Search

Background: Acetabular dysplasia has been theorized as a risk factor instability amongst common acetabular fractures, such as posterior wall (PW) fractures. However, common radiographic measurements often cannot be acquired in trauma patients. We evaluated axial computed tomography (CT) scans to identify novel, easily-obtained measurements that correlate with acetabular dysplasia for use in surgical indications and planning., Methods: Patients with known acetabular dysplasia undergoing elective periacetabular osteotomy were selected. A different group of patients without pelvic ring or acetabular fractures from an institutional trauma registry were selected as a comparison group. Standard indices of dysplasia were collected, such as center-edge angle (CEA). Acetabular geometric measurements were taken at three axial levels: 0 - cranial CT slice at the dome; 1 - cranial CT where the dome is an incomplete circle; 2 - cranial CT with femoral head visible. Distances between levels were also calculated: Levels 0-1 (Dome Height; DH), Levels 1-2 (Head Height; HH), and Dome-Head Difference (DH - HH = DHD)., Results: DH, HH, and DHD were all significantly correlated with CEA, Tonnis angle, and Sharp's angle in dysplastic hips. All dysplastic hips had DH ≤ 2.5 mm and HH ≥ 1.25 mm. DHD ≤ 0 mm was most specific (93.6 % sensitive, 77.3 % specific) for predicting dysplasia., Conclusion: DH ≤ 2.5 mm, HH ≥ 1.25 mm, and DHD ≤ 0 mm were independently associated with dysplasia on axial CT scans. These measurements may be quickly and easily used by trauma surgeons to assess a trauma-based axial CT scan for acetabular dysplasia., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Traumatologists are unable to predict hip instability based on CT scans and standard radiographs in posterior wall (PW) fractures comprising <50-60 % of the wall, necessitating an examination under anesthesia (EUA). Risk factors for instability have not been clarified, but acetabular dysplasia has been theorized as a potential etiology. Unfortunately, dysplasia is difficult to evaluate in the traumatic setting. The purpose of this study was to compare acetabular morphology between unstable and stable fractures with a novel method to detect dysplasia., Methods: Patients ≥ 18 years old with a PW fracture that underwent an EUA from 2013 to 2023 were retrospectively identified. For our experimental measurements, the axial distances on CT between the acetabular dome, lateral acetabular opening, and femoral head vertex were recorded. Acetabular geometry was quantified at these levels. Conventional dysplasia metrics (e.g., Tonnis angle) were obtained. Variables were compared between stable and unstable fractures., Results: 58 patients met inclusion criteria with 42 stable versus 16 unstable fractures. Unstable fractures had higher distances between the acetabular dome and femoral head vertex (p > 0.05). They had more cranial fracture exit points (p = 0.0015), lower femoral head coverage (p = 0.0102), and lower posterior acetabular sector angles (p = 0.0281). No other differences in acetabular geometry, demographics, injury characteristics, or other markers of dysplasia were identified., Conclusions: Unstable hips demonstrated a more recessed acetabular dome when compared to stable hips. Posterior acetabular femoral head coverage and cranial fracture exit point may be related to hip instability. A larger sample size is needed to validate these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Traumatic brain injury (TBI) can lead to neurodegenerative diseases such as Alzheimer's disease (AD) through mechanisms that remain incompletely characterized. Similar to AD, TBI models present with cellular metabolic alterations and modulated cleavage of amyloid precursor protein (APP). Specifically, AD and TBI tissues display increases in amyloid-β as well as its precursor, the APP C-terminal fragment of 99 a.a. (C99). Our recent data in cell models of AD indicate that C99, due to its affinity for cholesterol, induces the formation of transient lipid raft domains in the ER known as mitochondria-associated endoplasmic reticulum (ER) membranes ("MAM" domains). The formation of these domains recruits and activates specific lipid metabolic enzymes that regulate cellular cholesterol trafficking and sphingolipid turnover. Increased C99 levels in AD cell models promote MAM formation and significantly modulate cellular lipid homeostasis. Here, these phenotypes were recapitulated in the controlled cortical impact (CCI) model of TBI in adult mice. Specifically, the injured cortex and hippocampus displayed significant increases in C99 and MAM activity, as measured by phospholipid synthesis, sphingomyelinase activity and cholesterol turnover. In addition, our cell type-specific lipidomics analyses revealed significant changes in microglial lipid composition that are consistent with the observed alterations in MAM-resident enzymes. Altogether, we propose that alterations in the regulation of MAM and relevant lipid metabolic pathways could contribute to the epidemiological connection between TBI and AD., (© 2022. The Author(s).)

Chronic alcohol consumption leads to a spectrum of liver disease that is associated with significant global mortality and morbidity. Alcohol is known to deplete hepatic vitamin A content, which has been linked to the pathogenesis of alcoholic liver disease. It has been suggested that induction of Cytochrome P450 2E1 (CYP2E1) contributes to alcohol-induced hepatic vitamin A depletion, but the possible contributions of other retinoid-catabolizing CYPs have not been well studied. The main objective of this study was to better understand alcohol-induced hepatic vitamin A depletion and test the hypothesis that alcohol-induced depletion of hepatic vitamin A is due to CYP-mediated oxidative catabolism. This hypothesis was tested in a mouse model of chronic alcohol consumption, including wild type and Cyp2e1 -/- mice. Our results show that chronic alcohol consumption is associated with decreased levels of hepatic retinol, retinyl esters, and retinoic acid. Moreover, the depletion of hepatic retinoid is associated with the induction of multiple retinoid catabolizing CYPs, including CYP26A1, and CYP26B1 in alcohol fed wild type mice. In Cyp2e1 -/- mice, alcohol-induced retinol decline is blunted but retinyl esters undergo a change in their acyl composition and decline upon alcohol exposure like WT mice. In conclusion, the alcohol induced decline in hepatic vitamin A content is associated with increased expression of multiple retinoid-catabolizing CYPs, including the retinoic acid specific hydroxylases CYP26A1 and CYP26B1., Competing Interests: The authors have declared that no competing interests exist.

The discovery of contact sites was a breakthrough in cell biology. We have learned that an organelle cannot function in isolation, and that many cellular functions depend on communication between two or more organelles. One such contact site results from the close apposition of the endoplasmic reticulum (ER) and mitochondria, known as mitochondria-associated ER membranes (MAMs). These intracellular lipid rafts serve as hubs for the regulation of cellular lipid and calcium homeostasis, and a growing body of evidence indicates that MAM domains modulate cellular function in both health and disease. Indeed, MAM dysfunction has been described as a key event in Alzheimer disease (AD) pathogenesis. Our most recent work shows that, by means of its affinity for cholesterol, APP-C99 accumulates in MAM domains of the ER and induces the uptake of extracellular cholesterol as well as its trafficking from the plasma membrane to the ER. As a result, MAM functionality becomes chronically upregulated while undergoing continual turnover. The goal of this review is to discuss the consequences of C99 elevation in AD, specifically the upregulation of cholesterol trafficking and MAM activity, which abrogate cellular lipid homeostasis and disrupt the lipid composition of cellular membranes. Overall, we present a novel framework for AD pathogenesis that can be linked to the many complex alterations that occur during disease progression, and that may open a door to new therapeutic strategies., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The link between cholesterol homeostasis and cleavage of the amyloid precursor protein (APP), and how this relationship relates to Alzheimer's disease (AD) pathogenesis, is still unknown. Cellular cholesterol levels are regulated through crosstalk between the plasma membrane (PM), where most cellular cholesterol resides, and the endoplasmic reticulum (ER), where the protein machinery that regulates cholesterol levels resides. The intracellular transport of cholesterol from the PM to the ER is believed to be activated by a lipid-sensing peptide(s) in the ER that can cluster PM-derived cholesterol into transient detergent-resistant membrane domains (DRMs) within the ER, also called the ER regulatory pool of cholesterol. When formed, these cholesterol-rich domains in the ER maintain cellular homeostasis by inducing cholesterol esterification as a mechanism of detoxification while attenuating its de novo synthesis. In this manuscript, we propose that the 99-aa C-terminal fragment of APP (C99), when delivered to the ER for cleavage by γ-secretase, acts as a lipid-sensing peptide that forms regulatory DRMs in the ER, called mitochondria-associated ER membranes (MAM). Our data in cellular AD models indicates that increased levels of uncleaved C99 in the ER, an early phenotype of the disease, upregulates the formation of these transient DRMs by inducing the internalization of extracellular cholesterol and its trafficking from the PM to the ER. These results suggest a novel role for C99 as a mediator of cholesterol disturbances in AD, potentially explaining early hallmarks of the disease., (© 2020 The Authors. Published under the terms of the CC BY 4.0 license.)

Odontogenesis is a complex process, which involves the molecular interaction between the epithelium and ectomesenchyme called as epithelium mesenchymal interaction (EMI). Reduced enamel epithelium (REE) after tooth formation protects enamel from coming in contact with adjacent ectomesenchyme. Also, REE acts as a source of origin for odontogenic lesions, during the process of development of a lesion, disruption in REE may occur and lead to formed enamel coming in contact with adjacent ectomesenchyme leading to the formation of cementum like calcifications. REE may play a role in pathogenesis of hard tissue formation in odontogenic lesions., Competing Interests: None

Objective: Competing risk analysis is a powerful assessment for cancer risk factors and covariates. This method can better elucidate insurance status and other social determinants of health covariates in oral cavity cancer treatment, survival, and disparities., Study Design: Retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database., Methods: Data regarding patient characteristics, clinical stage at diagnosis, treatment, and survival data for 20,271 patients diagnosed with oral cavity cancer was extracted from the SEER 18 Regs Research Data including Hurricane Katrina Impacted Louisiana Cases from 1973 to 2014. All statistical analyses were performed using SAS 9.5 (SAS Institute Inc., Cary, NC). The Fine-Gray method for assessing impact, risk, and covariates was employed., Results: Medicaid patients presented with later stage disease, larger tumor size, more distant metastases, and more lymph node involvement at diagnosis compared to insured patients. Medicaid patients were less likely to receive cancer-directed surgery. Medicaid status was also associated with worse cancer-specific survival (subhazard ratios 1.87, 95% confidence interval 1.72-2.04, P < .0001) after adjustment for all covariates., Conclusion: This is the first study examining specifically how Medicaid status and social determinants of health covariates impact oral cavity cancer treatment and outcomes and is the first using methods validated for complex covariates. Patients with Medicaid present with more extensive oral cavity disease burden are less likely to receive definitive therapy and have significantly worse overall survival than those with other forms of insurance. This better identifies disparities and the need for improving health literacy, specifically for the at-risk Medicaid population, and can guide clinicians., Level of Evidence: NA Laryngoscope, 130:2160-2165, 2020., (© 2019 The American Laryngological, Rhinological and Otological Society, Inc.)

The readability, reliability, and quality of online hip preservation-related patient education materials from the top 20 orthopaedic academic centers in the United States were evaluated., Methods: The patient educational materials were evaluated with the following assessment tools: Flesch-Kincaid (FK) readability test, Flesch Reading Ease formula, LIDA instrument, and DISCERN tool. Videos were assessed using the Patient Educational Video Assessment Tool (PEVAT), an author-developed scoring system., Results: A total of 121 educational items were reviewed. Median (interquartile range) or mean ± SD of the FK level, Flesch Reading Ease, LIDA, and DISCERN scores were 11.00 (3.00), 47.32 ± 12.14, 41.00 (6.00), and 64.00 (7.00), respectively. Higher ranking was correlated with higher FK (ρ = -0.21, P value = 0.034), higher DISCERN score (ρ = -0.39, P value < 0.005), and a lower PEVAT score (r = 0.61, P value = 0.034). The PEVAT score found that 83% of videos were classified as high quality., Discussion: An analysis of the hip preservation patient education text articles found low readability. Overall, high ranking was associated with poorer readability, higher quality text content, and lower quality video content. Video content was found to be predominantly of high quality. Improving the educational accessibility and effect of hip preservation-related topics may result in improved treatment outcomes., Competing Interests: None of the following authors or any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Parsa, Mr. Nazal, Dr. Molenaars, Agrawal, and Dr. Martin., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4's role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

Mitochondria are responsible for the generation of ATP by oxidative phosphorylation; however, these multifaceted organelles regulate many other key cellular functions as well, such as calcium homeostasis, apoptosis, and biosynthesis of steroid hormones, heme and phospholipids. In order to carry out these functions, mitochondria establish physical and functional connections with other organelles such as the plasma membrane, lipid droplets/vesicles, peroxisomes, endosomes, and the endoplasmic reticulum. Dysregulation of any of the aforementioned processes or inter-organelle contacts can lead to mitochondrial dysfunction and subsequent changes in oxygen consumption and ATP production. Seahorse technology has become a critical tool for quantification of mitochondrial oxygen consumption and can help differentiate primary mitochondrial disorders from disorders where alterations in mitochondrial metabolism are consequences of a prior, upstream insult. In this chapter, we describe the application of Seahorse technology for assaying mitochondrial respiration in whole cells, permeabilized cells and isolated mitochondria. We leave it to the researcher's discretion to determine which of these approaches will generate the most physiologically relevant data based on the model system and research question at hand., (© 2020 Elsevier Inc. All rights reserved.)

Inter-organelle communication is a rapidly-expanding field that has transformed our understanding of cell biology and pathology. Organelle-organelle contact sites can generate transient functional domains that act as enzymatic hubs involved in the regulation of cellular metabolism and intracellular signaling. One of these hubs is located in areas of the endoplasmic reticulum (ER) connected to mitochondria, called mitochondria-associated ER membranes (MAM). These MAM are transient lipid rafts intimately involved in cholesterol and phospholipid metabolism, calcium homeostasis, and mitochondrial function and dynamics. In addition, γ-secretase-mediated proteolysis of the amyloid precursor protein 99-aa C-terminal fragment (C99) to form amyloid β also occurs at the MAM. Our most recent data indicates that in Alzheimer's disease, increases in uncleaved C99 levels at the MAM provoke the upregulation of MAM-resident functions, resulting in the loss of lipid homeostasis, and mitochondrial dysfunction. Here, we discuss the relevance of these findings in the field, and the contribution of C99 and MAM dysfunction to Alzheimer's disease neuropathology., (© 2020 Elsevier Inc. All rights reserved.)

Context: This retrospective study was planned to ascertain the relative frequency of odontogenic tumors (OTs) in an Indian population in the light of the latest World Health Organization (WHO) classification., Aim: To compare data with various reports from other parts of the world., Study Design: Retrospective study., Materials and Methods: The histopathology records and archived slides of all lesions diagnosed as "OT" in the Department of Oral Pathology and Microbiology of Government Dental teaching institute, Mumbai, Maharashtra, India, were recovered from the period January 1981-December 2016. A total of 250 lesions thus classified were reviewed for age, gender, site of tumor, and histopathologic typing. The tumors were reclassified according to the WHO 2017 criteria., Statistical Analysis: Microsoft Excel 2010 was used for statistical analysis., Results: In all, 250 cases of OTs were reported in a 35-year period. OTs in this study constituted 7.14% of all the 6797 registered biopsies. The most frequent histological type was ameloblastoma (AML) (30.8%), followed by odontoma (19.2%), unicystic ameloblastoma (18.4%), adenomatoid OT (14%), cementifying fibroma (6%), odontogenic myxoma and cementoblastoma (2.4% each), calcifying epithelial OT and odontogenic fibroma (2% each), ameloblastic fibroma (1.2%), squamous OT, dentinogenic ghost cell tumor, peripheral ameloblastoma, ameloblastic carcinoma and ameloblastic fibrosarcoma (odontogenic sarcoma) (0.4% each)., Conclusion: A frequency of 7.14% of OTs was observed in this study. AML comprised the single most common tumor of all OTs. This study observed geographic variations in the frequency and distribution of OTs., Competing Interests: None

Objective: Tissue macrophages induce and perpetuate proinflammatory responses, thereby promoting metabolic and cardiovascular disease. Lipoprotein lipase (LpL), the rate-limiting enzyme in blood triglyceride catabolism, is expressed by macrophages in atherosclerotic plaques. We questioned whether LpL, which is also expressed in the bone marrow (BM), affects circulating white blood cells and BM proliferation and modulates macrophage retention within the artery., Approach and Results: We characterized blood and tissue leukocytes and inflammatory molecules in transgenic LpL knockout mice rescued from lethal hypertriglyceridemia within 18 hours of life by muscle-specific LpL expression (MCKL0 mice). LpL-deficient mice had ≈40% reduction in blood white blood cell, neutrophils, and total and inflammatory monocytes (Ly6C/G hi ). LpL deficiency also significantly decreased expression of BM macrophage-associated markers (F4/80 and TNF-α [tumor necrosis factor α]), master transcription factors (PU.1 and C/EBPα), and colony-stimulating factors (CSFs) and their receptors, which are required for monocyte and monocyte precursor proliferation and differentiation. As a result, differentiation of macrophages from BM-derived monocyte progenitors and monocytes was decreased in MCKL0 mice. Furthermore, although LpL deficiency was associated with reduced BM uptake and accumulation of triglyceride-rich particles and macrophage CSF-macrophage CSF receptor binding, triglyceride lipolysis products (eg, linoleic acid) stimulated expression of macrophage CSF and macrophage CSF receptor in BM-derived macrophage precursor cells. Arterial macrophage numbers decreased after heparin-mediated LpL cell dissociation and by genetic knockout of arterial LpL. Reconstitution of LpL-expressing BM replenished aortic macrophage density., Conclusions: LpL regulates peripheral leukocyte levels and affects BM monocyte progenitor differentiation and aortic macrophage accumulation., (© 2018 American Heart Association, Inc.)

In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β-secretase to generate a 99-aa C-terminal fragment (C99) that is then cleaved by γ-secretase to generate the β-amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ-secretase activity is enriched in mitochondria-associated endoplasmic reticulum (ER) membranes (MAM) and that ER-mitochondrial connectivity and MAM function are upregulated in AD We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ-secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Neurologic diseases often affect the urinary tract and may be congential or acquired. The progressive nature of many neurologic diseases necessitates routine surveillance and treatment with a multidisciplinary approach. Urologic treatments may interact with pharmacologic or procedural interventions planned by other specialists, mandating close coordination of care and communication among providers. Primary care and nursing often can serve as the quarterbacks of the multidisciplinary team by identifying when a slowly progressive condition warrants further investigation and management by specialists., (Copyright © 2017 Elsevier Inc. All rights reserved.)

We describe an interesting case of intramural duodenal hematoma in an otherwise healthy male who presented to emergency room with gradually progressive abdominal pain, nausea, and vomiting. This condition was missed on initial evaluation and patient was discharged from emergency room with diagnosis of acute gastritis. After 3 days, patient came back to emergency room and abdominal imaging studies were conducted which showed that patient had intramural duodenal hematoma associated with gastric outlet obstruction and pancreatitis. Hematoma was the cause of acute pancreatitis as pancreatic enzymes levels were normal at the time of first presentation, but later as the hematoma grew in size, it caused compression of pancreas and subsequent elevation of pancreatic enzymes. We experienced a case of pancreatitis which was caused by intramural duodenal hematoma. This case was missed on initial evaluation. We suggest that physicians should be more vigilant about this condition.