Low-dose Administration Research Articles

The role of macrolides in chronic rhinosinusitis and nasal polyps.

Chronic rhinosinusitis (CRS) is a heterogeneous condition, so personalized treatment based on each patient's pathophysiology is essential, rather than a one-size-fits-all approach. Drug therapy for CRS has evolved significantly in recent years with the introduction of biologics, necessitating a reconsideration of the role of low-dose and long-term administration of a 14-membered ring macrolide (macrolide therapy) in the treatment of CRS. Recent research on the mechanisms of macrolide therapy and its proper use may assist physicians in improving patients' quality of life and reducing disease burden. A classification of the pathogenesis of CRS based on endotype has been proposed, with type 2 inflammation playing a particularly important role as a refractory factor. Macrolide therapy improves CRS via immunomodulatory and anti-inflammatory effects rather than antimicrobial action, and it is expected to be effective in patients with neutrophil-dominant inflammation. Understanding the effectiveness and limitations of macrolide therapy is critical for making the best treatment decisions, especially when combined with surgery and other pharmacologic therapies. Therefore, selecting appropriate patients for macrolide therapy is critical for achieving adequate therapeutic efficacy.

An energy-resolving photon-counting X-ray detector for computed tomography combining silicon-photomultiplier arrays and scintillation crystals.

X-ray photon-counting computed tomography (PCCT) has garnered considerable interest owing to its low-dose administration, high-quality imaging, and material decomposition characteristics. Current commercial PCCT systems employ compound semiconductor photon-counting X-ray detectors, which offer good energy resolution. However, the choice of materials is limited, and cadmium telluride or cadmium zinc telluride is mostly used. Although indirect radiation detectors can be used as alternatives to compound semiconductor detectors, implementing fine-pitch segmentation in such detectors is challenging. Here we designed an indirect fine-pitch X-ray photon-counting detector by combining miniaturized silicon photomultiplier arrays and fast scintillation crystals, with a pixel size of 250 µm, for future indirect PCCT. The fabricated array detector has the potential to discriminate photon energies with a 27% resolution at 122 keV, 296 µm spatial resolution, and charge-sharing inhibition ability.

Intracoronary administration of tenecteplase to prevent PCI-related myocardial infarction in patients with echo-attenuated coronary plaques: study protocol for a multicenter, prospective, randomized controlled trial

BackgroundPercutaneous coronary intervention (PCI)-related myocardial infarction (MI), especially the distal type associated with microvascular dysfunction, is not an uncommon complication of the procedure. Specific lesion features, the echo-attenuated plaques (EA) in particular, are well-established contributors to the pathogenesis of distal-type MI. These plaques are prone to disruption during PCI, leading to microvascular thrombosis and distal embolism. Tenecteplase (TNK), a 3rd-generation thrombolytic drug, has demonstrated effective thrombolytic capacity without significantly increasing the bleeding risk. Our study aims to evaluate whether a low-dose intracoronary TNK administration prior to PCI in patients with intravascular ultrasound (IVUS)-detected EA can reduce the occurrence of PCI-related MI and improve clinical outcomes.MethodsThis trial is designed as a multicenter, prospective randomized controlled trial with a 1-month follow-up. The primary outcome of the study is the incidence of PCI-related myocardial infarction (MI) occurring within 48 h after PCI, which serves as a valid surrogate endpoint for assessing the efficacy of tenecteplase-based PCI in preventing future major adverse cardiovascular events (MACE) in patients with EA (Bulluck, et. al, Eur Heart J 42:2630–42, 2021) {1b.1}. Secondary outcomes include the proportion of patients with elevated postoperative high-sensitivity cTnI exceeding 5, 10, 35, and 70 times of the normal baseline, incidence of coronary slow flow after stent implantation and post-dilation, frame count of angiographic flow after stent implantation and post-dilation, as well as the incidence of MACE during hospitalization and at the 1-month follow-up.DiscussionThis trial may demonstrate that an immediate intracoronary administration of low-dose TNK following PCI can effectively lower the incidence of PMI in patients with EA, while confirming the safety of this therapeutic approach.Trial registrationChinese Clinical Trial Registry (ChiCTR2400084840). Registered on May 27, 2024.

A potent broad-spectrum neutralizing antibody targeting a conserved region of the prefusion RSV F protein

Respiratory syncytial virus (RSV) poses a significant public health challenge, especially among children. Although palivizumab and nirsevimab, neutralizing antibodies (nAbs) targeting the RSV F protein, have been used for prophylaxis, their limitations underscore the need for more effective alternatives. Herein, we present a potent and broad nAb, named 5B11, which exhibits nanogram level of unbiased neutralizing activities against both RSV-A and -B subgroups. Notably, 5B11 shows a ~20-fold increase in neutralizing efficacy compared to 1129 (the murine precursor of palivizumab) and approximately a 3-fold increase in neutralizing efficacy against B18537 in comparison to nirsevimab. Cryo-electron microscopy analysis reveals 5B11’s mechanism of action by targeting a highly conserved epitope within site V, offering a promising strategy with potentially lower risk of escape mutants. Antiviral testing in a female cotton rat model demonstrated that low-dose (1.5 mg/kg) administration of 5B11 achieved comparable prophylactic efficacy to that achieved by high-dose (15 mg/kg) of 1129. Furthermore, the humanized 5B11 showed a superior in vivo antiviral activity against B18537 infection compared to nirsevimab and palivizumab. Therefore, 5B11 is a promising RSV prophylactic candidate applicable to broad prevention of RSV infection.

Delayed low-dose oral administration of 4'-fluorouridine inhibits pathogenic arenaviruses in animal models of lethal disease.

Development of broad-spectrum antiviral therapies is critical for outbreak and pandemic preparedness against emerging and reemerging viruses. Viruses inducing hemorrhagic fevers cause high morbidity and mortality in humans and are associated with several recent international outbreaks, but approved therapies for treating most of these pathogens are lacking. Here, we show that 4'-fluorouridine (4'-FlU; EIDD-2749), an orally available ribonucleoside analog, has antiviral activity against multiple hemorrhagic fever viruses in cell culture, including Nipah virus, Crimean-Congo hemorrhagic fever virus, orthohantaviruses, and arenaviruses. We performed preclinical in vivo evaluation of oral 4'-FlU against two arenaviruses, Old World Lassa virus (LASV) and New World Junín virus (JUNV), in guinea pig models of lethal disease. 4'-FlU demonstrated both advantageous pharmacokinetic characteristics and high efficacy in both of these lethal disease guinea pig models. Additional experiments supported protection of the infected animals even when 4'-FlU delivery was reduced to a low dose of 0.5 milligram per kilogram. To demonstrate clinical utility, 4'-FlU treatment was evaluated when initiated late in the course of infection (12 or 9 days after infection for LASV and JUNV, respectively). Delayed treatment resulted in rapid resolution of clinical signs, demonstrating an extended window for therapeutic intervention. These data support the use of 4'-FlU as a potent and efficacious treatment against highly pathogenic arenaviruses of public health concern with a virus inhibition profile suggesting broad-spectrum utility as an orally available antiviral drug against a wide variety of viral pathogens.

Dose-Related Effects and Bleeding Risk of Ketorolac in Pediatric Tonsillectomy.

To investigate the safety and effectiveness of dose-related ketorolac administration in children who underwent tonsillectomy. Data sourced from PubMed, SCOPUS, Embase, Web of Science, and Cochrane databases, encompassing literature from their inception until June 2024. The perioperative administration of ketorolac in comparison with a control group was included in this analysis. The outcomes assessed were postoperative pain levels; utilization patterns of analgesic medication in terms of quantity and frequency; and the incidence rates of postoperative nausea, vomiting, and bleeding. Eighteen studies with 11,729 patients that investigated. The ketorolac treatment group with postoperative bleeding had a higher incidence of primary bleeding (significant bleeding and operative bleeding control) compared to the control group. However, ketorolac treatment did not affect the risk of secondary bleeding. Subgroup analysis showed that 0.9 to 1 mg/kg of ketorolac significantly increases primary operative control (odds ratio [OR] = 4.0700 [1.6352; 10.1302]; I2 = 0.0%) and primary significant bleeding (OR = 2.3200 [1.1322; 4.7538]; I2 = 0.0%). On the other hand, 0.5 mg/kg ketorolac did not show any influence on primary operative control. The administration of ketorolac (both 0.9-1 and 0.5 mg/kg) led to a significant decrease in postoperative pain (2-24 hours), nausea, and vomiting compared to the control group. Low-dose (0.5 mg/kg) ketorolac administration to children could significantly reduce the risk of primary significant bleeding and surgical hemostasis compared to high-dose administration (0.9-1.0 mg/kg). In addition, low-dose ketorolac administration could provide sufficient pain control and reduce postoperative nausea and vomiting.

Potential mechanism of perillaldehyde in the treatment of nonalcoholic fatty liver disease based on network pharmacology and molecular docking

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic metabolic liver diseases worldwide. Perillaldehyde (4-propyl-1-en-2-ylcyclohexene-1-aldehyde, PA) is a terpenoid compound extracted from Perilla, which has effective pharmacological activities such as anti-inflammatory, antidepressant, and anticancer. This study aimed to explore the pharmacological effects of PA in intervening with NAFLD and reveal its potential mechanisms. Firstly, we identified the core targets of PA intervention therapy for NAFLD through network pharmacology and molecular docking techniques. After that, in vitro animal experiments such as H&E and Masson staining, immunofluorescence, immunohistochemistry, and Western blot were conducted to validate the results network effectively pharmacology predicted. Network pharmacology analysis suggested that PPAR-α may be the core target of PA intervention in NAFLD. H&E and Masson staining showed that after low-dose (50 mg/kg) PA administration, there was a noticeable improvement in fat deposition in the livers of NAFLD mice, and liver tissue fibrosis was alleviated. Immunohistochemical and immunofluorescence analysis showed that low dose (50 mg/kg) PA could reduce hepatocyte apoptosis, decrease the content of pro-apoptosis protein Bax, and increase the expression of anti-apoptosis protein Bcl-2 in NAFLD mice. Western blot results confirmed that low-dose (50 mg/kg) PA could increase the expression of PPAR-α and inhibit the expression of NF-κB in NAFLD mice. Our study indicated that PA could enhance the activity of PPAR-α and reduce the level of NF-κB in NAFLD mice, which may positively affect the prevention of NAFLD.

Low and sustained doses of erythropoietin prevent preterm infants from intraventricular hemorrhage

In addition to its hematopoietic function, erythropoietin (EPO) has demonstrated neuroprotective properties in preclinical studies, particularly in cases of reduced oxygenation or ischemia in the neonatal brain. While these findings have sparked optimism for its potential clinical application, the efficacy of EPO remains contentious in translational assays. Notably, while repeated administration of low doses of EPO has correlated with a decrease in adverse outcomes, the use of high EPO doses has shown either negligible or potentially detrimental effects on the incidence of brain injury. In this pilot study, we explored the effects of low and sustained doses of EPO (400 IU/kg) on the incidence of intraventricular hemorrhage (IVH) in premature infants. EPO was administered intravenously three times a week until the infants reached 32 weeks corrected gestational age. Our results indicate a significant decrease in the incidence of IVH with EPO treatment. Although, this study does not provide conclusive evidence on EPO's ability to reverse established IVH, these results strongly support the need for larger-scale clinical trials to further assess EPO's therapeutic potential.

Effect of low-dose aspirin on mid-luteal phase uterine Artery blood flow in women with unexplained recurrent pregnancy loss

Objectives: As a possible therapy for recurrent pregnancy loss, this study sought to ascertain if low-dose aspirin was effective in increasing uterine artery blood flow. Study Design: This investigation was structured as a single-arm clinical trial Patients and Methods: All participants were aged 39 years or younger and had no prior or current indications of abnormal glucose tolerance, thyroid dysfunction, hyperprolactinemia, or Antiphospholipid antibody syndrome. Bilateral assessments of the Systolic/Diastolic (S/D) ratio, Resistive Index (RI), and Pulsatility Index (PI) were conducted in the chosen patients in the mid-luteal phase, before to and following a minimum of two weeks of low-dose aspirin administration. Results: The results of this investigation showed significant variation in the S/D and PI prior to and following aspirin administration. There was no discernible shift in RI. The analysis revealed a statistically significant reduction in uterine artery PI after aspirin administration (1.92±0.29) compared to the pre-treatment value (2.22±0.27), with a p-value of 0.0001. Remarkably, the pulsatility indices of the left and right uterine arteries did not significantly differ from one another. Conclusion: For women who have a history of miscarriages, low-dose aspirin can be recommended as an adjuvant therapy as it effectively improves uterine artery blood flow in these patients. However, more well-designed research is required to ascertain whether improved pregnancy outcomes are correlated with improved uterine perfusion. The current study supported the aspirin guideline for women with a history of recurrent miscarriages by showing that aspirin treatment resulted in a reduction in uterine artery PI.

Structure-Function Correlation in Cobalt-Induced Brain Toxicity.

Cobalt toxicity is difficult to detect and therefore often underdiagnosed. The aim of this study was to explore the pathophysiology of cobalt-induced oxidative stress in the brain and its impact on structure and function. Thirty-five wild-type C57B16 mice received intraperitoneal cobalt chloride injections: a single high dose with evaluations at 24, 48, and 72 h (n = 5, each) or daily low doses for 28 (n = 5) or 56 days (n = 15). A part of the 56-day group also received minocycline (n = 5), while 10 mice served as controls. Behavioral changes were evaluated, and cobalt levels in tissues were measured with particle-induced X-ray emission. Brain sections underwent magnetic resonance imaging (MRI), electron microscopy, and histological, immunohistochemical, and molecular analyses. High-dose cobalt caused transient illness, whereas chronic daily low-dose administration led to long-term elevations in cobalt levels accompanied by brain inflammation. Significant neurodegeneration was evidenced by demyelination, increased blood-brain barrier permeability, and mitochondrial dysfunction. Treated mice exhibited extended latency periods in the Morris water maze test and heightened anxiety in the open field test. Minocycline partially mitigated brain injury. The observed signs of neurodegeneration were dose- and time-dependent. The neurotoxicity after acute exposure was reversible, but the neurological and functional changes following chronic cobalt administration were not.

Secondary prophylaxis of venous thromboembolism (VTE) with low dose apixaban or rivaroxaban in major-thrombophilia carriers.

Direct oral anticoagulants (DOACs) are widely used for treatment and secondary prophylaxis of venous thromboembolism (VTE) and represent the gold standard for VTE secondary prophylaxis, with low-intensity DOACs administration becoming increasingly used worldwide in such scenario. Albeit widespread DOACs usage there are few literature data regarding their efficacy and safety in major thrombophilia carriers and almost no data is available for low intensity apixaban and rivaroxaban as secondary VTE prophylaxis in such patients. The aim of our study is to evaluate and confront the efficacy and safety of low-dose DOACs for VTE secondary prophylaxis, in major thrombophilia carriers vs patients at high risk of VTE recurrence for other reasons. We retrospectively evaluated patients who required long-term anticoagulant secondary prophylaxis to prevent recurrent VTE, treated with apixaban 2.5mg BID or rivaroxaban 10mg daily and that were screened for thrombophilia. The examined patients were 339. Baseline characteristics such as sex, age, obesity rate, smoking, number of previous VTEs and comorbidities (such as cardiovascular diseases, diabetes, mild CKD) were equally distributed in either group. The median low-dose DOACs administration time was 19.20months (IQR 12.17-35.67). During low-dose DOACs treatment, 13 (3.8%) VTE recurrences were observed; 14 bleeding events were registered (4,1%), with no major bleeding (MB), 6 clinically relevant non major bleeding (CRNMB) (1.8%) and 8 minor bleeding (2.3%). No statistically significant difference in the rate of VTE recurrence and/or bleeding events emerged between major thrombophilia carriers and non-major thrombophilia carriers. In multivariate analysis increased risk of VTE recurrence was found for patients with cardiovascular comorbidities (HR 4.00 - p = 0.034) and for patients with more than one previous VTE episode (HR 5.14-p = 0.034). Our data suggest that low-dose DOACs may be effective and safe in secondary VTE prophylaxis for carriers of major thrombophilia with no increase in VTE recurrence and/or bleeding risk.

Modeling the pre-symptomatic stage of hemi-parkinsonian state in animals (rodents and monkeys)

The behavioral and functional states preceding the onset specific parkinsonian symptoms were studied at an early (pre-symptomatic) stage of hemi-parkinsonian syndrome development in rodents and monkeys. The pre-symptomatic stage of the hemi-parkinsonian syndrome was determined in rodents (mice and rats) treated by chronic administration of low doses of rotenone toxin. The consecutive steps of neuropathological traits development in rodents included the cognitive impairment at the 1st-2nd week of exposure to rotenone, minor movement disorders at the 3st-4nd week before the onset of severe motor dysfunction as well as some biochemical indicators. The latencies and amplitudes of visually guided saccades (VGS) while conditioned instrumental task performing were studied in nonhuman primates (Macaca mulatta) chronically treated with low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The elongation of VGS latencies and the decline of their accuracy were revealed with development of MPTP-induces syndrome but conditioned instrumental performance was not affected. The negative behavioral effects manifested in animals at the pre-symptomatic stage of toxins induced disease both in the rotenone model in rodents and in MPTP model in monkeys suggesting them as early markers of a hemi-parkinsonian syndrome.

Statin therapy improves locomotor muscle microvascular reactivity in patients with heart failure with preserved ejection fraction.

Peripheral microvascular dysfunction has been documented in patients with heart failure with preserved ejection fraction (HFpEF), which may be related to elevated levels of inflammation and oxidative stress. Unfortunately, few strategies have been identified to effectively ameliorate this disease-related derangement. Thus, using a parallel, double-blind, placebo-controlled design, this study evaluated the efficacy of 30-day atorvastatin administration (10 mg daily) on lower limb microvascular reactivity, functional capacity, and biomarkers of inflammation and oxidative stress in patients with HFpEF (statin, n = 8, 76 ± 6 yr; placebo, n = 8, 68 ± 9 yr). The passive limb movement (PLM)-induced hyperemic response and 6-min walk test (6MWT) distance were evaluated to assess ambulatory muscle microvascular function and functional capacity, respectively. Circulating biomarkers were also measured to assess the contribution of changes in inflammation and redox balance to these outcomes. The total hyperemic response to PLM, assessed as leg blood flow area under the curve (LBFAUC), increased following the statin intervention (pre, 60 ± 68 mL; post, 164 ± 90 mL; P < 0.01), whereas these variables were unchanged in the placebo group (P = 0.99). There were no significant differences in 6MWT distance following statin or placebo intervention. Malondialdehyde (MDA), a marker of lipid peroxidation, was significantly reduced following the statin intervention (pre, 0.68 ± 0.10; post, 0.51 ± 0.11; P < 0.01) while other circulating biomarkers were unchanged. Together, these data provide new evidence for the efficacy of low-dose statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to a diminution in oxidative stress.NEW & NOTEWORTHY This was the first study to investigate the impact of statin administration on locomotor muscle microvascular function in patients with HFpEF. In support of our hypothesis, the total hyperemic response to PLM, assessed as leg blood flow area under the curve, increased, and malondialdehyde, a marker of oxidative damage, was reduced following the statin intervention. Together, these data provide new evidence for the efficacy of statin administration to improve locomotor muscle microvascular reactivity in patients with HFpEF, which may be due, in part, to reduced oxidative stress.

Venous thromboembolism secondary prophylaxis in elderly people (over 75-year-old) with low-dose direct oral anticoagulants: single-center Italian experience

Nowadays, direct oral anticoagulants (DOACs) represent the gold standard for venous thromboembolism (VTE) treatment and VTE secondary prophylaxis; nevertheless, the percentage of elderly patients in major trials and literature data about DOACs usage for VTE secondary prophylaxis in the elderly are scant. Our retrospective study tried to evaluate low-dose DOACs efficacy and safety for elderly VTE secondary prophylaxis in a real-life setting. A cohort of 73 patients (≥ 75 years) considered at high risk of VTE recurrence was treated with apixaban 2.5 mg twice daily (b.i.d.) or rivaroxaban 10 mg daily as VTE secondary prophylaxis. The median low-dose DOACs administration time was 18.40 months. Three (4.1%) VTE recurrence events were observed, with four bleeding events registered (5.5%), including one major bleeding (MB) (1.4%) and two clinically relevant non major bleeding (CRNMB) (2.7%). Our data suggest that low-dose DOACs may be effective and well tolerated for secondary VTE prophylaxis in elderly patients at high risk of VTE recurrence.

The Outcome of Octogenarian Patients with Multiple Myeloma Treated Outside Clinical Studies, Focusing on Tolerability and Efficacy of Treatment.

Background: Data on the outcome of octogenarian multiple myeloma (MM) patients (pts), especially if treated outside clinical studies, are scanty. Aims and Methods: MM pts ≥ 80 years, treated at TASMC with first-line therapy between 2010 and 2023, were reviewed. Characteristics and outcomes were analyzed. Results: A total number of 101 pts, of whom 54 were males with a median age of 84 years (80-98), were included. Among them, 67.4% had a Charlson comorbidity index of ≥5, 37% had ISS-3 (International staging system) and 20% had Revised-ISS-3. In our study, 44.5% received doublets and 50.5% received triplets/quadruplets. A bortezomib-based regimen was applied in 87%, and IMiDs were used in 27.7%. Despite an upfront employment of a low lenalidomide dose, dose reductions were required in 48%. Grade ≥ 3 adverse events (AEs) (mainly infections) were documented in 36.6% of patients, including grade 5 events in 9%, all attributed to infections. The overall response rate was 69%, including 31% ≥ VGPRs (Very good partial response). Sixty-seven percent (67%) received second-line therapy, administered within a median period of 12 months (1-84). Within a median follow-up period of 36 m (1-141), the median overall survival (OS) approached 42 m (range: 1-141); being shorter in pts > 84 years (HR = 1.7, p = 0.03), pts with lung disease (HR = 1.8, p = 0.044) and pts with ISS = 3 and R-ISS = 3 (HR = 1.65, p = 0.0016 and HR = 2.45, p = 0.006, respectively); Conclusions: Octogenarians treated outside clinical studies often have a lower tolerance to treatment. Nevertheless, upfront administration of low doses of anti-MM agents provided a response in the majority of patients, translated into impressive OS. Nevertheless, mortality due to AEs was high, emphasizing the need for new, "octogenarian-oriented" treatment protocols.

No Short-Term Effect of Low-Dose Nicotine on Inflammation after Global Hypoxia in Newborn Piglets

Introduction: Perinatal asphyxia initiates cytokine release and complement activation with risk of brain damage. We assessed the effect of nicotine on innate immunity and hypothesized that nicotine infusion in a newborn piglet model of asphyxia would decrease the immune response and be neuroprotective. Methods: Newborn piglets (n = 41) were randomized to one of three groups after hypoxia: two groups receiving nicotine, (1) 18 µg/kg/h (n = 17), (2) 46 µg/kg/h (n = 15), and (3) control group receiving saline (n = 9). C3a, IL-6, TNF, and IL-10 were measured in plasma and IL-6 and IL-8 in microdialysis fluid from cerebral periventricular white matter, using immuno-assays. Results: Plasma C3a and IL-6 increased significantly from start to end hypoxia (mean 4.4 ± 0.55 to 5.6 ± 0.71 ng/mL and 1.66 ± 1.04 to 2.68 ± 0.71 pg/mL, respectively), while IL-10 and TNF increased significantly after 4 h (mean 1.4 ± 1.08 to 2.9 ± 1.87 and 3.3 ± 0.67 to 4.0 ± 0.58 pg/mL, respectively) (p < 0.001 for all). IL-6 increased significantly (p < 0.001) in microdialysis samples from end hypoxia to end experiment (mean 0.65 ± 0.88 to 2.78 ± 1.84 ng/mL). No significant differences were observed between the nicotine groups and the control group neither in plasma nor in microdialysis samples. Conclusion: Hypoxia leads to rapid release of cytokines in plasma and cerebral microdialysis fluid, and complement activation measured on C3a. However, low-dose nicotine administration did not affect the immune response.

Extracellular condensates (ECs) are endogenous modulators of HIV transcription and latency reactivation.

ECs isolated from SIV infected macaques (VEH|SIV ECs) is a positive regulator of LTR-dependent HIV transcription and production of infectious viral particles in vitro.ECs isolated from THC treated SIV infected macaques (THC|SIV ECs) prevents the transcription and reactivation of HIV in latently infected cells and prevents production of viral particles in vitro.ECs reprogram host transcriptome and secretome in manners that or suppress promote reactivation of latent HIV reservoir.The above highlights led to the conclusion that while VEH/SIV ECs robustly induced HIV RNA in latently HIV-infected cells, long-term low-dose THC administration enriched ECs for anti-inflammatory cargo that significantly diminished their ability to reactivate latent HIV.

The Effects of Subchronic Methamphetamine Administration on the NLRP3 Inflammasome, Memory Function, and Hippocampal Morphology

Background: While it is established that addictive doses of methamphetamine correlate with inflammation-mediated neurotoxic pathways, the extent of toxicity resulting from subchronic administration at lower doses remains uncertain. Objectives: This study aimed to investigate the subtle effects of daily subchronic methamphetamine (MA) administration on neuroinflammatory processes, cognitive dimensions, gene expression, and hippocampal morphology. Methods: The experimental study employed a longitudinal design with three groups (G1B, G2B, G3B) receiving methamphetamine (5 mg/kg, intraperitoneally, once daily) for 1, 2, or 3 weeks, respectively. Corresponding control groups (G1A, G2A, G3A) received 0.2 mL of normal saline. Spatial learning, novel object recognition, and passive avoidance tests were conducted to assess spatial, recognition, and fear avoidance memories. Hippocampal morphology was evaluated using Nissl staining, and the expressions of NLRP3, ASC, and caspase-1 genes were measured as markers of neuroinflammation. Results: Statistical analyses, including one-way and two-way ANOVA, showed that subchronic low-dose administration of MA led to significant activation of the inflammasome (NLRP3, ASC, and caspase-1), which may have resulted in pyramidal cell death in the hippocampus. The hippocampal structure in the CA1 region was completely disrupted. Spatial memory and passive avoidance learning were impaired in the MA groups, while recognition memory remained unaffected. Conclusions: The findings suggest that prolonged administration of 5 mg/kg of methamphetamine may be associated with significant inflammasome activation, pyramidal cell death, and mild cognitive decline. Contrary to previous evidence, even lower doses of methamphetamine taken over an extended period could be neurotoxic.

Factor Eight Inhibitor Bypass Activity Use in Cardiac Surgery: A Propensity-matched Analysis of Safety Outcomes.

Bleeding during cardiac surgery may be refractory to standard interventions. Off-label use of factor eight inhibitor bypass activity (FEIBA) has been described to treat such bleeding. However, reports of safety, particularly thromboembolic outcomes, show mixed results, and reported cohorts have been small. Adult patients undergoing cardiac surgery on cardiopulmonary bypass between July 1, 2018, and June 30, 2023, at Stanford Hospital (Stanford, California) were reviewed (n = 3,335). Patients who received FEIBA to treat postcardiopulmonary bypass bleeding were matched with those who did not by propensity scores in a 1:1 ratio using nearest neighbor matching (n = 352 per group). The primary outcome was a composite outcome of thromboembolic complications including any one of deep vein thrombosis, pulmonary embolism, unplanned coronary artery intervention, ischemic stroke, and acute limb ischemia, in the postoperative period. Secondary outcomes included renal failure, reoperation, postoperative transfusion, intensive care unit length of stay, and 30-day mortality. A total of 704 encounters was included in this propensity-matched analysis. The mean dose of FEIBA administered was 7.3 ± 5.5 U/kg. In propensity-matched multivariate logistic regression models, there was no statistically significant difference in odds ratios for thromboembolic outcomes, intensive care unit length of stay, or mortality. Patients who received more than 750 U FEIBA had an increased odds ratio for acute renal failure (odds ratio, 4.14; 95% CI, 1.61 to 10.36; P < 0.001). In multivariate linear regression, patients receiving FEIBA were transfused more plasma and cryoprecipitate postoperatively. However, only the dose range of 501 to 750 U was associated with an increase in transfusion of erythrocytes (β, 2.73; 95% CI, 0.68 to 4.78; P = 0.009) and platelets (β, 1.74; 95% CI, 0.85 to 2.63; P < 0.001). Low-dose FEIBA administration during cardiac surgery does not increase risk of thromboembolic events, intensive care unit length of stay, or mortality in a propensity-matched cohort. Higher doses were associated with increased acute renal failure and postoperative transfusion. Further studies are required to establish the efficacy of activated factor concentrates to treat refractory bleeding during cardiac surgery.

Ofatumumab in the treatment of multiple sclerosis - A summary of preclinical and clinical data

B-cell targeted therapies are highly effective in multiple sclerosis (MS). Most of these therapies are administered intravenously at long intervals. Ofatumumab, an anti-CD20 antibody that is administered subcutaneously at low doses on a monthly basis due to its high affinity to the target structure, became available for the treatment of MS in 2021. An overview of practice-relevant immunological and clinical data on ofatumumab is provided. The high affinity of ofatumumab to the target structure allows low dose and low volume administration, with the release and absorption profile after subcutaneous application allowing for high concentrations in the lymph nodes and gradual depletion of B-cells. Rapid onset of action is achieved as well as B-cell repletion within a few months in case of discontinuation of therapy. Long-term data show stable IgG levels over up to four years and high efficacy with respect to relapse rate, progression, and cognition. According to current study data, the effect compared to teriflunomide is greater the earlier therapy is initiated. Ofatumumab has a specific B-cell depletion pattern. CD20 expressing B-cell progenitor cells in the bone marrow are preserved and therefore also the inducibility and differentiation of plasma cells. The formation of a humoral immunological memory is therefore possible. Four-year study data showed no abnormalities in the rate of severe infections or malignancies. Ofatumumab is an innovative B-cell targeted therapy. It is highly effective with a good safety and tolerability profile, well controllable and maintains immunocompetence against pathogens.