Recalcitrant Lateral Epicondylitis: A Systematic Review on Current Nonoperative and Operative Treatment Modalities.

BACKGROUND: Lateral epicondylitis is a common cause of elbow pain that is generally self-limiting. For patients who have persistent symptoms refractory to conservative treatment, there is still no clear consensus on the most favorable treatment modality. The purpose of this systematic review was to synthesize the available literature regarding both nonoperative and operative treatment modalities for recalcitrant lateral epicondylitis (RLE) to provide insight into the efficacy of treatment options. METHODS: A systematic review was performed in accordance with the 2020 Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines, where the PubMed, MEDLINE/Ovid, CINAHL, Cochrane, and Scopus databases were queried to identify studies evaluating treatment options for RLE. RESULTS: A total of 27 studies with 1,958 patients were included. Of the reviewed studies, there were a wide variety of treatments including platelet-rich plasma injections, percutaneous tenotomies, and various arthroscopic and open procedures. CONCLUSION: There are a wide variety of treatment modalities available for RLE that have promising efficacy in the short, medium, and long terms. A comprehensive approach combining evidence-based and patient-centered care is critical for effective management of refractory symptoms. LEVEL OF EVIDENCE: Level IV. See Instructions for Authors for a complete description of levels of evidence.

IFNγ-IL12 axis regulates intercellular crosstalk in metabolic dysfunction-associated steatotic liver disease.

Obesity is a major cause of metabolic dysfunction-associated steatohepatitis (MASH) and is characterized by inflammation and insulin resistance. Interferon-γ (IFNγ) is a pro-inflammatory cytokine elevated in obesity and modulating macrophage functions. Here, we show that male mice with loss of IFNγ signaling in myeloid cells (Lyz-IFNγR2-/-) are protected from diet-induced insulin resistance despite fatty liver. Obesity-mediated liver inflammation is also attenuated with reduced interleukin (IL)-12, a cytokine primarily released by macrophages, and IL-12 treatment in vivo causes insulin resistance by impairing hepatic insulin signaling. Following MASH diets, Lyz-IFNγR2-/- mice are rescued from developing liver fibrosis, which is associated with reduced fibroblast growth factor (FGF) 21 levels. These results indicate critical roles for IFNγ signaling in macrophages and their release of IL-12 in modulating obesity-mediated insulin resistance and fatty liver progression to MASH. In this work, we identify the IFNγ-IL12 axis in regulating intercellular crosstalk in the liver and as potential therapeutic targets to treat MASH.

Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition.

Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition. Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.

Outcomes After Single-Stage Anatomic Multiligament Knee Reconstruction With Early Range of Motion in Adolescents.

Background: Multiligament knee injuries (MLKI), rare in adolescents, are challenging injuries that require complex surgical reconstruction. Historically, nonanatomic reconstructions have been associated with prolonged immobilization and failure to restore normal knee biomechanics, resulting in arthrofibrosis and high rates of graft failure. Purpose: To describe the clinical and patient-reported outcomes (PROs) for adolescent patients treated with single-stage anatomic multiligament knee reconstruction. Study Design: Case series; Level of evidence, 4. Methods: A single-center retrospective study was performed of patients ≤18 years old who underwent reconstruction of MLKIs by a single surgeon between 2014 and 2019 using a single-stage anatomic technique, with protected weightbearing and early range of motion. Complications were defined as infection, arthrofibrosis, deep vein thrombosis (DVT) or pulmonary embolus, and secondary surgery. PROs, including the pediatric version of the International Knee Documentation Committee (Pedi-IKDC) and the Tegner activity score, were obtained at a minimum of 2 years postoperatively. Results: Included were 30 patients (21 male, 9 female; mean age, 15.4 years). The most common ligamentous reconstruction types were anterior cruciate ligament (ACL) + fibular collateral ligament (12 patients; 40%) and ACL + medial collateral ligament (9 patients; 30%). Three patients (10%) had secondary surgeries, including irrigation and debridement of a granuloma, a staged osteochondral allograft transplantation to a lateral femoral condyle impaction fracture, and repair of a medial meniscal tear and lateral femoral condyle fracture associated with new injuries 2 years after ACL + fibular collateral ligament reconstruction. Two patients (7%) developed arthrofibrosis and 1 patient (3%) developed DVT. PRO scores obtained at a mean of 37 months postoperatively included a mean Pedi-IKDC of 87 (range, 52-92) and a median highest Tegner score at any point postoperatively of 9 (range, 5-10). Of the patients who were athletes before their injury, 70% returned to the same or higher level of sport postoperatively. Conclusion: Reconstruction of MLKI in this series of adolescents with single-stage anatomic techniques and early range of motion resulted in low rates of secondary surgery, few complications, and good knee function as well as PRO scores at mean 3-year follow-up.

Quality and Reliability Analysis of YouTube as a Source for Patient Education on Dupuytren's Contracture.

Purpose: This study seeks to assess the quality and reliability of YouTube videos on Dupuytren's contracture. Methods: The first 50 unique videos on Dupuytren's contracture were evaluated by searching YouTube for Dupuytren's contracture. Video metrics, source, and content type were recorded. Video reliability was assessed using the Journal of American Medical Association (JAMA) Benchmark criteria. Video educational quality was assessed using the Global Quality Score (GQS) and a Dupuytren's Contracture-Specific Score (DC-SS). Results: The total number of views for all 50 videos evaluated was 1,908,608 (mean, 38,172.16 ± 5,502.45 views). The mean reliability (JAMA) score was 2.21 ± 0.69 (range 0-4), the mean educational quality (GQS) score was 2.80 ± 1.28 (range 1-5), and the mean disease-specific (DC-SS) score was 6.05 ± 2.17 (range 0-15). Nonphysician health care professionals had the most popular videos, but the lowest DC-SS. GQS varied based on the video source, with physician-uploaded videos having the highest average quality scores. Physician source was an independent positive predictor of higher quality (GQS) (ß = 0.477). Conclusions: Videos on Dupuytren's contracture were frequently viewed on YouTube but had overall low educational quality and reliability. Of the videos that discussed collagenase as a treatment option, 40% failed to mention percutaneous needle aponeurotomy. Patients may be exposed to an incomplete set of treatment options. Educational content on YouTube should be interpreted cautiously and proper in-office education and high-quality resources for Dupuytren's contracture should be provided by physicians. Type of Study/Level of Evidence: Therapeutic IV.

Fluid intake behavior in women with refractory overactive bladder undergoing third line therapy.

INTRODUCTION AND OBJECTIVES: Fluid intake has been shown to be related to urinary symptoms, but no studies to date have investigated the effect of fluid intake on urinary symptoms in women with refractory overactive bladder (OAB). As this group of women are considered to have a possible unique pathophysiologic mechanism of OAB, we investigated the relationship between fluid intake, fluid intake behavior, and urinary symptoms in women with refractory OAB. METHODS: A prospective cross-sectional study of women with refractory OAB was conducted by assessing the relationship between fluid intake and lower urinary tract symptoms (LUTS) in women undergoing third line OAB therapies. Fluid intake and behavior were measured by the questionnaire based voiding diary and urinary symptoms were measured by the International Consultation on Incontinence Questionnaire for Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). The relationship between fluid intake and symptom severity was assessed using Spearman's rank correlation and χ2  tests. RESULTS: Of the 126 individuals undergoing third line therapy for OAB, 60 (48%) underwent intradetrusor onabotulinumtoxinA injection (BTX) injection, 42 (33%) peripheral tibial nerve stimulation, and 24 (19%) sacral neuromodulation. The mean total daily fluid intake was 2567.0 ± SD 1292.4 mL and did not differ significantly across treatment groups. Total fluid intake was weakly correlated with worse filling-type LUTS (r = 0.241, p = 0.007), and there was no relationship between LUTS and caffeinated fluid intake. Half (52%) of the subjects reported current fluid restricting behavior to control urinary symptoms, but this behavior was not correlated with LUTS severity (all p > 0.05). Patients that currently use tobacco have greater LUTS (current = 25.8 ± SD 9.5, former = 14.8 ± SD 6.1, never = 15.0 ± SD 6.1; p < 0.001). BMI was also positively correlated with worse incontinence symptoms (r = 0.351, p < 0.001). CONCLUSIONS: Fluid intake along with other lifestyle factors, including tobacco use and weight, are minimally related to the symptomatology seen in women with refractory OAB. Further studies are needed to assess if behaviors change during treatment with third line therapies, and if these behavioral changes may affect treatment response.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 1: Epidemiology, Early Development, and Cohorts From Around the World.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation, in partnership with the Hospital for Special Surgery, convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations and clinical research gaps gleaned from 5 presentations given in the "how hip osteoarthritis begins" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 4: Nonoperative Options, Machine Learning in Predicting Total Hip Arthroplasty, Robotics, and Phenotyping to Guide Precision Rehabilitation.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation (AF), in partnership with the Hospital for Special Surgery (HSS), convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations gleaned from presentations given in the "late-stage osteoarthritis" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City. It covers conservative treatment, decision-making in end-stage hip osteoarthritis, advancements in robotics, and the role of phenotyping in precision rehabilitation post-total hip arthroplasty (THA).

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 2: Detecting Hips at Risk: Early Biomechanical and Structural Mechanisms.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation (AF), in partnership with the Hospital for Special Surgery (HSS), convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations gleaned from 5 presentations given in the "early hip osteoarthritis" session of the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City. It also summarizes the workgroup recommendations from a small-group discussion on clinical research gaps.

Arthritis Foundation/HSS Workshop on Hip Osteoarthritis, Part 3: Rehabilitation and Exercise.

Far more publications are available for osteoarthritis of the knee than of the hip. Recognizing this research gap, the Arthritis Foundation (AF), in partnership with the Hospital for Special Surgery (HSS), convened an in-person meeting of thought leaders to review the state of the science of and clinical approaches to hip osteoarthritis. This article summarizes the recommendations gleaned from 5 presentations given on hip-related rehabilitation at the 2023 Hip Osteoarthritis Clinical Studies Conference, which took place on February 17 and 18, 2023, in New York City.

Rare vascular complication of ESWL pseudoaneurysm of arc of Buhler.

Extracorporeal shock wave lithotripsy (ESWL) is a standard treatment for nephrolithiasis. It is widely employed due to its relative safety profile when compared with other treatment options. Recognised complications include localised pain at site, steinstrasse, perinephric haematoma and ureteric obstruction. This report presents a rare non-documented complication of ESWL, pseudoaneurysm of the arc of Buhler, a branch artery of the superior mesenteric artery.

Crosstalk between corepressor NRIP1 and cAMP signaling on adipocyte thermogenic programming.

OBJECTIVES: Nuclear receptor interacting protein 1 (NRIP1) suppresses energy expenditure via repression of nuclear receptors, and its depletion markedly elevates uncoupled respiration in mouse and human adipocytes. We tested whether NRIP1 deficient adipocytes implanted into obese mice would enhance whole body metabolism. Since ß-adrenergic signaling through cAMP strongly promotes adipocyte thermogenesis, we tested whether the effects of NRIP1 knock-out (NRIP1KO) require the cAMP pathway. METHODS: NRIP1KO adipocytes were implanted in recipient high-fat diet (HFD) fed mice and metabolic cage studies conducted. The Nrip1 gene was disrupted by CRISPR in primary preadipocytes isolated from control vs adipose selective GsαKO (cAdGsαKO) mice prior to differentiation to adipocytes. Protein kinase A inhibitor was also used. RESULTS: Implanting NRIP1KO adipocytes into HFD fed mice enhanced whole-body glucose tolerance by increasing insulin sensitivity, reducing adiposity, and enhancing energy expenditure in the recipients. NRIP1 depletion in both control and GsαKO adipocytes was equally effective in upregulating uncoupling protein 1 (UCP1) and adipocyte beiging, while ß-adrenergic signaling by CL 316,243 was abolished in GsαKO adipocytes. Combining NRIP1KO with CL 316,243 treatment synergistically increased Ucp1 gene expression and increased the adipocyte subpopulation responsive to beiging. Estrogen-related receptor α (ERRα) was dispensable for UCP1 upregulation by NRIPKO. CONCLUSIONS: The thermogenic effect of NRIP1 depletion in adipocytes causes systemic enhancement of energy expenditure when such adipocytes are implanted into obese mice. Furthermore, NRIP1KO acts independently but cooperatively with the cAMP pathway in mediating its effect on adipocyte beiging.

Opioid Use in Pediatric Patients After Common Orthopaedic Surgeries.

BACKGROUND: The use and misuse of opioid medications is an epidemic and public health emergency. There are currently no standard guidelines for treating perioperative pain in the pediatric population. The purpose of this study is to describe opioid use among pediatric patients after common orthopaedic surgeries. METHODS: Patients between 5 and 20 years of age undergoing one of 7 common orthopaedic surgeries between the years 2018 to 2020 were prospectively studied. Patients and their families completed a medication logbook to track all doses of pain medication and associated pain scores. RESULTS: Three hundred forty-two patients completed the study, including 174 females and 168 males with a mean age of 14.0 years (range, 5 to 20 y). A total of 4351 tablets or liquid doses of the narcotic medication, 44% of the total prescribed, were consumed. Of the prescribed medication,56% remained unused. Nonsteroidal anti-inflammatory drug use was identified to be the only independent predictor of less narcotic use, with a mean of 5.1 tablets ( P = 0.003) and 1.7 days ( P < 0.01) less opioid consumed among these patients. Thirty-two (9.4%) patients consumed 100% of their prescriptions. Nonmedicinal methods of pain control, most commonly ice, were used by 77% of patients, and this was highly variable between procedures. Physicians were cited as a source of medication information by only 50% of patients, with high variability between procedures. CONCLUSIONS: Opioid medication use in children and adolescents after orthopaedic surgery is significantly less than the number of tablets prescribed, with 56% of the medication prescribed remaining unused in the postoperative period. Duration of narcotic use was longer than anticipated with a wide SD (4.7 d +/-3 d).We recommend orthopaedic surgeons responsibly prescribe pain medications using evidence-based data or the results of their own experience monitoring medication consumption. In addition, and important in the setting of the "opioid epidemic," physicians must counsel patients and families on postoperative pain expectations and appropriate medication use. LEVEL OF EVIDENCE: Level IV, prospective case series.

Peroneal Nerve Repair with Cross-Bridge Ladder Technique: Parallel End-to-Side Neurorrhaphies.

Background Multiple nerve transfer techniques are used to treat patients with nerve injuries when a primary repair is not possible. These techniques are categorized to end-to-end, end-to-side, and side-to-side neurorrhaphy. Our study aims to explore the utility of the cross-bridge ladder technique (H-shaped), which has shown promising results in animal models and probably underutilized clinically. Methods Four patients with significant loss of ankle dorsiflexion were seen in the clinic and underwent evaluation, including electrodiagnostic studies. A cross-bridge ladder repair technique was used between the tibial nerve as the donor and the common peroneal nerve as the recipient via one or two nerve grafts coapted in parallel with end-to-side neurorrhaphies. Dorsiflexion strength was measured preoperatively using the Medical Research Council (MRC) grading system and at each postoperative follow-up appointment. Results All four patients had suffered persistent and severe foot drop (MRC of 0) following trauma that had occurred between 6 and 15 months preoperatively. Three of the four patients improved to an MRC of 2 several months postoperatively. The last patient had an immediate improvement to an MRC of 2 by his first month and had a complete recovery of ankle dorsiflexion within 4 months from surgery. Conclusion We demonstrate the utility and clinical outcomes of the cross-bridge ladder technique in patients with persistent and prolonged foot drop following trauma. Both early and late recovery were seen while all patients regained motor function, with some patients continuing to improve up to the most recent follow-up. IRB Approval: Obtained 2013-1411-CP005.

Targeting Echinococcus multilocularis PIM kinase for improving anti-parasitic chemotherapy.

BACKGROUND: The potentially lethal zoonosis alveolar echinococcosis (AE) is caused by the metacestode larval stage of the tapeworm Echinococcus multilocularis. Current AE treatment options are limited and rely on surgery as well as on chemotherapy involving benzimidazoles (BZ). BZ treatment, however, is mostly parasitostatic only, must be given for prolonged time periods, and is associated with adverse side effects. Novel treatment options are thus urgently needed. METHODOLOGY/PRINCIPAL FINDINGS: By applying a broad range of kinase inhibitors to E. multilocularis stem cell cultures we identified the proto-oncogene PIM kinase as a promising target for anti-AE chemotherapy. The gene encoding the respective E. multilocularis ortholog, EmPim, was characterized and in situ hybridization assays indicated its expression in parasite stem cells. By yeast two-hybrid assays we demonstrate interaction of EmPim with E. multilocularis CDC25, indicating an involvement of EmPim in parasite cell cycle regulation. Small molecule compounds SGI-1776 and CX-6258, originally found to effectively inhibit human PIM kinases, exhibited detrimental effects on in vitro cultured parasite metacestode vesicles and prevented the formation of mature vesicles from parasite stem cell cultures. To improve compound specificity for EmPim, we applied a high throughput in silico modelling approach, leading to the identification of compound Z196138710. When applied to in vitro cultured metacestode vesicles and parasite cell cultures, Z196138710 proved equally detrimental as SGI-1776 and CX-6258 but displayed significantly reduced toxicity towards human HEK293T and HepG2 cells. CONCLUSIONS/SIGNIFICANCE: Repurposing of kinase inhibitors initially designed to affect mammalian kinases for helminth disease treatment is often hampered by adverse side effects of respective compounds on human cells. Here we demonstrate the utility of high throughput in silico approaches to design small molecule compounds of higher specificity for parasite cells. We propose EmPim as a promising target for respective approaches towards AE treatment.

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.

Candida Shunt Infection Causing Arachnoiditis and Hydrocephalus: A Case Report.

Arachnoiditis is a relatively rare condition and can result in long-term chronic and debilitating complications if not diagnosed early and treated properly. However, diagnosis of arachnoiditis is rare and knowledge of potential causes of this condition is still sparse. Current known causes of arachnoiditis include infections, trauma, spinal tumors, and iatrogenic causes induced via neurological interventions. Here, we present a case of a 65-year-old female who presented with arachnoiditis caused by Candida albicans infection from a contaminated ventriculoperitoneal (VP) shunt, placed following the development of hydrocephalus from subarachnoid hemorrhage. During her initial assessment, the possibility of arachnoiditis was raised after spinal magnetic resonance imaging (MRI) due to leg weakness and spasms with bladder dysfunction. However, further workup was not pursued after a normal spinal angiogram and lack of constitutional symptoms. She presented six months later with symptoms of fever and lower abdominal pain. She was diagnosed with fungal arachnoiditis after a computerized tomography (CT) of the abdomen showed thickening of the fascia around the shunt catheter and fluid collections near the tip of the shunt in the abdominal cavity after hospitalization. The diagnosis was made after an ultrasound-guided tap of the same area revealed budding yeast and cerebrospinal fluid (CSF) showed growths of Candida albicans. Her shunt was removed, and she received intravenous (IV) antifungals and recovered. MRI should be considered with clinical presentations that are characteristic of arachnoiditis. Symptoms from fungal infections are usually dramatic; however, in some instances as in this case, they may follow a more progressive course. The patient should be extensively evaluated for infection, especially fungal, in interventions involving device placement even when minimally, but persistently, symptomatic.

Anaplastic Lymphoma Kinase Positive Mesenteric Inflammatory Myofibroblastic Tumor in Adult Woman.

Inflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms containing spindle cells and inflammatory components that can be locally aggressive. They have unclear biological behavior and may recur after resection. A 31-year-old woman presented with three months of cough, fatigue, weight loss, abdominal pain, anemia, and elevated inflammatory markers. CT showed a large well-circumscribed enhancing mass in the right colic mesentery. The patient underwent a laparoscopic right colectomy. Pathologic review showed fascicular spindle cells with admixed chronic inflammatory cells. Cells stained diffusely positive for SMA and anaplastic lymphoma kinase (ALK), diagnostic of an IMT. Post-operatively, the patient reported symptom resolution and had normalization of lab values. She remains disease-free at 20 months. IMT is rare in adults, accounting for 0.7%-1.0% of lung tumors. Up to 30% of patients present with elevated inflammatory markers. On imaging, IMTs are soft tissue masses with variable enhancement and fibrosis, often suspected to be malignant neoplasms. Up to 80% of IMTs are driven by altered tyrosine kinase signaling and half of IMTs express ALK, which may be treated in unresectable/recurrent cases using ALK-inhibitors. IMT may recur in 10%-15% of patients. The roles of adjuvant treatments are unclear given the rarity and unpredictable biological behavior. Long-term follow-up with regular radiologic and laboratory surveillance is recommended given possible local recurrence. IMTs are best managed in a multidisciplinary setting given their unpredictable nature. Surgery is the mainstay of IMT treatment with long-term control expected in >80% of adult patients.

Muscle-generated BDNF (brain derived neurotrophic factor) maintains mitochondrial quality control in female mice.

Mitochondrial remodeling is dysregulated in metabolic diseases but the underlying mechanism is not fully understood. We report here that BDNF (brain derived neurotrophic factor) provokes mitochondrial fission and clearance in skeletal muscle via the PRKAA/AMPK-PINK1-PRKN/Parkin and PRKAA-DNM1L/DRP1-MFF pathways. Depleting Bdnf expression in myotubes reduced fatty acid-induced mitofission and mitophagy, which was associated with mitochondrial elongation and impaired lipid handling. Muscle-specific bdnf knockout (MBKO) mice displayed defective mitofission and mitophagy, and accumulation of dysfunctional mitochondria in the muscle when they were fed with a high-fat diet (HFD). These animals also have exacerbated body weight gain, increased intramyocellular lipid deposition, reduced energy expenditure, poor metabolic flexibility, and more insulin resistance. In contrast, consuming a BDNF mimetic (7,8-dihydroxyflavone) increased mitochondrial content, and enhanced mitofission and mitophagy in the skeletal muscles. Hence, BDNF is an essential myokine to maintain mitochondrial quality and function, and its repression in obesity might contribute to impaired metabolism.Abbreviation: 7,8-DHF: 7,8-dihydroxyflavone; ACACA/ACC: acetyl Coenzyme A carboxylase alpha; ACAD: acyl-Coenzyme A dehydrogenase family; ACADVL: acyl-Coenzyme A dehydrogenase, very long chain; ACOT: acyl-CoA thioesterase; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2, beta; BDNF: brain derived neurotrophic factor; BNIP3: BCL2/adenovirus E1B interacting protein 3; BNIP3L/NIX: BCL2/adenovirus E1B interacting protein 3-like; CCL2/MCP-1: chemokine (C-C motif) ligand 2; CCL5: chemokine (C-C motif) ligand 5; CNS: central nervous system; CPT1B: carnitine palmitoyltransferase 1b, muscle; Cpt2: carnitine palmitoyltransferase 2; CREB: cAMP responsive element binding protein; DNM1L/DRP1: dynamin 1-like; E2: estrogen; EHHADH: enoyl-CoenzymeA hydratase/3-hydroxyacyl CoenzymeA dehydrogenase; ESR1/ER-alpha: estrogen receptor 1 (alpha); FA: fatty acid; FAO: fatty acid oxidation; FCCP: carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone; FFA: free fatty acids; FGF21: fibroblast growth factor 21; FUNDC1: FUN14 domain containing 1; HADHA: hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha; HFD: high-fat diet; iWAT: inguinal white adipose tissues; MAP1LC3A/LC3A: microtubule-associated protein 1 light chain 3 alpha; MBKO; muscle-specific bdnf knockout; IL6/IL-6: interleukin 6; MCEE: methylmalonyl CoA epimerase; MFF: mitochondrial fission factor; NTRK2/TRKB: neurotrophic tyrosine kinase, receptor, type 2; OPTN: optineurin; PA: palmitic acid; PARL: presenilin associated, rhomboid-like; PDH: pyruvate dehydrogenase; PINK1: PTEN induced putative kinase 1; PPARGC1A/PGC-1α: peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; PRKAA/AMPK: protein kinase, AMP-activated, alpha 2 catalytic subunit; ROS: reactive oxygen species; TBK1: TANK-binding kinase 1; TG: triacylglycerides; TNF/TNFα: tumor necrosis factor; TOMM20: translocase of outer mitochondrial membrane 20; ULK1: unc-51 like kinase 1.

Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue.

Insulin and IGF-1 are essential for adipocyte differentiation and function. Mice lacking insulin and IGF-1 receptors in fat (FIGIR-KO, fat-specific IGF-1 receptor and insulin receptor-KO) exhibit complete loss of white and brown adipose tissue (WAT and BAT), glucose intolerance, insulin resistance, hepatosteatosis, and cold intolerance. To determine the role of FOXO transcription factors in the altered adipose phenotype, we generated FIGIR-KO mice with fat-specific KO of fat-expressed Foxos [Foxo1, Foxo3, Foxo4] (F-Quint-KO). Unlike FIGIR-KO mice, F-Quint-KO mice had normal BAT, glucose tolerance, insulin-regulated hepatic glucose production, and cold tolerance. However, loss of FOXOs only partially rescued subcutaneous WAT and hepatosteatosis, did not rescue perigonadal WAT or systemic insulin resistance, and led to even more marked hyperinsulinemia. Thus, FOXOs play different roles in insulin/IGF-1 action in different adipose depots, being most important in BAT, followed by subcutaneous WAT and then by visceral WAT. Disruption of FOXOs in fat also led to a reversal of insulin resistance in liver, but not in skeletal muscle, and an exacerbation of hyperinsulinemia. Thus, adipose FOXOs play a unique role in regulating crosstalk between adipose depots, liver, and ß cells.