The Urgent Need for Disaster Education as a Core Competency in Accredited Schools and Colleges of Public Health by the Council on Education for Public Health.

Public Health is essential to disaster preparedness, mitigation, response, and recovery. This has never been more evident than during the COVID-19 pandemic when public health was the disaster response lead. However, students are graduating from accredited schools and colleges of public health with limited or no education in disaster management. This is a crisis unto itself, and it is incumbent upon The Council on Education for Public Health (CEPH) to take immediate action. Public health preparedness should be recognized as a core element in public health curricula, and practical experiences, such as drills and simulations, are necessary to equip students with the confidence and competencies needed in high-stress situations. The need for such preparedness education extends beyond the COVID-19 pandemic. It is a crucial step for creating a resilient and competent public health workforce capable of safeguarding community health in the face of complex and emerging challenges.

Variability in rod to bone distance needed in pelvic subcutaneous internal fixation to avoid nerve compression: A tridimensional population-based study.

INTRODUCTION: Pelvic internal fixation has become a popular method for treatment of unstable pelvic ring injuries. Although successful, one complication is femoral nerve palsy from compression of the connecting rod. In light of this complication, this study was designed to evaluate sagittal inclinations of the rod and the feasibility of using a rod with a constant curvature. HYPOTHESIS: It is hypothesized that that there is a connection between the sagittal inclination of the rod and the rod to bone distance, as well as single rod can be contoured with a constant curvature to be used in the majority of all patients. METHODS: Three dimensional models of pelvis CTs from a single level 1 trauma center were created and imported into a program where software superimposed a pre-contoured rod in the sagittal planes upon the pelvic slices. The sagittal inclination was deemed acceptable is no interference occurred between the area of compression risk and the rod. For each pelvis and considered sagittal rod inclination, the rod radius of curvature (ROC), minimal rod to bone distance (RTB) and transverse inclinations (φL and φR) were measured at which the pedicle screws should be inserted to follow the direction of the smallest RTB. RESULTS: The sagittal inclinations feasible for all subjects were between 15° to 30°. In this sagittal range, the average RTB varied in values ranging from 4.0±0.9mm to 25.4±11.4mm (p<0.01). Only 46% of subjects allowed a rod with constant curvature. DISCUSSION AND CONCLUSION: Our study found that a rod to bone distance of 15mm was not safe for all models. As well, many subject models did not allow placement of pre-contoured rod. Patient specific templating of pelvic subcutaneous internal fixation is strictly needed to limit complications. LEVEL OF EVIDENCE: VII; Basic Science.

Mentoring experience of new surgeons during their transition to independent practice: A nationwide survey.

BACKGROUND: New surgeons are faced with inadequate mentoring when first entering practice. Our study examined challenges faced by young surgeons during their transition in practice and their mentoring experience when entering practice. METHODS: An article-based survey was mailed in August 2019 to general, colorectal, vascular, and cardiothoracic surgeons that became members of the American College of Surgeons within the past 5 years. RESULTS: A total of 853 of 2,915 surveys were completed (29.3% response rate). Both female (38%) and male (62%) surgeons participated. The 3 most common challenges during the transition to practice were confidence building (26.0%), adjusting to a new institutional culture (16.9%), and business and administrative aspects of practice (16.3%). First job attrition rate 44.2%, with the mean duration of the first job being 3.28 ± 0.17 years. Nearly one-third (28.3%) of respondents were not mentored when they first entered practice. The proportion of nonmentored young surgeons leaving their first job (64.3%) was almost twice as that of surgeons who received mentoring (36.3%). Furthermore, the mean duration of the first job was significantly shorter in nonmentored versus mentored surgeons (3.16 ± 0.26 vs 3.76 ± 0.25 years; P < .05). A significant number (43.3%) of respondents reported a desire to be mentored by retired surgeons. CONCLUSION: Our survey highlights the importance of mentoring for young surgeons during their transition into practice. With many young surgeons being enthusiastic about mentoring by retired surgeons, specific programs are necessary to better use their expertise.

Retired Surgeons as Mentors for Surgical Training Graduates Entering Practice: An Underutilized Resource.

OBJECTIVE: Our study evaluated the willingness of retired surgeons to mentor newly trained surgeons. SUMMARY BACKGROUND DATA: Although mentoring is very important during the transition in practice, many novice surgeons are faced with inadequacy or lack of mentoring. METHODS: A survey regarding mentorship of new surgeons was sent in April 2018 to retired general, colorectal, vascular, and cardiothoracic surgeons that are members of the American College of Surgeons. The analysis of the data was performed in September 2018 and October 2018. RESULTS: A total of 2295 of 5282 surveys were completed (43.4% response rate). Mean age was 79.0 ±â€Š0.8 years, mean retirement age was 63.9 ±â€Š0.1 years, and mean interval since retirement was 15.2 ±â€Š0.9 years. Most retired surgeons were in private practice (66.4%), with other practice environments, including academic teaching hospital (12%), academic/private combination (11.3%), employment by community hospital or health system (6.4%), veteran affairs institution (2.7%), military hospital (1%), and Indian Health Service (0.09%). Approximately a third (31.1%) of respondents were not mentored when they first entered practice. The vast majority (98.3%) of participants considered mentoring beneficial during transition in practice. More than half (51.2%) of retired surgeons are interested in mentoring recently trained surgeons, with most of them (81.8%) willing to mentor even for free. CONCLUSION: Our findings suggest that a significant number of retired surgeons are enthusiastic about mentoring young surgeons during their transition in practice. Specific programs are necessary to meet the needs of newly hired surgeons and better utilize the expertise of retired surgeons.

Scattering-Based Light-Sheet Microscopy for Rapid Cellular Imaging of Fresh Tissue.

BACKGROUND AND OBJECTIVES: Light-sheet microscopy (LSM) is a novel imaging technology that has been used for imaging fluorescence contrast in basic life science research. In this paper, we have developed a scattering-based LSM (sLSM) for rapidly imaging the cellular morphology of fresh tissues without any exogenous fluorescent dyes. STUDY DESIGN/MATERIALS AND METHODS: In the sLSM device, a thin light sheet with the central wavelength of 834 nm was incident on the tissue obliquely, 45° relative to the tissue surface. The detection optics was configured to map the light sheet-illuminated area onto a two-dimensional imaging sensor. The illumination numerical aperture (NA) was set as 0.0625, and the detection NA 0.3. RESULTS: The sLSM device achieved a light sheet thickness of less than 6.7 µm over 284 µm along the illumination optical axis. The detection optics of the sLSM device had a resolution of 1.8 µm. The sLSM images of the swine kidney ex vivo visualized tubules with similar sizes and shapes to those observed in histopathologic images. The swine duodenum sLSM images revealed cell nuclei and villi architecture in superficial lesions and glands in deeper regions. CONCLUSIONS: The preliminary results suggest that sLSM may have the potential for rapidly examining the freshly-excised tissue ex vivo or intact tissue in vivo at microscopic resolution. Further optimization and performance evaluation of the sLSM technology will be needed in the future. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Mentorship of Surgical Interns: Are We Failing to Meet Their Needs?

OBJECTIVE: This study aimed to determine the challenges faced by surgical trainees during their internship and to explore their experience with mentoring. DESIGN: An internet-based survey comprised of 30 questions was distributed to 59 surgical interns to evaluate their internship experience at the conclusion of the academic year 2018 to 2019. SETTING: Four academic medical centers in Boston, Massachusetts. PARTICIPANTS: Both preliminary as well as categorical general surgery interns were included in the study. Twenty-five responses were received (response rate of 42.4%). RESULTS: The majority of surgical interns (80%) reported having a mentor during their intern year. Gender as well as mentor career status/prestige were both the highest rated factors in selection of a mentor, (4.67/5 and 4.33/5 respectively). Mentoring topics varied by the career status of the mentor, with most surgical interns (80%) selecting senior faculty members for mentoring on career planning, clinical training, and research. Surgical interns relied only on junior faculty members to discuss work-life integration. Very few surveyed interns (only 1 in 10) discussed work-life integration with their mentors despite this being reported as the most significant challenge of their internship year. Only 15% of the interns reported that the effectiveness of the mentor-mentee relationship was reviewed by program administration. About one third (30%) of interns reported that they would not feel comfortable reporting a failed mentorship to their program director. Furthermore, 40% of the surgical interns were not given an option to choose a new mentor in case of failed mentoring. CONCLUSIONS: Surgical interns report high work demands and challenges with worklife integration in their first year of surgical training, however only a small minority of interns discuss this with their mentors. Surgical residency programs should better supervise and adjust mentoring of surgical interns in order to maximize their performance and wellness.

Smartphone epifluorescence microscopy for cellular imaging of fresh tissue in low-resource settings.

Disease diagnosis in low-resource settings can be challenging due to the lack of equipment and trained personnel required for histologic analysis. In this paper, we have developed a smartphone-based epifluorescence microscope (SeFM) for imaging fresh tissues at sub-cellular resolution. SeFM provides similar resolution and field of view (FOV) as those used during histologic analysis. The SeFM device achieved the lateral resolution of 0.57 µm and provided microscopy images over a sample area larger than 500 µm. The material cost was low, approximately $3,000. Preliminary images of human pancreatic tumor specimens clearly visualized cellular details. Quantitative analysis showed that using an excess dose of a chemotherapy drug significantly reduced the tumor-specific fluorescence signal, confirming the specificity of the drug and the detection potential of SeFM.

Implementation of an Intraoperative Instructional Timeout Just Prior to Stapler Use Improves Proficiency of Surgical Stapler Usage by Surgery Residents.

INTRODUCTION: With the fragmented rotational structure of training, exposure to surgical staplers is not uniform across surgical residents. Traditionally, educational sessions dedicated to instruction in surgical staplers have taken place outside the operating room. This study implemented and evaluated an intraoperative timeout immediately prior to stapler use in cases with surgical residents. METHODS: During general surgery cases from June 1, 2017 until December 31, 2017, surgical teams, including the surgical attending, surgical resident, and scrub nurse participated in an intraoperative instructional timeout, during which proper use of linear or circular staplers was reviewed. At the conclusion of the timeout, residents were required to demonstrate proper stapler assembly and verbalize all technical steps involved in stapler use. Duration of each timeout was recorded. Immediately following the case, a pre-post survey was administered to each participating junior (R1-R2) or senior (R4-R5) surgical resident. The primary outcome was change in stapler use knowledge by surgical residents. Survey questions with Likert scale responses were analyzed using paired ttests, and responses from junior residents were compared to those from senior residents with independent t tests. RESULTS: Forty-three general surgery cases involved stapler use during the study period and implemented an intraoperative instructional timeout. The educational intervention increased stapler use knowledge significantly in all surgical residents. Prior to the timeout, junior residents reported significantly higher anxiety related to stapler usage compared to their senior counterparts; anxiety scores in junior residents decreased significantly for use of both linear and circular staplers. The mean timeout duration was 2.9 minutes (standard deviation 0.9 minutes, range 1.2-4.6 minutes). All participating surgical residents recommended routine implementation of an instructional timeout prior to intraoperative stapler use. CONCLUSIONS: An intraoperative timeout dedicated to stapler teaching is effective in increasing proficiency and easing anxiety in all levels of surgical residents. Further research is warranted to determine whether this educational intervention would translate into fewer stapler use errors and decreased intraoperative complications.

Playing the Surgical Technologist Role by Surgery Residents Improves Their Technical and Nontechnical Skills.

BACKGROUND: The present study was designed to implement and evaluate an interprofessional surgical technologist-to-surgical resident training program for junior general surgery residents aimed at enhancing their operating room skills. This program would be incorporated into the general surgery educational curriculum. MATERIAL AND METHODS: Under the guidance and supervision of a surgical technologist, first-year and second-year general surgery residents performed the perioperative and intraoperative tasks that are the responsibilities of the surgical technologist for 16 inguinal/umbilical hernia and 15 laparoscopic appendectomy/cholecystectomy operations performed by attending surgeons assisted by other surgical residents from June 01, 2017 until December 31, 2017. A pretraining and post-training survey comprised 25 ranked questions (using a four-point Likert scale), and four Yes/No questions were administered to volunteer general surgery residents. RESULTS: Paired t-test analysis showed that playing the role of the surgical technologist by the junior surgery residents significantly improved (P < 0.0001) their assessment of operating room technical skills (knowledge and skills to prepare for the case and maintain a sterile field, understanding of the operative steps, knowledge of surgical instruments and their handling) as well as their nontechnical skills (situational awareness, understanding the importance of collaboration, teamwork, and communication). The answers to the binary Yes/No questions showed that all participating residents expect to use the experience gained from this training, would recommend this training session to a colleague, and support including this training session in their educational curriculum. CONCLUSIONS: The findings of this study suggest a significant educational benefit of incorporating interprofessional, surgical technologist-to-surgical resident training into the educational curriculum of the junior general surgery residents.

The Infectious Disease Network (IDN): Development and Use for Evaluation of Potential Ebola Cases in Georgia.

In response to the 2014 Ebola virus disease (EVD) outbreak in West Africa, the Georgia Department of Public Health developed the Infectious Disease Network (IDN) based on an EVD preparedness needs assessment of hospitals and Emergency Medical Services (EMS) providers. The network consists of 12 hospitals and 16 EMS providers with staff specially trained to provide a coordinated response and utilize appropriate personal protective equipment (PPE) for the transport or treatment of a suspected or confirmed serious communicable disease patient. To become a part of the network, each hospital and EMS provider had to demonstrate EVD capabilities in areas such as infection control, PPE, waste management, staffing and ongoing training, and patient transport and placement. To establish the network, the Georgia Department of Public Health provided training and equipment for EMS personnel, evaluated hospitals for EVD capabilities, structured communication flow, and defined responsibilities among partners. Since March 2015, the IDN has been used to transport, treat, and/or evaluate suspected or confirmed serious communicable disease cases while ensuring health care worker safety. Integrated infectious disease response systems among hospitals and EMS providers are critical to ensuring health care worker safety, and preventing or mitigating a serious communicable disease outbreak. (Disaster Med Public Health Preparedness. 2018;12:765-771).

mTORC1-S6K1 inhibition or mTORC2 activation improves hippocampal synaptic plasticity and learning in Angelman syndrome mice.

Emerging evidence is implicating abnormal activation of the mechanistic target of rapamycin (mTOR) pathway in several monogenetic neuropsychiatric disorders, including Angelman syndrome (AS), which is caused by deficiency in maternally inherited UBE3A. Using an AS mouse model, we show that semi-chronic rapamycin treatment improves long-term potentiation (LTP) and actin polymerization in hippocampal slices, spine morphology, and fear-conditioning learning. Activity of mTORC1 and of its downstream substrate, S6K1, was increased in hippocampus of AS mice. However, mTORC2 activity, as reflected by PKCα levels, was decreased. Both increased mTORC1 and decreased mTORC2 activities were reversed by semi-chronic rapamycin treatment. Acute treatment of hippocampal slices from AS mice with rapamycin or an S6K1 inhibitor, PF4708671, improved LTP, restored actin polymerization, and normalized mTORC1 and mTORC2 activity. These treatments also reduced Arc levels in AS mice. Treatment with Torin 1, an inhibitor of both mTORC1 and mTORC2, partially rescued LTP and actin polymerization in hippocampal slices from AS mice, while partially impairing them in wild-type (WT) mice. Torin 1 decreased mTORC1 and increased mTORC2 activity in slices from AS mice but inhibited both mTORC1 and mTORC2 in WT mice. Finally, an mTORC2 activator, A-443654, increased hippocampal LTP in AS mice and actin polymerization in both WT and AS mice. Collectively, these results indicate that events set in motion by increased mTORC1 and decreased mTORC2 activities, including increased Arc translation and impaired actin remodeling, are crucial in AS pathogenesis. Therefore, selectively targeting these two master kinase complexes may provide new therapeutic approaches for AS treatment.

Antimicrobial Formulation and Delivery in the Prevention of Surgical Site Infection.

BACKGROUND: A number of adjunct antimicrobial measures have been studied in an attempt to reduce surgical site infection (SSI) rates. In addition to parenteral antibiotic prophylaxis, these measures include oral antibiotics in bowel preparation for colorectal surgery, antiseptic/antimicrobial irrigation, antimicrobial sutures, local antibiotics, skin incision antibacterial sealants, and antimicrobial dressings. It is the purpose of this review to study the evidence behind each of these measures and to evaluate relevant data for recommendations in each area. METHODS: A systematic review of the literature through PubMed was performed. RESULTS: Need for adequate dosing and re-dosing of intravenous peri-operative antibiotics, duration of antibiotic usage past wound closure, and the use of antibiotic bowel preparation in colorectal surgery are well defined in the published literature. However, data on local antimicrobial measures remain controversial. CONCLUSIONS: Proper dosing and re-dosing of prophylactic intravenous antibiotics should become standard practice. Continuation of intravenous antibiotic prophylaxis beyond wound closure is unnecessary in clean cases and remains controversial in clean-contaminated and complex cases. Oral antibiotic bowel preparation is an important adjunct to intravenous antibiotic prophylaxis in colorectal surgery. The use of topical antimicrobial and antiseptic agents such as antibacterial irrigations, local antimicrobial application, antimicrobial-coated sutures, antibacterial wound sealants, and antimicrobial impregnated dressings in the prevention of SSI is questionable.

Academic-community partnerships for sustainable preparedness and response systems.

Academic institutions possess tremendous resources that could be important for community disaster response and preparedness activities. In-depth exploration of the role of academic institutions in community disaster response has elicited information about particular academic resources leveraged for and essential to community preparedness and response; factors that contribute to the decision-making process for partner engagement; and facilitators of and barriers to sustainable collaborations from the perspectives of academic institutions, public health and emergency management agencies, and national association and agency leaders. The Academic-Community Partnership Project of the Emory University Preparedness and Emergency Response Research Center in collaboration with the Association of Schools of Public Health convened an invitational summit which included leadership from the National Association of County and City Health Officials, Association of State and Territorial Health Officials, Directors of Public Health Preparedness, Department of Health and Human Services Office of the Assistant Secretary for Preparedness and Response, CDC Office of Public Health Preparedness and Response, Association of Schools of Public Health, Association of American Medical Colleges, Association of Academic Health Centers, American Association of Colleges of Nursing, Council of State and Territorial Epidemiologists, and American Association of Poison Control Centers. From this convention, emerged recommendations for building and sustaining academic-public health-community collaborations for preparedness locally and regionally.

Bronchogenic cyst masquerading as an adrenal tumor: a case of mistaken identity.

OBJECTIVE: To describe a patient with a bronchogenic cyst that was erroneously diagnosed as an adrenal tumor and the surgical management strategy to address the operative challenges. METHODS: We summarize the clinical presentation, diagnostic workup, surgical management, and pathologic features of the study patient and review the pertinent literature. RESULTS: In this report, we present the case of a 23-year-old woman who underwent retroperitoneoscopic exploration after imaging identified an enlarging left adrenal lesion. Preoperative biochemical testing confirmed that the mass was nonfunctional. No lesion was found after a thorough retroperitoneoscopic exploration under standard high insufflation pressure. Serendipitously, low-pressure inspection for hemostasis after failed exploration enabled discovery of an intradiaphragmatic mass that proved to be a bronchogenic cyst rather than an adrenal tumor. Not only was this a difficult operative dilemma, but it was also an unusual presentation for this tumor. CONCLUSIONS: Discovery of a retroperitoneal or intradiaphragmatic bronchogenic cyst is a rare occurrence. The unusual location and tumor characteristics contributed to near surgical failure. The fortuitous surgical strategy of low-pressure inspection allowed visualization of the tumor for definitive resection.

Hemorrhagic shock as the initial manifestation of pheochromocytoma: report of a sequential management strategy.

OBJECTIVE: To describe a patient presenting with hemorrhagic shock attributable to bleeding pheochromocytomas and the sequential management strategy used for treating this patient. METHODS: We summarize the clinical presentation, diagnostic work-up, surgical management, and pathologic features of our patient and review the pertinent literature. RESULTS: A 38-year-old man with multiple endocrine neoplasia type 2A and bilateral pheochromocytomas presented initially with nearly fatal retroperitoneal and intraperitoneal hemorrhage rather than the characteristic hypertensive paroxysms. After lifesaving operative intervention and a 5-month period of rehabilitation and convalescence, the patient underwent bilateral retroperitoneoscopic adrenalectomy as definitive treatment. Thus, the abdomen that had been operated on multiple times because of hemorrhage was left undisturbed, and the patient had a successful recovery. CONCLUSION: Near-fatal intraperitoneal hemorrhage is a very rare initial manifestation of pheochromocytoma. Our current patient with bilateral pheochromocytomas presented in this dramatic manner. This case shows that a sequential management strategy of damage-control surgical treatment followed by future resection of the tumors after appropriate a-adrenergic blockade is a safe and effective therapeutic option.

Large parathyroid tumors have an increased risk of atypia and carcinoma.

BACKGROUND: Risk for atypia and carcinoma in large parathyroid tumors is not known. Atypia and carcinoma were determined in small (<2 g) and large (≥2 g) tumors in patients undergoing parathyroidectomy for primary hyperparathyroidism. METHODS: The study was a retrospective analysis of a 5-year prospective database. Tumor weight, histopathology, age, gender, calcium, and parathyroid hormone levels were registered. Patients with 4-gland disease were not included. RESULTS: Among 353 parathyroid tumors, 313 weighed <2 g and 40 weighed ≥2 g. There was no difference in age between groups. Patients with large tumors were more frequently men and had higher calcium and parathyroid hormone levels. Atypia was found in 4 of 313 (1.3%) and 7 of 40 (17.5%) small and large tumors, respectively (P < .05). Corresponding figures for carcinoma were 1 of 313 (.3%) and 2 of 40 (5.0%) (P < .05). CONCLUSIONS: Large parathyroid tumors have increased risk for atypia and carcinoma. Even so, most large parathyroid tumors are benign.

Sepsis and glucocorticoids downregulate the expression of the nuclear cofactor PGC-1beta in skeletal muscle.

Muscle wasting during sepsis is at least in part regulated by glucocorticoids and is associated with increased transcription of genes encoding the ubiquitin ligases atrogin-1 and muscle-specific RING-finger protein-1 (MuRF1). Recent studies suggest that muscle atrophy caused by denervation is associated with reduced expression of the nuclear cofactor peroxisome proliferator-activated receptor-γ coactivator (PGC)-1ß and that PGC-1ß may be a repressor of the atrogin-1 and MuRF1 genes. The influence of other muscle-wasting conditions on the expression of PGC-1ß is not known. We tested the influence of sepsis and glucocorticoids on PGC-1ß and examined the potential link between downregulated PGC-1ß expression and upregulated atrogin-1 and MuRF1 expression in skeletal muscle. Sepsis in rats and mice and treatment with dexamethasone resulted in downregulated expression of PGC-1ß and increased expression of atrogin-1 and MuRF1 in the fast-twitch extensor digitorum longus muscle, with less pronounced changes in the slow-twitch soleus muscle. In additional experiments, adenoviral gene transfer of PGC-1ß into cultured C2C12 myotubes resulted in a dose-dependent decrease in atrogin-1 and MuRF1 mRNA levels. Treatment of cultured C2C12 myotubes with dexamethasone or PGC-1ß small interfering RNA (siRNA) resulted in downregulated PGC-1ß expression and increased protein degradation. Taken together, our results suggest that sepsis- and glucocorticoid-induced muscle wasting may, at least in part, be regulated by decreased expression of the nuclear cofactor PGC-1ß.

Sepsis increases the expression and activity of the transcription factor Forkhead Box O 1 (FOXO1) in skeletal muscle by a glucocorticoid-dependent mechanism.

Sepsis-induced muscle wasting has severe clinical consequences, including muscle weakness, need for prolonged ventilatory support and stay in the intensive care unit, and delayed ambulation with risk for pulmonary and thromboembolic complications. Understanding molecular mechanisms regulating loss of muscle mass in septic patients therefore has significant clinical implications. Forkhead Box O (FOXO) transcription factors have been implicated in muscle wasting, partly reflecting upregulation of the ubiquitin ligases atrogin-1 and MuRF1. The influence of sepsis on FOXO transcription factors in skeletal muscle is poorly understood. We tested the hypothesis that sepsis upregulates expression and activity of FOXO transcription factors in skeletal muscle by a glucocorticoid-dependent mechanism. Sepsis in rats increased muscle FOXO1 and 3a mRNA and protein levels but did not influence FOXO4 expression. Nuclear FOXO1 levels and DNA binding activity were increased in septic muscle whereas FOXO3a nuclear levels were not increased during sepsis. Sepsis-induced expression of FOXO1 was reduced by the glucocorticoid receptor antagonist RU38486 and treatment of rats with dexamethasone increased FOXO1 mRNA levels suggesting that the expression of FOXO1 is regulated by glucocorticoids. Reducing FOXO1, but not FOXO3a, expression by siRNA in cultured L6 myotubes inhibited dexamethasone-induced atrogin-1 and MuRF1 expression, further supporting a role of FOXO1 in glucocorticoid-regulated muscle wasting. Results suggest that sepsis increases FOXO1 expression and activity in skeletal muscle by a glucocorticoid-dependent mechanism and that glucocorticoid-dependent upregulation of atrogin-1 and MuRF1 in skeletal muscle is regulated by FOXO1. The study is significant because it provides novel information about molecular mechanisms involved in sepsis-induced muscle wasting.

Experimental hyperthyroidism in rats increases the expression of the ubiquitin ligases atrogin-1 and MuRF1 and stimulates multiple proteolytic pathways in skeletal muscle.

Muscle wasting is commonly seen in patients with hyperthyroidism and is mainly caused by stimulated muscle proteolysis. Loss of muscle mass in several catabolic conditions is associated with increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF1 but it is not known if atrogin-1 and MuRF1 are upregulated in hyperthyroidism. In addition, it is not known if thyroid hormone increases the activity of proteolytic mechanisms other than the ubiquitin-proteasome pathway. We tested the hypotheses that experimental hyperthyroidism in rats, induced by daily intraperitoneal injections of 100 microg/100 g body weight of triiodothyronine (T3), upregulates the expression of atrogin-1 and MuRF1 in skeletal muscle and stimulates lysosomal, including cathepsin L, calpain-, and caspase-3-dependent protein breakdown in addition to proteasome-dependent protein breakdown. Treatment of rats with T3 for 3 days resulted in an approximately twofold increase in atrogin-1 and MuRF1 mRNA levels. The same treatment increased proteasome-, cathepsin L-, and calpain-dependent proteolytic rates by approximately 40% but did not influence caspase-3-dependent proteolysis. The expression of atrogin-1 and MuRF1 remained elevated during a more prolonged period (7 days) of T3 treatment. The results provide support for a role of the ubiquitin-proteasome pathway in muscle wasting during hyperthyroidism and suggest that other proteolytic pathways as well may be activated in the hyperthyroid state.