Effects of periadolescent fluoxetine and paroxetine on elevated plus-maze, acoustic startle, and swimming immobility in rats while on and off-drug

<p>Abstract</p> <p>Rationale</p> <p>Whether selective serotonin reuptake inhibitors (SSRIs) exposure during adolescent brain development causes lasting effects remains unresolved.</p> <p>Objective</p> <p>Assess the effects of fluoxetine and paroxetine 60 days after adolescent exposure compared with when on-drug.</p> <p>Methods</p> <p>Male Sprague-Dawley littermates (41 litters) were gavaged on postnatal days 33-53 with fluoxetine (3 or 10 mg/kg/day), paroxetine (3, 10 or, 17 mg/kg/day), or water; half were tested while on-drug (21 litters) and half after 60 days off-drug (20 litters).</p> <p>Results</p> <p>The highest dose of the drugs reduced body weight gain during treatment that rebounded 1 week post-treatment. On-drug, no significant group differences were found on elevated plus maze time-in-open, zone entries, or latency to first open entry; however, the high dose of paroxetine significantly reduced head-dips (N = 20/group). No significant effects were found on-drug for acoustic startle response/prepulse inhibition (ASR/PPI) although a trend (p < 0.10) was seen, which after combining dose levels, showed a significant increase in ASR amplitude for both fluoxetine and paroxetine (N = 20-21/group). No differences on immobility time were seen in the Porsolt forced swim test or in plasma corticosterone at the end of forced swim (N-19-21/group). Off-drug, no effects were seen in the elevated plus maze (N = 16/group), ASR/PPI (N = 20/group), forced swim (N = 19-20/group), or plasma corticosterone (N = 19/group). At the doses tested, fluoxetine and paroxetine induced minor effects with drug on-board but no residual, long-term adverse effects in rats 60 days after drug discontinuation.</p> <p>Conclusions</p> <p>The data provide no evidence that fluoxetine or paroxetine have long-term adverse effects on the behaviors measured here after adolescent to young adult exposure.</p

Behavioral and neuroanatomical consequences of cell-type specific loss of dopamine D2 receptors in the mouse cerebral cortex

Developmental dysregulation of dopamine D2 receptors (D2Rs) alters neuronal migration, differentiation, and behavior and contributes to the psychopathology of neurological and psychiatric disorders. The current study is aimed at identifying how cell-specific loss of D2Rs in the cerebral cortex may impact neurobehavioral and cellular development, in order to better understand the roles of this receptor in cortical circuit formation and brain disorders. We deleted D2R from developing cortical GABAergic interneurons (Nkx2.1-Cre) or from developing telencephalic glutamatergic neurons (Emx1-Cre). Conditional knockouts (cKO) from both lines, Drd2fl/fl, Nkx2.1-Cre+ (referred to as GABA-D2R-cKO mice) or Drd2fl/fl, Emx1-Cre+ (referred to as Glu-D2R-cKO mice), exhibited no differences in simple tests of anxiety-related or depression-related behaviors, or spatial or nonspatial working memory. Both GABA-D2R-cKO and Glu-D2R-cKO mice also had normal basal locomotor activity, but GABA-D2R-cKO mice expressed blunted locomotor responses to the psychotomimetic drug MK-801. GABA-D2R-cKO mice exhibited improved motor coordination on a rotarod whereas Glu-D2R-cKO mice were normal. GABA-D2R-cKO mice also exhibited spatial learning deficits without changes in reversal learning on a Barnes maze. At the cellular level, we observed an increase in PV+ cells in the frontal cortex of GABA-D2R-cKO mice and no noticeable changes in Glu-D2R-cKO mice. These data point toward unique and distinct roles for D2Rs within excitatory and inhibitory neurons in the regulation of behavior and interneuron development, and suggest that location-biased D2R pharmacology may be clinically advantageous to achieve higher efficacy and help avoid unwanted effects.Fil: Lee, Gloria S.. Florida State University; Estados UnidosFil: Graham, Devon L.. Florida State University; Estados UnidosFil: Noble, Brenda L.. Florida State University; Estados UnidosFil: Trammell, Taylor S.. Florida State University; Estados UnidosFil: McCarthy, Deirdre M.. Florida State University; Estados UnidosFil: Anderson, Lisa R.. Florida State University; Estados UnidosFil: Rubinstein, Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; ArgentinaFil: Bhide, Pradeep G.. Florida State University; Estados UnidosFil: Stanwood, Gregg D.. Florida State University; Estados Unido

Remembering Ada Long, May 20, 1945–February 4, 2024

As part of the National Collegiate Honors Council’s collection of essays honoring the life and work of Dr. Ada Long (1945–2024), the authors reflect on the personal and professional impact she has made in the honors experience. See https://youtube.com/live/EwdleBW1Rf8?feature=share to view the entire Celebration of Life that was held June 8, 2024

Association of Gangrenous, Suppurative, and Exudative Findings With Outcomes and Resource Utilization in Children With Nonperforated Appendicitis.

IMPORTANCE: The clinical significance of gangrenous, suppurative, or exudative (GSE) findings is poorly characterized in children with nonperforated appendicitis. OBJECTIVE: To evaluate whether GSE findings in children with nonperforated appendicitis are associated with increased risk of surgical site infections and resource utilization. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used data from the Appendectomy Targeted Database of the American College of Surgeons Pediatric National Surgical Quality Improvement Program, which were augmented with operative report data obtained by supplemental medical record review. Data were obtained from 15 hospitals participating in the Eastern Pediatric Surgery Network (EPSN) research consortium. The study cohort comprised children (aged ≤18 years) with nonperforated appendicitis who underwent appendectomy from July 1, 2015, to June 30, 2020. EXPOSURES: The presence of GSE findings was established through standardized, keyword-based audits of operative reports by EPSN surgeons. Interrater agreement for the presence or absence of GSE findings was evaluated in a random sample of 900 operative reports. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day postoperative surgical site infections (incisional and organ space infections). Secondary outcomes included rates of hospital revisits, postoperative abdominal imaging, and postoperative length of stay. Multivariable mixed-effects regression was used to adjust measures of association for patient characteristics and clustering within hospitals. RESULTS: Among 6133 children with nonperforated appendicitis, 867 (14.1%) had GSE findings identified from operative report review (hospital range, 4.2%-30.2%; P \u3c .001). Reviewers agreed on presence or absence of GSE findings in 93.3% of cases (weighted κ, 0.89; 95% CI, 0.86-0.92). In multivariable analysis, GSE findings were associated with increased odds of any surgical site infection (4.3% vs 2.2%; odds ratio [OR], 1.91; 95% CI, 1.35-2.71; P \u3c .001), organ space infection (2.8% vs 1.1%; OR, 2.18; 95% CI, 1.30-3.67; P = .003), postoperative imaging (5.8% vs 3.7%; OR, 1.70; 95% CI, 1.23-2.36; P = .002), and prolonged mean postoperative length of stay (1.6 vs 0.9 days; rate ratio, 1.43; 95% CI, 1.32-1.54; P \u3c .001). CONCLUSIONS AND RELEVANCE: In children with nonperforated appendicitis, findings of gangrene, suppuration, or exudate are associated with increased surgical site infections and resource utilization. Further investigation is needed to establish the role and duration of postoperative antibiotics and inpatient management to optimize outcomes in this cohort of children

Creatine Transporter (CrT; Slc6a8) Knockout Mice as a Model of Human CrT Deficiency

Mutations in the creatine (Cr) transporter (CrT; Slc6a8) gene lead to absence of brain Cr and intellectual disabilities, loss of speech, and behavioral abnormalities. To date, no mouse model of CrT deficiency exists in which to understand and develop treatments for this condition. The purpose of this study was to generate a mouse model of human CrT deficiency. We created mice with exons 2–4 of Slc6a8 flanked by loxP sites and crossed these to Cre:CMV mice to create a line of ubiquitous CrT knockout expressing mice. Mice were tested for learning and memory deficits and assayed for Cr and neurotransmitter levels. Male CrT−/y (affected) mice lack Cr in the brain and muscle with significant reductions of Cr in other tissues including heart and testes. CrT−/y mice showed increased path length during acquisition and reversal learning in the Morris water maze. During probe trials, CrT−/y mice showed increased average distance from the platform site. CrT−/y mice showed reduced novel object recognition and conditioned fear memory compared to CrT+/y. CrT−/y mice had increased serotonin and 5-hydroxyindole acetic acid in the hippocampus and prefrontal cortex. Ubiquitous CrT knockout mice have learning and memory deficits resembling human CrT deficiency and this model should be useful in understanding this disorder

Protocol of a randomized controlled trial of the Tobacco Tactics website for operating engineers

<p>Abstract</p> <p>Background</p> <p>Recent research indicates that 35 percent of blue-collar workers in the US currently smoke while only 20 percent of white-collar workers smoke. Over the last year, we have been working with heavy equipment operators, specifically the Local 324 Training Center of the International Union of Operating Engineers, to study the epidemiology of smoking, which is 29% compared to 21% among the general population. For the current study funded by the National Cancer Institute (1R21CA152247-01A1), we have developed the Tobacco Tactics website which will be compared to the state supported 1-800-QUIT-NOW telephone line. Outcome evaluation will compare those randomized to the Tobacco Tactics web-based intervention to those randomized to the 1-800-QUIT-NOW control condition on: a) 30-day and 6-month quit rates; b) cotinine levels; c) cigarettes smoked/day; d) number of quit attempts; and e) nicotine addiction. Process evaluation will compare the two groups on the: a) contacts with intervention; b) medications used; c) helpfulness of the nurse/coach; and d) willingness to recommend the intervention to others.</p> <p>Methods/Design</p> <p>This will be a randomized controlled trial (N = 184). Both interventions will be offered during regularly scheduled safety training at Local 324 Training Center of the International Union of Operating Engineers and both will include optional provision of over-the-counter nicotine replacement therapy and the same number of telephone contacts. However, the Tobacco Tactics website has graphics tailored to Operating Engineers, tailored cessation feedback from the website, and follow up nurse counseling offered by multimedia options including phone and/or email, and/or e-community. Primary Analysis of Aim 1 will be conducted by using logistic regression to compare smoking habits (e.g., quit rates) of those in the intervention arm to those in the control arm. Primary analyses for Aim 2 will compare process measures (e.g., medications used) between the two groups by linear, logistic, and Poisson regression.</p> <p>Discussion</p> <p>Dissemination of an efficacious work-site, web-based smoking cessation intervention has the potential to substantially impact cancer rates among this population. Based on the outcome of this smaller study, wider scale testing in conjunction with the International Environment Technology Testing Center which services Operating Engineers across North America (including US, Mexico, and Canada) will be conducted.</p> <p>Trial registration</p> <p>NCT01124110</p

Mechanism of KMT5B haploinsufficiency in neurodevelopment in humans and mice.

Pathogenic variants in KMT5B, a lysine methyltransferase, are associated with global developmental delay, macrocephaly, autism, and congenital anomalies (OMIM# 617788). Given the relatively recent discovery of this disorder, it has not been fully characterized. Deep phenotyping of the largest (n = 43) patient cohort to date identified that hypotonia and congenital heart defects are prominent features that were previously not associated with this syndrome. Both missense variants and putative loss-of-function variants resulted in slow growth in patient-derived cell lines. KMT5B homozygous knockout mice were smaller in size than their wild-type littermates but did not have significantly smaller brains, suggesting relative macrocephaly, also noted as a prominent clinical feature. RNA sequencing of patient lymphoblasts and Kmt5b haploinsufficient mouse brains identified differentially expressed pathways associated with nervous system development and function including axon guidance signaling. Overall, we identified additional pathogenic variants and clinical features in KMT5B-related neurodevelopmental disorder and provide insights into the molecular mechanisms of the disorder using multiple model systems