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Enhancing the translational relevance of the nicotine drug discrimination paradigm in rat model
No full textPurpose: Drug discrimination has over the past 50 years been used as a tool for understanding mechanisms of drug addiction. As an operant conditioning-based technique, it is largely influenced by the specific rat training conditions such as training dose and pre-treatment time (PT). A nicotine training dose of 0.4 mg/kg at a PT of 15 min is widely used in nicotine discrimination studies. This dose in rats, however, produces a peak plasma concentration that comparatively exceeds the peak plasma concentration in tobacco smokers. Pharmacokinetic studies have shown that smaller doses of nicotine in rats produce peak plasma concentrations that closely resemble that in human cases. The question that remains is whether rats can be trained to discriminate these smaller doses of nicotine. Our goal was therefore to re-evaluate nicotine training conditions in rats and find that which is trainable and produces a translatable pharmacokinetic profile. Methods: Using a two-bar drug discrimination operant chamber, six rats trained to discriminate 0.4 mg/kg of nicotine tartrate at a PT of 15 min were tested at a fixed dose (0.4 mg/kg) of nicotine tartrate, but at different intervals after injection (0, 5, 15, 30, 60, 120, 240 min). This test was repeated but at a fixed dose of 0.1 mg/kg. Subsequently, a nicotine dose effect (0.01, 0.025, 0.05, 0.1, 0.2, 0.4 mg/kg) was conducted at a fixed pre-treatment time (5 min). Percentage of drug lever responses were recorded in all studies to measure substitution and analyzed using repeated measures ANOVA. Results: The time course study conducted with 0.4 mg/kg showed full substitution (100% nicotine lever response) at a PT of 5 min, with 240 min as the longest duration of action. The dose effect study at a fixed PT of 5 min showed full substitution at 0.1 mg/kg. At that, the discriminative effects of nicotine faded within 15 min. Conclusion: These findings show even at lower doses and shorter PTs, rats can perceive nicotine, and therefore can be trained using a lower nicotine dose of 0.1 mg/kg and at a shorter PT of 5 min (an onset that more closely resembles the onset in humans after smoking a cigarette compared to 15 min PT) Using these training conditions in place of the high training dose (0.4 mg/kg) and the long PT (15 min) provides a nicotine discrimination model of higher translational relevance to nicotine smoking studies in humans.NIDA : 1U18DA052553-0
Cervical Myelopathy secondary to Hirayama Disease in 16-year-old male
No full text16-year-old male with past medical history of asthma presented to the ED with a chief complaint of months of persistent numbness, tingling and twitching sensations in his left calf and toes. The patient also noted weakness, paresthesia and loss of muscle mass of his left hand and wrist, and inability to straighten his fourth and fifth digit. Physical exam showed weakened hand grip and wrist flexion/extension with left forearm and intrinsic hand muscle atrophy. Patient had a positive Hoffman sign and brisk reflexes with no other neurologic deficits. CK elevated at 296. MRI of the brain showed volume loss with signal abnormality and enhancement in the lower cervical spinal cord (C4-C7). Findings were consistent with a non-acute, non-expansile myelopathy.
Hirayama Syndrome (HS) is a rare condition caused by anterior movement of the posterior dural sac of the cervical spine during neck flexion, resulting in cord compression. Although a self-limiting condition, HS can cause chronic motor disabilities, including weakness of the extremities and loss of fine motor movements: resulting in diffuse muscle atrophy and contractures. Early interventions are key to preventing complications. Cervical collars have shown to be very effective. Nerve conduction studies can show the extent of nerve loss and possibility for reinnervation.
If not treated early, cervical fusion is the only remaining intervention for HS, resulting in severe loss of cervical mobility, leading to functional, social and occupational disability. Education on prognosis and prevention of motor deficits will facilitate informed decision making, expedite diagnosis, and encourage patient compliance. Physical therapy has shown to not only reduce long term complications, but also help patients with residual motor deficits reach functional independence
Role of mitophagy in ocular neurodegeneration
Get PDFNeurons in the central nervous system are among the most metabolically active cells in the body, characterized by high oxygen consumption utilizing glucose both aerobically and anaerobically. Neurons have an abundance of mitochondria which generate adequate ATP to keep up with the high metabolic demand. One consequence of the oxidative phosphorylation mechanism of ATP synthesis, is the generation of reactive oxygen species which produces cellular injury as well as damage to mitochondria. Mitochondria respond to injury by fusion which serves to ameliorate the damage through genetic complementation. Mitochondria also undergo fission to meet an increased energy demand. Loss of mitochondria is also compensated by increased biogenesis to generate new mitochondria. Damaged mitochondria are removed by mitophagy, an autophagic process, in which damaged mitochondria are surrounded by a membrane to form an autophagosome which ultimately fuses with the lysosome resulting in degradation of faulty mitochondria. Dysregulation of mitophagy has been reported in several central nervous system disorders, including, Alzheimer's disease and Parkinson's disease. Recent studies point to aberrant mitophagy in ocular neurodegenerative disorders which could be an important contributor to the disease etiology/pathology. This review article highlights some of the recent findings that point to dysregulation of mitophagy and it's underlying mechanisms in ocular neurodegenerative diseases, including, glaucoma, age-related macular degeneration and diabetic retinopathy.The author(s) declare financial support was received for the research, authorship, and/or publication of this article. The work was supported by NEI (EY028179) to RK
Oral Health Disparities among LGB and Non-LGB Individuals in the United States, 2007-2016
No full textPurpose. Although oral health in America has generally improved over recent decades, health disparities in the field have remained an issue for several marginalized groups, one such being lesbian, gay, and bisexual (LGB) individuals. Few studies have investigated oral health outcomes in LGB individuals in comparison with their heterosexual counterparts. As such, the aim of this study was to examine potential oral health disparities among a national sample of American adults and investigate sex-differences in the association between sexual orientation and poor oral health.
Methods. We used pooled data (2007-2016) from the National Health and Nutrition Examination Survey (NHANES) for men and women aged 18-59. Multiple imputation methods were used to impute missing data. Multiple logistic regression models were used to examine the association between sexual orientation and self-reported oral health, both overall and separately for men and women.
Results. A total of 20,298 responses were included in this analysis. Compared with heterosexuals, LGB individuals had higher odds of reporting poor oral health than heterosexuals in both the unadjusted (OR = 1.20 95% CI = 1.04-1.38) and adjusted (OR= 1.21 95% CI 1.04-1.40), combined analyses. In the unadjusted sex-stratified analyses, sexual orientation was found to have a statistically significant association with poor oral health in females (OR= 1.51 95% CI = 1.26-1.79). After adjusting for covariates, women who were LGB had a 38% statistically significant increased odds of having poor oral health compared with their heterosexual counterparts (OR= 1.38 95% CI 1.14-1.67). Sexual orientation was not associated with poor oral health in males, with adjusted odds close to null comparing LBG men with their heterosexual counterparts (OR = 0.98, 95% CI = 0.74 - 1.29).
Conclusion. This study explored oral health disparities among a large national sample of LGB Americans. Widening disparities continue to persist among minority populations, despite recent progress made in oral health settings. The findings in this study add to the information base of disparities prevalent in the field of oral health and may inform future interventions and public health frameworks
Diversified use of Non-invasive Biomarkers in Study Protocol and Screen failure in Non-Alcoholic Steatohepatitis (NASH)
No full textThis study examines how non-invasive biomarkers of NASH are introduced into the study protocol and whether this has an impact on screen failure. The study will investigate the use of non-invasive biomarkers in the design of study protocols for NASH drug trials and will also examine if screening approaches established using non-invasive biomarkers can reduce screen failure
30th Annual Research Appreciation Day Abstract Book
Get PDFAbstracts submitted for the thirtieth annual Research Appreciation Day. RAD 2023 was the third all-virtual RAD
The Effects of Low Dose Naltrexone in Children with Chronic Pain
No full textBackground: Naltrexone is an FDA-approved opioid antagonist. At one-tenth the usual dosage, it is thought to have antinociceptive effects mediated through microglial cell inactivation, which can be helpful for chronic pain states, such as fibromyalgia, in adults.[1,2] The percentage of youth that are affected from chronic pain conditions is estimated to be at 15-35%.[3] The present study is the first to examine the efficacy of low-dose naltrexone (LDN) in treating chronic pain in pediatric patients.
Methods: A retrospective chart review was conducted on pediatric patients who were prescribed LDN between 2019 and 2022 for a chronic pain condition. At the start of LDN treatment and for each pain-clinic visit in the subsequent year, pain scores and functional disability inventory (FDI) scores were collected. Multilevel cumulative logit models and multilevel linear models were used to determine the effect of time of LDN on pain and FDI scores, respectively.
Results: There were 168 patients who met inclusion criteria. As compared to visits without LDN, there was no statistically significant difference in pain scores for visits in which the patient had been on LDN for 0-2 months (p=0.88) or for ≥2 months (p=0.25). As compared to visits without LDN, FDI scores significantly decreased after taking LDN for ≥2 months (p< 0.001) but not for 0-2 months (p=0.12).
Conclusion: Children who took LDN had a significant improvement in daily function as compared to before taking LDN.
Citations:
1. Parkitny, L., & Younger, J. (2017). Reduced Pro-Inflammatory Cytokines after Eight Weeks of Low-Dose Naltrexone for Fibromyalgia. Biomedicines, 5(2), 16.
https://doi.org/10.3390/biomedicines50200162. YOUNGER, J., NOOR, N., MCCUE, R., MACKEY, S. (2013). LOW-DOSE NALTREXONE FOR THE TREATMENT OF FIBROMYALGIA. ARTHRITIS AND RHEUMATISM. HTTPS://DOI.ORG/10.1002/ART.37734
3. KING, S., CHAMBERS, C. T., HUGUET, A., MACNEVIN, R. C., MCGRATH, P. J., PARKER, L., & MACDONALD, A. J. (2011). THE EPIDEMIOLOGY OF CHRONIC PAIN IN CHILDREN AND ADOLESCENTS REVISITED: A SYSTEMATIC
REVIEW. PAIN, 152(12), 2729–2738
Forming a Grant Idea: Framework
Get PDFThe Forming a Grant Idea: Framework worksheet is a practical process of identifying grant ideas using a framework developed by Community Engagement Librarian, Lorraine Sheldon. Explore a series of themes and questions to identify parameters for a potential grant. This worksheet was originally included as part of a presentation hosted by the Network of the National Library of Medicine, Health Bytes webinar series held on January 11, 2023
Single Agent Opioid vs Combination Agent Opioids in Postoperative Pain Control
No full textIntroduction: Treating post-surgery pain in pediatric populations often involves combination opiates, commonly hydrocodone and oxycodone. Unfortunately, this approach can lead to confusion for parents and concerns for overdose, as half of pediatric opioid prescriptions are considered high-risk. An opioid stewardship committee was established to oversee prescribing guidelines at Cook Children’s Medical Center (CCMC). This large-scale retrospective study examined whether educational interventions increased the likelihood of single-agent opioid prescriptions for post-surgery pain. This practice allows providers to more freely utilize NSAIDs and acetaminophen for postoperative pain.
Methods: This was a retrospective single-center quality improvement (QI) project of all patients, who were prescribed opioids after surgery at CCMC in Fort Worth, TX between 3/1/2018 and 2/28/2022. Logistic regression was used to determine whether likelihood of single-agent (vs. combination) opioid prescriptions differed by intervention and department.
Results: There were 5227 (38.30%) pre-intervention procedures and 8419 (61.70%) post-intervention procedures. Post-intervention procedures (vs. pre-intervention) were statistically significantly more likely to result in single-agent, rather than combination, opioid prescriptions (88.10% vs. 8.84%, OR=79.62, p<0.0001), and likelihood of single-agent opioid prescriptions significantly differed by department (p<0.0001). The proportion of single-agent opioids prescribed increased post-intervention in all 7 departments examined, and the proportion increased by 70% in the 3 departments with the most procedures: orthopedics, urology, and otolaryngology.
Conclusion: Ongoing educational efforts by the Opioid Stewardship Committee have resulted in a sustained change in prescribing practices in multiple surgical departments from the use of combination to single-agent opioids
APOE and immunity: Research highlights
No full textINTRODUCTION: At the Alzheimer's Association's APOE and Immunity virtual conference, held in October 2021, leading neuroscience experts shared recent research advances on and inspiring insights into the various roles that both the apolipoprotein E gene (APOE) and facets of immunity play in neurodegenerative diseases, including Alzheimer's disease and other dementias. METHODS: The meeting brought together more than 1200 registered attendees from 62 different countries, representing the realms of academia and industry. RESULTS: During the 4-day meeting, presenters illuminated aspects of the cross-talk between APOE and immunity, with a focus on the roles of microglia, triggering receptor expressed on myeloid cells 2 (TREM2), and components of inflammation (e.g., tumor necrosis factor alpha [TNFalpha]). DISCUSSION: This manuscript emphasizes the importance of diversity in current and future research and presents an integrated view of innate immune functions in Alzheimer's disease as well as related promising directions in drug development