Large Doses Research Articles

Formulating abiraterone acetate-HPMCAS-based amorphous solid dispersions: insights into in vitro and biorelevant dissolution assessments and pharmacokinetic evaluations.

Abiraterone acetate (ABTA) is used as a primary treatment for metastatic castration-resistant prostate cancer. Its low aqueous solubility results in inadequate dissolution and poor oral bioavailability (<10%), necessitating the consumption of large doses of ABTA (1000 mg per day) for desired efficacy. The aim of this study is to enhance the solubility, dissolution, and bioavailability of ABTA through amorphous solid dispersions (SDs). ABTA-SD was prepared via a solvent granulation method with different grades of hydroxypropyl methylcellulose acetate succinate (HPMCAS 716 and 912). The theoretical solubility parameter between ABTA and HPMCAS was below 7 MPa1/2, indicating miscibility between the drug and the polymer according to the Hansen solubility parameter. HPMCAS showed a remarkable recrystallization inhibition of up to 180 min compared to the free drug (10 min), maintaining the soluble drug in supersaturation state and exhibiting the "spring and parachute" phenomenon. ABTA-SD exhibited a higher solubility (1.16-fold to 52-fold) in different media than free ABTA. The results of DSC, PXRD, ATR-FTIR, and FE-SEM indicated that the crystallinity of ABTA was completely transformed to an amorphous form and maintained in the SD formulation. In vitro and bio-relevant dissolution behavior of ABTA was studied in various dissolution media, indicating the higher dissolution of ABTA-SD than that of free ABTA. The pharmacokinetic study conducted in Wistar rats revealed that C max and AUC0-t of the optimized ABTA-SD formulation were significantly enhanced by 1.92-fold and 2.87-fold, respectively, compared to those of free ABTA.

The hematopoietic activity of EPO is unfavorable to the treatment of bleomycin-induced pulmonary fibrosis in mice

The main function of erythropoietin (EPO) is to promote hematopoiesis and improve anemia. In addition, EPO also has many non-hematopoietic effects such as anti-inflammation, anti-apoptosis and anti-oxidation. To achieve the protective effects, large doses of EPO are required, so the probability of side effects increases. Previous studies have revealed that EPO can improve pulmonary fibrosis in mice, but it has not been clarified whether the hematopoiesis of EPO contributes to amelioration of pulmonary fibrosis and whether EPO improves overall mortality. Our results show that EPO decreases hydroxyproline content, α-sma and col-1 protein levels in mice with bleomycin-induced pulmonary fibrosis. However, compared with the control group, the weight loss and mortality rate of the EPO group were not improved, while the number of red blood cells (RBCs), hemoglobin (Hb), red cell width distribution-coefficient of variation (RDW-CV) and hematocrit (HCT) were significantly higher. Furthermore, we observed massive thrombosis in the lung of EPO treated lung fibrosis mice but not in control mice. Therefore, our results show that in the condition of lung fibrosis, the hematopoietic activity of exogenous EPO is not conducive to its tissue protective effect.

Trends in the use and nonmedical use of sedatives-hypnotics in the population aged 12 to 64 years in Taiwan: a comparative analysis of the national surveys in 2014 and 2018

BackgroundMany countries, including Taiwan, have tightened regulations on prescribing sedatives-hypnotics over the concern of their associated adverse health effects. However, it remains seldom investigated whether different age-sex strata have differential trends in national surveys over time for either the use or nonmedical use (NMU) of sedatives-hypnotics. Comparing Taiwan’s two national surveys in 2014 and 2018, we aimed to examine (1) the population’s trends for the prevalence of past-year use and NMU of sedatives-hypnotics overall and in age-sex strata; (2) trends for sociodemographic subgroups for those age-sex strata with significant changes in past-year use and NMU of sedatives-hypnotics over time; and (3) trends for sources of and motives for NMU of sedatives-hypnotics.MethodsThe national survey enrolled 17,837 participants in 2014 (response rate = 62.2%) and 18,626 participants in 2018 (response rate = 64.6%) of citizens aged 12–64 years. Each participant anonymously completed a computer-assisted self-interview. The questionnaire consisted of sociodemographic variables and the use of various psychoactive substances and sedative-hypnotics, among others. NMU of sedative-hypnotics was defined as using the drug without a prescription, or more frequently, or in larger doses than prescribed. To compare the prevalence between the two waves, we conducted multivariable logistic regression analysis and the difference-in-differences in prevalence was examined with an interaction term between survey year and sex.ResultsWe found decreasing trends in young adult (18–39 years old) males for both past-year use (3.07–2.29%) and NMU (0.84–0.18%), but increasing trends in adolescents (0.42–0.80%) and young adult females (2.91–3.81%) for past-year use and in adolescents (0.16–0.39%) and middle-aged adult (40–64 years old) females (0.73–1.14%) for past-year NMU of sedatives-hypnotics. Among the young and middle-aged adult females, the increasing trends for past-year use and NMU, respectively, were found to occur mainly in certain sociodemographic subgroups, with alcohol users being the overlapping subgroup.ConclusionsThe differential trends over time of past-year use or NMU of sedatives-hypnotics in different age-sex strata in the population have policy implications to curtail the increasing trend over time.

Revolutionizing X-ray Imaging: A Leap toward Ultra-Low-Dose Detection with a Cascade-Engineered Approach.

X-ray detection technology is essential in various fields, including medical imaging and security checks. However, exposure to large doses of X-rays poses considerable health risks. Therefore, it is crucial to reduce the radiation dosage without compromising detection efficiency. To address this concern, we propose an innovative cascade-engineered approach that uses two interconnected single-crystal devices to mitigate dark current and enhance the detection limit. Using laboratory-grown methylammonium lead bromide (MAPbBr3) perovskite single crystals, we engineered devices that significantly reduced detection thresholds and improved signal-to-noise ratios (SNRs). The detection threshold dropped from 590 nGy·s-1 with the conventional method to 100 nGy·s-1 using the cascade approach, surpassing the most recent record of 500 nGy·s-1 achieved for MAPbBr3 devices under nearly identical conditions. The dark current was halved compared to that of conventional devices, and spatial resolution improved from 5.6 to 8.5 lp·mm-1. Imaging trials confirmed improved resolution and effectiveness at low doses, highlighting the approach's potential for medical diagnostics that prioritizes reducing radiation exposure without compromising image quality. The groundbreaking nature of this approach is highlighted by its adaptability across diverse electrical environments and crystal types, as evident in CdTe crystals, indicating its potential for widespread utilization in low-dose leakage monitoring and commercial X-ray devices.

Development and Application of High-Internal-Phase Water-in-Oil Emulsions Using Amphiphilic Nanoparticle-Based Emulsifiers.

High-internal-phase water-in-oil (W/O) emulsions generated in situ have garnered considerable attention as novel profile control systems. However, conventional emulsifiers are unreactive and poorly dispersed in water, necessitating large dosages and resulting in poor injectivity. In this study, we synthesized amphiphilic nanoparticles (SiO2-NH2-DAC NPs) containing amine and long-chain alkyl groups using a one-pot method and investigated the stabilized emulsion properties. Our results indicated that W/O emulsions with a water-to-oil ratio (WOR) of 7:3 to 8:2 could be prepared with just 0.1 wt% of SiO2-NH2-DAC NPs under neutral and basic conditions, with demulsification occurring under acidic conditions (pH = 2.1), demonstrating the pH-responsiveness of the W/O emulsions. The emulsion viscosity increased from 150 to 2555 mPa·s at different WORs. An additional 18.7% oil recovery was achieved using SiO2-NH2-DAC NPs in a heterogeneous core, highlighting their potential as a promising profile control candidate.

Synthesis of bagasse-derived magnetic biochar for the removal of fluoride from water solution

ABSTRACT Fluoride levels in drinking water pose a significant environmental threat, and adsorption is a common technique. However, many adsorbent materials have drawbacks such as poor adsorption capabilities, extended contact times, high pH levels, and large dosages. A biochar-based magnetic composite adsorbent has been developed for water defluoridation using a chemical co-precipitation process to immobilize iron particles on the biochar surface. X-ray diffraction analysis, Fourier transformed infrared spectroscopy, Brunauer–Emmett–Teller, and scanning electron microscopy were used to analyse the composite. The central composite design was used to design laboratory tests, which included four input variables: solution pH, dosage, contact time, and initial concentration. The adsorbent dosage was 5.92 g/L, the aqueous pH was 5.79, the contact time was 66.48 min, and the initial fluoride concentration was 12.38 mg/L. The removal efficiency was predicted to be 98.61%, with a 98.55% removal efficiency at optimum conditions. The study concluded that the composite adsorbent can be a reliable and sustainable solution for fluoride removal from water.

A Mucous Permeable Local Delivery Strategy Based on Manganese-Enhanced Bacterial Cuproptosis-like Death for Bacterial Pneumonia Treatment.

Bacterial pneumonia is one of the most challenging global infectious diseases with high morbidity and mortality. Considering the antibiotic abuse and resistance of bacterial biofilms, a variety of metal-based materials have been developed. However, due to the high oxygen environment of the lungs, some aerobic infection bacteria have high tolerance to oxygen and ROS, and most of the metal-based materials based on ROS may not achieve good therapeutic effects. Inspired by the sensitivity of cuproptosis to aerobic respiratory cells, we designed a copper composite antibacterial nanoparticle and found that it can effectively induce cuproptosis-like death in the aerobic bacteria of the lungs. To address the challenge of in vivo application of cuproptosis, manganese dioxide was first incorporated to deplete protective glutathione, which can interact with copper and thus hinder the interaction of copper with proteins and assist in antibacterial action through immune enhancement. Cuproptosis-like death also requires a large number of copper ions. To meet this demand, we deliver positively hydrophilic modified composite nanoparticles that effectively penetrate the lung mucus layer directly to the lungs through local administration, and the copper ions are further released rapidly by the acidic environment at the infected site, which can further destroy bacterial biofilms in synergy with manganese. This drug-delivery system can effectively treat pneumonia caused by aerobic bacteria and avoid systemic toxicity that can be caused by large doses of copper.

Evaluation of Cardioprotective Activity of &lt;i&gt;Corchorus aestuans&lt;/i&gt; L. Leaves

Background: The effectiveness of several medicinal herbs with antioxidant qualities in MI has been assessed and demonstrated. Corchorus aestuans L. is one such medicinal plant that has been shown to have hypocholesteremic and antioxidant properties. C. aestuans L. is also well-known for its bitter tonic, cardiotonic, and stomach relieving properties. Aim: In order to assess the impact of C. aestuans methanol extract against ISO-induced changes in myocardial enzymes, antioxidant status, and cardiac pathology in experimentally induced myocardial infarction, this study was conducted. Methods: Male wistar albino rats were used to create an Isoproterenol (ISO) induced Myocardial Infarction (MI) in order to study the possible cardiovascular preventative effects of the methanol extract of the medicinal plant C. aestuans. Six groups of eight animals each were created from the 180-250 g range of animals, and during the study, the animals in groups one (normal control) and two (model control) were given distilled water. Group three received ascorbic acid (250 mg/kg), while groups four to six received methanol extract of C. aestuans (MECA; 50, 100, and 150 mg/kg, respectively) once a day for 28 days. Animals in group’s two to six received the first dosage of ISO (100 mg/kg, S.C.) on day 27 and the second dose 24 hours later. Rats were anesthetized using chloroform, then their hearts were isolated and serum was collected. Twelve hours following the second large dose, the rats anesthetized, killed, and samples of their hearts and serum were taken. After the heart was cleaned with ice-cold saline, it was weighed. A histology study was conducted on heart tissue, while biochemical markers were analyzed in serum and heart homogenate. Results: When isoproterenol was administered, the concentrations of CK-MB (Creatinine Kinase - Myocardial Band), LDH (Lactate Dehydrogenase), and NA+ (Sodium) increased dramatically, but the concentrations of K+ (Potassium) and MDA (Malondialdehyde) dropped. The incidence of these alterations was dramatically decreased by ascorbic acid and MECA (Methanol extract of C. aestuans) treatment. Consequently, the cardioprotective effect can be explained by decreased levels of cardiac marker enzymes. Conclusion: MECA (50 mg / kg, 100 mg / kg and 150 mg /kg p.o. once for 28 days) attenuated serum enzymes and marker, increased tissue calcium and sodium levels, decreased potassium levels, and inhibited lipid peroxidation to significantly counteract the effect of experimentally induced MI.

Robot-assisted technique can achieve accurate screw placement in four-corner fusion and reduce operative difficulty: a cadaver study

BackgroundThe purpose of this study is to explore the feasibility and accuracy of a robot-assisted technique in four-corner fusion compared with traditional freehand operation.MethodsTwenty cadaver specimens were randomly assigned to the robot-assisted group and freehand groups. Three screws were placed percutaneously to fix the capitate-lunate joint, lunate-triquetrum joint, and triquetrum-hamate-capitate joint in each specimen by robot-assisted or freehand technique. The offset between the actual and planned screw positions was determined by merging the images of intraoperative and postoperative CT scans in the robot-assisted group. The centrality of the screw, time-consuming, drilling attempts, and radiation exposure were compared between the two groups.ResultsThe mean offset between the actual and planned screw position was 1.09 (SD: 0.56) mm. The offset at the start point of the screw was significantly lower than that at the endpoint. There was no significant difference in the centrality of the screws, surgical time between the two groups. The number of drilling attempts and the radiation dose received by surgeons were significantly lower in the robot-assisted group.ConclusionsAlthough there was no significant difference in screw centrality between the two groups, the slight offset between the actual and planned screw positions confirmed the feasibility of the robot-assisted technique in four-corner fusion. The robot-assisted technique has advantages in reducing the difficulty of surgery and protecting the surgeon from exposure to large doses of radiation.

Comparative analysis of ferric carboxymaltose and iron sucrose in treating iron deficiency anemia in perimenopausal women with heavy menstrual bleeding: a randomized controlled trial.

To evaluate the impact of intravenous ferric carboxymaltose (FCM) compared to iron sucrose (ISC) in perimenopausal women with heavy menstrual bleeding (HMB) and anemia. This prospective, open-label, randomized controlled trial enrolled perimenopausal women (40-50 years) with HMB and hemoglobin levels between 6-10 g/dL, intolerant or non-compliant to oral iron therapy. The study compared FCM and ISC by assessing hematological parameters, including hemoglobin, ferritin, and iron levels, over a 12-week period. The patients were followed up at 3, 6, and 12 weeks after initiation. The adverse effects were also evaluated. The study included 60 perimenopausal women, with 30 in each group. The baseline patient characteristics were comparable. FCM demonstrated a statistically significant higher mean increase in hemoglobin (4.97 g/dL) than ISC (4.63 g/dL) over 12 weeks. The proportion of patients achieving correction of anemia (Hb ≥12%) was higher in the FCM group (75.9% vs. 65.5%). Serum ferritin levels were significantly higher in the FCM group after 3 weeks. Adverse effects were minimal and comparable between the groups. Although the direct cost of FCM is high, its ability to be administered in larger doses may result in lower total costs. In perimenopausal women with heavy menstrual bleeding and iron deficiency anemia, FCM and ISC show comparable efficacy in increasing hemoglobin levels with similar side effect profiles. This study highlights the potential benefits of FCM and calls for further exploration of these therapies in diverse patient populations.

Massive entry of BK Polyomavirus induces transient cytoplasmic vacuolization of human renal proximal tubule epithelial cells.

BK polyomavirus (BKPyV) is a ubiquitous human virus that establishes a persistent infection in renal tubular epithelial cells and mainly causes disease in kidney transplant recipients. The closely related simian polyomavirus SV40 is known to cause cytoplasmic vacuolization in simian kidney cells, possibly increasing progeny release and cell death. This study aimed to determine whether BKPyV causes cytoplasmic vacuolization in primary human renal proximal tubule epithelial cells (RPTECs) and to investigate its potential role in the replication cycle. Using a large infectious dose (MOI 100-1000), a fraction of RPTECs (10-72%) showed early-wave vacuolization from 3 hours post-infection (hpi), which was mainly reversed by 36 hpi. Independent of the infectious dose, late-wave vacuolization occurred around the timepoint of progeny release. BKPyV receptor binding and internalization were required, as neuraminidase pretreatment and preincubation or treatment with a BKPyV-specific neutralizing antibody prevented early or late-occurring vacuolization. Microscopy revealed that the vacuoles were enlarged acidic endo-/lysosomal structures (dextran, EEA1, Rab5, Rab7, LAMP1, and/or Lysoview positive) that contained membrane-bound BKPyV. Time-lapse microscopy and quantitative PCR revealed that cell death and progeny release preceded late-wave vacuolization, mainly affecting cells directly neighboring the lysed cells. Thus, vacuolization had little impact on cell death or progeny release. Addition of the V-ATPase inhibitor Bafilomycin A1 at 0 hpi blocked vacuolization and BKPyV replication, but addition at 2 hpi only blocked vacuolization, suggesting that continuous endosomal acidification and maturation is needed for vacuole formation, but not for BKPyV replication. Our study shows that a massive uptake of BKPyV in RPTECs induces transient enlargement of endo-/lysosomes and is an early event in the viral replication cycle. Vacuolization gives no clear benefit for BKPyV and is possibly the result of a transiently overloaded endocytic pathway. Focal vacuolization around lysed cells suggests that the spread of BKPyV is preferably local.

Design, Synthesis, and Evaluation of Novel Thiazole-Containing Algicides Inspired by Bacillamide A.

The pursuit of highly effective, low-toxicity, and eco-friendly algicides for controlling and eradicating harmful algal blooms (HABs) is of paramount importance. The natural allelochemical bacillamide A has displayed impressive algicidal activity against harmful algae with favorable safety profiles. However, the poor synthetic efficiency and large dose requirements of bacillamide A limit its further application. In this paper, 17 thiazole-containing bacillamide derivatives (BDs) were designed and synthesized in three linear steps as potential algicides. Eight compounds (6a, 6c, 6j, 7b, 7c, 7d, 7e, and 7g) displayed potent inhibitory effects against Prorocentrum minimum, Skeletonema costatum, and Alexandrium pacificum, and they had similar or better activity than the positive control (CuSO4) and bacillamide A. Compound 6a exhibited the most potent algicidal activity against S. costatum (half-maximal effective concentration [EC50] = 0.11 μg/mL), being 23-fold more potent than bacillamide A, 28-fold more potent than CuSO4, and 39-fold more potent than Diuron. Compound 6j exhibited significant algicidal activity against the toxic dinoflagellates P. minimum (EC50 = 1.0 μg/mL) and A. pacificum (EC50 = 0.47 μg/mL), being 3-5-fold more potent than natural bacillamide A, Diuron, and CuSO4. Micrographs and SEM images revealed that 6j induced cell wall rupture and cellular content leakage. Biochemical and physiological studies indicated that 6j might partially disrupt the antioxidant and photosynthetic systems in algal cells, resulting in morphological changes, cell wall rupture, and inclusion leakage. Our work suggests that 6j has a distinct mode of action from CuSO4 and provides a promising candidate for the development of new algicides, worthy of further investigation.

Spinal cord blood flow elevation with systemic vasopressor noradrenaline is partly mediated by vasodilation of spinal arteries due to reduced expression of alpha adrenoreceptors

Background context. Elevation of mean arterial blood pressure (MAP) has been proposed to raise spinal cord blood flow (SCBF) after traumatic spinal cord injury (TSCI). Current clinical guidelines for cervical TSCI suggest maintaining MAP 85-90 mmHg for 5-7 days using vasopressors, e.g., noradrenaline. However, it remains unknown whether these interventions that promote an increased systemic MAP result in improved perfusion in the spinal cord. The local effect of vasopressors on the spinal cord arteries also remains unknown. PurposeThe aim of this study was to investigate whether the increased systemic MAP results in increased SCBF, and secondly, to examine the mechanism behind noradrenaline (NA) action in spinal cord arteries. Study design. An experimental animal study. Methods. The study included nine 38-42 kg landrace pigs. In six pigs, MAP was gradually elevated using NA and continuous SCBF was recorded by laser doppler flowmetry. Spinal cord samples from these six pigs were excised for isolation of spinal cord arteries that were used for ex-vivo vascular function assessment in isometric myograph. Segments of mesentery from another three pigs were used to dissect mesenteric small arteries that were also studied in myograph, as control peripheral arteries. Other spinal cord and mesenteric arterial segments from the same biopsies were dissected and snap-frozen for the following expression analysis. Adrenoceptor's expression in arteries of all included animals was assessed with quantitative PCR. Results. The controlled mixed model found that SCBF was lower at MAP below 50 mmHg and that SCBF increased significantly in the MAP range of 50-100 mmHg (p = 0.02). Further increase of MAP did not significantly affect SCBF (at MAP range of 100-150 mmHg, p = 0.15; at 150-200 mmHg, p = 0.51). However, SCBF significantly increased over the study time-course (at 80 min, p = 0.002; at 100 min, p < 0.001), which was dependent on the experimental duration being a confounder of increased exposure to large doses of NA.Isolated spinal arteries did not contract to NA ex-vivo and even showed a tendency for vasorelaxation. This relaxation was abolished by β-adrenoceptor inhibitor, propranolol. In contrast, mesenteric arteries were contracted by NA and propranolol potentiated this contraction. Mesenteric arteries showed a higher expression of α1A adrenoceptors than spinal arteries, while no significant difference was found in other adrenoceptor isoforms. Conclusions. We found SCBF reduced at MAP below 50 mmHg and that the SCBF increased significantly in MAP range between 50-100 mmHg. Elevating MAP above 100 mmHg was not associated with a further increase in SCBF. We also showed that NA increases SCBF in-vivo and relaxes spinal arteries ex-vivo. This effect was associated with a low arterial expression of α adrenoceptors over β adrenoceptors in the spinal cord. Clinical significance. These findings challenge the assumption that SCBF is solely dictated by MAP within autoregulatory limits, emphasizing the necessity of considering noradrenaline-induced vasorelaxation in the spinal arteries of TSCI patients.

The participation of monoamines in the realization of vasopressin analgesic effects during electrical stimulation of paws in rats

BACKGROUND: Arginine vasopressin has been implicated in the modulation of stress and pain. The influence of a synthetic analogue of arginine vasopressin, 1-deamino-8-D-arginine-vasopressin, оn pain sensitivity, stress reactivity, levels of monoamines and brain neurotrophic factor in a model of paw electrical stimulation in rats has not been studied. AIM: The aim was to evaluate the effect of a synthetic vasopressin analog, 1-deamino-8-D-arginine-vasopressin, on pain sensitivity and the content of norepinephrine, serotonin, dopamine, brain neurotrophic factor in the parietal cortex and spinal cord in electrocutaneous paw stimulation test in rats. MATERIALS AND METHODS: The study was conducted on male Wistar rats who were injected with 1-deamino-8-D-arginine-vasopressin intranasally once a day for 5 days in small (single 20 ng, course 100 ng) and large doses (single 2 ug, course 10 ug). The content of brain neurotrophic factor in the parietal cortex and spinal cord, and corticosterone in blood serum were determined using enzyme immunoassay. The levels of norepinephrine, serotonin, dopamine and their metabolites in the brain were evaluated using high-performance liquid chromatography. RESULTS: 1-Deamino-8-D-arginine-vasopressin in different doses reduced pain sensitivity in rats, more pronounced when administered in large doses. The peptide in small doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid, a metabolite of serotonin; in the spinal cord, it reduced the content of 5-hydroxyindolacetic acid. 1-Deamino-8-D-arginine-vasopressin in high doses in the parietal cortex increased the content of dopamine and reduced the levels of 5-hydroxyindolacetic acid; in the spinal cord ― reduced the content of serotonin and 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine; increased the levels of norepinephrine and homovanilic acid, a metabolite of dopamine. The peptide had no effect on corticosterone levels in the blood and brain neurotrophic factor levels in the brain in rats. CONCLUSIONS: The analgesic effects of 1-deamino-8-D-arginine-vasopressin were revealed with intranasal administration in different subendocrine doses. Regardless of the administered doses, dopamine and serotonin at the supraspinal level were involved in peptide-induced anesthesia; serotonin at the spinal cord level. More pronounced analgesia with the administration of 1-deamino-8-D-arginine-vasopressin in high doses was due to the additional involvement of dopamine and norepinephrine at the spinal cord level.

Interpreting the biological effects of protons as a function of physical quantity: linear energy transfer or microdosimetric lineal energy spectrum?

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the “dose and LET” physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LETd) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LETd. However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LETd (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LETd alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model.

Decreasing IV magnesium infusion time to improve delivery of patient care.

Hypomagnesemia is a common issue in patients with cancer due to magnesium wasting drugs like calcineurin inhibitors, chemotherapy sides effects such as diarrhea, and poor oral intake. Historically, magnesium has been given over prolonged infusions due to concern for rapid elimination of magnesium when large doses are administered. At UW Health, magnesium was given at a rate of 1g/60 min. A prolonged infusion rate often creates logistical issues including limited IV access, incompatibility concerns and increased chair time. The purpose of this project is to increase the infusion rate of IV magnesium without compromising therapeutic repletion, benefit, and safety. The magnesium infusion rate was increased to the following rates: 4g/60 min, 2g/30 min, 1g/15 min. The primary outcome is the grams of IV magnesium replaced per outpatient visit between the pre-intervention (prolonged) and post-intervention (rapid) groups. Secondary outcomes include assessment of differences in chair time between groups and total incidence of critical magnesium lab values. There was no statistically significant difference in magnesium requirements per outpatient visit between a prolonged and rapid magnesium infusion rate (2.18g vs 2.15g; p = 0.49). Additionally, there was no difference in number of outpatient visits (3 vs 3; p = 1). The average chair time was decreased by 110 min per outpatient encounter between the prolonged and rapid magnesium infusion rate, which was determined to be clinically and statistically significant. This study suggests that there is no difference in magnesium requirements between a rapid or prolonged magnesium infusion in both solid and liquid tumor patients.

An efficient polyaluminum lanthanum silicate coagulant for phosphorus removal and algal bloom control

Due to the advantages of convenient operation and low cost, the use of coagulants is considered a promising method for algae bloom harvesting. However, large dosages, poor algal bloom control rates, and limited phosphorus removal efficiency restrict the usage of most coagulants. In this study, a novel polyaluminum lanthanum silicate (PALS) coagulant was used to remove phosphorus and control algal bloom. The results of isotherm study showed that phosphorus adsorption on PALS fitted Freundlich model, indicating chemisorption and heterogeneous multilayer adsorption were the mechanisms of phosphorus adsorption by PALS. The maximum phosphorus adsorption capacity of PALS by Langmuir model was 485.30 mg/g. According to the algal bloom control experiments, the removal of algae and phosphorus was slight at low dosages of PALS (2 mg/L and 5 mg/L). Short-term control of the algal bloom was observed within 2 days in PALS-10 group, but the bloom recovered afterward, while phosphorus and algae were almost completely removed in PALS-15 and PALS-20. When the dosage of PALS was ≤ 10 mg/L, PALS coated the algal cell surfaces and induced mild oxidative stress, showing a little damage to cell integrity. However, the PALS dose over 15 mg/L could effectively capture algal cells through charge neutralization, cause severe oxidative stress, strongly upregulate the expression of selected five genes, significantly damage cell integrity, and lead to algae lysis. These findings demonstrated that PALS is a promising coagulant for phosphorus removal and algal bloom control in eutrophic waters, and the minimum threshold of its usage was 15 mg/L.

Cannabis and Cannabinoid Signaling: Research Gaps and Opportunities.

Cannabis and its products have been used for centuries for both medicinal and recreational purposes. The recent widespread legalization of cannabis has vastly expanded its use in the United States across all demographics except for adolescents. Meanwhile, decades of research have advanced our knowledge of cannabis pharmacology and particularly of the endocannabinoid system with which the components of cannabis interact. This research has revealed multiple targets and approaches for manipulating the system for therapeutic use and to ameliorate cannabis toxicity or cannabis use disorder. Research has also led to new questions that underscore the potential risks of its widespread use, particularly the enduring consequences of exposure during critical windows of brain development or for consumption of large daily doses of cannabis with high content Δ 9-tetrahydrocannabinol. This article highlights current neuroscience research on cannabis that has shed light on therapeutic opportunities and potential adverse consequences of misuse and points to gaps in knowledge that can guide future research. SIGNIFICANCE STATEMENT: Cannabis use has escalated with its increased availability. Here, the authors highlight the challenges of cannabis research and the gaps in our knowledge of cannabis pharmacology and of the endocannabinoid system that it targets. Future research that addresses these gaps is needed so that the endocannabinoid system can be leveraged for safe and effective use.

Assessment of the Impact of Dietary Supplementation with Epigallocatechin Gallate (EGCG) on Antioxidant Status, Immune Response, and Intestinal Microbiota in Post-Weaning Rabbits.

This study was conducted to investigate the impact of EGCG on antioxidant stress, immune response, and intestinal microbiota flora in post-weaning rabbits. A total of 144 40 d Ira rabbits (equally divided by sex), were randomly allocated to six treatments. with five groups receiving doses of 200, 400, 600, 800, and 1000 mg/kg of EGCG, while one group served as a control without EGCG. Over 48 days, this study the assessed growth performance, antioxidant capacity, immune system, intestinal morphology, and cecal microbiota in the rabbits. The results showed that EGCG did not affect growth performance; however, significant linear and quadratic correlations were observed between the MDA, T-AOC, and GSH-Px activities in the liver and jejunum (p < 0.05). Quadratic effects were observed for the spleen and thymus indexes and serum IgG levels with increasing EGCG dosages (p < 0.05). Additionally, positive linear and quadratic effects were found on the ileal villus height and the villus height/crypt depth ratio. The relative abundances of Euryarchaeota, Patescibacteria, and Synergistota were significantly enriched in rabbits fed with high dosages (600-1000 mg/kg) of EGCG. Conclusively, the addition of large doses of EGCG (400-800 mg/kg) can effectively suppress oxidative stress and alleviate weaning stress, thereby contributing to the protection of post-weaning rabbits.

Jianpi-Huatan-Huoxue-Anshen formula ameliorates gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with H22 hepatocellular carcinoma.

Jianpi-Huatan-Huoxue-Anshen formula [Tzu-Chi cancer-antagonizing & life-protecting II decoction (TCCL)] is a Chinese medical formula that has been clinically shown to reduce the gastrointestinal side effects of chemotherapy in cancer patients and improve their quality of life. However, its effect and mechanism on the intestinal microecology after chemotherapy are not yet clear. To discover the potential mechanisms of TCCL on gastrointestinal inflammation and microecological imbalance in chemotherapy-treated mice transplanted with hepatocellular carcinoma (HCC). Ninety-six mice were inoculated subcutaneously with HCC cells. One week later, the mice received a large dose of 5-fluorouracil by intraperitoneal injection to establish a HCC chemotherapy model. Thirty-six mice were randomly selected before administration, and feces, ileal tissue, and ileal contents were collected from each mouse. The remaining mice were randomized into normal saline, continuous chemotherapy, Yangzheng Xiaoji capsules-treated, and three TCCL-treated groups. After treatment, feces, tumors, liver, spleen, thymus, stomach, jejunum, ileum, and colon tissues, and ileal contents were collected. Morphological changes, serum levels of IL-1β, IL-6, IL-8, IL-10, IL-22, TNF-α, and TGF-β, intestinal SIgA, and protein and mRNA expression of ZO-1, NF-κB, Occludin, MUC-2, Claudin-1, and IκB-α in colon tissues were documented. The effect of TCCL on the abundance and diversity of intestinal flora was analyzed using 16S rDNA sequencing. TCCL treatment improved thymus and spleen weight, thymus and spleen indexes, and body weight, decreased tumor volumes and tumor tissue cell density, and alleviated injury to gastric, ileal, and colonic mucosal tissues. Among proteins and genes associated with inflammation, IL-10, TGF-β, SIgA, ZO-1, MUC-2, and Occludin were upregulated, whereas NF-κB, IL-1β, IL-6, TNF-α, IL-22, IL-8, and IκB-α were downregulated. Additionally, TCCL increased the proportions of fecal Actinobacteria, AF12, Adlercreutzia, Clostridium, Coriobacteriaceae, and Paraprevotella in the intermediate stage of treatment, decreased the proportions of Mucipirillum, Odoribacter, RF32, YS2, and Rikenellaceae but increased the proportions of p_Deferribacteres and Lactobacillus at the end of treatment. Studies on ileal mucosal microbiota showed similar findings. Moreover, TCCL improved community richness, evenness, and the diversity of fecal and ileal mucosal flora. TCCL relieves pathological changes in tumor tissue and chemotherapy-induced gastrointestinal injury, potentially by reducing the release of pro-inflammatory factors to repair the gastrointestinal mucosa, enhancing intestinal barrier function, and maintaining gastrointestinal microecological balance. Hence, TCCL is a very effective adjuvant to chemotherapy.