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Background: Current guidelines recommend resection with primary anastomosis with diverting loop ileostomy over Hartmann's procedure if deemed safe for acute diverticulitis. The primary objective of the current study was to compare the utilization of these strategies and describe nationwide ostomy closure patterns and readmission outcomes within 1 year of discharge., Methods: This was a retrospective, population-based, cohort study of United States Hospitals reporting to the Nationwide Readmissions Database from January 2011 to December 2019. There were 35,774 patients identified undergoing non-elective primary anastomosis with diverting loop ileostomy or Hartmann's procedure for acute diverticulitis. Rates of ostomy closure, unplanned readmissions, and complications were compared. Cox proportional hazards and logistic regression models were used to control for patient and hospital-level confounders as well as severity of disease., Results: Of the 35,774 patients identified, 93.5% underwent Hartmann's procedure. Half (47.2%) were aged 46-65 years, 50.8% female, 41.2% publicly insured, and 91.7% underwent open surgery. Primary anastomosis was associated with higher rates of 1-year ostomy closure (83.6% vs. 53.4%, p < 0.001) and shorter time-to-closure [median 72 days (Interquartile range 49-103) vs. 115 (86-160); p < 0.001]. Primary anastomosis was associated with increased unplanned readmissions [Hazard Ratio = 2.83 (95% Confidence Interval 2.83-3.37); p < 0.001], but fewer complications upon stoma closure [Odds Ratio 0.51 (95% 0.42-0.63); p < 0.001]. There were no differences in complications between primary anastomosis and Hartmann's procedure during index admission [Odds Ratio = 1.13 (95% Confidence Interval 0.96-1.33); p = 0.137]., Conclusion: Patients who undergo primary anastomosis for acute diverticulitis are more likely to undergo ostomy reversal and experience fewer postoperative complications upon stoma reversal. These data support the current national guidelines that recommend primary anastomosis in appropriate cases of acute diverticulitis requiring operative treatment., (© 2024. The Author(s).)

Objective: The aim of this study was to examine the association between race, experience of microaggressions, and implicit bias in surgical training., Background: There is persistent underrepresentation of specific racial and ethnic groups in the field of surgery. Prior research has demonstrated significant sex differences among those who experience microaggressions during training. However, little research has been conducted on the association between race and experiences of microaggressions and implicit bias among surgical trainees., Methods: A 46-item survey was distributed to general surgery residents and residents of surgical subspecialties through the Association of Program Directors in Surgery listserv and social media platforms. The questions included general information/demographic data and information about experiencing, witnessing, and responding to microaggressions during surgical training. The primary outcome was the prevalence of microaggressions during surgical training by self-disclosed race. Secondary outcomes were predictors of and adverse effects of microaggressions., Results: A total of 1624 resident responses were obtained. General surgery residents comprised 825 (50.8%) responses. The female-to-male ratio was nearly equal (815:809). The majority of respondents identified as non-Hispanic White (63.4%), of which 5.3% of residents identified as non-Hispanic Black, and 9.5% identified as Hispanic. Notably, 91.9% of non-Hispanic Black residents (n=79) experienced microaggressions. After adjustment for other demographics, non-Hispanic Black residents were more likely than non-Hispanic White residents to experience microaggressions [odds ratio (OR): 8.81, P <0.001]. Similar findings were observed among Asian/Pacific Islanders (OR: 5.77, P <0.001) and Hispanic residents (OR: 3.35, P <0.001)., Conclusions: Race plays an important role in experiencing microaggressions and implicit bias. As the future of our specialty relies on the well-being of the pipeline, it is crucial that training programs and institutions are proactive in developing formal methods to address the bias experienced by residents., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine the prevalence, nature, and source of microaggressions experienced by surgical residents during training., Summary and Background Data: The role of microaggressions in contributing to workplace culture, individual performance, and professional satisfaction has become an increasingly studied topic across various fields. Little is known about the prevalence and impact of microaggressions during surgical training., Methods: A 46-item survey distributed to current surgical residents in training programs across the United States via the Association of Program Directors in Surgery listserv and social media platforms between January and May 2020. Survey questions explored the frequency and extent of events of experiencing, witnessing, and responding to microaggressions in the workplace. The primary outcome was the occurrence of microaggressions experienced by surgical residents. Secondary outcomes included the nature, impact, and responses to these events., Results: A total of 1624 responses were collected, with an equal distribution by self-identified gender (female, n = 815; male, n = 809). The majority of trainees considered themselves heterosexual (n = 1490, 91.7%) and White (n = 1131, 69.6%). A majority (72.2%, n = 1173) of respondents reported experiencing microaggressions, most commonly from patients (64.1%), followed by staff (57.5%), faculty (45.3%), and co-residents (38.8%). Only a small proportion (n = 109, 7.0%) of residents reported these events to graduate medical education office/program director. Nearly one third (30.8%) of residents said they experienced retaliation due to reporting of micro-aggressions., Conclusions: Based on this large, national survey of general surgery and surgical subspecialty trainees, microaggressions appear to be pervasive in surgical training. Microaggressions are rarely reported to program leadership, and when reported, can result in retaliation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.)

Introduction: Small Bowel Obstruction (SBO) is a common reason for emergency department (ED) visits in the United States. However, little is known regarding the clinical course of these patients. This study aims to identify all patients presenting to the ED in New York State with SBO and follow their clinical course., Methods: The New York SPARCS administrative database was used to identify all patients who presented to an ED with the diagnosis of SBO from 2012 to 2014. Patients were followed to identify discharges from the ED, admissions, operations, 30-day readmissions, transfers, and in-hospital death., Results: Between 2012 and 2014, 43,567 ED visits (events) from 35,646 patients were identified, with 2824 (6.5%) resulting in direct discharge from the ED. A majority (n = 31,193; 71.6%) of ED visits were admitted to the presenting institution without surgery, while 7673 (17.6%) were admitted and underwent surgery. A minority (n = 1947; 4.5%) were transferred to a tertiary center. The overall 30-day readmission rate was 17.9%. Those who underwent surgery were more likely to experience in-hospital death but less likely to have 30-day readmission., Conclusion: To our knowledge, this is the first study that examines the disposition of all patients presenting to the ED with SBO in a large statewide cohort. The majority of admitted patients underwent non-operative management, with overall low rates of readmission, transfer, and in-hospital death.

Background: Some bariatric procedures have been associated with increased gastroesophageal reflux disease (GERD) symptoms; however, there are limited data on the long-term changes to the esophagus across bariatric procedures, and how preoperative esophageal disease is impacted by bariatric surgery., Objectives: To estimate incidence of GERD, esophagitis, Barrett's esophagus, and esophageal adenocarcinoma before and after bariatric surgery and to identify potential risk factors for these conditions., Setting: Retrospective analysis of New York State Database (SPARCS)., Methods: Adult patients undergoing bariatric surgery (Roux-en-Y gastric bypass, adjustable gastric banding, laparoscopic sleeve gastrectomy, and biliopancreatic diversion) from 1995 to 2010. Multivariable Cox proportional hazard models were used to examine the association between preoperative diagnosis, surgery type, and postoperative diagnosis., Results: A total of 48,967 records were analyzed; 30.3% had a diagnosis of GERD at the time of surgery and .4% had a diagnosis of esophagitis and Barrett's. Preoperative GERD/esophagitis/Barrett's was associated with higher risk of GERD, esophagitis, and Barrett's, but not esophageal adenocarcinoma, postoperatively. Roux-en-Y gastric bypass patients had lowest risk of being diagnosed with GERD postoperatively. Overall, esophageal adenocarcinoma incidence in the sample was .04%; the rate among patients with preoperative GERD and Barrett's was .1% and .9%, respectively. Incidence of esophageal adenocarcinoma did not differ by bariatric surgery type., Conclusions: Preoperative diagnosis is a risk factor for postoperative esophageal disease after bariatric surgery. Adjustable gastric banding and laparoscopic sleeve gastrectomy are associated with higher risk of postoperative GERD and esophagitis compared with Roux-en-Y gastric bypass. Incidence of esophageal adenocarcinoma did not differ by surgery type., (Copyright © 2020 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To compare cholecystectomy (CCY) and nonoperative treatment (no-CCY) for acute cholecystitis in pregnancy., Summary of Background Data: Current Society of Gastrointestinal and Endoscopic Surgery guidelines recommend CCY over nonoperative management of acute cholecystitis during pregnancy, and the American College of Obstetricians and Gynecologists recommend medically necessary surgery regardless of trimester. This approach has been recently questioned., Methods: Pregnant women admitted with acute cholecystitis were identified using the Nationwide Readmission Database 2010-2015. Propensity-score adjusted logistic regression models were used to compare CCY and no-CCY. The primary outcome was a composite measure of adverse maternal-fetal outcomes (intrauterine death/stillbirth, poor fetal growth, abortion, preterm delivery, C-section, obstetric bleeding, infection of the amniotic fluid, venous thromboembolism)., Results: There were 6390 pregnant women with acute cholecystitis: 38.2% underwent CCY, of which 5.1% were open. Patients were more likely to be managed operatively in their second trimester (First 43.9%, Second 59.1%, Third 34.2%; P < 0.01). Patients managed with CCY did not differ in age, insurance, income, Charlson Comorbidity Index, diabetes or obesity when compared to no-CCY (all P > 0.05), but were less likely to have a previous C-section, gestational diabetes, preeclampsia/eclampsia or be in the third trimester (P ≤ 0.01). Risk-adjusted analyses showed that no-CCY was associated with significantly increased maternal-fetal complications during the index admission [odds ratio 3.0 (95% confidence interval 2.08-4.34), P < 0.01] and 30-day readmissions [odds ratio 1.61 (confidence interval % CI 1.12-2.32), P < 0.01]., Conclusions: Contrary to current guidelines, most pregnant women admitted in the US with acute cholecystitis are managed nonoperatively. This is associated with over twice the odds of maternal-fetal complications in addition to increased readmissions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Within surgical education, there has been a recent emphasis on preparing medical students for the rigors of residency in an effort to improve confidence and technical preparedness throughout postgraduate training. The aim of this study is to test the impact of a boot camp course using the American College of Surgeons-based curriculum and objective, observer-based rating tools on both subjective confidence and objective skills of fourth-year medical students., Materials and Methods: Informed consent was obtained on the first day of the boot camp. Before any teaching, students performed 5 tasks (patient handoff, suturing, knot tying, central line placement, and chest tube placement), which were scored using objective rating tools provided by the American College of Surgeons. Students also completed 2 confidence measures. After 2 weeks of dedicated teaching and review, students were scored on the 5 same tasks and repeated the confidence measures., Results: Fourth-year medical students (N = 12) who had matched into surgical subspecialties were invited to participate in a 2-week surgical boot camp. All students beginning the study completed the study. The average age was 26.7 years; 25% of students were female. Subspecialties represented included general surgery (n = 5), orthopedics (n = 3), integrated plastics (n = 2), urology (n = 1), and neurosurgery (n = 1). Scores on objective skills improved significantly in all 5 tasks measured. Confidence improved significantly on individual task items, while overall self-efficacy remained unchanged., Conclusions: Implementation of a 2-week, multimodal surgical boot camp improved student performance on objectively rated surgical skills and increased student confidence., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Importance: To our knowledge, there has been little research conducted on the attitudes of residents toward their pregnant peers and parental leave., Objective: To examine the perceptions of current surgery residents regarding parental leave., Design, Setting, and Participants: A 36-item survey was distributed to current US general surgery residents and residents in surgical subspecialties through the Association of Program Directors in Surgery listserv and social media platforms. Questions were associated with general information/demographics, parental leave, having children, and respondents' knowledge regarding the current parental leave policy as set by the American Board of Surgery. The study was conducted from August to September 2018 and the data were analyzed in October 2018., Main Outcomes and Measures: Main outcomes included the attitudes of residents toward pregnancy and parental leave, parental leave policy, and the association of parental leave with residency programs., Results: A total of 2188 completed responses were obtained; of these, 1049 (50.2%) were women, 1572 (75.8%) were white, 164 (7.9%) were Hispanic/Latinx, 75 (3.6%) were African American, 2 (0.1%) were American Indian or Alaskan Native, 263 (12.7%) were Asian, and 5 (0.2%) were Native Hawaiian or Pacific Islander. From the number of residents who had/were expecting children (581 [28.6%]), 474 (81.6%) had or were going to have a child during the clinical years of residency. Many residents (247 [42.5%]) took fewer than 2 weeks of parental leave. Many residents did not feel supported in taking parental leave (177 [30.4%] did not feel supported by other residents and 190 [32.71%] did not feel supported by the faculty). Only 83 respondents (3.8%%) correctly identified the current American Board of Surgery parental leave policy. Residents who took parental leave identified a lack of a universal leave policy, strain on the residency program, a loss of education/training time, a lack of flexibility of programs, and a perceived or actual lack of support from faculty/peers as the top 5 biggest obstacles to taking leave during the clinical years of residency., Conclusions and Relevance: Most of the modifiable factors that inhibit residents from having children during residency are associated with policies (eg, a lack of universal leave policy and lack of flexibility) and personnel (eg, a strain on the residency program and lack of support from peers/faculty). These data suggest that policies at the level of the Accreditation Council for Graduate Medical Education or Resident Review Committee (RRC), as well as education and the normalization of pregnancy during training, may be effective interventions.

Introduction: Percutaneous cholecystostomy tube (PCT) placement is often the management of severe acute cholecystitis in the unstable patient. PCT can be later reversed and cholecystectomy performed. The purpose of this study is to investigate the incidence of subsequent cholecystectomy and clinical factors associated with subsequent procedure., Methods: The SPARCS, an administrative database, was used to search all patients undergoing PCT placement between 2000 and 2012 in the state of New York. Using a unique identifier, all patients were followed for subsequent cholecystectomy procedures for at least 2 years. Patients were also followed up to 2014 for potential CBD injury during subsequent laparoscopic (LC) or open cholecystectomy (OC). Univariate and multivariable regression analysis were performed when appropriate., Results: There were 9738 patients identified who underwent PCT placements. The incidence of patients who had a PCT in 2000-2012, which subsequently underwent cholecystectomy increased from 25.0% in 2000 to 31.7% in 2012. In addition, patients undergoing subsequent LC increased from 11.8% in 2000 to 22.2% in 2012, while the incidence of OC decreased from 13.2% in 2000 to 9.5% in 2012. After accounting for other confounding factors, younger male patients, race as white compared to black, who didn't have any complications during PCT placement were more likely to undergo subsequent cholecystectomy (p < 0.05). Average time to LC was 122.0 days versus 159.6 days for OC (p < 0.0001). From the patients who underwent cholecystectomy following PCT, 47 patients experienced CBD injury (1.6%)., Conclusions: Incidence of cholecystectomy following PCT increased during the study period. Surgeons seem to be more comfortable performing LC as rate of LC increased from 11.8 to 22.2%. However, rate of CBD injury is higher during subsequent cholecystectomy compared to that of the general population. Caution should be used when performing subsequent cholecystectomy following PCT, as these procedures may be more technically challenging.

Background: Pathways for enhanced recovery after surgery (ERAS) have been shown to improve length-of-stay (LOS) and post-operative complications across various surgical fields, however there is a lack of evidence-based studies in bariatric surgery. Specifically, the value of early feeding within an ERAS program in bariatric surgery is unclear. The objective of the current study was to determine the effect of early feeding on LOS for patients who underwent primary or revisional laparoscopic sleeve gastrectomy (LSG) and Roux-en-y gastric bypass (RYGB)., Methods: Retrospective single institution study of implementation of a new diet protocol in which initiation of oral intake changed from post-operative day 1 to day 0. LOS and 30-day events were compared. Patients were excluded if they were planned for 23-h stay, had significant intra-operative complications, or required reoperation within the same admission. Mann-Whitney U tests were done to compare LOS and chi-squared tests to compare 30-day events pre- and post-intervention., Results: A total of 244 patients were included; 84.4% were primary cases. 50.8% of cases occurred prior to early feeding implementation. Median age was 43.5 years (IQR 33-53) and majority of patients were female (78.7%). Median LOS was 32.6 (IQR 30.0-50.6). Median LOS across the whole sample was shorter in the early feeding group (36.2 vs. 31.0 h; p < 0.001). This difference remained statistically significant for primary, but not revisional cases. Post-operative events at 30 days were similar between pre- and post-intervention groups., Conclusions: Early feeding the day of surgery is associated with significantly shorter LOS for patients who undergo bariatric surgery with no difference in 30-day readmissions.

Background: Publicly reported hospital scores are used by patients to make health care-related decisions; however, their relationship to clinical outcomes is unknown., Methods: Through the use of the New York Statewide Planning and Research Cooperative System database, the association between two commonly used scores (Healthgrades and Centers for Medicare & Medicaid Services Hospital Compare) and four clinical outcomes was evaluated in several surgical fields (general, colorectal, hepatobiliary, foregut, and bariatric)., Results: After adjusting for patient-level factors, patients from facilities with greater Healthgrades scores were less likely to develop any complication after general surgery operations (P = .0013). Also, greater Healthgrades scores were associated with less 30-day readmissions and emergency department visits for general surgery operations only (P = .0061 and P = .0013, respectively). In addition, greater Healthgrades scores were significantly associated with a lesser hospital length of stay for colorectal, foregut, and general surgery operations. Greater Centers for Medicare & Medicaid Services Hospital Compare scores were significantly associated with less 30-day readmissions and lesser hospital length of stay for specific operative groups., Conclusion: Although some specialties demonstrated a correlation, there was no consistent relationship between publicly reported hospital scores and surgical outcomes that contributed to clinically meaningful use for patients or operations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Data regarding gender disparities in surgeon case volumes across subspecialties is sparse., Methods: Through the use of the New York SPARCS database, top 25 yearly performers of major surgical procedures were identified for each year from 2000 to 2014. Gender and academic affiliation was determined., Results: Breast surgery had the highest number (51.6%) of female top performers by surgical volume. Higher number of female surgeons in bariatric and breast surgery were associated with academic institutions (p < 0.001). Significantly higher number of female plastic surgeons were associated with community institutions (p = 0.02). While there was an increase in female top performers during the study period, the number of female top performing surgeons remained disproportionately low compared to male top performing surgeons. There were no female surgeons among the top performers in vascular, orthopedics, cardiac, and urology during the studied period., Conclusions: There is a gender disparity in surgeon case volumes. While some subspecialties showed some increase in female top performers, the majority remained male-dominated fields during the fifteen-year period., (Published by Elsevier Inc.)

Background: As the number of older adults in the United States continues to grow, there will be increasing demands on health care providers to address the needs of this population. Cancer is of particular importance, with over half of all cancer survivors older than 65 years. In addition, depression, pain, and fatigue are concerns for older adults with cancer and have been linked to poorer physical outcomes., Methods: For this retrospective chart review, 1012 eligible participants were identified via a query of the Electronic Medical Record for all patients referred to 1 of 4 Survivorship Clinics at Memorial Sloan Kettering Cancer Center. All patients were between the ages of 30 to 55 (younger adults) and >65 (older adults). Depression was measured using the Patient Health Questionnaire-9 (PHQ-9)., Results: The overall rate of depression in this sample of adult cancer survivors was 9.3%. There were no differences in the rates of clinically significant depression (defined as PHQ-9 score ≥10) between younger and older adult cohorts. However, there was a small trend toward higher mean PHQ-9 scores in the younger adult cohort (3.42 vs 2.95; t = 1.763, P = .10). Women reported greater rates of depression and higher pain and fatigue scores. Hispanic/Latino patients also reported significantly greater rates of depression., Conclusion: There were no observed differences in depression between older and younger adult cancer survivors. Gender and ethnic discrepancies in depression were observed. Future research should focus on understanding the nature of these differences and targeting interventions for the groups most vulnerable to depression after cancer treatment., (Copyright © 2017 John Wiley & Sons, Ltd.)

Postthrombotic syndrome (PTS) is an important outcome in children with deep vein thrombosis (DVT). There are several instruments to measure PTS, and no accepted "gold standard." The objective of this cross-sectional prospective study was to compare the prevalence of PTS in patients above 8 years old with a history of DVT using 3 scales: the Villalta scale, a pediatric modification of the Villalta scale, and the Manco-Johnson instrument. Forty-four subjects (22 females) were enrolled; mean age 16.6 years (SD 3.6 y). The majority had a lower extremity DVT. The average duration from DVT to PTS assessment was 2.6 years. The proportion of subjects with PTS using the adult Villalta scale was 11%, which was significantly less than the 66% of patients identified using both pediatric scales (P<0.0001). The majority of patients with PTS as determined by the pediatric scales had mild PTS. There was significant discordance between the prevalence of PTS using the Villalta scale compared with the 2 pediatric scales. This is especially relevant when considering which instrument to use in adolescent patients. This study demonstrates that PTS, as defined by these scales, is not a well-defined or standardized outcome, particularly when comparing adult and pediatric instruments.

Background: Increasingly, new HIV infections among people who use drugs are attributed to sexual risk behavior. However, HIV prevention research targeting persons with opioid dependence continues to focus on drug injection practices. Moreover, despite the rising prevalence of prescription opioid dependence in the United States, little is known about HIV risk in this population., Methods: This study examined the prevalence of sexual risk behavior among patients with opioid dependence who primarily use prescription opioids for non-medical purposes. As part of a multi-site clinical trial, participants (N = 653) completed a baseline assessment that included the Risk Behavior Survey., Results: In the past month, 74% were sexually active. Of these, most had opposite sex partners (97.3%) and vaginal intercourse (97.1%); anal intercourse was uncommon (3.1%). The majority reported unprotected intercourse (76.5%), but few had multiple partners (11.3%). Unprotected intercourse was associated with history of other substance dependence (adjusted odds ratio [AOR] = 1.73), and having multiple partners was associated with concurrent cocaine use (AOR = 2.54). Injection drug use in the past month was rare (2.5%)., Conclusions: While the majority of sexually active participants engaged in unprotected intercourse, the proportion with multiple sex partners was low relative to other samples of persons who use illicit drugs. Among persons with non-medical prescription opioid dependence, those who concurrently use other substances may be at elevated risk for HIV infection. Comprehensive assessment of substance abuse history among individuals dependent upon prescription opioids is critical for identifying patients who may require additional clinical interventions to reduce HIV sexual risk behavior., (© American Academy of Addiction Psychiatry.)

This study examined HIV transmission risk behavior among 63 patients with bipolar disorder (BD), major depressive disorder, and no mood disorder; half had substance use disorders (SUDs). Patients with BD were more likely than others to report unprotected intercourse with HIV-negative partners and <95 % adherence to antiretroviral medications. In multivariate models, BD and SUD were independent predictors of both risk behaviors. Participants with poorer medication adherence were more likely to have detectable HIV viral loads and unprotected intercourse with HIV-negative partners. Patients with BD deserve careful evaluation and HIV prevention services to reduce HIV transmission risk behaviors.

Mice lacking p107 exhibit a white adipose deficiency yet do not manifest the metabolic changes typical for lipodystrophy, and instead exhibit low levels of serum triglycerides and a normal liver phenotype. When fed a high fat diet, p107-null mice still did not accumulate fat in the liver, and display markedly elevated energy expenditures together with an increased energy preference for lipids. Skeletal muscle was therefore examined, as this is normally the major tissue involved in whole body lipid metabolism. Notably, p107-deficient muscle express increased levels of peroxisome proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) and contained increased numbers of the pro-oxidative type I and type IIa myofibers. Chromatin immunoprecipitation revealed binding of p107 and E2F4 to the PGC-1alpha proximal promoter, and this binding repressed promoter activity in transient transcription assays. Ectopic expression of p107 in muscle tissue in vivo results in a pronounced 20% decrease in the numbers of oxidative type IIa myofibers. Lastly, isolated p107-deficient muscle tissue display a threefold increase in lipid metabolism. Therefore, p107 determines the oxidative state of multiple tissues involved in whole body fat metabolism, including skeletal muscle.

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 (2 weeks) 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 (c) 2010 Elsevier B.V. All rights reserved.)

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)-[11C]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)-[11C]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)-[11C]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.

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.

Despite almost a decade of research since the identification of uncoupling protein-3 (UCP3), the molecular mechanisms and physiological functions of this mitochondrial anion carrier protein are not well understood. Because of its highly selective expression in skeletal muscle and the existence of mitochondrial proton leak in this tissue, early reports proposed that UCP3 caused a basal proton leak and increased thermogenesis. However, gene expression data and results from knockout and overexpression studies indicated that UCP3 does not cause basal proton leak or physiological thermogenesis. UCP3 expression is associated with increases in circulating fatty acids and in fatty acid oxidation (FAO) in muscle. Fatty acids are also well recognized as activators of the prototypic UCP1 in brown adipose tissue. This has led to hypotheses implicating UCP3 in mitochondrial fatty acid translocation. The corresponding hypothesized physiological roles include facilitated FAO and protection from the lipotoxic effects of fatty acids. Recent in vitro studies of physiological increases in UCP3 in muscle cells demonstrate increased FAO, and decreased reactive oxygen species (ROS) production. Detailed mechanistic studies indicate that ROS or lipid by-products of ROS can activate a UCP3-mediated proton leak, which in turn acts in a negative feedback loop to mitigate ROS production. Altogether, UCP3 appears to play roles in muscle FAO and mitigated ROS production. Future studies will need to elucidate the molecular mechanisms underlying increased FAO, as well as the physiological relevance of ROS-activated proton leak.

The Rb family, Rb, p107, and p130, play important roles in cell cycle control and cellular differentiation, and Rb has been suggested to regulate adipocyte differentiation. We report here that mice lacking p107 displayed a uniform replacement of white adipose tissue (WAT) with brown adipose tissue (BAT). Mutant WAT depots contained mutilocular adipocytes that expressed elevated levels of PGC-1alpha and UCP-1 typical of BAT. WAT from p107-/- mice contained markedly elevated numbers of adipogenic precursors that displayed downregulated expression of pRb. Consistent with the hypothesis that pRb is required for adult adipocyte differentiation, Cre-mediated deletion of Rb in adult primary preadipocytes blocked their differentiation into white adipocytes. Importantly, pRb was observed to bind the PGC-1alpha promoter and repress transcription. Therefore, p107 and pRb regulate PGC-1alpha expression to control the switch between white and brown adipocyte differentiation from a common pool of presumptive adult progenitors in fat tissue.

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 FBNF1 rats at 6 mo of age and continued for 12 or 18 mo. Mean whole body VO2 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 VO2 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 mV. Mitochondrial H2O2 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.

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 H(2)O(2) production. Six-month-old male FBNF(1) 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 H(2)O(2) 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 H(2)O(2) 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.

Reductions in cellular oxygen consumption (Vo2) 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 Vo2 in resting cells. We hypothesized that CR leads to decreased proton leak with consequential decreases in Vo2, 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 Vo2. Whole body Vo2 decreased with CR at all time points, whereas mass-adjusted Vo2 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 Vo2 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 (Deltap) and state 4 Vo2 and the latter to increases in Deltap and decreases in state 4 Vo2. Results from metabolic control analyses of oxidative phosphorylation are consistent with the idea that short- and medium-term responses are distinct. Mitochondrial H2O2 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 Vo2 and ROS production may be a mechanism for the actions of CR.

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, H2O2 production, lipid peroxidation, and protein carbonyls were measured in mitochondria from FBNF1 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. H2O2 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 H2O2 production at this age or stage of restriction in liver.