metabolism, and wellbeing in SCI.
This single-site, randomized, placebo-controlled, parallel group trial will enroll 88 community-dwelling men and women, 19 to 70 years of age, with cervical and thoracic level of SCI, ASIA Impairment Scale grade: A, B, C, or D, 6 months or later after an SCI. Participants randomized to the multimodality intervention will undergo 16 weeks of home-based FES-LC and AE training plus testosterone undecanoate. Testosterone undecanoate injections will be administered by study staff in clinic or by a visiting nurse in the participant's home. The control group will receive 16 weeks of home-based FES-LC and AE exercise plus placebo injections. The primary outcome of this trial is peak aerobic capacity, measured during an incremental exercise testing protocol. Secondary outcomes include whole body and regional lean and adipose tissue mass; muscle strength and power; insulin sensitivity, lipids, and inflammatory markers; SCI functional index and wellbeing (mood, anxiety, pain, life satisfaction and depressive symptoms); and safety.
We anticipate that a multimodality intervention that simultaneously addresses multiple physiological impairments in SCI will result in increased aerobic capacity and greater improvements in other musculoskeletal, metabolic, functional and patient-reported outcomes compared to the control intervention. The findings of this study will have important implications for improving the care of people living with an SCI.
ClinicalTrials.gov : ( NCT03576001 ). Prospectively registered: July 3, 2018.
Despite advancements in understanding the pathophysiology of Multiple Myeloma (MM), the cause of rapid progressing disease in a subset of patients is still unclear. MM's progression is facilitated by ...complex interactions with the surrounding bone marrow (BM) cells, forming a microenvironment that supports tumor growth and drug resistance. Understanding the immune microenvironment is key to identifying factors that promote rapid progression of MM. To accomplish this, we performed a multi-center single-cell RNA sequencing (scRNA-seq) study on 102,207 cells from 48 CD138
BM samples collected at the time of disease diagnosis from 18 patients with either rapid progressing (progression-free survival (PFS) < 18 months) or non-progressing (PFS > 4 years) disease. Comparative analysis of data from three centers demonstrated similar transcriptome profiles and cell type distributions, indicating subtle technical variation in scRNA-seq, opening avenues for an expanded multicenter trial. Rapid progressors depicted significantly higher enrichment of GZMK
and TIGIT
exhausted CD8
T-cells (P = 0.022) along with decreased expression of cytolytic markers (PRF1, GZMB, GNLY). We also observed a significantly higher enrichment of M2 tolerogenic macrophages in rapid progressors and activation of pro-proliferative signaling pathways, such as BAFF, CCL, and IL16. On the other hand, non-progressive patients depicted higher enrichment for immature B Cells (i.e., Pre/Pro B cells), with elevated expression for markers of B cell development (IGLL1, SOX4, DNTT). This multi-center study identifies the enrichment of various pro-tumorigenic cell populations and pathways in those with rapid progressing disease and further validates the robustness of scRNA-seq data generated at different study centers.
The TORCH time-of-flight detector Harnew, N.; Gao, R.; Hadavizadeh, T. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
03/2023, Letnik:
1048
Journal Article
Recenzirano
Odprti dostop
TORCH is a large-area time-of-flight (ToF) detector, proposed for the Upgrade-II of the LHCb experiment. It will provide charged hadron identification over a 2–20 GeV/c momentum range, given a 9.5m ...flight distance from the LHC interaction point. To achieve this level of performance, a 15ps timing resolution per track is required. A TORCH prototype module having a 1250×660×10mm3 fused-silica radiator plate and equipped with two MCP-PMTs has been tested in a 8GeV/c CERN test-beam. Single-photon time resolutions of between 70–100ps have been achieved, dependent on the beam position in the radiator. The measured photon yields agree with expectations.
Status of the TORCH time-of-flight project Harnew, N.; Bhasin, S.; Blake, T. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
02/2020, Letnik:
952
Journal Article
Recenzirano
Odprti dostop
TORCH is a time-of-flight detector, designed to provide charged π∕K particle identification up to a momentum of 10GeV/c for a 10m flight path. To achieve this level of performance, a time resolution ...of 15 ps per incident particle is required. TORCH uses a plane of quartz of 1 cm thickness as a source of Cherenkov photons, which are then focussed onto square Micro-Channel Plate Photomultipliers (MCP-PMTs) of active area 53 × 53mm2, segmented into 8 × 128 pixels equivalent. A small-scale TORCH demonstrator with a customised MCP-PMT and associated readout electronics has been successfully operated in a 5GeV/c mixed pion/proton beam at the CERN PS facility. Preliminary results indicate that a single-photon resolution better than 100ps can be achieved. The expected performance of a full-scale TORCH detector for the Upgrade II of the LHCb experiment is also discussed.
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