10 research outputs found
Successful strategy to improve the specificity of electronic statin–drug interaction alerts
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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
IMMUNOENDOCRINE RESPONSE TO MARINE CORPS MARTIAL ARTS TRAINING
Jacob A. Siedlik, Jake A. Deckert, Trent J. Herda, Joseph P. Weir, FACSM, Philip M. Gallagher & John P. Vardiman
Department of Health, Sport, and Exercise Science, University of Kansas, Lawrence, Kansas
Military training programs are rigorous and involve periods of intense physical activity in a high psychologically stressful environment. Quantifying the interplay between exposure to acute physical and psychological stress events and the lymphocyte subpopulations in the peripheral circulation may aid the development of training strategies for military and first responder personnel. PURPOSE: This study’s purpose is to map the trajectory of the immunoendocrine response to training in the Marine Corps Martial Arts Program. METHODS: 10 male marines (age 20 ±1.4y, body mass 74.76 ± 8.96kg, height 177.5 ± 7.44cm) were recruited for participation. Subjects were observed 3 times during a 9-week period. Serial blood samples for cortisol, norepinephrine (NE), epinephrine (EPI) and absolute CD4+ and CD8+ cells were collected before training and during the recovery period (Immediate Post, 15, 30, 45 and 60min). Variables were quantified using summary measures (area-under-the-curve (AUC), time to peak value and peak value) and analyzed using RMANOVAs. Pearson product moment correlations were calculated. RESULTS: There were no significant differences across visits for any of the summary or baseline measures. EPI (69±46.54pcg/ml, 70.6±46.12pcg/ml, 58.5±42.57pcg/ml), NE (880.3±670pcg/ml, 886.4±353.22pcg/ml, 874.1±578.12pcg/ml), CD4+ (744.4±182.15cells/ul, 944.9±326.46cells/ul, 900.6±217.58cells/ul), and CD8+ (664.8±204.89cells/ul, 939.1±443.69cells/ul, 833±238.8cells/ul) cells all reached peak values immediately post training. Times to peak value for cortisol (22.02±6.71mcg/dl, 20.91±5.92mcg/dl, 19.66±3.85mcg/dl) were 18, 7.5, and 9 minutes for Visits 1-3 respectively. As the time intervals between blood collections were 15 minutes, these are interpreted as a peak between 15-30min for Visit 1 and peaks between 0-15min for Visits 2-3. For Visits 1 and 2, CD4+ and CD8+ cells were significant correlated (.728, p=.017 and .712, p=.021). CONCLUSION: The lack of significant differences in AUC values across visits suggests the subject’s acute physiological responses to the training stress are not attenuated with repeated exposures. The observed decrease in the CD4/CD8 ratio immediately post training is not associated with an immunosuppressive response but is driven by an increase in CD8+ cells. Future research should investigate signaling molecules that may preferentially mobilize CD8+ cells in response to acute stress exposure.
Supported by a grant through the Office of Naval Research