Iron oxide nanoparticles for magnetically-guided and magnetically-responsive drug delivery.

In this review, we discuss the recent advances in and problems with the use of magnetically-guided and magnetically-responsive nanoparticles in drug delivery and magnetofection. In magnetically-guided nanoparticles, a constant external magnetic field is used to transport magnetic nanoparticles loaded with drugs to a specific site within the body or to increase the transfection capacity. Magnetofection is the delivery of nucleic acids under the influence of a magnetic field acting on nucleic acid vectors that are associated with magnetic nanoparticles. In magnetically-responsive nanoparticles, magnetic nanoparticles are encapsulated or embedded in a larger colloidal structure that carries a drug. In this last case, an alternating magnetic field can modify the structure of the colloid, thereby providing spatial and temporal control over drug release.

Survival of skyrmions along granular racetracks at room temperature.

Skyrmions can be envisioned as bits of information that can be transported along nanoracetracks. However, temperature, defects, and/or granularity can produce diffusion, pinning, and, in general, modification in their dynamics. These effects may cause undesired errors in information transport. We present simulations of a realistic system where both the (room) temperature and sample granularity are taken into account. Key feasibility magnitudes, such as the success probability of a skyrmion traveling a given distance along the racetrack, are calculated. The results are evaluated in terms of the eventual loss of skyrmions by pinning, destruction at the edges, or excessive delay due to granularity. The model proposed is based on the Fokker-Planck equation resulting from Thiele's rigid model for skyrmions. The results could serve to establish error detection criteria and, in general, to discern the dynamics of skyrmions in realistic situations.

Understanding Prognostic Factors for Human Papillomavirus Vaccination: A Rural Community Case-Control Study.

HPV vaccination coverage rates can vary depending on several factors. The main objective of this study is to identify possible independent prognostic factors that have an impact on HPV vaccination in a rural community, specifically related to sexual and reproductive health. A case-control, retrospective, community-based study was carried out on women aged 15 to 40 in the primary health centers of Southern Catalonia's Terres de l'Ebre region, Spain, from 1 January 2020 to 31 December 2022. A random sample of 520 women with an average age of 29.3 (SD 7.8) years old was included in the study. Independent prognostic factors: age OR 0.680 (95% CI: 0.635-0.729, p < 0.001), immigrant origin OR 0.215 (95% CI: 0.109-0.422, p < 0.001), and HPV PCR OR 7.402 (95% CI: 2.504-21.880, p < 0.001). The variables that showed a barrier effect for HPV vaccination were age (OR 0.680, 95% CI 0.635-0.729, p < 0.001), and immigrant origin (OR 0.215, 95% CI 0.109-0.422, p < 0.001). The variable that showed a facilitating effect for HPV vaccination was HPV PCR (OR 7.402, 95% CI 2.504-21.880, p < 0.001).

Early Diagnosis of Atrial Fibrillation and Stroke Incidence in Primary Care: Translating Measurements into Actions-A Retrospective Cohort Study.

(1) Background: AF-related strokes will triple by 2060, are associated with an increased risk of cognitive decline, and alone or in combination, will be one of the main health and economic burdens on the European population. The main goal of this paper is to describe the incidence of new AF associated with stroke, cognitive decline and mortality among people at high risk for AF. (2) Methods: Multicenter, observational, retrospective, community-based studies were conducted from 1 January 2015 to 31 December 2021. The setting was primary care centers. A total of 40,297 people aged ≥65 years without previous AF or stroke were stratified by AFrisk at 5 years. The main measurements were the overall incidence density/1000 person-years (CI95%) of AF and stroke, prevalence of cognitive decline, and Kaplan-Meier curve. (3) Results: In total, 46.4% women, 77.65 ± 8.46 years old on average showed anAF incidence of 9.9/103/year (CI95% 9.5-10.3), associated with a four-fold higher risk of stroke (CI95% 3.4-4.7), cognitive impairment(OR 1.34 (CI95% 1.1-1.5)), and all-cause mortality (OR 1.14 (CI95% 1.0-1.2)), but there was no significant difference in ischemic heart disease, chronic kidney disease, or peripheral arteriopathy. Unknown AF was diagnosed in 9.4% and of these patients, 21.1% were diagnosed with new stroke. (4) Conclusions: The patients at high AF risk (Q4th) already had an increased cardiovascular risk before they were diagnosed with AF.

Analgesic and antiallodynic effects of antidepressants after infiltration into the rat.

Tricyclic antidepressants (TCA) have potent local anesthetic properties and may produce a long-lasting pain blockade that could be of interest in relieving chronic pain states such as neuropathic pain, but there are only few data comparing their dose-response curves of analgesic activity under the same experimental conditions. This study examines the time course of pain-relieving properties of 7 TCA in heat-induced paw withdrawal after subcutaneous administration. Mixed inhibitors of norepinephrine and serotonin uptake (amitriptyline, nortriptyline, imipramine, desipramine, doxepin) and selective inhibitors of serotonin uptake (fluoxetine and fluvoxamine) were assayed. The TCA with the longest analgesic activity were selected to test its antiallodynic effect in the neuropathic pain model of chronic sciatic nerve constriction injury. Bupivacaine was used as a reference drug in both experiments. A dose versus time of maximal analgesic effect curve was constructed for each drug. The longest analgesic effect was obtained for doxepin and imipramine. Although low doses of amitriptyline showed the same activity than doxepin, higher doses failed to reach the same effect. Selective inhibitors of serotonin showed no action at all doses tested. In the chronic sciatic nerve constriction injury model, doxepin and, to a smaller degree, amitriptyline and imipramine protected from allodynia; bupivacaine was ineffective. The antiallodynic effect always lasted less long than the analgesic effect. These observations provide support for the potential use of TCA as durable analgesics. Doxepin overall showed the most outstanding results in pain relief.

Risk of Atrial Fibrillation, Ischemic Stroke and Cognitive Impairment: Study of a Population Cohort ≥65 Years of Age.

PURPOSE: To evaluate a model for calculating the risk of AF and its relationship with the incidence of ischemic stroke and prevalence of cognitive decline. MATERIALS AND METHODS: It was a multicenter, observational, retrospective, community-based study of a cohort of general population ≥6ct 35 years, between 01/01/2016 and 31/12/2018. Setting: Primary Care. Participants: 46,706 people ≥65 years with an active medical history in any of the primary care teams of the territory, information accessible through shared history and without previous known AF. Interventions: The model to stratify the risk of AF (PI) has been previously published and included the variables sex, age, mean heart rate, mean weight and CHA2DS2VASc score. Main measurements: For each risk group, the incidence density/1000 person/years of AF and stroke, number of cases required to detect a new AF, the prevalence of cognitive decline, Kendall correlation, and ROC curve were calculated. RESULTS: The prognostic index was obtained in 37,731 cases (80.8%) from lowest (Q1) to highest risk (Q4). A total of 1244 new AFs and 234 stroke episodes were diagnosed. Q3-4 included 53.8% of all AF and 69.5% of strokes in men; 84.2% of all AF and 85.4% of strokes in women; and 77.4% of cases of cognitive impairment. There was a significant linear correlation between the risk-AF score and the Rankin score (p < 0.001), the Pfeiffer score (p < 0.001), but not NIHSS score (p 0.150). The overall NNS was 1/19. CONCLUSION: Risk stratification allows identifying high-risk individuals in whom to intervene on modifiable risk factors, prioritizing the diagnosis of AF and investigating cognitive status.

Accelerating, guiding, and compressing skyrmions by defect rails.

Magnetic skyrmions are promising candidates as information carriers in spintronic devices. The transport of individual skyrmions in a fast and controlled way is a key issue in this field. Here we introduce a platform for accelerating, guiding and compressing skyrmions along predefined paths. The guiding mechanism is based on two parallel line defects (rails), one attractive and the other repulsive. Numerical simulations, using parameters from state-of-the-art experiments, show that the speed of the skyrmions along the rails can be increased up to an order of magnitude with respect to the non-defect case whereas the distance between rails can be as small as the initial radius of the skyrmions. In this way, the flux of information that can be coded and transported with magnetic skyrmions could be significantly increased.

Oil-in-water nanoemulsions are suitable for carrying hydrophobic compounds: Indomethacin as a model of anti-inflammatory drug.

Oil-in-water nanoemulsions are increasingly being used as delivery systems for encapsulating lipophilic components in functional food, personal care and pharmaceutical products. In the current study, we developed a multimodal platform to carry hydrophobic indomethacin or magnetic nanoparticles, or both. As a consequence, this platform has great potential for therapeutic or imaging purposes. By optimizing the system composition and homogenization conditions, a nanoemulsion with a mean droplet diameter of about 200nm and a low polydispersity index (<0.2) was formed. The plain nanoemulsion was shown to be innocuous in cellular studies and did not present acute toxicity (observed in a rat model). More interesting was the finding that nanoemulsions loaded with indomethacin presented a significantly different anti-inflammatory than the free drug.

Alterations of motor activity circadian rhythm in rats with adjuvant arthritis.

Adjuvant arthritis in rats produces alterations in the motor activity circadian rhythm. Specifically arthritic animals show a decrease in the total daily motor activity and an advance in the acrophase of the rhythm. Slight changes are also observed in the power content of the circadian harmonic as well as in the amplitude.

Thermal hyperalgesia and light touch allodynia after intradermal Mycobacterium butyricum administration in rat.

We examined the time course (7 weeks) of thermal hyperalgesia and light touch allodynia in rats after intradermal administration of Mycobacterium butyricum. Nociceptive thresholds to heat and light touch were assessed. Paw edema and temperature, motor function, body weight, and propioception were also tested. Some rats developed arthritis (named AA rats) but others did not (named non-AA rats). Both groups were compared with healthy animals. Persistent hyperalgesia was found in both groups; in AA rats it appeared before clinical evidence of arthritis. Transient allodynia ocurred only after edema development and fell when edema decreased. Motor function was impaired only in AA rats. The results of this study demonstrate that hyperalgesia, but not allodynia, appeared after Mycobacterium butyricum in both groups, suggesting that changes in sensitivity were not merely the result of local hypersensitivity of the inflamed tissue, but may also be due to alterations in nociception in the central nervous system.

Assessment of diclofenac permeation with different formulations: anti-inflammatory study of a selected formula.

The aim of this study was to improve the transdermal permeation of sodium diclofenac. Permeation studies were carried out in vitro using human skin (0.4 mm thick) from plastic surgery as a membrane. Four liquid formulations of 1% (w/w) sodium diclofenac were assayed: three ternary solvent systems (M4, M5, M6) and one microemulsion (M3). A 1% (w/w) solution of sodium diclofenac and a commercially available semisolid preparation were tested as reference formulations. The following permeation parameters for diclofenac were assessed: permeability coefficient, flux and drug permeated and retained in the skin at 24 h. The highest values of these parameters were obtained with formula M4, which contains transcutol 59.2%, oleic acid 14.9% and d-limonene 5% (w/w) as permeation enhancers. The anti-inflammatory activity of this formula was compared with that of the semisolid preparation on carrageenan-induced paw edema in rats. As expected from in vitro results, the M4 diclofenac delivery system showed higher activity than the semisolid preparation, both when applied locally (to the inflammation area) and when applied systemically (to the back). Neither treatment irritated the skin when tested on rabbits in a 72-h trial. These results suggest that topical delivery of sodium diclofenac with an absorption enhancer such as a mixture of oleic acid and d-limonene (M4) may be an effective medication for both dermal and subdermal injuries.

External magnetic field-induced selective biodistribution of magnetoliposomes in mice.

This study looked at the effect of an external magnet on the biodistribution of magnetoliposomes intravenously administrated in mice (8 mg iron/kg) with and without induced acute inflammation. Our results showed that due to enhanced vascular permeability, magnetoliposomes accumulated at the site of inflammation in the absence of an external magnetic field, but the amount of iron present increased under the effect of a magnet located at the inflammation zone. This increase was dependent on the time (20 or 60 min) of exposure of the external magnetic field. It was also observed that the presence of the magnet was associated with lower amounts of iron in the liver, spleen, and plasma than was found in mice in which a magnet had not been applied. The results of this study confirm that it is possible to target drugs encapsulated in magnetic particles by means of an external magnet.

Effect of magnet implant on iron biodistribution of Fe@C nanoparticles in the mouse.

The in vivo biodistribution of Fe@C nanoparticles (NP) was tested in mice bearing an inflammatory focus induced by injecting carrageenan into an air pouch previously formed on their back. The animals were intravenously injected NP with a high (60 mg/kg) or a low iron dose (6 mg/kg) and sacrificed 2 h later. Blood and organ samples (liver, spleen, lung, and kidney) were obtained; washed exudates were also collected. Iron concentration in plasma, blood cells, organs, and exudates was determined by flameless atomic-absorption-spectroscopy after digestion of organic material. Pouch exudate volume increased in all groups of mice with experimental inflammation. After i.v. administration of the high and low dose of NP, iron in exudate increased by 83.3% and 92.2%, respectively. A similar increase in hepatic iron appeared after the high dose (78%), but no increase appeared after the low dose. When the magnet was present, a 157% and 119% increase of iron in exudate appeared after both doses of NPs, but only the high dose of NP increased iron liver (60%). The presence of a magnetic field in the pouch favored selective biodistribution of NP in the inflammatory focus. These results indicate that mice with an inflammatory compartment are suitable for primary screening of different NP types. They also show that selective biodistribution is greater when a low dose of NP was used and that distribution in the target organ was increased by the magnetic field.

Magnetoliposomes prepared by reverse-phase followed by sequential extrusion: characterization and possibilities in the treatment of inflammation.

Anionic ferrofluid was encapsulated in 200nm-diameter liposomes. The process involved phase-reverse evaporation followed by sequential extrusion. Magnetoliposomes were characterized by transmission electron microscopy, Doppler laser electrophoresis, SQUID magnetometry, dynamic light scattering and iron content by atomic absorption spectrophotometry. The absence of hysteresis of the magnetic power of particles at room temperature is characteristic of a material with superparamagnetic properties. The encapsulation efficiency was determined for several iron/phospholipid ratios, and this parameter ranged from 0.016 to 0.024mg iron per mmole of phospholipids, depending on the initial magnetite concentration. In comparison with magnetoliposomes that were obtained solely by extrusion, this method afforded significantly better encapsulation (P=0.0002). Magnetic particles were intravenously administered to healthy or inflammation-induced mice. After 1h, the content of iron was determined in exudates, liver, spleen and plasma. Magnetoliposomes accumulated in the exudates collected from the inflammation site, which suggests that these particles could be loaded with the drugs needed to treat some inflammatory processes.