Eliminated Group Differences Research Articles

Fisetin Supplementation Improves Age‐Related Vascular Endothelial Function by Suppressing Cellular Senescence and Mitochondrial Oxidative Stress

Age‐related vascular endothelial dysfunction is mediated by excess reactive oxygen species (ROS)—mitochondria (mito) being a key source—which can reduce nitric oxide (NO) bioavailability. Cellular senescence, a fundamental mechanism of aging, may exacerbate mito ROS and be a potential therapeutic target to combat age‐related vascular dysfunction.PurposeTo determine if treatment with the natural flavonoid fisetin improves endothelial function with aging by suppressing cellular senescence, scavenging excess whole‐cell and mito ROS, and increasing NO bioavailability.Methods & ResultsOld (27 mo) male C57BL/6 mice were treated with vehicle (V; 10% EtOH, 30% PEG400 and 60% Phosal 50 PG; n = 9) or fisetin (Fis; 50 mg/kg/day in V; n = 10) by oral gavage following a 1 wk on – 2 wk off – 1 wk on dosing paradigm.Endothelial functionEndothelial function was assessed by ex vivo carotid artery endothelium‐dependent dilation (EDD) and endothelium‐independent dilation (EID) to increasing doses of acetylcholine and sodium nitroprusside, respectively. EDD was greater in Fis vs V treated mice (Peak EDD [%]: 97 ± 1 vs 84 ± 3, P < .05) and no differences were observed among groups in EID (P = .54).Cellular senescenceFis‐treated mice had lower vascular abundance of p16, an established marker of cellular senescence (Fis, .12 ± .01 vs V, .19 ± .02 chemiluminescence units [CU], P < .05). Next, we administered Fis or V to old (27 mo) p16‐3MR mice (a model that allows for clearance of senescent cells with ganciclovir [GCV]; n = 6/group). Fis‐treated p16‐3MR mice had greater EDD (Peak EDD [%]: Fis, 93 ± 2 vs V, 74 ± 5, P < .05). Ex vivo carotid artery incubations with GCV eliminated group differences in EDD, suggesting that Fis reduced senescent cells to improve EDD.Whole‐cell ROSElectron paramagnetic resonance (EPR) spectroscopy was used to assess whole‐cell vascular (aortic) ROS. Fis‐treated mice had lower whole‐cell ROS (Fis, 4703 ± 455 vs V, 8173 ± 1243 amplitude units [AU], P < .05). Incubation with the ROS scavenger TEMPOL eliminated group differences in EDD, implying that Fis ameliorated ROS‐related suppression of EDD.Mito ROSEPR was used to assess vascular mito ROS. Fis‐treated mice had lower mito ROS (Fis, 2527 ±440 vs V, 6603 ± 1956 AU, P < .05). Further, Fis‐treated mice had lower abundance of vascular p‐p66SHC, a recognized marker of mito oxidative stress (Fis, .029 ± .003 vs V, .049 ± .008 CU, P < .05) and greater abundance of Mn superoxide dismutase, a mito antioxidant enzyme (Fis, .41 ± .1 vs V, .20 ± .02 CU, P < .05). Incubation with the mito‐specific antioxidant, MitoQ, eliminated group differences in EDD, implying that Fis ameliorated mito ROS‐related suppression of EDD.NOAddition of the NO‐synthase inhibitor, L‐NAME, abolished group differences in EDD suggesting Fis improved age‐related EDD impairments by increasing NO bioavailability.ConclusionFisetin supplementation may be a novel strategy to target excess cellular senescence and thereby reduce mito ROS to improve NO‐mediated endothelial function with aging.

Cellular Senescence and the Associated Secretome Contribute to Age‐Related Vascular Dysfunction

Age‐related vascular dysfunction (e.g., large elastic artery [aorta] stiffening and endothelial dysfunction) is mediated by excess reactive oxygen species (ROS) leading to lower nitric oxide (NO) bioavailability. The upstream mechanisms mediating excess ROS are mostly unknown. Cellular senescence is a principal mechanism of aging and the senescence associated secretory phenotype (SASP) may exacerbate ROS.PurposeTo: 1) determine if senescent cell clearance (senolysis) lowers aortic stiffness (pulse wave velocity [PWV]) and increases endothelial function (endothelium‐dependent dilation [EDD]), and if these effects are mediated by reduced ROS and increased NO bioavailability; and 2) isolate the influence of the circulating SASP on age‐related vascular dysfunction.Methods and ResultsYoung (6 mo) and old (27 mo) adult male and female p16‐3MR mice were treated with vehicle ([V]; saline) or a p16‐3MR senolytic, ganciclovir (GCV; 25 mg/kg/day) injected intraperitoneally for 5 days. This resulted in 4 groups/sex (Young‐V [YV], n = 23; Young‐GCV [Y‐GCV]; n = 16, Old‐V [OV]; n = 22, Old‐GCV [O‐GCV]; n = 21). No sex differences were observed, so results were combined.Aortic Stiffness. Aortic PWV (aPWV) was assessed pre and post V and GCV treatment. Old mice had higher aPWV at baseline vs young (aPWV [cm/sec]: O‐GCV, 450 ± 16; OV, 441 ± 13; YV, 352 ± 7; Y‐GCV, 351 ± 12; P<.05). Following GCV treatment, old mice had reduced aPWV (pre: 441 ± 13 vs post: 375 ± 5 cm/sec, P< .05), which was not different from YV (P= .63) or Y‐GCV (P= .72). These data suggest that cellular senescence mediates aortic stiffening with advancing age.Endothelial function. OV animals had impaired ex vivocarotid artery EDD to acetylcholine (an established assay of endothelial function) relative to young and GCV treatment resulted in greater peak EDD (Peak EDD [%]: O‐GCV, 95 ± 1; OV, 83 ± 4; YV, 93 ± 4; Y‐GCV, 95 ± 1; P<.05). Addition of the NO‐synthase inhibitor, L‐NAME, abolished group differences suggesting the age‐related increase in cellular senescence reduced EDD by lowering NO bioavailability. Administration of the ROS scavenger TEMPOL eliminated group differences in EDD, implying that cellular senescence causes endothelial dysfunction with aging by amplifying ROS.SASP. To determine the effect of the circulating SASP on aortic stiffness, we incubated aortic rings from young adult (6 mo) male and female C57BL/6 mice, with plasma from sex‐matched OV and O‐GCV mice, or under fetal bovine serum (control). Following a 48h incubation, we assessed intrinsic mechanical wall stiffness (elastic modulus [EM]), an established ex vivomeasure of aortic stiffness. OV plasma resulted in 1.5 ± .01‐fold greater EM vs control (P< .05), which did not occur in O‐GCV plasma (P= 0.84 vs control), suggesting the SASP may increase age‐related aortic stiffening.Conclusion. The circulating SASP factors may be a mechanism by which cellular senescence induces age‐related vascular dysfunction, and as such, these processes represent novel therapeutic targets.

Treatment Optimization of Pelvic External Beam Radiation With/or Vaginal Brachytherapy for Patients with Stage I to II High-Risk Endometrioid Adenocarcinoma: A Retrospective Multi-Institutional Analysis

For stage I to II high-risk endometrioid adenocarcinoma patients, the optimal adjuvant radiotherapy modality remains controversial. The present study sought to optimize the treatment of pelvic external beam radiation (EBRT) with/or vaginal brachytherapy (VBT) for high-risk endometrioid adenocarcinoma patients in multiple radiation oncology centers across China.This article retrospectively reviewed stage I to II resected endometrioid adenocarcinoma patients treated at 13 radiation centers from Jan. 1999 to Dec. 2015. Patients were eligible if they had high-risk features (stage IB Grade 3 disease or stage II Grade 1-3 disease) on the basis of ESMO-ESGO-ESTRO risk group consensus.A total of 218 patients were included in the analysis. Lymphadenectomy was achieved in 87.2% of all patients. Fifty-one patients received adjuvant EBRT (EBRT group), 25 patients received VBT (VBT group), and 142 patients were administered EBRT combined with VBT (EBRT + VBT group). The three groups were comparable in baseline characteristics, except that the proportion of stage IBand Grade 3 disease in the VBT group was significantly higher and their age was older (P < 0.05). For all patients, the median overall survival was not reached. Survival analysis showed that OS, DFS, LRFS and DMFS were significantly different among the three groups. Two out of three groups were compared with each other, and the results demonstrated that DFS, LRFS and DMFS were worse in the VBT group than in the EBRT (P < 0.05) or EBRT + VBT group (P < 0.05). The EBRT + VBT group was associated with significantly improved OS compared to the VBT group. There was no significant difference in survival outcomes between the EBRT group and EBRT + VBT group. A propensity matching analysis was performed to eliminate group differences, and 50 patients were successfully matched. The results demonstrated that DFS and LRFS were significantly improved in the pelvic radiation group compared to the VBT group. Chemotherapy did not significantly improve survival for all patients, while a trend towards a better prognosis was shown for patients with lymphovascular invasion or deep myometrial invasion. Regarding the failure pattern, distant failure accounted for most. Patients in the VBT group had significantly increased local and regional recurrence rates than patients in the EBRT or EBRT + VBT group. Acute and chronic radiation-induced toxicities were well tolerated for all patients.For patients with postoperative stage I to II high-risk endometrioid adenocarcinoma, compared with VBT alone, pelvic radiation significantly improved DFS, LRFS and DMFS with tolerable adverse effects. Survival outcomes were not significantly different between the EBRT and EBRT + VBT modalities.W. Wang: None. L. Zou: None. T. Wang: None. Z. Liu: None. J. He: None. X. Sun: None. W. Zhong: None. F. Zhao: None. X. Li: None. S. Li: None. H. Zhu: None. Z. Ma: None. S. Sun: None. M. Jin: None. F. Zhang: None. X. Hou: None. L. Wei: None. K. Hu: None.

Treatment optimization of pelvic external beam radiation and/or vaginal brachytherapy for patients with stage I to II high-risk Endometrioid adenocarcinoma: a retrospective multi-institutional analysis

BackgroundFor stage I to II high-risk endometrioid adenocarcinoma patients, the optimal adjuvant radiotherapy modality remains controversial. The present study sought to optimize the treatment of pelvic external beam radiation (EBRT) with/or vaginal brachytherapy (VBT) for high-risk endometrioid adenocarcinoma patients in multiple radiation oncology centers across China.MethodsThis article retrospectively reviewed stage I to II patients with resected endometrioid adenocarcinoma treated at 13 radiation centers from 1999 to 2015. Patients were eligible if they had high-risk features (stage IB Grade 3 disease or stage II Grade 1–3 disease) on the basis of ESMO-ESGO-ESTRO risk group consensus.ResultsA total of 218 patients were included. Fifty-one patients received EBRT, 25 patients received VBT, and 142 patients were administered EBRT combined with VBT. The three groups were comparable in baseline characteristics, except the proportion of stage IB and Grade 3 disease in the VBT group was significantly higher and their age was older. Survival analysis showed that OS, DFS, LRFS and DMFS were significantly different among the three groups. Two out of three groups were compared with each other, and results demonstrated that DFS, LRFS and DMFS were worse in the VBT group than in the EBRT or EBRT + VBT group. The 3-year OS rates were 95.2, 85.2 and 95.1% in the EBRT, VBT and EBRT + VBT groups, respectively (p = 0.043). There was no significant difference in survival outcomes between EBRT group and EBRT + VBT group. A propensity matching analysis was performed to eliminate group differences. The results demonstrated that DFS and LRFS were significantly improved in the pelvic radiation group compared to the VBT group. Distant failure accounted for most of the failure patterns. Patients in the VBT group had significantly increased local and regional recurrence rates than patients in the EBRT or EBRT + VBT group. Acute and chronic radiation-induced toxicities were well tolerated for all patients.ConclusionFor patients with postoperative stage I to II high-risk endometrioid adenocarcinoma, compared with VBT alone, radiotherapy modalities including EBRT significantly improved DFS, LRFS and DMFS with tolerable adverse effects. Overall survival was not significantly different between EBRT and EBRT + VBT modalities.

Cellular senescence mediates doxorubicin‐induced arterial dysfunction via activation of mitochondrial oxidative stress and the mammalian target of rapamycin

The mechanisms underlying arterial dysfunction (large elastic artery [e.g., aorta] stiffening and vascular endothelial dysfunction) caused by the common chemotherapeutic agent doxorubicin (DOXO) are incompletely understood. Purpose To determine if clearance of senescent cells (senolysis) following DOXO would: 1) prevent aortic stiffening via reduced aortic intrinsic mechanical wall stiffness (elastic modulus [EM]), in part due to inhibition of the mammalian target of rapamycin (mTOR); and 2) prevent endothelial dysfunction by preserving nitric oxide (NO) bioavailability and inhibiting excess mitochondrial reactive oxygen species (mtROS) production. Results Young adult (4 mo) p16-3MR male (n = 5-9) and female (n = 3-5) mice received a single IP injection of DOXO (10 mg/ml in saline) or vehicle (V; saline). One week after DOXO, a p16+ senolytic used in p16-3MR mice, ganciclovir (GCV; 25 mg/kg/day x 5 days), or vehicle (V; saline x 5 days) were administered IP, resulting in 4 groups/sex (DOXO-V; DOXO-GCV; V-V; V-GCV) that were studied 3 weeks later. No sex differences were observed, so results were combined. Aortic Stiffness No pre-treatment differences in aortic stiffness (aortic pulse wave velocity [PWV]) were found. DOXO increased aortic PWV by 17% in DOXO-V (P = 0.03), which was prevented by senolysis (DOXO-GCV, Pre vs Post treatment: P = 0.88). These group differences in aortic PWV were explained by differences in aortic EM, which was higher in DOXO-V mice vs. all groups (P = 0.02), suggesting senolysis prevented the increased EM with DOXO. Next, we assessed the mTOR-mediated contribution to aortic EM by incubating (48h) aortic rings from all groups with the mTOR inhibitor, rapamycin, or sham (DMSO). EM was higher in sham-incubated DOXO-V vs. V-V rings (2579±200 vs. 1900±54 kPa, P = 0.04). Rapamycin lowered aortic EM in the DOXO-V group (rapamycin vs. sham: 1604±115 vs. 2579±200 kPa, P = 0.02), which eliminated group differences. This suggests senolysis prevents aortic stiffening caused by DOXO via mTOR inhibition. Endothelial function DOXO impaired isolated carotid artery endothelium-dependent dilation (EDD) to acetylcholine, an established bioassay of endothelial function (DOXO-V vs V-V: 62±5 vs 93±2 %, P < 0.0001), which was fully prevented with senolysis (DOXO-GCV: 95±1%). Addition of the NO-synthase inhibitor, L-NAME, abolished group differences, suggesting senolysis following DOXO preserves EDD by maintaining NO bioavailability. Administration of the mt-targeted antioxidant MitoQ eliminated group differences in EDD, suggesting excess mtROS impaired endothelial function in the DOXO-V group, which was prevented with senolysis. Conclusion Arterial dysfunction with DOXO is mediated by cellular senescence. mTOR and mtROS may be therapeutic targets to prevent/treat DOXO-mediated arterial dysfunction.

Aldosterone impairs coronary adenosine-mediated vasodilation via reduced functional expression of Ca2+-activated K+ channels

Elevated plasma aldosterone (Aldo) levels are associated with greater risk of cardiac ischemic events and cardiovascular mortality. Adenosine-mediated coronary vasodilation is a critical cardioprotective mechanism during ischemia; however, whether this response is impaired by increased Aldo is unclear. We hypothesized that chronic Aldo impairs coronary adenosine-mediated vasodilation via downregulation of vascular K+ channels. Male C57BL/6J mice were treated with vehicle (Con) or subpressor Aldo for 4 wk. Coronary artery function, assessed by wire myography, revealed Aldo-induced reductions in vasodilation to adenosine and the endothelium-dependent vasodilator acetylcholine but not to the nitric oxide donor sodium nitroprusside. Coronary vasoconstriction to endothelin-1 and the thromboxane A2 mimetic U-46619 was unchanged by Aldo. Additional mechanistic studies revealed impaired adenosine A2A, not A2B, receptor-dependent vasodilation by Aldo with a tendency for Aldo-induced reduction of coronary A2A gene expression. Adenylate cyclase inhibition attenuated coronary adenosine dilation but did not eliminate group differences, and adenosine-stimulated vascular cAMP production was similar between Con and Aldo mice. Similarly, blockade of inward rectifier K+ channels reduced but did not eliminate group differences in adenosine dilation whereas group differences were eliminated by blockade of Ca2+-activated K+ (KCa) channels that blunted and abrogated adenosine and A2A-dependent dilation, respectively. Gene expression of several coronary KCa channels was reduced by Aldo. Together, these data demonstrate Aldo-induced impairment of adenosine-mediated coronary vasodilation involving blunted A2A-KCa-dependent vasodilation, independent of blood pressure, providing important insights into the link between plasma Aldo and cardiac mortality and rationale for aldosterone antagonist use to preserve coronary microvascular function.NEW & NOTEWORTHY Increased plasma aldosterone levels are associated with worsened cardiac outcomes in diverse patient groups by unclear mechanisms. We identified that, in male mice, elevated aldosterone impairs coronary adenosine-mediated vasodilation, an important cardioprotective mechanism. This aldosterone-induced impairment involves reduced adenosine A2A, not A2B, receptor-dependent vasodilation associated with downregulation of coronary KCa channels and does not involve altered adenylate cyclase/cAMP signaling. Importantly, this effect of aldosterone occurred independent of changes in coronary vasoconstrictor responsiveness and blood pressure.

Executive Function Skills in School-Age Children With Autism Spectrum Disorder: Association With Language Abilities.

This article reviews research on executive function (EF) skills in children with autism spectrum disorder (ASD) and the relation between EF and language abilities. The current study assessed EF using nonverbal tasks of inhibition, shifting, and updating of working memory (WM) in school-age children with ASD. It also evaluated the association between children's receptive and expressive language abilities and EF performance. In this study, we sought to address variables that have contributed to inconsistencies in this area of research-including task issues, group comparisons, and participant heterogeneity. EF abilities in children with ASD (n = 48) were compared to typically developing controls (n = 71) matched on age, as well as when statistically controlling for group differences in nonverbal cognition, socioeconomic status, and social communication abilities. Six nonverbal EF tasks were administered-2 each to evaluate inhibition, shifting, and WM. Language abilities were assessed via a standardized language measure. Language-EF associations were examined for the ASD group as a whole and subdivided by language status. Children with ASD exhibited significant deficits in all components of EF compared to age-mates and showed particular difficulty with shifting after accounting for group differences in nonverbal cognition. Controlling for social communication-a core deficit in ASD-eliminated group differences in EF performance. A modest association was observed between language (especially comprehension) and EF skills, with some evidence of different patterns between children on the autism spectrum with and without language impairment. There is a need for future research to examine the direction of influence between EF and language. It would be beneficial for EF interventions with children with ASD to consider language outcomes and, conversely, to examine whether specific language training facilitates aspects of executive control in children on the autism spectrum. https://doi.org/10.23641/asha.7298144.

Are RAN deficits in university students with dyslexia due to defective lexical access, impaired anchoring, or slow articulation?

The purpose of this study was to examine different hypotheses in relation to RAN deficits in dyslexia. Thirty university students with dyslexia and 32 chronological-age controls were assessed on RAN Digits and Colors as well as on two versions of RAN Letters and Objects (one with five items repeated 16 times and one with 20 items repeated four times). In addition, participants were tested on discrete letter and object naming, phonological awareness, orthographic knowledge, and speed of processing, and the RAN Letters and Objects total times were partitioned into pause times and articulation times. Results showed first that the dyslexia group was slower than the control group on all RAN tasks and the differences remained significant after controlling for discrete naming time. Second, both groups were slower in the large item set condition (20× 4) than in the small set condition (5× 16). Third, the dyslexia group was slower than the control group in both the pause and the articulation times. Although none of the processing skills was sufficient on its own to eliminate group differences in RAN Letters components, phonological awareness, and orthographic processing were sufficient on their own to eliminate group differences in the RAN Objects pause time. Taken together, our findings suggest that the deficits in RAN are not due to impaired anchoring, but rather due to subtle impairments in lexical access (specific to alphanumeric RAN), serial processing, and articulation.

Effects of Sedentary Aging and Lifelong Exercise on Left Ventricular Systolic Function.

The current study examined whether age-related changes in left ventricular (LV) longitudinal systolic function is an adaptation to a more sedentary lifestyle and can be preserved by lifelong exercise training. A cross-sectional examination of 18 sedentary young (37 ± 6 yr), 29 sedentary seniors (71 ± 5 yr, 0-3 exercise sessions per week), and 26 seniors (68 ± 5 yr) who had performed a committed level (four to seven exercise sessions per week) of lifelong (>25 yr) exercise. Invasive right heart catheterization (pulmonary capillary wedge pressure) and noninvasive measures of LV function were collected at the following conditions: 1) supine rest, 2) during LV unloading (lower body negative pressure), and 3) LV loading (saline infusion). Ejection fraction and preload-recruitable stroke work (PRSW) were used to describe global LV systolic function, while peak systolic tissue velocity and longitudinal strain (LS) indicate LV longitudinal systolic function. To adjust LS for aging and training-related differences in LV preload and afterload, LV end-diastolic volume and end-systolic pressure (ESP) were included as covariates in ANCOVA models. Ejection fraction and PRSW were unaffected by aging or lifelong exercise (P = 0.22, P = 0.08, respectively). Peak systolic tissue velocities decreased with aging (P < 0.001) and sedentary seniors had a smaller LS compared with young (P = 0.023) and lifelong exercisers (P = 0.046). Preload-recruitable stroke work, ESP as a covariate did not alter group differences; however, LV end-diastolic volume eliminated group differences between senior groups. Longitudinal strain was preload dependent (P < 0.001), which was independent of aging and lifelong exercise. Sedentary aging leads to a reduction in systolic LS, which is attenuated by committed lifelong exercise due to improved LV diastolic filling.

Episodic future thinking following vmPFC damage: Impaired event construction, maintenance, or narration?

Functional neuroimaging and lesion studies show that the ventromedial prefrontal cortex (vmPFC) is implicated in episodic future thinking (EFT), yet its role remains unclear. In this study, we sought to (a) confirm recent findings of impaired EFT in patients with lesions to the vmPFC (vmPFC patients) using a new task, and (b) investigate the influence of nonepisodic mechanisms, namely, narrative construction and working memory maintenance, on vmPFC patients' EFT performance. vmPFC patients and healthy participants imagined future events using pictures as cues, described pictures, or described pictures while maintaining them in working memory after an observation phase. Compared with the controls, vmPFC patients produced less specific reports across all conditions, as indicated by fewer internal (episodic) but a similar number of external (semantic) details. However, controlling for description and working memory performance did not eliminate group differences in EFT. Moreover, vmPFC damage reduced the proportion of internal-to-total details for EFT only. These results indicate that EFT problems in vmPFC patients are not merely the reflection of problems in maintaining in working memory and narrating events, but, more likely, of an impairment upstream, in creating novel events. (PsycINFO Database Record

WAT apoC-I secretion: role in delayed chylomicron clearance in vivo and ex vivo in WAT in obese subjects

Reduced white adipose tissue (WAT) LPL activity delays plasma clearance of TG-rich lipoproteins (TRLs). We reported the secretion of apoC-I, an LPL inhibitor, from WAT ex vivo in women. Therefore we hypothesized that WAT-secreted apoC-I associates with reduced WAT LPL activity and TRL clearance. WAT apoC-I secretion averaged 86.9 ± 31.4 pmol/g/4 h and 74.1 ± 36.6 pmol/g/4 h in 28 women and 11 men with BMI ≥27 kg/m(2), respectively, with no sex differences. Following the ingestion of a (13)C-triolein-labeled high-fat meal, subjects with high WAT apoC-I secretion (above median) had delayed postprandial plasma clearance of dietary TRLs, assessed from plasma (13)C-triolein-labeled TGs and apoB48. They also had reduced hydrolysis and storage of synthetic (3)H-triolein-labeled ((3)H)-TRLs in WAT ex vivo (i.e., in situ LPL activity). Adjusting for WAT in situ LPL activity eliminated group differences in chylomicron clearance; while adjusting for plasma apoC-I, (3)H-NEFA uptake by WAT, or body composition did not. apoC-I inhibited in situ LPL activity in adipocytes in both a concentration- and time-dependent manner. There was no change in postprandial WAT apoC-I secretion. WAT apoC-I secretion may inhibit WAT LPL activity and promote delayed chylomicron clearance in overweight and obese subjects. We propose that reducing WAT apoC-I secretion ameliorates postprandial TRL clearance in humans.

Executive functions and the contribution of short-term memory span in children with specific language impairment.

An increasing number of results show that specific language impairment (SLI) is often associated with impairments in executive functions (EF), but the nature, extent, and generality of these deficits is yet unclear. The aim of the paper is to present results from verbal and nonverbal tasks examining EF in children with SLI and their age-matched typically developing (TD) peers. 31 children with SLI were tested on verbal and nonverbal versions of simple and complex span, fluency, N-back, and Stroop tasks. Their performance was compared with 31 TD children matched on age and nonverbal IQ. The design allows us to examine whether executive functions are similarly affected in SLI in verbal and nonverbal tasks. The SLI group showed difficulties in verbal versions of complex span (listening span task) and fluency but not in inhibition (Stroop tasks) relative to TD age-matched children. Including simple verbal span (digit span) as a covariate eliminated group differences on both verbal tasks. Children with SLI were found to be impaired on several verbal measures of EF, but these differences were largely due to more fundamental deficits in verbal short-term span.

Does depression matter in neuropsychological performances in anorexia nervosa? A descriptive review.

This review aims to examine the impact of depressive symptoms on the assessment of cognitive flexibility, central coherence, and decision-making in individuals with anorexia nervosa (AN). An online search was carried out using PubMed and PsycInfo. Articles were selected for review if they were published in English between 1990 and 2014 and used the Wisconsin Card Sorting Test, the Trail Making Task parts A and B, the Brixton Test, the Rey-Osterrieth Complex Figure Test, and/or the Iowa Gambling Task. Sixty-two studies were included. Thirty (48%) of the studies statistically assessed the association between depression and neurocognition in AN versus healthy controls. Where significant correlations were found, it became clear that the more serious the depression, the greater the neuropsychological impairment. Only six (10%) studies examined whether increased depressive symptoms were able to eliminate the differences between individuals with AN and healthy controls, and one study found that depressive symptoms did eliminate group differences in cognitive flexibility and decision-making. Only a subgroup of articles on neuropsychology in AN adjusted for depression. However, given the role of depression that some articles suggest, future studies should pay closer attention to the evaluation of this potential confounder.

Traits linked to executive and reward systems functioning in clients undergoing residential treatment for substance dependence

Traits presumed to reflect dopaminergic reward and prefrontal executive systems functioning were assessed in 100 clients undergoing residential treatment for substance dependence and a community sample of 107 social drinkers. All participants completed self-report measures of impulsivity, alexithymia, frontal systems dysfunction, sensitivity to rewards and punishments, dispositional mindfulness, alcohol use, illicit drug use, mood and demographic characteristics. The percentage of in-patients meeting the criterion for alexithymia was more than twice as high as in the community sample (p<.0001). Multivariate analysis of covariance controlling for age, education, head injury and gender revealed significant differences (p<.0001) between clinical and community samples such that clients scored higher on negative moods, frontal systems dysfunction, reward sensitivity, punishment sensitivity and impulsivity, and lower on dispositional mindfulness. Time in treatment was correlated only with negative mood, supporting the stability of the trait measures; controlling for negative mood eliminated group differences on punishment sensitivity and mindfulness only. Results are consistent with the notion that addiction is linked to reward sensitivity and frontal lobe deficits, with associated implications.

Everyday emotional experience of adults with attention deficit hyperactivity disorder: evidence for reactive and endogenous emotional lability.

Emotional lability (EL), characterized by negative emotional traits and emotional instability, is frequently reported in children and adults with attention deficit hyperactivity disorder (ADHD). However, EL is primarily assessed using retrospective self-report, which is subject to reporting bias and does not consider the potential influence of positive and negative everyday experiences. Ambulatory assessment was carried out in 41 men with ADHD without co-morbidity, current medication or substance abuse, and 47 healthy control participants. Reports of negative and positive emotions (irritability, frustration, anger, happiness, excitement) and the occurrence of bad and good events were completed eight times daily during a working week. Group differences in emotional intensity and instability were investigated using multilevel models, and explored in relation to bad and good events and the Affective Lability Scale - Short Form (ALS-SF), an EL questionnaire. The ADHD group reported significantly more frequent bad events, heightened intensity and instability of irritability and frustration, and greater intensity of anger. The results for positive emotions were equivocal or negative. Bad events significantly contributed to the intensity and instability of negative emotions, and showed a stronger influence in the ADHD group. However, covariation for their effect did not eliminate group differences. Small-to-moderate correlations were seen between intensity and instability of negative emotions and the ALS-SF. Adults with ADHD report heightened intensity and instability of negative emotions in daily life. The results suggest two components of EL in ADHD: a reactive component responsive to bad events and an endogenous component, independent of negative everyday events.

Effects of hindlimb unloading and radiation on vasodilator responses in skeletal muscle arteries (1106.18)

Long‐term spaceflight leads to extensive changes to the microvasculature as a result of weightlessness, which may be compounded by the effects of radiation exposure. The purpose of this study was to assess the individual and combined effects of hindlimb unloading (HU) and radiation (Rad) on vasodilator responses in the skeletal muscle microcirculation.Adult male C57BL/6 mice were randomized to one of four groups: control, HU (tail suspension for 10‐11 days), Rad (100cGy of 150MeV protons and 20cGy of 800MeV 56Fe), and HU‐Rad. Gastrocnemius feed arteries were isolated, cannulated and pressurized for in vitro study. Endothelium‐dependent (ACh, 10‐9‐10‐4 M) and ‐independent (Dea‐NONOate, 10‐9‐10‐4 M) vasodilator responses were evaluated. NOS and COX inhibitors (L‐NAME and Indomethacin) were used to determine which endothelium‐dependent signaling pathways were altered.In all treatment groups endothelium‐dependent and ‐independent vasodilator responses were significantly impaired compared to controls (max ACh dilation: 91±2%). ACh‐induced vasodilation was less in the HU‐Rad (68±3%) group than in HU (79±1%) or Rad (80±2%) alone. Independent and simultaneous treatment with L‐NAME and indomethacin reduced vasodilation and eliminated group differences. Dea‐NONOate‐induced vasodilation was reduced to a greater degree in the Rad and HU‐Rad groups.These findings suggest that the combination of insults experienced during spaceflight lead to significant impairment of vasodilatory function, mediated through endothelium‐dependent reductions in NOS signaling and vascular smooth muscle dysfunction.Grant Funding Source: Supported by NSBRI, NCC 9‐58‐44

Imagining the future: Degraded representations of future rewards and events in schizophrenia.

Over the course of life, most people work toward temporally distant rewards such as university degrees or work-related promotions. In contrast, many people with schizophrenia show deficits in behavior oriented toward long-term rewards, although they function adequately when rewards are more immediately present. Moreover, when asked about possible future events, individuals with schizophrenia show foreshortened future time perspectives relative to healthy individuals. Here, we take the view that these deficits are related and can be explained by cognitive deficits. We compared the performance of participants with schizophrenia (n = 39) and healthy participants (n = 25) on tasks measuring reward discounting and future event representations. Consistent with previous research, we found that relative to healthy participants, those with schizophrenia discounted the value of future rewards more steeply. Furthermore, when asked about future events, their responses were biased toward events in the near future, relative to healthy participants' responses. Although discounting and future representations were unrelated in healthy participants, we found significant correlations across the tasks among participants with schizophrenia, as well as correlations with cognitive variables and symptoms. Further analysis showed that statistically controlling working memory eliminated group differences in task performance. Together these results suggest that the motivational deficits characteristic of schizophrenia relate to cognitive deficits affecting the ability to represent and/or evaluate distant outcomes, a finding with important implications for promoting recovery from schizophrenia.

Neuropsychological, impulsive personality, and cerebral oxygenation correlates of undergraduate polysubstance use

While the relationship between cognitive deficits and impulsive-sensation seeking has been acknowledged in prior research, the impact of impulsive personality style on substance-related cognitive deficits has not been completely elucidated. The present study explored factors related to decision making and executive functioning in 23 polysubstance-using undergraduates and 23 healthy normal controls. Participants' cerebral oxygenation was measured using near-infrared spectroscopy. Polysubstance users performed worse on the Iowa Gambling Task (IGT), Wisconsin Card Sorting Test (WCST), and N-Back than did personality-matched controls. They also displayed less dorsolateral prefrontal oxygenation during the IGT. The polysubstance group reported more antisocial characteristics and lower positive affect; controlling for these variables eliminated group differences on the N-Back reaction time. Results suggest that cognitive decrements can be observed in polysubstance-using undergraduates without a lifetime burden of substance use, even after accounting for impulsivity. Results also highlight the importance of considering the contribution of positive mood and antisocial characteristics on executive functioning in polysubstance use.

Sentence comprehension in young adults with developmental dyslexia

This study investigated the effects of syntactic complexity on written sentence comprehension in compensated adults with dyslexia. Because working memory (WM) plays a key role in processing complex sentences, and individuals with dyslexia often demonstrate persistent deficits in WM, we hypothesized that individuals with dyslexia would perform more poorly on tasks designed to assess the comprehension of syntactic structures that are especially taxing on WM (e.g., passives, sentences with relative clauses). Compared to their nondyslexic peers, individuals with dyslexia were significantly less accurate and marginally slower on passive sentences. For sentences containing relative clauses, the dyslexic group was also less accurate but did not differ in response times. Covarying WM and word reading in both analyses eliminated group differences showing that syntactic deficits in adults with dyslexia are constrained by both WM and word-reading ability. These findings support previous research showing that syntactic processing deficits are characteristic of dyslexia, even among high-achieving students.

Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study

Changes in Relative Glucose Metabolic Rate Following Cortisol Administration in Aging Veterans with Posttraumatic Stress Disorder: An FDG-PET Neuroimaging Study