Background: Macrophages serve as a depot for HIV type-1 (HIV-1) in the central nervous system. To efficiently target macrophages, we developed nanocarriers for potential brain delivery of activated nucleoside reverse transcriptase inhibitors (NRTIs) called nano-NRTIs. Methods: Nanogel carriers consisting of poly(ethylene glycol) (PEG)- or Pluronic-polyethylenimine (PEI) biodegradable networks, star PEG-PEI or poly(amidoamine) dendrimer-PEI-PEG dendritic networks, as well as nanogels decorated with brain-targeting peptide molecules, specifically binding to the apolipoprotein E receptor, were synthesized and evaluated. Nano-NRTIs were obtained by mixing aqueous solutions of zidovudine 5′-triphosphate or didanosine 5′-triphosphate and nanocarriers, followed by freeze-drying. Intracellular accumulation, cytotoxicity and antiviral activity of nano-NRTIs were monitored in monocyte-derived macrophages (MDMs). HIV-1 viral activity in infected MDMs was measured by a reverse transcriptase activity assay following treatment with nano-NRTIs. Mitochondrial DNA depletion in MDMs and human HepG2 cells was assessed by quantitative PCR. Results: Nanogels were efficiently captured by MDMs and demonstrated low cytotoxicity, and no antiviral activity without drugs. All nano-NRTIs demonstrated high efficacy of HIV-1 inhibition at drug levels as low as 1 μmol/l, representing a 4.9- to 14-fold decrease in 90% effective drug concentrations as compared with NRTIs, whereas 50% cytotoxicity effects started at 200x higher concentrations. Nano-NRTIs with a core-shell structure and decorated with brain-targeting peptides displayed the highest antiviral efficacy. Mitochondrial DNA depletion, a major cause of NRTI neurotoxicity, was reduced threefold compared with NRTIs at application of selected nano-NRTIs. Conclusions: Nano-NRTIs demonstrated a promising antiviral efficacy against HIV-1 in MDMs and showed strong potential as nanocarriers for delivery of antiviral drugs to macrophages harbouring in the brain.

Evidence suggests that estrogen signaling is involved in sex differences in the prevalence rates and control of asthma, but the expression patterns of estrogen receptor variants and estrogen function in the lung are not well established. We investigated the expression of major estrogen receptor variants occurring naturally and after the development of allergen-induced airway hyperreactivity in a murine model of allergic asthma, along with the role of estrogen signaling in small-airway ciliary motion and smooth muscle contraction. Female BALB/c mice were sensitized with ovalbumin, and estrogen receptor expression patterns were examined by immunofluorescence and Western blot analysis. Time-lapse video and photodiode-based displacement measurement systems were used to assess the effects of estrogen signaling on airway ciliary beat frequency and smooth muscle contraction. We found that a novel variant of estrogen receptor (ER)–α, ER-α36, is expressed in airway epithelial and smooth muscle cells. ER-α36 was predominately localized on the plasma membranes of airway cells. After sensitization to allergen, the expression levels of ER-α36 increased significantly (P < 0.01), whereas the expression of ER-β and ER-α66 did not significantly change. Estrogen treatment in vitro resulted in a rapid increase in airway cilia motion in a dose-dependent fashion, but did not exert any effect on airway smooth muscle contraction. We speculate that the up-regulation of estrogen receptor expression associated with allergen-induced airway hyperresponsiveness may constitute a protective mechanism to facilitate the clearance of mucus. The identification and localization of specific estrogen receptor subtypes in the lung could lead to newer therapeutic avenues aimed at addressing sex differences of asthma susceptibility.

Objectives: Migraine is a prevalent neurological disorder severely impacting children and adolescents, yet only one pharmacological treatment is approved for ages 6−12 years. Remote electrical neuromodulation (REN) is a nonpharmacological, prescribed, wearable device cleared by the Food and Drug Administration for acute and/or preventive treatment of migraine with or without aura in patients 12 years and older. This study evaluates REN's safety and efficacy in ages 6−11 years.Methods: Prospective acute treatment of migraine data were collected through the REN device (Nerivio) smartphone application. Endpoints were device safety (primary); consistent treatment efficacy (headache pain, functional disability, associated migraine symptoms), and REN‐medication combinations 2 h post‐treatment.Results: Children (n = 293), median age 11 years (interquartile range = 9−11), 73.7% girls, conducted 5493 REN treatments. No adverse events were reported. Efficacy in at least 50% of REN treatments was calculated from all patients who voluntarily reported pain levels, symptoms, and/or disability at treatment onset and at 2 h post‐treatment, with 72.2% (13/18) of patients reporting pain relief, 36.0% (9/25) pain freedom, 83.3% (15/18) functional disability relief, and 38.9% (7/18) functional disability freedom. Migraine‐associated symptoms disappeared in at least 50% of REN treatments in 70.0% (7/10) of patients for nausea/vomiting, 50.0% (4/8) phonophobia, and 22.2% (2/9) photophobia; 63.6% (7/11) reported freedom from at least one associated symptom. REN was used as a standalone treatment, with over‐the‐counter medications, and with prescribed headache medications in 45.4%, 34.4%, and 20.9% of treatments, respectively.Interpretation: REN may serve as a safe and efficacious acute treatment of migraine for children. Providers and families seeking a safe, effective, pill‐ and needle‐free treatment option for children suffering from migraine may consider REN.