The intersection of COVID-19, school, and headaches: Problems and solutions.

OBJECTIVE: To equip clinicians with recommendations specific to concerns related to the novel coronavirus disease 2019 (COVID-19), which impact the physical, emotional, and social health of youth with headache disorders. BACKGROUND: COVID-19 has affected societies on a global scale including children and youth with chronic headache disorders. Many concerns are predicted to arise in the 2020-2021 school year, whether classes are conducted in-person or virtually. METHODS: Clinical impressions were combined with a review of the literature, although limited due to the recent nature of this issue. RESULTS: We describe recommendations to support caregivers and youth as they face changes expected with the return to school in the fall of 2020. CONCLUSION: Although there are significant concerns for caregivers and youth with migraine given the context of changes related to the pandemic, there are many recommendations that can help minimize exacerbations of the physical, emotional, and social health of youth with chronic migraine.

The Influence of Lifestyle Factors on the Burden of Pediatric Migraine.

There is a gap in patient education and coaching of lifestyle factors related to pediatric migraine, which nurses are in a unique position to fill in order to provide comprehensive care to these patients. In order to help fill this gap, we conducted a targeted review of studies examining migraine and lifestyle factors in children and adolescents. Studies older than 2010, studies examining adults above the age of 18, studies not available in the English language, and secondary sources were excluded from the review. A final sample of 42 studies was included in this review. Lifestyle factors including stress, sleep, obesity, and diet were identified as playing a significant role in increasing the frequency, severity, and duration of migraine attacks in pediatric patients. Based on these findings, a framework is discussed for practical applications of this knowledge by nursing staff working in primary and specialty care clinics.

"Managing" the Placebo Effect: The Single-Blind Placebo Lead-in Response in Two Pain Models.

OBJECTIVE: "Placebo effects" in analgesic medication trials for chronic pain are pervasive; however, little is known regarding mechanisms or factors that may influence the presence or magnitude of these effects. Our objective is to consider elements of the placebo response in the context of two pain models using a "single-blind placebo lead-in" design (SBPLI). METHODS: As part of two pilot drug trials using knee osteoarthritis (KOA) and non-radicular low back pain (LBP) subjects, SBPLI protocols were conducted. We examined whether gender and/or diagnosis affected placebo responses as observed in changes in patient self-reported pain, depressive and pain anxiety symptoms. We also evaluated the placebo response on performance-based tests (stair climbing, range of motion (ROM), sit to stand repetitions, and 6-minute treadmill distance). RESULTS: VAS Pain Intensity (Now) values decreased significantly during the SBPLI for the sample as a whole, but the effects appeared stronger among LBP subjects. CES-D short form values (depressive symptoms) did not decrease significantly during the SBPLI for the sample as a whole, but some placebo effects appeared to emerge for women in the KOA group. PASS values (pain anxiety symptoms) decreased significantly, albeit mildly, during the SBPLI for the sample as a whole.Stair Climb (time) revealed no significant SBPLI effects. Bend Forward to Floor (ROM) increased significantly at the end of the SBPLI period for the sample as a whole, but the effects appeared stronger among KOA subjects. Sit to Stand Repetitions increased during the SBPLI for the sample as a whole. Treadmill Distance did not change significantly from Visit 1 to Visit 2; however, a significant Sex difference for the KOA group was found such that women showed greater Treadmill Distance at Visit 2. CONCLUSION: Placebo effects emerged across psychometric and performance-based measures, indicating the pervasiveness of this phenomenon. In this design, diagnostic and (to a lesser extent) gender categories differentials were observed during the placebo period. The SBPLI design may prove not only a robust method in studying the placebo phenomena, but also as a design element to mitigate some aspects of the placebo response in clinical trials.

Nano-NRTIs demonstrate low neurotoxicity and high antiviral activity against HIV infection in the brain.

Antiviral therapy using nucleoside reverse transcriptase inhibitors (NRTIs) is neurotoxic and has low efficiency in eradication of HIV-1 harbored in central nervous system (CNS). Previously, we reported that active 5'-triphosphates of NRTIs encapsulated in cationic nanogels (nano-NRTIs) suppress HIV-1 activity more efficiently than NRTIs and exhibit reduced mitochondrial toxicity [Vinogradov SV, Poluektova LY, Makarov E, Gerson T, Senanayake MT. Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity. Antivir Chem Chemother. 2010; 21:1-14. Makarov E, Gerson T, Senanayake T, Poluektova LY, Vinogradov. Efficient suppression of Human Immunodeficiency Virus in Macrophages by Nano-NRTIs. Antiviral Res. 2010; 86(1):A38-9]. Here, we demonstrated low neurotoxicity and excellent antiviral activity of nano-NRTIs decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor. Nano-NRTIs induced lower levels of apoptosis and formation of reactive oxygen species, a major cause of neuron death, than free NRTIs. Optimization of size, surface decoration with AP significantly increased brain accumulation of nano-NRTIs. The efficient CNS delivery of nano-NRTIs resulted in up to 10-fold suppression of retroviral activity and reduced virus-associated inflammation in humanized mouse model of HIV-1 infection in the brain. Our data provide proof of the advanced efficacy of nano-NRTIs as safer alternative of current antiviral drugs. FROM THE CLINICAL EDITOR: This team of investigators demonstrated low neurotoxicity and excellent anti-HIV activity of nano-nucleoside reverse transcriptase inhibitors decorated with the peptide (AP) binding brain-specific apolipoprotein E receptor, providing proof of enhanced efficacy and a safer alternative compared with current antiviral drugs.

A Prospective Evaluation of the Effects of the COVID-19 Pandemic on Youth with Primary Headache Disorders.

Alterations in certain academic and social/family routines during the COVID-19 pandemic have been speculated to be either a risk factor or buffer for poor health outcomes for youth with stress-sensitive health conditions such as primary headache disorders. The current study evaluated patterns and moderators of pandemic impacts on youth with primary headache disorders, with an aim of extending our understanding of the relationship between stress, resilience, and outcomes in this population. Children recruited from a headache clinic in the midwestern United States reported on their headaches, schooling, routines, psychological stress, and coping at four timepoints ranging from within a few months of the pandemic onset to a long-term follow-up 2 years later. Changes in headache characteristics over time were analyzed for association with demographics, school status, altered routines, and stress, and coping. At baseline, 41% and 58% of participants reported no change in headache frequency or intensity, respectively, relative to pre-pandemic levels, with the remainder almost equally divided between reporting an improvement or worsening. The results of multilevel growth model analyses indicated that headache intensity remained more elevated over time since the start of the pandemic for respondents whose stress scores were relatively higher (b = 0.18, t = -2.70, p = 0.01), and headache-related disability remained more elevated over time for older respondents (b = 0.01, t = -2.12, p = 0.03). The study results suggest, overall, that the outcomes of primary headache disorders in youth were not systematically altered by the COVID-19 pandemic.

Expression and function of a novel variant of estrogen receptor-α36 in murine airways.

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-ß 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.

Multifunctional peptide-PEG intercalating conjugates: programmatic of gene delivery to the blood-brain barrier.

PURPOSE: To enhance transfection efficacy of pDNA through the application of multifunctional peptide-PEG-tris-acridine conjugates (pPAC) and the formation of biodegradable core-shell polyplexes for gene delivery to the blood-brain barrier (BBB). METHODS: pPAC-mediated transfection was compositionally optimized in mouse BBB cells (bEnd.3). Cellular uptake and trafficking, and brain accumulation of pDNA was evaluated by fluorescent imaging and histochemistry. We constructed anti-MRP4 siRNA-producing vectors and evaluated the efficacy of MRP4 down-regulation of MRP4 by Western blot and qPCR, and its effect on the uptake of (3)H-AZT, an MRP4 substrate. RESULTS: A core-shell gene delivery system (GDS) was assembled from pDNA and pPAC, carrying multifunctional peptides with NLS, TAT, and brain-specific BH, or ApoE sequences, and biodegradable pLPEI polyamine. This GDS demonstrated better cellular and nuclear accumulation, and a 25-fold higher transfection efficacy in slow-dividing bEnd.3 cells compared to ExGen500. Inclusion of brain-targeting pPAC enhanced in vivo accumulation of functional pDNA in brain capillaries. Treatment by encapsulated anti-MRP4 siRNA-producing pDNA caused transient down-regulation of MRP4, and, after intravenous injection in Balb/c mice, enhanced AZT uptake in the brain by 230-270%. CONCLUSIONS: The pPAC represent novel efficient components of GDS that could find various gene therapy applications, including genetic modulation of the BBB.

Nano-NRTIs: efficient inhibitors of HIV type-1 in macrophages with a reduced mitochondrial toxicity.

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 200× 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.