Low-dose Administration Research Articles

Androgen and inhibin B levels during ovarian stimulation before and after 8 weeks of low-dose hCG priming in women with low ovarian reserve.

Does 8 weeks of daily low-dose hCG administration affect androgen or inhibin B levels in serum and/or follicular fluid (FF) during the subsequent IVF/ICSI cycle in women with low ovarian reserve? Androgen levels in serum and FF, and inhibin B levels in serum, decreased following 8 weeks of hCG administration. Recently, we showed that 8 weeks of low-dose hCG priming, in between two IVF/ICSI treatments in women with poor ovarian responder (anti-Müllerian hormone (AMH) <6.29 pmol/l), resulted in more follicles of 2-5 mm and less of 6-10-mm diameter at the start of stimulation and more retrieved oocytes at oocyte retrieval. The duration of stimulation and total FSH consumption was increased in the IVF/ICSI cycle after priming. Hypothetically, hCG priming stimulates intraovarian androgen synthesis causing upregulation of FSH receptors (FSHR) on granulosa cells. It was therefore unexpected that antral follicles were smaller and the stimulation time longer after hCG priming. This might indicate a different mechanism of action than previously suggested. Blood samples were drawn on stimulation day 1, stimulation days 5-6, trigger day, day of oocyte retrieval, and oocyte retrieval + 5 days in the IVF/ICSI cycles before and after hCG priming (the control and study cycles, respectively). FF was collected from the first aspirated follicle on both sides during oocyte retrieval in both cycles. The study was conducted as a prospective, paired, non-blinded, single-center study conducted between January 2021 and July 2021 at a tertiary care center. The 20 participants underwent two identical IVF/ICSI treatments: a control cycle including elective freezing of all blastocysts and a study cycle with fresh blastocyst transfer. The control and study cycles were separated by 8 weeks (two menstrual cycles) of hCG priming by daily injections of 260 IU recombinant hCG. Women aged 18-40 years with cycle lengths of 23-35 days and AMH <6.29 pmol/l were included. Control and study IVF/ICSI cycles were performed in a fixed GnRH-antagonist protocol. Inhibin B was lower on stimulation day 1 after hCG priming (P = 0.05). Dehydroepiandrosterone sulfate (DHEAS) was significantly lower on stimulation day 1 (P = 0.03), and DHEAS and androstenedione were significantly lower on stimulation days 5-6 after priming (P = 0.02 and P = 0.02) The testosterone level in FF was significantly lower in the study cycle (P = 0.008), while the concentrations of inhibin B and androstenedione in the FF did not differ between the study and control cycles. A lower serum inhibin B in the study cycle corresponds with the antral follicles being significantly smaller after priming, and this probably led to a longer stimulation time in the study cycle. This contradicts the theory that hCG priming increases the intraovarian androgen level, which in turn causes more FSHR on developing (antral up to preovulatory) follicles. However, based on this study, we cannot rule out that an increased intra-follicular androgen level was present at initiation of the ovarian stimulation, without elevating the androgen level in serum and that an increased androgen level may have rescued some small antral follicles that would have otherwise undergone atresia by the end of the previous menstrual cycle. We retrieved significantly more oocytes in the Study cycle, and the production of estradiol per follicle ≥10-mm diameter on trigger day was comparable in the study and control cycles, suggesting that the rescued follicles were competent in terms of producing oocytes and steroid hormones. The sample size was small, and the study was not randomized. Our study design did not allow for the measurement and comparison of androgen levels or FSHR expression in small antral follicles before and immediately after the hCG-priming period. The results make us question the mechanism of action behind hCG priming prior to IVF. It is important to design a study with the puncture of small antral follicles before and immediately after priming to investigate the proposed hypothesis. Improved cycle outcomes, i.e. more retrieved oocytes, must be confirmed in a larger, preferably randomized study. This study was funded by an unrestricted grant from Gedeon Richter awarded to the institution. A.P. reports personal consulting fees from PregLem SA, Novo Nordisk A/S, Ferring Pharmaceuticals A/S, Gedeon Richter Nordics AB, Cryos International, and Merck A/S outside the submitted work and payment or honoraria for lectures from Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, Merck A/S, and Theramex and Organon & Co and payment for participation in an advisory board for Preglem. Grants to the institution have been provided by Gedeon Richter Nordics AB, Ferring Pharmaceuticals A/S, and Merck A/S, and equipment and travel support has been given to the institution by Gedeon Richter Nordics AB. The remaining authors have no conflicts of interest to declare. ClinicalTrials.gov Identifier: NCT04643925.

Tetrapleura tetraptera and Xylopia aethiopica Consumption Fluctuate Estrogen Levels

Extract of Tetrapleura tetraptera and Xylopia aethiopica have been used in the management and treatment of various ailments. This study investigated and compared the effects of ethanolic extract of both plants on estrogen in female wistar rats. Twenty-four rats were randomly divided into eight groups (n=3): one group for control and groups 2-8 served as experimental test groups. At the end of twenty-five days of oral administration of Tetrapleura tetraptera and Xylopia aethiopica extract, the test rats were sacrificed under chloroform anaesthesia and estrogen was measured using enzyme-linked immunosorbent assay (ELISA) method. Results showed significant reduction in serum estrogen after administration of low dose of Tetrapleura tetraptera in Group 2 rats at P &lt; 0.05, but a non-significant increase and decrease in serum estrogen level in Groups 3 and 4 respectively at P &lt; 0.05. Xylopia aethiopica extract caused a non- significant decrease in serum Estrogen level in Groups 5 and 6, but a non-significant increase in estrogen level of Group 7 at P &lt; 0.05. In contrast, serum estrogen was significantly increased in Group 8 rats at P &lt; 0.05 when Tetrapleura tetraptera and Xylopia aethiopica extracts were administered simultaneously. In conclusion, results obtained in this study suggest that individually, both Tetrapleura tetraptera and Xylopia aethiopica can affect the secretion and concentration of estrogen. The combination of extract of both plants could exert a positive effect on female fertility by increasing the levels of Estrogen.

Balanced volatile sedation with isoflurane in critically ill patients with aneurysmal subarachnoid hemorrhage - a retrospective observational study.

In patients with severe aneurysmal subarachnoid hemorrhage (SAH) deep sedation is often used early in the course of the disease in order to control brain edema formation and thus intracranial hypertension. However, some patients do not reach an adequate sedation depth despite high doses of common intravenous sedatives. Balanced sedation protocols incorporating low-dose volatile isoflurane administration might improve insufficient sedation depth in these patients. We retrospectively analyzed ICU patients with severe aneurysmal SAH who received isoflurane in addition to intravenous anesthetics in order to improve insufficient sedation depth. Routinely recorded data from neuromonitoring, laboratory and hemodynamic parameters were compared before and up to 6 days after initiation of isoflurane. Sedation depth measured using the bispectral index improved in thirty-six SAH patients (-15.16; p = 0.005) who received additional isoflurane for a mean period of 9.73 ± 7.56 days. Initiation of isoflurane sedation caused a decline in mean arterial pressure (-4.67 mmHg; p = 0.014) and cerebral perfusion pressure (-4.21 mmHg; p = 0.013) which had to be balanced by increased doses of vasopressors. Patients required increased minute ventilation in order to adjust for the increase in PaCO2 (+2.90 mmHg; p < 0.001). We did not detect significant increases in mean intracranial pressure. However, isoflurane therapy had to be terminated prematurely in 25% of the patients after a median of 30 h due to episodes of intracranial hypertension or refractory hypercapnia. A balanced sedation protocol including isoflurane is feasible for SAH patients experiencing inadequately shallow sedation. However, therapy should be restricted to patients without impaired lung function, hemodynamic instability and impending intracranial hypertension.

CCRL2 Expression by Specialized Lung Capillary Endothelial Cells Controls NK-cell Homing in Lung Cancer.

Patterns of receptors for chemotactic factors regulate the homing of leukocytes to tissues. Here we report that the CCRL2/chemerin/CMKLR1 axis represents a selective pathway for the homing of natural killer (NK) cells to the lung. C-C motif chemokine receptor-like 2 (CCRL2) is a nonsignaling seven-transmembrane domain receptor able to control lung tumor growth. CCRL2 constitutive or conditional endothelial cell targeted ablation, or deletion of its ligand chemerin, were found to promote tumor progression in a Kras/p53Flox lung cancer cell model. This phenotype was dependent on the reduced recruitment of CD27- CD11b+ mature NK cells. Other chemotactic receptors identified in lung-infiltrating NK cells by single-cell RNA sequencing (scRNA-seq), such as Cxcr3, Cx3cr1, and S1pr5, were found to be dispensable in the regulation of NK-cell infiltration of the lung and lung tumor growth. scRNA-seq identified CCRL2 as the hallmark of general alveolar lung capillary endothelial cells. CCRL2 expression was epigenetically regulated in lung endothelium and it was upregulated by the demethylating agent 5-aza-2'-deoxycytidine (5-Aza). In vivo administration of low doses of 5-Aza induced CCRL2 upregulation, increased recruitment of NK cells, and reduced lung tumor growth. These results identify CCRL2 as an NK-cell lung homing molecule that has the potential to be exploited to promote NK cell-mediated lung immune surveillance.

Antioxidant hepatic lipid metabolism can be promoted by orally administered inorganic nanoparticles

Accumulation of inorganic nanoparticles in living organisms can cause an increase in cellular reactive oxygen species (ROS) in a dose-dependent manner. Low doses of nanoparticles have shown possibilities to induce moderate ROS increases and lead to adaptive responses of biological systems, but beneficial effects of such responses on metabolic health remain elusive. Here, we report that repeated oral administrations of various inorganic nanoparticles, including TiO2, Au, and NaYF4 nanoparticles at low doses, can promote lipid degradation and alleviate steatosis in the liver of male mice. We show that low-level uptake of nanoparticles evokes an unusual antioxidant response in hepatocytes by promoting Ces2h expression and consequently enhancing ester hydrolysis. This process can be implemented to treat specific hepatic metabolic disorders, such as fatty liver in both genetic and high-fat-diet obese mice without causing observed adverse effects. Our results demonstrate that low-dose nanoparticle administration may serve as a promising treatment for metabolic regulation.

Effect of Low Doses of Dexamethasone on Experimental Pulmonary Tuberculosis.

Tuberculosis (TB) is the deadliest disease caused by a bacterial agent. Glucocorticoids (GCs) have a typical anti-inflammatory effect, but recently it has been shown that they can present proinflammatory activity, mainly by increasing molecules from innate immunity. In the current study, we evaluated the effect of low doses of dexamethasone on Mycobacterium tuberculosis in vivo and in vitro. We used an established mice model of progressing tuberculosis (TB) in the in vivo studies. Intratracheal or intranasal dexamethasone therapy administered with conventional antibiotics in the late stage of the disease decreased the lung bacilli load and lung pneumonia, and increased the survival of the animals. Finally, the treatment decreased the inflammatory response in the SNC and, therefore, sickness behavior and neurological abnormalities in the infected animals. In the in vitro experiments, we used a cell line of murine alveolar macrophages infected with Mtb. Low-dose dexamethasone treatment increased the clearance capacity of Mtb by MHS macrophages, MIP-1α, and TLR2 expression, decreased proinflammatory and anti-inflammatory cytokines, and induced apoptosis, a molecular process that contributes to the control of the mycobacteria. In conclusion, the administration of low doses of dexamethasone represents a promising adjuvant treatment for pulmonary TB.

Long-term evaluation of viability of microfilariae and intravenously transplanted adult Dirofilaria immitis in microfilaremic dogs treated with low-dose, short- and long-treatment regimens of doxycycline and ivermectin

BackgroundMicrofilarial (mf) counts were monitored over 21.3 months for any rebound that might occur in counts, and adulticidal efficacy was assessed following administration of low dosage with short- and long-treatment regimens of doxycycline and ivermectin to heartworm-microfilaremic dogs.MethodsTwelve heartworm-naïve beagles infected with 10 pairs of adult Dirofilaria immitis by intravenous transplantation were randomly allocated to three groups of four dogs. All treatments started on day 0. On day 0, Group 1 (short-treatment regimen) received doxycycline orally at 10 mg/kg once daily for 30 days plus ivermectin orally (minimum, 6 mcg/kg) on days 0 and 30. Group 2 (long-treatment regimen) received doxycycline orally at 10 mg/kg once daily until individual dogs became mf-negative (72–98 days) and ivermectin every other week until individual dogs became mf-negative (6–7 doses). Group 3 was the untreated control. Mf counts and antigen (Ag) tests were conducted. Dogs were necropsied for recovery and enumeration of heartworms on day 647.ResultsDay −1 mean mf counts were 15,613, 23,950, and 15,513 mf/ml for groups 1, 2, and 3, respectively. Mean counts for Groups 1 and 2 declined until days 239 and 97, respectively, when all were negative. Group 3 had high mf counts throughout the study. There was not a rebound in mf counts in any of the treated dogs after they became amicrofilaremic. All dogs in group 1 and group 3 were Ag-positive throughout the study and had at least one live female worm at necropsy. All dogs in treated Group 2 were positive for Ag through day 154, but were antigen-negative on days 644 and 647, as all had only male worms. Mean live adult worm recoveries for Groups 1, 2, and 3 were 6.8 (range, 5–8), 3.3 (range, 1–6), and 16.0 (range, 14–17), respectively, with a percent reduction in adult worm counts of 57.5% for Group 1 and 79.3% for Group 2.ConclusionsThese data lend support to the use of the American Heartworm Society Canine Guidelines for adulticide therapy recommending the initiation of doxycycline plus a macrocyclic lactone (ML) at the time of the heartworm-positive diagnosis.Graphical

Sub-hypnotic dose of midazolam is effective in reducing intraoperative nausea and vomiting during cesarean sections under spinal anesthesia

Background &amp; Objectives: Intra and postoperative nausea and vomiting under regional anesthesia is a common problem in cesarean sections. Globally, the incidence has been documented to be from 40−80%, and various drugs have been used to control it. We aimed to determine if a subhypnotic dose of midazolam will be effective to reduce intraoperative nausea and vomiting during an elective cesarean section under spinal anesthesia.&#x0D; Methodology: A randomized interventional study was done through a period of 6 months from March 11, 2019 to September 11, 2019 and included 100 full term pregnant women undergoing elective cesarean sections (CS) under spinal anesthesia. The participants were allocated to one of two groups: Midazolam group (received midazolam 1 mg bolus then 1.0 mg/h infusion after umbilical cord clamping), and placebo group (received normal saline). Bellville score was used to evaluate nausea and vomiting (N/V). The hemodynamic parameters were monitored at three-minute intervals.&#x0D; Results: No statistically significant differences were noted between study groups regarding mean arterial pressure, heart rate and total ephedrine used in the two groups. Intraoperative nausea and vomiting were recorded midazolam (81.6%) with a significant association between prevention of intraoperative N/V and receiving midazolam. Insignificant association was noticed between the level of sedation and receiving midazolam.&#x0D; Conclusion: Administration of low dose of midazolam during cesarean sections under spinal anesthesia can lessen intraoperative nausea/vomiting without significantly effect on blood pressure or heart rate and without any negative side effects.&#x0D; Abbreviations: BMI – Body Mass Index; CS - Cesarean Section; LA – Local Anesthesia; N/V - Nausea/Vomiting; RASS - Richmond Agitation Sedation Score SA - Spinal Anesthesia&#x0D; Key words: Nausea; Vomiting; Anesthesia, Spinal; Midazolam; Cesarean Section&#x0D; Citation: Ibrahem IG. Sub-hypnotic dose of midazolam is effective in reducing intraoperative nausea and vomiting during cesarean sections under spinal anesthesia. Anaesth. pain intensive care 2023;27(4):485−489; DOI: 10.35975/apic.v27i4.2087&#x0D; Received: October 12, 2022; Reviewed: May 16, 2023; Accepted: June 23. 2023

Possible involvement of Interleukin-17A in the deterioration of prepulse inhibition on acoustic startle response in mice.

Proinflammatory cytokines such as interleukin-6 (IL-6) and IL-17A have been implicated in the pathophysiology of schizophrenia which often shows sensorimotor gating abnormalities. This study aimed to examine whether a proinflammatory cytokine, IL-17A, induces impairment in sensorimotor gating in mice. We also examined whether IL-17A administration affects GSK3α/β protein level or phosphorylation in the striatum. Recombinant mouse IL-17A (low-dose: 0.5 ng/mL and high-dose: 50 ng/mL with 10 μL/g mouse body weight, respectively) or vehicle was intraperitoneally administered into C57BL/6 male mice 10 times in 3 weeks (sub-chronic administration). Prepulse inhibition test using acoustic startle stimulus was conducted 4 weeks after the final IL-17A administration. We evaluated the effect of IL-17A administration on protein level or phosphorylation of GSK3α/β in the striatum by using Western blot analysis. Administration of IL-17A induced significant PPI deterioration. Low-dose of IL-17A administration significantly decreased both GSK3α (Ser21) and GSK3β (Ser9) phosphorylation in mouse striatum. There was no significant alteration of GSK3α/β protein levels except for GSK3α in low-dose IL-17A administration group. We demonstrated for the first time that sub-chronic IL-17A administration induced PPI disruption and that IL-17A administration resulted in decreased phosphorylation of GSKα/β at the striatum. These results suggest that IL-17A could be a target molecule in the prevention and treatment of sensorimotor gating abnormalities observed in schizophrenia.

Phase 1 studies of D07001-F4 and D07001-softgel capsule: Oral metronomic gemcitabine in subjects with advanced solid tumors.

3148 Background: Metronomic chemotherapy with frequent, low dose administration may not only retain the anticancer feature of conventional, periodic maximum tolerated dose (MTD)-based, parenteral chemotherapy, but also possess other novel properties such as immune enhancement and angiogenesis suppression. D07001 is an absorption, enhanced oral gemcitabine originally developed as liquid form (D07001-F4), then further refined into D07001-softgel capsule to enhance therapeutical applicability. Herein, we report the results of two phase I studies that evaluated the dose-limiting toxicity (DLT), pharmacokinetics (PK), bioavailability (BA) and maximum tolerated dose (MTD) of D07001-F4 and D07001-softgel capsules in subjects with refractory, advanced solid tumors. Methods: Both studies applied 3+3 dose escalation design. Referring to a similar trial by EIi Lilly, in the first Phase I study (NCT01800630), eligible subjects received a bolus intravenous injection of 5 mg gemcitabine in run-in period then D07001-F4 thrice per week for 2 weeks followed by 1 week rest with escalating doses from 2 to 80 mg. Since no dose-limiting toxicity (DLT) was observed even at maximum 80mg dose-level (DL) in this study, another Ib study (NCT03531320) with the uses of refined D07001-softgel capsule and a modified regimen without the resting period was conducted in subjects with refractory gastrointestinal malignancies to investigating the DLT, maximum tolerated dose (MTD) and PK. The test dose of this Ib study was from 40 to 120 mg (40, 60, 80, 120), in which the bridging dose of 40 mg was employed based on its equivalence to the dose of 80 mg in the first Phase I study. Results: A total of 53 eligible patients were enrolled, 34 (10 DL) and 19 (5+1 DL) in the Phase I and Ib studies, respectively. Comparing to parenteral gemcitabine, the mean oral bioavailability of D07001-F4 was about 39%. No DLT was observed in all planned DL, until the 120 mg DL of D07001-softgel capsules, in which 2/6 patients had DLTs (grade 3 hepatotoxicity and grade 3 anorexia, respectively). An addition 100 mg DL was tested (without DLT in a 3 patient cohort) and determined as MTD. Cmax and AUC(0-48h) of gemcitabine metabolite (dFdU) on C1D1 were largely dose-dependent and comparable for two formulations at bridging dose levels. Despite similar trend for dFdC, more inter-individual variation was observed. The mean dFdC Cmax at MTD of D07001-softgel capsules was 24 ng/mL (0.09 mM) and half-life of 5 hours. Grade &gt;3 anorexia (10.5%) and diarrhea (10.5%) were observed in Phase Ib extension study. Conclusions: The results suggest the feasibility of oral gemcitabine treatment with D07001-softgel capsules, which is well-tolerated for continuous dosing and deserves further clinical investigation. Clinical trial information: NCT01800630 , NCT03531320 .

Protective effects of long-term nitrate administration against ovariectomy-induced kidney dysfunction in rats.

Menopause is associated with higher risks of chronic kidney disease. We determined the effect of nitrate on ovariectomy-induced kidney dysfunction METHODS: Control, ovariectomized (OVX), control + nitrate, and OVX + nitrate female Wistar rats (n = 10/group); sodium nitrate (100mg/L) administered in drinking water for 9months. Glomerular filtration rate (GFR) and albumin excretion rate (AER) were calculated from serum and urine parameters. At month 9, serum and kidney levels of nitric oxide (NO) metabolites (NOx), oxidative stress indices, and mRNA expression of endothelial NO synthase (eNOS) were measured; with histological analyses of the kidney. Compared to controls, OVX rats had lower GFR (31%, p = 0.0079), higher glomerular tuft volume (30%, p = 0.0402), and Bowman's capsule space (39%, p = 0.0224). OVX rats had lower serum NOx (33%, p = 0.0061) and kidney eNOS mRNA expression (34%, p = 0.0368). Nitrate administration to: (i) control rats increased serum NOx (59%, p < 0.0001), with no effect on other parameters; (ii) OVX rats increased serum (85%, p < 0.0001) and kidney (106%, p = 0.0008) NOx values, and restored kidney eNOS expression to normal value. Nitrate administration to OVX rats increased GFR (36%, p = 0.0361) and restored glomerular tuft volume and Bowman's capsule space to normal values. In OVX rats, it also increased serum catalase (CAT) activity, serum and kidney total antioxidant capacity (TAC), and decreased serum malondialdehyde (MDA). Low-dose long-term nitrate administration protects against ovariectomy-induced kidney dysfunction in rats. This effect is associated with reducing ovariectomy-induced oxidative stress and restoring eNOS-derived NO deficiency in systemic circulation and the kidney.

Low-Dose Ketamine-Induced Deficits in Arbitrary Visuomotor Mapping in Monkeys.

Ketamine, an NMDA antagonist, is widely used in clinical settings. Recently, low-dose ketamine has gained attention because of its promising role as a rapid antidepressant. However, the effects of low-dose ketamine on brain function, particularly higher cognitive functions of primate brains, are not fully understood. In this study, we used two macaques as subjects and found that acute low-dose ketamine administration significantly impaired the ability for arbitrary visuomotor mapping (AVM), a form of associative learning (AL) essential for flexible behaviors, including executions of learned stimuli-response contingency or learning of new contingencies. We conducted in-depth analyses and identified intrinsic characteristics of these ketamine-induced functional deficits, including lowered accuracy, prolonged time for planning and movement execution, increased tendency to make errors when visual cues are changed from trial to trial, and stronger impact on combining associative learning and another key higher cognitive function, working memory (WM). Our results shed new light on how associative learning relies on the NMDA-mediated synaptic transmission of the brain and contribute to a better understanding of the potential acute side effects of low-dose ketamine on cognition, which can help facilitate its safe usage in medical practice.

Adolescent exposure to low-dose THC disrupts energy balance and adipose organ homeostasis in adulthood

One of cannabis' most iconic effects is the stimulation of hedonic high-calorie eating-the "munchies"-yet habitual cannabis users are, on average, leaner than non-users. We asked whether this phenotype might result from lasting changes in energy balance established during adolescence, when use of the drug often begins. We found that daily low-dose administration of cannabis' intoxicating constituent, Δ9-tetrahydrocannabinol (THC), to adolescent male mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, enhanced thermogenesis, and impaired cold- and β-adrenergic receptor-stimulated lipolysis. Further analyses revealed that this phenotype is associated with molecular anomalies in the adipose organ, including ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring "pseudo-lean" state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.

Blue light promotes vitamin C-mediated ferroptosis of melanoma through specifically upregulating transporter SVCT2 and generating Fe2+

Vitamin C (VC)-based cancer therapy is a promising therapeutic approach for a variety of cancers due to its profound effects on redox reactions and metabolic pathways. However, high administration dosage of VC for necessary therapeutic efficacy for cancers increases the risk of overt side effects and limits its clinical use. Here, we show cutaneous blue light irradiation can specifically upregulate the sodium-dependent vitamin C transporter 2 (SVCT2) of the tumor and increase effectively the VC concentration at the tumor sites by an overall low dosage administration. In the mouse melanoma model, blue light stimulates the SVCT2 expression through the nuclear factor-kappa B (NF-κB) signaling pathway both in vitro and in vivo. The increased cellular VC together with Fe2+ generated by blue light simultaneously elevate cellular oxidative stress and trigger the ferroptosis of melanoma. With this revealed mechanism, the synergistic actions of blue light on the VC transporter and Fe2+ generation lead to a ca. 20-fold reduction in the administration dosage of VC with an effective melanoma elimination and prolonged survival. The work defines the killing mechanism of blue light on VC-based cancer therapy and provides a practical approach for promoting VC uptake. This light-assisted VC therapy is not only highly efficient for melanoma but also considerable for a broad clinical utility.

Development of a Urine Metabolomics Biomarker-Based Prediction Model for Preeclampsia during Early Pregnancy

Preeclampsia (PE) is a condition that poses a significant risk of maternal mortality and multiple organ failure during pregnancy. Early prediction of PE can enable timely surveillance and interventions, such as low-dose aspirin administration. In this study, conducted at Stanford Health Care, we examined a cohort of 60 pregnant women and collected 478 urine samples between gestational weeks 8 and 20 for comprehensive metabolomic profiling. By employing liquid chromatography mass spectrometry (LCMS/MS), we identified the structures of seven out of 26 metabolomics biomarkers detected. Utilizing the XGBoost algorithm, we developed a predictive model based on these seven metabolomics biomarkers to identify individuals at risk of developing PE. The performance of the model was evaluated using 10-fold cross-validation, yielding an area under the receiver operating characteristic curve of 0.856. Our findings suggest that measuring urinary metabolomics biomarkers offers a noninvasive approach to assess the risk of PE prior to its onset.

A Case of Akathisia After Administration of a Very Low Dose of Mirtazapine.

Otsuki, Koji MD, PhD; Tsukitaku, Masashi MD; Sato, Kouhei MD; Sunami, Makoto MD, PhD; Inagaki, Masatoshi MD, PhD Author Information

Moderate doses of Mucuna pruriens seed powder is safe and improves sperm count and motility

BackgroundConventional remediation techniques involving male fertility include hormonal therapy, in vitro fertilization and surgery. However, the use of natural products continues to be a popular option. Emerging new products that have not been well investigated is the use of Mucuna pruriens seed powder. AimThis study aimed at determining the efficacy and safety of Mucuna pruriens (MP) seed powder on the male fertility using normal animal models. MethodologyFour groups of seven (7) male Sprague-Dawley rats were used. Groups comprised Control (distilled water), Low dose (500 mg/kg b.wt MP), Medium dose (1000 mg/kg b.wt MP) and high dose (2000 mg/kg b.wt MP). Test groups were administered aqueous crude extract of MP by gavage over 90 days. Upon sacrifice, the following assays were performed: FSH, testosterone, oestrogen, PSA, semen analyses, histology of reproductive organs, and general haematological and biochemical analyses. ResultsFSH increased, whilst oestrogen decreased, across groups: however, it was not statistically significant between groups. Although testosterone increases were not statistically significant, increases were dose-dependant. Sperm count increased significantly between the Control and Medium dose groups (p<0.001). Motility significantly increased with the Medium and High dose groups compared to Control group (p = 0.022, p = 0.029, respectively). Additionally, immotility significantly decreased in all treatment groups compared to control group (p = 0.013). No abnormality was observed in biochemical, haematological and histological analyses. ConclusionThis study demonstrates a margin of safety and improved spermogram pattern between the low and medium dose administration of Mucuna pruriens seed powder.

Reduced-Dose Systemic Fibrinolysis in Massive Pulmonary Embolism: A Pilot Study.

Severe pulmonary embolism (PE) has a high mortality rate, which can be lowered by thrombolytic therapy (TT). However, full-dose TT is associated with major complications, including life-threatening bleeding. The aim of this study was to explore the efficacy and safety of extended, low-dose administration of tissue plasminogen activator (tPA) on in-hospital mortality and outcomes in massive PE. This was a single-center, prospective cohort trial at a tertiary university hospital. A total of 37 consecutive patients with massive PE were included. A peripheral intravenous infusion was used to administer 25 mg of tPA over 6 hours. The primary endpoints were in-hospital mortality, major complications, pulmonary hypertension, and right ventricular dysfunction. The secondary endpoints were 6-month mortality and pulmonary hypertension and right ventricular dysfunction 6 months after the PE. The mean age of the patients was 68.76±14.54 years. The mean pulmonary artery systolic pressure (PASP; 56.51±7.34 mmHg vs. 34.16±2.81 mmHg, P<0.001) and right/left ventricle diameter (1.37±0.12 vs. 0.99±0.12, P<0.001) decreased significantly after TT. Tricuspid annular plane systolic excursion (1.43±0.33 cm vs. 2.07±0.27 cm, P<0.001), myocardial performance index (0.47±0.08 vs. 0.55±0.07, P<0.001), and systolic wave prime (9.6±2.8 vs. 15.3±2.6) increased significantly after TT. No major bleeding or stroke was observed. There was one in-hospital death and two additional deaths within 6 months. No cases of pulmonary hypertension were identified during follow-up. The results of this pilot study suggest that an extended infusion of low-dose tPA is a safe and effective therapy in patients with massive PE. This protocol was also effective in decreasing PASP and restoring right ventricular function.

Prophylactic low-dose paracetamol for ductal closure and neurodevelopmental outcome in very preterm infants.

To investigate the direct effect of prophylactic low-dose paracetamol administration for ductal closure on neurodevelopmental outcome in very preterm infants who did not receive ibuprofen or surgical ligation for treatment of a patent ductus arteriosus. Infants < 32 gestational weeks born 10/2014-12/2018 received prophylactic paracetamol (paracetamol group, n = 216); infants born 02/2011-09/2014 did not receive prophylactic paracetamol (control group, n = 129). Psychomotor (PDI) and mental (MDI) outcome were assessed using Bayley Scales of Infant Development at 12 and 24 months corrected age. Our analyses showed significant differences in PDI and MDI at age 12 months (B = 7.8 (95% CI 3.90-11.63), p < 0.001 and B = 4.2 (95% CI 0.81-7.63), p = 0.016). At age 12 months, the rate of psychomotor delay was lower in the paracetamol group (OR 2.22, 95% CI 1.28-3.94, p = 0.004). There was no significant difference between the rates of mental delay at any time-point. All group differences remained significant after adjustment for potential confounders (PDI 12 months B = 7.8 (95% CI 3.77-11.34), p < 0.001, MDI 12 months B = 4.3 (95% CI 0.79-7.45), p = 0.013, PDI < 85 12 months OR 2.65 (95% CI 1.44-4.87), p = 0.002). We found no impairment of psychomotor and mental outcome at age 12 and 24 months in very preterm infants after prophylactic low-dose paracetamol administration.

Glycolytic stress deteriorates 229E virulence to improve host defense response

Viral infection treatment is a difficult task due to its complex structure and metabolism. Additionally, viruses can alter the metabolism of host cells, mutate, and readily adjust to harsh environments. Coronavirus stimulates glycolysis, weakens mitochondrial activity, and impairs infected cells. In this study, we investigated the efficacy of 2-DG in inhibiting coronavirus-induced metabolic processes and antiviral host defense systems, which have not been explored so far. 2-Deoxy-d-glucose (2-DG), a molecule restricting substrate availability, has recently gained attention as a potential antiviral drug. The results revealed that 229E human coronavirus promoted glycolysis, producing a significant increase in the concentration of fluorescent 2-NBDG, a glucose analog, particularly in the infected host cells. The addition of 2-DG decreased its viral replication and suppressed infection-induced cell death and cytopathic effects, thereby improving the antiviral host defense response. It was also observed that administration of low doses of 2-DG inhibited glucose uptake, indicating that 2-DG consumption in virus-infected host cells was mediated by high-affinity glucose transporters, whose levels were amplified upon coronavirus infection. Our findings indicated that 2-DG could be a potential drug to improve the host defense system in coronavirus-infected cells.