Runx1 is highly expressed in osteoblasts, however, its function in osteogenesis is unclear. We generated mesenchymal progenitor-specific (Runx1f/fTwist2-Cre) and osteoblast-specific ...(Runx1f/fCol1α1-Cre) conditional knockout (Runx1 CKO) mice. The mutant CKO mice with normal skeletal development displayed a severe osteoporosis phenotype at postnatal and adult stages. Runx1 CKO resulted in decreased osteogenesis and increased adipogenesis. RNA-sequencing analysis, Western blot, and qPCR validation of Runx1 CKO samples showed that Runx1 regulates BMP signaling pathway and Wnt/β-catenin signaling pathway. ChIP assay revealed direct binding of Runx1 to the promoter regions of Bmp7, Alk3, and Atf4, and promoter mapping demonstrated that Runx1 upregulates their promoter activity through the binding regions. Bmp7 overexpression rescued Alk3, Runx2, and Atf4 expression in Runx1-deficient BMSCs. Runx2 expression was decreased while Runx1 was not changed in Alk3 deficient osteoblasts. Atf4 overexpression in Runx1-deficient BMSCs did not rescue expression of Runx1, Bmp7, and Alk3. Smad1/5/8 activity was vitally reduced in Runx1 CKO cells, indicating Runx1 positively regulates the Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 signaling pathway. Notably, Runx1 overexpression in Runx2-/- osteoblasts rescued expression of Atf4, OCN, and ALP to compensate Runx2 function. Runx1 CKO mice at various osteoblast differentiation stages reduced Wnt signaling and caused high expression of C/ebpα and Pparγ and largely increased adipogenesis. Co-culture of Runx1-deficient and wild-type cells demonstrated that Runx1 regulates osteoblast-adipocyte lineage commitment both cell-autonomously and non-autonomously. Notably, Runx1 overexpression rescued bone loss in OVX-induced osteoporosis. This study focused on the role of Runx1 in different cell populations with regards to BMP and Wnt signaling pathways and in the interacting network underlying bone homeostasis as well as adipogenesis, and has provided new insight and advancement of knowledge in skeletal development. Collectively, Runx1 maintains adult bone homeostasis from bone loss though up-regulating Bmp7/Alk3/Smad1/5/8/Runx2/ATF4 and WNT/β-Catenin signaling pathways, and targeting Runx1 potentially leads to novel therapeutics for osteoporosis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Orthopaedic trauma presents a unique and complex challenge in the initial phase of the coronavirus 2019 (COVID-19) global crisis. Little is currently known about the surgical practices in orthopaedic ...emergencies in the early days of the COVID-19 outbreak (1). This is a retrospective case series of 10 orthopaedic trauma patients who underwent fracture fixation in March 2020. Of the 10 patients testing COVID-19 positive, there were a total of 16 long bone fractures, 5 pelvic ring fractures, and 1 lumbar burst fracture. There were 7 (70%) males in this cohort. Two (20%) of the COVID-positive patients did not develop fever, leukocytosis, respiratory insufficiency, or positive imaging findings and were younger (average age 25.5 years) with fewer comorbidities (average 0.5) compared with the 8 symptomatic COVID-19–positive patients (56.6 years with 1.88 comorbidities). Advancement of COVID-19 pathogenesis with lung opacities and prolonged intubation occurred in all 5 patients who remained on ventilation postoperatively (range 9 hours–11 days). At the time of most recent follow-up, all patients survived, 1 continues to require ventilation support, 1 remains admitted without ventilation support, and 8 (80%) were discharged to home.
LEVEL OF EVIDENCE:Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Purulent pericarditis is an extremely rare entity with only a few reported cases so far. This condition deserves prompt diagnosis because of its significant mortality rate if left untreated. A ...76-year-old man with a past medical history of coronary artery disease (CAD) with percutaneous coronary intervention (PCI) to the left anterior descending artery (LAD) and right circumflex artery (RCA), ischemic cardiomyopathy with moderately reduced ejection fraction (EF 45-50%), peripheral artery disease (PAD), COVID-19 pneumonia complicated by fibrotic lung disease (on 3 liters of home oxygen), type-2 diabetes mellitus (T2DM), hypertension (HTN), hyperlipidemia (HLD), and chronic kidney disease (CKD) stage III presented with complaints of pleuritic chest pain and shortness of breath. On hospital day 1, he was afebrile and hemodynamically stable with physical exam remarkable for bibasilar crackles and dry gangrene of his right first toe. He developed progressive altered mental status, hypotension, oliguric renal failure, and respiratory distress on hospital day 6. On exam at this time, he had an elevated jugular venous distension (JVD) of 12-14 cm water, pericardial friction rub with decreased heart sounds, and orthopnea; all were consistent with cardiac tamponade clinically. An electrocardiogram (EKG) showed new ST elevations in leads I, II, and aVL with ST depression in aVR and V1 with only mild elevation in troponin I to 0.07 ng/mL. A transthoracic echocardiogram (TTE) was done on hospital day 7 and showed a moderate sized pericardial effusion with inferior vena cava (IVC) enlargement but no atrial collapse, ventricular collapse, IVC collapse, or respiratory variation in the mitral and tricuspid inflow velocities. Blood cultures grew methicillin-resistant Staphylococcus aureus (MRSA) on hospital day 6, and he was started on intravenous (IV) vancomycin. The differential diagnosis for his enlarging pericardial effusion included purulent pericarditis, uremic pericarditis, or hemorrhagic effusion. He had urgent diagnostic and therapeutic pericardiocentesis with removal of 350 milliliters of fluid. The pericardial fluid was cloudy, tan-brown with a gram stain showing gram-positive cocci in clusters and cultures growing MRSA, which confirmed the diagnosis of purulent pericarditis secondary to MRSA infection. After the pericardiocentesis, his blood pressure, respiratory distress, and renal failure improved. The source of the bacteremia was from osteomyelitis of his gangrenous, right toe with bone biopsy growing both MRSA and Streptococcus anginosus. He underwent toe amputation for definitive source control. He was discharged on hospital day 24 with a plan to complete 6 weeks of IV vancomycin.
The USMLE Step 1 examination has been used as an objective measure for comparing residency applicants. Recently, the National Board of Medical Examiners and the Federation of State Medical Boards ...decided that the USMLE Step 1 examination will transition to a pass/fail result starting no earlier than 2022. The purpose of this study was to investigate the perspective of medical students who applied for orthopaedic surgery residency positions during the 2019 to 2020 interview cycle on the USMLE scoring change, and the potential effect this change may result in for future applicants and the residency selection process.
A 15-item anonymous web-based survey was sent to 1,090 orthopaedic surgery residency applicants from four regionally diverse residency programs. The survey elicited attitudes toward the transition of the Step 1 examination to pass/fail and perspectives this change may or may not have on the residency selection process.
Responses were received from 356 applicants (32.7%). The majority (61.6%) disagreed with the change to pass/fail scoring, and 68.5% do not believe that the change will decrease stress levels in medical students. For interview invitations, respondents chose Step 2 clinical knowledge, letters of recommendation, and performance on away rotations as the most influential factors in the absence of a Step 1 score.
Most of the students surveyed who applied for an orthopaedic surgery residency position during the most recent application cycle disagreed with the National Board of Medical Examiner/Federation of State Medical Board decision to change Step 1 to pass/fail and feel that this change may have disadvantage in certain student groups while either increasing or having no effect on medical student stress.
IV.
Clear and Bright: An Elusive Cause of Hypoxemia Edwards, Diep; Gelber, Allan C.; Sennett, Rachel ...
The American journal of medicine,
March 2023, 2023-03-00, 20230301, Letnik:
136, Številka:
3
Journal Article
Glatiramer acetate (GA) has been used for the treatment of relapsing multiple sclerosis (MS) since 1996. We describe a 59-year-old woman with well-controlled MS on long-term GA who presented with ...three weeks of jaundice and dark-colored urine and elevated liver enzymes and had biopsy-proven drug induced liver injury. The patient underwent expedited liver transplant evaluation and successfully underwent deceased donor liver transplant. Our case illustrates the first case of acute liver failure (ALF) associated with Glatiramer acetate use requiring liver transplantation. Patients on GA should have long term regular liver monitoring.
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