Differential alterations in gene expression profiles contribute to time-dependent effects of nandrolone to prevent denervation atrophy

<p>Abstract</p> <p>Background</p> <p>Anabolic steroids, such as nandrolone, slow muscle atrophy, but the mechanisms responsible for this effect are largely unknown. Their effects on muscle size and gene expression depend upon time, and the cause of muscle atrophy. Administration of nandrolone for 7 days beginning either concomitantly with sciatic nerve transection (7 days) or 29 days later (35 days) attenuated denervation atrophy at 35 but not 7 days. We reasoned that this model could be used to identify genes that are regulated by nandrolone and slow denervation atrophy, as well as genes that might explain the time-dependence of nandrolone effects on such atrophy. Affymetrix microarrays were used to profile gene expression changes due to nandrolone at 7 and 35 days and to identify major gene expression changes in denervated muscle between 7 and 35 days.</p> <p>Results</p> <p>Nandrolone selectively altered expression of 124 genes at 7 days and 122 genes at 35 days, with only 20 genes being regulated at both time points. Marked differences in biological function of genes regulated by nandrolone at 7 and 35 days were observed. At 35, but not 7 days, nandrolone reduced mRNA and protein levels for FOXO1, the mTOR inhibitor REDD2, and the calcineurin inhibitor RCAN2 and increased those for ApoD. At 35 days, correlations between mRNA levels and the size of denervated muscle were negative for RCAN2, and positive for ApoD. Nandrolone also regulated genes for Wnt signaling molecules. Comparison of gene expression at 7 and 35 days after denervation revealed marked alterations in the expression of 9 transcriptional coregulators, including Ankrd1 and 2, and many transcription factors and kinases.</p> <p>Conclusions</p> <p>Genes regulated in denervated muscle after 7 days administration of nandrolone are almost entirely different at 7 versus 35 days. Alterations in levels of FOXO1, and of genes involved in signaling through calcineurin, mTOR and Wnt may be linked to the favorable action of nandrolone on denervated muscle. Marked changes in the expression of genes regulating transcription and intracellular signaling may contribute to the time-dependent effects of nandrolone on gene expression.</p

Effects of midodrine and L-NAME on systemic and cerebral hemodynamics during cognitive activation in spinal cord injury and intact controls

This is the published version.We previously showed that increases in mean arterial pressure (MAP) following administration of midodrine hydrochloride (MH) and nitro-L-arginine methyl ester (L-NAME) resulted in increased mean cerebral blood flow velocity (MFV) during head-up tilt in hypotensive individuals with spinal cord injury (SCI) and question if this same association was evident during cognitive activation. Herein, we report MAP and MFV during two serial subtraction tasks (SSt) given before (predrug) and after (postdrug) administration of MH; (10 mg), L-NAME (1 mg/kg) or no drug (ND) in 15 subjects with SCI compared to nine able-bodied (AB) controls. Three-way factorial analysis of variance (ANOVA) models were used to determine significant main and interaction effects for group (SCI, AB), visit (MH, L-NAME, ND), and time (predrug, postdrug) for MAP and MFV during the two SSt. The three-way interaction was significant for MAP (F = 4.262; P = 0.020); both MH (30 ± 26 mmHg; P < 0.05) and L-NAME (27 ± 22 mmHg; P < 0.01) significantly increased MAP in the SCI group, but not in the AB group. There was a significant visit by time interaction for MFV suggesting an increase from predrug to postdrug following L-NAME (6 ± 8 cm/sec; P < 0.05) and MH (4 ± 7 cm/sec; P < 0.05), regardless of study group, with little change following ND (3 ± 3 cm/sec). The relationship between change in MAP and MFV was significant in the SCI group following administration of MH (r2 = 0.38; P < 0.05) and L-NAME (r2 = 0.32; P < 0.05). These antihypotensive agents, at the doses tested, raised MAP, which was associated with an increase MFV during cognitive activation in hypotensive subjects with SCI

Prevalence of Abnormal Systemic Hemodynamics in Veterans with and without Spinal Cord Injury

Advances in the clinical management of patients with acute and chronic spinal cord injury (SCI) have contributed to extended life expectancies; however longevity in those with SCI remains below that of the general population.(1) Reduced longevity in the SCI population has been attributed to increased incidence of age-associated chronic illnesses,(2) premature cardiovascular aging,(3) and increased prevalence of heart disease, stroke (4) and diabetes mellitus, (5) compared to the general population. In fact, cardiovascular disease (CVD) is now a leading cause of morbidity and mortality in the SCI population, which may be amplified due to increased risk factors such as inactivity, chronic inflammation, and impairment in autonomic cardiovascular control.(6) The American Spinal Injury Association (ASIA) impairment scale (AIS) is used to document remaining motor and sensory function following SCI; (7, 8) however, the degree of autonomic nervous system impairment is not considered within this classification schema.(9, 10) That said, impaired autonomic control of the cardiovascular system after SCI results in measurable changes in heart rate (HR) and blood pressure (BP) that loosely reflect the level and completeness of SCI documented using the AIS classification, (11, 12) but may also reflect orthostatic positioning.(6, 12, 13) The impact of these changes in HR and BP on cardiovascular health and longevity is not fully appreciated in the SCI population; however, prior to identifying the consequences of these cardiovascular abnormalities, prevalence rates of HR and BP values which fall outside the expected normal range should be documented. The International Standards to Document Autonomic Function (post-SCI) initially established guidelines for the assessment of HR and BP abnormalities in 2009, (10) which was updated in 2012, but the thresholds remained consistent. (14) Specifically, bradycardia is defined as a HR ≤ 60 beats/minute (bpm) and tachycardia as a HR ≥ 100 bpm. (14) Hypotension is defined as a systolic BP (SBP) ≤ 90 mmHg and a diastolic BP (DBP) ≤ 60 mmHg; hypertension is SBP ≥ 140 and/or DBP ≥ 90 mmHg. (14) While these definitions comply with standards established in the non-SCI population, due to decentralized cardiovascular control, they may not be appropriate for use in the SCI population. In addition, relatively recent evidence has emerged which associates adverse outcomes in the general population using other HR (15, 16) and BP (17-21) thresholds. Beyond the clinical consequences of alterations in HR and BP, persons with SCI may experience loss of independence and life quality related to the inability to adequately maintain cardiovascular homeostasis; however, until we gain a better understanding of the prevalence of these abnormalities, the development and testing of effective treatment strategies will not be a priority. Therefore, the goal of this investigation was to assess HR and BP in veterans with (SCI) and without SCI (non SCI). Similar to a recent report, (6) we hypothesized that level of SCI (i.e., the higher the lesion level the greater the prevalence of abnormal HR and BP recordings) and orthostatic positioning (i.e., increased prevalence of abnormal HR and BP recordings in the seated versus the supine position) would influence the prevalence of HR and BP abnormalities. In addition, we hypothesized that the prevalence of comorbid cardiovascular medical conditions, current smoking status, age and use of prescription anti-hypertensive (anti-HTN) medications would influence the prevalence of HR and BP abnormalities in veterans with and without SCI

Applied Meteorology Unit (AMU) Quarterly Report Second Quarter FY-14

This report summarizes the Applied Meteorology Unit (AMU) activities for the second quarter of Fiscal Year 2014 January - March 2014)

Extension into the entrance channel of HIV-1 reverse transcriptase—Crystallography and enhanced solubility

Non-nucleoside inhibitors of HIV-1 reverse transcriptase (HIV-RT) are reported that feature extension into the entrance channel near Glu138. Complexes of the parent anilinylpyrimidine 1 and the morpholinoethoxy analog 2j with HIV-RT have received crystallographic characterization confirming the designs. Measurement of aqueous solubilities of 2j, 2k, the parent triazene 2a, and other NNRTIs demonstrate profound benefits for addition of the morpholinyl substituent.Fil: Bollini, Mariela. University of Yale; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Frey, Kathleen M.. University of Yale. School of Medicine; Estados UnidosFil: Cisneros, José A.. University of Yale; Estados UnidosFil: Spasov, Krasimir A.. University of Yale. School of Medicine; Estados UnidosFil: Das, Kalyan. Rutgers University; Estados UnidosFil: Bauman, Joseph D.. Rutgers University; Estados UnidosFil: Arnold, Eddy. Rutgers University; Estados UnidosFil: Anderson, Karen S.. University of Yale. School of Medicine; Estados UnidosFil: Jorgensen, William L.. University of Yale; Estados Unido

Acceptability of novel lifelogging technology to determine context of sedentary behaviour in older adults

<strong>Objective:</strong> Lifelogging, using body worn sensors (activity monitors and time lapse photography) has the potential to shed light on the context of sedentary behaviour. The objectives of this study were to examine the acceptability, to older adults, of using lifelogging technology and indicate its usefulness for understanding behaviour.<strong> </strong><strong>Method:</strong> 6 older adults (4 males, mean age: 68yrs) wore the equipment (ActivPAL^TM and Vicon Revue^TM/SenseCam^TM) for 7 consecutive days during free-living activity. The older adults’ perception of the lifelogging technology was assessed through semi-structured interviews, including a brief questionnaire (Likert scale), and reference to the researcher&#39;s diary. <strong>Results:</strong> Older adults in this study found the equipment acceptable to wear and it did not interfere with privacy, safety or create reactivity, but they reported problems with the actual technical functioning of the camera. <strong>Conclusion:</strong> This combination of sensors has good potential to provide lifelogging information on the context of sedentary behaviour

Surgical stabilization versus nonoperative treatment for flail and non-flail rib fracture patterns in patients with traumatic brain injury

Purpose Literature on outcomes after SSRF, stratified for rib fracture pattern is scarce in patients with moderate to severe traumatic brain injury (TBI; Glasgow Coma Scale ≤ 12). We hypothesized that SSRF is associated with improved outcomes as compared to nonoperative management without hampering neurological recovery in these patients. Methods A post hoc subgroup analysis of the multicenter, retrospective CWIS-TBI study was performed in patients with TBI and stratified by having sustained a non-flail fracture pattern or flail chest between January 1, 2012 and July 31, 2019. The primary outcome was mechanical ventilation-free days and secondary outcomes were in-hospital outcomes. In multivariable analysis, outcomes were assessed, stratified for rib fracture pattern. Results In total, 449 patients were analyzed. In patients with a non-flail fracture pattern, 25 of 228 (11.0%) underwent SSRF and in patients with a flail chest, 86 of 221 (38.9%). In multivariable analysis, ventilator-free days were similar in both treatment groups. For patients with a non-flail fracture pattern, the odds of pneumonia were significantly lower after SSRF (odds ratio 0.29; 95% CI 0.11–0.77; p = 0.013). In patients with a flail chest, the ICU LOS was significantly shorter in the SSRF group (beta, − 2.96 days; 95% CI − 5.70 to − 0.23; p = 0.034). Conclusion In patients with TBI and a non-flail fracture pattern, SSRF was associated with a reduced pneumonia risk. In patients with TBI and a flail chest, a shorter ICU LOS was observed in the SSRF group. In both groups, SSRF was safe and did not hamper neurological recovery