The activation of oxidative damage, neuroinflammation, and mitochondrial dysfunction has been implicated in secondary pathomechanisms following spinal cord injury (SCI). These pathophysiological processes lead to cell death and are tightly regulated by nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling. Here, we investigated whether activation of Nrf2/ARE is neuroprotective following SCI. Female Fischer rats were subjected to mild thoracic SCI (T8) using the New York University injury device. As early as 30 min after SCI, levels of Nrf2 transcription factor were increased in both nuclear and cytoplasmic fractions of neurons and astrocytes at the lesion site and remained elevated for 3 days. Treatment of injured rats with sulforaphane, an activator of Nrf2/ARE signaling, significantly increased levels of Nrf2 and glutamate-cysteine ligase (GCL), a rate-limiting enzyme for synthesis of glutathione, and decreased levels of inflammatory cytokines, interleukin-1b (IL-1b) and tumor necrosis factor-a (TNF-a) thus leading to a reduction in contusion volume and improvement in coordination. These results show that activation of the Nrf2/ARE pathway following SCI is neuroprotective and that sulforaphane is a viable compound for neurotherapeutic intervention in blocking pathomechanisms following SCI.
Introduction As of July 2021, three vaccines have been issued Emergency Use Authorization (EUA) by the U.S. Food and Drug Administration (FDA) to combat SARS-CoV-2 with over 65% of U.S. adults having received at least one vaccine dose. However, up to 35% of the population are hesitant or refuse to get vaccinated. As reproductive toxicity studies were not conducted prior to EUA, adults have expressed concern about potential adverse effects of the vaccines on fertility and reproductive health. Objective We evaluated the current reasons for COVID-19 vaccine hesitancy among the unvaccinated U.S. population and identified their demographic characteristics. Methods Amazon Mechanical Turk (MTurk) was used to survey the vaccine hesitancy reasons amongst unvaccinated U.S. adult population between June 30, 2021-July 1, 2021. The project title listed for survey participants during distribution was “Covid-19 Vaccine Hesitancy Survey”. The study was reviewed by the Institutional Review Board, and it was deemed an exemption. Users with addresses in the U.S., over the age of 18, and received no doses of any coronavirus vaccine at any time were invited to complete an anonymous 32-question survey with an estimated completion time of less than 10 minutes. The first part of the survey focused on identifying attitudes toward the COVID-19 vaccines while the latter queried demographic information such as age, race/ethnicity, and relationship status. Quantitative data was analyzed using by two-sample Z-test on Microsoft Excel (version 16.44) and MATLAB (version R2021a). Results A total of 914 unvaccinated adults completed our survey (response rate 91.4%) with 53% of respondents identifying as cis-male and 42% as cis-female. Of the participants, 58% indicated ‘COVID-19 vaccine side effects or other potential unknown long-term effects’ as their reason for remaining unvaccinated and 39% of them believed that ‘COVID-19 vaccines can negatively impact reproductive health and/or fertility’. Among those participants that were concerned that COVID-19 vaccines could impact fertility, 42% (p = 0.010) lived in urban settings, 46% (p > 0.001) were married, and 38% (p = 0.020) of individuals were born outside of the U.S. About 1/2 of the participants stated that more information and research conducted on the COVID-19 vaccines would encourage them to get vaccinated. Conclusions A large portion of the U.S. population remain fearful of the potential side effects associated with the coronavirus vaccines and more specifically negative impacts to their future reproductive health. These results objectively evidence that fertility concerns are significantly contributing to vaccine hesitancy and may continue to be a barrier for years to come if no interventions are made. With almost half of the participants yearning for more information and research this highlights the need for intense investigation and publicly available data on the effect of coronavirus vaccines on fertility. Disclosure No
Introduction Men taking testosterone therapy (TT) have potential side effects such as polycythemia, testicular atrophy, and decreased spermatogenesis. Recent evidence has shown that the modality of delivery may affect the prevalence of these side effects. We hypothesized that intranasal short-acting testosterone will have a lower rate of polycythemia than injectable long-acting testosterone because shorter-acting formulations can more closely mimic normal physiology. Objective To compare the effects of Natesto and Testosterone Cypionate (TC) on hematocrit and serum testosterone levels in testosterone deficient men over 4 months. Methods This Phase IV, randomized, open-label clinical trial was performed on 30 symptomatic, testosterone deficient men with at least two serum testosterone levels below 300 ng/dL drawn before 10AM. Men were randomized (1:1) to receive either Natesto three times per day (5.5mg per nostril) and intramuscular TC (200mg) once every two weeks. Hematocrit and serum testosterone were evaluated before and after four months. The primary outcome was changes in hematocrit. Secondary outcomes were changes in E, DHT, PSA and 17-OHP. Data analysis was performed using two-sample and single-sample T tests, and determination of equal or unequal variances was computed using F tests. Results The median participant age was 45 years old. At baseline, serum T of all participants was 239.6 ng/dL and hematocrit of 43.1. Prevalence of participants who screened positive for OSA on STOP-BANG questionnaire for Natesto and TC group were 75% and 78%, respectively. The 4-month change in hematocrit in the Natesto group (-1.1 from baseline) was significantly less than the change in hematocrit seen in the TC group (+5.1 from baseline), (p < 0.001, t = -7.6). Prevalence of polycythemia (HCT > 52%) after 4 months was 0% in Natesto group and 5.5% in TC. Both groups increased testosterone levels above baseline at 1 and 4 months, with a larger increase seen in the TC group compared to Natesto (p = 0.029, t = 1.71), (Figure 1B). In the Natesto group, secondary outcomes E, DHT, PSA, and 17-OHP changed -2.9 (p = 0.54), +4.3 (p = 0.64), +0.34 (p = 0.52), and +1.6 (p = 0.88) from baseline, respectively (Figure 1C). In the TC group, secondary outcomes E, DHT, PSA, and 17-OHP changed +21.2 (p= 0.019), +4.3 (p = 0.64), -0.34 (p = 0.52), and -42.9 (p > 0.001) from baseline, respectively (Figure 1C). Conclusions Short-acting nasal testosterone does not appear to increase serum hematocrit when compared to intramuscular testosterone cypionate, while both modalities returned men to a eugonadal serum testosterone level (>300 ng/dL) in 83% of men. In men who are at risk of developing polycythemia (obstructive sleep apnea, high baseline hematocrit), nasal testosterone gel or other short acting formulations should be strongly considered. Disclosure Yes, this is sponsored by industry/sponsor: Acerus Pharmaceuticals Clarification Industry funding only - investigator initiated and executed study
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