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1.
J Orthop Trauma ; 2024 Aug 12.
Article in English | MEDLINE | ID: mdl-39133522

ABSTRACT

OBJECTIVES: To compare outcomes and complications between non-operative and operative management of femur and tibia fractures in patients with paraplegia or quadriplegia from chronic spinal cord injury (SCI). METHODS: Design: Retrospective cohort study. SETTING: Three Level-1 Trauma centers. PATIENT SELECTION CRITERIA: All adult patients with paraplegia or quadriplegia due to a chronic SCI with operative or nonoperative treatment of a femoral or tibial shaft fracture from 01/01/2009 through 12/31/2019 were included. OUTCOME MEASURES AND COMPARISONS: Outcomes collected included range of motion, pain, return to baseline activity, extent of malunion and treatment complications (infection, pressure ulcers, nonunion, DVT/PE, stroke, amputation, death). Comparison between operative and nonoperative treatment were made for each outcome. RESULTS: Fifty-nine patients with acute lower extremity fracture in the setting of chronic SCI fulfilled inclusion criteria with a median age of 46 years in the operative group and 47 years in the non-operative group. Twelve patients (70.6%) in the nonoperative group were male with 32 (76.2%) male patients in the operative group. Forty-six patients (78%) presented as low energy trauma. Differences were seen between operative and non-operative management for pressure ulcers (19% vs 52.9%, p=0.009) and mean VAS pain score at first follow-up (1.19 vs 3.3, p=0.03). No difference was seen for rates of infection, nonunion, DVT/PE, stroke, amputation, death, return to baseline activity, and range of motion. CONCLUSIONS: Tibial and femoral shaft fractures commonly resulted from low energy mechanisms in patients with chronic SCI. Operative treatment seemed to decrease morbidity in these patients via lowered rates of pressure ulcers and decreased pain compared to non-operative management. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

2.
Geriatr Orthop Surg Rehabil ; 15: 21514593241273312, 2024.
Article in English | MEDLINE | ID: mdl-39144450

ABSTRACT

Introduction: A minority of geriatric hip fracture patients pursue non-operative treatment. Compared with surgical patients, non-operative patients have higher mortality rates. However, patient satisfaction following non-operative vs operative treatment has not been investigated extensively. The purpose of this study was to compare satisfaction among non-operatively vs operatively treated hip fracture patients. Methods: We identified patients aged 60+ years with proximal femur fractures treated over a 10-year period. Excluded were patients with isolated greater/lesser trochanteric fractures. Patients or relatives were asked to complete a 6-question survey about their treatment satisfaction. Results: Survey responses from 56 operative and 28 non-operative patients were recorded. Overall, 91.1% of operative and 82.1% of non-operative patients were satisfied with their treatment course (P = 0.260). However, only 71.4% of non-operative patients were satisfied with treatment option explanations vs 83.9% of operative patients (P = 0.014). While only 64.3% of non-operative respondents were satisfied with the ultimate treatment outcome (vs 85.7% of operative patients, P = 0.025), 89.3% of patients in each cohort would choose the same treatment plan again. Discussion: Our findings highlight the complexity of defining patient satisfaction, particularly in a geriatric hip fracture population. Unlike previous studies, we chose a direct approach to quantifying patient satisfaction by asking participants specifically about satisfaction with treatment outcome and the overall treatment course. Additional survey questions were then included to assess factors considered important in treatment satisfaction, such as health care provider treatment explanations, post-treatment mobility, and palliative care service involvement. Conclusions: We identified significant differences between non-operatively and operatively treated geriatric hip fracture patients regarding satisfaction with the explanation of treatment options, and ultimate treatment outcomes. There was no significant difference in overall satisfaction with the treatment course or likelihood of choosing the same treatment again. Further research investigating patient satisfaction following geriatric hip fracture treatment is warranted.

3.
OTA Int ; 7(3 Suppl): e313, 2024 May.
Article in English | MEDLINE | ID: mdl-38708043

ABSTRACT

Open fracture management is a common challenge to orthopaedic trauma surgeons and a burdensome condition to the patient, health care, and entire society. Fracture-related infection (FRI) is the leading morbid complication to avoid during open fracture management because it leads to sepsis, nonunion, limb loss, and overall very poor region-specific and general functional outcomes. This review, based on a symposium presented at the 2022 OTA International Trauma Care Forum, provides a practical and evidence-based summary on key strategies to prevent FRI in open fractures, which can be grouped as optimizing host factors, antimicrobial prophylaxis, surgical site management (skin preparation, debridement, and wound irrigation), provision of skeletal stability, and soft-tissue coverage. When it is applicable, strategies are differentiated between optimal resource and resource-limited settings.

4.
Osteoporos Int ; 35(7): 1165-1171, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38561550

ABSTRACT

Joint replacement surgery is common in older adults, leading to increasing periprosthetic fracture (PPFx) occurrence. We reviewed all PPFx seen over a 4-year period at an academic hospital. Clinical osteoporosis could be diagnosed based on existing data in 104 (67%) at the time of PPFx. Periprosthetic fractures are generally osteoporosis-related. PURPOSE: Periprosthetic fractures (PPFx) cause morbidity, mortality, and cost. This study's purpose was to describe osteoporosis-related data available at the time of PPFx. METHODS: The electronic medical record (EMR) of PPFx patients seen over 4 years in a university orthopedic practice were reviewed. Demographic data and osteoporosis relevant parameters were collected. Prior DXA studies were reviewed, and L1 Hounsfield unit (HU) measurements were performed on CT scans obtained within 2 years before PPFx. Clinical osteoporosis was defined as prior diagnosis, prescribed osteoporosis treatment, T-score ≤ - 2.5, HU ≤ 100, or prior fracture. RESULTS: Records of 156 PPFx patients (115 F/41 M), mean (SD) age 75.4 (11.9), were reviewed. Almost all 153/156 (98%) of these fractures were femoral. Falls caused 139 (89%); 12 (8%) were spontaneous. Mean time post-arthroplasty was 7.9 (6.3) years. Prior fragility fracture(s) occurred in 72 (46%); 14 were PPFx. Osteoporosis was previously diagnosed in 45 (29%) and medications prescribed in 41 (26%). Prior to PPFx, DXA data were available in 62, mean (SD) lowest T-score was - 1.9 (0.9) and was ≤ - 2.5 in 19. CT data were available in 46; mean (SD) L1 HU was 79.0 (29.4) and was ≤ 100 in 35. Based on existing data, clinical osteoporosis could have been diagnosed in 104 (67%) at the time of PPFx. CONCLUSION: Periprosthetic fractures are osteoporosis-related. They occur in older adults, often female, and result from falls; BMD, when assessed, is low. Data available at the time of PPFx often allows osteoporosis diagnosis; this should prompt evaluation and pharmacologic treatment consideration.


Subject(s)
Absorptiometry, Photon , Osteoporosis , Osteoporotic Fractures , Periprosthetic Fractures , Humans , Osteoporotic Fractures/etiology , Osteoporotic Fractures/diagnostic imaging , Female , Aged , Periprosthetic Fractures/diagnosis , Periprosthetic Fractures/etiology , Male , Osteoporosis/complications , Osteoporosis/diagnosis , Absorptiometry, Photon/methods , Aged, 80 and over , Bone Density/physiology , Tomography, X-Ray Computed/methods , Missed Diagnosis/statistics & numerical data , Retrospective Studies , Arthroplasty, Replacement, Hip , Bone Density Conservation Agents/therapeutic use , Middle Aged , Arthroplasty, Replacement, Knee
5.
J Orthop Trauma ; 38(4): 183-189, 2024 Apr 01.
Article in English | MEDLINE | ID: mdl-38206761

ABSTRACT

OBJECTIVE: To determine whether intrawound vancomycin changes the bacteriology of surgical site infection pathogens and investigate the emergence of antibiotic-resistant pathogens. DESIGN: Secondary analysis of phase III, prospective, randomized clinical trial. SETTING: Thirty-six US trauma centers. PATIENT SELECTION CRITERIA: Patients who became infected after fixation of tibial plateau or pilon fracture. OUTCOME MEASURES AND COMPARISONS: Pathogen types and bacterial susceptibilities as determined from routine clinical culture in the operating room. RESULTS: Seventy-four patients were studied who were 67.5% male with a mean age of 48.6 years. A lower proportion of gram-positive cocci was observed in the vancomycin powder compared with the standard-of-care group (3.7% vs. 8.0%, P = 0.01). Methicillin-resistant Staphylococcus aureus infection incidence was comparable in both the vancomycin powder and the standard-of-care groups, but rates of methicillin-susceptible S. aureus infections were lower in the treatment group (1.4% vs. 4.8%, P = 0.01). The incidence of coagulase-negative Staphylococci and gram-negative rod infections were similar in both groups. There was no significant difference in susceptibilities between groups in rates of vancomycin-resistant enterococcus. CONCLUSIONS: Topical vancomycin powder decreases the likelihood of gram-positive infections consistent with the biologic activity of vancomycin. Fewer methicillin-susceptible S. aureus and coagulase-negative Staphylococci infections were observed in the group treated with vancomycin powder. An effect of vancomycin powder on methicillin-resistant S. aureus infection risk was not detected given the low incidence in both the intrawound vancomycin and the standard-of-care groups. There was no emergence of gram-negative rod infections or increased resistance patterns observed. Use of topical vancomycin powder does not seem to produce infections in these patients with greater antibiotic resistance than would have occurred without its use. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.


Subject(s)
Bacteriology , Methicillin-Resistant Staphylococcus aureus , Staphylococcal Infections , Female , Humans , Male , Middle Aged , Anti-Bacterial Agents , Coagulase/pharmacology , Coagulase/therapeutic use , Methicillin/pharmacology , Methicillin/therapeutic use , Powders/pharmacology , Prospective Studies , Staphylococcal Infections/microbiology , Staphylococcus aureus , Surgical Wound Infection/drug therapy , Surgical Wound Infection/epidemiology , Surgical Wound Infection/prevention & control , Vancomycin
6.
Biochim Biophys Acta Mol Basis Dis ; 1870(2): 166978, 2024 02.
Article in English | MEDLINE | ID: mdl-38061598

ABSTRACT

Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.


Subject(s)
Microglia , Neurodegenerative Diseases , Humans , Brain/metabolism , Immunity, Innate , Microglia/metabolism , Neurodegenerative Diseases/metabolism , Phagocytosis/genetics , Phospholipase C gamma/genetics , Phospholipase C gamma/metabolism , Phospholipase C gamma/pharmacology
8.
OTA Int ; 6(3 Suppl): e261, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37533441

ABSTRACT

Pelvic ring injuries typically occur from high-energy trauma and are often associated with multisystem injuries. Prompt diagnosis of pelvic ring injuries is essential, and timely initial management is critical in the early resuscitation of polytraumatized patients. Definitive management of pelvic ring injuries continues to be a topic of much debate in the trauma community. Recent studies continue to inform our understanding of static and dynamic pelvic ring stability. Furthermore, literature investigating radiographic and clinical outcomes after nonoperative and operative management will help guide trauma surgeons select the most appropriate treatment of patients with these injuries.

9.
Foot Ankle Orthop ; 8(3): 24730114231188108, 2023 Jul.
Article in English | MEDLINE | ID: mdl-37506111

ABSTRACT

Displaced calcaneal fractures encompass a spectrum of fracture patterns, many of which are associated with soft tissue complications. Displaced tongue-type calcaneal fractures often cause pressure on the posterior heel skin, particularly when treatment is delayed. Resultant partial- or full-thickness skin necrosis presents significant challenges to the treating surgeon. In this article, the authors report on a case of full-thickness skin necrosis associated with a displaced tongue-type calcaneus fracture. The authors describe the use of a specialized heel window casting technique, which eliminates posterior heel pressure and greatly facilitates soft tissue surveillance and local wound care. The article also reviews the literature on soft tissue complications associated with displaced calcaneus fractures.

10.
J Orthop Trauma ; 37(5): 237-242, 2023 05 01.
Article in English | MEDLINE | ID: mdl-36728997

ABSTRACT

OBJECTIVE: To compare the mortality rate between geriatric patients with hip fracture treated nonoperatively and a matched cohort treated operatively. DESIGN: Retrospective Observational Matched Cohort Study. SETTING: Academic Level 1 Trauma Center. PATIENTS: Geriatric patients who sustained femoral neck and intertrochanteric/peritrochanteric fractures, excluding isolated greater trochanteric fractures. All patients older than 65 years with hip fractures over a 10-year period were identified. Operative patients were matched at a 2:1 ratio, when possible, to nonoperative patients based on Charlson Comorbidity Index and American Society of Anesthesiologists score. INTERVENTION: Nonoperative treatment or operative treatment (femoral neck fractures: cannulated screw fixation or hemiarthroplasty; intertrochanteric/peritrochanteric fractures: sliding hip screw or cephalomedullary nail fixation; or proximal femoral locking plate). MAIN OUTCOMES: Mortality calculated at 30 and 90 days, and 1-year after injury. Mortality was compared between groups using logistic regression while controlling for age, CVA/TIA, and dementia. RESULTS: Seven hundred seventy-two patients (171 nonoperative and 601 operative) were initially identified. After applying the matching algorithm, 128 nonoperative and 239 operative patients were included in the analysis. There were no significant differences in age, sex, Charlson Comorbidity Index, or American Society of Anesthesiologists score between the cohorts. Nonoperative patients had a significantly higher 1-year mortality rate than operative patients [46.1% vs. 18.0%, Odds Ratio (95% confidence interval): 3.85 (2.34-6.41), P < 0.001]. CONCLUSIONS: Geriatric patients with hip fracture treated nonoperatively had a 1-year mortality rate of 46.1%, more than double the rate among operative patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


Subject(s)
Hip Fractures , Aged , Humans , Bone Screws , Cohort Studies , Hip Fractures/surgery , Retrospective Studies , Treatment Outcome
11.
eNeuro ; 10(1)2023 01.
Article in English | MEDLINE | ID: mdl-36599670

ABSTRACT

Wnt signaling is crucial for synapse and cognitive function. Indeed, deficient Wnt signaling is causally related to increased expression of DKK1, an endogenous negative Wnt regulator, and synapse loss, both of which likely contribute to cognitive decline in Alzheimer's disease (AD). Increasingly, AD research efforts have probed the neuroinflammatory role of microglia, the resident immune cells of the CNS, which have furthermore been shown to be modulated by Wnt signaling. The DKK1 homolog DKK2 has been previously identified as an activated response and/or disease-associated microglia (DAM/ARM) gene in a mouse model of AD. Here, we performed a detailed analysis of DKK2 in mouse models of neurodegeneration, and in human AD brain. In APP/PS1 and APPNL-G-F AD mouse model brains as well as in SOD1G93A ALS mouse model spinal cords, but not in control littermates, we demonstrated significant microgliosis and microglial Dkk2 mRNA upregulation in a disease-stage-dependent manner. In the AD models, these DAM/ARM Dkk2+ microglia preferentially accumulated close to ßAmyloid plaques. Furthermore, recombinant DKK2 treatment of rat hippocampal primary neurons blocked WNT7a-induced dendritic spine and synapse formation, indicative of an anti-synaptic effect similar to that of DKK1. In stark contrast, no such microglial DKK2 upregulation was detected in the postmortem human frontal cortex from individuals diagnosed with AD or pathologic aging. In summary, the difference in microglial expression of the DAM/ARM gene DKK2 between mouse models and human AD brain highlights the increasingly recognized limitations of using mouse models to recapitulate facets of human neurodegenerative disease.


Subject(s)
Alzheimer Disease , Neurodegenerative Diseases , Mice , Humans , Rats , Animals , Alzheimer Disease/pathology , Microglia/metabolism , Wnt Signaling Pathway , Neurodegenerative Diseases/metabolism , Brain/metabolism , Disease Models, Animal , Mice, Transgenic , Intercellular Signaling Peptides and Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Proteins
12.
Front Aging Neurosci ; 14: 1056067, 2022.
Article in English | MEDLINE | ID: mdl-36533176

ABSTRACT

Neuroinflammation and hyperexcitability have been implicated in the pathogenesis of neurodegenerative disease, and new models are required to investigate the cellular crosstalk involved in these processes. We developed an approach to generate a quantitative and reproducible triculture system that is suitable for pharmacological studies. While primary rat cells were previously grown in a coculture medium formulated to support only neurons and astrocytes, we now optimised a protocol to generate tricultures containing neurons, astrocytes and microglia by culturing in a medium designed to support all three cell types and adding exogenous microglia to cocultures. Immunocytochemistry was used to confirm the intended cell types were present. The percentage of ramified microglia in the tricultures decreases as the number of microglia present increases. Multi-electrode array recordings indicate that microglia in the triculture model suppress neuronal activity in a dose-dependent manner. Neurons in both cocultures and tricultures are responsive to the potassium channel blocker 4-aminopyridine, suggesting that neurons remained viable and functional in the triculture model. Furthermore, suppressed neuronal activity in tricultures correlates with decreased densities of dendritic spines and of the postsynaptic protein Homer1 along dendrites, indicative of a direct or indirect effect of microglia on synapse function. We thus present a functional triculture model, which, due to its more complete cellular composition, is a more relevant model than standard cocultures. The model can be used to probe glia-neuron interactions and subsequently aid the development of assays for drug discovery, using neuronal excitability as a functional endpoint.

14.
Injury ; 53(11): 3814-3819, 2022 Nov.
Article in English | MEDLINE | ID: mdl-36064758

ABSTRACT

BACKGROUND: Tibial plateau fractures with an ipsilateral compartment syndrome are a clinical challenge with limited guidance regarding the best time to perform open reduction and internal fixation (ORIF) relative to fasciotomy wound closure. This study aimed to determine if the risk of fracture-related infection (FRI) differs based on the timing of tibial plateau ORIF relative to closure of ipsilateral fasciotomy wounds. METHODS: A retrospective cohort study identified patients with tibial plateau fractures and an ipsilateral compartment syndrome treated with 4-compartment fasciotomy at 22 US trauma centers from 2009 to 2019. The primary outcome measure was FRI requiring operative debridement after ORIF. The ORIF timing relative to fasciotomy closure was categorized as ORIF before, at the same time as, or after fasciotomy closure. Bayesian hierarchical regression models with a neutral prior were used to determine the association between timing of ORIF and infection. The posterior probability of treatment benefit for ORIF was also determined for the three timings of ORIF relative to fasciotomy closure. RESULTS: Of the 729 patients who underwent ORIF of their tibial plateau fracture, 143 (19.6%) subsequently developed a FRI requiring operative treatment. Patients sustaining infections were: 21.0% of those with ORIF before (43 of 205), 15.9% at the same time as (37 of 232), and 21.6% after fasciotomy wound closure (63 of 292). ORIF at the same time as fasciotomy closure demonstrated a 91% probability of being superior to before closure (RR, 0.75; 95% CrI, 0.38 to 1.10). ORIF after fasciotomy closure had a lower likelihood (45%) of a superior outcome than before closure (RR, 1.02; 95% CrI; 0.64 to 1.39). CONCLUSION: Data from this multicenter cohort confirms previous reports of a high FRI risk in patients with a tibial plateau fracture and ipsilateral compartment syndrome. Our results suggest that ORIF at the time of fasciotomy closure has the highest probability of treatment benefit, but that infection was common with all three timings of ORIF in this difficult clinical situation.


Subject(s)
Compartment Syndromes , Tibial Fractures , Humans , Retrospective Studies , Fracture Fixation, Internal/methods , Bayes Theorem , Surgical Wound Infection/etiology , Risk Factors , Tibial Fractures/complications , Tibial Fractures/surgery , Compartment Syndromes/surgery , Compartment Syndromes/complications , Cohort Studies , Treatment Outcome
15.
Brain ; 145(12): 4349-4367, 2022 12 19.
Article in English | MEDLINE | ID: mdl-36074904

ABSTRACT

Parkinson's disease is a common incurable neurodegenerative disease. The identification of genetic variants via genome-wide association studies has considerably advanced our understanding of the Parkinson's disease genetic risk. Understanding the functional significance of the risk loci is now a critical step towards translating these genetic advances into an enhanced biological understanding of the disease. Impaired mitophagy is a key causative pathway in familial Parkinson's disease, but its relevance to idiopathic Parkinson's disease is unclear. We used a mitophagy screening assay to evaluate the functional significance of risk genes identified through genome-wide association studies. We identified two new regulators of PINK1-dependent mitophagy initiation, KAT8 and KANSL1, previously shown to modulate lysine acetylation. These findings suggest PINK1-mitophagy is a contributing factor to idiopathic Parkinson's disease. KANSL1 is located on chromosome 17q21 where the risk associated gene has long been considered to be MAPT. While our data do not exclude a possible association between the MAPT gene and Parkinson's disease, they provide strong evidence that KANSL1 plays a crucial role in the disease. Finally, these results enrich our understanding of physiological events regulating mitophagy and establish a novel pathway for drug targeting in neurodegeneration.


Subject(s)
Mitophagy , Parkinson Disease , Humans , Genome-Wide Association Study , Mitophagy/physiology , Neurodegenerative Diseases , Parkinson Disease/metabolism , Protein Kinases/genetics , tau Proteins/genetics
16.
ACS Chem Neurosci ; 13(13): 2060-2077, 2022 07 06.
Article in English | MEDLINE | ID: mdl-35731924

ABSTRACT

The Wnt signaling suppressor Notum is a promising target for osteoporosis, Alzheimer's disease, and colorectal cancers. To develop novel Notum inhibitors, we used an X-ray crystallographic fragment screen with the Diamond-SGC Poised Library (DSPL) and identified 59 fragment hits from the analysis of 768 data sets. Fifty-eight of the hits were found bound at the enzyme catalytic pocket with potencies ranging from 0.5 to >1000 µM. Analysis of the fragments' diverse binding modes, enzymatic inhibitory activities, and chemical properties led to the selection of six hits for optimization, and five of these resulted in improved Notum inhibitory potencies. One hit, 1-phenyl-1,2,3-triazole 7, and its related cluster members, have shown promising lead-like properties. These became the focus of our fragment development activities, resulting in compound 7d with IC50 0.0067 µM. The large number of Notum fragment structures and their initial optimization provided an important basis for further Notum inhibitor development.


Subject(s)
Crystallography, X-Ray
17.
J Med Chem ; 65(10): 7212-7230, 2022 05 26.
Article in English | MEDLINE | ID: mdl-35536179

ABSTRACT

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer's disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l (ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6a and 6b as a pair of outstanding hits. Fragment development of 6 delivered 8l that restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8l to be selective against serine hydrolases, kinases, and drug targets.


Subject(s)
Enzyme Inhibitors , Esterases , Brain/metabolism , Crystallography, X-Ray , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Esterases/metabolism , Wnt Signaling Pathway
19.
Mol Psychiatry ; 27(7): 3024-3033, 2022 07.
Article in English | MEDLINE | ID: mdl-35296808

ABSTRACT

Growing evidence supports a role for deficient Wnt signalling in Alzheimer's disease (AD). First, the Wnt antagonist DKK1 is elevated in AD brains and is required for amyloid-ß-induced synapse loss. Second, LRP6 Wnt co-receptor is required for synapse integrity and three variants of this receptor are linked to late-onset AD. However, the expression/role of other Wnt signalling components remain poorly explored in AD. Wnt receptors Frizzled1 (Fzd1), Fzd5, Fzd7 and Fzd9 are of interest due to their role in synapse formation/plasticity. Our analyses showed reduced FZD1 and FZD7 mRNA levels in the hippocampus of human early AD stages and in the hAPPNLGF/NLGF mouse model. This transcriptional downregulation was accompanied by reduced levels of the pro-transcriptional histone mark H4K16ac and a concomitant increase of its deacetylase Sirt2 at Fzd1 and Fzd7 promoters in AD. In vitro and in vivo inhibition of Sirt2 rescued Fzd1 and Fzd7 mRNA expression and H4K16ac levels at their promoters. In addition, we showed that Sirt2 recruitment to Fzd1 and Fzd7 promoters is dependent on FoxO1 activity in AD, thus acting as a co-repressor. Finally, we found reduced levels of SIRT2 inhibitory phosphorylation in nuclear samples from human early AD stages with a concomitant increase in the SIRT2 phosphatase PP2C. This results in hyperactive nuclear Sirt2 and favours Fzd1 and Fzd7 repression in AD. Collectively, our findings define a novel role for nuclear hyperactivated SIRT2 in repressing Fzd1 and Fzd7 expression via H4K16ac deacetylation in AD. We propose SIRT2 as an attractive target to ameliorate AD pathology.


Subject(s)
Alzheimer Disease , Receptors, Wnt , Alzheimer Disease/genetics , Animals , Epigenetic Repression , Frizzled Receptors , Humans , Mice , RNA, Messenger , Sirtuin 1 , Sirtuin 2 , Wnt Signaling Pathway
20.
Orthopedics ; 45(4): e207-e210, 2022.
Article in English | MEDLINE | ID: mdl-35245134

ABSTRACT

The field of orthopedic surgery continues to grow rapidly in popularity. Ninety percent of orthopedic residents pursue fellowship training after residency, representing the highest rate of subspecialty training among surgical specialties. The goal of this study was to determine the factors considered most important by pediatric orthopedic fellowship program directors (PDs) in evaluating applicants and determining a rank list. A web-based survey was sent to all 42 US pediatric orthopedic fellowship programs. The PDs were contacted through publicly accessible email addresses found on program websites or the Pediatric Orthopaedic Society of North America website. Respondents were asked to indicate the fellowship program size and the number of applicants interviewed and ranked each year. The PDs were then asked to rank a list of 12 factors to reflect the relative importance of these criteria in evaluating fellowship applicants. Three emails were sent: 1 at the initial survey release and 2 reminder emails at 2 and 4 weeks. Surveys were anonymous. The overall response rate was 69% (29 of 42). Of the responding PDs, 48% (14 of 29) indicated that the interview was the most important factor in ranking fellowship applicants, whereas 31% (9 of 29) considered the applicant's letters of recommendation most important. Personal connections to the applicant or letter writer and research experience were each considered most important by 10% of responding PDs. Nearly half (48%) of responding PDs considered in-person interviews the most important factor in ranking fellowship applicants. Our results provide useful information for medical students and orthopedic residents planning to pursue fellowship training in pediatric orthopedics. [Orthopedics. 2022;45(4):e207-210.].


Subject(s)
Internship and Residency , Orthopedics , Child , Fellowships and Scholarships , Humans , Orthopedics/education , Surveys and Questionnaires
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