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Altered sympathetic nervous activity has been linked to the development and persistence of obesity, partly relating to overfeeding. Binding of the selective, positron-emitting phosphodiesterase-4 (PDE4) inhibitor (R)-[[sup.11]C]rolipram provides a direct index of the CAMP-hydrolyzing enzyme PDE4. This study examines progressive alterations in PDE4 in a high-fat-fed obese animal model. (R)-[[sup.11]C]Rolipram was injected into diet-induced obese (DIO) and diet-resistant (DR) rats; the animals were killed after 45 min, tissues were extracted, and radioactivity was quantified. Responsiveness of PDE4 to acute noradrenaline (NA) stimulation was determined by 3 h pretreatment with the NA reuptake inhibitor desipramine. There was minimal variance in caloric intake, weight gain, fasting glucose, insulin, and energy expenditure (indirect calorimetry) measures. Basal (R)-[[sup.11]C]rolipram binding was comparable between DIO and DR rats at 2 or 8 weeks of feeding. The normal increase of PDE4 levels in response to elevated NA by desipramine pretreatment was ablated in PDE4-rich tissues, including brain, heart, and skeletal muscle, of DIO animals after 8 weeks of high-fat diet. Lean DR rats maintained PDE4 responsiveness indicative of a normal NA signal transduction. Key words: diet-induced thermogenesis, sympathetic nervous system, noradrenergic signaling, (R)-[[sup.11]C]rolipram, positron emission tomography, high-fat diet, obesity. Une modification de l'activite nerveuse sympathique a ete liee au developpement et au maintien de l'obesite, decoulant en partie d'une suralimentation. La fixation de l'inhibiteur selectif de la phosphodiesterase-4 (PDE4) emetteur de positons, (R)-[[sup.11]C]rolipram, fournit un indice direct de l'enzyme PDE4 hydrolysant l'AMPc. La presente etude examine les modifications progressives de la PDE4 dans un modele animal obese soumis a une diete hyperlipidique. On a injecte le (R)-[[sup.11]C]rolipram a des rats rendus obeses par la diete (OD) et a des rats resistants a la diete (RD), sacrifie les animaux apres 45 min, extrait les tissus et quantifie la radioactivite. On a determine la reactivite de la PDE4 a une stimulation aigue induite par la noradrenaline (NA), 3 h apres un pretraitement avec l'inhibiteur de recapture de NA, desipramine. On a observe une variance minimale dans les mesures de l'apport calorique, de gain corporel, de glucose a jeun, d'insuline et de depense energetique (calorimetrie indirecte). La retention basale de (R)-[[sup.11]C]rolipram a ete comparable chez les rats OD et RD apres 2 ou 8 semaines de diete. L'augmentation normale des taux de PDE4 en reponse a l'augmentation de NA par le pretraitement a la desipramine a ete supprimee dans les tissus riches en PDE4, dont le cerveau, le coeur et le muscle squelettique, des animaux OD apres 8 semaines de diete hyperlipidique. Les rats RD maigres ont maintenu une reactivite de la PDE4 indiquant une transduction de signal normale par la NA. Mots-cles : thermogenese induite par la diete, systeme nerveux sympathique, signalisation noradrenergique, (R)-[[sup.11]C]rolipram, tomographie d'emission de positons, diete hyperlipidique, obesite. [Traduit par la Redaction], Introduction Obesity confers elevated risk for several comorbidities, including type 2 diabetes mellitus, hypertension, and cardiovascular disease (Kannel et al. 1967; Poirier et al. 2006). The sympathetic nervous system (SNS) [...]

Calorie restriction (CR) without malnutrition increases life span and delays the onset of a variety of diseases in a wide range of animal species. However, the mechanisms responsible for the retardation of aging with CR are poorly understood. We proposed that CR may act, in part, by inducing a hypometabolic state characterized by decreased reactive oxygen species (ROS) production and mitochondrial proton leak. Here, we examine the effects of long-term CR on whole animal energetics as well as muscle mitochondrial energetics, ROS production, and ROS damage. CR was initiated in male FBN[F.sub.1] rats at 6 mo of age and continued for 12 or 18 too. Mean whole body V[O.sub.2] was 34.6 (P < 0.01) and 35.6% (P < 0.001) lower in CR rats than in controls after 12 and 18 mo of CR, respectively. Body mass-adjusted V[O.sub.2] was 11.1 and 29.5% lower (both P < 0.05) in CR rats than in controls after 12 and 18 mo of CR. Muscle mitochondrial leak-dependent (State 4) respiration was decreased after 12 mo compared with controls; however, after 18 mo of CR, there were slight but not statistically significant differences. Proton leak kinetics were affected by 12 mo of CR such that leak-dependent respiration was lower in CR mitochondria only at protonmotive force values exceeding 170 inV. Mitochondrial [H.sub.2][O.sub.2] production and oxidative damage were decreased by CR at both time points and increased with age. Muscle UCP3 protein content increased with long-term CR, consistent with a role in protection from ROS but inconsistent with the observed decrease or no change in proton leak. oxidative phosphorylation; oxidative stress; metabolic control analysis; aging

Reductions in cellular oxygen consumption (V[O.sub.2]) and reactive oxygen species (ROS) production have been proposed as mechanisms underlying the anti-aging effects of calorie restriction (CR). Mitochondria are a cell's greatest 'sink' for oxygen and also its primary source of ROS. The mitochondrial proton leak pathway is responsible for 20-30% of V[O.sub.2] in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in V[O.sub.2], ROS production, and cellular damage. Here, we report the effects of short-term (2-wk, 2-mo) and medium-term (6-mo) CR (40%) on rat muscle mitochondrial proton leak, ROS production, and whole animal V[O.sub.2]. Whole body V[O.sub.2] decreased with CR at all time points, whereas mass-adjusted V[O.sub.2] was normal until the 6-mo time point, when it was 40% lower in CR compared with control rats. At all time points, maximal leak-dependent V[O.sub.2] was lower in CR rats compared with controls. Proton leak kinetics indicated that mechanisms of adaptation to CR were different between short- and medium-term treatments, with the former leading to decreases in protonmotive force ([DELTA]p) and state 4 V[O.sub.2] and the latter to increases in [DELTA]p and decreases in state 4 V[O.sub.2]. Results from metabolic control analyses of oxidative phosphorylation are consistent with the idea that short- and medium-term responses are distinct. Mitochondrial [H.sub.2][O.sub.2] production was lower in all three CR groups compared with controls. Overall, this study details the rapid effects of short- and medium-term CR on proton leak, ROS production, and metabolic control of oxidative phosphorylation. Results indicate that a reduction in mitochondrial V[O.sub.2] and ROS production may be a mechanism for the actions of CR. aging; oxidative stress; oxidative phosphorylation; uncoupling protein

Energy restriction (ER), without malnutrition, is the only environmental intervention that consistently increases maximum life span in laboratory rodents. One theory proposes that a reduction in energy expenditure and reactive oxygen species production is the mechanism responsible for this action of ER. To further test this theory, proton leak, [H.sub.2][O.sub.2] production, lipid peroxidation, and protein carbonyls were measured in mitochondria from FBN[F.sub.1] rats fed either a control or 40% ER diet (onset at 6 mo of age). Liver mitochondria were isolated at 7 and 12 mo of age. Liver weight decreased 25 and 36% at 1 and 6 mo of ER, respectively (P < 0.05). ER resulted in an increase (P < 0.05) in percent total polyunsaturates, n-6 polyunsaturates, and total unsaturates (6 mo only) in mitochondrial lipids. These changes, however, were not associated with significant alterations in mitochondrial function. State 4 respiration and membrane potential were not different (P > 0.05) between groups at either assessment period. Similarly, proton leak kinetics were not different between control and ER animals. Top-down metabolic control analysis and its extension, elasticity analysis, were used at the 6-mo assessment and revealed no difference in control of the oxidative phosphorylation system between control and ER rats. [H.sub.2][O.sub.2] production with either succinate or pyruvate/malate substrates was also not different (P > 0.05) between groups at either time point. In conclusion, ER did not alter proton leak or [H.sub.2][O.sub.2] production at this age or stage of restriction in liver. calorie restriction; energy expenditure; mitochondrial lipids; aging; oxidative stress

Abstract: Calorie restriction (CR), without malnutrition, consistently increases lifespan in all species tested, and reduces age-associated pathologies in mammals. Alterations in mitochondrial content and function are thought to underlie some of the effects of CR. Previously, we reported that rats subjected to variable durations of 40% CR demonstrated a rapid and sustained decrease in maximal leak-dependent respiration in skeletal muscle mitochondria. This was accompanied by decreased mitochondrial reactive oxygen species generation and increased uncoupling protein-3 protein (UCP3) expression. The aim of the present study was to determine the contribution of UCP3, as well as the adenine nucleotide translocase to these functional changes in skeletal muscle mitochondria. Consistent with previous findings in rats, short-term CR (2weeks) in wild-type (Wt) mice resulted in a lowering of the maximal leak-dependent respiration in skeletal muscle mitochondria, without any change in proton conductance. In contrast, skeletal muscle mitochondria from Ucp3-knockout (KO) mice similarly subjected to short-term CR showed no change in maximal leak-dependent respiration, but displayed an increased proton conductance. Determination of ANT activity (by measurement of inhibitor-sensitive leak) and protein expression revealed that the increased proton conductance in mitochondria from CR Ucp3-KO mice could be entirely attributed to a greater acute activation of ANT. These observations implicate UCP3 in CR-induced mitochondrial remodeling. Specifically, they imply the potential for an interaction, or some degree of functional redundancy, between UCP3 and ANT, and also suggest that UCP3 can minimize the induction of the ANT-mediated ‘energy-wasting’ process during CR. [Copyright &y& Elsevier]

The yeast sir2 gene and its orthologues in Drosophila and C. elegans have well-established roles in lifespan determination and response to caloric restriction. We have studied mice carrying two null alleles for SirT1, the mammalian orthologue of sir2, and found that these animals inefficiently utilize ingested food. These mice are hypermetabolic, contain inefficient liver mitochondria, and have elevated rates of lipid oxidation. When challenged with a 40% reduction in caloric intake, normal mice maintained their metabolic rate and increased their physical activity while the metabolic rate of SirT1-null mice dropped and their activity did not increase. Moreover, CR did not extend lifespan of SirT1-null mice. Thus, SirT1 is an important regulator of energy metabolism and, like its orthologues from simpler eukaryotes, the SirT1 protein appears to be required for a normal response to caloric restriction. [ABSTRACT FROM AUTHOR]

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1. Employing a clinical case vignette, participants will build frameworks for serious illness conversations with transgender patients when lived gender expression is challenged by medical circumstances. 2. Utilizing an example of effective collaboration between a primary surgical team and Palliative Care team, participants will analyze useful ways to support vulnerable LGBTQI+ patients. Our case presents a unique example where valued aspects of a transgender woman's gender expression conflicted with life-prolonging care, demonstrating how interprofessional Palliative Care teams can complement primary team efforts in serious illness conversations. Acknowledging that physical changes attached to identity can have disproportionate emotional effects was key to success in her care. Historically, LGBTQI+ individuals have faced numerous inequities in American medicine. Transgender individuals have been especially vulnerable in situations of serious illness when lived gender identity and expression may be challenged. This case presents a unique example where valued aspects of transgender woman's gender expression conflicted with likely curative care, demonstrating how interprofessional Palliative Care teams can navigate such discussions. A 56 year old Black, transgender woman with history of breast augmentation, vaginoplasty, and cosmetic silicone hip and buttock injections done overseas in the 1990s was admitted for right buttock wound worsening despite outpatient limited debridement and wound vac. Admission imaging showed significant necrosis of the silicon-injected tissues in her bilateral buttocks and hips so the surgical team recommended serial wide tissue debridement with significant deformity expected. Due to the impact of surgery on the patient's identity and expression, she initially declined intervention. Through careful exploration with the surgical and Palliative Care teams, the patient shared the tremendous amount of loss represented by pursuing likely curative yet image-altering surgery. Validation and recognition of this loss allowed the patient to move forward with surgical intervention. Ongoing palliative social work support and surgical attending advocacy have been key to maintaining dignity thorough her prolonged hospitalization. This patient had excellent continuity and rapport with her surgeon and access to life-saving interventions, however she could not accept the plan until teams looked at her glamorous photos and worked through her anticipatory grief. Acknowledging that physical changes attached to identity can have disproportionate emotional effects was key to success in her care. Involving Palliative teams can seem like punishment for the dissenting patient but our interprofessional team along with an advocacy-minded surgical team resulted in acceptance of a goal-concordant aggressive care plan. Diversity, Equity, Inclusion, Belonging, Justice; Communication [ABSTRACT FROM AUTHOR]

Abstract: Mitochondrial membrane fatty acid composition has been proposed to play a role in determining mitochondrial proton leak rate. The purpose of this study was to determine if feeding rats diets with different fatty acid sources produces changes in liver proton leak and H2O2 production. Six-month-old male FBNF1 rats were fed diets with a primary fat source of either corn or fish oil for a 6-month period. As expected, diet manipulations produced substantial differences in mitochondrial fatty acid composition. These changes were most striking for 20:4n6 and 22:6n3. However, proton leak and phosphorylation kinetics as well as lipid and protein oxidative damage were not different (P>0.10) between fish and corn oil groups. Metabolic control analysis, however, did show that control of both substrate oxidation and phosphorylation was shifted away from substrate oxidation reactions to increased control by phosphorylation reactions in fish versus corn oil groups. Increased mitochondrial H2O2 production was observed in corn versus fish oil-fed rats when mitochondria were respiring on succinate alone or on either succinate or pyruvate/malate in the presence of antimycin A. These results show that mitochondrial H2O2 production and the regulation of oxidative phosphorylation are altered in liver mitochondria from rats consuming diets with either fish or corn oil as the primary lipid source. [Copyright &y& Elsevier]

Background: Women account for 19 % of practicing surgeons in the United States, with representation decreasing with higher academic rank. Less is known about the proportion of women in editorial leadership positions at surgical journals. The objective of this study was to examine gender representation among editorial leadership at high-impact surgical journals., Methods: The five journals with the highest impact factors in general, cardiothoracic, plastics, otolaryngology, orthopedics, urology, vascular, and neurosurgery were identified. Data were abstracted on the proportion of women editors-in-chief (EIC) and editorial board members between 2010 and 2020 to determine how these demographics changed over time., Results: Multiple fields had no women EIC over the past decade (orthopedics, urology, cardiothoracic, neurosurgery). In all other fields, women were a minority of EIC. In 2020, women made up 7.9 % of EIC and 11.1 % of editorial boards in surgical journals., Conclusions: Women remain under-represented among leadership at high-impact surgical journals, with varying improvement over the past decade among different subspecialties., (Copyright © 2021 Elsevier Inc. All rights reserved.)