Characteristics of Traumatic Versus Atraumatic Rotator Cuff Tears in Patients Under 50 Years of Age.

BACKGROUND:  The prevalence of rotator cuff tears (RCTs) is known to be lower in younger patients compared to older patients. Recent studies in patients less than 50 years of age who sustain an RCT have focused on etiology, pathogenesis, and clinical outcomes following treatment. There are fewer studies that have focused on the demographics and clinical characteristics that may predispose this patient population to develop a tear. The purpose of this study is to evaluate the difference in risk factors for degenerative tears compared to traumatic tears in patients under 50 years of age. METHODS: This single-center retrospective study utilized an internal registry of patients who had RCT injuries identified by the International Classification of Diseases (ICD)-10 code M75.1x and confirmed by MRI between 2018 and 2023. Patients 50 years of age or younger were included and then classified into traumatic versus atraumatic RCT etiology groups. Demographics, tear characteristics, and clinical comorbidities were compared between the cohorts. Statistical analyses included a two-sided student's t-test, Wilcoxon rank-sum test, Chi-square test, and Fisher's exact test. RESULTS: A total of 177 patients under 50 years of age were identified. There was a higher prevalence of traumatic tears (59.9% vs. 40.1%; p = 0.008), the majority of whom identified as male (75.5% vs. 49.3%, p<0.001) when compared to the atraumatic cohort. Full-thickness tears were more likely to be traumatic (p = 0.04) and seen in patients insured by workers' compensation (p = 0.05). There was no significant difference in the age or preoperative comorbidities between the two groups. CONCLUSIONS: Our study reveals a higher incidence of traumatic RCTs in a younger patient group. Sex, severity of tear, and workers' compensation were found to differ between traumatic and atraumatic cohorts. Further research is required to understand the interplay of these factors in younger patients' tear risk.

Current trends and perspectives of scoliosis research society travel fellows.

PURPOSE: This study aims to measure the impact of the Scoliosis Research Society's travel fellowship on a spinal surgeon's career. METHODS: A non-incentivized survey was sent to 78 previous SRS junior travel fellows from 1993 to 2021. The questionnaire assessed fellowship influence on academic and administrative positions, professional society memberships, and commercial relationships. The trend of these quantitative measures was created according to a compounded annual growth rate (CAGR) calculation of the reported values. The Scopus database was queried for all fellows' publication counts and h-index before the fellowship, as well as 3 years, 5 years, and currently after the fellowship. A control cohort of matched surgeons who did not participate in travel fellowships was used to compare research productivity measures relative to travel fellows. RESULTS: This study had a 73% response rate. Over the periods of 3-5 years after the fellowship, and up to the present, the mean publication count increased by 31.0%, 31.6%, and 46.4%, respectively. Over the same interval, the mean h-index increased by 19.5%, 17.3%, and 11.3%, respectively. From the year of their respective fellowship to present day, the fellows observed a mean CAGR of + 3.2% in academic positions, + 6.7% in administrative positions, + 2.3% in society memberships, and + 4.7% in commercial relations. Previous fellows concurred the fellowship changed their clinical practice (42.1% Strongly Agree, 36.8% Agree), expanded their network (71.9% Strong Agree, 24.6% Agree), expanded their research (33.3% Strongly Agree, 54.4% Agree), and improved their surgical technique (33.3% Strongly Agree, 49.1% Agree). CONCLUSION: Robust feedback from previous fellows suggests a traveling fellowship has a meaningful impact on a surgeon's research productivity and career achievements.

Trends and Rates of Reporting of Race, Ethnicity, and Social Determinants of Health in Spine Surgery Randomized Clinical Trials: A Systematic Review.

STUDY DESIGN: A systematic review. OBJECTIVE: We characterized the rates of sociodemographic data and social determinants of health (SDOH) reported in spinal surgery randomized control trials (RCTs) and the association between these RCTs' characteristics and their rates of reporting on race, ethnicity, and SDOH variables. SUMMARY OF BACKGROUND DATA: Although numerous institutions maintain guidelines and recommendations regarding the inclusion and reporting of sociodemographic and SDOH variables in RCTs, the proportion of studies that ultimately report such information is unclear, particularly in spine surgery. MATERIALS AND METHODS: We searched the MEDLINE, PubMed, and Embase databases for published results from spinal surgery RCTs from January 2002 through December 2022, and screened studies according to prespecified inclusion criteria regarding analysis and reporting of sociodemographic and SDOH variables. RESULTS: We analyzed 421 studies. Ninety-six studies (22.8%) reported race, ethnicity, or SDOH covariates. On multivariate analysis, study size [rate ratio (RR)=1.18; 95% CI, 1.06-1.32], public/institutional funding (RR=2.28; 95% CI, 1.29-4.04), and private funding (RR=3.27; 95% CI, 1.87-5.74) were significantly associated with reporting race, ethnicity, or SDOH variables. Study size (RR=1.26; 95% CI, 1.07-1.48) and North American region (RR=21.84; CI, 5.04-94.64) were associated with a higher probability of reporting race and/or ethnicity. Finally, study size (RR=1.27; 95% CI, 1.10-1.46), public/institutional funding (RR=2.68; 95% CI, 1.33-5.39), focus on rehabilitation/therapy intervention (RR=2.70; 95% CI, 1.40-5.21), and nonblinded study groups (RR=2.70; 95% CI, 1.40-5.21) were associated with significantly higher probability of reporting employment status. CONCLUSION: Rates of reporting race, ethnicity, and SDOH variables were lower in the spinal surgery RCTs in our study than in RCTs in other medical disciplines. These reporting rates did not increase over a 20-year period. Trial characteristics significantly associated with higher rates of reporting were larger study size, North American region, private or public funding, and a focus on behavioral/rehabilitation interventions. LEVEL OF EVIDENCE: Level III.

Differences in Risk Factors for Rotator Cuff Tears in Young Versus Old Individuals.

Background The etiology of rotator cuff tears is thought to be multifactorial with current literature that varies with regard to identifiable risk factors. The purpose of this retrospective review was to identify risk factors for full-thickness rotator cuff tears and determine whether they differ in young versus older individuals. Methods To determine the presence or absence of a rotator cuff tear, 1,561 patients with a shoulder MRI were reviewed. If a tear was present, it was further classified into a partial or full-thickness tear. Demographic variables and clinical data were collected and analyzed with a two-sided Student's t-test or Wilcoxon rank sum test for continuous variables and a Chi-square test or Fisher's exact test for categorical variables. Age and BMI were dichotomized using receiver operator curves. Results Charlson Comorbidity Index, age, BMI, sex, race, and work status were all factors that variably affected a patient's risk of experiencing a rotator cuff tear, with different factors carrying more influence on outcomes within those who are older versus those who are younger. Gender and race were found to differ as risk factors between young and older individuals. Conclusion We were able to identify risk factors overall associated with increased odds of sustaining a full-thickness rotator cuff tear. Our analyses also showed differences in the effect of gender and race as risk factors between young and older patients with rotator cuff tears. This finding may aid clinicians in counseling patients on more specific risks for their given age.

Crosslinked-hybrid nanoparticle embedded in thermogel for sustained co-delivery to inner ear.

Treatment-induced ototoxicity and accompanying hearing loss are a great concern associated with chemotherapeutic or antibiotic drug regimens. Thus, prophylactic cure or early treatment is desirable by local delivery to the inner ear. In this study, we examined a novel way of intratympanically delivered sustained nanoformulation by using crosslinked hybrid nanoparticle (cHy-NPs) in a thermoresponsive hydrogel i.e. thermogel that can potentially provide a safe and effective treatment towards the treatment-induced or drug-induced ototoxicity. The prophylactic treatment of the ototoxicity can be achieved by using two therapeutic molecules, Flunarizine (FL: T-type calcium channel blocker) and Honokiol (HK: antioxidant) co-encapsulated in the same delivery system. Here we investigated, FL and HK as cytoprotective molecules against cisplatin-induced toxic effects in the House Ear Institute - Organ of Corti 1 (HEI-OC1) cells and in vivo assessments on the neuromast hair cell protection in the zebrafish lateral line. We observed that cytotoxic protective effect can be enhanced by using FL and HK in combination and developing a robust drug delivery formulation. Therefore, FL-and HK-loaded crosslinked hybrid nanoparticles (FL-cHy-NPs and HK-cHy-NPs) were synthesized using a quality-by-design approach (QbD) in which design of experiment-central composite design (DoE-CCD) following the standard least-square model was used for nanoformulation optimization. The physicochemical characterization of FL and HK loaded-NPs suggested the successful synthesis of spherical NPs with polydispersity index < 0.3, drugs encapsulation (> 75%), drugs loading (~ 10%), stability (> 2 months) in the neutral solution, and appropriate cryoprotectant selection. We assessed caspase 3/7 apopototic pathway in vitro that showed significantly reduced signals of caspase 3/7 activation after the FL-cHy-NPs and HK-cHy-NPs (alone or in combination) compared to the CisPt. The final formulation i.e. crosslinked-hybrid-nanoparticle-embedded-in-thermogel was developed by incorporating drug-loaded cHy-NPs in poloxamer-407, poloxamer-188, and carbomer-940-based hydrogel. A combination of artificial intelligence (AI)-based qualitative and quantitative image analysis determined the particle size and distribution throughout the visible segment. The developed formulation was able to release the FL and HK for at least a month. Overall, a highly stable nanoformulation was successfully developed for combating treatment-induced or drug-induced ototoxicity via local administration to the inner ear.

A Comparison of Demographic Diversity Between Orthopaedic Surgery Residents and ACGME Foot and Ankle Fellows From 2007 to 2022.

Background: Academic medicine emphasizes the need to recruit a diverse workforce in graduate medical education. Orthopaedic surgery residency has demonstrated efforts to model program compositions with evolving US demographics. However, it remains unclear whether orthopaedic fellowships, particularly foot and ankle, also reflect these efforts. Methods: Using the publicly available Accreditation Council for Graduate Medical Education (ACGME) Data Resource Book, a census of the gender and racial/ethnic identities of orthopaedic foot and ankle fellows, as well as active orthopaedic surgery residents, were compiled from 2007 to 2022. Linear trend analysis was conducted to evaluate the trends of orthopaedic residents and foot and ankle fellows, with a Pearson correlation for comparison. Results: Prior analysis demonstrated no significant change in sex and ethnic diversity of fellows from 2006 to 2015. The majority of foot and ankle fellows were White (31%-69%) and male (63%-88%). Linear analysis demonstrated growing diversity in female and non-White active orthopaedic surgery residents. Similarly, there was an increasing number of female foot and ankle fellows (0%-38%) reflective of the trend in orthopaedic residency (12%-20%); however, there was no significant change among racial/ethnic identities. Pearson correlation analysis between the trend of orthopaedic residency residents and foot and ankle fellows suggests moderate correlation among female, Asian, and "Unknown" racial/ethnic categories. Conclusion: The proportion of foot and ankle female fellows in ACGME-accredited fellowships has matched or exceeded the percentage of female orthopaedic residents. Despite increased diversity of orthopaedic surgery residents over the past 2 decades, ACGME-accredited foot and ankle fellowships do not yet reflect similar trends among racial/ethnic minorities. Level of Evidence: Level III, retrospective cohort study.

Role of Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Signaling in Liver and Metabolic Diseases.

MAP4K4 is a serine/threonine protein kinase belonging to the germinal center kinase subgroup of sterile 20 protein family of kinases. MAP4K4 has been involved in regulating multiple biologic processes and a plethora of pathologies, including systemic inflammation, cardiovascular diseases, cancers, and metabolic and hepatic diseases. Recently, multiple reports have indicated the upregulation of MAP4K4 expression and signaling in hyperglycemia and liver diseases. This review provides an overview of our current knowledge of MAP4K4 structure and expression, as well as its regulation and signaling, specifically in metabolic and hepatic diseases. Reviewing these promising studies will enrich our understanding of MAP4K4 signaling pathways and, in the future, will help us design innovative therapeutic interventions against metabolic and liver diseases using MAP4K4 as a target. SIGNIFICANCE STATEMENT: Although most studies on the involvement of MAP4K4 in human pathologies are related to cancers, only recently its role in liver and other metabolic diseases is beginning to unravel. This mini review discusses recent advancements in MAP4K4 biology within the context of metabolic dysfunction and comprehensively characterizes MAP4K4 as a clinically relevant therapeutic target against liver and metabolic diseases.

A case of necrotizing fasciitis initially misdiagnosed as cellulitis.

INTRODUCTION AND IMPORTANCE: Necrotizing Fasciitis (NF) is a life-threatening, rapidly progressive infection of the skin and underlying soft tissues. Bacterial pathogens induce a toxic-shock reaction that reduces vascular flow, causing thrombosis, sepsis, and tissue necrosis. Treatment consists of immediate IV antibiotics and oftentimes surgical intervention. We present a case of acute NF that was misdiagnosed as cellulitis. CASE PRESENTATION: A 17-year-old male was transferred to an emergency department from a rural hospital for further management of right lower extremity cellulitis and suspected sepsis. On examination, there was an ulcerated lesion on his right lower leg. Within 4 h, the patient underwent fasciotomy and debridement. The patient was hospitalized for 10 days, received a 3-week-course of Cefazolin, and underwent a meshed split-thickness skin graft. By the end of his hospital stay, he showed significant clinical improvement. CLINICAL DISCUSSION: Misdiagnosis of NF will almost always lead to a poorer prognosis. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score is used to differentiate NF from other soft tissue infections. Yet, other diagnostic clues such as presentation or pain out of proportion to physical findings may be more relevant clinical indicators for a NF diagnosis. Moreover, though imaging findings of NF may be relevant, surgical fascial examination must not be delayed for the purpose of imaging. It is also important to note that cellulitis and NF do share a disease spectrum. CONCLUSION: A life-threatening NF infection may seem to be a benign-appearing case of cellulitis, and thus early detection is vital.

In vitro calibration and in vivo validation of phenomenological corrosion models for resorbable magnesium-based orthopaedic implants.

Metallic bioresorbable orthopaedic implants based on magnesium, iron and zinc-based alloys that provide rigid internal fixation without foreign-body complications associated with permanent implants have great potential as next-generation orthopaedic devices. Magnesium (Mg) based alloys exhibit excellent biocompatibility. However, the mechanical performance of such implants for orthopaedic applications is contingent on limiting the rate of corrosion in vivo throughout the bone healing process. Additionally, the surgical procedure for the implantation of internal bone fixation devices may impart plastic deformation to the device, potentially altering the corrosion rate of the device. The primary objective of this study was to develop a computer-based model for predicting the in vivo corrosion behaviour of implants manufactured from a Mg-1Zn-0.25Ca ternary alloy (ZX10). The proposed corrosion model was calibrated with an extensive range of mechanical and in vitro corrosion testing. Finally, the model was validated by comparing the in vivo corrosion performance of the implants during preliminary animal testing with the corrosion performance predicted by the model. The proposed model accurately predicts the in vitro corrosion rate, while overestimating the in vivo corrosion rate of ZX10 implants. Overall, the model provides a "first-line of design" for the development of new bioresorbable Mg-based orthopaedic devices. STATEMENT OF SIGNIFICANCE: Biodegradable metallic orthopaedic implant devices have emerged as a potential alternative to permanent implants, although successful adoption is contingent on achieving an acceptable degradation profile. A reliable computational method for accurately estimating the rate of biodegradation in vivo would greatly accelerate the development of resorbable orthopaedic implants by highlighting the potential risk of premature implant failure at an early stage of the device development. Phenomenological corrosion modelling approach is a promising computational tool for predicting the biodegradation of implants. However, the validity of the models for predicting the in vivo biodegradation of Mg alloys is yet to be determined. Present study investigates the validity of the phenomenological modelling approach for simulating the biodegradation of resorbable metallic orthopaedic implants by using a porcine model that targets craniofacial applications.

A National Survey of Neonatologists' Perspectives on Probiotics Use in Neonatal Intensive Care Units in the U.S.A.

Introduction: Most recent clinical reports from the American Academy of Pediatrics (AAP) concluded current evidence does not support routine universal administration of probiotics to preterm infants, particularly those with birth weight <1000 grams. Despite this, the use of probiotics is increasing in US neonatal intensive care units (NICU).Objectives: Collaborating with the Perinatal Neonatal Medicine of AAP, we conducted a national survey to obtain neonatologist opinion on probiotics use.Methods: Survey questionnaires were sent to 3000 neonatologists via email.Results: Of 3000 potential respondents, 249 (8.3 %) completed the survey. Seventy-five (30%) neonatologists working in 23 different NICUs reported using probiotics in their practice, while 168 (70%) neonatologists working in 54 different NICUs reported not using probiotics. Of those not currently use probiotics, 49% indicated they would consider using probiotics in the future vs. 12% indicating they would not use probiotics. The most common indication for probiotics use was average gestational age < 32 weeks and mean birth weight < 1500 grams. Probiotics were discontinued at mean gestational age of 35 weeks. Respondents who prescribe probiotics were more likely to work in a setting without fellowship or residency training (48% vs 20%). Probiotics users were more often from the West (29 % vs 7%) and less often from Northeast (5% vs 34%) compared to non-users. The proportion of those using probiotics did not significantly differ by NICU size, NICU level, or years working in a NICU. Similac Tri-Blend, Evivo, and Culturelle were the top three probiotics used in the respondent's NICU.Conclusion: Though a majority of respondents are not currently using probiotics in their NICU, a large number of nonusers are interested in using probiotics in the future. Differences continue to exist in the brand of probiotics used in US NICUs.

Development of a Novel Risk Stratification Score to Predict 30-Day Mortality in Cervical Trauma Patients: CLAAD Score.

STUDY DESIGN: Case control. OBJECTIVE: Traumatic cervical spine injuries are associated with a substantial risk of mortality. The aim of this study is to develop a novel mortality prediction model for patients with cervical trauma who require operative treatment. SUMMARY OF BACKGROUND DATA: Patients with cervical spine trauma have a high risk of postoperative complications and mortality. There are few reliable systems that can accurately predict mortality after surgery for cervical spine trauma, and those that do exist are typically not specific to cervical trauma. MATERIALS AND METHODS: The National Surgical Quality Improvement Program (NSQIP) database was used to identify patients undergoing surgery for cervical spine trauma. Univariate analyses were performed to identify variables associated with mortality. Variables that were found to be significant in the univariate models were compiled into a multivariable model. The final model was compared with the American Society of Anesthesiologists (ASA), a modified Charlson comorbidity index (mCCI), and the 5-factor modified frailty index (mFI-5) in respect to predicting 30-day mortality after cervical trauma. The score was then externally validated using the Nationwide Inpatient Sample (NIS) database. RESULTS: Fifty-five (6.7%) of 822 patients did not survive 30 days after surgery. The final multivariable logistic regression model consisted of the following variables: circumferential fusion "C." long "L" fusion (more than 4 levels), anemia "A," age over 60 "A," and dialysis "D." The risk of mortality increased with increasing CLAAD score, with mortality rates of 0.9%, 3.1%, 7.4%, 22.7%, and 14.3% for scores of 0, 1, 2, 3, and 4, respectively. The CLAAD model had an AUC of 0.73 for predicting mortality after cervical trauma. CONCLUSIONS: The CLAAD score is a simple and effective system that can help identify patients at risk of increased mortality within 30 days of cervical trauma. LEVEL OF EVIDENCE: Level III.

Increased Time to Fixation After Traumatic Spinal Cord Injury Influenced by Race and Insurance Status.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVES: Although the optimal timing of surgical intervention for traumatic spinal cord injury (TSCI) is controversial, early intervention has been recognized as being beneficial in several studies. The objective of this study was to evaluate the socioeconomic factors that may delay time to surgical fixation in the management of TSCI. METHODS: The present study utilized the Trauma Quality Improvement Program (TQIP) dataset to identify patients aged greater than 18 undergoing spinal fusion for TSCI from 2007-2016. Patients were divided into subgroups based on race and insurance types. Multivariable linear regression was used to compare time to procedure based on race and payer type while adjusting for demographic and injury-specific factors. Significance was set at P < .05. RESULTS: Using multivariable analysis, Hispanic and Black patients were associated with significantly increased time to fixation of 12.1 h (95% CI 5.5-18.7, P < .001), and 20.1 h (95% CI 12.1-28.1, P < .001), respectively compared to White patients. Other cohorts based on racial status did not have significantly different times to fixation (P > .05). Medicaid was associated with an increased time to fixation compared to private insurance (11.6 h, 95% CI 3.9-19.2, P = .003). CONCLUSIONS: Black and Hispanic race and Medicaid were associated with statistically significant increases in time to fixation following TSCI, potentially compromising quality of patient care and resulting in poorer outcomes. More research is needed to elucidate this relationship and ensure equitable care is being delivered.

Trends in Volume and Charges of Retinal Tear Patients in the Emergency Department.

PURPOSE: To characterize retinal tears (RTs) and calculate the economic burden of RTs that present to the emergency department (ED) in the US. METHODS: We used a large national ED database to retrospectively analyze RTs that presented to the ED from 2006 to 2019. Using extrapolation methods, national of the RT patient ED volume, demographics, comorbidities, disposition, inpatient (IP) charges, and ED charges were calculated. RESULTS: During the period between 2006 and 2019, 15841 ED encounters had RT listed as the primary diagnosis. The average annual RT ED encounters was 2,640 ± 856 and comprised an average of 6.4 × 10-5% of all ED visits annually. The number and ED percentage of RT encounters did not change during this time period (p = .22, p = .67, respectively). Most patients were males, Caucasian, paid with private insurance, and admitted to EDs in the Northeast. The most common comorbidities were hypertension (19%), a history of cataracts (15%), and diabetes (7.2%). During this time period, RTs charges added up to more than $79 million and $33 million in the ED and IP settings, respectively. Mean per-encounter ED and IP charges increased by 145% (p = .0008) and 86% (p = .0047), respectively. CONCLUSION: Despite the stable number of RT patients presenting to the ED, RTs place a significant economic burden to the healthcare system, which increases yearly. We recommend physicians and policy makers to work together to pass laws that could prevent the increasing healthcare charges.

Advancements in metabolic-associated steatotic liver disease research: Diagnostics, small molecule developments, and future directions.

Metabolic (dysfunction)-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, is a growing global health concern with no approved pharmacological treatments. At the same time, there are no standard methods to definitively screen for the presence of MASLD because of its progressive nature and symptomatic commonality with other disorders. Recent advances in molecular understanding of MASLD pathophysiology have intensified research on development of new drug molecules, repurposing of existing drugs approved for other indications, and an educated use of dietary supplements for its treatment and prophylaxis. This review focused on depicting the latest advancements in MASLD research related to small molecule development for prophylaxis or treatment and diagnosis, with emphasis on mechanistic basis at the molecular level.

Role of ERK1/2 Signaling in Cinnabarinic Acid-Driven Stanniocalcin 2-Mediated Protection against Alcohol-Induced Apoptosis.

We have previously shown that a bona fide aryl hydrocarbon receptor (AhR) agonist, cinnabarinic acid (CA), protects against alcohol-induced hepatocyte apoptosis via activation of a novel AhR target gene, stanniocalcin 2 (Stc2). Stc2 translates to a secreted disulfide-linked hormone, STC2, known to function in cell development, calcium and phosphate regulation, angiogenesis, and antiapoptosis-albeit the comprehensive mechanism by which the CA-AhR-STC2 axis confers antiapoptosis is yet to be characterized. In this study, using RNA interference library screening, downstream antiapoptotic molecular signaling components involved in CA-induced STC2-mediated protection against ethanol-induced apoptosis were investigated. RNA interference library screening of kinases and phosphatases in Hepa1 cells and subsequent pathway analysis identified mitogen-activated protein kinase (MAPK) signaling as a critical molecular pathway involved in CA-mediated protection. Specifically, phosphorylation of ERK1/2 was induced in response to CA treatment without alterations in p38 and JNK signaling pathways. Silencing Stc2 in Hepa1 cells and in vivo experiments performed in Stc2-/- (Stc2 knockout) mice, which failed to confer CA-mediated protection against ethanol-induced apoptosis, showed abrogation of ERK1/2 activation, underlining the significance of ERK1/2 signaling in CA-STC2-mediated protection. In conclusion, activation of ERK1/2 signaling in CA-driven AhR-dependent Stc2-mediated protection represents a novel mechanism of protection against acute alcohol-induced apoptosis. SIGNIFICANCE STATEMENT: Previous studies have shown the role of stanniocalcin 2 (Stc2) in cinnabarinic acid (CA)-mediated protection against alcohol-induced apoptosis. Here, using RNA interference library screening and subsequent in vivo studies, the functional significance of ERK1/2 activation in CA-induced Stc2-mediated protection against acute ethanol-induced apoptosis was identified. This study is thus significant as it illustrates a comprehensive downstream mechanism by which CA-induced Stc2 protects against alcoholic liver disease.

Role of Hepatic Aryl Hydrocarbon Receptor in Non-Alcoholic Fatty Liver Disease.

Numerous nuclear receptors including farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptors, pregnane X receptor, hepatic nuclear factors have been extensively studied within the context of non-alcoholic fatty liver disease (NAFLD). Following the first description of the Aryl hydrocarbon Receptor (AhR) in the 1970s and decades of research which unveiled its role in toxicity and pathophysiological processes, the functional significance of AhR in NAFLD has not been completely decoded. Recently, multiple research groups have utilized a plethora of in vitro and in vivo models that mimic NAFLD pathology to investigate the functional significance of AhR in fatty liver disease. This review provides a comprehensive account of studies describing both the beneficial and possible detrimental role of AhR in NAFLD. A plausible reconciliation for the paradox indicating AhR as a 'double-edged sword' in NAFLD is discussed. Finally, understanding AhR ligands and their signaling in NAFLD will facilitate us to probe AhR as a potential drug target to design innovative therapeutics against NAFLD in the near future.

The Relationship between Circulating APOA-1 and Atherosclerosis Initiation and Progression in Psoriasis.

APOA-1 is central to the high-density lipoprotein function of reverse cholesterol transport measured by cholesterol efflux capacity. Psoriasis is a systemic inflammatory disease associated with poor cholesterol efflux capacity and accelerated noncalcified coronary burden (NCB) as measured by coronary computed tomographic angiography. In this study, we characterized the relationship between APOA-1, cholesterol efflux capacity, and progression of NCB over 4 years. Consecutively recruited participants with psoriasis underwent coronary computed tomographic angiography for NCB quantification (Medis QAngio, Leiden, The Netherlands) at baseline (n = 310) and at four years (n = 124). Blood was assessed for cardiometabolic biomarkers. The lowest quartile of APOA-1 was associated with cardiometabolic blood markers (insulin, homeostatic model assessment for insulin resistance, and cholesterol efflux capacity) and higher NCB (P < 0.001). The low APOA-1 quartile had higher NCB at 4 years (ß = -0.36, P = 0.02) in fully adjusted models. Finally, a 10-unit decrease of APOA-1 was associated with a 16% increase in NCB progression over 4 years (OR = 0.83, 95% confidence interval = 0.70-0.99, P = 0.04). In addition to being associated with cardiometabolic disease, low APOA-1 was associated with more NCB over time. These findings show that low APOA-1 is correlated with initiation and progression of coronary artery disease and may have clinical utility in identifying high-risk populations for development of cardiovascular disease.

Interplay between biochemical processes and network properties generates neuronal up and down states at the tripartite synapse.

Neuronal up and down states have long been known to exist both in vitro and in vivo. A variety of functions and mechanisms have been proposed for their generation, but there has not been a clear connection between the functions and mechanisms. We explore the potential contribution of cellular-level biochemistry to the network-level mechanisms thought to underlie the generation of up and down states. We develop a neurochemical model of a single tripartite synapse, assumed to be within a network of similar tripartite synapses, to investigate possible function-mechanism links for the appearance of up and down states. We characterize the behavior of our model in different regions of parameter space and show that resource limitation at the tripartite synapse affects its ability to faithfully transmit input signals, leading to extinction-down states. Recovery of resources allows for "reignition" into up states. The tripartite synapse exhibits distinctive "regimes" of operation depending on whether ATP, neurotransmitter (glutamate), both, or neither, is limiting. Our model qualitatively matches the behavior of six disparate experimental systems, including both in vitro and in vivo models, without changing any model parameters except those related to the experimental conditions. We also explore the effects of varying different critical parameters within the model. Here we show that availability of energy, represented by ATP, and glutamate for neurotransmission at the cellular level are intimately related, and are capable of promoting state transitions at the network level as ignition and extinction phenomena. Our model is complementary to existing models of neuronal up and down states in that it focuses on cellular-level dynamics while still retaining essential network-level processes. Our model predicts the existence of a "final common pathway" of behavior at the tripartite synapse arising from scarcity of resources and may explain use dependence in the phenomenon of "local sleep." Ultimately, sleeplike behavior may be a fundamental property of networks of tripartite synapses.